Cross sectional imaging of truncal and quadriceps muscles relates to different functional outcomes in cancer.

INTRODUCTION: Following the consensus definition of cancer cachexia, more studies are using CT scan analysis of truncal muscles as a marker of muscle wasting. However, how CT-derived body composition relates to function, strength and power in patients with cancer is largely unknown. AIMS: We aimed to describe the relationship between CT truncal (L3) skeletal muscle index (SMI) and MRI quadriceps cross sectional area with lower limb strength, power and measures of complex function. METHODS: Patients undergoing assessment for potentially curative surgery for oesophagogastric or pancreatic cancer were recruited from the regional upper gastrointestinal (UGI) or hepatopancreaticobiliary (HPB) multi-disciplinary team meetings. Maximum Isometric Knee Extensor Strength (IKES) and Maximum Leg Extensor Power (Nottingham Power Rig) (LEP) were used as measures of lower limb performance. Both Sit to Stand (STS) and Timed Up and Go (TUG) were used as measures of global complex muscle function. Muscle SMI was measured from routine CT scans at the level of the third lumbar vertebrae (L3) and MRI scan was used for the assessment of quadriceps muscles. Linear regression analysis was performed for CT SMI or MRI quadriceps as a predictor of each measure of performance. RESULTS: Forty-four patients underwent assessment. Height and weight were significantly related to function in terms of quadriceps power, while only weight was associated with strength (P < 0.001). CT SMI was not related to measures of quadriceps strength or power but had significant association with more complex functional measures (P = 0.006, R2 = 0.234 and 0.0019, R2 = 0.175 for STS and TUG respectively). In comparison, both gross and fat-subtracted measures of quadriceps muscle mass from MRI were significantly correlated with quadriceps strength and power (P < 0.001), but did not show any significant association with complex functional measures. CONCLUSION: CT SMI and MRI quadriceps have been shown to reflect different aspects of functional ability with CT SMI being a marker of global muscle function and MRI quadriceps being specific to quadriceps power and strength. This should therefore be considered when choosing outcome measures for trials or definitions of muscle mass and function.

Contemporary thoughts on the management of Spigelian hernia.

BACKGROUND: Spigelian hernias are said to be a rare condition of the elderly population, usually arising below the arcuate line. Local experience has led us to challenge these commonly held beliefs. METHODS: Operations for Spigelian hernia from 2006-2016 were identified from the Edinburgh Lothian Surgical Audit computerised database and case notes were reviewed. RESULTS: One hundred and one patients underwent surgery for 107 Spigelian hernias in the 10-year period. The female-to-male ratio was 2:1. Ages ranged from 32 to 88 with a median of 64 years. Sixty-five operations were done open and 42 were laparoscopic. Twelve of the 27 for which the precise anatomic location was recorded were situated above the arcuate line. Twenty-nine hernias had small defects and comprised interstitial fat only with no peritoneal sac. Ages in this group ranged from 32 to 80 (median = 48 years). All presented with intermittent local pain and/or swelling, although in three patients the hernias were impalpable. Those three also underwent ultrasound, CT and/or laparoscopy, but the hernias were only identified after open surgical exploration. The remaining 78 cases had peritoneal sacs of varying size with defects up to 9 cm across, and all were identified on imaging and/or laparoscopy. Ages ranged from 38 to 88 (median = 67 years; p < 0.01). Eighteen patients presented as emergencies and all were in this group. CONCLUSION: Spigelian hernias may be more common than we think and are probably under-diagnosed. They commonly arise above the arcuate line. We describe three clinical stages: Stage 1 hernias are those without peritoneal sacs and tend to arise in younger patients, can be difficult to diagnose and may not seen at laparoscopy. Stages 2 and 3 hernias arise in older patients, do have peritoneal sacs, are visible at laparoscopy and are more likely to present as emergencies. Stage three hernias are too large for laparoscopic repair. The differences between stages likely reflect the natural history of the condition, which begins as extraperitoneal fat protrusion and progresses over many years to develop a peritoneal sac.

Phase I/II trial of formoterol fumarate combined with megestrol acetate in cachectic patients with advanced malignancy.

