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PURPOSE The therapeutic management of pancreatic neuroendocrine tumors (PanNETs) is based on pathological tumor grade assessment. A noninvasive imaging method to grade tumors would facilitate treatment selection. This study evaluated the ability of quantitative image analysis derived from computed tomography (CT) images to predict PanNET grade. METHODS Institutional database was queried for resected PanNET (2000-2017) with a preoperative arterial phase CT scan. Radiomic features were extracted from the primary tumor on the CT scan using quantitative image analysis, and qualitative radiographic descriptors were assessed by two radiologists. Significant features were identified by univariable analysis and used to build multivariable models to predict PanNET grade. RESULTS Overall, 150 patients were included. The performance of models based on qualitative radiographic descriptors varied between the two radiologists (reader 1: sensitivity, 33%; specificity, 66%; negative predictive value [NPV], 63%; and positive predictive value [PPV], 37%; reader 2: sensitivity, 45%; specificity, 70%; NPV, 72%; and PPV, 47%). The model based on radiomics had a better performance predicting the tumor grade with a sensitivity of 54%, a specificity of 80%, an NPV of 81%, and a PPV of 54%. The inclusion of radiomics in the radiographic descriptor models improved both the radiologists' performance. CONCLUSION CT quantitative image analysis of PanNETs helps predict tumor grade from routinely acquired scans and should be investigated in future prospective studies.

Understanding the molecular and phenotypic profile of colorectal cancer (CRC) in West Africa is vital to addressing the regions rising burden of disease. Tissue from unselected Nigerian patients was analyzed with a multigene, next-generation sequencing assay. The rate of microsatellite instability is significantly higher among Nigerian CRC patients (28.1%) than patients from The Cancer Genome Atlas (TCGA, 14.2%) and Memorial Sloan Kettering Cancer Center (MSKCC, 8.5%, P, Understanding the molecular and phenotypic profile of colorectal cancer (CRC) in West Africa is important for early detection and treatment. Here, the authors use a multigene next-generation sequencing panel to identify genomic differences in Nigerian CRCs compared to those from TCGA and MSKCC cohorts.

Prosthetic rehabilitation in patients undergoing reconstructive surgery using vascularized free flaps is challenging, and functional rehabilitation of the patient with a fixed prosthesis is rare. Virtually planned maxillofacial reconstruction including simultaneous dental implantation according to the prosthodontic ideal position of the implants could further enhance dental rehabilitation. The data of 21 patients undergoing fibula free flap reconstructive surgery with CAD/CAM patient-specific reconstruction plates during the years 2015-2018 were analysed, including the applicability of the virtual plan, flap survival, duration of surgery, ischemia time, simultaneous dental implantation, implant exposure, and postoperative complications. The virtual plan could be translated to surgery in all cases. In total, 76 dental implants were simultaneously placed during primary reconstruction in the 21 patients. For 38.1% of these patients, the implants could be uncovered in secondary surgery; the mean duration until exposure was 7.6 months. The implant survival rate was 97.4% (74/76). Wound infection requiring a secondary intervention occurred in 23.8% of patients during follow-up. Virtually planned reconstruction with a fibula free flap, simultaneous dental implantation, and CAD/CAM plates allows early and functional dental rehabilitation. A dental workflow should be integrated into the virtual planning, and prosthetically favourable implant positions should determine the position of the fibula segments.

Aggressive or restricted perioperative fluid management has been shown to increase complications in patients undergoing microsurgery. Goal-directed fluid therapy (GDFT) aims to administer fluid, vasoactive agents, and inotropes according to each patient's hemodynamic indices. This study assesses GDFT impact on perioperative outcomes of autologous breast reconstruction (ABR) patients, as there remains a gap in management understanding. We hypothesize that GDFT will have lower fluid administration and equivocal outcomes compared to patients not on GDFT.A single-center retrospective review was conducted on ABR patients from January 2010-April 2017. An enhanced recovery after surgery (ERAS) using GDFT was implemented in April 2015. With GDFT, patients were administered intraoperative fluids and vasoactive agents according to hemodynamic indices. Patients prior to April 2015 were included in the pre-ERAS cohort. Primary outcomes included the amount and rate of fluid delivery, urine output (UOP), vasopressor administration, major (i.e., flap failure) and minor (i.e., seroma) complications, and length of stay (LOS).Overall, 777 patients underwent ABR (ERAS: 312 and pre-ERAS: 465). ERAS patients received significantly less total fluid volume (ERAS median: 3750 mL [IQR: 3000-4500 mL]; pre-ERAS median: 5000 mL [IQR 4000-6400 mL]; and p0.001), had lower UOP, were more likely to receive vasopressor agents (47% vs 35% and p0.001), and had lower LOS (ERAS: 4 days [4-5]; pre-ERAS: 5 [4-6]; and p0.001) as compared to pre-ERAS patients. Complications did not differ between cohorts.GDFT, as part of ERAS, and the prudent use of vasopressors were found to be safe and did not increase morbidity in ABR patients. GDFT provides individualized perioperative care to the ABR patient.

