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.

Comparing T2 and T2-T3 ablation in thoracoscopic sympathectomy for palmar hyperhidrosis: a randomized control trial.

BACKGROUND: Thoracoscopic sympathectomy is a useful therapeutic option for palmar hyperhidrosis. Surgeons differ in the level of the sympathetic chain ablated. This study aimed to compare the blockade of the T2 with levels T2 and T3 to verify the effectiveness of different ablation levels in relieving hyperhidrosis symptoms. METHODS: For patients undergoing bilateral thoracoscopic sympathectomy for palmar hyperhidrosis, T2-T3 ablation is performed bilaterally. In our series, 25 consecutive patients were blindly randomized to undergo unilateral T2 and T3 ablation followed by contralateral ablation of level T2 only. The patients were followed up and analyzed for comparison of symptoms bilaterally, compensatory hyperhidrosis, and levels of satisfaction postoperatively. RESULTS: The study group consisted of 25 patients with a male:female ratio of 3:2 and a mean age of 32 years (range, 19-50 years). The mean operative time was 35 min. The patients were followed up for a mean period of 23 months (range, 2-65 months). All 25 patients confirmed that their palmar sweating resolved postoperatively, with both palms equally dry. Of the 25 patients, 20 (80%) complained of compensatory hyperhidrosis, which also was bilaterally symmetric. The areas involved were trunk (80%), lower limbs (32%), and armpits (12%). Overall, 80% of the patients were very satisfied with the procedure. The remaining 20% experienced mild to moderate compensatory hyperhidrosis, which did not seem to affect their lifestyle. CONCLUSION: The findings show that T2 ablation in thoracoscopic sympathectomy for palmar hyperhidrosis is as effective as T2-T3 ablation in terms of symptomatic relief, recurrence, compensatory hyperhidrosis, and patient satisfaction.

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.

Development of an E-learning System for the Endoscopic Diagnosis of Early Gastric Cancer: An International Multicenter Randomized Controlled Trial.

BACKGROUND: In many countries, gastric cancer is not diagnosed until an advanced stage. An Internet-based e-learning system to improve the ability of endoscopists to diagnose gastric cancer at an early stage was developed and was evaluated for its effectiveness. METHODS: The study was designed as a randomized controlled trial. After receiving a pre-test, participants were randomly allocated to either an e-learning or non-e-learning group. Only those in the e-learning group gained access to the e-learning system. Two months after the pre-test, both groups received a post-test. The primary endpoint was the difference between the two groups regarding the rate of improvement of their test results. FINDINGS: 515 endoscopists from 35 countries were assessed for eligibility, and 332 were enrolled in the study, with 166 allocated to each group. Of these, 151 participants in the e-learning group and 144 in the non-e-learning group were included in the analysis. The mean improvement rate (standard deviation) in the e-learning and non-e-learning groups was 1·24 (0·26) and 1·00 (0·16), respectively (P<0·001). INTERPRETATION: This global study clearly demonstrated the efficacy of an e-learning system to expand knowledge and provide invaluable experience regarding the endoscopic detection of early gastric cancer (R000012039).

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.

Outcomes of atypical symptoms attributed to gastroesophageal reflux treated by laparoscopic fundoplication.

BACKGROUND: The introduction of laparoscopic fundoplication (LF) has lowered the threshold for operation in patients with symptoms attributed to gastroesophageal reflux. We sought to determine whether the outcomes in patients referred for atypical symptoms (pulmonary, pharyngolaryngeal, and pain syndromes) were as good as those referred for correction of heartburn and regurgitation (typical symptoms). METHODS: Thirty-five of 150 consecutive patients undergoing LF with a minimum of 12 months of follow-up were referred primarily for correction of atypical symptoms. A standard preoperative evaluation included endoscopy, manometry, upper gastrointestinal contrast radiography, and 24-hour pH probe testing (33 of 35 patients with atypical symptoms). Patients completed a symptom questionnaire administered by a study nurse before the operation and 3 and 12 months after the operation. Symptoms were scored from 0 to 10. RESULTS: Heartburn was relieved by LF in 93% of patients, whereas only 56% of patients had relief of atypical symptoms. Furthermore, the degree of improvement in typical symptoms was greater than that seen for atypical symptoms as measured by the 0 to 10-symptom rating score (improvement in typical symptoms = 6.2 vs improvement in atypical symptoms = 4.4 [p = 0.01]). The response rate for laryngeal, pulmonary, and epigastric/chest pain symptoms was 78%, 58%, and 48%, respectively. Analysis of factors associated with relief of atypical symptoms revealed that response to a preoperative trial of omeprazole or H2-blockers was significantly associated with successful surgical outcome (p = 0.03). Six of seven patients with laryngeal symptoms who had acid reflux above the cricopharyngeal level shown by dual-probe pH testing had relief of the symptoms after LF. Manometric findings (amplitude of esophageal body contractions, propagation of contractions, and lower esophageal sphincter resting pressure) neither predicted nor correlated with relief of atypical symptoms after the operation. CONCLUSIONS: Relief of atypical symptoms attributed to gastroesophageal reflux by LF is less satisfactory and more difficult to predict than relief of heartburn and regurgitation. The only useful preoperative predictors of relief of atypical symptoms in this study were the response to pharmacologic acid suppression and dual-probe pH testing (only in patients with laryngeal symptoms).

