Liver resection for metastatic uveal melanoma: experience from a supra-regional centre and review of literature.

Management of liver metastases from uveal melanoma (LMUM) requires multimodal approach. This study describes evolution of liver resection for LMUM, reviewing current literature and institutional outcomes. Records of patients referred to the Melanoma Multi-Disciplinary Team between February 2005 and August 2018 were reviewed. All publications describing surgery for LMUM were identified from PubMed, Embase, and Google Scholar. Thirty-one of 147 patients with LMUM underwent laparoscopic liver biopsy, and 29 (14 females) had liver resections. Nineteen liver resections were performed locally [7 major (≥3 seg), 14 laparoscopic] without major complications or mortality. Overall survival positively correlated with the time from uveal melanoma to LMUM (Spearman's rho rs = 0.859, P < 0.0001). Overall and recurrence-free survivals were comparable following R1 or R0 resections (OS 25 vs. 28 months, P = 0.404; RFS 13 vs. 6 months, P = 0.596). R1 resection cohort had longer lead-time (median 100 vs. 24 months, P = 0.0408). Eleven publications describing liver resection for LMUM were identified and included in the narrative review. Surgery for LMUM is safe and complements multidisciplinary management. Despite heterogeneity in literature, time from diagnosis of uveal melanoma to LMUM remains a key factor affecting survival after liver resection.

Metastatic mixed VIPoma/PPoma-induced diarrhoea causing renal failure.

Summary: Vasoactive intestinal peptide-secreting tumours (VIPomas) are an extremely rare form of functional pancreatic neuroendocrine tumour with an estimated annual incidence of 1 in 10 million. Associated tumour hypersecretion of other peptides, including pancreatic polypeptide (PPomas), may also be seen. These malignancies classically present with a defined triad of refractory diarrhoea, hypokalaemia and metabolic acidosis known as Verner-Morrison syndrome. Diagnosis is frequently delayed, and the majority of patients will have metastatic disease at presentation. Symptoms are usually well controlled with somatostatin analogue administration. Here we report a case of metastatic mixed VIPoma/PPoma-induced diarrhoea causing renal failure so severe that ultrafiltration was required to recover adequate renal function. Learning points: Profuse, watery diarrhoea is a common presenting complaint with a multitude of aetiologies. This, combined with the rarity of these tumours, makes diagnosis difficult and frequently delayed. A functional neuroendocrine tumour should be suspected when diarrhoea is unusually extreme, prolonged and common causes have been promptly excluded. These patients are likely to be profoundly unwell on presentation. They are extremely hypovolaemic with dangerous electrolyte and metabolic abnormalities. Aggressive initial rehydration and electrolyte replacement are imperative. A somatostatin analogue should be commenced as soon as the diagnosis is suspected. This is an extreme example of Verner-Morrison syndrome. We are unaware of another case where renal failure secondary to diarrhoea and dehydration was so severe that renal replacement therapy was required to restore adequate renal function, further emphasising how critically unwell these patients can be. Both the primary tumour and metastases showed a remarkably good and rapid response to somatostatin analogue administration. Cystic change and involution were noted on repeat imaging within days. Prior to his illness, this patient was extremely high functioning with no medical history. His diagnosis was an enormous psychological shock, and the consideration and care for his psychological well-being were a crucial part of his overall management. It highlights the importance of a holistic approach to cancer care and the role of the clinical nurse specialist within the cancer multidisciplinary team.

Chemosaturation with percutaneous hepatic perfusion of melphalan for metastatic uveal melanoma.

