Surgery

Introduction

Metastatic bone disease is a relatively common event in the advanced stages of many malignancies.¹ Bone-modifying agents decrease the incidence of skeletal-related events (SREs) such as spinal cord compression and bone fracture, as well as the need for skeletal radiotherapy or surgery.²

Bone modifying agents such as intravenous bisphosphonates (IV BPs) (e.g. pamidronate and zoledronic acid) and denosumab are approved for prevention of SREs. IV BPs are primarily used and effective in the treatment and management of cancer related conditions such as multiple myeloma (MM), and breast cancer with skeletal metastases, because they reduce bone pain, hypercalcemia, and the risk of pathologic fractures.³

Denosumab, a receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor, represents a breakthrough in the treatment of osteoporosis, MM, and bone metastases. The Food and Drug Administration (FDA) approved it in 2010 for the prevention of SREs in patients with bone metastases and in 2011 for the prevention of endocrine-therapy induced bone loss in patients taking aromatase inhibitors for breast cancer and in patients with non-metastatic prostate cancer.

Three international, randomised, double-blind, double-dummy phase III studies have evaluated denosumab versus zoledronic acid for the treatment of SREs in breast and prostate cancers, and in combined solid tumours and MM. Denosumab’s superior efficacy over zoledronic acid was demonstrated in the studies of patients with advanced breast or prostate cancer, as well as in a pre-specified integrated analysis of all patients enrolled across the three studies.⁴

In the 2014 position paper of the American Association of Oral and Maxillofacial Surgeons (AAOMS), the nomenclature “bisphosphonate-related osteonecrosis of the jaw” changed to “medication related osteonecrosis of the jaw” (MRONJ). MRONJ is defined as cases in which all of the following 3 characteristics are present⁵:

• current or previous treatment with antiresorptive or antiangiogenic agents
• exposed bone or bone that can be probed through an intraoral or extra-oral fistula in the maxillofacial region that has persisted for longer than 8 weeks
• no history of radiation therapy to the jaws or obvious metastatic disease to the jaws

Other terminologies used previously include “denosumab related osteonecrosis of the jaw” (DRONJ), and “antiresorptive agent-induced ONJ” (ARONJ).

The aetiopathogenesis of MRONJ related to denosumab therapy remains enigmatic, and hypotheses have focused on reduced bony turnover, infection, toxicity of the soft tissue, and antiangiogenesis. The epidemiology also remains unclear, and reported incidence varies widely.⁶ Overall, it is estimated that bone necrosis can develop in about 0.7-1.9% of patients with malignancy who are given high-potency IV BPs (such as zoledronic acid), and in 0.01–0.1% of those with osteoporosis who take low-potency oral BPs (such as alendronate). Data relevant to denosumab given subcutaneously in patients with metastatic cancer and osteoporosis seem to replicate those when IV high-potency BPs are administered.⁷ The risk of osteonecrosis of the jaw (ONJ) is higher in patients exposed to concomitant antiagiogenic medication. The individuals’ risk of ONJ is further determined by factors such as the potency of agent, cumulative dosage or duration of antiresorptive treatment, route of administration, comorbidities and local factors such as periodontal disease.^8,9 Oral hygiene plays a significant role with evidence supporting a strong correlation between bacteria associated with periodontal disease and MRONJ.¹⁰

MRONJ typically manifests as painful and often infected areas of necrotic bone, which subsequently may lead to severe chronic pain and facial disfigurement. This adversely affects the ability to eat, speak and lowers the quality of life. Adverse events related to RANKL inhibitors are usually considered to be infrequent and low in occurrence. Unfortunately from our recent clinical experience at Sheffield Teaching Hospitals' Trust, there have been several new cases presented in a very short period of time. In this paper we present a case series of MRONJ related to denosumab therapy since adverse events of denosumab in the mandible or maxilla have received relatively little attention.

The aim of this article is to highlight the elevated risk of MRONJ in patients receiving denosumab treatment and educate all health care providers involved in the management of such patients. Furthermore, the mechanisms of denosumab, comparison with bisphosphonates and the reported management strategies are reviewed.

Mechanism of Denosumab

Denosumab is an antiresorptive agent that exists as a human IgG2 monoclonal antibody and inhibits the binding of the receptor activator of nuclear factor kappa-B ligand (RANKL) to RANK (Receptor Activator of Nuclear Factor kappa-B). The binding normally signals the proliferation of osteoclasts, as RANK is expressed on the surface of osteoclasts and their precursors, whereas its ligand, RANKL, is a membrane bound protein expressed by bone marrow stromal cells, osteoblasts and T-lymphocytes. The activation of RANK is integral to the function of osteoclasts. Osteoprotegerin binds to membrane bound RANKL on osteoblast which in turns decreases the osteoclastic activity and in theory negatively effects bone turnover. Denosumab acts similarly to osteoprotegerin but has a higher affinity for RANKL.^11-13

Denosumab follows nonlinear, dose-dependent pharmacokinetics. The bioavailability of one subcutaneous denosumab injection is 61% and serum concentrations are detected within 1 hour. Maximum serum concentrations occur in 5-21 days and cessation of osteoclast activity occurs within six hours of the subcutaneous injection. The normal function is restored approximately six to nine months later, whilst bone turnover returns to normal shortly after this.¹⁴ Based upon monoclonal antibody pharmacokinetics, denosumab is most likely cleared by the reticuloendothelial system with minimal renal filtration and excretion thus avoiding nephrotoxicity. Its elimination half-life is 32 days, and it does not incorporate into bone.¹⁵

It is currently marketed as Prolia® and Xgeva®, approved by FDA. Prolia® is administered subcutaneously every six months and has shown to reduce the incidence of new vertebral, non-vertebral, and hip fractures in osteoporotic patients.^16,17 Xgeva® is also effective in reducing SRE related to metastatic bone disease from solid tumours when administered intravenously on a monthly basis.^17,18

RANKL Inhibitors and BPs Pharmacokinetics

There are fundamental differences between denosumab and BPs with regard to their mode of action. Denosumab is an antibody and acts extracellularly whereas BPs act intracellularly. As such, BPs must be present in the circulation and available for reuptake into bone for prolonged periods to function.¹⁹ There is not any evidence of drug recycling with RANKL inhibitors, and therefore it is suggested that their adverse effects can be reversible with discontinuation, in fact leading to a transient rebound phenomenon, which can be restored, with subsequent treatment.^14,20 On the other hand, recycling of BPs in the circulation system has been proposed as a reason for the long duration of action even after cessation which can be up to 12 years.

The US FDA-approved manufacturer’s package insert for both zolendronate and pamidronate states that “there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ in patients who require dental procedures during therapy and that clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/ risk assessment”. The package insert for denosumab does not address the issue of treatment continuation in patients who develop MRONJ to date.

Denosumab is a circulating protein capable of distributing throughout extravascular space. It is expected to reach all sites within bone including intracortical sites unlike with BPs. BPs have strong affinity for hydroxyapatite and bone mineral which limits their even distribution throughout the skeleton, particularly to sites deep within the bone.^19,21 This can explain the more profound inhibition of bone remodelling with denosumab than that seen with BPs.

Case Series

Case 1

A 55 year-old lady referred to a dedicated Oral Surgery nerve injury clinic for an opinion and management of her left sided inferior alveolar nerve (IAN) paraesthesia. The patient presented with a history of numbness in the left sided inferior alveolar nerve distribution following removal of the left mandibular second premolar (LL5) in July 2014. She was asymptomatic until she had the LL5 removed and since had suffered with constant pain and numbness. A year later, she had removal of the left mandibular first molar (LL6) and gave a history of recurrent infections and excruciating pain in her mandible over the past two months. On presentation she had an obvious submental swelling and left sided IAN anaesthesia.

Medically she was diagnosed with breast cancer in 2011, for which she underwent wide local excision followed by chemotherapy. She then was placed on unknown clinical trial that we identified at the time to be denosumab trial, following liaison with the Oncology team. She is currently receiving intravenous denosumab every three months.

Clinical examination revealed a grossly mobile anterior mandible with widespread bony necrosis and associated osteomyelitis. Sensory testing revealed complete anaesthesia in the left sided IAN distribution secondary to MRONJ.

An OPG (Orthopantogram) and CBCT (Cone-Beam Computerised Tomography) revealed an extensive patchy area of ill-defined bone loss in the anterior mandible extending posteriorly to the premolar/molar areas bilaterally (Fig 1).

Figure 1 A) OPG showing non-healing sockets in the left mandible with extensive bony destruction together with periosteal reaction extending to the right mandible as shown by the arrows.

Rather interestingly, the bony destruction was evident bilaterally with the patient only having had extraction of teeth in the left mandible (Fig 1). This could be the case of spontaneous ONJ in the right mandible or an extensive ONJ arising from simple extractions on the left side.

Figure 2 3D reconstruction of the CBCT image demonstrating extensive bony destruction involving the lower border of anterior mandible in keeping with a spreading chronic bony infection and clinical presentation of submental swelling as showing by arrows.

Case 2

A 66-year-old female referred by her general medical practitioner (GMP) with a 3-month history of delayed healing following a tooth extraction in the left posterior mandible. She had moderate to severe discomfort and reported multiple previous infections and purulent discharge from the area, which treated with multiple courses of antibiotics. In addition, she reported discomfort from the root treated right mandibular first and second premolar teeth (LR4 and LR5).

Medically she was diagnosed with breast cancer over 10 years ago for which she underwent resection followed by chemotherapy. Three years ago, she diagnosed with metastatic deposits and therefore has been receiving intravenous denosumab every six weeks since then. Other medications include steroids, chemotherapy agents, antihypertensives and analgesics. She did not receive any radiotherapy or BPs treatment in the past.

Clinical presentation revealed a heavily restored dentition with chronic generalised periodontal disease. There was evidence of widespread bone loss clinically and radiographically. The slow healing socket in the left mandible was visible but did not have any exposed bone (Fig 3). The lower right first and second premolar teeth (LR4 and LR5) were clinically and radiographically sound.

Figure 3. Non-healing socket in the left posterior mandible with no evidence of exposed bone or suppuration as showing by white arrow. Gingiva recession (black arrows) is evident in the LL6 and LL5 teeth in keeping with chronic periodontal disease.

Figure 4 Coronal sections of CBCT A and B showing multiple lytic areas within the inferior cortex of the mandible and incomplete healing of the extraction sockets.

On follow-up appointments, the patient suffered multiple repeated infections in the right and left posterior mandible and due to deteriorating periodontal disease, the LR4, LR5, LR6 were extracted by her own general dental practitioner (GDP) due to severe mobility. All three extraction sockets failed to heal (Fig 5) leading to an extensive area of exposed bone in the right mandible, extending from the lower right first premolar (LR4) to lower left first molar (LL6) region. Conservative management was embarked which included antibiotics, chlorhexidine mouthwash and routine oral hygiene appointments. Selective sharp bone trimming and three sequestrectomies were undertaken. At the same time, liaison with the patient’s oncologist resulted in cessation of the denosumab therapy and complete resolution of her oral symptoms.

Figure 5 Clinical picture of exposed necrotic bone (white arrows) following simple extractions of periodontally involved teeth.

Case 3

A 76-year-old lady referred to the Oral Surgery department by her GDP with a 3-month history of a non-healing lower left first premolar (LL4) socket. The patient was treated with two courses of antibiotics prior to referral which provided only temporary relief to her symptoms.

Medically she was diagnosed with breast cancer 10 years ago and recently commenced intravenous denosumab for metastatic disease. She also receives hormone therapy and palliative radiotherapy to the spine.

On clinical examination, there was a partially healed LL4 socket with a rather granulomatous appearance. There was no clinical evidence of suppuration or bony exposure. Radiographs confirmed the absence of bony infill in the socket. Local debridement and biopsy of the granulomatous tissue was performed to exclude any metastatic disease. Biopsy report confirmed the presence of inflammation tissue.

Figure 6 CBCT scan; A and B sagittal views, C axial view and D 3D reconstruction. Extensive periosteal reaction extending from the midline of the mandible to the left molar region is evident in keeping with chronic osteomyelitis secondary to MRONJ.

Liaison with the microbiologist suggested a long-term antibiotic course to arrest osteomyelitis. Further liaison with the oncology team, resulted in denosumab being stopped for 4 months. On subsequent review appointments, patient’s symptoms improved however, there is now an area of exposed bone in the LL4 region as shown in Fig 7.

Figure 7 Clinical photo illustrating exposed bone (white arrow) in the LL4 region without evidence of local infection.

Case 4

A 65-year-old lady referred to the Oral Surgery department by her GDP with a history of a sore upper mouth and jaw underneath the dentures which is unable to wear.

Medically she was diagnosed with disseminated breast malignancy including bone metastases 3 years ago and for that, she is on exemestane and IV Denosumab monthly.

Clinical examination revealed multiple draining sinuses in the anterior maxilla. There was a partially healed LL4 socket with a rather granulomatous appearance and tenderness on palpation. There was neither discharge from the area nor any exposed bone. Radiographs confirmed the absence of bony infill in the LL4 socket. Local debridement and biopsy of the granulomatous tissue was performed to exclude any potential malignancy and it was confirmed as inflammation tissue.

Figure 8 CBCT scan; A axial view, B and C 3D reconstruction. A 25mm fragment of right anterior maxilla is beginning to sequestrate. This extends from the anterior margin of the right maxillary sinus approximately to the position of the upper left lateral incisor, crossing the midline. The sequestrated fragment involves the lateral margin of the nasal cavity. There is bilateral moderate mucosal thickening in the maxillary sinuses. Extensive periosteal reaction extending from the midline of the mandible to the left molar region is evident in keeping with chronic osteomyelitis secondary to MRONJ.

Table 1 Summary of cases

Discussion

ONJ associated with antiresorptive therapy deserves distinction from other causes and diseases/medications associated with the development of osteonecrosis of the jaw. AAOMS recently published stage specific treatment recommendation for MORNJ.²² The various stages and suggested stage-specific treatment strategies are not evidence-based, and in particular, stage 0 disease is not universally accepted. AAOMS recommendations echoed those stated in previous years for BRONJ, namely supporting conservative therapy, with aggressive surgery offered only to symptomatic patients. In contrast, the MRONJ guideline report from the German Dental and the German Oral and Maxillofacial Associations refrains from recommending therapy at least for certain stages of the disease. This might be attributed to the pitfalls of current MRONJ criteria. Furthermore, due to poor guidelines specifically related to RANKL inhibitors, no agreement exists on a universally acceptable therapy strategy of such cases.

Management strategies are largely based on expert opinion rather than experimental data. It includes prevention, conservative and surgical modalities. Prevention of the condition is the gold standard. It is highly recommended all patients have a comprehensive dental examination and preventive dentistry (pre-emptive extraction of unsalvageable teeth and optimised periodontal health) before commencing antiresorptive therapy.^23,24 Oral hygiene should be kept meticulous during the course of therapy as periodontal disease and associated bacteria claim to be implicated in this condition and also observed in these cases.

The success rate of conservative treatment regimens range from less than 20% ^25,26 to above 50%^27,28 although some cases become chronic and develop complications.²⁹

Microbial cultures from areas of exposed bone are not always helpful since normal oral microbes are isolated. However, when there is extensive soft tissue involvement, microbial cultures may help to define comorbid oral infections, which may guide the selection of an appropriate antibiotic regimen.³⁰

Regardless of the stage of disease, areas of necrotic bone that are a source of chronic soft tissue irritation and loose bony sequestra should be removed or recontoured so that soft tissue healing can be optimised. This is in line with our clinical experience. The extraction of symptomatic teeth within exposed, necrotic bone should be considered as it appears unlikely that extraction will worsen the established necrotic process. Otherwise, surgical resection of necrotic bone should generally be reserved for refractory or advanced cases.³¹ Resection may occasionally result in even larger areas of exposed and painful infected bone.³²

A recently published MISSION study⁷ reported that the AAOMS system misclassified/ underestimated the severity of the disease at a rate of about 1 in 3, in particular in patients suffering from MRONJ stage 1 and 2. The authors conclude that these findings may explain why the treatment of stage 3 ONJ, namely surgery with success rate over 85%^33,34, has been deemed to be more predictable and therefore yields more favourable outcomes than the treatment of stages 1 and 2.³⁵

Denosumab is characterised by reversibility of its effect after treatment discontinuation, in contrast with bisphosphonates. This is in line with our findings since cessation of denosumab in two cases helped to improve their symptoms significantly.

MRONJ has been reported to occur after a mean administration period of 39.3 months and 35 infusions in oncology patients.²³ It is interesting that all published cases of denosumab-related ONJ occurred early after commencement of therapy, independent of the number of previous administrations.^36,37 In our experience, all patients developed MRONJ within the first 3 months of teeth extractions; well ahead of the reported period and number of administrations of denosumab.

Furthermore, all four cases have had extensive lytic lesions developed following removal of a single tooth. The common radiographic findings in all cases include:

• non-healing extraction socket
• areas of focal and diffuse sclerosis
• thickened lamina dura
• early sequestrum formation
• reactive periosteal bone
• osteolysis of cortical and spongious bone

These findings, although common in MRONJ cases, have had extensive bony involvement and rapid progression of ONJ, demonstrating a far more aggressive nature of the disease compared to that seen with BPs.

In our experience, not all patients are adequately informed of the risks and adverse events of denosumab therapy. This highlights the importance of educating patients and inter-professional communication regarding the prevention and best management of MRONJ cases. In one of the cases, the lack of patient education concerning denosumab side effects and the failure of inter-professional communication had a detrimental effect on the patient’s overall management and subsequently patient’s oral health.

Table 2 Important Points

Conclusion

We present our experience with denosumab-related ONJ from Sheffield Teaching Hospital’s NHS Trust. This case series should contribute to the existing sparse clinical literature on this topic. The pathogenesis, treatment and outcome of ONJ are complex and multifactorial. Patients treated with denosumab may be more prone to developing ONJ even without a precipitating dental event. ONJ may have a more aggressive profile and develop significantly earlier in patients receiving denosumab. Prevention of ONJ still remains the most important goal, and this is most directly accomplished by avoiding invasive dental procedures and establishing inter-professional communication.

