Overall Survival in Patients with Endometrial Cancer Treated with Dostarlimab plus Carboplatin-Paclitaxel in the Randomized ENGOT-EN6/GOG-3031/RUBY Trial.

BACKGROUND: Part 1 of the RUBY trial (NCT03981796) evaluated dostarlimab plus carboplatin-paclitaxel compared with placebo plus carboplatin-paclitaxel in patients with primary advanced or recurrent endometrial cancer. At the first interim analysis, the trial met one of its dual-primary endpoints with statistically significant progression-free survival benefits in the mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) and overall populations. Overall survival (OS) results are reported from the second interim analysis. PATIENTS AND METHODS: RUBY is a phase 3, global, double-blind, randomized, placebo-controlled trial. Part 1 of RUBY enrolled eligible patients with primary advanced stage III or IV or first recurrent endometrial cancer who were randomly assigned (1:1) to receive either dostarlimab (500 mg) or placebo, plus carboplatin-paclitaxel every 3 weeks for 6 cycles followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. OS was a dual-primary endpoint. RESULTS: A total of 494 patients were randomized (245 in dostarlimab arm; 249 in placebo arm). In the overall population, with 51% maturity, RUBY met the dual-primary endpoint for OS at this second interim analysis, with a statistically significant reduction in the risk of death (HR = 0.69; 95% CI, 0.54-0.89; P = 0.0020) in patients treated with dostarlimab plus carboplatin-paclitaxel versus carboplatin-paclitaxel alone. The risk of death was lower in the dMMR/MSI-H population (HR = 0.32; 95% CI, 0.17-0.63; nominal P = 0.0002) and a trend in favor of dostarlimab was seen in the mismatch repair proficient/microsatellite stable (MMRp/MSS) population (HR = 0.79; 95% CI, 0.60-1.04; nominal P = 0.0493). The safety profile for dostarlimab plus carboplatin-paclitaxel was consistent with the first interim analysis. CONCLUSIONS: Dostarlimab in combination with carboplatin-paclitaxel demonstrated a statistically significant and clinically meaningful overall survival benefit in the overall population of patients with primary advanced or recurrent endometrial cancer while demonstrating an acceptable safety profile.

Defect detection by multi-axis infrared process monitoring of laser beam directed energy deposition.

Laser beam directed energy deposition (DED-LB) is an attractive additive manufacturing technique to produce versatile and complex 3D structures on demand, apply a cladding, or repair local defects. However, the quality of manufactured parts is difficult to assess by inspection prior to completion, and parts must be extensively inspected post-production to ensure conformance. Consequently, critical defects occurring during the build go undetected. In this work, a new monitoring system combining three infrared cameras along different optical axes capable of monitoring melt pool geometry and vertical displacement throughout deposition is reported. By combining multiple sensor data, an automated algorithm is developed which is capable of identifying the formation of structural features and defects. An intersecting, thin-walled geometry is used to demonstrate the capability of the system to detect process-induced porosity in samples with narrow intersection angles, which is validated using micro-CT observations. The recorded results indicate the root cause of this process-induced porosity at the intersection, and it is shown that advanced toolpath planning can eliminate such defects. The presented methodology demonstrates the value of multi-axis monitoring for identifying both defects and structural features, providing an advancement towards automated detection and alert systems in DED-LB.

Assessment of immune biomarkers and establishing a triple negative phenotype in gynecologic cancers.

