Phase I PIANO trial-PIPAC-oxaliplatin and systemic nivolumab combination for gastric cancer peritoneal metastases: clinical and translational outcomes.

INTRODUCTION: Pressurized intraperitoneal aerosol chemotherapy-oxaliplatin (PIPAC-OX) induces direct DNA damage and immunogenic cell death in patients with gastric cancer peritoneal metastases (GCPM). Combining PIPAC-OX with immune checkpoint inhibition remains untested. We conducted a phase I first-in-human trial evaluating the safety and efficacy of PIPAC-OX combined with systemic nivolumab (NCT03172416). METHODS: Patients with GCPM who experienced disease progression on at least first-line systemic therapy were recruited across three centers in Singapore and Belgium. Patients received PIPAC-OX at 90 mg/m2 every 6 weeks and i.v. nivolumab 240 mg every 2 weeks. Translational studies were carried out on GCPM samples acquired during PIPAC-OX procedures. RESULTS: In total, 18 patients with GCPM were prospectively recruited. The PIPAC-OX and nivolumab combination was well tolerated with manageable treatment-related adverse events, although one patient suffered from grade 4 vomiting. At second and third PIPAC-OX, respectively, the median decrease in peritoneal cancer index (PCI) was -5 (interquartile range: -12 to +1) and -7 (interquartile range: -6 to -20) and peritoneal regression grade 1 or 2 was observed in 66.7% (6/9) and 100% (3/3). Translational analyses of 43 GCPM samples revealed enrichment of immune/stromal infiltration and inflammatory signatures in peritoneal tumors after PIPAC-OX and nivolumab. M2 macrophages were reduced in treated peritoneal tumor samples while memory CD4+, CD8+ central memory and naive CD8+ T-cells were increased. CONCLUSIONS: The first-in-human trial combining PIPAC-OX and nivolumab demonstrated safety and tolerability, coupled with enhanced T-cell infiltration within peritoneal tumors. This trial sets the stage for future combinations of systemic immunotherapy with locoregional intraperitoneal treatments.

PIPAC nebulizer: How to test the new devices in the market, expert recommendations.

Pressurized intraperitoneal aerosol chemotherapy, named PIPAC, is now used in many centers around the world and as an intraperitoneal drug delivery system for treatment of peritoneal carcinomatosis. Recently, many of us have encountered problems during PIPAC procedures due to changes in material and production features of the original PIPAC nebulizer. Concomitantly, new PIPAC nebulizers proposed by other manufacturers are being launched on the market; which claim that they are the same as the original device in delivering PIPAC. However, these new devices are all different in terms of materials, technical characteristics and costs. We have considered that, to maintain the acquired results of PIPAC, we must ensure that the new systems are equivalent. The characteristics deemed essential by the expert group are as follows: 1: The nebulizer must be able to create droplets through an injector pressure between 10 and 20 bars, 2: The mean droplet size must be 3 micrometers, with 95% of the droplets between 0 and 10 micrometers, 3: The diffusion angle must be 70 degrees, which is the minimum.

Endoscopic ultrasonography for gastric cancer: does it influence treatment?

BACKGROUND: This study aimed to evaluate the utility and shortcomings of endoscopic ultrasound (EUS) in tumor node metastasis (TNM) staging of gastric cancer and its influence on treatment. METHODS: The series included 126 patients (65 men and 44 women) with gastric cancer who underwent EUS from July 1997 to June 2003 at the National University Hospital, Singapore. The final analysis included 109 patients ranging in age from 29 to 97 years (mean, 63.13 years). RESULTS: EUS staging for primary disease: Specimen histology was available for 102 of the 109 patients who underwent surgery. The accuracy was 79% for T1, 73.9% for T2, 85.7% for T3, and 72.7% for T4. The overall accuracy was 80.4%. EUS staging for nodes: The sensitivity of EUS for detecting nodal disease was 74.2% for N0, 78% for N1, 53.8% for N2, and 50% for N3. Overall, the N staging by EUS showed a sensitivity of 82.8%, a specificity of 74.2%, a positive predictive value of 85.4%, a negative predictive value of 70.2%, and an accuracy of 77.7%. Radical gastrectomy was proposed for 95 patients on the basis of the staging with EUS and computed tomography (CT) scan, and 87 patients (91.6%) underwent the surgery. Preoperative staging accurately predicted the operative strategy for 89% of the patients. No significant predictor for accuracy was achieved by performing a logistic regression analysis for the correct staging of T stage using EUS and adjusting for tumor location (middle part/distal third/whole stomach vs proximal/cardioesophageal) (p = 0.873), operator (p = 0.546), and subject's sequence (initial 50 vs last 50 cases) (p = 0.06). CONCLUSION: Ultrasound is the most accurate and reliable method for the preoperative staging of gastric carcinomas, and it is mandatory if a tailored therapeutic approach is planned according to stage.