CASE REPORT

A 61-year-old lady underwent a modified radical mastectomy and axillary clearance in 2008 for a carcinoma of the left breast. Histopathology examination revealed two tumours within the left breast; a 16mm Grade 2 lobular carcinoma with probable vascular invasion and a 9mm Grade 1 infiltrating ductal carcinoma with no vascular invasion. She had clear resection margins. 21 out of 34 removed lymph nodes were positive for metastatic deposits. The tumour was oestrogen receptor positive and HER2 negative. She was staged as T1 N3a Mx and the tumour had a Nottingham Prognostic Index of 5.32. Metastatic workup revealed no distant metastasis.

Postoperatively, she required aspiration of a seroma but her recovery was otherwise satisfactory. She received adjuvant chemotherapy in the form of three cycles of Fluorouracil, Epirubicin and Cyclophosphamide and 3 cycles of Docetaxel. In addition, she had postoperative radiotherapy to the chest wall and supraclavicular fossa (40 Gy in 15 Fractions over 3 weeks) and hormonal therapy with Letrozole 2.5mg once daily.

The patient opted to undergo a prophylactic right mastectomy in 2010. She was regular in follow up and appeared to be free of disease recurrence for 6 years.

Her past surgical history included abdominal hysterectomy and bilateral salpingo-ophorectomy for fibroid disease as well as varicose vein stripping. She is a non-smoker and doesn’t consume alcohol. She had a family history of colon and cervical cancer in her uncle and sister respectively.

The patient visited the surgical outpatient clinic complaining of abdominal cramps, altered bowel habits and fatigue of a few months duration. There was no associated rectal bleeding, haematemesis, melaena, weight loss or urinary symptoms. Physical examination was unremarkable but she was noted to have gradually worsening renal function. Her symptoms were at first attributed to side effects of intravenous antibiotic treatment, which she received during an admission for cellulitis. She had already undergone an upper GI endoscopy which showed oesophagitis and ulceration; biopsies were within normal limits. She received treatment with proton pump inhibitors but her symptoms persisted.

A non-contrast abdominal CT scan was done, on account of her poor renal function, which showed bilateral hydronephrosis and thickening of the postero-superior aspect of the bladder wall. Considering the limitations of the non-contrast study, there were no other abnormalities. A colonoscopy was also done to investigate her altered bowel habit and it revealed a benign-looking stricture in the sigmoid about 25cm from the anal verge which was easily bypassed by the scope.

Figure 1. Benign stricture on flexible sigmoidoscopy

Biopsies of the sigmoid stricture showed an infiltrate of small to medium sized tumour cells in the submucosa, which had an Indian file pattern. They were positive for AE1/AE3 (pancytokeratins) and negative for CD68. They were positive for CK7 and negative for CK20, strongly positive for oestrogen receptors and HER2 negative. Taken in conjunction with the patient’s past history of an invasive lobular carcinoma of the breast, the appearance was consistent with a metastatic lobular carcinoma.

Figure 2. Clusters and cords of cells with positive cytoplasm for the cytokeratin immunostain CK7. Although the classical ‘Indian filing’ of lobular carcinoma is not well seen, the image clearly demonstrates that the large bowel glands are negative (normally CK20+, CK7-) and that the infiltrate is beneath the glandular mucosa (i.e. not originating from dysplastic glands within the mucosa and raising the possibility of infiltration from outside the bowel wall). The magnification is x200. Lobular carcinoma is usually CK7 +, CK20 -, ER +.

Figure 3. The same cells with their nuclei staining positively with an immunostain to oestrogen receptors. There are a few short chains of ‘Indian filing’ with the cells appearing rather rectangular in shape with straight margins. You can make out slight ‘moulding’ of the nuclei as they press against one another. The magnification is x 400.

Figure 4. Haematoxylin and Eosin section at 400 magnification. This shows a diffuse infiltrate of single cells with eccentric nuclei.

The patient required a right nephrostomy and a cystoscopy with left double J ureteric stent insertion to address her hydronephrosis and deteriorating renal function before undergoing restaging of her disease.

DISCUSSION

In patients with history of breast cancer, isolated GI metastases are less common than benign disease processes or second primaries of the GI tract.^1.2 In a retrospective review, 73 out of 12001 cases of breast cancer had gastrointestinal metastases, out of which 24 were to the colorectum³ and invasive lobular carcinoma was the commonest histological subtype. ^3.4 However, sixteen percent of patients with breast cancer have GI metastases at postmortem examination¹.

There might be a long interval of time between the diagnosis of breast cancer and development of gastrointestinal metastasis which together with their rare occurrence and nonspecific clinical and radiological manifestations adds to the diagnostic challenge. The median interval between the diagnosis and the development of GI metastasis was reported to be 6 years (range 0.25 to 12.5 years) by Schwarz et al ⁵with 25 years being the longest reported in the literature.⁶ Because of this long interval the history of a primary breast cancer can be missed. This also highlights the importance of long term follow up and maintaining an index of suspicion when these patients develop GI symptoms.

In our case, the interval between the diagnosis of breast cancer and colonic metastasis was 81 months. Her GI symptoms were initially attributed to side effects of antibiotic treatment for cellulitis and dyspepsia before investigating her with a colonoscopy. Even at colonoscopy the appearance was that of a smooth benign-looking stricture which did not seem to harbour any sinister pathology

Histological examination is probably the most reliable tool to make a diagnosis and it is prudent in such cases to compare the specimen with the original breast tumour. In this case, there were two primary tumours; an invasive ductal carcinoma as well as a lobular carcinoma but the metastatic disease favoured the lobular component, which is consistent with other published reports in the literature. The reasons why metastases favour lobular carcinoma are poorly understood. One explanation is the loss of E-cadherin expression, a molecule involved in cellular adhesion, in invasive lobular carcinoma⁷. A similar case in which the primary was a mixed ductal and lobular type with lobular subtype colonic metastasis was reported by Uygun et al.⁸ Immunohistochemistry can also help in establishing a diagnosis. Metastatic breast cancers tend to be positive for Oestrogen or Progesterone receptors as well as Gross Cystic Disease Fluid Protein-15.^{9, 10} It is, however, worth noting that primary colonic cancers can be oestrogen receptor positive in 30 to 70% of cases.¹¹

Accurate histopathological diagnosis probably saved our patient an unnecessary surgical treatment for a primary colonic neoplasm as the main focus of her treatment should be systemic therapy for metastatic breast cancer.

CONCLUSION

GI tract metastases from breast cancer are a rare occurrence. The patients may present after a long interval from the original diagnosis and the clinical and radiological features are nonspecific with the diagnosis often established on histological examination. Moreover, the history of breast cancer may not be elicited in all cases and these patients may present to a gastroenterologist or colorectal surgeon rather than a breast surgeon or oncologist. Therefore, remaining vigilant to this possibility is advised in any patient with a history of breast cancer who presents with unexplained GI symptoms.

Introduction

Oesophageal cancer (OC) is the eighth most common cancer affecting an estimated 481,000 people worldwide with a rapidly rising incidence. Due to the poor prognosis of patients with these cancers it is the sixth leading cause of cancer related mortality with 406,000 deaths.^1,2 Although the overall 5-year survival has increased from 4% in the 1970s³ to currently ranging between 15 to 20%⁴, it remains a challenge to treat as clinical presentation is often late and diagnosis is made at advanced stages. Incidence and mortality rates for OCs are two fold higher in males compared to females, however this ratio rises to up to 5-10:1 for oesophageal adenocarcinomas. Cohort studies have shown that the incidence of OC increases with age; the average of onset is between 65 to 70 years. ¹⁴ This article seeks to discuss the epidemiology, diagnosis and staging, prevention and current trends in the management of OC.

Methods

We searched PubMed/MEDLINE, EMBASE and Cochrane Library and Central Register of Controlled Trials (CENTRAL) databases up to November 2014. Our search strategy used a combination of MeSH, textwords, and appropriate words variants of “oesophagus”, “cancer”, “epidemiology”, “adenocarcinoma”, or “squamous cell carcinoma”, and “staging”, “transhiatal oesophagectomy”, “transthoracic oesophagectomy”, “chemotherapy”, “radiotherapy”. This was supplemented with selected systematic reviews, evidence based guidelines and consensus statements.

Epidemiology

There have been major changes in the epidemiology of OC over the last thirty years. The two key histological types of OC are adenocarcinoma and squamous cell carcinoma (SCC) and they differ significantly in their fundamental patterns of incidence and aetiological factors. Oesophageal SCC comprises the majority of cases worldwide and represents 90% of all OCs in most Eastern countries. However the incidence of adenocarcinoma has risen rapidly over the last three decades and it is now the predominant histological type in Western Europe, USA and Australia, particularly amongst white males.^{5, 6} There are other rare histological types, which include lymphoma, leiomyosarcoma, melanoma, rhabdomyosarcoma and small cell carcinoma.⁷ OC accounts for almost 3% of all cancers in the UK and is the ninth most common malignancy in the UK. There were 8,173 new cases in 2008; incidence rates have increased over the last thirty years in the UK and are now one of the highest in Europe.⁸ Incidence rates of OC differ markedly by geographical locations and between ethnic groups; overall, rates are twice as high in less developed regions compared with more-developed regions and the highest rates occur in Asia. In this region, especially in Iran, Turkey, Kazakhstan and China, a very high incidence of oesophageal SCC exists with greater than 100 cases per 100,000 population annually. A similar trend is also seen in South Africa.^9-12 In contrast, the rate of rise in incidence of oesophageal adenocarcinoma in more-developed countries has exceeded that of oesophageal SCC, which has remained the same or decreased. Oesophageal adenocarcinoma now comprises approximately 50% of all OCs in these countries. ¹³

Who gets oesophageal cancer?

The aetiology of OC is multifactorial, with interactions between environmental risk exposures and genetic factors. These can be divided between the two different histological types of OC.

Pathology of oesophageal tumours

Oesophageal tumours are classified as epithelial and non epithelial. Epithelial tumours include papilloma, intraepithelial neoplasia, carcinoma and carcinoid tumours. Non epithelial tumours include leiomyoma, lipoma and gastrointestinal stromal tumours (Table 1).

Table 1: WHO histological classification of oesophageal tumours

Oesophageal adenocarcinoma

Established risk factors for oesophageal adenocarcinoma (Fig. 1) include gastro-oesophageal reflux disease, Barrett’s oesophagus, obesity, male sex, tobacco smoking and a low intake of fruit and vegetables.^{15, 16} There is evidence to suggest that previous infection with Helicobacter Pylori and the use of non-steroidal anti-inflammatory drugs may decrease the risk of OC. ¹⁷

Fig. 1: Adenocarcinoma of the oesophagus (from Lewin et al. Gastrointestinal pathology and its clinical implications)

Barrett’s oesophagus (Fig. 2) occurs when there is metaplastic change in the lining of the oesophagus from normal stratified squamous mucosa to single layered columnar glandular mucosa with variable degrees of goblet cell differentiation.¹⁸ This transition usually occurs in the context of chronic gastro-oesophageal reflux disease, which causes exposure of the epithelium to refluxate. Gastro-oesophageal reflux disease is a major contributory factor and 5% of people with reflux disease develop Barrett’s oesophagus. The estimated prevalence of Barrett’s oesophagus is just under 2% amongst adults in the West and the annual incidence is approximately 0.1%. However, there is evidence to suggest that the rate of diagnosis is increasing by 2% annually.¹⁹ There has been a rise in the incidence of gastro-oesophageal reflux disease, which may be explained by a number of factors. The rise in the prevalence of obesity, specifically central and intra-abdominal obesity has been found to have a link with oesophageal adenocarcinoma. This can be explained by the fact that an increase in adiposity will cause a rise in intra-abdominal pressure thereby increasing reflux that may be asymptomatic. However, studies also suggest that obesity is a strong independent risk factor for oesophageal adenocarcinoma regardless of gastro-oesophageal reflux symptoms implying an underlying link. ^{20, 21} Another factor that may contribute to the rise in reflux disease is the increased use of drugs that relax the lower oesophageal sphincter. There is evidence to suggest that individuals with previous H. Pylori infections are less likely to develop oesophageal adenocarcinoma.²² This might be explained by the gastric atrophy that results from this infection, which will reduce the acidity and quantity of gastric secretions and thus decreasing the chances of gastro-oesophageal reflux. However, the prevalence of H. Pylori infections is decreasing in the Western population, which may contribute to the rising incidence of oesophageal adenocarcinoma. Gastro-oesophageal junction (GOJ) adenocarcinoma was classified by Siewert and Stein into three types. Type I arises from 1 to 5 cm proximal to the GOJ (tumours of the distal oesophagus), type II arises from 1 cm proximal to 2 cm distal to the GOJ (true cardiacarcinoma), and type III arises from 2 to 5 cm distal to the GOJ (subcardial gastric carcinoma). ⁶¹

Fig. 2: Barrett’s oesophagus (adapted from WHO classification of oesophageal tumours)

Oesophageal squamous cell carcinoma

The major risk factors for the development of oesophageal SCC (Fig. 3,4) are tobacco use and alcohol consumption; particularly a combination of both.^{23, 24} Nitrosamine exposure in tobacco smoking and the alcohol metabolite aldehyde, which is a known carcinogen, are probably the underlying reasons for these two risk factors. The high incidence of oesophageal SCC in Northern China, Iran and areas of Southern Africa may be related to a diet rich in nitrosamines and deficient in trace elements and vitamins A & C.

Other risk factors for oesophageal SCC in the Western world include low socioeconomic status, poor oral hygiene, achalasia, history of thoracic radiation, caustic injury, hereditary tylosis and Plummer-Vinson Syndrome.²⁵

Fig. 3: Squamous cell carcinoma of the oesophagus

Fig. 4: Microscopic picture of squamous cell carcinoma (adapted from WHO classification of oesophageal tumours)

How does oesophageal cancer present clinically?

Patients presenting with symptoms of OC almost invariably have advanced disease. The most common presenting symptom is progressive dysphagia with 74% of patients reporting difficulty swallowing.²⁶ This is graded according to the following: ²⁷

• Grade 1: Able to swallow most foods
• Grade 2: Able to swallow soft foods only
• Grade 3: Able to swallow liquids only
• Grade 4: Unable to swallow anything

17% of patients will also report pain on swallowing food and liquids (odynophagia). ²⁶ Typically, patients with oesophageal adenocarcinoma will be white males with a background of gastro-oesophageal reflux disease who have developed dysphagia. On the other hand, patients with oesophageal SCC will present with dysphagia, associated with weight loss and a history of smoking and increased alcohol intake may exist.

Other less common symptoms include dyspnoea, cough, hoarseness, acute haemorrhage and pain which may be retrosternal, back or right upper abdominal. These will usually represent the existence of metastatic disease.

Physical examination is often normal; positive clinical findings may include cachexia, lymphadenopathy and hepatomegaly in the presence of metastases.

How is oesophageal cancer diagnosed?

It is essential to have a low threshold if cancers are to be detected at an early, treatable stage. National Institute for Health and Clinical Excellence (NICE) guidelines state that a patient presenting with symptoms suggestive of upper gastrointestinal cancer should be referred to a team specialising in the management of these cancers. Specifically; patients of any age presenting with dyspepsia in association with alarm symptoms should be urgently referred for endoscopy or to a specialist. The classical ‘alarm’ symptoms associated with OC includes dysphagia, vomiting, anorexia, weight loss and symptoms associated with gastro-intestinal blood loss. Patients aged 55 or more with persistent, recent onset, and unexplained dyspepsia should be referred urgently for an endoscopy.

Diagnosis is usually made by oesophago-gastro-duodenoscopy where multiple biopsy samples must be taken from any mucosal abnormality to exclude early tumours. Suspicious lesions including oesophageal strictures may require repeated biopsies if initial results are negative.

Once diagnosis is made patients should be urgently referred to an Upper Gastro-intestinal team at a specialist centre for investigations to stage disease and further management.

Staging oesophageal cancers

It is essential to accurately stage disease to exclude patients with widespread metastatic disease for whom surgery will not be curative and to identify subgroups of patients who will require neo-adjuvant therapies. Whilst it is difficult to completely eliminate the possibility of ‘open and shut’ cases where tumours are found to be inoperable at the time of surgery; it is important to develop a staging strategy with investigations and procedures that help to minimise this risk. The TNM (Tumour, Node, Metastasis) staging system is used to classify the depth of tumour invasion into or through the oesophageal wall, the status of regional lymph nodes and metastases to distant sites. The TNM7 categories are shown in Tables 2 and the current stage groupings is shown in Table 3. ²⁸

Table 2: TNM7 staging system

Table 3: Stage classification for oesophageal cancer in the 2010 TNM7 staging system

Initial staging assessment includes Computed Tomography (CT) (Fig. 5) of the thorax, abdomen and pelvis and its major role will be in evaluating the T stage to detect local tumour invasion into adjacent structures and determining the presence or absence of metastatic disease. However CT will not be able to determine the depth of tumour invasion. Endoscopic ultrasound (EUS) (Fig. 6) is the main modality used to stage the primary tumour and primarily aids in distinguishing T1 lesions from T2-4 lesions. This method has an accuracy ranging from between 73% to 89% in tumour staging.²⁹ Accurately distinguishing tumour stage will affect treatment as T1 lesions may be treated with endoscopic therapy or with oesophagectomy whereas T2-4 lesions may require neo-adjuvant chemo-radiotherapy prior to surgery. EUS is also used for evaluation of regional lymph nodes however although sensitivity is approximately 80%, the specificity is lower at approximately 70%. ³⁰ It is best to perform a EUS-guided lymph node biopsy for confirmation of involvement.

Fig. 5: CT scan shows irregular wall thickening of the esophagus and enlarged metastatic lymph node.