Robotically assisted laparoscopic cholecystectomy: a pilot study.

HYPOTHESIS: Since the advent of laparoscopic surgery in 1987 and the introduction of robotics into medicine in 1991, medical technology has advanced to robotic applications in performing surgery. In our study, we investigated the feasibility of performing simple laparoscopic maneuvers and laparoscopic cholecystectomy using a robotic surgical system. DESIGN: The study used a ZEUS robotic system (Computer Motion Inc, Goleta, Calif), consisting of 3 interactive robotic arms fixed at the operating table and remotely controlled by the surgeon. After initial training, using a bench model and 3 isolated porcine livers to perform cholecystectomy, 7 female pigs underwent robotically assisted laparoscopic cholecystectomy. The surgeon, seated at the console, manipulated the 3-mm laparoscopic instruments and performed the surgery. RESULTS: Robotically assisted laparoscopic cholecystectomy was accomplished in all 7 pigs, with a mean operative time of 46 minutes (range, 30-62 minutes). There were no complications. The mean time to setup of the robotic system decreased from 30 minutes to 14 minutes. All the robotic maneuvers were performed without any particular difficulties, and the movements were stable, accurate, and reliable, with good control. CONCLUSIONS: Our preliminary experimental study showed that robotically reproduced laparoscopic maneuvers, such as tying, suturing, dissection, clipping, and cautery, seemed to be as accurate and as fast as maneuvers made without robotics. We conclude that our initial experimental and animal study confirmed the feasibility of robotically assisted laparoscopic cholecystectomy. Further reports are needed to show that robotics can be used for clinical applications in surgery.

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.

Use of laparoscopy in the management of mesenteric venous thrombosis.

Mesenteric vein thrombosis is a relatively rare cause of intestinal ischemia. We present a case of idiopathic superior mesenteric and portal vein thrombosis, which was not associated with any infarcted bowel. The patient was treated successfully with anticoagulation using low-molecular weight heparin and warfarin, and did not require bowel resection. This case highlights the value of diagnostic laparoscopy for assessing intestinal viability in this situation, showing how it avoids the morbidity and complications associated with a formal laparotomy.

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.

Thoracolaparoscopic repair of traumatic diaphragmatic rupture.

Diaphragmatic rupture may occur after blunt or penetration trauma caused by the application of a powerful external force. Diaphragmatic rupture usually is repaired via laporotomy and/or thoracotomy, depending on the associated organ injury. The case of a 49-year-old man with traumatic rupture of the left hemidiaphragm is presented. Preoperatively, diaphragmatic rupture with herniation of the stomach into the left thoracic cavity was confirmed by computed tomography scan of the thorax. Under thoracoscopic guidance, the stomach, spleen, and omentum were repositioned in the abdominal cavity, and the rupture site (10 cm) was closed by nonabsorbable suture. A subsequent laparoscopy was performed to assess the efficacy of the repair and the absence of any abdominal organ injury. The patient was discharged from hospital without any respiratory or abdominal symptoms. Our report confirms that in the case of a patient with penetration injuries to the lower chest and upper abdomen, a combined thoracoscopic and laparoscopic approach may offer both diagnostic and therapeutic benefits with reduced surgical trauma. We conclude that thoracoscopic repair of traumatic diaphragmatic rupture can be used safely when no abdominal organ injuries are found.

Right-sided colonic diverticular disease as a source of lower gastrointestinal bleeding.

Right-sided colonic diverticular disease is a distinct disease entity uncommon in the West. Occasionally, the condition may be complicated by hemorrhage and present as lower gastrointestinal bleeding. We report a series of 25 cases of bleeding right colon diverticulosis and discuss its presentation and management. Patients were selected from the colonoscopic reports of all 190 patients presented with suspected acute lower gastrointestinal bleeding in National University Hospital, Singapore, from 1988 to 1994. Fifty-seven patients (30%) had bleeding diverticulosis in which 25 patients (44%) suffered from right-sided disease. Sixty-four per cent of patients had a history of hypertension. Patients presented with either fresh blood in stools or melena. Fifteen patients (60%) required blood transfusion (median, 2 units). Colonoscopy showed blood clots in the right colon in 15 cases (60%) and active bleeding from the right colon diverticula in 3 patients (12%). The bleeding stopped spontaneously in 16 patients (64%). The other 9 patients required surgery because of continuous or recurrent bleeding. All had a right hemicolectomy performed. The hospital stay was 13 days in this group, compared with 5 days for those undergoing conservative treatment (P = 0.0004). There were no deaths. No patients had further bleeding episodes during a median 7-month follow-up.

Early experience with laparoscopic radical gastrectomy for advanced gastric cancer.