Periampullary diverticulum: a case of bleeding from a periampullary diverticulum.

INTRODUCTION: Duodenal diverticula are uncommon and usually asymptomatic. Complications like bleeding, perforation and biliary fistulae are rare. The management of a bleeding duodenal diverticulum can be challenging. With the improvement of endoscopic techniques, many of the cases reported in the literature were managed with endoscopic methods. We present a case report of bleeding duodenal diverticulum. CLINICAL FEATURES: The patient was treated successfully with endoscopic haemostasis during her first epidsode when she initially presented with bleeding duodenal diverticulum, but recurred after 2 months. TREATMENT: Despite initial endoscopic haemostasis during her second episode, she rebled after 2 days, necessitating surgical management. OUTCOME: After suture ligation of the ulcer, the patient recovered and there was no more recurrence. CONCLUSION: Periampullary diverticulum is a rare source of gastrointestinal bleeding, which can be challenging to diagnose and treat. A multidisciplinary approach encompassing radiology, endoscopy and surgery is most effective.

Computed tomography of the thorax for gastric cancer staging: Is it necessary?

BACKGROUND: The utility of computed tomography scans of the thorax, abdomen, and pelvis for gastric cancer staging has been recommended in many countries. However, the validity of the use of computed tomography thorax in gastric cancer staging has not been challenged. METHODS: A retrospective review was conducted on our gastric cancer registry from 1998 till 2012 in the National University Hospital, Singapore. We performed computed tomography thorax only in selected cases. We defined isolated lung metastasis as the presence of suspicious findings on computed tomography thorax in the absence of metastasis elsewhere. RESULTS: A total of 808 gastric cancer cases were reviewed. The mean age of the patients was 66 years (standard deviation 13.53), and 67% were male. In all, 238 patients (30%) had metastatic disease at presentation, and 1 (0.42%) had isolated lung metastasis. The most common site of metastasis was intra-abdominal (73.8%). Among the patients who underwent surgery, the overall distant recurrence rate was 30%, of which only 83 (30%) patients had lung metastasis and all had concurrent metastasis in an intra-abdominal site. CONCLUSION: The rarity of isolated lung metastasis in gastric cancer suggests the limited value of computed tomography thorax as a routine staging tool for gastric cancers.

Robotic-assisted laparoscopic cholecystectomy.

We report a case of laparoscopic cholecystectomy that was performed using a robotic surgical system. A 70-year-old woman underwent laparoscopic robotic cholecystectomy ZEUS, the robotic system used in our study, has three interactive robotic arms fixed to the side of the operating table. The arms are controlled by the surgeon, who sits at a remote computer console. The surgeon's movements can be scaled down, and tremor is filtered out. The robotic-assisted laparoscopic cholecystectomy was completed in 42 min. The time to set up the robot was 22 mins. All of the surgically reproducible robotic maneuvers were performed without any particular difficulty. The robotic movements were stable, accurate, and reliable, as well as easy to control with precision. Our preliminary experience indicates that robotic laparoscopic cholecystectomy is safe and can be as fast as conventional laparoscopic cholecystectomy. However, further clinical applications of robotic surgery are needed to confirm this observation.

Ondansetron in the prevention of postoperative nausea and vomiting after laparoscopic cholecystectomy: a prospective randomized study.

BACKGROUND: There is an increased incidence of postoperative nausea and vomiting (PONV) after laparoscopic cholecystectomy. The aim of the study was to evaluate the efficacy of intravenous ondansetron, a 5-HT anatagonist, for prevention from PONV after laparoscopic cholecystectomy. METHODS: Sixty-eight patients were entered into the study. Thirty-six patients were randomized to receive a single intravenous dose of 4 mg of ondansetron before extubation. Thirty-two patients received no prophylaxis. There were no differences in terms of sex ratio, age, ASA status, and duration of operation between the two study groups. Patients were interviewed by an independent observer to assess the postoperative pain and nausea using visual analog score. Patients' satisfaction scores to the procedure were measured. RESULTS: There was no complication in the series. Pain scores at 2 and 24 h after operation and analgesics consumption were not different between the two groups. For the patients who received ondansetron, the mean (SD) nausea score at 2 and 24 h was 1.5 (1.2) and 1.4 (1.4), respectively. The score for the control group was 1.4 (1.0) and 1.2 (0.5), respectively. There was also no difference in episodes of vomiting and usage of antiemetics between the two groups. Both groups were equally satisfied with the procedures. CONCLUSION: Routine use of ondansetron does not reduce the incidence of postoperative nausea and vomiting after laparoscopic cholecystectomy.