OBJECTIVE: Immuno-oncology (IO) has rapidly evolved, with many IO therapies either approved or under investigation for multiple malignancies. Biomarkers exist that can predict response to IO therapies including PD-L1 expression, microsatellite instability (MSI), and total mutation burden (TMB). This paper serves to analyze the presence of these biomarkers across gynecologic cancers. METHODS: A total of 16,300 gynecologic cancer specimens submitted for molecular profiling to Caris Life Sciences were reviewed. Immunohistochemistry was performed using the SP142 anti-PD-L1 clone and assessed for intensity. Next-generation sequencing, immunohistochemistry, and fragment analysis were used to determine MSI status. TMB was measured by counting all non-synonymous missense mutations found per tumor not previously described as germline alterations. Chi-Square, Fisher Exact, and the Kruskal-Wallis test were used to compare cohorts. RESULTS: Of 16,300 specimens, 54.1% were ovarian, 37.2% uterine, 7.2% cervical, 0.3% vulvar, 1.2% vaginal, with 0.1% unspecified. MSI-H was most frequent in uterine cancer (17.7%) and only 1% of ovarian cancers. PD-L1 expression was present in 38.3% of cervical and 62.5% of vulvar cancers, but less than 8% of ovarian and uterine cancers. TMB-H was present in 21.1% cervical, 19.7% uterine, and 5% ovarian cancers. Few specimens exhibited a "triple positive" phenotype - 0.3% ovarian, 1.5% uterine, and 1.5% cervical. Associations were seen between MSI, TMB, and PD-L1 across all cancer types. CONCLUSIONS: The frequency of individual biomarkers pertinent to IO therapy varies by cancer type. HPV-driven genital tract cancers have higher frequencies of PD-L1 expression, MSI-H, and TMBH. Endometrial cancers are characterized by MSI-H and TMB, whereas ovarian cancers have a low frequency of MSI-H and modest PD-L1 or TMBH. The incidence of 'triple positive" cases was less than 2%.

Overall survival results of AGO-OVAR16: A phase 3 study of maintenance pazopanib versus placebo in women who have not progressed after first-line chemotherapy for advanced ovarian cancer.

OBJECTIVE: The AGO-OVAR16 study was designed to test the efficacy, safety, and tolerability of pazopanib maintenance after first-line chemotherapy in patients with newly diagnosed advanced ovarian cancer (AOC). METHODS: Nine hundred and forty patients with histologically confirmed AOC, International Federation of Gynecology and Obstetrics (FIGO) stage II-IV, were randomized in a 1:1 ratio to receive either 800 mg pazopanib once daily or placebo for up to 24 months, unless there was disease progression, toxicity, withdrawal of consent, or death. The primary endpoint (investigator-assessed progression-free survival [PFS]) was met and previously reported. The results of final analyses of overall survival (OS) are reported here. RESULTS: A third OS interim analysis showed futility and led to study closure and a final OS analysis after last patient last visit. At the time of the final OS analysis, 494 (89.7% of the planned 551) events had occurred. No difference was observed in OS between pazopanib and placebo. The hazard ratio (HR) was 0.960 (95% confidence interval [CI]: 0.805-1.145), and the median OS from randomization was 59.1 months in pazopanib and 64.0 months in placebo arms. For the East Asian patients, similar to the first three interim OS analyses, a numerical negative trend was observed favoring placebo (HR, 1.332; 95% CI: 0.863-2.054). Exploratory analyses showed a trend for a longer time to first subsequent anti-cancer therapy or death with pazopanib over placebo (HR, 0.829; 95% CI: 0.713-0.965), with a median estimate of 19.0 and 14.5 months, respectively. No new safety signals were observed. CONCLUSION: Although pazopanib prolonged PFS, this was not associated with improvement in median OS. CLINICAL TRIAL INFORMATION: ClinicalTrials.gov: NCT00866697.

Treatment of patients with recurrent epithelial ovarian cancer for whom platinum is still an option.

BACKGROUND: Ovarian cancer remains the most deadly gynecologic cancer with the majority of patients relapsing within 3 years of diagnosis. Traditional treatment paradigms linked to platinum sensitivity or resistance are currently being questioned in the setting of new diagnostic methods and treatment options. DESIGN: Authors carried out review of the literature on key topics in treatment of recurrent epithelial ovarian cancer (EOC) when platinum is still an option; including secondary surgical cytoreduction, chemotherapy, novel treatment options, and maintenance therapy. A treatment algorithm is proposed. RESULTS: Molecular characterization of EOC is critical to help guide treatment decisions. The role of secondary cytoreductive surgery is currently being evaluated with results from Gynecologic Oncology Group (GOG) 213 and anticipated results from DESKTOP III clinical trials. Chemotherapy backbone has remained relatively unchanged but utilizing non-platinum-based regimens is under investigation. In addition, maintenance therapy with anti-angiogenic therapy and Poly (ADP-ribose) Polymerase (PARP) inhibitors has emerged as the standard of care. Novel combinations, including immunotherapy and anti-angiogenesis agents, may further change the current landscape. CONCLUSIONS: The treatment of recurrent EOC is rapidly changing. Clinical trial design will need to continue to evolve as many novel therapies move to the upfront setting. Ultimately, the treatment of patients with recurrent EOC must incorporate individual patient and tumor factors.