Uveal melanoma, the most common primary ocular malignancy in adults, carries a poor prognosis: 50% of patients develop the metastatic disease with a 10-25% 1-year survival and no established standard of care treatment. Prior studies of melphalan percutaneous hepatic perfusion (M-PHP) have shown promise in metastatic uveal melanoma (mUM) patients with liver predominant disease but are limited by small sample sizes. We contribute our findings on the safety and efficacy of the procedure in the largest sample population to date. A retrospective analysis of outcome and safety data for all mUM patients receiving M-PHP was performed. Tumour response and treatment toxicity were evaluated using RECIST 1.1 and Common Terminology Criteria for Adverse Events v5.03, respectively. 250 M-PHP procedures were performed in 81 patients (median of three per patient). The analysis demonstrated a hepatic disease control rate of 88.9% (72/81), a hepatic response rate of 66.7% (54/81), and an overall response rate of 60.5% (49/81). After a median follow-up of 12.9 months, median overall progression-free (PFS) and median overall survival (OS) were 8.4 and 14.9 months, respectively. There were no fatal treatment-related adverse events (TRAE). Forty-three grade 3 (29) or 4 (14) TRAE occurred in 23 (27.7%) patients with a significant reduction in such events between procedures performed in 2016-2020 vs. 2012-2016 (0.17 vs. 0.90 per patient, P < 0.001). M-PHP provides excellent response rates and PFS compared with other available treatments, with decreasing side effect profile with experience. Combination therapy with systemic agents may be viable to further advance OS.

Implementation of enhanced recovery after surgery for pancreatoduodenectomy increases the proportion of patients achieving textbook outcome: A retrospective cohort study.

BACKGROUND: Enhanced Recovery After Surgery (ERAS) for patients undergoing pancreatoduodenectomy is associated with reduced length of stay (LOS) and morbidity. However, external validating of the impact is difficult due to the multimodal aspects of ERAS. This study aimed to assess implementation of ERAS for pancreatoduodenectomy with a composite measure of multiple ideal outcome indicators defined as 'textbook outcome' (TBO). METHODS: In a tertiary referral center, 250 patients undergoing pancreatoduodenectomy were included in ERAS (May 2012-January 2017) and compared to a cohort of 125 patients undergoing traditional perioperative management (November 2009-April 2012). TBO was defined as proportion of patients without prolonged LOS, Clavien-Dindo ≥ III complications, postoperative pancreatic fistula, postpancreatectomy hemorrhage, bile leakage, readmissions or 30-day/in-hospital mortality. Additionally, overall treatment costs were calculated and compared using bootstrap independent t-test. RESULTS: The two cohorts were comparable in terms of demographic and surgical details. Implementation of ERAS was associated with reduced median LOS (10 days vs 13 days, p < 0.001) and comparable overall complication rate (62.0% vs 61.6%, p = 0.940) when compared to the traditional management group. In addition, a higher proportion of patients achieved TBO (56.4% vs 44.0%, p = 0.023) when treated according to ERAS principles. Furthermore, ERAS was associated with reduced mean total costs (£18132 vs £19385, p < 0.005). CONCLUSION: Implementation of ERAS for patients undergoing pancreatoduodenectomy is beneficial for both patients and hospitals. ERAS increased the proportion of patients achieving TBO and reduced overall costs. TBO is a potential measure for the evaluation of ERAS.

Alternative Fistula Risk Score for Pancreatoduodenectomy (a-FRS): Design and International External Validation.