PURPOSE: The aim of this study was to test the safety, tolerability and efficacy of a novel combination of an anabolic ß2-agonist and an appetite stimulant in patients with cancer cachexia. METHODS: Thirteen patients (M/F 5:8) with advanced malignancy and involuntary weight loss received oral formoterol (80 µg/day) and megestrol acetate (480 mg/day) for up to 8 weeks. Quadriceps size (MRI), quadriceps and hand-grip strength, lower limb extensor power, physical activity and quality of life were measured at baseline and at 8 weeks. Response criteria were specified pre-trial, with a major response defined as an increase in muscle size ≥ 4 % or function ≥ 10 %. RESULTS: Six patients withdrew before 8 weeks, reflecting the frail, comorbid population. In contrast, six out of seven (86 %) patients completing the course achieved a major response for muscle size and/or function. In the six responders, mean quadriceps volume increased significantly (left 0.99 vs. 1.05 L, p=0.012; right 1.02 vs. 1.06 L, p=0.004). There was a trend towards an increase in quadriceps and handgrip strength (p>0.05). The lack of appetite symptom score declined markedly (76.2 vs. 23.8; p=0.005), indicating improvement. Adverse reactions were few, the commonest being tremor (eight reports), peripheral oedema (three), tachycardia (two) and dyspepsia (two). CONCLUSIONS: In this frail cohort with advanced cancer cachexia, an 8-week course of megestrol and formoterol in combination was safe and well tolerated. Muscle mass and/or function were improved to a clinically significant extent in most patients completing the course. This combination regimen warrants further investigation in larger, randomized trials.

mRNA profiling of the cancer degradome in oesophago-gastric adenocarcinoma.

BACKGROUND: Degradation of the extracellular matrix is fundamental to tumour development, invasion and metastasis. Several protease families have been implicated in the development of a broad range of tumour types, including oesophago-gastric (OG) adenocarcinoma. The aim of this study was to analyse the expression levels of all core members of the cancer degradome in OG adenocarcinoma and to investigate the relationship between expression levels and tumour/patient variables associated with poor prognosis. METHODS: Comprehensive expression profiling of the protease families (matrix metalloproteinases (MMPs), members of the ADAM metalloproteinase-disintegrin family (ADAMs)), their inhibitors (tissue inhibitors of metalloproteinase), and molecules involved in the c-Met signalling pathway, was performed using quantitative real-time reverse transcription polymerase chain reaction in a cohort of matched malignant and benign peri-tumoural OG tissue (n=25 patients). Data were analysed with respect to clinico-pathological variables (tumour stage and grade, age, sex and pre-operative plasma C-reactive protein level). RESULTS: Gene expression of MMP1, 3, 7, 9, 10, 11, 12, 16 and 24 was upregulated by factors >4-fold in OG adenocarcinoma samples compared with matched benign tissue (P<0.01). Expression of ADAM8 and ADAM15 correlated significantly with tumour stage (P=0.048 and P=0.044), and ADAM12 expression correlated with tumour grade (P=0.011). CONCLUSION: This study represents the first comprehensive quantitative analysis of the expression of proteases and their inhibitors in human OG adenocarcinoma. These findings implicate elevated ADAM8, 12 and 15 mRNA expression as potential prognostic molecular markers.

Plasma MIC-1 correlates with systemic inflammation but is not an independent determinant of nutritional status or survival in oesophago-gastric cancer.

