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Background: No evidence currently exists characterising global outcomes following major cancer surgery, including esophageal cancer. Therefore, this study aimed to characterise impact of high income countries (HIC) versus low and middle income countries (LMIC) on the outcomes following esophagectomy for esophageal cancer.Method: This international multi-center prospective study across 137 hospitals in 41 countries included patients who underwent an esophagectomy for esophageal cancer, with 90-day follow-up. The main explanatory variable was country income, defined according to the World Bank Data classification. The primary outcome was 90-day postoperative mortality, and secondary outcomes were composite leaks (anastomotic leak or conduit necrosis) and major complications (Clavien-Dindo Grade III - V). Multivariable generalized estimating equation models were used to produce adjusted odds ratios (ORs) and 95% confidence intervals (CI95%).Results: Between April 2018 to December 2018, 2247 patients were included. Patients from HIC were more significantly older, with higher ASA grade, and more advanced tumors. Patients from LMIC had almost three-fold increase in 90-day mortality, compared to HIC (9.4% vs 3.7%, p < 0.001). On adjusted analysis, LMIC were independently associated with higher 90-day mortality (OR: 2.31, CI95%: 1.17-4.55, p = 0.015). However, LMIC were not independently associated with higher rates of anastomotic leaks (OR: 1.06, CI95%: 0.57-1.99, p = 0.9) or major complications (OR: 0.85, CI95%: 0.54-1.32, p = 0.5), compared to HIC.Conclusion: Resections in LMIC were independently associated with higher 90-day postoperative mortality, likely reflecting a failure to rescue of these patients following esophagectomy, despite similar composite anastomotic leaks and major complication rates to HIC. These findings warrant further research, to identify potential issues and solutions to improve global outcomes following esophagectomy for cancer.

