Increased multimodality treatment options has improved survival for Hepatocellular carcinoma but poor survival for biliary tract cancers remains unchanged.

BACKGROUND: Primary hepatobiliary cancer incidence in the UK is rising and survival rates are low. Surgery is the main curative option for these cancers, but multimodality therapies are expanding. The aim of our original study was to determine trends in survival, over an 8-year period, of patients treated for primary hepatobiliary cancers at our tertiary referral Centre. METHOD: Patients treated for the most common types of primary hepatobiliary cancers, namely Hepatocellular carcinoma (HCC), Cholangiocarcinoma and Gallbladder cancer between January 2009 and December 2016 were retrospectively analysed from a prospective database linked to UK Hospital Episode Statistics data. RESULTS: A total of 1536 patients with primary hepatobiliary cancers were assessed and treatment plans formulated at our supra-regional specialist Hepatobiliary MDT. The primary hepatobiliary cancers treated were HCC (n = 836), Cholangiocarcinoma (n = 516), and Gallbladder cancer (n = 184). Survival for all the 3 cancers was significantly better with curative treatment. Overall median survival times were 350, 180, and 150 days respectively for HCC, Cholangiocarcinoma and Gallbladder cancer. Excluding best supportive care patients, the respective survival figures were 900, 600, and 400 days. Survival for HCC patients improved over time and was significantly increased in the final 3 years of the study (p ≤ 0.011 for all). Cholangiocarcinoma and Gallbladder cancer survivals were poor and did not change significantly over time. CONCLUSION: HCC outcome has improved in association with expanded multimodal therapies. Survivals for cholangiocarcinoma and gallbladder cancer remain poor in parallel with limited expansion of multimodal therapies highlighting an unmet therapeutic need for biliary tract cancers.

The effect of neoadjuvant chemotherapy and chemoradiotherapy on exercise capacity and outcome following upper gastrointestinal cancer surgery: an observational cohort study.

BACKGROUND: In 2014 approximately 21,200 patients were diagnosed with oesophageal and gastric cancer in England and Wales, of whom 37 % underwent planned curative treatments. Potentially curative surgical resection is associated with significant morbidity and mortality. For operable locally advanced disease, neoadjuvant chemotherapy (NAC) improves survival over surgery alone. However, NAC carries the risk of toxicity and is associated with a decrease in physical fitness, which may in turn influence subsequent clinical outcome. Lower levels of physical fitness are associated with worse outcome following major surgery in general and Upper Gastrointestinal Surgery (UGI) surgery in particular. Cardiopulmonary exercise testing (CPET) provides an objective assessment of physical fitness. The aim of this study is to test the hypothesis that NAC prior to upper gastrointestinal cancer surgery is associated with a decrease in physical fitness and that the magnitude of the change in physical fitness will predict mortality 1 year following surgery. METHODS: This study is a multi-centre, prospective, blinded, observational cohort study of participants with oesophageal and gastric cancer scheduled for neoadjuvant cancer treatment (chemo- and chemoradiotherapy) and surgery. The primary endpoints are physical fitness (oxygen uptake at lactate threshold measured using CPET) and 1-year mortality following surgery; secondary endpoints include post-operative morbidity (Post-Operative Morbidity Survey (POMS)) 5 days after surgery and patient related quality of life (EQ-5D-5 L). DISCUSSION: The principal benefits of this study, if the underlying hypothesis is correct, will be to facilitate better selection of treatments (e.g. NAC, Surgery) in patients with oesophageal or gastric cancer. It may also be possible to develop new treatments to reduce the effects of neoadjuvant cancer treatment on physical fitness. These results will contribute to the design of a large, multi-centre trial to determine whether an in-hospital exercise-training programme that increases physical fitness leads to improved overall survival. TRIAL REGISTRATION: ClinicalTrials.gov NCT01325883 - 29(th) March 2011.

The effect of neoadjuvant chemotherapy on physical fitness and survival in patients undergoing oesophagogastric cancer surgery.