OBJECTIVE: The aim of this study was to develop an alternative fistula risk score (a-FRS) for postoperative pancreatic fistula (POPF) after pancreatoduodenectomy, without blood loss as a predictor. BACKGROUND: Blood loss, one of the predictors of the original-FRS, was not a significant factor during 2 recent external validations. METHODS: The a-FRS was developed in 2 databases: the Dutch Pancreatic Cancer Audit (18 centers) and the University Hospital Southampton NHS. Primary outcome was grade B/C POPF according to the 2005 International Study Group on Pancreatic Surgery (ISGPS) definition. The score was externally validated in 2 independent databases (University Hospital of Verona and University Hospital of Pennsylvania), using both 2005 and 2016 ISGPS definitions. The a-FRS was also compared with the original-FRS. RESULTS: For model design, 1924 patients were included of whom 12% developed POPF. Three predictors were strongly associated with POPF: soft pancreatic texture [odds ratio (OR) 2.58, 95% confidence interval (95% CI) 1.80-3.69], small pancreatic duct diameter (per mm increase, OR: 0.68, 95% CI: 0.61-0.76), and high body mass index (BMI) (per kg/m increase, OR: 1.07, 95% CI: 1.04-1.11). Discrimination was adequate with an area under curve (AUC) of 0.75 (95% CI: 0.71-0.78) after internal validation, and 0.78 (0.74-0.82) after external validation. The predictive capacity of a-FRS was comparable with the original-FRS, both for the 2005 definition (AUC 0.78 vs 0.75, P = 0.03), and 2016 definition (AUC 0.72 vs 0.70, P = 0.05). CONCLUSION: The a-FRS predicts POPF after pancreatoduodenectomy based on 3 easily available variables (pancreatic texture, duct diameter, BMI) without blood loss and pathology, and was successfully validated for both the 2005 and 2016 POPF definition. The online calculator is available at www.pancreascalculator.com.

Surgeons' assessment versus risk models for predicting complications of hepato-pancreato-biliary surgery (HPB-RISC): a multicenter prospective cohort study.

BACKGROUND: Several studies advise the use of risk models when counseling patients for hepato-pancreato-biliary (HPB) surgery, but studies comparing these models to the surgeons' assessment are lacking. The aim of this study was to assess whether risk prediction models outperform surgeons' assessment for the risk of complications in HPB surgery. METHODS: This prospective study included adult patients scheduled for HPB surgery in three centers in the UK and the Netherlands. Primary outcome was the rate of postoperative major complications. Surgeons assessed the risk prior to surgery while blinded for the formal risk scores. Risk prediction models were retrieved via a systematic review and risk scores were calculated. For each model, discrimination and calibration were evaluated. RESULTS: Overall, 349 patients were included. The rate of major complications was 27% and in-hospital mortality 3%. Surgeons' assessment resulted in an AUC of 0.64; 0.71 for liver and 0.56 for pancreas surgery (P = 0.020). The AUCs for nine existing risk prediction models ranged between 0.57 and 0.73 for liver surgery and between 0.51 and 0.57 for pancreas surgery. CONCLUSION: In HPB surgery, existing risk prediction models do not outperform surgeons' assessment. Surgeons' assessment outperforms most risk prediction models for liver surgery although both have a poor predictive performance for pancreas surgery. REGISTRATION INFORMATION: REC reference number (13/SC/0135); IRAS ID (119370). TRIALREGISTER.NL: NTR4649.

Percutaneous hepatic perfusion with melphalan in uveal melanoma: A safe and effective treatment modality in an orphan disease.

BACKGROUND: Metastatic uveal melanoma (UM) carries a poor prognosis; liver is the most frequent and often solitary site of recurrence. Available systemic treatments have not improved outcomes. Melphalan percutaneous hepatic perfusion (M-PHP) allows selective intrahepatic delivery of high dose cytotoxic chemotherapy. METHODS: Retrospective analysis of outcomes data of UM patients receiving M-PHP at two institutions was performed. Tumor response and toxicity were evaluated using RECIST 1.1 and Common Terminology Criteria for Adverse Events (CTCAE) v4.03, respectively. RESULTS: A total of 51 patients received 134 M-PHP procedures (median of 2 M-PHPs). 25 (49%) achieved a partial (N = 22, 43.1%) or complete hepatic response (N = 3, 5.9%). In 17 (33.3%) additional patients, the disease stabilized for at least 3 months, for a hepatic disease control rate of 82.4%. After median follow-up of 367 days, median overall progression free (PFS) and hepatic progression free survival (hPFS) was 8.1 and 9.1 months, respectively and median overall survival was 15.3 months. There were no treatment related fatalities. Non-hematologic grade 3-4 events were seen in 19 (37.5%) patients and were mainly coagulopathic (N = 8) and cardiovascular (N = 9). CONCLUSIONS: M-PHP results in durable intrahepatic disease control and can form the basis for an integrated multimodality treatment approach in appropriately selected UM patients.