Background: Use of long-term PI-based therapy can improve outcomes across treatment settings in MM. However, there are various physical, geographical, and/or socioeconomic barriers to prolonged therapy with parenteral PIs in community practice. The US MM-6 study (NCT03173092) is assessing in-class transition (iCT) from parenteral bortezomib (V)-based induction to all-oral ixazomib-based therapy with ixazomib-lenalidomide-dexamethasone (IRd) in the diverse US community population. The objective of the study is to increase the duration of PI-based treatment, while maintaining quality of life and improving outcomes. We previously reported efficacy and safety results for the first 101 US MM-6 patients (Girnius Blood 2020). Here we have analyzed updated data for this patient subset with an additional 11 months of follow-up to further evaluate efficacy and safety, and to determine reasons for premature (within 4 cycles of IRd) discontinuation. Methods: Transplant-ineligible/delayed-transplant (≥24 months) NDMM patients at US community sites, who had achieved stable disease or better after 3 cycles of V-based induction, received IRd (ixazomib 4 mg, days 1, 8, 15; lenalidomide 25 mg, days 1-21; dexamethasone 40 mg, days 1, 8, 15, 22) for up to 39 × 28-day cycles or until disease progression or unacceptable toxicity. The primary endpoint is 2-year progression-free survival (PFS). Rates of partial response (PR), very good PR (VGPR), and complete response (CR), and duration of therapy are key secondary endpoints. For the current analysis, sites with patients who discontinued US MM-6 were queried for more detailed information. Results: As of June 1, 2020, 101 patients had been enrolled and treated at 21 sites. Median age was 73 years (range, 48-90 years), with 81% aged >65 years; 97% had ≥1 comorbidity at the start of IRd therapy. Efficacy data after an additional 11 months of follow-up (data cut-off: May 4, 2021) showed that iCT to IRd improved responses (Table 1). Overall response rate (ORR) had improved from 65% (CR 9%, VGPR 25%, PR 32%), at the end of 3 cycles of V-based induction, to 78% (molecular CR [mCR] 1%, stringent CR [sCR] 3%, CR 32%, VGPR 25%, PR 17%) following iCT to IRd. Thirty-three patients (33%) were still ongoing on therapy at the latest data cut-off; median duration of IRd was 11.7 months and overall median duration of therapy (for all PI-based therapy, including V-based induction) was 14.6 months. At a median follow-up of 18.5 months, the 18-month PFS rate was 84%. The safety profile of IRd was consistent with previous clinical studies. Grade ≥3 treatment-emergent adverse events (TEAEs) were reported in 64% of patients and treatment-related serious TEAEs in 12% (including 4 on-study deaths), while 16% of TEAEs led to study drug discontinuation. Sixty-eight patients (67%) had completed or discontinued the study since first patient enrolment on November 15, 2017. Among these patients, 14 (21%) discontinued within 2 cycles of IRd and 27 (40%) discontinued within 4 cycles; reasons for discontinuation are presented in Table 2. Conclusions: With longer follow-up, use of iCT from V-based induction to IRd to achieve long-term PI-based therapy in NDMM patients demonstrates efficacy via improved response rates and acceptable PFS in this real-world setting. Over 80% of US MM-6 patients were aged >65 years and most had ≥1 comorbidity prior to study entry. The rate of patients discontinuing within 4 cycles of iCT (7 cycles of PI-based therapy in total) is concerning because these patients may not receive the full benefit of long-term PI-based treatment. To date, the majority of premature discontinuations were reported as being due to patient request (44%) followed by TEAEs (30%). Expanded site education and closer patient follow-up to reduce premature discontinuations will be addressed in the planned US MM7 iCT study in relapsed/refractory MM. Figure 1 Figure 1. Disclosures Rifkin: Coherus: Membership on an entity's Board of Directors or advisory committees; Fresenius-Kabi: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; McKesson: Current Employment, Current equity holder in publicly-traded company; Amgen: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb (Celgene): Membership on an entity's Board of Directors or advisory committees. Noga: Takeda Oncology: Current Employment. Girnius: Beigene: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Honoraria, Speakers Bureau; Genentech: Honoraria; Celgene: Speakers Bureau; BMS: Honoraria, Speakers Bureau. Bogard: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Manda: Morphosys: Honoraria; Genmab: Current equity holder in publicly-traded company. Yimer: Texas Oncology: Current Employment; Pharmacyclics: Speakers Bureau; Amgen: Speakers Bureau; Sanofi: Speakers Bureau; GSK: Speakers Bureau; Beigene: Speakers Bureau; Janssen: Speakers Bureau; Astrazeneca: Speakers Bureau; Karyopharm: Current equity holder in publicly-traded company, Speakers Bureau. Whidden: Takeda Oncology: Current Employment. Birhiray: Bayer: Honoraria; Incyte: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Seattle Genetics: Honoraria; Coheris: Honoraria; Kyte Pharma: Honoraria; Celgene: Honoraria; Helsin: Honoraria; Amgen: Honoraria, Speakers Bureau; Pfizer: Speakers Bureau; BMS: Speakers Bureau; Tessaro: Speakers Bureau; AstraZeneca: Speakers Bureau; Alexion: Consultancy; Abbvie: Consultancy, Honoraria; Lilly: Speakers Bureau; Exelexis: Speakers Bureau; Clovis Oncology: Speakers Bureau; Sanofi Oncology: Speakers Bureau; Genomic Health: Speakers Bureau; Puma: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Jansen Bioncology: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Twumasi-Ankrah: Takeda: Current Employment. Guo: Takeda Oncology: Current Employment. Bernal-Mizrachi: Kodikaz Therapeutic Solutions: Consultancy, Current holder of individual stocks in a privately-held company, Patents & Royalties; Bigene: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Winship Cancer Institute of Emory University: Current Employment. OffLabel Disclosure: Real-world evaluation of long-term use of the oral proteasome inhibitor ixazomib in combination with lenalidomide and dexamethasone for the treatment of newly diagnosed multiple myeloma in non-transplant patients with stable disease after 3 cycles of a bortezomib-based induction

AUY922 is an inhibitor of heat shock protein 90 (Hsp90). Hsp90 inhibitors induce kit degradation in preclinical gastrointestinal stromal tumor (GIST) models. This trial was designed to determine the progression-free survival (PFS) of patients with GIST refractory to or intolerant of imatinib and sunitinib.Eligible patients received AUY922 70 mg/mg(2) by intravenous (IV) infusion on days 1, 8, and 15 of 21-day cycles. Treatment continued until progression or unacceptable toxicity.Between December 2011 and January 2015, 25 patients were enrolled (median age, 63 years; 56% male) and received a median of 2 cycles (range: 1-12) of AUY922 treatment. Thirty-four patients were planned, but enrollment was stopped early due to slow accrual. Median PFS was 3.9 months (95% CI: 2.5, 5.3) and median OS was 8.5 months (95% CI: 5.2, 16.7). Radiographic response was evaluated in 21 patients; one patient achieved PR (4%) with another 15 having best response of stable disease (60%). The most common treatment-related adverse event was diarrhea (60% all grades). Reversible ocular toxicities that resulted in drug hold (24%) or reduction (8%) were also observed.AUY922 produced a median PFS which compares favorably to historical controls of placebo (6 weeks) for patients refractory to treatment with imatinib. While diarrhea and ocular toxicities were common, the majority of patients received treatment until disease progression.