Fig. 6: Endoscopic ultrasound (EUS) of oesophagus showing T3 tumour

FDG-PET (¹⁸F-fluoroudeoxyglucose PET) (Fig. 7) is a key modality for the detection of distant metastatic disease in OC.^{31, 32} PET may reveal previously occult distant metastases in nodal and non-nodal sites with a sensitivity of 67% and high specificity of 97%. ³³ It can also reveal metastases to bone, which may not be detected using conventional methods. An investigation has shown PET to be the only modality that predicted intended curative resection and it may also be used to prevent unnecessary surgical explorations.³⁴ The use of PET has been shown in a study to change the management of patients from curative to palliative due to detection of previously unknown metastases.³⁵ It has also been used in a prospective study to assess response early after neo-adjuvant chemotherapy to determine the need for urgent surgery or further chemotherapy. The usage of CT and PET in combination has become increasingly available and is useful in selective cases.³⁶

Fig. 7: FDG PET/CT image demonstrating increased uptake at the distal oesophagus and coeliac lymph node in oesophageal cancer case

Minimally invasive surgery is also used as a method to stage OC in many specialist centres.³⁷ A staging laparoscopy can visualise the primary tumour, identify metastases such as hepatic and regional nodal and can accurately detect intraperitoneal dissemination of disease, which may not have been appreciated on other radiological staging investigations. Samples of peritoneal ascites or washings for cytology can also be obtained at this stage if present.

Endoscopic mucosal resection (EMR) can provide accurate histological staging for high grade dysplasia and intramucosal carcinomas. ³⁸ In many cases EMR alone can be a therapeutic intervention depending on the depth of invasion on the specimen.

Treatment

The management of OCs requires a multi-disciplinary team approach involving surgeons, oncologists, radiologists, pathologists, specialist nurses, dietitians and specialists from other specialties if required. Patients considered for surgery or chemo-radiotherapy will require a fitness assessment. In addition to pulmonary function tests, ECG and echocardiogram, cardio-pulmonary exercise testing (CPEX/CPET) is now being increasingly used to assess fitness for major surgery.

OCs can be managed with surgery, chemotherapy or radiotherapy, a combination of the three or palliation in many cases. Disease that is locally advanced without signs of distant metastases is treated with an intention to cure and this will involve a multimodal approach. Metastatic, disseminated and recurrent disease will be treated with palliative intent with chemotherapy to increase survival or measures such as radiotherapy or stent placement for symptomatic relief.

Surgical

Surgical resection can be part of a multimodal approach or alone and is the main option for curative treatment. There are a number of surgical procedures that can be used however it is important to ensure removal of macroscopic and microscopic tumour in association with dissection of lymph nodes with either method as these are vital prognostic factors following surgery.

Open oesophagectomy (OO):

Options for resection include trans-hiatal oesophagectomy and transthoracic approaches and the choice of approach will depend on the location of the tumour, access to lymph nodes and surgeon preference. An Ivor Lewis oesophagectomy (also known as Lewis-Tanner oesophagectomy) involves abdominal mobilization of the stomach and right thoracic approach for resection of the oesophagus. The three-stage modified McKeown oesophagectomy involves a laparotomy, right thoracotomy and neck anastomosis. A resection margin 8-10 cm proximally and 7 cm distally is recommended to achieve an R0 resection (recommendation class IIB, level of evidence C). The next step is to construct a conduit for the anastomosis and this can be achieved by using a gastric tube, large or small bowel. A gastric tube is preferred due to the following factors; ease of use, tension free and longest term conduit survival (recommendation class IIA, level of evidence C). The anastomosis can be performed in the chest or the neck. This relies on multiple factors such as ease of the anastomosis, tension on the repair, ability to diagnose and treat complications and the oncological status. Circular staplers or hand sewn technique usually used with no significant differences in the outcomes. A drainage procedure such as pyloroplasty is recommended to avoid delayed gastric emptying (recommendation class I, level of evidence B). ⁶²

Radical oesophagectomy using either approach has a perioperative mortality of 5-10% and morbidity of 30-40%. ³⁹ Lymph node dissection plays an important role owing to the extensive submucosal lymphatic drainage of the oesophagus. This has meant that nearly 80% of patients undergoing surgery have positive lymph nodes and prognostically this is of importance.^{40, 41} However, there has been controversy with regards to the extent of lymph node dissection required. For optimal staging 10 lymph nodes for T1 and 20-30 lymph nodes for T2 and T3 tumours should be harvested. ⁶² In order to perform a curative resection for carcinoma of the middle and lower third of the oesophagus it is recommended to dissect the abdominal and mediastinal lymph nodes. Three-field lymphadenectomy in the abdomen, chest and neck, is performed in Japan for oesophageal SCC.⁴² Proponents of radical lymphadenectomy argue that it does allow optimal staging, improves loco-regional disease free survival improving the quality of life for these patients.

Minimally invasive oesophagectomy (MIO):

Minimally invasive approaches, which involve laparoscopic mobilisation of the stomach, thoracoscopic mobilisation of the oesophagus and hybrid or robotic approaches, are increasing in many specialist centres. Benefits of this approach include shorter recovery times, decreased post-operative pain and reduced cardiopulmonary complications without jeopardising the oncological outcomes. Luketich et al. reported a mortality rate of 1.7%, leak 5% and empyema 6% following MIO. ⁶³Several randomised controlled trials (RCTs) and comparative studies were conducted to investigate the efficacy and outcomes of MIO. A study by Li et al was conducted on 407 patients underwent MIO and OO found that the overall incidence of complications was lower in the MIO patients. The incidence of pulmonary complications was 20.7% in contrast to 39.7% in the OO group. However, there was no difference in the overall survival among the groups. Another comparative retrospective study by Mu et al. didn’t reveal any difference in the morbidity, anastomotic leak rate, pulmonary complications and length of stay between the approaches and the authors concluded that both techniques are equivalent. ^{63, 64}

Neo-adjuvant chemotherapy

This aims to improve operability; achieving this by shrinking the tumour prior to surgery, down-staging the disease as well as treating occult metastatic disease. Response to treatment can be assessed prior to surgery with repeat radiological investigations. It is now common for patients in the UK with locally advanced disease to undergo neo-adjuvant chemotherapy followed by resection. This is based on the results of a multi-centre study conducted by the Medical Research Council (OEO2), which showed a 9% improvement in two-year survival in patients given 2 cycles of Cisplatin and 5-Fluorouracil chemotherapy compared to those who were not. Five-year survival with surgery alone was 17%, compared with 23% with neoadjuvant chemotherapy.⁴³ The MRC Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial randomized patients to chemotherapy with surgery or to surgery alone and it was found that patients in the chemotherapy group (who received Epirubicin, Cisplatin and infused 5-Fluorouracil, ‘ECF’) had a significant improvement in progression-free survival and a 13% increase in 5-year survival.⁴⁵

In a meta-analysis of neoadjuvant chemotherapy, there was an overall all-cause absolute survival benefit of 7% at 2 years with the addition of chemotherapy. When analysed by subtype, chemotherapy had no significant effect on mortality for patients with squamous cell carcinoma; however, there was a significant survival benefit for patients with oesophageal adenocarcinoma (HR 0.78; p=0.014). ⁴⁷

As a result of this evidence, neoadjuvant chemotherapy is a standard of care for patients with operable mid and lower oesophageal and GOJ adenocarcinoma. The ongoing MRC OEO5 trial is evaluating optimal neoadjuvant chemotherapy regimens: 4 cycles of chemotherapy with ‘ECX’ (Epirubicin, Cisplatin and Capecitabine) compared to two cycles Cisplatin and 5-Fluorouracil, as in OEO2.⁴⁴

Patients who are deemed suitable for surgical management of mid or distal oesophageal (including GOJ) adenocarcinomas are referred to the GI oncology team to assess fitness for chemotherapy. Many of the criteria assessed are similar to those in the pre-operative assessment, particularly performance status and medical comorbidities. Significant history of renal disease or cardiovascular disease, especially ischaemic heart disease would be a relative contraindication to systemic chemotherapy. Toxicities from chemotherapy are wide-ranging and include gastrointestinal upset, hair loss, skin rash, neurotoxicity, renal toxicity, bone marrow suppression (with risk of neutropaenic sepsis, thrombocytopaenia, and anaemia), cardiovascular toxicity, and chemotherapy-related fatigue. In the MAGIC trial, three cycles of epirubicin, cisplatin and capecitabine (ECX) chemotherapy were given both before and after surgery, and approximately one quarter of patients had CTCAE grade 3 or 4 neutropaenia. ⁴⁵

The REAL 2 trial ⁴⁸ was a 2x2 factorial non-inferiority comparison of cisplatin versus oxaliplatin and 5-fluorouracil (5-FU) versus oral capectiabine in patients with oesophageal, gastro-oesophageal junction and gastric tumours. Treatment was given as triplet chemotherapy: epirubicin plus platinum agent (cisplatin or oxaliplatin) plus 5-FU or capecitabine. The trial results showed that oxaliplatin was at least as effective as cisplatin, and oral capectibine was at least as effective as intravenous 5-fluorouracil. There was less grade 3 and 4 neutropaenia with oxaliplatin versus cisplatin, but this was offset by an increase in neuropathy and diarrhoea. As a result of this trial, EOX chemotherapy can be used as an alternative to ECX in both the neoadjuvant and metastatic settings (Table 4).

Table 4: Efficacies of major combination chemotherapy drugs

Neo-adjuvant chemo-radiotherapy

In contrast to the UK, patients in the USA commonly receive neo-adjuvant chemo-radiotherapy (CRT) for locally advanced oesophageal carcinoma. There is evidence that preoperative CRT is superior to surgery alone. A meta-analysis of ten randomised controlled trials showed a hazard ratio for all-cause mortality of 0.81 (95% CI 0.70 to 0.93; p=0.002). This corresponded to a 13% absolute survival benefit at 2 years.⁴⁷ In the subgroup analysis of the Dutch CRT trial (which used paclitaxel and carboplatin combination chemotherapy), the beneficial effect was more pronounced in patients with squamous cell carcinoma (HR 0.34; 95% CI 0.17 to 0.65) compared to adenocarcinoma (HR 0.82; 95% CI 0.58 to 1.16).⁴⁹

There has been no direct head-to-head comparison of neoadjuvant chemotherapy and neoadjuvant CRT in the context of a phase III randomised control trial. Concerns regarding the added morbidity of CRT have meant that chemotherapy alone is the standard neoadjuvant treatment of choice in the UK. However, the role of neoadjuvant CRT is currently being reassessed in the Neo-SCOPE trial.

Definitive chemo-radiotherapy (CRT)

According to current UK consensus guidelines, CRT is the definitive treatment of choice for localised squamous cell carcinoma of the proximal oesophagus. ⁵⁰ Localised squamous cell carcinoma of the middle or lower oesophagus may be treated with CRT alone, or CRT plus surgery. ⁵⁰

In a pivotal study, US Intergroup RTOG-8501 randomised 121 patients with squamous cell carcinoma or adenocarcinoma to receive CRT (cisplatin and 5-Fluorouracil with 50 Gray in 25 fractions), or radiotherapy alone (64 Gray in 32 fractions). This trial ⁴⁶, together with a subsequent systematic review ⁵⁵, demonstrated a survival superiority of CRT over radiotherapy alone (1-year mortality odds ratio 0.61; 95% CI 0.31 to 0.89; p<0.001). This was at the expense of increased toxicity.

This and similar studies ^56-57 have demonstrated a remarkably consistent median survival of 14-18 months and 2 year overall survival of 30-40% with CRT.

CRT practice in the UK is somewhat varied, but within the authors’ multidisciplinary team Cisplatin and 5-Fluorouracil chemotherapy is given in weeks 1 and 5 of a five-and-a-half week course of radiotherapy. The radiation dose used is 50.4 Gray in 28 daily fractions, treating Mondays to Fridays. An alternative radiation dose-fractionation which is supported by the Royal College of Radiologists guidelines is 50 Gray in 25 daily fractions. ⁵⁸

There are few trials directly comparing surgery alone with CRT. A study of 80 patients with squamous cell carcinoma randomised to surgery or CRT failed to show superiority of either strategy in terms of early disease free survival or overall survival. ⁵¹ Adding surgery to CRT can improve local control rates compared with CRT alone, but combined-modality therapy has not been shown to improve survival. It predictably also leads to significantly more treatment-related morbidity.⁵²

The French FFCD 9102 trial recruited 444 patients with potentially resectable OC (90% squamous cell carcinoma) to receive induction CRT. Those patients who showed evidence of response to CRT were then randomised to further CRT or surgery. Median overall survival was 19.3 months in the CRT alone arm, and 17.7 months in those randomised to surgery. The trial met its endpoint of non-inferiority for 2 year overall survival. Again, toxicity was shown to be significantly higher in patients who received both CRT and surgery.⁵³

Although definitive CRT is a current recommended standard of care for localised squamous cell carcinoma of the oesophagus, there is insufficient evidence to to support either a surgical or non-surgical approach ⁵⁰. Surgery should be considered in patients who have histologically-confirmed residual disease at the end of CRT.

For patients deemed unsuitable for surgery with localised adenocarcinoma of the oesophagus, CRT is a valid option for treatment. An American case series of 25 patients with a median age of 77 years showed that CRT using two cycles of mitomycin-C and 5-fluorouracil in combination with radiation (dose 50.4Gy in 28 daily fractions) was effective and tolerable. 68% of these patients had no evidence of residual disease on post-treatment endoscopy. This small series of patients had a two year overall survival of 64%, with a median overall survival of 35 months.⁵⁴

Salvage surgery after definitive CRT

Local recurrence occurs within the first year in 10-30% of patients treated with definitive CRT.⁵⁰ Salvage curative oesophagectomy may be considered within a multidisciplinary team setting. Repeat staging investigations including a CT-PET and EUS are required before a final decision for salvage surgery is made. Survival benefit is limited, and such surgery is associated with an increased in-hospital mortality rate and increased morbidity.⁵⁹ Informing patients of the potential high risks and poor outcomes is an integral part of the decision-making process for salvage surgery.

Palliation

The majority of patients diagnosed with OC are never treated with curative intent as a result of advanced disease or their physical fitness and comorbidities not allowing for radical treatment. It also includes patients who have developed recurrent or metastatic disease following resection. For this group of patients, there are a number of palliative treatments available for relief of symptoms, prolonging and maximising their quality of life. Once again, a multidisciplinary, holistic approach is required to provide the best treatment.

Treatments to provide symptomatic relief such as dysphagia can include intraluminal brachytherapy, endoscopic stenting using self-expanding metal stents or repeated endoscopic dilatations. Dysphagia can also be palliated by chemotherapy or external beam radiotherapy. Laser-thermal Nd-YAG endoluminal tumour destruction and photodynamic therapy can also be administered however this requires a number of treatments and may be more suitable for short exophytic tumours. It is essential to manage pain and nutrition and feeding options through a gastrostomy, jejunostomy or even intravenously can be provided to ensure adequate nutritional status. In addition to providing symptomatic relief it is important to also ensure that these patients receive social and psychological support by identifying and addressing the needs of the patients as well as their carers.

Palliative radiotherapy can be offered to patients with symptomatic primary oesophageal tumours in the context of metastatic or inoperable disease. Palliative dose and fractionation options are varied, but include 27 Gray in 6 fractions treating twice a week for 3 weeks; 30 Gray in 10 fractions treating daily for 2 weeks; 20 Gray in 5 fractions treating daily for 1 week.⁵⁸ The aim of such radiation treatment is to palliate dysphagia. This effect is not immediate, and therefore patients with significant dysphagia are better served initially by endoscopic stenting.

Chemotherapy has been shown to be effective in improving symptoms and overall survival. Patients with good performance status are offered combination chemotherapy. This can be with EOX, as per the MAGIC trial, ⁴⁵or with Cisplatin and 5-Fluorouracil, with or without the addition of Epirubicin (CF or ECF). 5-Fluorouracil can be substituted for oral Capecitabine (i.e. CX or ECX) without any adverse effects on outcomes.⁴⁵

When choosing palliative systemic chemotherapy for patients with incurable OC, the primary aim should be about maximising quality of life. Improvements in outcome with more intensive chemotherapy regimens, such as docetaxel, cisplatin and 5-Fluorouracil, have been shown to be offset by significantly more toxicity.⁶⁰ As a result, Docetaxel containing regimens are not approved in the UK for this indication.⁵⁰

Conclusions

The incidence of oesophageal carcinoma is increasing and despite advances in management and treatment the overall prognosis remains poor. It is essential to recognize and diagnose early, to have a clear pathway for subsequent investigations to ensure accurate staging. This will allow appropriate therapy to be administered to ensure the best possible outcomes are achieved. Treatment of OC is still a challenge however recent advances in surgery, endoscopic treatments and new therapeutic agents will hopefully improve prognosis.

Introduction 

Hydatid disease is due to Echinococcus species commonly granulosus sometimes multilocularis. The common locations of hydatid cyst are the liver (65% to 75%) and lungs (25%-30%) ^1,2,3. Hydatid disease rarely develops in some locations such as the spleen, kidney, bones, heart, brain, peritoneum, myocardium and muscles (1-4%)¹. In our review of literature, concomitant paraspinal and intrahepatic hydatid is reported rarely.

Case Report

A 25 year old male presented with backache on the right for 1 month and fullness in the right paraspinal region. No history of trauma, fever, burning micturition, pain in abdomen, weight loss or hematuria.

On clinical examination he had non ballotable lump in the right paraspinal region, measuring 15x5x5cm with ill defined margins intra muscular plane extending from the posterior subcostal margin to the iliac region with no overlying skin changes and no organomegaly.

Blood investigations including liver function tests and kidney function tests were normal. Ultrasound examination revealed hepatomegaly with thick walled cystic lesion in the right lobe of the liver and the in muscle plane in the right renal angle region. 

CT abdomen (P+C) revealed a well defined hypodence non-enhancing cystic lesion measuring 45x40 cm seen in the right lobe of the liver with peripheral calcification with another lesion of similar morphology of size 14x5x3.6cm in the right paraspinal muscles with no intercommunication between them and no bone, spinal canal alteration or compression of the right kidney.

Figure 1: Right paraspinal hydatid

Figure 2: Intrahepatic hydatid

Figure 3: Coronal  view of CT image

The diagnosis of paraspinal hydatid cyst was confirmed. As the patient was symptomatic for paraspinal hydatid cyst only and the size of the hepatic cyst was small, exploration of the right paraspinal region was done after 21 days of antiscolicidal treatment. There was a cyst measuring 15x5x5 cm beneath  the oblique and lattisimus dorsi ,superficial to the psoas muscle without invasion into it .The cyst opened multiple daughter cysts along with pus evacuated. The cyst excised in totto without rupture & spillage. Negative suction drain was kept. Post operatively on day 3 the drain was removed, stitches removed on day 10 and discharged. Histopathology confirmed diagnosis. 