IL-12 and IL-15 induce the expression of CXCR6 and CD49a on peripheral natural killer cells.

INTRODUCTION: Murine hepatic NK cells exhibit adaptive features, with liver-specific adhesion molecules CXCR6 and CD49a acting as surface markers. METHODS: We investigated human liver-resident CXCR6+ and CD49a+ NK cells using RNA sequencing, flow cytometry, and functional analysis. We further assessed the role of cytokines in generating NK cells with these phenotypes from the peripheral blood. RESULTS: Hepatic CD49a+ NK cells could be induced using cytokines and produce high quantities of IFNγ and TNFα, in contrast to hepatic CXCR6+ NK cells. RNA sequencing of liver-resident CXCR6+ NK cells confirmed a tolerant immature phenotype with reduced expression of markers associated with maturity and cytotoxicity. Liver-resident double-positive CXCR6 + CD49a+ hepatic NK cells are immature but maintain high expression of Th1 cytokines as observed for single-positive CD49a+ NK cells. We show that stimulation with activating cytokines can readily induce upregulation of both CD49a and CXCR6 on NK cells in the peripheral blood. In particular, IL-12 and IL-15 can generate CXCR6 + CD49a+ NK cells in vitro from NK cells isolated from the peripheral blood, with comparable phenotypic and functional features to liver-resident CD49a+ NK cells, including enhanced IFNγ and NKG2C expression. CONCLUSION: IL-12 and IL-15 may be key for generating NK cells with a tissue-homing phenotype and strong Th1 cytokine profile in the blood, and links peripheral activation of NK cells with tissue-homing. These findings may have important therapeutic implications for immunotherapy of chronic liver disease.

Outcome and Learning Curve in 159 Consecutive Patients Undergoing Total Laparoscopic Hemihepatectomy.

Importance: Widespread implementation of laparoscopic hemihepatectomy is currently limited by its technical difficulty, paucity of training opportunities, and perceived long and harmful learning curve. Studies confirming the possibility of a short and safe learning curve for laparoscopic hemihepatectomy could potentially benefit the further implementation of the technique. Objective: To evaluate the extent and safety of the learning curve for laparoscopic hemihepatectomy. Design, Setting, and Participants: A prospectively collected single-center database containing all laparoscopic liver resections performed in our unit at the University Hospital Southampton National Health Service Foundation Trust between August 2003 and March 2015 was retrospectively reviewed; analyses were performed in December 2015. The study included 159 patients in whom a total laparoscopic right or left hemihepatectomy procedure was started (intention-to-treat analysis), including laparoscopic extended hemihepatectomies and hemihepatectomies with additional wedge resections, at a tertiary referral center specialized in laparoscopic hepato-pancreato-biliary surgery. Main Outcomes and Measures: Primary end points were clinically relevant complications (Clavien-Dindo grade ≥III). The presence of a learning curve effect was assessed with a risk-adjusted cumulative sum analysis. Results: Of a total of 531 consecutive laparoscopic liver resections, 159 patients underwent total laparoscopic hemihepatectomy (105 right and 54 left). In a cohort with 67 men (42%), median age of 64 years (interquartile range [IQR], 51-73 years), and 110 resections (69%) for malignant lesions, the overall median operation time was 330 minutes (IQR, 270-391 minutes) and the median blood loss was 500 mL (IQR, 250-925 mL). Conversion to an open procedure occurred in 17 patients (11%). Clinically relevant complications occurred in 17 patients (11%), with 1% mortality (death within 90 days of surgery, n = 2). Comparison of outcomes over time showed a nonsignificant decrease in conversions (right: 14 [13%] and left: 3 [6%]), blood loss (right: 550 mL [IQR, 350-1150 mL] and left: 300 mL [IQR, 200-638 mL]), complications (right: 15 [14%] and left: 4 [7%]), and hospital stay (right: 5 days [IQR, 4-7 days] and left: 4 days [IQR, 3-5 days]). Risk-adjusted cumulative sum analysis demonstrated a learning curve of 55 laparoscopic hemihepatectomies for conversions. Conclusions and Relevance: Total laparoscopic hemihepatectomy is a feasible and safe procedure with an acceptable learning curve for conversions. Focus should now shift to providing adequate training opportunities for centers interested in implementing this technique.