The safety and efficacy of laparoscopic splenectomy in the management of benign hematologic diseases is well established. However, most consider the laparoscopic approach to splenectomy in trauma patients contraindicated. We present a 76-year-old Jehovah's Witness who sustained a blunt abdominal trauma, rib fractures, and grade III splenic injury. She continued to lose blood, albeit slowly, for which she underwent preemptive urgent laparoscopic splenectomy with the use of the red cell saver. The operating time was 65 minutes. She was discharged on the 16th postoperative day after recovering from fractured ribs with subsequent pulmonary atelectasis and basal pneumonia. Whereas the majority of grade I to III splenic injuries in adults can be managed conservatively, some 20% will fail and require emergency splenectomy for delayed rupture of the spleen. In a Jehovah's Witness patient, early splenectomy for injury with the use of red cell saver is advised. This may be accomplished laparoscopically in the hemodynamically noncompromised patient.

Advancements in surgical technique and technology have facilitated safe laparoscopic liver resection in selected patients. The aim of this study is to evaluate the feasibility and outcome of laparoscopic liver resection. Patients with lesions situated in the anterior and left lateral segments were selected for laparoscopic resection. Data were collected prospectively. Between 2003 and 2007, 24 patients (12 males) with a median (range) age of 65 (30–83) years underwent 24 laparoscopic hepatic resections for presumed colorectal metastases (n = 20) and other indications (n = 4). The resections included left hepatic lobectomy (n = 14), other resections of two or three segments with or without metastasectomy (n = 5), left hemihepatectomy (n = 2) and unisegmentectomy (n = 3). All procedures were completed laparoscopically. Median operating time was 155 min. Estimated median (range) blood loss was 100 (25–1100) ml and one patient received two units blood transfusion. The operative morbidity rate was 4%, and there were no operative deaths. The median (range) postoperative hospital stay was 3 (1–14) days. At median (range) follow-up of 13.5 (5–36) months, 4 patients (21%) had disease recurrence and 17 patients (89%) remained alive. In selected patients with lesions in the anterior and left lateral segments, laparoscopic liver resection is feasible, achieves adequate cancer resection and is associated with smooth and rapid recovery. Long-term follow-up data are required for oncological results.

We evaluated the safety and feasibility of delayed urgent laparoscopic cholecystectomy (LC) performed beyond 72 hours to overcome the logistical difficulties in performing early urgent LC within 72 hours of admission with acute cholecystitis (AC), and to avoid earlier readmission with recurrent AC in patients awaiting delayed interval. Patients admitted with AC were scheduled for urgent LC. Patients who underwent early urgent LC were compared with those who had delayed urgent surgery. Fifty consecutive patients underwent urgent LC for AC within 2 weeks of admission. There were no conversions and no bile duct injuries. Delayed surgery (n = 36) neither prolonged operating time (90 vs 85 minutes), nor increased operative morbidity (9.7% vs 7.7%) or mortality (2.4% vs 7.7%) compared with early surgery (n = 14). Although delayed surgery was associated with shorter postoperative hospital stay (1 vs 2 days, P = 0.029), it prolonged total hospital stay (9 vs 5 days, P < 0.0001). Delay of LC beyond 72 hours neither increases operative difficulty nor prolongs recovery. It might be more cost effective to schedule patients who could not undergo early urgent LC but are responding to conservative treatment for an early interval LC within 2 weeks of presentation with AC.

Laparoscopic bypass surgery for the palliation of gastric and biliary obstruction is associated with a rapid recovery. This study aimed to extend its application to other aspects in the management of patients with periampullary cancer. Between 2001 and 2004, 21 patients (median age, 68 years) underwent laparoscopic gastric (n = 8), biliary (n = 5), and combined gastric and biliary (n = 8) bypass. In addition to its therapeutic role (n = 12), indications included a concomitant prophylactic gastric (n = 3) and biliary (n = 2) bypass as well as pre- 1 Whipple’s relief of deep jaundice at the time of staging laparoscopy (n = 3). Construction of the biliary bypass to the gallbladder (n = 11) or bile duct (n = 2) was based on preoperative imaging. All procedures were completed laparoscopically. The median operating times for gastric, biliary, and combined bypass were 75, 60, and 130 min, respectively. The addition of a prophylactic bypass did not significantly prolong the operating time, as compared with a single therapeutic bypass. One patient died postoperatively of aspiration pneumonia. The postoperative hospital stay (median, 4 days) was not significantly influenced by the type of bypass. No recurrence of or new obstructive symptoms developed during the follow-up period after a therapeutic or prophylactic bypass. Applications of laparoscopic gastric and biliary bypass can safely be expanded to include a prophylactic role and preresection relief of obstructive jaundice. Prophylactic bypass surgery does not prolong operating time or hospital stay significantly and prevents future onset of obstructive symptoms.