Use of the laparoscopic approach for the management of gastric cancer is still in the developmental phase. The authors present their experience with laparoscopic radical gastrectomy for advanced gastric cancer. Between September 1997 and August 1999, four laparoscopic gastrectomies for gastric carcinoma were performed on two male and two female patients (mean age, 61.5 years). One D2 total radical gastrectomy and three D2 subtotal distal gastrectomies were performed, using a totally laparoscopic approach. Mean operative time was 210 minutes. There were no intraoperative complications. All four patients recovered uneventfully from surgery and began oral feeding on the third postoperative day. Median postoperative stay was 7 days (range, 6-9). All patients were alive 8 months to 3 years after the operation, with no cancer recurrences. This series shows that laparoscopic radical gastrectomy for moderately advanced cancers can produce good results in terms of safety and oncologic adequacy.

Experience of percutaneous endoscopic gastrostomy at Massachusetts General Hospital--indications and complications.

BACKGROUND: Percutaneous Endoscopic Gastrostomy (PEG) is a relatively new method to deliver nutrition to patients with inadequate caloric intake who have a functionally intact gastrointestinal tract. METHODS: This is a retrospective review of 58 consecutive patients who were referred to the Surgical Endoscopy Unit, Massachusetts General Hospital for placement of PEG in 1996. The current indications, methods, and results of PEG will be discussed. RESULTS: Of this series, all but one patient had the PEG successfully placed. Indications included head and neck cancer (29 patients); neurological disorders (21 patients); burns (3 patients); respiratory failure (2 patients), and aspirations (2 patients). Fifty-four percent of cases were performed with local anaesthesia. There was one complication (2%) with no procedural-related mortality. CONCLUSION: PEG is an easy and safe procedure. It is a good alternative to provide enteral feeding in selected patients.

Endoscopic extraperitoneal inguinal hernia repair: a series of 182 repairs.

INTRODUCTION: The local experience of endoscopic totally-extraperitoneal hernia repair in a major teaching hospital is reviewed. METHODS: Between 1997 and 2003, 141 consecutive patients underwent 182 totally-extraperitoneal hernia repairs for inguinal hernia. 100 patients had unilateral hernia and 41 patients had bilateral hernias. The mean age was 51 years (range 20 to 83 years). RESULTS: The mean operation duration was 70 minutes. Bilateral repairs took 24 percent longer than for unilateral repairs (82 versus 66 minutes). However, the mean operative duration for the last 55 (30 percent) cases decreased to 55 minutes. Four patients (2.8 percent) had conversion to open surgery and ten patients had minor complications, mostly groin seroma that resolved. Overall, there were seven hernia recurrences (3.8 percent) in the series. However, no hernia recurrence was present in the last 63 patients (45 percent). Recurrences were higher when the mesh was not anchored than when the mesh was fixed with a tacking device (p value is less than 0.01). The mean inpatient hospital stay was 1.4 days. Of the last 30 patients (21 percent), 70 percent were performed as outpatients. CONCLUSION: Endoscopic extraperitoneal hernia repair offers the appropriate patient a viable alternative to open hernia surgery. To achieve good results, adequate cases should be performed to overcome the learning curve, and the mesh should be anchored to the inguinal floor to prevent recurrences.

In vivo diagnosis of esophageal cancer using image-guided Raman endoscopy and biomolecular modeling.

The aim of this work was to evaluate the biochemical foundation and clinical merit of multimodal image-guided Raman endoscopy technique for real-time in vivo diagnosis of cancer in the esophagus during clinical endoscopic examinations. A novel fiber-optic Raman endoscopy system was utilized for in vivo esophageal Raman measurements at 785 nm laser excitation within 0.5 second under the multimodal wide-field endoscopic imaging (white light reflectance (WLR) imaging, narrow-band imaging (NBI) and autofluorescence imaging (AFI) guidance. A total of 75 esophageal tissue sites from 27 patients were measured, in which 42 in vivo Raman spectra were from normal tissues and 33 in vivo Raman spectra were from malignant tumors as confirmed by histopathology. The biomolecular modeling (non-negativity-constrained least-squares minimization (NNCLSM) utilizing six basis reference spectra from the representative biochemicals (i.e., actin, collagen, DNA, histones, triolein and glycogen) were employed to estimate the biochemical compositions of esophageal tissue. The resulting diagnostically significant fit coefficients were further utilized through linear discriminant analysis (LDA) and leave-one tissue site-out, cross validation method to develop diagnostic algorithms for esophageal cancer diagnosis. High-quality in vivo Raman spectra in the range of 800-1800 cm-1 can be acquired from normal and cancerous esophageal mucosa in real-time under multimodal endoscopic imaging guidance. Esophageal cancer tissue showed distinct Raman signals mainly associated with cell proliferation, lipid reduction, abnormal nuclear activity and neovasculation. The fit coefficients for actin, DNA, histones, triolein, and glycogen were found to be most significant for construction of the LDA diagnostic model, giving rise to an accuracy of 96.0% (i.e., sensitivity of 97.0% and specificity of 95.2%) for in vivo diagnosis of esophageal cancer. This study demonstrates that multimodal image-guided Raman endoscopy technique in conjunction with biomolecular modeling has promising potential for the real-time, in vivo diagnosis and detection of esophageal cancer during clinical endoscopic examination.