BACKGROUND: Macrophage inhibitory cytokine-1(MIC-1) is a potential modulator of systemic inflammation and nutritional depletion, both of which are adverse prognostic factors in oesophago-gastric cancer (OGC). METHODS: Plasma MIC-1, systemic inflammation (defined as plasma C-reactive protein (CRP) of > or =10 mg l(-1) or modified Glasgow prognostic score (mGPS) of > or =1), and nutritional status were assessed in newly diagnosed OGC patients (n=293). Healthy volunteers (n=35) served as controls. RESULTS: MIC-1 was elevated in patients (median=1371 pg ml(-1); range 141-39 053) when compared with controls (median=377 pg ml(-1); range 141-3786; P<0.001). Patients with gastric tumours (median=1592 pg ml(-1); range 141-12 643) showed higher MIC-1 concentrations than patients with junctional (median=1337 pg ml(-1); range 383-39 053) and oesophageal tumours (median=1180 pg ml(-1); range 258-31 184; P=0.015). Patients showed a median weight loss of 6.4% (range 0.0-33.4%), and 42% of patients had an mGPS of > or =1 or plasma CRP of > or =10 mg l(-1) (median=9 mg l(-1); range 1-200). MIC-1 correlated positively with disease stage (r(2)=0.217; P<0.001), age (r(2)=0.332; P<0.001), CRP (r(2)=0.314; P<0.001), and mGPS (r(2)=0.336; P<0.001), and negatively with Karnofsky Performance Score (r(2)=-0.269; P<0.001). However, although MIC-1 correlated weakly with dietary intake (r(2)=0.157; P=0.031), it did not correlate with weight loss, BMI, or anthropometry. Patients with MIC-1 levels in the upper quartile showed reduced survival (median=204 days; 95% CI 157-251) when compared with patients with MIC-1 levels in the lower three quartiles (median=316 days; 95% CI 259-373; P=0.036), but MIC-1 was not an independent prognostic indicator. CONCLUSIONS: There is no independent link between plasma MIC-1 levels and depleted nutritional status or survival in OGC.

The relationship between hospital volume and post-operative mortality rates for upper gastrointestinal cancer resections: Scotland 1982-2003.

BACKGROUND: Centralisation of surgical treatment of cancer has resulted in improved outcomes. We aimed to determine evidence of benefit for specialised management of upper gastrointestinal cancer in high-volume centres in Scotland. METHODS: Discharge records of patients undergoing oesophagectomy, gastrectomy, hepatectomy or pancreatectomy between 1982 and 2003 were identified. Hospital data were analysed on a year-by-year basis to derive 'hospital-years'. Hospital-years were divided into quartiles by volume, and were analysed with regard to in-hospital mortality during the operative admission [Chi-square test (chi(2)) and Chi-square test for trend (chi(2)(trend))]. RESULTS: 10,625 patients and 982 in-hospital deaths were included. In-hospital mortality rates declined during the study period: oesophagectomy 11.7-7.9%; gastrectomy 11.2-7.2%; hepatectomy 11.1-3.0%; and pancreatectomy 8.3-4.9%. For all resections except gastrectomy, mortality decreased as quartile of hospital-year volume increased (oesophagectomy: chi(2)p=0.006, chi(2)(trend)p=0.001; hepatectomy: chi(2)p=0.004, chi(2)(trend)p=0.003; pancreatectomy: chi(2)p=0.002, chi(2)(trend)p=0.001). ORs of death were lower for oesophagectomy (OR=0.58; 95%CI=0.39, 0.88; p=0.009) and pancreatectomy (OR=0.35; 95%CI=0.19, 0.64; p<0.001) in hospital-years within highest-volume quartiles compared with lowest. Scattergraphs of all resection types demonstrated inverse power relationships between number of resections per hospital-year and mortality. CONCLUSION: Concentration of cancer care has had major effects on health service delivery in Scotland. Centralisation should be supported in surgical management of upper gastrointestinal cancer.

Basic surgical training in the era of the European Working Time Directive: what are the problems and solutions?

BACKGROUND AND AIMS: Imposed reductions in working hours will impact significantly on the ability of surgical trainees to achieve competency. The objective of this study was to obtain the opinions of Scottish surgical trainees concerning the training they receive, in order to inform and guide the development of future, high-standard training programmes. METHODS: An anonymous questionnaire was sent to basic surgical trainees on the Edinburgh, Aberdeen and Dundee Basic Surgical Rotations commencing after August 2002. RESULTS: Thirty six questionnaire responses were analysed. Very few of the returned comments were complimentary to the existing training structure; indeed, most comments demonstrated significant trainee disappointment. Despite "regular" exposure to operative sessions, training tutorials and named consultant trainers, the most common concern was a perceived lack of high-quality, structured, operative exposure and responsibility. Textbooks and journals remain the most frequently utilised learning tools, with high-tech systems such as teleconferencing, videos, CD-ROMS, and DVDs being poorly exploited. CONCLUSIONS: Current surgical training is not meeting the expectation of the majority of its trainees. To solve this problem will require extensive revision of attitudes and current educational format. A greater emphasis on the integration of 21st century learning tools in the training programme may help bridge this gap.