The purpose of this study was to assess the safety and efficacy of the combination of panobinostat and carfilzomib in patients with relapsed/refractory multiple myeloma. Patients with multiple myeloma who had relapsed after at least one prior treatment were eligible to participate. In the dose escalation part of the study a standard 3+3 design was used to determine the maximum tolerated dose of four planned dose levels of the combination of carfilzomib and panobinostat. Panobinostat was administered on days 1, 3, 5, 15, 17, and 19. Carfilzomib was administered on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Treatment was continued until progression or intolerable toxicity. Forty-four patients were accrued into the trial, 13 in the phase I part and 31 in the phase II part of the study. The median age of the patients was 66 years and the median number of prior therapies was five. The expansion dose was established as 30 mg panobinostat, 20/45 mg/m(2) carfilzomib. The overall response rate was 67% for all patients, 67% for patients refractory to prior proteasome inhibitor treatment and 75% for patients refractory to prior immune modulating drug treatment. At a median follow up of 17 months, median progression-free survival was 7.7 months, median time to progression was 7.7 months, and median overall survival had not been reached. The regimen was well tolerated, although there were several panobinostat dose reductions. In conclusion, the combination of panobinostat and carfilzomib is feasible and effective in patients with relapsed/refractory multiple myeloma. (Trial registered at ClinicalTrials.gov: NCT01496118).

BACKGROUND AND AIMS Gallstone ileus (GSI) is an uncommon complication of gallstone disease that usually occurs in debilitated elderly patients in whom the minimal trauma of laparoscopic surgery might be advantageous. The outcome of laparoscopic surgery in 3 consecutive patients with GSI is presented, and its role is discussed. METHODS The laparoscopic approach was attempted in all patients with suspected GSI. RESULTS Three consecutive patients (2 female) aged 64 to 85 years with a median American Society of Anesthesiology score of 3E were admitted with small bowel obstruction. A laparoscopic enterolithotomy was carried out in all patients, and was completed successfully with a median operative time of 90 minutes. There were no intraoperative or postoperative complications, and the median postoperative hospital stay was 5 days. CONCLUSIONS Small bowel obstruction due to GSI may be safely managed using minimally invasive surgery with suggested benefits in these elderly patients.

Despite the benefits of the laparoscopic approach to splenectomy, its application in patients with massive splenomegaly (splenic weightor= 1000 g) remains controversial. In this study we evaluated the safety and feasibility of laparoscopic splenectomy for massive splenomegaly compared with open splenectomy.One surgeon applied the laparoscopic approach to splenectomy to all comers with massive splenomegaly, while other surgeons carried out the surgery through a laparotomy. The outcomes of the two approaches were compared on an intention-to-treat basis. Results of continuous variables are shown as medians.Fifteen patients underwent laparoscopic splenectomy between 2000 and 2005, and 13 underwent open splenectomy between 1996 and 2003. The two groups were comparable for age, sex, American Society of Anesthesiologists score, and splenic weight (1.3 vs. 1.1 kg). There was one conversion (6.6%) to open surgery. Although laparoscopic splenectomy was associated with significantly longer operating time (175 vs. 90 minutes, P0.001), it carried lower postoperative morbidity and mortality (13.3 vs. 30.8% and 0 vs. 7.7%, respectively). Laparoscopic splenectomy was associated with significantly lower total dose (29 vs. 264 mg morphine-equivalent, P0.0001) and duration of opiate usage (1 vs. 4 days, P0.0001); duration of parenteral hydration (24 vs. 96 hours, P = 0.006) and more rapid resumption of oral diet (24 vs. 72 hours, P = 0.017); and a shorter postoperative hospital stay (3 vs. 10 days, P0.0001).The laparoscopic approach to splenectomy for massive splenomegaly is feasible and safe. Despite a longer operating time, the postoperative recovery following laparoscopic splenectomy is smoother, with lower morbidity and shorter postoperative hospital stay compared with open splenectomy.