Diagnostic double strike in the emergency room - two cases of complete pancreatic ruptures due to bicycle handlebar injuries on two consecutive days.

BACKGROUND: Pancreatic injuries are rare in cases of blunt abdominal trauma and therefore easily misdiagnosed at time of hospital admission. They are associated with a significantly elevated morbidity and lethality. Bicycle handlebar injuries are the most common cause of pancreatic trauma in children and adolescents. CASE PRESENTATION: We report two cases of a 23-year-old Caucasian woman and a 15-year-old Caucasian boy who presented to our clinic with a similar history of a bicycle accident on 2 consecutive days. Both suffered from a fall from a bicycle with bicycle handlebar injury 4 and 6 days prior to admission in our clinic. Emergency distal pancreatectomies were performed in both cases. CONCLUSIONS: Pancreatic injuries must be highly suspected in bicycle handlebar injuries, even if amylase/lipase levels or ultrasound findings seem unremarkable. The best initial strategies are early computed tomography and a quick referral to a level 1 trauma center. Distal pancreatectomy is the treatment of choice in cases of complete rupture of the pancreatic body.

Quality of life in patients with advanced epithelial ovarian cancer (EOC) randomized to maintenance pazopanib or placebo after first-line chemotherapy in the AGO-OVAR 16 trial. Measuring what matters-patient-centered end points in trials of maintenance therapy.

Background: Health-related quality of life (HRQoL) was a secondary end point in AGO-OVAR 16, which randomized 940 patients with EOC after first-line chemotherapy to maintenance pazopanib (PZ) or placebo (P). Additional post hoc analyses were carried out to investigate additional patient-centered end points. Patients and methods: HRQoL was measured with EORTC-QLQ-C30, QLQ-OV28 and EQ-5D-3L. Pre-specified end points included mean differences in HRQoL between treatment arms. Exploratory analyses included quality-adjusted progression-free survival (QAPFS), impact of specific symptoms and progressive disease (PD) on HRQoL and time to second-line chemotherapy. The objective was to provide clinical perspective to the significant median PFS gain of 5.6 months with PZ. Results: There were statistically significant differences between PZ and P in QLQ-C30 global health status [5.5 points; 95% confidence interval (CI), 0.7-10.4, P = 0.024] from baseline to 25 months, but not EQ-5D-3L (0.018 points; 95% CI - 0.033 to 0.069, P = 0.485). The impact of diarrhea was captured in QLQ-OV28 Abdominal/GI-Symptoms scale (8.1 points; 95% CI 3.6-12.5, P = 0.001). QAPFS was 386 days (95% CI 366-404 days) with PZ versus 359 days (95% CI 338-379 days) with placebo (P = 0.052). PD was associated with a decline in HRQoL (P < 0.0001). Median time to second-line chemotherapy was 19.7 months with PZ and 15.0 months with P [hazard ratio (HR) 0.72, 95% CI 0.69-0.86, P = 0.0001]. Conclusions: There were small to no significant mean score differences in global HRQoL and EQ5D-3L between PZ and placebo, respectively, despite the increased toxicity of PZ. Exploratory end points including QAPFS, impact of specific symptoms on HRQoL during treatment and at PD help place the PFS gain with PZ in context and interpret the results. Additional patient-centered end points should be considered in trials of maintenance therapy in EOC beyond mean differences in HRQoL scores alone, to support the benefit to patients of prolongation of PFS. Clinical Trials Registration Number: NCT00866697.