Variation in dermcidin expression in a range of primary human tumours and in hypoxic/oxidatively stressed human cell lines.

Dermcidin acts as a survival factor in a variety of cancer cell lines under hypoxia or oxidative stress. The aim of this study was to evaluate dermcidin expression in cell lines following simulation of tumour microenvironmental conditions and in a range of primary tumours. Tumour tissues were collected from patients with oesophageal (28 samples), gastric (20), pancreatic (five), bile duct (one) and prostatic (52) carcinomas as well as 30 benign tissue samples, for assessment of dermcidin mRNA levels using real-time PCR. Dermcidin expression was assessed in prostatic and pancreatic cancer cell lines, with and without induction of hypoxia or oxidative stress. Dermcidin mRNA expression was very low or absent in both unstressed and stressed prostate cell lines. None of the primary prostate tissue, benign or malignant, expressed dermcidin mRNA. Only two (4%) of the gastro-oesophageal cancer samples expressed moderate quantities of dermcidin mRNA. However, three (60%) of the pancreatic cancer samples and the single cholangiocarcinoma specimen had moderate/high levels of dermcidin expression. Of the two pancreatic cancer cell lines, one expressed dermcidin moderately but neither showed a response to hypoxia or oxidative stress. Expression of dermcidin in human primary tumours appears highly variable and is not induced substantially by hypoxia/oxidative stress in cell line model systems. The relationship of these findings to dermcidin protein levels and cell survival remains to be determined.

Increased expression of phosphorylated forms of RNA-dependent protein kinase and eukaryotic initiation factor 2alpha may signal skeletal muscle atrophy in weight-losing cancer patients.

Previous studies suggest that the activation (autophosphorylation) of dsRNA-dependent protein kinase (PKR) can stimulate protein degradation, and depress protein synthesis in skeletal muscle through phosphorylation of the translation initiation factor 2 (eIF2) on the alpha-subunit. To understand whether these mediators are important in muscle wasting in cancer patients, levels of the phospho forms of PKR and eIF2alpha have been determined in rectus abdominus muscle of weight losing patients with oesophago-gastric cancer, in comparison with healthy controls. Levels of both phospho PKR and phospho eIF2alpha were significantly enhanced in muscle of cancer patients with weight loss irrespective of the amount and there was a linear relationship between phosphorylation of PKR and phosphorylation of eIF2alpha (correlation coefficient 0.76, P=0.005). This suggests that phosphorylation of PKR led to phosphorylation of eIF2alpha. Myosin levels decreased as the weight loss increased, and there was a linear relationship between myosin expression and the extent of phosphorylation of eIF2alpha (correlation coefficient 0.77, P=0.004). These results suggest that phosphorylation of PKR may be an important initiator of muscle wasting in cancer patients.

Biomarkers for cancer cachexia: is there also a genetic component to cachexia?

INTRODUCTION: Cancer cachexia is a severe debilitating disorder, which causes significant morbidity and mortality. In clinical practice, cachexia is often not treated until a late stage, when therapeutic options are limited. OBJECTIVE: It is therefore of great interest to analyse early biomarkers of this syndrome. CONCLUSION: In this review article, we summarise recent biomarkers found in various body compartments. We also explore the likelihood of a genetic predisposition to cachexia and focus on the potential role of single nucleotide polymorphisms in genes coding for pro- and anti-inflammatory cytokines, and 'atrogenes' associated with wasting in skeletal muscle.

Paraileostomy recontouring by collagen sealant injection: a novel approach to one aspect of ileostomy morbidity. Report of a case.