Natural killer cell maturation markers in the human liver and expansion of an NKG2C+KIR+ population.

BACKGROUND: Selected populations of murine natural killer (NK) cells possess memory features to haptens, cytokines, and viruses. Liver-specific adhesion molecules CXCR6 and CD49a have been identified as surface markers in mice. In people, expansion of long-lived terminally differentiated NKG2C+ populations occur in the blood after viral infection. We aimed to compare intrahepatic and blood NK cell receptor expression to determine the existence of CD49a+ and CXCR6+ NK cells in human liver and define the maturation status of NKG2C+ NK cells at this site. METHODS: Tissue samples were taken from the liver margin of 39 patients with hepatic metastases and flushed with chelating buffer followed by collagenase or mechanical digestion. Paired peripheral blood samples were taken from 15 patients, the remainder being unpaired. Mononuclear cells were isolated by ficoll separation and cell surface staining performed for CD3, CD56, CD16, CD57, CD117, CD161, CD158a, CD158b, CD49a, CD49b, CXCR6, NKG2C, and NKp46. Statistical analysis to compare intrahepatic and blood NK cell receptor expression included the median, IQR, and Mann-Whitney U test. FINDINGS: Frequencies of NK cell precursors were similar in the liver and the blood (0·91% [0·62-3·26] vs 0·87 [0·41-1·52]); however, expression of all later markers of maturity were reduced including CD16 (47% [40·4-61·4] vs 88·7 [82·2-93·2], p<0·0001), CD57 (30·7% [25·0-53·9] vs 73·4 [70·4-87·6], p=0·0003), and KIR (11·2% [7·5-14·5] vs 26·7 [17·3-30·8], p<0·0001). Expanded hepatic CD16- NK cells were particularly immature with reduced CD57 and increased CD161 compared with the blood. NKG2C+ NK cells were found in similar frequencies in liver and blood. The hepatic NKG2C+ population was terminally differentiated, as in the circulation, but demonstrated a three-fold increase in KIR expression compared with NKG2C- counterparts, which was not seen in the blood. As in previously published research in mice, CD49a+ and CXCR6+ NK cells were liver resident (6·5% [3·9-14·6] liver vs 2·1 [1·3-4·3] blood, p<0·0001, and 65·3 [48·1-75·2] vs 4·5 [1·43-12·12], p=0·0039, respectively). Both populations were immature, with reduced KIR expression. INTERPRETATION: We have shown that the liver contains an expanded population of immature CD16- NK cells. These cells might traffic from the blood and then differentiate into hepatic-specific CD49a+ and CXCR6+ NK cells. The function of these subsets is unknown but their immaturity hints against memory. Terminally differentiated NKG2C+ cells show KIR expansion in the human liver and probably represent an antigen-experienced population, raising the question of whether the liver is a site of NK cell memory acquisition. FUNDING: MRC Clinical Research Fellowship.

Laparoscopic Parenchymal-Sparing Resections for Nonperipheral Liver Lesions, the Diamond Technique: Technical Aspects, Clinical Outcomes, and Oncologic Efficiency.