Erratum to: The management of intra-abdominal infections from a global perspective: 2017 WSES guidelines for management of intra-abdominal infections.

[This corrects the article DOI: 10.1186/s13017-017-0141-6.].

Circumportal Pancreas-a Must Know Pancreatic Anomaly for the Pancreatic Surgeon.

PURPOSE: Circumportal pancreas is a rare congenital pancreatic anomaly with encasement of the portal vein and/or the superior mesenteric vein by pancreatic tissue. It is often overlooked on cross-sectional imaging studies and can be encountered during pancreatic surgery. Pancreatic head resection with circumportal pancreas is technically difficult and bears an increased risk of postoperative pancreatic fistula. MATERIALS AND METHODS: A retrospective chart review of our data base for all patients who had undergone pancreatic head resection between 2004 and 2015 was performed. RESULTS: We identified six patients out of 1102 patients who had undergone pancreatic head surgery in the study period. CT-scan and MRI were never able to identify circumportal pancreas prior to surgery. The right hepatic an artery derived from the superior mesenteric artery in four cases (67%). Additional resection of the pancreatic body was always performed. Postoperative course was uneventful in all cases without occurrence of pancreatic fistula. CONCLUSIONS: Circumportal pancreas is a rare entity every pancreatic surgeon should be aware of. It is difficult to identify on cross-sectional imaging studies. A right hepatic artery arising from the superior mesenteric artery should raise suspicion of circumportal pancreas. Additional pancreatic tissue resection should be performed during pancreatic head resections to avoid pancreatic fistula.

[Distal Pancreatectomy with Autologous Fibrin Sealant - Implementation of an Established Concept of Tissue Sealing in Pancreatic Surgery]. / Die Pankreaslinksresektion mit autologem Fibrinkleber ­ Anwendung eines etablierten Versiegelungskonzepts in der Pankreaschirurgie.

Background: Postoperative pancreatic fistulas (POPF) remain a major concern after distal pancreatectomy. Irrespective of the technique to close the pancreatic remnant, pancreatic fistulas will occur in approximately 30 % of patients undergoing distal pancreatectomy. For the first time ever, autologous fibrin sealant (Vivostat®) was used to additionally seal the pancreatic remnant after a distal pancreatectomy. The aim was to analyse whether this changes the postoperative outcome. Patients/Material and Methods: In 2015, a technical case series was performed in 15 patients who underwent distal pancreatectomy. The pancreatic remnant was additionally sealed with autologous fibrin sealant (Vivostat®). Results: A postoperative pancreatic fistula (POPF) occurred in 5/15 patients (33 %). One patient had a POPF grade A (1/15, 6.7 %), whereas a POPF grade B occurred in 4/15 patients (26.7 %). 75 % (3/4) of the patients with a POPF grade B were sufficiently treated with antibiotics, whereas a CT-guided percutaneous drainage had to be placed only in one case. Conclusion: Autologous fibrin sealant is simple to apply and seems to be well tolerated. However, it does not seem to avoid the development of postoperative pancreatic fistulas after distal pancreatectomy.

[Clostridium difficile in visceral surgery]. / Clostridium difficile in der Viszeralchirurgie.