Figure 4: Intraoperrative photograph

Figure 5: Photograph of multiple daughter cysts

Discussion

Hydatid disease is most prevalent in sheep and cattle-breeding areas, which is where the first step in the chain of transmission occurs. The causative agent is introduced to the dog (the primary host) through the faeces of livestock. The minute larval form of E. granulosus lives in the small intestine of the dog species. The eggs are passed in the faecesof an infected dog and can be transferred to mammal (man – intermediate host) that ingests them. After ingestion, the embryos are released from the eggs, traverse the intestinal mucosa and disseminate systemically via venous and lymphatic channels  and develop into hydatid cysts in various body parts.

The cysts cannot easily grow in muscles due to their contractility and  lactic acid content. The wall of a cyst in the muscle is formed by three layers: the inner germina, intermediate and outer granulomatous adventitial layer. The most common skeletal sites include hip, thigh, shoulder and humerus regions. Hydatid cysts are frequently asymptomatic¹. The latent period of cyst development varies between 5 and 20 years^4,5.

Serological tests are widely used to diagnose hydatid cysts. However, positive serological results do not confirm, nor negative results exclude the disease^1,6. The imaging features of hydatid cysts are well described in the literature. Ultrasound scans are a sensitive, safe, non-invasive method. It is the procedure of choice for the diagnosis of cysts with a “honeycomb” pattern (type 3), as observed in our patient. Gharbi’s classification provides morphological description on ultrasound. Type 1-pure fluid collection, type 2-fluid collection with split wall (floating membrane), type 3-fluid collection with septa, type 4-heterogenous echographic pattern, type 5-reflecting thick walls.

As seen in our case the cyst fluid appears anechoic at USS, yields an attenuation value of 3-30HU at CT. Calcifications in the cyst wall as in our case are best detected on CT scans. CT has the advantage of detecting smaller cysts when located outside the liver and sometimes differentiating  parasitic from non-parasitic cysts, for follow-up studies during chemotherapy. Other diagnostic means such as fine needle aspiration should be avoided because of dangerous anaphylactic reactions⁷.

Surgery is the optimal treatment for hydatid cyst. Open cyst evacuation is indicated for gharbi types 4 & 5, posterior cysts, central cysts, more than 3 cysts, large cysts, heavy calcification, infected cysts with above criteria, biliary communication, pulmonary communication and peritoneal rupture. Laparoscopic evacuation is indicated in Gharbi type 1 or 2, anterior cysts, peripheral cysts,1-3 cysts, small cysts, no or minimal calcification. Pericystectomy is complete resection of cyst wall without entering the cyst cavity.

Alternative therapy with non-toxic scolocidal agents or combination chemotherapy using imidazole derivatives, particularly albendazol, has been advocated in the management of patients with recurrence and high risk of contamination⁸.

Introduction:

Ganglioneuroma is a rare, benign, neuroblastic tumour that originates from the neural crest cells. Ganglioneuroma, ganglioneuroblastoma and neuroblastoma are three maturational manifestations of a common neoplasm in the progressive order of loss of differentiation. Ganglioneuromas may be found anywhere along the line of the embryonic neural crest, from clivus to sacrum and are very rare in the pelvis. Less than twenty cases have been described in the literature with various presentations based upon location including extradural, retroperitoneal, spinal, thoracic and one solely intradural medullary location. Ganglioneuromas may stay asymptomatic for a long period and  give rise to no pressure symptoms either due to slow growth leading to progressive increase in size accompanied by adaptive changes. Ganglioneuromas demonstrate long-term disease-free survival even with an incomplete surgical removal. Here we present a case of a girl aged 11 years with pelvic ganglioneuroma.

Case Report:

A girl aged eleven years was brought from a remote hilly area in Pakistan by her mother to the city hospital many miles away. She had noticed that her daughter’s lower abdomen had progressively enlarged over last few months. Her menstrual cycle was normal so the mother was concerned that despite not being pregnant, her daughter had a distended abdomen as if she was pregnant She had a good appetite and unaltered bowel and bladder function. She had no heartburn, regurgitation, nausea, vomiting, heamatemesis or melaena. She denied any bleeding par rectum, shortness of breath, cough, loss of consciousness or convulsions. Her past medical history was mundane. She had not had any surgery in the past and was not taking any medication. Examination revealed a smooth, large, fixed hard mass in the right lower abdomen and pelvis. It was palpable in the pelvis on rectal examination which was otherwise normal.  Liver or spleen was not palpable and she had no ascites. Her chest was clear, heart sounds were normal and there were no neurological abnormalities. Laboratory tests including FBC, LFT, U&E and Creatinine were normal. Her MRI  scan was not of a good quality due to limitation of resources and technology at place of her diagnosis, but it showed an 11.4 x 11.8cm solid, well-defined mass arising from pelvis and extending up to the umbilicus. The mass showed intermediate low signals on T1 and hyper intense signals on T2 images (Fig. 1). Mid line surgical exploration was undertaken which showed a large, solid, retroperitoneal mass arising from sacral nerves within the pelvis. Mass was lying in front of great vessels, overlapping the confluence of common iliac vessels. The left ureter was displaced laterally while the right ureter was lying over the mass. The mass was excised completely. Post operative course was uneventful and patient was discharged home on the fifth post operative day.

Figure1: MRI showing showing a large soft tissue mass.

Macroscopically, the specimen was a 13x13x5cm rounded well-encapsulated mass (Fig. 2). Upon sectioning in vitro, mass was seen to be solid, whorled and grey white. Microscopically, groups and singly scattered ganglion cells were seen with surrounding neural tissue. There was no evidence of atypia, mitosis or necrosis. Features were suggestive of a ganglioneuroma. (Figure 3) The patient was well at two months follow up and required no further treatment.

Figure2: Photograph of the resected specimen shows a well-encapsulated ovoid mass.

Figure 3 Microscopy showing scattered ganglion admist neuronal cells

Discussion:

Neuroblastoma, ganglioneuroblastoma and ganglioneuromas are tumours of  sympathetic nervous system that arise from the neural crest cells.¹ These tumours differ only in their progressive degree of cellular and extracellular maturity, with ganglioneuroma being the most mature hence well differentiated and neuroblastoma being the least.² Ganglioneuroma are rare, benign and slow growing. They may occur spontaneously or as a down grading from therapy for Neuroblastoma with either chemotherapy or radiation.³ International Neuroblastoma Pathology Classification (INPC) has been devised after studying 552 such tumours. Out of 300 with favourable prognosis three groups were identified as; ganglioneuroma maturing (GN-M), ganglioneuroblastoma intermixed (GNB-I) and ganglioneuroblastoma nodular with favourable subset (GNB-N-FS). These are resectable in 91% cases in one or more surgical sessions. In contrast, the remaining 252 tumours had unfavourable prognosis and were called ganglioneuroblastoma nodular unfavourable subset (GNB-N-US). This group was not amenable to surgical resection and usually already had metastasis at the time of presentation.⁴

Ganglioneuromas although are mostly sporadic, may be associated with Neurofibromatosis (Von Recklinghausens Disease) and  Multiple Endocrine Neoplasia type II (MEN).¹ Ganglioneuroma usually presents before the second decade and rarely after the sixth.² The median age at diagnosis has been reported to be approximately 7 years. There is a slight female preponderance.⁵ The common locations are the posterior mediastinum, and the retroperitoneal space. Retroperitoneal pelvic location is very rare and only few case histories have been reported.¹

Although retroperitoneal ganglioneuromas are usually asymptomatic, some patients may get compression symptoms, diarrhea, hypertension, virilization and myasthenia gravis owing to release of certain peptides.¹ Radiological examination may localize the lesion. MRI may show low intensity on T1-weighted images and heterogenous hyper intensity on T2-weighted images with gradual increasing enhancement on dynamic images.⁶

Surgical excision is sufficient for treatment of ganglioneuromas. Chemotherapy or radiotherapy has no role in the treatment. Even with an incomplete excision, close follow up alone may be adequate. If any progression of the tumour is seen then repeat laparotomy may be indicated.²

Conclusion:

Although pelvic ganglioneuroma is a very rare lesion, it should be considered in the differential diagnosis of any abdomeno-pelvic mass. As it is a slow growing tumour, gross total surgical removal with preservation of organ function is a feasible surgical option.

Introduction:

Although one cell type may predominate, teratomas usually comprise of tissue from all three embryonic germ layers^1. Generally arising from the gonads, they may be found in extra-gonadal sites such as sacro-coccygeal region, mediastinum, neck and retroperitoneum.² Here we report a case of retroperitoneal teratoma in an adult with successful surgical treatment. Its clinical presentation, diagnosis and treatment are reviewed.

Case Report:

A woman aged 28 years presented with pain in the right hypochondrium of one year duration. There was no associated bowel or urinary symptom. Examination showed minimal fullness in the right hypochondrium. Routine blood tests and urinalysis were within normal limits. A plain abdominal radiograph showed calcification in the right side of the abdomen (Fig. 1). Ultrasonography demonstrated 13.6 x 8.1 cm soft tissue mass in the retro-peritoneum between liver and the right kidney. It was heterogeneous, well circumscribed with sharply defined borders, and had some calcification and cystic areas. CT abdomen revealed a hypo-dense lesion between liver and the right kidney. It had fatty attenuation with internal hyper-dense areas representing calcification. (Fig. 2). Provisional diagnosis of a retroperitoneal teratoma was made and an open exploration was performed with a right sub-costal incision. There was a large cystic mass behind the ascending colon, duodenum and the pancreas. It was located in the retroperitoneal compartment. There were dense, fibrous adhesions of the mass with aorta but entire cystic mass was excised successfully.

Post operatively this tumor mass measuring 5 x 5 cm was excised in vitro and found to be filled with yellowish creamy material containing hair, sebum and bony tissue. Microscopically it was confirmed to be a cystic teratoma with no malignancy. Stratified squamous epithelium with sebaceous and sweat glands, hair shafts, calcification, few bony spicules and bone marrow elements were all demonstrated. (Fig. 3). The post operative course was uneventful and she was well at the 2 months follow up.

Figure 1. Plain abdominal radiograph showing radio-opaque shadow (arrow heads) in the  right upper abdomen.

Figure 2: Computed Tomography showing an encapsulated mass that contains multiple tissue elements including fat and areas of calcification.

Figure 3: Microscopic examination of the tumor showing squamous epithelium (SE), hair shaft (HS), sebaceous glands (SBG) 

Discussion:

Teratomas are congenital tumours arising from pluri-potential embryonic cells and therefore have several recognizable somatic tissues³, Teratomas are usually localized to the ovaries, testis, anterior mediastinum or the retro-peritoneal area in descending order of frequency.⁴ Teratomas constitute less than 10% of all primary retroperitoneal tumours and hence are relatively uncommon⁵. Furthermore, retroperitoneal teratomas occur mainly in children and have been very rarely described in the adults. Half of these cases present in children less than 10 years of age and only a fifth of them present after 30 years of age. Retroperitoneal teratomas are often located near the upper pole of the kidney with preponderance on the left. The case described here is therefore unusual in that it was a primary retroperitoneal teratoma in an adult, on the right side and with adhesions to the aorta.

Retroperitoneal teratomas are seen in females twice as commonly than males.   Teratomas are usually benign if they are cystic and contain sebum or mature tissue. They are more likely to be malignant if they are solid and have immature embryonic tissue like fat, cartilage, fibrous and bony elements.⁶ In these regards our case is similar to other described cases as our patient is also female and as her teratoma was cystic, it  showed lack of malignancy.

Teratomas are usually asymptomatic as the retroperitoneal space is extensive enough to allow for their free growth. When compression of the surrounding structure occurs, patients may get compression symptoms.The diagnosis of a retroperitoneal teratoma cannot be made on clinical grounds alone. Ultrasound and computed tomography are important in its diagnosis and may show the presence of calcification, teeth or fat. Calcification on the rim of tumour or inside the tumour is seen in 53-62% of teratomas and although radiologically three quarters of patients with a benign teratoma may have calcification within it, a quarter of malignant cases may also demonstrate calcification.  Computed tomography is better than Ultrasonography in defining the extent and spread of teratoma to the surrounding organs.⁷

The prognosis is excellent for benign retroperitoneal teratoma if complete resection can be accomplished.

Introduction:

Payment by results was introduced across the National Health Service (NHS) in 2005. It’s aim was to provide a pricing structure (tariff) for the whole country with some allowance for geographical variation^1-2. The system uses Healthcare Resource Group codes (HRG) in which treatments in similar cost brackets have the same codeA price / tariff is derived from each hospital patient episode and the patient’s registered Primary Care Trust (PCT) is billed accordingly.

In order to generate an HRG code data is collected by the hospital clinical coding department including primary diagnosis, comorbidity (which incurs an extra charge if applicable), and complications, surgical procedure, age and duration of stay⁴. Diagnoses (either primary, co morbidities or complications) are coded using ICD-10 codes. Surgical procedure is defined using OPCS-4 codesA piece if software is then utilised to allocate the HRG code. Each HRG code represents a tariff, which is the average cost of a treatment nationwide. Minor regional adjustments are made to reflect the cost of living².

Payment by results covers all admissions, attendance in accident & emergency departments and outpatients attendances⁵. The 2004 NHS Improvement plan designated 18 weeks as a target for referral to treatment (RTT)⁶. It is a common misconception that trauma patients do not account for considerable income within the NHS. Trauma is often seen as the poor relation when compared with elective work where a target based culture now prevails. Elective targets must be met or hospital trusts can incur financial penalty. This situation is not apparent for trauma due to the acute nature of service delivery in the majority of cases. The burden of trauma work can block elective admissions and is seen by some as a barrier to target attainment. At least 36% of orthopaedic surgeons in the United Kingdom describe trauma as part of their sub-specialist interestWe aimed to assess the throughput and income generated from one week of trauma workload and compared this with the elective throughput in our unit for the same week. This was performed by means of a prospective study. We are not aware of any published work in this specific area.

Methods:

We followed all acute patients admitted to our trauma unit between 21/02/2008 and 28/02/2008. This represented a “trauma week” which is how the consultant rota is organised in our trust. We then compared this with the throughput in our elective unit for the same calendar period. No surgeons were on leave this week and no theatre sessions were cancelled other than the on call trauma consultant’s elective operating sessions. Our trust is a busy district general hospital with over 500 beds and approximately 55,000 emergency attendances per year. The orthopaedic directorate is staffed by ten full time consultants and serves a population of 315,000 patients.

All patient details were recorded prospectively and followed until the end of their inpatient episode. Case notes were then reviewed with the coding department and ICD-10 and OPCS-4 codes were generated. Their length of stay and other required variables were reviewed in order to generate the correct HRG code. Once the analysis was complete income for the trauma and elective groups were calculated.

Results:

Trauma:

48 patients were admitted (22 male) of which 36 required operative intervention. This utilised 14 theatre sessions. Mean age was 53.75 years (range: 7-93, median: 59). Median stay was 4 days with a mean of 13.3. The median and mean trim points (expected duration of stay before extra charges incurred by PCT) were 14.5 and 26.7 days respectively. Other consultants operated on 6 patients. This was either due to expertise in a specific area or space on an elective list utilised to reduce backlog. The income generated by these cases is included in the trauma total due to them being acute trauma interventions rather than elective cases. These results are summarised in tables 1 and 2.

Table 1: Demographic & Income Data of Trauma and Elective Patients

Table 2: Income by Anatomic Region

Of the 48 patients admitted 12 required no operative intervention. These cases were general ‘run of the mill’ admissions such as soft tissue infections for intravenous antibiotics, undisplaced fractures where home circumstances obstructed discharge, soft tissue injuries for further investigation and back pain. These will not be discussed further but the income generated (£31,127) does go towards the total. The median stay was 2 days with a mean stay 8.5 days (range: 1 – 47). This reflects the broad comorbidities and social circumstances of this subset.

The group requiring operative intervention included hip fractures (11 patients). Of these, seven required dynamic hip screw fixation but were deemed “complex” due to their comorbidities and therefore attracted the higher tariff rate (£6685). One displaced intracapsular fracture required total hip replacement, attracting a tariff of £7261. One patient required revision from a dynamic hip screw to an intramedullary device and then revision to a total hip arthroplasty. The tariff price was £19,479. The remaining fractured neck of femur patients attracted between £4379 and £6711 dependent on operative procedure. The median stay was 26 days (mean: 14, range 9 – 107). One patient required closed manipulation of a dislocated total hip replacement attracting a tariff price of £1034 and an inpatient stay of one day. In addition one acetabular fracture was sustained requiring open reduction and internal fixation. It attracted a tariff price of £4262 and an inpatient stay of seventeen days.

One patient required open reduction and internal fixation of a patella fracture attracting a tariff of £2405 and was an inpatient for 10 days. Another patient with septic arthritis required two arthroscopic knee washouts, attracting a tariff of £5941 and was an inpatient for 26 days.

Seven ankle fractures were admitted requiring operative intervention, all of these attracted a tariff of £2405 except one, which attracted £4262 due to co morbidity and complexity of injury. The median stay in this group was six days (mean: 4.9, range: 2-7).

Thirteen patients sustained hand and wrist injuries requiring operative intervention. Of these there were two tendon repairs, two abscesses drained and one digital terminalisation. Five wrist fractures required either manipulation and plaster application, closed reduction and Kirschner wiring or open reduction and internal fixation by means of a volar plate. Three fractures of the base of the thumb were manipulated and percutaneously K-wired. These patients attracted a tariff of between £1048 and £3227. Median stay was one day (mean: 1.36, range: 1 – 3). Three of these cases were managed by our hand surgeon on a trauma list.

One patient admitted with cauda equina syndrome required microdiscectomy attracting a tariff of £1271 and was an inpatient for one day. This was performed by one of our spinal surgeons on a trauma list.