Capsular contracture is a severe complication to breast surgery with implants. Previous studies suggest multiple risk factors are associated with capsular contracture, but the etiology is still unknown. We performed a literature review to investigate existing studies on histological analyses of breast implant capsules and how clinical risk factors impact the capsule morphology. The literature search was conducted in PubMed. Studies that performed histological analyses of breast implant capsules were included. Animal studies or studies with a study population of less than five patients were excluded. Fifty-two studies were included. The histological analyses showed that the breast implant capsules were organized in multiple layers with an inner layer of synovial-like metaplasia which was reported to diminish in capsules with capsular contracture. The remaining layers of the capsule mostly consisted of collagen. The alignment of the collagen fibers differed between contracted and non-contracted capsules, and capsules with higher Baker grade were generally thickest and contained more tissue inflammation. Studies investigating capsules affected by radiotherapy found a more pronounced inflammatory response and the capsules were generally thicker and fibrotic compared with nonirradiated capsules. The included studies offer valuable insights into the histological changes caused by capsular contracture and their relation to clinical risk factors. Further studies with larger sample sizes and more strict inclusion criteria are needed to further investigate implant capsules and the role of the synovial-like metaplasia for the development of capsular contracture. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors https://www.springer.com/00266 .

OBJECTIVE We sought to compare overall survival (OS) and disease control for patients with localized pancreatic ductal adenocarcinoma (PDAC) treated with ablative dose radiotherapy (A-RT) versus resection. SUMMARY BACKGROUND DATA Locoregional treatment for PDAC includes resection when possible or palliative RT. A-RT may offer durable tumor control and encouraging survival. METHODS This was a single-institution retrospective analysis of patients with PDAC treated with induction chemotherapy followed by A-RT [≥98 Gy biologically effective dose (BED) using 15-25 fractions in 3-4.5 Gy/fraction] or pancreatectomy. RESULTS One hundred and four patients received A-RT (49.8%) and 105 (50.2%) underwent resection. Patients receiving A-RT had larger median tumor size after induction chemotherapy [3.2 cm (undetectable-10.9) vs 2.6 cm (undetectable-10.7), P < 0.001], and were more likely to have celiac or hepatic artery encasement (48.1% vs 11.4%, P

Purpose: Lymph node metastasis (LNM) drastically reduces survival after resection of intrahepatic cholangiocarcinoma (IHC). Optimal treatment is ill defined, and it is unclear whether tumor mutational profiling can support treatment decisions. Experimental Design: Patients with liver-limited IHC with or without LNM treated with resection (N = 237), hepatic arterial infusion chemotherapy (HAIC; N = 196), or systemic chemotherapy alone (SYS; N = 140) at our institution between 2000 and 2018 were included. Genomic sequencing was analyzed to determine whether genetic alterations could stratify outcomes for patients with LNM. Results: For node-negative patients, resection was associated with the longest median overall survival [OS, 59.9 months; 95% confidence interval (CI), 47.2–74.31], followed by HAIC (24.9 months; 95% CI, 20.3–29.6), and SYS (13.7 months; 95% CI, 8.9–15.9; P < 0.001). There was no difference in survival for node-positive patients treated with resection (median OS, 19.7 months; 95% CI, 12.1–27.2) or HAIC (18.1 months; 95% CI, 14.1–26.6; P = 0.560); however, survival in both groups was greater than SYS (11.2 months; 95% CI, 14.1–26.6; P = 0.024). Node-positive patients with at least one high-risk genetic alteration (TP53 mutation, KRAS mutation, CDKN2A/B deletion) had worse survival compared to wild-type patients (median OS, 12.1 months; 95% CI, 5.7–21.5; P = 0.002), regardless of treatment. Conversely, there was no difference in survival for node-positive patients with IDH1/2 mutations compared to wild-type patients. Conclusions: There was no difference in OS for patients with node-positive IHC treated by resection versus HAIC, and both treatments had better survival than SYS alone. The presence of high-risk genetic alterations provides valuable prognostic information that may help guide treatment.