BACKGROUND: Surgical management of liver lesions has moved toward "parenchymal-sparing" strategies. Although open parenchymal-sparing liver resections are supported by encouraging results, the applicability of the laparoscopic approach for nonperipheral tumors is still questionable. Our aim was to assess the feasibility, safety, and oncologic adequacy of laparoscopic parenchymal-sparing liver resection for nonperipheral lesions with a description of the technique adopted in this setting. STUDY DESIGN: A prospectively collected single-center database of 517 laparoscopic liver resections was reviewed. Laparoscopic nonperipheral parenchymal-sparing liver resections (LapPSLRs), that is, entirely intraparenchymal limited resections performed on nonperipheral lesions, were selected. Intra- and perioperative outcomes were analyzed along with 3-year actuarial survival for patients with colorectal liver metastases. RESULTS: The group comprised 49 LapPSLRs. Colorectal liver metastases were the most frequent diagnosis (n = 24 patients). Lesions were located in segments 8, 7, 4a, and 3 in 51%, 8.2%, 36.7%, and 4.1% of cases, respectively. Conversion occurred in 4 patients (8%). Intra- and postoperative short-term outcomes were calculated for the 24 isolated LapPSLR (not associated with any concurrent liver resection). Median operative time and blood loss were 215 minutes and 225 mL, respectively. Pringle maneuver was used in 75% of cases. Postoperative 90-day mortality was nil and morbidity rate was 12.5%. Median postoperative stay was 3 days. Median tumor-free margin was 4 mm and 100% R0 rate was achieved for all LapPSLRs with curative intent. Three-year overall, recurrence-free, and disease-free survival rates were 100%, 65.2%, and 69.6%, respectively. CONCLUSIONS: Laparoscopic parenchymal-sparing liver resections for nonperipheral liver lesions are feasible and can be performed safely without compromising perioperative and oncological outcomes.

Pure laparoscopic liver resection for large malignant tumors: does size matter?

BACKGROUND: Laparoscopic liver resection (LLR) for large malignant tumors can be technically challenging. Data on this topic are scarce, and many question its feasibility, safety, and oncologic efficiency. This study aimed to assess outcomes of LLR for large (≥ 5 cm) and giant (≥ 10 cm) malignant liver tumors. METHODS: A prospectively collected database of 422 LLRs was reviewed from August 2003 to August 2013. The data for 52 patients undergoing LLR for large malignant tumors were analyzed. A subgroup analysis of giant tumors also is reported. RESULTS: During the period studied, 52 LLRs were performed (males, 53.8 %; mean age, 64.6 years) for large malignant tumors. Colorectal liver metastasis was the most common indication (42.3 %). The 52 LLRs included 32 major (61.5 %) and 20 minor (38.5 %) LLRs for tumors with a mean diameter of 83 mm. The median operative time was 240 min [interquartile range (IQR), 150-330 min], and the blood loss was 500 ml (IQR, 200-1,373 ml). Eight conversions (15.4 %) were performed. Six patients experienced complications (11.5 %). Among the 44 patients with successful LLRs, two patients (4.5 %) had an R1 resection. The median hospital stay was 5 days (range, 1-21 days), and no mortality occurred during a 90-day period. A subgroup analysis of patients with giant tumors showed greater blood loss (p = 0.002) and a longer operative time (p = 0.052) but no difference in terms of conversions (p = 0.64) or complications (p = 0.32). CONCLUSION: The findings showed that LLR is feasible and safe for large malignant tumors and can be performed with acceptable morbidity and oncologic efficiency. When used for giant malignant tumors, LLR is associated with greater blood loss and a longer operative time but no increase in complications.

Laparoscopic left pancreatectomy: current concepts.

The minimally invasive approach has been slow to gain acceptance in the field of pancreatic surgery even though its advantages over the open approach have been extensively documented in the medical literature. The reasons for the reluctant use of the technique are manifold. Laparoscopic distal or left sided pancreatic resections have slowly become the standard approach to lesions of the pancreatic body and tail as a result of evolution in technology and experience. A number of studies have shown the potential advantages of the technique in terms of safety, blood loss, oncological and economic feasibility, hospital stay and time to recovery from surgery. This review aims to provide an overview of the recent advances in the field of laparoscopic left pancreatectomy (LLP) and discuss potential future developments.