Elective:

71 procedures were performed (36 female). This utilised 22 theatre sessions. Mean age was 49.51 years, (11 – 87 median: 47). Mean stay was 2.3 days. The median and mean trimpoints were 2 and 6.35 days respectively. Cases were divided by anatomical region. A table of income for both trauma and elective patients by anatomical region is included (Table 2).

Twelve patients had hip procedures performed. These included hip injections (n=2, tariff £615), sciatic nerve exploration (n=1, tariff £1217), cemented total hip arthroplasty (n=2, tariff £4304), uncemented total hip arthroplasty (n=1, £5305), resurfacing hip arthroplasty (n=5, £4023) and revision hip arthroplasty (n=1, £7185).

Twelve patients had knee procedures performed. These consisted of total knee replacements (n=3, tariff £5613), unicompartmental knee replacements (n=4, £5613), one anterior cruciate ligament reconstruction (£1863), knee arthroscopies (n=2, tariff £1063), one removal of metal work (tariff £1063) and one scar revision (tariff £1091).

Four patients had foot and ankle procedures performed and these all attracted £1217 tariff price. They consisted of one ganglion excision, one hallux valgus correction, one excision of Morton’s neuroma and one ankle arthroscopy.

Nine patients had upper limb procedures performed. These comprised carpal tunnel decompression (n =1 £1217), radial head excision (n=1 £1217), shoulder stabilisations (n=3 £1217), subacromial decompression (n=1 £1217), acromiclavicular joint excision (n=1 £1063), diagnostic shoulder arthroscopy (n=1 £1217) and arthroscopic cuff repair (n=1 £1887).

34 patients had spinal procedures performed. Inpatient stay ranged from 0 to 5 days with trimpoints of 1 – 13 days. These ranged from nerve root injections (n=23, tariff £522), discography (n=3, tariff £615), microdiscectomy and interspinous distraction (n=2, tariff £3192), decompression, fusions and instrumentation (n= 5, tariff £4252 - £5140), and kyphoplasty (n=1, tariff negotiated: no HRG code. Income £1506). Total income for the spinal group was £44,887.

It can be seen from the data that a wide range of trauma and elective surgery was performed and that the elective group was admittedly younger and had a shorter hospital stay (Table 1). Our unit has the benefit of two spinal surgeons who operate a local and tertiary practice, which changes the demographic of our cohort slightly; other units may not have this factor adjusting their income.

The tariff income for the elective group was £150,318, which was lower than that for the trauma group of £171,941.

Discussion:

This paper is, as far as we are aware the first to compare elective and trauma orthopaedic throughput in a busy district general hospital. It would be bold not to draw attention to our studies limitations. We analysed only one week in the financial year and we accept that seasonal variation may occur. The weather for the week in question involved no snow or ice and was warmer than average for this time of year (5.2°C)¹⁰. We do not feel that severe weather influenced our admissions. Previous studies have assessed the effect of seasonal variation on admissions rate. One was in a winter sports resort in Switzerland and unsurprisingly showed a positive correlation between season and fracture incidence¹¹. Another study based in Tasmania showed no variation in either vitamin D levels or incidence of femoral neck fracture¹². This goes against the findings of a study based at three latitudes, which showed a high seasonal peak in Scotland, Hong Kong and New ZealandOur locality has a temperate climate with no local winter sports resorts; our experience of seasonal variation is minor.

Miscoding and therefore error in calculations may have occurred; as both the authors and experienced coders reviewed the casenotes the likelihood of this is limited.

Our most important finding was that the mean income per trauma patient (£3658.32) was higher than that for an elective patient (£2045.13) and was statistically significant (p=0.001). The HRG code and income generated represents the money actually received by the hospital from the primary care trust. We openly admit that trauma patients represent a larger burden for the hospital. They have a tendency to be older, have complex co-morbidity and have increased length of stay. They are therefore more costly than elective patients. One study performed in a large university hospital calculated the mean cost for a hip fracture to be £8978.56 (range £3450 - £72,564), this rose to £25,940.44 if there was a superficial wound infection (range £4387 - £93,976) and £34,903 if there was a deep infection (range £9408 - £93,976)¹⁴.

Although actual income from the PCT was higher the trauma group will have been loss making on account of the hip fracture group. Whilst this is hard to quantify it seems likely given the calculations portrayed in the Nottingham study of 3686 patientsInpatient costs for the trauma group ignoring theatre costs amount to approximately £204,000. This exposes a lack of appreciation of this group’s requirements in comparison with fit elective hip patients and probably inequality in trauma coding for these patients.

Our study has not tackled implant costs partly due to the fact that inpatient costs have significantly dwarfed these but also due to the fact that we consider these a relatively fixed overhead, costs being determined by local bulk purchase agreements. The consequence on overall study outcome would be minimal given that trauma implants are several orders of magnitude cheaper than elective joint prostheses.

It became apparent to us during the course of our study that trauma can be under resourced when compared with elective care. The background team currently provided for trauma patients include the on call medical team (Consultant Orthopaedic Surgeon, Specialist Registrar and Senior House officer). In addition there are ward nursing staff, anaesthetist, theatre staff, occupational therapists and physiotherapists. On the elective side there are 4 waiting list clerks, 3 surgical assistants, 3 preoperative clinic sisters as well as reception staff and the background medical team (anaesthetist, consultant orthopaedic surgeon, specialist registrar and senior house officer). In the elective setting the aim is identification and optimisation of comorbidities pre-operatively and discharge planning to ensure throughput and turnover of patients. We admit that pre admission screening is not applicable to trauma but faster throughput could ensure improved efficiency and reduced duration of stay.

Our elective patients have a 30-bed ward with an additional 8-bed day case unit; the trauma ward has 24 inpatient beds. The elective unit has 7 registered nurses and 4 health care assistants; on the trauma ward this figure is 4 and 3 respectively. Our elective patients have 2.5 full time equivalent physiotherapists whilst our trauma patients have 1.5.

This situation is probably not dissimilar to the situation in many units elsewhere in the country. This work has shown that trauma income is higher than that for elective work and from this we can infer that if resources were directed accordingly then length of stay could be reduced and profit could be a possibility. A recent paper using hospital episode statistics (HESS) data has shown that length of stay fell quickly once payment by results was implemented¹⁵. What was unclear was whether this represented a real change in efficiencies or simply a change in data manipulation by trusts. HESS data has repeatedly been noted to be inaccurate with a range from 10 to 98% dependent on region and disease group.^16-17. In a 2006 statement by the then Health Minister Mr. A Burnham it was quoted that £88m pounds was being wasted from 390,000 extra unnecessary bed days¹⁸. This was based on the cost of an elective bed being £225 per day with acute beds being significantly more (approximately £320 in one study)The total stay for 66 elective patients was 118 days whereas that for 48 trauma patients was 637 days. Several outliers hugely increased the figure for trauma. Ten trauma patients represented 464 days of inpatient care. If the inpatient stay was reduced by one day for fractured neck of femur patients alone, this amounts to 500 less days per year and approximately £160,000 per year reduction in overhead costs for the trust.

One study in the USA assessed the use of a caseworker to expedite discharge for elderly patients with hip fractures¹⁹. The study did not utilise extra physiotherapy and occupational therapy support. Findings were increased theatre, anaesthetic and blood product costs in elderly patients. Increasing age did not correlate with length of stay, cost of stay or income for the hospital. They found that a case manager did reduce the average stay but did not reduce the overall cost. The NHS would do well to note these findings - in many trusts patient flow practitioners are being employed to try and expedite discharge and increase patient turnover. We feel that this money could be channelled into rehabilitation services to effect prompt rehabilitation and discharge.

One final issue is the variation in income between secondary and tertiary centres for certain injuries. One acetabular fracture underwent fixation generating £4262. If this had been referred to a tertiary centre a supplementary specialised service code would have been applicable generating more income (up to 70% in some cases) when intervention was identical. We agree that certain injuries require tertiary treatment by a team with high volume experience and specialised skills. There is an income chasm between the income generated between secondary and tertiary centres for the same injury, which seems perverse.

Overall trauma income was higher than elective income, but still ran at a loss. This was on account of the length of stay of the hip fracture patients and current coding underestimating their true cost to the trust. There is a disparity between rehabilitation services provided for trauma and elective patients, which needs to be addressed to improve efficiency.

Introduction

Patients with morbid obesity suffer a wide range of symptoms that relate to their oesophagus and stomach. It is rather paradoxical that patients who are overweight suffer the symptoms of difficulty in swallowing, pain during eating or pain after eating because the symptoms of eating difficulty do not translate into weight reduction. There are a range of underlying causes that include gastro-oesophageal reflux disease, dysmotility in the oesophagus, peptic ulceration and the nature and pattern of dietary intake.  The pathophysiology of gastro-oesophageal reflux disease and of dysphagia will be considered. The detrimental effects of the treatments of balloons, gastric bands and gastric bypass will be described and options for management discussed.  The serious complications of adenocarcinoma and its premalignant precursor, Barrett’s oesophagus will be reviewed.

Gastro-oesophageal reflux disease (GORD)

GORD is highly prevalent in obese people with increasing BMI a risk factor for developing the disease. The relation between GORD and obesity has been studied for decades and there have been conflicting results. A person with BMI of ³30 kg/m²   is 3 times more likely to suffer from heartburn and acid regurgitation ¹.

Though the mechanism of this is poorly understood, a number of epidemiological studies have proven this association. Since recently, more evidence has emerged in favour of a positive association ². In 2000, Lagergren et al, based on a population based interview study on 820 Swedish, concluded that GOR symptoms occurred independent of BMI ³. His claim was supported by two previous studies, one of which used oesophageal pH measure and other assessed the impact of weight loss on symptom relief ^{4, 5}. A contrary view has emerged since this, with large number of western studies showing a positive association ^{1, 2, 6-12}. This, however, has not been the case with Asian and Afro-Caribbean population. In a large population study with various ethnicities, a strongly positive association was found between BMI and GOR symptoms in white population. This was not the case in Asian and black population ¹³, a view re-iterated by another study from Iran ¹⁴. The overall incidence of GORD is high in western world between 10% and 20%, compared to 5% in Asia ⁶.

The mechanism of GORD in obesity is very poorly understood. Various theories have been postulated and the evidence for each is discussed below, including the theory that the patho-physiology of reflux in the morbidly obesity could differ from others and might require a different therapeutic approach ⁹

Increased intra-abdominal pressure as a cause of reflux

Increasing intra-abdominal pressure has been hypothesised to be the cause for reflux symptoms. Increasing BMI has been shown to increase intra-gastric pressure and pressure study in a prospective cohort has shown 10% increase in intra-gastric pressure with rise in each unit of BMI ¹⁵. A pH and manometry study in general population with GORD showed a higher pressure gradients across the Oesophago-gastric junction than that in controls both before and during transient lower oesophageal sphincter relaxation. This phenomenon is thought to be caused by increased intra-gastric pressure, supporting the above theory ¹⁶.

Lower oesophageal sphincter dysfunction as a cause

Kuper et al showed a dysfunction of LOS and altered oesophageal motility even in asymptomatic patients with morbid obesity using pH and manometry study (BMI >40 kg/m²) ¹⁷and Wu et al showed an abnormal post-prandial LOS with prolonged transient lower oesophageal relaxation ^{18, 19}.These findings were re-iterated by ayazi et al, showing obese patients to be more than twice as likely to have a mechanically defective LOS ²⁰.   However, another study back in 1987 had shown a similar LOS pressure in normal weight and obese patients, though the gastro-oesophageal pressure gradient to LOS pressure ratio was high in obese ²¹.

Diet

The amount or composition of dietary intake and its relation to GORD has been studied. There is some evidence that volume, fat content and a high-caloric diet increases the oesophageal acid exposure time, giving rise to symptoms ^22-24. This would suggest an improvement of symptoms with reduction of these in the diet. More studies have shown an improvement in reflux symptoms with improved diet ^25-29. But, there is no convincing evidence to implicate the role of diet in reflux symptoms of obese patients.

Hiatus hernia

The incidence of hiatus hernia is over 50% in morbid obesity ³⁰. Hiatus has been shown to be predicted by intra-gastric pressure, gastro-oesophageal presssure gradient and BMI. BMI has in turn been shown to predict the former two. This confirms a positive association between BMI and presence of hiatus hernia ³¹. High BMI is more likely to have oesophago-gastric junction disruption, leading to hiatal hernia and an augmented gastro-oesophageal pressure gradient, providing a perfect scenario for reflux to occur ³². The incidence of defective LES was twice as much in obese patients with hiatus hernia, compared to obese without it ²⁰. Hiatus hernia thus plays a role in the obese patients and the subsequent development of GORD ³³.

Poor mobility and mental state

There is no evidence to support the theory of reflux symptoms secondary to poor mobility and depression in the morbidly obese patients.

Treatment of GORD in obesity

Medical therapy

Medical therapy with a PPI remains the first line of treatment of GORD symptoms in obesity as in patients with a normal BMI. No guidelines are available for dose adjustments in the obese patients ³⁴. They continue to receive the standard therapy, adjusted to the severity of disease and symptoms.

Endoluminal therapy

Endoluminal therapy was introduced recently as treatment alternative for GORD and has shown promising results. This looked a safe option for use in obese patients. However, published results have shown high rate of post-operative PPI requirement in the obese patients ³⁵. Further evidence has to emerge before this option can be recommended for use in the obese patients.

Balloon

Intra-gastric balloon therapy has been an established temporary procedure for weight loss. GORD symptoms in obese tends to improve with weight loss, but as studies have shown, a balloon insertion tended to worsen symptoms ^{36, 37}. Balloon is hence not considered an option for treatment of obesity with patients with reflux symptoms.

Gastric band

Gastric banding provides a sufficient anti-reflux barrier in most of the obese patients with GORD. Abnormal manometric findings like increased LES (lower oesophageal sphincter) residual pressure and peristaltic wave duration are frequently encountered after banding. The clinical significances of these manometric abnormalities are not clear ³⁸. The oesophageal stasis caused by the band could explain the reflux in patients during longer follow up. Though, the reflux from the distal stomach is prevented by the gastric band, formation of a proximal pouch predisposes to stasis and reflux. This is more common in patients with preoperatively defective oesophageal motility. The studies suggesting a good GORD symptom control following banding had shorter follow up, explaining the results ^{39, 40}. Hence it could be concluded that gastric banding may aggravate GORD symptoms and cause oesophageal dilatation, especially in patients with pre-operative motility defects. Routine pre-operative testing should be done and alternative bariatric surgical procedures such as Roux-en-Y gastric bypass considered in these patients   ^41-43.

Sleeve Gastrectomy (Vertical gastric banding)

Gastrectomy reduces weight, but not gastro-oesophageal acid reflux. Although this procedure has been shown to have anti-reflux properties ⁴⁴, it has fallen to disrepute in terms of relieving the reflux symptoms, especially with the superior results of RYGB ^45-48. A number of these cases requiring revision, due to reflux symptoms, have been reported ^49-51.

Gastric Bypass Vs Anti-reflux surgery

Though laparoscopic fundoplication is the standard operation for GORD, gastric bypass has been shown to improve the reflux symptoms in the morbidly obese, apart from reducing their weight and obesity related co-morbid conditions such as diabetes mellitus, hypertension etc. Patterson et al. showed an equivalent symptomatic improvement and objective DeMeester score improvement with Laparoscopic Nissen fundoplication and laparoscopic gastric bypass. The LES (lower oesophageal sphincter) pressure was also noted to improve, following bypass ⁵². This was in light of an earlier report of 31% recurrence rate of reflux symptoms following laparoscopic Nissen’s in obese patients ⁵³. Hence, morbidly obese patients with GORD should be offered laparoscopic gastric bypass as a surgical option ^{27, 30, 54-59}.

The improvement in GORD symptoms after gastric bypass is related to the way that the operation staples off the distal 90% or more of the stomach body and antrum, removing any possibility that acid generated in this part of the stomach can reach the oesophagus.  The parietal cell mass within the small gastric pouch that is left attached to the oesophagus, the complete elimination of duodeno-gastric reflux owing to a long Roux limb, and decrease in intra-abdominal pressure with weight loss all contribute to an almost total reflux control in all patients. The overall complications secondary to this procedure were lower than in laparoscopic fundoplication ⁵⁴. It is also the procedure of choice for previous other weight-loss surgery, when reflux symptoms develop ^49-51. Thus, a bariatric team prior to surgical intervention should review obese patients with GORD symptoms.

Dysphagia in obesity

Dysphagia in obesity is often related to the interventions used to treat obesity, though it can be primary in nature.

Various modalities of interventions available in obesity have been discussed above. Intra-gastric balloon therapy can be complicated by its displacement into the distal stomach, precipitating dysphagia and outlet obstruction. Gastric bands can be overfilled, causing this problem, and a slipped band or a band eroding through the stomach wall can also lead to dysphagia ^60-64. There has been no report of gastric bypass resulting in dysphagia, in the literature.

It is our understanding that patients with obesity may present with primary oesophageal dysmotility. Although there is little published literature on this issue, it is our hypothesis that fatty infiltration of the oesophageal wall and myenteric plexus may result in a poor amplitude peristaltic contraction.

Other oesophageal conditions associated with obesity

Barrett’s Oesophagus

This is characterised by the replacement of the normal squamous epithelium of the lower oesophagus by a specialised metaplastic columnar epithelium. Barrett’s oesophagus is a known risk factor for oesophageal adenocarcinoma, with a 30 to 125 times increased risk compared to general population ⁶⁵. Risk factors leading to Barrett’s have been poorly understood, though GORD is widely believed to be the main risk factor ^66-68. Since several studies have found an association between obesity and GORD ^{1, 2, 6-12}, and obesity as a risk factor for Barrett's have gained momentum in the recent year. Abdominal obesity or waist circumference has been shown to be more associated with Barrett’s than BMI ⁶⁹.