Bovine lactoferricin (LFcinB) has antimicrobial and immunomodulatory properties; however, the effects on diabetic wound healing remain poorly understood. The wound healing potential of LFcinB was investigated with in vitro, ex vivo, and in vivo models. Cell migration and proliferation were tested on keratinocytes and on porcine ears. A type 1 diabetic mouse model was also used to evaluate wound healing kinetics, bacterial diversity patterns, and the effect of LFcinB on oxidative stress, macrophage phenotype, angiogenesis, and collagen deposition. LFcinB increased keratinocyte migration in vitro (p < 0.05) and ex vivo (p < 0.001) and improved wound healing in diabetic mice (p < 0.05), though not in normoglycemic control mice. In diabetic mouse wounds, LFcinB treatment led to the eradication of Bacillus pumilus, a decrease in Staphylococcus aureus, and an increase in the Staphylococcus xylosus prevalence. LFcinB increased angiogenesis in diabetic mice (p < 0.01), but this was decreased in control mice (p < 0.05). LFcinB improved collagen deposition in both diabetic and control mice (p < 0.05). Both oxidative stress and the M1-to-M2 macrophage ratios were decreased in LFcinB-treated wounds of diabetic animals (p < 0.001 and p < 0.05, respectively) compared with saline, suggesting a downregulation of inflammation in diabetic wounds. In conclusion, LFcinB treatment demonstrated noticeable positive effects on diabetic wound healing., Graphical Abstract, Topical delivery of bovine lactoferricin (LFcinB) has antimicrobial and immunomodulatory actions and improves wound closure and changes the bacterial diversity of diabetic wounds. Hallmarks of diabetic wound healing impairments like inflammation, oxidative stress, disrupted angiogenesis, and collagen deposition improved by LFcinB indicate its therapeutic potential.

Background Plasmacytoid urothelial carcinoma (PUC) is a rare, aggressive histologic variant of urothelial cancer characterised by a diffuse growth pattern and CDH1 mutation. We studied the efficacy of preoperative platinum-based chemotherapy in nonmetastatic PUC and immune checkpoint inhibitors (ICIs) in advanced PUC. Methods Cases of nonmetastatic PUC and advanced PUC treated with ICIs at our institution were identified. Outcomes were compared to those of a published cohort of patients with urothelial carcinoma not otherwise specified. Results We identified 81 patients with nonmetastatic PUC. Of the patients with localised disease who underwent neoadjuvant chemotherapy, pathologic complete response and downstaging rates were 12 and 21%, respectively. Pathologic downstaging was not associated with significant improvement in clinical outcomes. Up to 18% of localised disease and 28% of locally advanced cases had unresectable disease at the time of surgery. ICI-treated advanced PUC (N = 21) had progression-free and overall survival of 4.5 and 10.5 months, respectively, and a 38% response rate. FGFR3 and DNA damage response gene alterations were observed in 3 and 15% of cases, respectively. Conclusions PUC is associated with high disease burden and poor chemosensitivity. Increased awareness and recognition of this disease variant will allow for new treatment strategies.

Objective To determine the prevalence of sexual harassment and perceptions of gender disparities affecting the careers of physicians in gynecologic oncology. Methods We conducted a survey of US physician members of the Society of Gynecologic Oncology. Participants were queried about demographics, sexual harassment experiences during training/practice, and perceptions of gender disparities in compensation and career advancement. Responses were categorized as “never” versus “ever” and compared using Fisher's exact test. Results The survey was sent to 1566 members—405 (255 females, 147 males, 3 other) responded (response rate 26%). Sixty-four percent reported having experienced sexual harassment during training/practice. Sexual harassment was experienced by 71% of females and 51% of males. Of these respondents, only 14.5% reported it. Reasons for not reporting included: “incident did not seem important enough” (40%); “did not think anything would be done about it” (37%); and “fear of reprisal” (34%). Female respondents were more likely to report gender affected their career advancement (34% vs. 10%; p ≤ .001) and compensation (64% vs. 19%; p ≤ .001); males were more likely to report no gender income disparity (91% vs. 57%; p ≤ .001). Conclusions Sexual harassment during training/practice appears common among male and female gynecologic oncologists. Although most are aware of how to report an incident, few do so, mostly for fear of reprisal or concern nothing will be done. Despite practicing in a field defined by caring for women, female physicians more often perceive gender influences their compensation and career advancement. Awareness of these issues can lead to their elimination from our specialty.