BACKGROUND: Neoadjuvant chemotherapy (NAC) followed by surgery for resectable oesophageal or gastric cancer improves outcome when compared with surgery alone. However NAC has adverse effects. We assess here whether NAC adversely affects physical fitness and whether such an effect is associated with impaired survival following surgery. METHODS: We prospectively studied 116 patients with oesophageal or gastric cancer to assess the effect of NAC on physical fitness, of whom 89 underwent cardiopulmonary exercise testing (CPET) before NAC and proceeded to surgery. 39 patients were tested after all cycles of NAC but prior to surgery. Physical fitness was assessed by measuring oxygen uptake (VO2 in ml kg(-1) min(-1)) at the estimated lactate threshold (θL) and at peak exercise (VO2 peak in ml kg(-1) min(-1)). RESULTS: VO2 at θL and at peak were significantly lower after NAC compared to pre-NAC values: VO2 at θL 14.5 ± 3.8 (baseline) vs. 12.3 ± 3.0 (post-NAC) ml kg(-1) min(-1); p ≤ 0.001; VO2 peak 20.8 ± 6.0 vs. 18.3 ± 5.1 ml kg(-1) min(-1); p ≤ 0.001; absolute VO2 (ml min(-1)) at θL and peak were also lower post-NAC; p ≤ 0.001. Decreased baseline VO2 at θL and peak were associated with increased one year mortality in patients who completed a full course of NAC and had surgery; p = 0.014. CONCLUSION: NAC before cancer surgery significantly reduced physical fitness in the overall cohort. Lower baseline fitness was associated with reduced one-year-survival in patients completing NAC and surgery, but not in patients who did not complete NAC. It is possible that in some patients the harms of NAC may outweigh the benefits. Trials Registry Number: NCT01335555.

Impact of specialized multi-disciplinary approach and an integrated pathway on outcomes in hilar cholangiocarcinoma.

AIMS: To assess the outcomes of patients with hilar cholangiocarcinoma following referral to a specialist multi-disciplinary team. METHODS: Over an 11-year period, patients referred with hilar cholangiocarcinoma were identified from a prospectively maintained registry. Collated data included demographics, operative findings and histo-pathological data. Survival differences and prognostic factors were determined. RESULTS: 345 patients were referred with hilar cholangiocarcinoma, of which 57 (16.5%) patients had surgery. Prior to 2008, of 143 patients referred, only 17 (11.9%) patients underwent surgery, compared to 40 (19.8%) of 202 patients referred from 2008 onwards (p = 0.051). In the surgery group, the majority of patients underwent left hemi-hepatectomy (n = 19). In addition, portal vein (n = 5), hepatic artery (n = 2) and inferior vena cava (n = 3) resections were performed. The R0 resection rate was 73.7%. The morbidity and mortality rates were 59.6% and 14.0%, respectively. The median disease-free survival was 16 (4-101) months. The presence of lymph node metastasis (p = 0.002) was the only predictor of poorer disease-free survival. The 5-year overall survival was 39.5% and was significantly better than that of the palliative group (p < 0.001). CONCLUSIONS: Surgery is the optimal treatment option for patients with hilar cholangiocarcinoma and is associated with better overall survival. Prompt referral to tertiary centres with a core team of clinicians to manage this difficult condition may allow more patients to come to potentially curative surgical resections.

Endoscopic therapy in the management of malignant biliary obstruction.

Malignant biliary obstruction is often caused by tumour within the biliary tree, or extrinsic compression. This often results in patients becoming jaundiced causing a significant associated morbidity. The majority of malignant biliary obstruction is due to inoperable disease, and therefore the mainstay of palliating jaundice is stent placement at endoscopic retrograde cholangiopancreatography (ERCP). Cross-sectional imaging is necessary to determine if stenting is appropriate and to guide stent placement. This is especially important in patients with hilar cholangiocarcinoma, where drainage should be undertaken in specialist centres. Self-expanding metal stents are preferable to plastic stents and are cost effective if survival is likely to be more than 6 months. With the exception of pancreatic carcinoma, traditional non-operative disease modifying treatments for biliary malignancies have shown only limited benefit. This particularly relates to radio and chemotherapy. Photodynamic therapy is a relatively new modality of treatment that appears to be effective in patients with local but inoperable cholangiocarcinoma and is capable of prolonging survival.

An unusual case of Turcot's syndrome associated with ileal adenocarcinoma, intestinal non-Hodgkin's lymphoma, and duodenal adenocarcinoma. Review of the classification and genetic basis of Turcot's syndrome.