A recent systematic review showed a statistically significant relation between increasing BMI and Barrett’s ⁷⁰. However, two older systematic reviews had found a rather week relation between these two, showing a need for further well designed studies ^{71, 72}. To mention a few studies, Jacobson et al showed a positive relation between BMI and Barrett’s in women, independent of GORD, though the waist circumference was not found to have any association ⁷³and Stein at al., found a positive relation between BMI and Barrett’s in war veterans ⁷⁴. Abdominal obesity or circumference appears to be more influential in the incidence of Barrett’s oesophagus in another study ⁷⁵. There is however, little evidence to suggest an increased progression of Barrett’s to neoplasia in obesity ⁶⁹

Obesity is a modifiable risk factor and if proven to be a risk for Barrett’s and subsequent neoplasia, resources can be directed at modifying this, as there is evidence to suggest the regression Barrett’s with weight loss ⁶⁹. Barrett’s have been shown to regress with weight loss following gastric bypass and hence this has been recommended as bariatric procedure of choice in the morbidly obese with Barrett’s ^76-79. A precise endoscopic evaluation before bariatric surgery with continuing postsurgical surveillance in patients with known Barrett's oesophagitis, and early evaluation in patients who develop new symptoms of GERD after bariatric surgery is suggested ^{80, 81}

Adenocarcinoma of oesophagus

The incidence of oesophageal adenocarcinoma has increased about 400% during the past three decades, the most rapid rate of increase of any cancer in the United States ^82-84. The association between high BMI and oesophageal adenocarcinoma is strong and well established, though the mechanism of this is still unclear. The risk is higher with increasing BMI, especially in men ^85-94. Obesity has also been shown to play a role in adenocarcinomas with a family history ⁹⁵. The incidence of adenocarcinoma of the cardia of stomach has not been so strongly related to BMI ^{96, 97}. Squamous cell carcinoma of oesophagus has not shown any association to obesity either ^{85, 93, 94, 98, 99}. Few studies have negated the association of obesity with oesophageal adenocarcinoma, but many were due to the fact that they included oesophageal and proximal stomach together ⁹⁶. The majority of these cancers arise from a background of premalignant Barrett’s oesophagus, though less than 10% of the patients with oesophageal adenocarcinoma were known to have Barrett’s oesophagus previously. Presently there is no evidence that strongly supports any specific strategy to screen a subgroup of the population at risk for Barrett’s oesophagus and adenocarcinoma of the oesophagus ¹⁰⁰.

A number of studies have also looked at the mechanism or pathway of this metaplasia-dysplasia-adenocarcinoma sequence.  Visceral adiposity rather than BMI is thought to have a greater role in chronic inflammation and subsequent neoplasia. It has a clear association with Barrett’s as above. Increasing abdominal girth increases the risk of adenocarcinoma and it has been shown for Barrett’s ⁹⁸. Visceral fat is hypothesised as a major producer of interleukin-6, adinopectin, leptin and other adipokines that may be associated with the development of various gastro-intestinal cancers ^101-103. More specifically, insulin-like growth factor has been implicated in the pathogenesis of adenocarcinoma in the obese ¹⁰⁴. Oesophago-gastric tumours after bariatric surgery, has been reported, though rare. This condition, when occurs, requires the close collaboration of the bariatric team to achieve a successful oncological result, due to the altered anatomy like the blood supply to the gastric pouch and excluded stomach ¹⁰⁵.

Conclusion

Obesity is associated with oesophageal disease, benign and malignant, and both the effects of obesity and the effects of it’s treatment can aggravate oesophageal symptoms. The management of reflux and of dysphagia in obese patients requires a broad understanding of these issues.

Introduction

Currently, peripheral vascular disease (PVD), causing an inadequate oxygen supply to the limbs, globally affects no less than 3–10% of the population¹. Peripheral vascular disease, including diabetic foot, arteriosclerosis obliterans, and thromboangitis obliterans, commonly affect the arteries supplying the leg. Based on the severity of the symptoms, usually two clinical presentations are distinguished: intermittent claudication (IC) is characterised by pain upon walking while critical limb ischaemia (CLI) is a more severe form in which pain occurs at rest and which is accompanied by necrosis and ulceration.

Although several clinical studies show promising results, larger randomised, blinded, placebo-controlled trials are needed to provide definite proof of the clinical effects of adult stem cell therapy in these patients. In addition, questions regarding the cell population(s) to be used, optimal dose, and routes of administration will have to be addressed. If doctors and scientists can establish safe protocols for stem cell use, everyone can benefit from the full potential of the remarkable and possibly life-saving stem cell therapies.

Introduction  A hydatid cyst is the larval stage of a small tapeworm, Echinococcus granulosus. This is an emerging zoonotic parasitic disease throughout the world, thought to cause an annual loss of US $193,529,740.¹ Hydatid cysts are more prevalent in Australia, New Zealand, South America, Russia, France, China, India, the Middle East and Mediterranean countries.^2,3,4 They are most commonly (about 50-75%) seen in children and young adults.^4,5,6 The liver is the most common organ involved (77%), followed by the lungs (43%).^7,8,9,10 However, some researchers report that the lung is the most common organ involved in children, possibly due to bypass of the liver by lymphatics, and higher incidental findings in the lungs when children are assessed for other respiratory infections.^8,11,12,13 Hydatid cysts have been reported in the brain (2%),^{3,4,5,7,8,14,15} heart (2%),^8,10,13,16 kidneys (2%),^9,10,11 orbit (1%),^17,18 spinal cord (1%),^3,19 spleen,⁴ spine,^3,8 spermatic cord²⁰ and soft tissues.⁸ However, in the Mediterranean region, the incidence of brain hydatid cysts have been reported higher (7.4-8.8%).²¹ Surgery remains the treatment of choice, although recently some new modalities have been described.^5,8,22 Careful removal of the lesion is of considerable importance, otherwise fatal complications are inevitable.^23,24,25 We describe the case of a 6 year old boy who came to our department with various neurological manifestations. The main purpose of this study is to demonstrate the unusual symptoms of the patient and the enormity of the operated cyst, which was fully resected without rupture. Case Report A 6-year-old boy was referred to our Neurosurgery Department with a four week history of ataxia and left sided weakness. His vital signs were normal and his Glasgow Coma Scale (GCS) was 15. The symptoms had started about six months ago with numbness and parasthesia of the toes. Subsequently he developed intermittent nausea and vomiting. He then started to develop left sided weakness and finally ataxia. He also had a few focal convulsions but did not complain of headache. Fundoscopy revealed bilateral frank papilloedema. On examination, the patient had nystagmus and a positive Romberg’s test. Laboratory data showed mild leucocytosis without any significant rise in eosinophils, and liver enzymes were normal. The enzyme-linked immunosorbent assay (ELISA) for hydatid cysts was negative. Plain chest X-ray and ultrasound scan of the abdomen and pelvis were also normal. Brain computed tomography (CT scan) of the frontal and parietal lobes demonstrated a single large, spherical, well-defined, thin-walled homogenous cyst, with an inner density similar to that of cerebrospinal fluid (CSF), and a wall which did not show enhancement [fig 1(a)]. This cystic structure caused a mass effect and a midline shift towards the left, as well as hydrocephalus, possibly due to obstruction. Magnetic resonance imaging (MRI) of the brain showed cystic signal intensity similar to that of CSF, without ring enhancement or oedema [fig 2].   Fig 1 (a): Pre-operative unenhanced CT scan which shows a large CSF density cystic lesion on the right side causing mass effect and midline shift to the left. There is no peri-lesional oedema. Fig 1 (b): Post-operative CT scan of the lesion shows a large void which can lead to dangerous collapse. Mild haematoma is also seen. Fig 2 (a): T1-weighted axial MRI of the brain demonstrates a cyst density similar to CSF. Fig 2 (b): T2-weighted MRI shows no ring enhancement or oedema. The periventricular hyperintensity of the left side is probably due to obstructive hydrocephalus. Fig 3: This shows the cyst removed in toto after operation. The cyst appears creamy and smooth. After summation of all the above data, the diagnosis of a hydatid cyst was made and a right frontotemporoparietal craniotomy was performed. A large cystic structure (14×14×12 cm) was delivered with utmost care to avoid rupture and spillage [fig 3]. A hydatid cyst was confirmed by pathology reports.  A post-operative CT scan showed a large space without any residual matter [fig 1(b)]. Post-operatively, albendazole 15 mg/kg was started and continued for four weeks. The patient showed marked improvement in his neurological deficit and was discharged after one week with close follow-up. Discussion/Review Of Literature Life CycleHydatidosis is caused by Echinococcus granulosus, which occurs mainly in dogs. Humans who act as intermediate hosts get infected incidentally by ingesting eggs from the faeces of the infected animal. The eggs hatch inside the intestines and penetrate the walls, entering blood vessels and eventually reach the liver where they may form cysts or move on towards the lungs. Even after pulmonary filter, a few still make it to the systemic circulation and can lodge in almost any part of the body, including the brain, heart and bones.^{2,3,8,14,16,26} Brain hydatid cysts are relatively rare and only account for up to 2% of total cases.^4,5,7  The actual percentage may be higher than what we have in literature, due to under-reporting. Brain hydatid cysts can be primary (single) or secondary (multiple).^2,3,4,5,7 The latter are thought to arise from the multiple scolices released from the left side of the heart following cyst rupture in the heart^2,3,5,27 or due to spontaneous, traumatic or surgical rupture of a solitary cranial cyst.^3,5 Cysts mostly involve the territory of the middle cerebral artery^4,7 but other regions like intraventricular, posterior fossa and the orbit have also been reported.^15,17,18,28 The wall of the cyst consists of an inner endocyst (germinal layer) and outer ectocyst (laminated layer). The host reacts to the cyst forming a pericyst (fibrous capsule), which provides nutrients to the parasite. In the brain, due to minimal reaction, the pericyst is very thin. The endocyst produce scolices which bud into the cyst cavity and may sediment within the hydatid cavity, commonly known as hydatid sand.^3,14,29,30 Presentation and DiagnosisMost hydatid cysts are acquired in childhood and are manifested during early adulthood.^8,29 Cysts develop insidiously, usually being asymptomatic initially, and present with protean clinical and imaging features.^3,5,6 In previous studies the most common presenting symptoms were headache and vomiting.^{4,5,7,14,15,28} Also in the literature, patients reported ataxia, diplopia, hemiparesis, abducens nerve palsy and even coma.^5,7,15,28 Surprisingly, in the present study the patient did not have a headache and presented with parasthesia and numbness of the toes. Later he developed left sided weakness, convulsions and finally ataxia, which correlate with previous studies. Diagnosis of a hydatid cyst can sometimes be confused with other space occupying lesions of the brain, especially abscesses, neoplasms and arachnoid cysts.^14,31  In this study the patient had bilateral frank papilloedema which is also mentioned in earlier reports.^4,28  The Casoni and Weinberg tests, indirect haemagglutination, eosinophilia and ELISA are used in diagnosing hydatid cysts, but as brain tissue evokes minimal response many results tend to be false negatives.^2,5,8,25  In our case also, serology for hydatid cyst was negative. CT scan and MRI are used frequently in diagnosing the cystic lesions.^{3,8,14,23,32,33}  However, MRI is considered superior in demonstrating the cyst rim.^{5,8,11,21,32,34}  On CT scan, a solitary cyst appears as well-defined, spherical, smooth, thin-walled and homogeneous, with an inner density similar to CSF, and non-enhancing walls.^11,29,32The wall may appear iso-dense to hyper-dense on CT scan^3,8, and rarely, may become calcified.^11,29,32 There is usually no surrounding brain parenchymal oedema, which if exists along with ring enhancement, indicates inflammation and infection. ^{7,11,32,33,34,35} Ring enhancement and peri-lesional oedema differentiates brain abscesses and cystic neoplasms from uncomplicated hydatid cysts.^3,8 These findings can in fact sometimes cause dilemma and misdiagnosis and lead to catastrophic events.¹⁴ The cyst shows low signal intensity on T1-weighted, and high signal intensity on T2-weighted MRI.² MRI may also show peri-lesional oedema not seen on regular CT scan imaging.⁷ MRI may prove superior in determining exact cyst location, presence of super-added infections and cystic contents, and also in surgical planning and ruling out other diagnostic possibilities.^14,33 We strongly recommend MRI for better evaluation of cystic brain lesions. Spontaneous cystic rupture can lead to different appearances depending on which layers have been obliterated, and produce some specific signs.³ When only the endocyst ruptures, cyst contents are held by the outer pericyst giving a peculiar water lily sign, which is pathognomic.^3,8 TreatmentThough still in infancy, medical therapy for small or inoperable brain hydatid cysts has been promising. Albendazole alone or in combination with other compounds, such as praziquantel, has been reported with favourable results as an adjunct and, in certain circumstances, as the primary mode of treatment.^2,36,37,38 It is reported that albendazole results in the disappearance of up to 48% of cysts and a substantial reduction in size of the cysts in another 28%.² The duration of the treatment is four weeks or more, and recently many authors have favoured a prolonged therapy. The change in levels of cyst markers such as alanine, succinate, acetate and lactate, measured before and during treatment on Proton Magnetic Resonance Spectroscopy (MRS), correlate well with shrinkage and resolution of cyst findings on conventional MRI and help in evaluating the efficacy of chemotherapy.³⁹ Cysts may drain into ventricles or rupture completely, causing spillage of contents into the subarachnoid space, leading to fatal anaphylactic shock, meningitis or local recurrence.^3,5,22,25 Surgery is the mainstay for treating intracranial hydatid cysts and the aim is to excise the cysts entirely without rupture, which can otherwise lead to catastrophic events as described earlier ^2,3,14,25. The Dowling-Orlando technique remains the preferred method, in which the cyst can be delivered by lowering the head of the operating table and instilling warm saline between the cyst and the surrounding brain.⁴⁰ Even minimal spillage can cause deleterious effects (1 ml of hydatid sand contains 400,000 scolices).¹⁴ The thin cyst wall, periventricular location and micro-adhesions to the parenchyma are the main problems encountered during the surgical procedure.^1,22 The large cavity remaining after the cystic removal can lead to many serious complications, such as cortical collapse, hyperpyrexia, brain oedema and cardio-respiratory failure.⁵ Recurrence remains a major concern, which is managed by both antihelminthic chemotherapy and surgery. In a study conducted by Ciurea et al, 25% of the patients had recurrence, which highlights the need for long term follow up.²³ In the present study, due to the huge size of the cyst and progressive neurological deficit, it was not wise to completely rely on medical therapy. Surgery was performed and post-operatively albendazole was started as an adjunct. We recommend that for treating brain hydatid cyst, the size of the cyst, multiplicity, location and neurological deficit must all be taken into consideration. 

The surveillance and treatment of Barrett’s Oesphagus remains an area of interest and controversy. This is heightened by the inability to discriminate those patients with BO which are most likely to progress to high grade dysplasia and then to adenocarcinoma of the oesophagus. This places greater emphasis on the endoscopic surveillance programme to identify this potentially pre-malignant state at an early stage. Future advances, particularly in endoscopic techniques, will help to increase efficacy of treatment and minimise complication rates. Further developments include progress in identification of genetic biomarkers which may help elucidate those patients at greatest risk. The management of Barrrett’s Oesophagus is becoming increasingly more important, particularly with the rise in incidence of oesophageal carcinomas in the Western world. The issues to address therefore include the identification and screening of at-risk groups and the further management from diagnosis of BO. Patients with chronic GORD symptoms are most in need of screening. Currently this should include the gold-standard four quadrant biopsy technique. This may include techniques to enhance visualisation as described above. In the authors opinion, non-biopsy screening does not carry enough evidence to support its use in replacement of biopsy as of yet. Medical treatment with PPI (if necessary in high-dose) as well as surgical treatment of GORD are essential considerations in the prevention and treatment of BO. Their use in combination with endoscopic therapy has proven benefits as outlined. Of the endoscopic therapies, the lack of complications combined with excellent post-procedure rates of disease elimination seen with RFA are most encouraging. Oesophagectomy should be reserved for those patients with disease not amenable to conservative or endoscopic therapy.  Continual research is required to help us gain more understanding into the pathogenesis of this condition, enabling us to effectively target and manage BO appropriately.   

Introduction

         

Laparoscopic fundoplication (LF) has been emerging as the procedure of choice for selected patients with symptomatic and problematic reflux disease since the first described case by Dallemagne in 1991 (1). This was followed by a rapid expansion into routine clinical practice shortly afterwards. With increased acceptance and availability of laparoscopy as a safe surgical modality there has been a huge increase in the number of patients undergoing LF. This has probably been due to increased willingness of patients and referring doctors to consider the less invasive procedure, rather than the older ‘open’ surgical treatment, with its more rapid recovery, smaller incisions and earlier return to work and to normal daily activities.

Patient referral patterns have also changed over the last decade with the main indication for consideration of LF being patient choice, a general unwillingness to take long term medication as well as ineffective or intolerance of medications and relapse of symptoms (5-6). Several advantages of LF have been described by recent data including shorter hospital stay, less requirement for analgesia, and sooner return to work (7-9). These have to be offset against procedure specific complications including gastro-oesophageal perforation, pneumothorax, dysphagia, and bleeding (2-4). However, the other main downside to LF is the learning curve during which there are an increased number of complications. Previous reports have suggested the learning curve to be around 20 for an individual surgeon and 50 for an institution (10-12).

In a recent meeting of the Upper GI group at the Royal College of Surgeons there was discussion concerning the incidence and management of dysphagia following laparoscopic fundoplication (13 Bill Owen Day RCS (Eng) 2004). There is a paucity of data available in this regard with a general paucity of negative or unequivocal results in the literature equating to a selection bias towards only positive data and positive reporting of good results.

Therefore the aim of the present study was to look critically at the learning curve and, with respect to operative complications, with specific regard to the incidence and management of dysphagia in a personal series of patients who underwent a laparoscopic fundoplication in a District General Hospital in the United Kingdom.

Patients and Methods

From December 1997 to February 2004, 75 patients who underwent laparoscopic fundoplication under the care of a single consultant surgeon in a district general hospital were included in this study. It became routine practice for LF to be performed by one dedicated surgical team (JMT) who kept a complete prospective list of procedures. This series was complete and the hand written records of all the procedures were used to identify patients undergoing operations for LF with or without reduction and repair of Para-oesophageal hernia during the study period. These records were cross-checked with the theatre logbook, hospital computer system as well as with the surgeon’s own record. This ensured full inclusion in the analysis of patients.