Gastric adenocarcinoma occurring in a young patient with common variable immunodeficiency syndrome.

Patients with common variable immunodeficiency syndrome (CVID) have an increased risk of gastric adenocarcinoma. We describe a case of gastric adenocarcinoma in a 29-year-old man with CVID. He complained of dyspepsia and weight loss. Endoscopy showed an antral lesion. He underwent subtotal gastrectomy with postoperative adjuvant chemoradiation, and remained disease-free for three years. CVID is a predisposing factor for gastric adenocarcinoma. Gastric complaints are common among these patients and should be viewed seriously. Endoscopy is performed to detect any pathology. Premalignant conditions like chronic atrophic gastritis, intestinal metaplasia and dysplasia require regular endoscopic surveillance in these high-risk patients.

Total transvaginal endoscopic abdominal wall hernia repair: a NOTES survival study.

HYPOTHESIS: Natural orifice transluminal endoscopic surgery (NOTES) has gained widespread interest as a potentially less invasive alternative to laparoscopic surgery or, else, an evolution as the next-generation surgery. The main objective of this study was to assess the safety of transluminal abdominal wall hernia repair for potential human application by specifically investigating the feasibility and challenges of using a transvaginal approach. DESIGN: NOTES ventral hernia repair via a transvaginal approach. SETTING: University Hospital (National University Health System, Singapore). PARTICIPANTS: The study utilized five female pigs (30-40 kg) between 5 and 7 months of age, which underwent abdominal wall hernia repair using a transvaginal approach. INTERVENTION: The procedures were performed using a double-channel endoscope under general endotracheal anesthesia. A mesh was placed and fixed to the abdominal wall using standard laparoscopic and endoscopic equipment. The animals survived for 2 weeks and were then euthanized and a necropsy performed. MAIN OUTCOME MEASURES: To assess the safety and feasibility of NOTES ventral hernia repair in a survival experimental model. RESULTS: All of the procedures could be safely performed using the standard equipment. At the necropsy, all meshes were well in place and mild adhesions were recorded in one animal with a small abscess in the subcutaneous area. CONCLUSION: This novel approach seems technically challenging but feasible using equipment and accessories currently available for conventional laparoscopic and interventional endoscopy with low intra-abdominal contamination and sepsis. New procedure-specific instruments and equipment need to be developed to allow the surgeon safer access and more degrees of instrument freedom.

Diagnostic laparoscopy in the evaluation of right lower abdominal pain: a one-year audit.

INTRODUCTION: Acute appendicitis is the commonest cause for right lower abdominal pain. Clinical features, laboratory and imaging investigations are either not very sensitive or specific, and neither is therapeutic. We aimed to define the role of diagnostic laparoscopy in patients with right lower abdominal pain. METHODS: Data was collected retrospectively from January 1, 2005 to December 31, 2005. Patients admitted to the Emergency Department and subsequently transferred to the Department of Surgery, National University Hospital, Singapore, with right lower abdominal pain and who eventually underwent diagnostic laparoscopy were evaluated. RESULTS: 691 patients with right lower abdominal pain were admitted with suspected diagnosis of appendicitis. Diagnostic laparoscopy was undertaken in 103 patients aged 17-71 years old. Of the 83 females, 78 (94 percent) were premenopausal . Histology-proven acute appendicitis was diagnosed in 78 (75.7 percent) patients. Interestingly, within this group, 25.6 percent had other concomitant pathologies found on laparoscopy. 25 patients had a normal appendix; gynaecological causes accounted for pain in 15 of these 25 (60 percent) cases. In four (3.9 percent) patients, no pathology was found. Complication rate was 1.9 percent, which included ileus in two patients. In 32 (31.1 percent) patients, diagnostic laparoscopy altered the management plan, requiring either intervention or care by a subspecialty. CONCLUSION: Diagnostic laparoscopy is useful in evaluating patients with right lower abdominal pain, especially in those with equivocal signs of acute appendicitis. It also has the additional benefit of being therapeutic. Premenopausal women benefit the most from this procedure.