BACKGROUND: For surgeons the early identification of patients with clostridium difficile infections (CDI) is important, because the incidence and virulence of this potentially life-threatening disease are increasing. OBJECTIVES: The aim of this study was to describe the frequency of CDI among surgical patients, to analyze which treatment was successful and to define which factors were associated with mortality. METHODS: A retrospective analysis of patients with CDI was performed. RESULTS: From January 2004 to June 2012 the overall incidence of CDI among all departments at the St. Josef Hospital, Ruhr University Bochum was 0.6 % (1669 out of 301,919 patients). In 2004 the number of surgical patients with CDI was 1 which increased to 41 in 2011. Before the diagnosis of CDI was made 84 % (151 out of 179) of patients had received an antibiotic treatment. Conservative management of CDI was performed with metronidazole in 75 % (134 out of 179), 60 % (107 out of 179) received vancomycin, while 44 % (79 out of 179) received a combination of metronidazole and vancomycin, tygecycline or fidaxomidin. The overall mortality was 7 % (12 out of 179). There was a significant association with mortality for patients with sepsis, readmission to the intensive care unit (ICU), requirement for vasopressor therapy and intubation with mechanical ventilation. In 4 % of patients (7 out of 179) colectomy was carried out. Despite maximum intensive care management, 86 % (6 out of 7) of patients who underwent colectomy ultimately died. CONCLUSION: Although conservative management is successful for most patients with CDI, the mortality is high for patients who require intensive care management secondary to CDI. Mortality after colectomy for CDI is almost 100 %, mostly because the operation is usually only performed as a last resort in patients with sepsis. The most important risk factor for CDI is a prior antibiotic therapy.

Overview of a chemoresponse assay in ovarian cancer.

The objective of this review is to summarize recent scientific and medical literature regarding chemoresponse assays or chemotherapy sensitivity and resistance assays (CSRAs), specifically as applied to epithelial ovarian cancer. A total of sixty-seven articles, identified through PubMed using the key words "in vitro chemoresponse assay," "chemo sensitivity resistance assay," "ATP," "HDRA," "EDR," "MiCK," and "ChemoFx," were reviewed. Recent publications on marker validation, including relevant clinical trial designs, were also included. Recent CSRA research and clinical studies are outlined in this review. Published findings demonstrate benefits regarding patient outcome with respect to recent CSRAs. Specifically, analytical and clinical validations, as well as clinical utility and economic benefit, of the most common clinically used CSRA in the United States support its use to aid in making effective, individualized clinical treatment selections for patients with ovarian cancer.

Effects of intra-arterial octreotide on pancreatic texture: a randomized controlled trial.

BACKGROUND AND AIMS: Octreotide is suggested to harden the pancreas, thus facilitating the construction of a pancreatic anastomosis and lowering the risk of postoperative fistula. We tested the hypothesis that intra-arterial application of octreotide in the gastroduodenal artery during pancreatectomy may increase pancreatic hardness. MATERIAL AND METHODS: A single-center, prospective, double-blinded, randomized controlled trial with parallel assignment was conducted. Patients planned for a pancreatoduodenectomy or a total pancreatectomy, who had a palpatory and durometer proven (<40 Shore units) soft pancreas, were assigned to receive intraoperatively either 5 mL 500µg octreotide or 5 mL 0.9% saline solution as a bolus injection in the gastroduodenal artery. Pancreatic hardness was measured before, early, and late after intervention. The investigator performing the durometer measurements and pathologist were masked to group assignment. The primary outcome was increased pancreatic hardness. Analysis was by intention to treat. This trial is registered at http://www.clinicaltrials.gov (ID NCT01400100). RESULTS: A total of 12 patients received octreotide and 13 received saline solution. Pancreatic hardness marginally increased in the octreotide group: 0.67 ± 2.3 Shore units, whereas it decreased in the control group: -2.15 ± 2.7 Shore units. The difference was statistically significant, p = 0.029 (95% confidence interval = -4.87 to -0.77). Histology did not find any correlate for this clinically irrelevant hardening effect. CONCLUSIONS: A single bolus application of octreotide did not deliver a clinically relevant increase in pancreatic hardness. Future studies on the hardening effect of octreotide should employ repeated or continuous preoperative administration of this drug.

[Hepaticojejunostomy after pancreatic head resection - technical aspects for reconstruction of small and fragile bile ducts with T-tube drainage]. / Die Technik der Hepatikojejunostomie mit T-Drainage bei der Rekonstruktion schmalkalibriger Gallengänge nach Pankreaskopfresektion.