Purpose: To determine if a targeted exome panel utilizing matched normal DNA can accurately detect germline and somatic HLA genes in patients with synovial sarcoma (SS) and whether select HLA-A*02 genotypes are prognostic or predictive of outcome in metastatic SS. Experimental Design: Patients with metastatic SS consented to HLA typing by a Clinical Laboratory Improvement Amendments (CLIA)-certified test to determine eligibility for a clinical trial of NY-ESO-1–specific engineered T cells restricted to carriers of HLA-A*02:01, -A*02:05, or -A*02:06 (HLA-A*02 eligible). HLA genotype was determined from Memorial Sloan Kettering Integrated Molecular Profiling of Actionable Cancer Targets (MSK-IMPACT), where feasible, and somatic loss of heterozygosity (LOH) in HLA alleles was identified. Overall survival (OS) was estimated and stratified by HLA-A*02 eligibility. Results: A total of 23 patients had HLA genotyping by a CLIA-certified lab and MSK-IMPACT. Ninety percent (108/110) of the sequenced alleles were concordant between IMPACT and the outside lab. LOH of HLA genes was detected in three tumors, one had loss of HLA-A*02:01. In total, 66 patients were screened for T-cell therapy and 20 (30%) were HLA-A*02 eligible on outside testing. Univariate analysis of OS from the time of metastasis found HLA-A*02 eligibility was marginally associated with shorter OS [HR = 1.95; 95% confidence interval (CI), 0.995–3.813; P = 0.052]. On multivariate analysis, older age and larger tumor size, but not HLA-A*02 eligibility, were significantly associated with decreased OS. HLA-A*02 eligibility did not impact OS after chemotherapy or pazopanib in the metastatic setting. Conclusions: Targeted gene panels like MSK-IMPACT may accurately report HLA type and identify loss of somatic HLA alleles. In a multivariable model, HLA-A*02 eligibility was not significantly associated with OS in patients with metastatic SS.

BACKGROUND: Colonic tuft cells are epithelial chemosensory cells involved in barrier integrity, modulation of inflammatory responses and gut homeostasis. Recent evidence indicates an involvement of tuft cells in ulcerative colitis pathogenesis, though mechanisms remain largely unknown.Here, we quantified the colonic tuft cell population in patients with quiescent ulcerative colitis as compared to patients without identified colonic disease (controls).METHODS: In this retrospective study, we obtained endoscopic colonic sigmoid biopsies from 14 patients with quiescent ulcerative colitis and from 17 controls. In a blinded central-reading design, we identified tuft cells by immunohistochemistry using a cyclooxygenase-1 antibody as a marker and performed a simple counting by visual inspection. Poisson regression was employed for statistics and results were adjusted for gender, age and smoking status.RESULTS: Ulcerative colitis patients demonstrated a 55% reduced tuft cell count in colonic mucosa compared with the control group (95% confidence limit: range 31-71%, P = 0.0002). Ulcerative colitis patients had a mean tuft cells count of 46 tuft cells/mm (95% CI, 36-59), while controls demonstrated a mean of 104 tuft cells/mm (95% CI, 79-136). No interactions of other covariates, such as age, smoking status, total duration of ulcerative colitis disease and duration of clinical remission prior to study inclusion were detected between ulcerative colitis patients and controls.CONCLUSION: Quiescent ulcerative colitis patients have a relatively low number of colonic tuft cells. Further studies are warranted to explore the potential involvement of tuft cells in ulcerative colitis pathogenesis.