The groups were not randomised and ‘all comers’ where included in the study. However, Group 1 consisted of the first 20 LF whereas Group 2 included LF (numbers 21-75). Informed consent was obtained in writing prior to surgery. At least a single dose of prophylactic antibiotics (of either a third generation cephalosporin or co-amoxiclav) was administered at induction; all patients received standard thromboprophylaxis (subcutaneous clexane, TEDS, intermittent pneumatic calf compression).

Patients underwent a laparoscopic fundoplication as briefly described below. The patient was placed in the lithotomy position with reversed Trendelberg tilt; a pneumoperitoneum was created and 4 ports inserted. The liver was elevated using a ‘Nathanson’ liver retractor placed through a 5 mm epigastric incision. Initially the right and left limbs of the right crus are dissected alongside the pancreaticogastric and phrenogastric ligaments. A window is created behind the distal oesophagus. A Penrose drain is passed through the gap. The short gastric vessels are divided using a harmonic scalpel (Ethicon, USA), if required. The crural limbs are approximated using 2, 2-0 ethibond sutures to leave a hiatus 1 cm wider than the oesophagus. A laparoscopic babcock is placed behind the oesophagus and the gastric fundus is brought left to right behind the oesophagus and bought round to meet with the remaining portion of the fundus anteriorly. Two (or rarely three) sutures of 2-0 ethibond were used for the fundoplication. The upper suture included a bite of the anterior hiatal margin to anchor the wrap. Of note, the important feature of the procedure is the creation of a ‘floppy’ tension free fundoplication. This is hugely aided by good mobilisation of the gastric fundus with its associated ligaments and if required, division of the short gastric vessels. Notably, one must carefully create a window behind the oesophagus and an overlap of no longer than 3 cms length and one must stay high up on the fundus in order to avoid the creation of a ‘2’ compartment stomach syndrome’.

Post-operatively all patients were treated in an identical manner. As soon as tolerated after the operations the patients were allowed the consumption of water; diet and analgesia were made available as soon after surgery as required by individual patients. Complications were noted as they occurred during the follow-up period. Both general and specific complications were documented for at least 6 months. Furthermore, patient demographics, details of operations, all complications and follow-up data were kept. Follow up for the purpose of this audit involved completion of a proforma at a minimum post operative period of one year and a maximum of eight years.

All patients where regularly reviewed daily on the ward whilst they were in-patients and in the outpatients at 4-6 week intervals or sooner should the need arise by the surgical team. Thereafter they were given a “see on request” appointment. Data on patient and procedure related morbidity and acceptability was also collected.

At the time of the study contact was made via the telephone and a questionnaire was completed. A telephone survey asking the patient four questions,

1. Where they happy with the operation
2. Would they reccomend the procedure to a friend
3. Had there symptoms resolved
4. If they had had post op dysphagia had it resolved

The data was reviewed and analysed in conjunction with our department of medical statistics. Analysis was performed using the Mann-U test. Multivariate analysis of the means was performed using the Kruskal-Wallis Test.

Results

Overall the 75 patients who underwent laparoscopic fundoplication consisted of 44 males (59%) and 31 females (41%). The mean age was 47.0 years (range 22-80 years). Group 1, which consisted of the first 20 LF cases included 11 male and 9 females. The mean age was 53.25 years (range 32-80). Group 2, which consisted of the LF cases numbering 21-75 included 33 male and 22 females. The mean age was 44.8 years (range 22-78). Both groups were well matched across the above parameters with no statistical differences (Table A). Only 4 patients were obese (5%), smoker (n=10, 14%), 7 patients suffering with Hypertension (10%) and one with diabetes mellitus (2%) and were equivalently represented in both groups (data not shown).

Presenting features are shown in Table B. Notably, the commonest presenting complaints included regurgitation of acid/ food in 79% (n=59), heartburn in 73% (n=55) and pain and discomfort 53% (n=35). Other complaints included dysphagia 21% (n=16), cough/wheeze 19% (n=14) and excess salivation 18% (n=13).

Table A: Patient Demographics

Table B: Presenting Features

Patients underwent pre-operative evaluation with Upper GI endoscopy 88% (n=66), pH manometry 47% (n=35) and barium swallow 32% (n=24). Previous to this procedure all patients (100%) were on or had been during some part of their illness on therapeutic doses of proton pump inhibitors.

There was a significant difference between the operating times in the two groups. Thus in Group 1 the average operating time was 190 minutes (range120-240 minutes) whereas in Group 2 the average operating time was 144 minutes (range 75-195 minutes, P <0.05).

Table C: Post Op Mild and Moderate Complications<

One of the major aims of the study was to record post-operative complications. Table C shows all mild and moderate complications which resolved completely with conservative management. Of note Table F shows that dysphagia occurred in up to 40 of our patients. Table F shows the distribution of dysphagia in both groups. In group A (n=20) the are 15 patients who complained with dysphagia (75%) of which 5 settled spontaneously and 10 required further investigation with OGD +/- dilation. in group B (n=55), 25 patients suffered with dysphagia all of which settled with conservative management. Our initial policy was to perform an OGD and dilate prophylactically; however, this was abandoned halfway through the study. It was found that the dysphagia settled in all patients with conservative management. Furthermore, other mild/moderate complications, of note included regurgitation of stomach contents (7/75) and port-site discomfort (6/75), all of which also resolved spontaneously

Table D: Major Complications Groups 1 & 2

Table E: Conversion to Open Surgery

Major complications are shown in Table D. Of note there are three conversions to ‘Open’ surgery in Group 1 and five in Group 2 (Table E). In detail, four cases (two in each group) were converted early because of poor or very difficult access. They included difficulty in reducing the stomach and omentum from the mediastinum into the abdomen, unable to reach the hiatus despite placing the ports as high as possible, dense adhesions between the liver and stomach and G-O junction thereby leaving no access to the hiatus and simply impossible access to the upper stomach. Further, oesophageal perforation which was caused by intra-operative insertion of a nasogastric bougie (Group 1), this was repaired laparoscopically with no sequelae. Other reasons for conversions included perforation of the greater curve of the stomach due to the fact that there was thickened fatty tissue around the greater curve of the stomach and spleen which produced a perforation while dissecting the stomach free. Also in Group 2 there was one pneumothorax and in another patient there was marked desaturation on creation of the pneumoperitoneum and in both cases it was deemed safer to open the patient.

Table F: Dysphagia Group

Relaparotomy occurred in three patients; one developed severe pain and clinical shock at 24 hours and it was found on laparotomy to have a perforated oesophagus, the second patient we found disruption of the wrap (requiring re-operation and refashioning the wrap) and a final patient developed small bowel obstruction.

Finally a telephone survey at the conclusion of the study managed to contact 70/75 patients. It was found that overall 68/70 patients were satisfied with their procedure and would recommend the procedure to a relative or friend.

Discussion

Gastro-oesophageal reflux disease (GORD) is the commonest disorder of the Upper GI tract affecting approximately between 10-40% of most western populations and with rising incidence (11). In Australia it has shown to consume around 10% of the national expenditure on prescription drugs. Fortunately the majority of patients settle with simple measures including weight loss and reductions in smoking, caffeine and chocolate consumptions. Furthermore, better timing of meals as well as increasing the number of pillows and raising the head end of the bed can lead to improved symptoms. The advent of H₂- receptor antagonist (H₂RA) and later proton pump inhibitors (PPIs) has led to symptom control in the majority of patients. However, patients on maximum therapy who remain symptomatic or who develop complications (i.e. haemorrhage, oesophagitis, strictures) or those who refuse long term medication are deemed candidates for surgical intervention.

LF has emerged as the procedure of choice for GORD. The present study, which is a personal single surgeon series, shows that laparoscopic fundoplication is a safe and effective procedure with low rates of long-term complications. Importantly, post operatively these patients may develop dysphagia which settles with conservative measures in the vast majority of cases (13).

There is no doubt that for LF a ‘learning curve’ exists but there is debate about the actual numbers. Most studies suggest that it is around 20 for an individual and around 50 for a department (12), thus in the present study we compared our first 20 (classically thought to be within the learning curve) with the next 55 in order to assess major complications, conversions to open procedure. We found that in Group 1 there were 3 major complications (15%) whereas in the next 55 cases there were five (9%). Indeed only one major complication in Group 1 and two in Group 2 could be considered as technical, they were oesophageal and gastric perforations the rest being post operative pneumonia, PE and major desaturation. There were no deaths in either group. This was in keeping with previously published series (14-16).

Previously published data and our own observations revealed that there were significant post operative rates of dysphagia. In the present series dysphagia was the single commonest complication experienced by 53% of patients (n=40). Initially these were investigated with barium swallow and OGD and treated aggressively with early dilation (Group 1) however this strategy was abandoned after it was found that the vast majority of our patients resolved their dysphagia with conservative treatment. From thereon we adopted a very conservative approach reassuring the patient and keeping within close contact until the dysphagia resolved. We reserved dilatation for only highly resistant dysphagia or patients who where non-compliant with conservative treatment. We found that clear explanations pre-operatively, regular reassurance and assessment was generally all that was required. In Group 2 (21-75) none of the patients required dilation for dysphagia. It is almost universal that patients undergoing LF will have a degree of dysphagia. However what is now accepted and reflected from the experience from the present study is that dysphagia after LF should only cause concern if severe, presenting with severe pain, uncontrolled retching and vomiting requiring immediate surgical revision (17). Most commonly this is due to over-tightening of the hiatus or with poor mobilisation and a 360 degree wrap. This may be related to the learning curve, being more common in the earlier cases in a personal series. In our series 53% of patients (n=40) experienced dysphagia. This is comparable to previous reported data (2,16). Notably, Fontaumard et al reported a dysphagia rate of 78% (40/51). The reason for this post operative dysphagia has been thought to be related to the type of procedure. In our series all patients underwent a Nissen type of repair however evidence is now emerging that the incidence of dysphagia and gas related complications are reduced following anterior partial fundoplication (19,20). This is shown from the data of two recent randomised controlled studies. Baigrie et al (18) in a double-blind, randomized study compared laparoscopic Nissen total fundoplication and anterior partial fundoplication. There were no differences in mean heartburn scores between groups but dysphagia scores for both liquids and solids were lower after anterior fundoplication. Also Ludemann et al (19) compared total fundoplication for gastro-oesophageal reflux disease with an anterior 180 degrees partial fundoplication. Both achieved effective reflux control but the partial wrap was associated with fewer side-effects in the short term than total fundoplication. After 5 years, dysphagia, measured by a visual analogue score for solid food and a composite dysphagia score, was worse at 5 years after total fundoplication.

Our study confirms what has previously been shown with the learning curve for LF and its acceptability. It has also clearly highlighted that post operative dysphagia is common and affects a significant number of patients post operatively. However in our study we found that this was best managed conservatively and the almost all resolved spontaneously. There is no evidence to support early intervention unless the symptoms are very severe and occur very soon after surgery, when the patient should be taken back to theatre for another look. The specific causes of the dysphagia are not known but it is postulated that it is due to increased pressure as the upper part of the wrap augments the pressure of the lower oesophageal sphincter causing it to become over competent. Over time this mechanism relaxes leading to an improvement in dysphagia with simple conservative therapy. Furthermore, there was a hugely positive satisfaction score on a simple telephone survey suggesting symptom control from this procedure.

References

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Treatment of low back pain remains a dilemma. In the USA more than 300 thousand back surgeries are performed each year. For about 10% to 39% patients, pain may continue or even get worse after back surgeries¹. This condition is called failed back surgery syndrome. In the USA, about 80,000 new cases of failed back surgery syndrome are accumulated each year². Pathological changes such as recurrent disc herniation, arachnoiditis, scar tissue formation, poor surgical indication, misdiagnosis, and surgical technique failure can all contribute to the failure of surgery. Pain after back surgery is difficult to treat. Many patients have to live with pain for the rest of their lives with severe disability.

Over the last several decades, our understanding of the causes of low back pain has been challenged. With a sensitivity up to 95%³, MRI has been used a gold standard for the diagnosis of spine disease such as lumbar disc herniation. With the MRI evidence of a disc herniation and nerve root compression, patients are more easily convinced surgery is their best and only option. However, the reliability of MRI as the evidence for surgical decision has been questioned. An early study found that in a group of asymptomatic volunteers at age of 60 years or older, about 57% had abnormal MRI findings including disc herniation and spinal stenosis⁴. Follow up studies have yielded similar results. Now it is widely accepted that degenerative disc disease, such as disc herniation is a common finding in asymptomatic adults. Even though at the age of 60 years or older, 57% or more may have abnormal MRI findings in the lumbar spine, however, only less than 20% of this group of people have chronic low back pain. A recent study also suggested a lack of correlation between imaging findings of spine degenerative change and back pain⁵. Simply, degenerative change in the lumbar spine, such as a herniated disc, is not necessary painful.

The results of these studies have changed our belief in the relationship between lumbar disc herniation and back pain. It is believed that back and leg pain in the presence of acute disc herniation is not merely the result of a pinched nerve root, rather it is more related to the inflammation of the nerve roots and nerve endings around the herniated disc or it may be the combined results of chemical inflammation and mechanical compression⁶. A herniated disc is not a sole indication for back surgery and up to 70% to 95% of patients may be pain free after 12 months without major intervention⁷. The primary goal of treatment of lumbar radicular pain should be the suppression of inflammation, relieving the pain and restoring function rather than removal of the herniated disc. Before one chooses an open back surgery the following options should be considered:

Diagnosis: Low back pain can be related to a herniated disc, nerve root irritation, annular tear, facet joint arthritis, muscle spasm, injuries to the ligament, sacroiliac joint arthritis and referred pain from visceral organs. An MRI finding of a herniated disc, no matter how large, is not enough to justify surgery. A thorough history and physical examination is tantamount to judge whether the herniated disc is the real source for the ongoing pain.

Medications: Non-steroid anti-inflammatory medications should be offered as the first line medication to patients with mild back pain. Early administration of oral steroid medication in patients with acute sciatica may lead to slightly more rapid improvement in pain, mental well-being, and disability scores⁸. Anti-depressants, especially tricyclic antidepressants, are often used to treat patients with chronic back pain.

Physical therapy, massage therapy and chiropractic management have been widely used for treatment of back pain and lumbar radicular pain, even though the value of these treatment modalities have yet to be proven.

Spine injections: Multiple double blind, clinical controlled studies have confirmed the clinical efficacy of lumbar epidural steroid injection (LESI) in relieving the acute radicular pain due to herniated nucleus pulposus, speeding the rate of recovery and return to function⁹. The pain relieving effect of LESI may last up to three months. Inflammatory mediators, such as phospholipase A2, have been implicated in lumbar radiculopathy and disc herniation and have been the focus of recent research. Lumbar epidural steroid injections can decrease pain by suppressing the function of inflammatory mediators. As long as the patient is pain free and is without any neurological deficits, a herniated disc should not be a clinical concern. Even though LESI alone may not decrease the necessity of back surgery, it will be intriguing to investigate whether a combination of LESI and other treatment such as physical therapy and life style modification will decrease the need for surgery.

Minimally invasive surgery: Minimally invasive surgery offers another alternative in the treatment of back pain. These treatments include chymopapaine, percutaneous nucleotome, automated percutaneous lumbar discectomy, laser discectomy, neucleoplasty and disc deKompressor. The advantage of the minimally invasive techniques is that it leaves no or minimal scar after the surgery. Among the minimal invasive techniques, laser discectomy has a reported success rate of 80% to 90%¹⁰. Neucleoplasty and disc deKompressor have been recently introduced with early non-controlled studies showing success rates up to 78%¹¹. These procedures are still not widely accepted and more studies are needed to confirm their clinical efficacy.

Life style modification: Low back pain can often be the result of improper lifestyle choices. Smoking can increase the risk of low back pain¹². Obesity can worsen back pain and contribute to disk degeneration¹³. Heavy lifting, sport related injuries and motor vehicle accidents can cause back pain. Education to patients with low back pain is critical to help them recover from back pain and prevent future back pain. Smoking cessation and weight control should be strongly recommended to back pain patients. Proper exercise techniques should be taught. Patients, especially those with spinal stenosis often have difficulty walking due to neurological claudication. Treadmills and long distance walking exercise may exacerbate back pain. Some studies suggested therapeutic aquatic exercise is potentially beneficial to patients suffering from chronic low back pain¹⁴.

Conclusion: Lumbar spine surgery can potentially provide quick pain relief and functional recovery. There are many downsides to surgery however that would include post laminectomy surgery syndrome and a lack of proven long term benefit. Because of these risks one should be very careful in determining surgical candidacy. A preliminary study¹⁵ has provided the evidence that the rate of back surgery can potentially be decreased through appropriate education and application of evidence-based medicine for patients, general practitioners and spine surgeons. Conservative treatment with the combination of medications, physical therapy, spinal injections and life style modification should be tried before surgery is considered.

References:

1. Graz B, Wietlisbach V, Porchet F, et al. Prognosis or "curabo effect?": physician prediction and patient outcome of surgery for low back pain and sciatica. Spine 2005 June 15;30(12):1448-52.

2. Ragab A, Deshazo RD. Management of back pain in patients with previous back surgery. Am J Med 2008 April;121(4):272-8.

3. Mullin WJ, Heithoff KB, Gilbert TJ, Jr., et al. Magnetic resonance evaluation of recurrent disc herniation: is gadolinium necessary? Spine 2000 June 15;25(12):1493-9.

4. Boden SD, Davis DO, Dina TS, et al. Abnormal magnetic-resonance scans of the lumbar spine in asymptomatic subjects. A prospective investigation. J Bone Joint Surg Am 1990 March;72(3):403-8.

5. Kalichman L, Kim DH, Li L, Guermazi A, et al. Spondylolysis and spondylolisthesis: prevalence and association with low back pain in the adult community-based population. Spine 2009 January 15;34(2):199-205.

6. Roberts S, Butler RC. Inflammatory mediators as potential therapeutic targets in the spine. Curr Drug Targets Inflamm Allergy 2005 April;4(2):257-66.

7. Legrand E, Bouvard B, Audran M, et al. Sciatica from disk herniation: Medical treatment or surgery? Joint Bone Spine 2007 December;74(6):530-5.