Outcomes of adjuvant chemoradiotherapy after a radical gastrectomy and a D2 node dissection for gastric adenocarcinoma.

PURPOSE: Intergroup 0116 (INT-0116) established adjuvant chemoradiation as the standard of care for resected high-risk adenocarcinoma of the stomach in the United States. However, adjuvant chemoradiation remains controversial in many parts of Asia and Europe, where patients tend to undergo a more thorough D2 dissection. In INT-0116, 90% of patients had a limited or inadequate node dissection (D0 or D1). Also, 17% of patients in the chemoradiation arm had to discontinue treatment because of toxicities. The objectives of this retrospective study are to report the clinical outcomes of a cohort of patients who were mostly treated with a D2 node dissection and received adjuvant chemoradiation as per INT-0116, and the toxicities of chemoradiation in the context of more aggressive surgery. METHODS: After the results of INT-0116 became apparent, we adopted an institutional policy whereby patients who would otherwise fit the inclusion criteria of INT-0116 received adjuvant chemoradiation. Between March 1999 and November 2004, 70 consecutive patients with pathologic stage T3, T4, or node-positive disease were treated according to the chemoradiation arm of INT-0116. Patients received intravenous 5-fluorouracil 425 mg/m and leucovorin 20 mg/m in cycles 1, 3, and 4. Concurrent chemoradiation was given in cycle 2 and consisted of bolus 5-fluorouracil and leucovorin and radiotherapy (45 Gy over 25 fractions in 5 weeks). All patients were operated on by dedicated Japan-trained Surgical Oncologists. RESULTS: Sixty-seven patients (96%) had a D2 nodal dissection. Sixty-five patients (93%) had negative pathologic margins (R0 resection) and 5 (7%) had microscopically involved margins (R1 resection). The median follow-up was 27 months (range, 10.1-60.3). The 3-year overall survival, disease-free survival, and local control were 60.6%, 54.1%, and 84.3%, respectively. Of the 30 patients who relapsed, 5 (17%) had isolated locoregional recurrences only. The National Cancer Institute--Common Terminology Criteria version 3.0 acute grade 3 or 4 gastrointestinal and hematological toxicity rates were 15.7% and 4.3%, respectively. Toxicities led to chemotherapy dose-reductions in 18 patients and dose-delay in 19 patients. Including chemotherapy dose-reductions and delays, 66 patients (94%) completed the entire chemoradiation regimen. There were no toxicity-related deaths. CONCLUSION: In our cohort of 70 patients who had a more thorough D2 node dissection, adjuvant chemoradiation was well tolerated with acceptable toxicities and reasonable tumor control.

Endoscopic screening for gastric cancer.

BACKGROUND & AIMS: Population endoscopic screening for gastric cancer is generally deemed not to be cost-effective except in Japan, where its prevalence is very high. However, in the absence of screening, patients present with advanced disease, and prognosis is poor. We conducted a cost utility analysis to determine whether endoscopic screening for stomach cancer in intermediate-risk population would be cost-effective and to better define the high-risk groups in the population who would benefit from such strategy. METHODS: Cost-effectiveness analysis was performed by using a Markov Model. Simulation was performed on Singapore (intermediate-risk) population and various high-risk subgroups. Comparison was made between 2-yearly endoscopic mass screening program versus no screening. Data sources were extracted from relevant studies published from 1980-2004 identified via systematic PUBMED search. Main outcome measures were deaths caused by stomach cancer averted, cost per life saved, and incremental cost-effectiveness ratio expressed as cost per quality-adjusted life year (QALY) saved. RESULTS: Screening of high-risk group of Chinese men (age-standardized rate, 25.9/100,000) from 50-70 years old is highly cost-effective, with cost benefit of United States $26,836 per QALY. Screening this cohort of 199,000 subjects prevents 743 stomach cancer deaths and saves 8234 absolute life years. Cost of averting 1 cancer death is United States $247,600. Cost-effectiveness was most sensitive to incidence of stomach cancer and cost of screening endoscopy. CONCLUSIONS: Screening of stomach cancer in moderate to high-risk population subgroups is cost-effective. Targeted screening strategies for stomach cancer should be explored.