Background: This study investigated the effect of the reduced dose of systemic chemotherapy (SYS) on recurrence patterns in patients receiving adjuvant hepatic artery infusion (HAI) chemotherapy after complete colorectal liver metastases (CRLM) resection. Methods: Patients undergoing complete CRLM resection between 2000 and 2007 were selected from a prospectively maintained database and categorized as receiving SYS or HAI + SYS. Those with pre and/or intraoperative extrahepatic disease, documented death, or recurrence within 30 days of CRLM resection were excluded. Competing risk, Fine and Gray's tests were used to compare SYS versus HAI + SYS for time‐to‐organ recurrence. Results: Of 361 study patients, 153 (42.4%) received SYS and 208 (57.6%) received HAI + SYS. The median follow‐up for survivors was 100 (range = 12–185) and 156 months (range = 18–217) for SYS and HAI + SYS, respectively. The 5‐year cumulative incidence (CI) of any liver recurrence was greater for those receiving SYS (SYS = 41.9% vs. HAI + SYS = 28.6%, p = .005). The 5‐year CI of developing any lung or extrahepatic recurrence for SYS patients was 36.2% and 47.9% compared with 44.5% (p = .242) and 51.7% (p = .551), respectively, in patients receiving HAI + SYS. Conclusion: Despite the reduced dose of SYS, adjuvant HAI + SYS after CRLM resection is not associated with a significantly increased risk of extrahepatic recurrence.

Objective: Parathyroid hormone (PTH) is a key hormone in regulation of calcium homeostasis and its secretion is regulated by calcium. Secretion of PTH is attenuated during intake of nutrients, but the underlying mechanism(s) are unknown. We hypothesized that insulin acts as an acute regulator of PTH secretion. Methods: Intact PTH was measured in plasma from patients with T1D and matched healthy individuals during 4-h oral glucose tolerance tests (OGTT) and isoglycemic i.v. glucose infusions on 2 separate days. In addition, expression of insulin receptors on surgical specimens of parathyroid glands was assessed by immunochemistry (IHC) and quantitative PCR (qPCR). Results: The inhibition of PTH secretion was more pronounced in healthy individuals compared to patients with T1D during an OGTT (decrementalAUC0–240min: −5256 ± 3954 min × ng/L and −2408 ± 1435 min × ng/L, P = 0.030). Insulin levels correlated significantly and inversely with PTH levels, also after adjusting for levels of several gut hormones and BMI (P = 0.002). Expression of insulin receptors in human parathyroid glands was detected by both IHC and qPCR. Conclusion: Our study suggests that insulin may act as an acute regulator of PTH secretion in humans.

BACKGROUND: After resection of colorectal liver metastases (CRLM), recurrent disease in the liver is a major cause of death, but may be reduced with the addition of adjuvant hepatic arterial infusion (HAI) chemotherapy to systemic chemotherapy (SYS). OBJECTIVE: This study investigates organ-specific causes of death in patients receiving adjuvant HAI and SYS compared with adjuvant SYS alone. METHODS: Between 2000 and 2007, patients undergoing complete CRLM resection were identified from a prospectively maintained liver resection database and categorized as receiving HAI+SYS or SYS only. Using newly constructed definitions, mortality was attributed to specific organs (liver, lung, peritoneum, and brain) or infection. Univariate models and cumulative incidence functions were generated using competing risks methods. RESULTS: Of 361 eligible patients, 208 (57.6%) received HAI+SYS and 153 (42.4%) received SYS. The median follow-up among survivors was 142 months (range= 12–217 months). Ten-year overall survival was 50.6% in the HAI+SYS group compared to 30.9% in those receiving SYS (p= 0.004). The 5-year cumulative incidence of liver-related mortality was 6.8% in the HAI+SYS group compared to 14.3% in SYS group (p= 0.007). CONCLUSION: The addition of HAI to systemic chemotherapy after CRLM resection is associated with a 50% reduction in liver-related mortality at 5 years.

Delirium is the most common neuropsychiatric challenge in cancer patients, particularly in the critically ill population. Without a screening method and constant vigilance by providers, delirium is often misdiagnosed. The purpose of our pilot study was to determine if an educational program targeting critical care medicine advanced practice providers (APPs) and fellows in an oncologic intensive care unit would increase APP knowledge of delirium and their level of comfort with delirium screening and management. Thirty-one APPs and fellows participated in the program. Scores on knowledge-based delirium assessments increased significantly after the intervention and at the 3-month follow-up (p < .0001 and p < .0225, respectively). Providers’ comfort with delirium screening and management also improved after the intervention (p = .0020 and p < .0001, respectively) and decreased slightly at the 3-month follow-up (p = .1764 and p = .9840, respectively). A brief and focused APP-led educational initiative successfully improved knowledge of delirium and comfort with screening and management.