Relief of gastric outlet and distal biliary obstruction may be accomplished by open surgery or by minimally invasive techniques including endoscopic and laparoscopic approaches. We examined the feasibility and safety of laparoscopic gastric and biliary bypass in all patients with malignant and benign disease requiring surgical relief of obstructive symptoms.Patients with benign duodenal stricture or inoperable malignancy underwent therapeutic laparoscopic bypass surgery. Prophylactic gastric or biliary bypass was added in selected patients with nonmetastatic malignancy.Twenty-eight patients (17 of them female) with a median age of 67 years (range, 26-81 years) underwent 29 laparoscopic bypass procedures for malignant (n = 23) or benign (n = 6) disease. One patient who underwent a Roux-en-Y gastrojejunostomy for non-steroidal anti-inflammatory drug induced ulcer disease developed stenosis of the stoma that required laparoscopic refashioning 2 months later, accounting for the 29th procedure reported herein in 28 patients. Surgery included the construction of a single gastric (n = 16) or biliary (n = 5) bypass or a double bypass (n = 8), and an additional prophylactic bypass in 5 of 23 cancer patients (21.8%). All procedures were completed laparoscopically. The median operative time was 90 minutes (range, 60-153 minutes) and mean postoperative hospital stay was 4 days (range, 3-6 days). Complications developed following 4 procedures (13.8%) and 1 patient died (3.4%). No complications occurred in patients with prophylactic bypass. One patient required laparoscopic revision of the gastroenterostomy 2 months postoperatively, for benign disease. No recurrence of obstructive symptoms was observed in cancer patients during follow-up.Laparoscopic bypass surgery for distal biliary and gastric obstruction in patients with benign or malignant disease results in low morbidity and mortality and short postoperative hospital stay. The addition of prophylactic bypass in patients with nonmetastatic unresectable malignancy appears safe and effective.

20747 Background: Epidermal growth factor receptors (EGFR) are overexpressed in several human solid tumors including colorectal cancer, head and neck cancer, non-small cell lung cancer, pancreatic ...

The intravenous injection of cisplatin (10 mg kg ), the subcutaneous injection of apomorphine (0.125–1 mg kg ) and lisuride (0.001–0.1 mg kg ), the oral administration of ipecacuanha (0.3–2.4 mg kg ) and the intragastric administration of copper sulphate (25–100 mg kg ), induced a vomiting and retching response in the ferret. Pretreatment with dl-fenfluramine (5 mg kg i.p.) prevented or reduced the emesis induced by cisplatin, apomorphine, ipecacuanha and lisuride but failed to significantly antagonise copper sulphate-induced emesis. The 5-HT3 receptor antagonist ICS 205–930 (0.1 mg kg i.p.) prevented emesis induced by cisplatin and ipecacuanha but failed to prevent or significantly reduce the emesis induced by apomorphine, lisuride or copper sulphate. Dopamine receptor antagonists, including fluphenazine (0.1–1.0 mg kg i.p.), prevented apomorphine- and lisuride-induced emesis but were less potent or had inconsistent actions to antagonise cisplatin- or ipecacuanha-induced emesis and failed to inhibit the emesis induced by copper sulphate. The data indicate that dopamine and/or 5-HT3 receptor systems are involved in drug-induced emesis but that emesis caused by gastric irritation induced by copper sulphate is mediated by different receptor mechanisms.

The substituted benzamide derivatives, dazopride and metoclopramide, enhanced field stimulation-induced contractions of guinea-pig stomach strips and gastric emptying in the guinea-pig after peripheral, intracerebroventricular and intrahypothalamic injection. In the isolated vagal nerve preparation from the rabbit, both compounds were shown to be 5-hydroxytryptamine M-receptor antagonists. Dazopride and metoclopramide were equipotent in antagonising cisplatin-induced emesis in the ferret, whereas metoclopramide was approximately 200 times more potent than dazopride in antagonising the emesis caused by the dopamine agonist 2-di- n -propylamino-5,6-dihydroxytetralin in the marmoset. In behavioural tests which indicate dopamine receptor antagonism in the rat, metoclopramide induced catalepsy, antagonised amphetamine-induced stereotypy and the hyperactivity induced by the intrastriatal injection of dopamine, caused body asymmetry on unilateral injection into the striatum and also antagonised apomorphine-induced climbing and circling behaviour in the mouse. In contrast, dazopride had little or no action in these tests and failed to displace [ 3 H]spiperone in radioligand binding assays. The use of dazopride provides evidence to dissociate a dopamine receptor blockade from an ability to facilitate gastric emptying and to antagonise eisplatin-emesis, and indicates that antagonism of 5-hydroxytryptamine M-receptors is the essential basis of action for dazopride and plays an important role in the actions of metoclopramide.

The substituted benzamide derivative zacopride was found to antagonize competitively the effects of 5-hydroxytryptamine (5-HT) on the guinea-pig ileum, the rabbit vagus nerve and the von Bezold Jarisch reflex in the rat. The potency of zacopride was comparable with that of ICS 205–930 and it is concluded that zacopride possesses 5-HT3 receptor antagonizing properties.