A 38-year-old man with a history of colonic and small bowel polyposis and glioblastoma was investigated for dyspepsia. Upper GI endoscopy identified an abnormal area in the duodenum, confirmed by histology as high grade non-Hodgkin's B cell MALT lymphoma. Although cases of Turcot's syndrome (TS) (colonic polyposis and primary brain tumour occurring in the same patient) have been previously described, association with haematological malignancy is rare. This is the first report of intestinal lymphoma occurring in an adult with TS.

Predictive value of alarm features in a rapid access upper gastrointestinal cancer service.

AIMS: (i) To determine the value of individual alarm features for predicting cancer in subjects referred to a rapid access upper gastrointestinal cancer service; and (ii) to develop a clinical prediction model for cancer and to prospectively validate this model in a further patient cohort. METHODS: Patient demographics, referral indications, and subsequent diagnosis were recorded prospectively. Logistic regression analyses were employed to determine the predictive value of individual alarm features in an evaluation cohort of 1852 consecutive cases. The potential impact of applying a modified set of referral criteria was then examined in a validation cohort of 1785 patients. RESULTS: Evaluation cohort: mean age was 59 years; cancer prevalence 3.8%; and serious benign pathology 12.8%. Dysphagia (odds ratio (OR) 3.1), weight loss (OR 2.6), and age >55 years (OR 9.5) were found to be significant predictive factors for cancer but the value of other accepted alarm features was more limited. In particular, uncomplicated dyspepsia in those over 55 years was a negative predictive factor for cancer within this high risk cohort (OR 0.1). Validation cohort: the clinical prediction model would have selected 92% of cancer patients for fast track investigation while reducing the "two week rule" workload by 572 cases (31%). CONCLUSIONS: Fast track endoscopy in subjects fulfilling current criteria for suspected upper gastrointestinal malignancy results in a significant yield of cancer ( approximately 4%) and serious benign diseases such as peptic ulceration, strictures, and severe oesophagitis (13%). However, the predictive value of individual features for cancer varies widely. Uncomplicated dyspepsia in older subjects was a poor predictor of cancer. Application of narrower referral criteria for accessing fast track services may reduce pressures while retaining high sensitivity for cancer.

Is coeliac disease more prevalent in young adults with coexisting Type 1 diabetes mellitus and autoimmune thyroid disease compared with those with Type 1 diabetes mellitus alone?

AIM: It is known that patients with Type 1 diabetes mellitus are more prone to develop coeliac disease and that autoimmune thyroid disease occurs more frequently in patients with coeliac disease. We therefore assessed whether coeliac disease, either known or occult, occurs more frequently in young/middle aged adults with Type 1 diabetes and coexisting autoimmune thyroid dysfunction than in adults with Type 1 diabetes alone. METHODS: The prevalence of known coeliac disease was assessed in 509 (301 males, aged 16-55 years) patients with Type 1 diabetes, 28 (5.5%) of whom had treated autoimmune thyroid disease. In a second study 38 patients with Type 1 diabetes and coexisting autoimmune thyroid disease along with 112 patients with Type 1 diabetes alone were then screened for coeliac disease using serum IgA endomysial antibodies and IgA gliadin antibodies. RESULTS: Seven of the 509 patients (1.4%) had been diagnosed with coeliac disease and two of these had later developed autoimmune thyroid disease (both hypothyroid). The subsequent screening exercise found that one of the 38 patients with both Type 1 diabetes and thyroid disease had positive endomysial antibodies on screening. However, duodenal biopsy was negative for coeliac disease. There were two patients with positive endomysial antibodies in the group of 112 patients with diabetes only. Both had duodenal biopsy but only one was consistent with coeliac disease. CONCLUSION: The prevalence of known coeliac disease in this young adult Type 1 diabetes clinic in North-west England was 7/509 (1.4%). Two of these seven patients with coeliac disease were from the group of 28 who had autoimmune thyroid disease as well. Therefore we suggest that patients with known coeliac disease and Type 1 diabetes should be screened for autoimmune thyroid disease. The second screening study then found 3/150 (2%) to have a serological marker for coeliac disease. However, patients with both Type 1 diabetes and autoimmune thyroid disease were not more likely to have occult coeliac disease compared with those with Type 1 diabetes only.

Hepatic sarcoidosis complicated by hepatocellular carcinoma.