INTRODUCTION: Poorly fitting stoma appliances, resulting in stomal leakage and subsequent skin excoriation, remain a significant cause of ileostomy-related morbidity. One cause of ill-fitting stoma bags is the presence of parastomal dermal contour defects/irregularities. These may occur after surgical complications or change in patient weight and body habitus. METHODS: We report the case of a 29-year-old man who, after panproctocolectomy and formation of ileostomy for ulcerative colitis, experienced significant problems with stoma bag application because of dermal contour defects. As a result, he suffered from significant stomal leakage and skin excoriation. After a single treatment of cutaneous parastomal infiltration of porcine collagen (Permacol Injection), applied stoma bags achieved a watertight seal, and the patient experienced complete and sustained resolution of his symptoms. CONCLUSIONS: Porcine collagen is a safe, versatile, and relatively easy method of restoring irregular skin defects surrounding abdominal stomas, thus resolving the significant patient morbidity associated with ill-fitting stomal appliances. Such a technique avoids the need for surgical stoma refashioning, which may be associated with significant morbidity and unsatisfactory outcomes.

Secondary perineal hernia following open abdominoperineal excision of the rectum: report of a case and review of the literature.

This is a case report of a 46-year-old man who presented with a painful perineal lump four months after abdominoperineal excision of the rectum (APER) with pre-operative radiotherapy and adjuvant chemotherapy. Perineal hernia (suspected clinically) was confirmed by magnetic resonance imaging, and the patient underwent open Permacol mesh repair via a perineal approach. Symptomatic perineal herniation after surgical resection is a rare phenomenon, and the approach to management remains challenging. Several different surgical approaches and techniques of repair have been described. In this report, we review the literature surrounding the presentation, aetiology and repair of this unusual post-operative complication. Furthermore, our case confirms that closure of the hernial orifice with mesh via a perineal approach is a satisfactory technique.

The molecular mechanisms of skeletal muscle wasting: implications for therapy.

Skeletal muscle wasting is an important systemic manifestation of a wide range of diseases, including trauma, sepsis and cancer. The clinical consequences of muscle wasting undoubtedly include significant patient morbidity and worsened survival. Recently, there has been important progress in our understanding of the molecular mechanisms behind muscle wasting. In this review, the common systemic mediators, intracellular signalling pathways and effector mechanisms of skeletal muscle wasting are discussed with particular reference to different models of wasting and the development of novel therapeutic strategies.

Ventilatory and intensive care requirements following oesophageal resection.

INTRODUCTION: The aim of this study was to analyse the results of early postoperative extubation following oesophagectomy. PATIENTS AND METHODS: All patients who had undergone oesophageal resection between 1994 and 2001 were identified from a prospectively collected database. Their records were then reviewed in order to analyse morbidity and mortality along with intensive care unit (ICU) and ventilatory requirements. All patients were extubated immediately following surgery and monitored on a surgical high dependency unit (HDU). RESULTS: A total of 98 resections were undertaken (76 men; mean age, 64.3 years; range, 40-80 years). Surgical procedures were Ivor-Lewis (71), left thoraco-abdominal (15) and transhiatal (12) oesophagectomies. Overall, 8 patients died and 13 patients had anastomotic leaks. Sixteen patients required ventilation and admission to ICU, of whom 5 died. Three patients died on HDU following an elective decision not to transfer to ICU. Reasons for ventilation and ICU admission were anastomotic leaks (6), respiratory problems (6), left ventricular failure (1), cardiac arrest (1), small bowel herniation through the hiatus (1) and ischaemic stomach requiring revision of anastomosis (1). No patient required ventilation and admission to ICU within 48 h of original surgery. CONCLUSIONS: Patients undergoing oesophageal resection can be safely managed on a surgical HDU without routine postoperative ventilation. Although ventilation and ICU will be required in a significant number due to postoperative complications, this is unlikely to occur in the first 48 h. The requirement for an ICU bed to be available on the day of surgery should, therefore, no longer be considered necessary. This has important implications for the scheduling of elective oesophageal surgery.

Red herring: a rare cause of small bowel obstruction.

This is a case report of a 73-year-old man with a small bowel obstruction secondary to an incarcerated paracaecal hernia. His large right inguinal hernia, initially suspected as a potential source of obstruction, turned out to be a red herring. Congenital internal hernias are a very rare cause of bowel obstruction. In this report we review the literature and embryology behind these uncommon occurrences.