Aetio-pathogenesis and the management of spontaneous liver bleeding in the West: a 16-year single-centre experience.

BACKGROUND: Spontaneous liver bleeding (SLB) is a rare but potentially fatal complication. In contrast to the East, various benign pathologies are the source of SLB in the West. An accurate diagnosis and a timely implementation of appropriate treatment are crucial in the management of these patients. The present study presents a large Western experience of SLB from a specialist liver centre. METHODS: A retrospective analysis of patients presented with SLB between January 1995 and January 2011. RESULTS: Sixty-seven patients had SLB, 44 (66%) were female and the median age at presentation was 47 years. Abrupt onset upper abdominal pain was the presenting symptom in 65 (97%) patients. The aetiology for SLB was hepatic adenoma in 27 (40%), hepatocellular carcinoma (HCC) in 17 (25%) and various other liver pathologies in the rest. Emergency treatment included a conservative approach in 42 (64%), DSA and embolization in 6 (9%), a laparotomy and packing in 6 (9%) and a liver resection in 11 (16%) patients. Eleven (16%) patients had further planned treatments. Seven (10%) died during the same admission but the mortality was highest in patients with HELLP syndrome. At a median follow-up of 54 months all patients with benign disease are alive. The 1-, 3- and 5-year survival of patients with HCC was 59%, 35% and 17%, respectively. CONCLUSION: SLB is a life-threatening complication of various underlying conditions and may represent their first manifestation. The management should include initial haemostasis followed by appropriate staging investigations to provide a definitive treatment for each individual patient.

An international multicenter randomized controlled trial of G17DT in patients with pancreatic cancer.

OBJECTIVES: This study aimed to investigate G17DT, an immunogen producing neutralizing antibodies against the tumor growth factors amidated and glycine-extended forms of gastrin-17, in the treatment of pancreatic cancer. METHODS: A randomized, double-blind, placebo-controlled, group-sequential multicenter trial of G17DT in patients with advanced pancreatic cancer unsuitable for or unwilling to take chemotherapy. Inclusion criteria were a Karnofsky performance score of 60 or higher and a life expectancy of more than 2 months. Patients received G17DT or placebo emulsion at weeks 0, 1, 3, 24, and 52. The primary end point was survival, and secondary end points were tolerability, Karnofsky performance. RESULTS: A total of 154 patients were recruited: 79 G17DT and 75 placebo. A final analysis of the intention-to-treat population, using a proportional hazards model, stratifying by disease stage and adjusting for interim analysis, gave a hazard ratio for mortality of 0.75 (95% confidence interval, 0.51-1.10, P = 0.138; G17DT/placebo). A conventional analysis without adjustment for disease stage or interim analysis, censoring for chemotherapy and excluding protocol violators, gave median survival periods of 151 (G17DT) and 82 days (placebo) (log-rank test, P = 0.03).Patients developing anti-G17DT responses (73.8%) survived longer than nonresponders or those on placebo (median survival, 176 vs 63 vs 83; log-rank test, P = 0.003). G17DT was well tolerated.

Gastrin - active participant or bystander in gastric carcinogenesis?

Gastrin is a pro-proliferative, anti-apoptotic hormone with a central role in acid secretion in the gastric mucosa and a long-standing association with malignant progression in transgenic mouse models. However, its exact role in human gastric malignancy requires further validation. Gastrin expression is tightly regulated by two closely associated hormones, somatostatin and gastrin-releasing peptide, and aspects of their interaction may be deregulated during progression to gastric adenocarcinoma. Furthermore, agonists and antagonists of the receptors for all three hormones have shown modest clinical efficacy against gastric adenocarcinoma, which might provide useful information on the future combined use of these agents.