A case of a 63-year-old man with a long-standing history of portal hypertension secondary to hepatic sarcoidosis who developed hepatocellular carcinoma is reported.

Laser therapy in maintenance of the patency of expandable metal stents.

Re-establishment of the oesophageal lumen is the main focus of care in patients with dysphagia due to re-blockage of in situ expandable metal stent (EMS). A total of 51 patients aged 44-89 years were intubated with EMS for dysphagia due to inoperable oesophagogastric carcinoma. Of these patients, 25 required follow-up endoscopy at variable intervals after stent insertion; 17 patients were found to have significant tumour in-growth (9), overgrowth (4) or both (4). All these patients were treated with Nd-YAG (70 W/s) or diode laser (30-50 W, continuous) for maintenance of satisfactory swallowing. The intensity of tumour ablation was similar with both types of lasers but four patients being treated with Nd-YAG laser developed deformity of EMS. This complication was not encountered with diode laser. The timing of the stent insertion should be carefully chosen since the longer the stent is in situ, the greater is the likelihood of tumour ingrowth or overgrowth. The combination of endoscopic laser therapy (ELT) and EMS may offer the best palliation, particularly when patient survival of several months is anticipated. ELT can effectively deal with tumour in-growth and overgrowth but care must be exercised in the use of Nd-YAG which can damage the structure of the EMS.

The steroid vitamin D3 reduces cell proliferation in human duodenal epithelium.

1. The active metabolite of vitamin D3, 1,25-dihydroxyvitamin D3, controls calcium absorption in the human duodenum, an effect that is mediated by mucosal vitamin D receptor expression. Functional vitamin D receptor signalling in the human colon is suggested by the reduced colonic mucosal cell proliferation seen in response to 1,25-dihydroxyvitamin D3. Thus 1,25-dihydroxyvitamin D3 might be expected to reduce cell proliferation in the small-bowel epithelium. 2. We have used an organ-culture system combined with the metaphase arrest technique to study the effects of 1,25-dihydroxyvitamin D3 on human duodenal mucosal proliferation. To validate our technique, multiple human mucosal explants were established in organ culture and vincristine (0.6 micrograms/ml) was added at 10 h. Explants were removed sequentially from 10 to 15 h and metaphase arrest figures were demonstrated by using the Feulgen reaction. The mean number of metaphase arrest figures was plotted against time in culture to show a linear accumulation of metaphases between 11 and 15 h (correlation coefficient = 0.93, r2 = 0.87, P < 0.0001). The mean crypt cell production rate was 2.01 (0.27) cells/h per crypt. 3. Paired normal duodenal mucosal biopsies from six patients were then established in organ culture with or without 10(-10) mol/l (100 pmol/l) 1,25-dihydroxyvitamin D3. The crypt cell production rate was determined between 12 and 15 h after vincristine-induced metaphase arrest. 1,25-Dihydroxyvitamin D3 reduced the median crypt cell production rate from 2.42 (1.15-4.82) to 1.41 (0.03-2.05) cells/h per crypt (P < 0.05). Thus, vitamin D3 reduces human duodenal epithelial cell proliferation.

Percutaneous endoscopic gastrostomy: evaluation of insertion by an endoscopy nurse practitioner.

OBJECTIVE: To evaluate the success rate and complications of percutaneous endoscopic gastrostomy (PEG) insertion performed with an endoscopy nurse practitioner, rather than a second doctor, carrying out percutaneous gastric puncture. DESIGN: A prospective evaluation of one nurse'e performance. SETTING: The endoscopy unit in a district general hospital. METHODS: An experienced endoscopy nurse, who had undergone a specific training course in PEG insertion, participated in PEG placement in 50 unselected patients over a one year period. The outcome and complications were compared with 50 PEGs inserted over the same period by medical personnel. A standard 'pull' technique was used to insert a 15Fr tube under sedation and local anaesthetic. RESULTS: The nurse was successful in PEG placement in all patients. Immediate complications from the procedure occurred in two cases in both the nurse-assisted and doctor-assisted groups. These were directly related to the gastric puncture in only one patient in each group; the others were respiratory complications related to the gastroscopy (resulting in the death of one patient). Thirty-day mortality was 8% in the nurse-assisted group and 12% following doctor-assisted PEG (mainly due to progression of the underlying condition). Outcome at 3 months was similar in the two groups, except for a slightly lower incidence of stomal infection in the nurse-assisted group. CONCLUSION: The participation of an endoscopy nurse practitioner in the gastric puncture for PEG insertion appeared to be safe and effective and offered advantages in terms of the efficient provision of a PEG placement service, increased continuity of care for the patients and an enhanced professional role for the nurse involved.