BACKGROUND: After pancreatic head resection the reconstruction of small and fragile bile ducts is technically demanding, resulting in more postoperative bile leaks. One option for the reconstruction is the placement of a T-tube drainage at the site of the anastomosis. MATERIAL AND METHODS: Standard reconstruction after pancreatic head resection was an end-to-side hepaticojejunostomy with PDS 5.0, 15-25 cm distally from the pancreaticojejunostomy. For patients with a small bile duct diameter (≤ 5 mm) or a fragile bile duct wall the reconstruction was performed with PDS 6.0 and a T-tube drainage at the side of the anastomosis. RESULTS: The reconstruction with a T-tube drainage at the site of the anastomosis is technically easy to perform and offers the opportunity for immediate visualisation of the anastomosis in the postoperative period by application of water soluble contrast medium. If a bile leak occurs, biliary deviation through the T-tube drainage can enable a conservative management without revisional laparotomy in selected patients. Whether or not a conservative management of postoperative bile leaks will lead to more bile duct strictures is a subject for further investigations. CONCLUSION: A T-tube drainage at the site of the anastomosis can probably not prevent postoperative bile leaks from a difficult hepaticojejunostomy, but in selected patients it offers the opportunity for a conservative management resulting in less re-operations. Therefore we recommend the augmentation of a difficult hepaticojejunostomy with a T-tube drainage.

Light-switchable hemithioindigo-hemistilbene-containing peptides: ultrafast spectroscopy of the Z → E isomerization of the chromophore and the structural dynamics of the peptide moiety.

Two hemithioindigo-hemistilbene (HTI) derivatives, designed to operate as structural switches in peptides, as well as two HTI peptides are characterized by ultrafast spectroscopy in the visible and the infrared. The two HTI switches follow the reaction scheme published for other HTI compounds with a picosecond excited state reaction (τ(1) ≈ 6 ps) and isomerization from Z to E with τ(2) = 13 and 51 ps. As compared to the isolated chromophores, the isomerization reaction is slowed down in the chromopeptides to τ(2) = 24 and 69 ps. For the smaller peptide containing 6 amino acids, the structural changes of the peptide moiety observed via the IR spectrum in the amide I band follow the isomerization of the molecular switch closely. In the larger cyclic chromopeptide, containing 20 amino acids and mimicking a ß-hairpin structure in the Z-form of the chromophore, the peptide moiety also changes its structure during isomerization of the chromophore. However, the IR spectrum at the end of the observation period of 3 ns deviates significantly from the stationary difference spectrum. These signatures indicate that strong additional structural changes, e.g., breaking of interchain hydrogen bonds, also occur on longer time scales.

Changes in microglial activation within the hindbrain, nodose ganglia, and the spinal cord following subdiaphragmatic vagotomy.

Damage to peripheral nerve branches triggers activation of microglia in CNS areas containing motor neuron soma and primary afferent terminals of the damaged fibers. Furthermore, microglial activation occurs in areas containing the soma and terminals of spared nerve branches of a damaged nerve. Because the abdominal viscera are innervated by spinal afferents as well as vagal afferents and efferents, we speculated that spinal nerves might respond like spared nerve branches following damage to vagal fibers. Therefore, we tested the hypothesis that damage to the abdominal vagus would result in microglial activation in vagal structures-the nucleus of the solitary tract (NTS), dorsal motor nucleus of the vagus nerve (DMV), and nodose ganglia (NG)-as well as spinal cord (SC) segments that innervate the abdominal viscera. To test this hypothesis, rats underwent subdiaphragmatic vagotomy or sham surgery and were treated with saline or the microglial inhibitor, minocycline. Microglial activation was determined by quantifying changes in the intensity of fluorescent staining with a primary antibody against ionizing calcium adapter binding molecule 1 (Iba1). We found that subdiaphragmatic vagotomy significantly activated microglia in the NTS, DMV, and NG two weeks post-vagotomy. Microglial activation remained significantly increased in the NG and DMV for at least 42 days. Surprisingly, vagotomy significantly decreased microglial activation in the SC. Minocycline treatment attenuated microglial activation in all studied areas. Our results indicate that microglial activation in vagal structures following abdominal vagal damage is accompanied by suppression of microglial activation in associated areas of the spinal cord.