8. Holve RL, Barkan H. Oral steroids in initial treatment of acute sciatica. J Am Board Fam Med 2008 September;21(5):469-74.

9. Sethee J, Rathmell JP. Epidural steroid injections are useful for the treatment of low back pain and radicular symptoms: pro. Curr Pain Headache Rep 2009 February;13(1):31-4.

10. Goupille P, Mulleman D, Mammou S, et al. Percutaneous laser disc decompression for the treatment of lumbar disc herniation: a review. Semin Arthritis Rheum 2007 August;37(1):20-30.

11. Al-Zain F, Lemcke J, Killeen T, et al. Minimally invasive spinal surgery using nucleoplasty: a 1-year follow-up study. Acta Neurochir (Wien ) 2008 December;150(12):1257-62.

12. Mikkonen P, Leino-Arjas P, Remes J, et al. Is smoking a risk factor for low back pain in adolescents? A prospective cohort study. Spine 2008 March 1;33(5):527-32.

13. Hangai M, Kaneoka K, Kuno S, et al. Factors associated with lumbar intervertebral disc degeneration in the elderly. Spine J 2008 September;8(5):732-40.

14. Waller B, Lambeck J, Daly D. Therapeutic aquatic exercise in the treatment of low back pain: a systematic review. Clin Rehabil 2009 January;23(1):3-14.

15. Goldberg HI, Deyo RA, Taylor VM, et al. Can evidence change the rate of back surgery? A randomized trial of community-based education. Eff Clin Pract 2001 May;4(3):95-104.

Introduction

Since Longo first described it in 1998 (1), Stapled Haemorrhoidectomy (SH) has been emerging as the procedure of choice for symptomatic haemorrhoids. Several studies have shown it to be a safe, effective and relative complication free procedure with fewer days off work, reduced requirement for analgesia and rapid discharge (2-4). Historically symptomatic haemorrhoids have been dealt with by simple dietary modification, injection sclerotherapy, cryotherapy, band ligation and surgery (5-7).

Unfortunately there is no single optimum therapeutic option. Surgery for symptomatic haemorrhoids was popularised by the open Milligan–Morgan technique in the late 1930’s or one of its variations. Unfortunately, this has been associated with postoperative pain, the risk of severe haemorrhage, and more concerning the risk of anal stenosis (especially if skin bridges are not maintained) and sphincter injury.

Controversy exists as regards to the overall safety and acceptability of SH. On the one hand recent reports of SH have been positive especially in regards reduced postoperative pain and recovery and adverse functional sequelae. A study by Pavlitidsi  et al (8) included 80 patients with second to fourth degree hemorrhoidal disease in which patients were randomly allocated to undergo either the stapled Longo procedure (group 1) or Milligan-Morgan hemorrhoidectomy (group 2) under epidural anesthesia. SH had better postoperative pain scores with lower mean epidural morphine requirement and mean hospital stay.  Conversely, a recent review from New Zealand (9) suggested that SH was more expensive, and the results should be looked upon with caution.

Several studies have suggested that SH may be safely performed as a Day case procedure. Patients following SH had reduced, post operative pain, hospital stay, analgesic requirements and earlier return to work (21-23). Day Surgery procedures have been at the forefront of recent changes within the NHS in the fight to reduce waiting times and better patient care. It is not only popular with patients who are able to recover and convalesce at home in a familiar environment but also reduce the chances of a hospital acquired infection and large cost saving implications for the NHS. However, not every surgical procedure is amenable for Day surgery, and thus procedures which require only moderate amounts of analgesia, reduced post operative stay and few complications and further in 2001 the Audit Commission included Haemorrhoidectomy as one of its 25 procedures suitable for  Day Surgery  (24).

Therefore the present study was to look critically at the learning curve, operative complications, duration of hospital stay, analgesic requirements, cost effectiveness and patient satisfaction in at the personal series of the first 66 patients who underwent SH at Watford General Hospital, a District General Hospital in Hertfordshire, United Kingdom. The aim of the present work was to determine the suitability of SH as a routine day surgery procedure which is not routine in the UK.

Patients and Methods

From June 2001 to May 2005, 66 patients who underwent stapled haemorrhoidectomy were included in this study. It was routine practice that stapled haemorrhoidectomy was performed by one dedicated surgical team (JIL).

Informed consent was obtained in writing prior to surgery. During induction at least a single dose of prophylactic antibiotics (of either a third generation cephalosporin or co-amoxiclav) was administered.

In brief, under general anaesthesia, the patient is put in lithotomy position and a rigid sigmoidoscopy done to exclude any rectal lesions. Stay-sutures with 2-0 silk are applied at the 3, 6, 9 & 12 o’clock. The anus is dilated using with a proctoscope.

An anal ring is applied and fixed to the anal verge by the previously taken stay-sutures. The inner end of the ring must be reaching beyond the dentate line.

Purse-strung sutures are taken all around the anal mucosa on top of the haemorrhoids (beyond the dentate line) followed by a per-rectal examination to make sure that the muscle layer is not taken within the sutures so as to avoid postoperative anal stenosis. Similarly, in female patients, per-vaginal examination is done to insure that vaginal wall is not taken within the sutures. A specialized circular stapler is introduced into the anal canal and the two ends of the purse-strung sutures are passed through special holes in the stapler and tied. Stapler is tightened (the indicator reads between 3 & 4 cm depth) and fired. The stapler is kept closed in place compressing them for 30 seconds in order to encourage haemostasis. The staples line then is checked for bleeding points, for which 2/0 vicryl under-running sutures may be use for further haemostasis. Finally, the anus is packed with ‘spongistan’ as well as flagyl and voltarol suppositories.            

Post-operatively both groups were discharged when comfortable. Complications where noted as they occurred during the follow-up period at 4 weeks. Furthermore, a further telephone follow-up during July 2005 was done results from the survey are shown in table II.

The data was reviewed and analysed in conjunction with our department of medical statistics. Analysis was performed using the Mann-U test. Multivariate analysis of the means was performed using the Krushal-Wallis Test.

Results

Of the 66 patients that underwent a stapled haemorrhoidectomy 43 (65%) were male and 23 (35%) were female. The mean age was 49.8 years (range 16-78 years). Only 7 patients suffered with hypertension and one with diabetes mellitus.

There presenting complaints included rectal bleeding (bright red) in 86% (n=57) and pain and discomfort 53% (n=35). Other complaints included a sensation of something coming down (n=3), change in bowel habit (n=2), constipation (n=1), and incontinence (n=1).

All patients underwent evaluation with proctoscopy and rigid sigmoidoscopy. Further evaluation with colonoscopy (14%, n=9),  flexible sigmoidoscopy (9%, n=6), barium enema (9%, n=6) and anorectal MRI (1%, n=1) to rule out other associated pathologies accounting for their symptoms.

Previous to SH, 57 patients (87%) had undergone previous therapeutic manoeuvres in the form of injection sclerotherapy (76%) and banding of haemorrhoidal tissue (11%).

The operating time ranged between 15-40 minutes with an average of 24 minutes. There were no major complications although the majority of patients warranted oversewing of bleeding points around the staple line after the stapling procedure. 

Post-operative hospital stay revealed that 88%, (n=58) went home after overnight stay (within 24 hours) and only 1 patient had a 48 hours stay with only moderate strength analgesics (Voltarol) (Table 1).

At routine follow-up at 1 month, we found that nine patients (14%) had had minor degrees of faecal urgency, frequency and soiling rectal bleeding, all of which subsequently resolved. Only one patient had developed a peri-anal heamatoma, which was evacuated under local anaesthesia in the Outpatient Department. Further, only two patients had significant problems. One patient complained of pain and discomfort at four-week follow-up, which we think resulted from too low application of the stapler which resolved completely over a six month period with simple analgesics and a single case of rectal stenosis resulting from too high a stapling, which was referred to a specialised centre for further management (Table 2).  

Indeed, only 3 patients had recurrence of symptoms, which were treated with further sclerotherapy injection in the Out-patients department and one requiring re-stapled haemorrhoidectomy.

Follow-up was in the form of Out-patient review 4-6 weeks after the procedure and a telephone questionnaire up to 4 years after the operation the results of which are shown in Table 3-5. We can see that a third of the patients did not require or use analgesia after discharge and further 44% (n=29) needed just Voltarol. As regards to symptoms we can see that approximately two thirds of patients where off analgesics, and half had complete resolution and returned to work within a week. The satisfaction data shows that the immediately 90% of patients were completely satisfied with the procedure which increased to 98% on our follow up (6 months-4 years). 

Discussion

The present study shows that stapled haemorrhoidectomy is a safe and very well tolerated procedure which is amenable for Day Case Surgery. We have shown that this approach is significantly quicker than the classical conventional haemorrhoidectomy and better tolerated with reduced post-operative pain and analgesic requirements, good patient satisfaction and early return to work. Further the vast majority of patients (65/66) were discharged after overnight stay with mild and moderate oral analgesics. We have now adopted this as our technique of choice for haemorrhoidal disease. 

The optimal mode for haemorrhoidal disease has been an ongoing debate for over 20 years and can be achieved by either open conventional Milligan Morgan and associated procedures and more recently stapled haemorrhoidectomy.  Open haemorrhoidectomy has been associated with pain, discomfort, anal stenosis and a poor satisfaction scores (13-14). Several randomised clinical trials have compared Open haemorrhoidectomy with SH and have suggested an advantage with SH (2,3,15,16) however due to the fact that this is a new procedure there is a paucity of long term data.  

In our study we looked at the complications and patient related factors associated with SH these are shown on Tables 3-5. Minor complications included rectal bleeding, fecal urgency and perianal hematoma all of which resolved conservatively. One must note that although every effort is made to ensure that at the end of the procedure the operating site is haemostatically secure some passage of blood per rectum is considered inevitable, our data is from patient self assessments who may interpret this differently.  We were unable to consistently quantify this and relied upon patient testimonies. Also Van De Stadt (12) noted a 55% rate of persistent or recurrent symptoms as well as a 20% requiring recurrent or redo surgery and Thaha et al (11) showed post-defecation syndrome rate of 4%.

Major complications associated with SH have been reported mainly in the form of case reports. In our series of 66 patients we had only two major complications. One patient had quite a lot of pain and discomfort post-operatively and upon assessment in the Out-patient department it was found that the staple line was too low (i.e. less than 3 cms) and this may be encroaching on the dentate line. Fortunately the patient was very tolerant and resolved over six months with moderate analgesics. Furthermore, our other major complication the patient developed rectal stenosis and was referred to a specialised unit where he underwent a resection. We feel that this patients staple line was too high (i.e. above 4 cms). Thus the message is that although SH is a simple procedure the critical step is the application of the purse-string so that the staple line is between 3-3.5 cms as complications can arise if you are too high or too low which was recently confirmed in a study of acute haemorrhoidal crisis (17).

Several papers have expressed concern with post-operative pain, faecal urgency after SH (18-19). This has been postulated to be due to incorporation of the muscle layers in the purse-string. However a recent paper by Kam et al (20) in a series of 33 patients found no association between amount of resected muscle and incontinence.  Indeed, it is important to keep the purse-string suture superficial and not encroaching on the other bowel wall layers. 

Our study shows good patient satisfaction scores and symptom control (Tables 3-5). We have shown that almost all 98% (65/66) of patients were discharged after a maximum overnight stay. This has huge cost saving consequences and although the equipment costs are high for SH this is compounded by a short duration of the operation, shorter hospital stay, reduced analgesic requirement and quicker return to work with the Health Service coming up on top overall. Of note, we can see that over 50% (n=34) of patients were back to work within a week of the operation and this is further supported by the fact that the majority of patients required simple analgesics for short durations.

This study highlights the excellent results after SH, with all the advantages such as reduced pain and hospital stay, and an earlier return to work. Importantly there does not seem to be a learning curve and once a surgeon has attended a training day or supervised there seems to be no increase in complications. The complication rates are low and as we have shown earlier only a single complication requiring intervention.

In conclusion, our study demonstrates that the SH is a safe, effective and well tolerated procedure which seems to have all the requirements for Day case surgery. We have also shown that it is quick procedure and post operatively less painful and requiring only simple analgesia for a short period.  Thus we have adopted this technique as our procedure of choice and will consider it as a Day Case prodedure for symptomatic haemorrhoidal disease.

Table 1 : Duration Of Stay

 Table 2 : Complications

 Table 3 : Analgesia

 Table 4 : Analgesia

 Table 5 : Patient Satisfaction

 References

1. Longo A. Treatment of haemorrhoidal disease by reduction of mucosa and haemorrhoidal prolapse with a circular stapling device: a new procedure. 6th World Congress of Endoscopic Surgery. Mundozzi Editore: Naples, 1998;777-84.

 2. Boccasanta P, Capretti PG, Venturi M, Cioffi U, De Simone M, Salamina G, Contessini-Avesani E, Peracchia A. Randomised controlled trial between stapled circumferential mucosectomy and conventional circular hemorrhoidectomy in advanced hemorrhoids with external mucosal prolapse. Am J Surg. 2001;182(1):64-8.

 3. Shalaby R, Desoky A. Randomized clinical trial of stapled versus Milligan-Morgan haemorrhoidectomy. Br J Surg. 2001 Aug;88(8):1049-53.

 4. Ascanelli S, Gregorio C, Tonini G, Baccarini M, Azzena G. Long stapled haemorrhoidectomy versus Milligan-Morgan procedure: short- and long-term results of a randomised, controlled, prospective trial. Chir Ital. 2005 Jul-Aug;57(4):439-47.

5. Alonso-Coello P, Guyatt G, Heels-Ansdell D, Johanson J, Lopez-Yarto M, Mills E, Zhou Q, Alonso-Coello P. Laxatives for the treatment of hemorrhoids. Cochrane Database Syst Rev. 2005 Oct 19;(4):CD004649.

6. Ramzisham AR, Sagap I, Nadeson S, Ali IM, Hasni MJ. Prospective randomized clinical trial on suction elastic band ligator versus forceps ligator in the treatment of haemorrhoids. Asian J Surg. 2005 Oct;28(4):241-5.

7. Hardy A, Chan CL, Cohen CR. The surgical management of haemorrhoids--a review. Dig Surg. 2005;22(1-2):26-33.

8.Pavlidis T, Papaziogas B, Souparis A, Patsas A, Koutelidakis I, Papaziogas T. Modern stapled Longo procedure vs. conventional Milligan-Morgan hemorrhoidectomy: randomized controlled trial. Int J Colorectal Dis.2002;17(1):50-3.

9. Hill A. Stapled haemorrhoidectomy--no pain, no gain? N Z Med J. 2004 8;117(1203):U1104.

10. Peng BC, Jayne DG, Ho YH. Randomized trial of rubber band ligation vs. stapled hemorrhoidectomy for prolapsed piles. Dis Colon Rectum. 2003;46(3):291-7; discussion 296-7.

11. Shanmugam V, Thaha MA, Rabindranath KS, Campbell KL, Steele RJ, Loudon MA.Rubber band ligation versus excisional haemorrhoidectomy for haemorrhoids. Cochrane Database Syst Rev. 2005 Jul 20;(3):CD005034. Review.

12. Van de Stadt J, D'Hoore A, Duinslaeger M, Chasse E, Penninckx F; Belgian Section of Colorectal Surgery Royal Belgian Society for Surgery. Long-term results after excision haemorrhoidectomy versus stapled haemorrhoidopexy for prolapsing haemorrhoids; a Belgian prospective randomized trial. Acta Chir Belg. 2005 Feb;105(1):44-52.

13. Uba AF, Ihezue CH, Obekpa PO, Iya D, Legbo JN.Open haemorrhoidectomy revisited. Niger J Med. 2001;10(4):185-8

14. Arroyo A, Perez F, Miranda E, Serrano P, Candela F, Lacueva J, Hernandez H, Calpena R.Milligan-Morgan haemorrhoidectomy with ultrasonic scalpel. G Chir. 2003;24(11-12):422-7.

15. Khalil KH, O'Bichere A, Sellu D. Randomized clinical trial of sutured versus stapled closed haemorrhoidectomy. Br J Surg. 2000;87(10):1352-5

16. Hetzer FH, Demartines N, Handschin AE, Clavien PA. Stapled vs excision hemorrhoidectomy: long-term results of a prospective randomized trial. Arch Surg. 2002 ;137(3):337-40.

17. Kang JC, Chung MH, Chao PC, Lee CC, Hsiao CW, Jao SW.Emergency stapled haemorrhoidectomy for haemorrhoidal crisis. Br J Surg. 2005;92(8):1014-6.

18. Cheetham MJ, Mortensen NJ, Nystrom PO, Kamm MA, Phillips RK. Persistent pain and faecal urgency after stapled haemorrhoidectomy. Lancet. 2000 26;356:730-3.

19. Rowsell M, Bello M, Hemingway DM. Pain after stapled haemorrhoidectomy. Lancet. 2000 Dec 23-30;356(9248):2188; author reply 2190

20. Ravo B, Amato A, Bianco V, Boccasanta P, Bottini C, Carriero A, Milito G, Dodi G, Mascagni D, Orsini S, Pietroletti R, Ripetti V, Tagariello GB. Complications after stapled hemorrhoidectomy: can they be prevented? Tech Coloproctol. 2002;6(2):83-8.

21. Law WL, Tung HM, Chu KW, Lee FC. Ambulatory stapled haemorrhoidectomy: a safe and feasible surgical technique. Hong Kong Med J. 2003 Apr;9(2):103-7,

22. Ong CH, Chee Boon Foo E, Keng V. Ambulatory circular stapled haemorrhoidectomy under local anaesthesia versus circular stapled haemorrhoidectomy under regional anaesthesia. ANZ J Surg. 2005 Apr;75(4):184-6.

23.  Ascanelli S, Gregorio C, Tonini G, Baccarini M, Azzena G. Long stapled haemorrhoidectomy versus Milligan-Morgan procedure: short- and long-term results of a randomised, controlled, prospective trial. Chir Ital. 2005 Jul-Aug;57(4):439-47

24. Royal College of Surgeons of England (1992) Guidelines of day case surgery (revised edition), London: RCS.