Laser therapy in the palliation of dysphagia in oesophageal malignancy.

Dysphagia is a distressing symptom commonly found in patients with oesophageal malignancy. Endoscopic laser therapy, in isolation or in conjunction with other treatments, can offer effective palliation. The procedure is outlined together with discussion of the advantages and complications of this technique.

Is the number of surgical day cases a good indicator of rising drug costs?

There have been various attempts to reduce the expenditure on drugs-limited lists, drug formularies, prescribing policies, etc. The number of occupied beds in hospitals has fallen, and other indicators of hospital work have altered little. In spite of this, the expenditure on drugs by the hospitals in Wales has continued to rise. Taking two groups (antibiotics and anaesthetic agents) as examples of the high-cost drugs, the expenditure has been related to a number of indicators of the workload of a hospital. No clear relationship between any one indicator has been demonstrated although the number of surgical day cases is an important factor.

Cytokine mRNA expression in the mucosa of treated coeliac patients after wheat peptide challenge.

This study investigated the presence of mRNA coding for interferon gamma (IFN gamma), tumour necrosis factor alpha (TNF alpha), and interleukins 2 (IL2) and 6 (IL6), in the mucosa of four coeliac patients in remission who had been challenged with either gliadin or synthetic gliadin oligopeptides. Jejunal biopsy specimens from these patients, taken before and at two, four, and six hours after challenge, were hybridised with specific 35S-labelled DNA oligonucleotide probes. The lamina propria of all the patients contained significantly increased numbers of cytokine mRNA expressing cells four hours after challenge with gliadin or an oligopeptide corresponding to amino acids 31-49 of A-gliadin (peptide A). No significant changes were seen with the peptides corresponding to aminoacids 202-220 (peptide B) or 3-21 (peptide C) of A-gliadin, with the exception of one patient who showed a significant increase in the number of TNF alpha mRNA expressing cells four hours after challenge with peptide B. In vivo studies in coeliac disease have shown that significant histological changes occur in the mucosa of treated coeliac patients four hours after challenge with either gliadin or peptide A. These findings suggest that the histological changes seen previously in the mucosa of coeliac patients after wheat peptide challenge may be caused by increased expression of cytokines within the mucosa.

Expression of tumour necrosis factor-alpha, interleukin-6, and interleukin-2 mRNA in the jejunum of patients with coeliac disease.

BACKGROUND: A T-cell-mediated immune response may be responsible for the enteropathy seen in coeliac disease (CD), but it is unclear whether this is initiated in the epithelium or the lamina propria. We studied the site and number of cells expressing mRNA encoding the cytokines interleukin-2 (IL-2), IL-6, and tumour necrosis factor-alpha in jejunal biopsy specimens from patients with untreated or treated CD and normal controls. METHODS: Tissue sections were hybridized with 35S-labelled DNA oligonucleotide probes specific for each cytokine RNA sequence. Positive cells were counted in the lamina propria and epithelial compartments. RESULTS: For each cytokine significantly greater numbers of positive cells were found in the lamina propria of untreated CD patients. Few positive cells were detected in the epithelium of all three groups. CONCLUSIONS: This study shows that the immune response to gliadin appears to occur in the lamina propria and supports cell-mediated immunity in the pathogenesis of coeliac disease.

Detection of interferon gamma mRNA in the mucosa of patients with coeliac disease by in situ hybridisation.

In situ hybridisation has been used to study interferon gamma (IFN gamma) mRNA expression in the small intestine of patients with coeliac disease. Sections of jejunal biopsies were obtained from five patients with treated and five with untreated coeliac disease and five disease controls. These sections were hybridised with radiolabelled specific DNA oligonucleotide probes. The lamina propria of untreated coeliac disease patients contained a significantly increased number of IFN gamma producing cells compared with controls but there was no significant difference between the coeliac patients treated with a gluten free diet and controls. The results suggest that IFN gamma may play a part in the immunopathogenesis of coeliac disease.