Intra-operative hypotension is a known predictor of adverse events and poor outcomes following major surgery. Hypotension often occurs on induction of anaesthesia, typically attributed to hypovolaemia and the haemodynamic effects of anaesthetic agents. We assessed the efficacy of fluid optimisation for reducing the incidence of hypotension on induction of anaesthesia. This prospective trial enrolled 283 patients undergoing radical cystectomy and randomly allocated them to goal-directed fluid therapy (n = 142) or standard fluid therapy (n = 141). Goal-directed fluid therapy patients received fluid optimisation based on stroke volume response to passive leg raise before induction; those with positive passive leg raise received intravenous crystalloid fluid boluses until stroke volume was optimised. Baseline mean arterial pressure was measured on the morning of surgery and on arriving in the operating theatre. This post-hoc analysis defined haemodynamic instability as either a > 30% relative drop in mean arterial pressure compared with baseline or absolute mean arterial pressure < 55 mmHg, within 15 min of induction. Forty-two (30%) goal-directed fluid therapy patients underwent fluid optimisation after finding an intravascular fluid deficit via passive leg raise testing; 106 (75%) goal-directed fluid therapy and 112 (79%) standard fluid therapy patients met criteria for haemodynamic instability. There was no significant difference in the incidence of haemodynamic instability between the goal-directed fluid therapy and standard fluid therapy groups using absolute mean arterial pressure drop below 55 mmHg (p = 0.58) or using pre-surgical testing or pre-surgical mean arterial pressure values as baseline (p = 0.21, p = 0.89, respectively); however, the difference in the incidence of haemodynamic instability was significant using the operating theatre baseline mean arterial pressure (p = 0.004). We conclude that fluid optimisation before induction of general anaesthesia did not significantly impact haemodynamic instability.

Purpose To estimate the incidence of new prescription of enteral opioids on hospital discharge in opioid naive, non-surgical, critically ill patients and evaluate the risk factors associated with such occurrence. Methods Using hospital-wide and ICU databases, we retrospectively identified all patients (≥ 18 years old) who were admitted to the 20-bed adult ICU of Memorial Sloan Kettering Cancer Center (MSKCC) between July 1, 2015 and April 20, 2020. Patients' electronic medical records (EMR) were retrieved and patient demographics, peri-ICU admission data were captured and analyzed. Results During the study period, a total of 3755 opioid naive patients were admitted to the ICU and 848 patients met the inclusion criteria. Among these, 346 (40.8%) patients were discharged with a new opioid prescription. Age at ICU admission, preadmission use of benzodiazepine, and antidepressants, a diagnosis of sepsis, and use of mechanical ventilation, antidepressants or, opioid infusion for greater than 4 h during the ICU stay, hospital length of stay (LOS), and days between ICU discharge and hospital discharge were independently associated with increased odds of a new opioid prescription. Conclusions A significant proportion of opioid naive non-surgical ICU survivors receive a new opioid prescription on hospital discharge.

Background PI3K pathway activation is common in endometrial cancer. We evaluated the safety and efficacy of the dual PI3K/mTOR inhibitor, LY3023414, in patients with advanced endometrial cancer harboring activating mutations in the PI3K pathway. Methods We conducted a single-arm phase 2 study of monotherapy LY3023414. Eligible patients had advanced endometrial cancer of any grade, prior management with 1-4 cytotoxic lines, and PI3K pathway activation prospectively defined as a loss-of-function PTEN alteration or activating alteration in PIK3CA, AKT1, PIK3R1, PIK3R2, or MTOR. The primary objective was best overall response rate (ORR) per RECIST 1.1. Results Twenty-eight patients were treated; histologies included endometroid (39%), carcinosarcoma (25%), serous (21%), and mixed (14%). Patients were heavily pretreated, with a median of 2 prior cytotoxic lines (range, 1-3). The most common alterations involved PIK3CA (68%), PTEN (43%), and PIK3R1 (32%). In the 25 efficacy-evaluable patients, the ORR was 16% (90% CI, 7%-100%), and the clinical benefit rate was 28% (90% CI, 16%-100%). Four patients had a confirmed partial response, and 2 responses lasted for >9 months. The median progression-free survival and overall survival were 2.5 months (95% CI, 1.2-3.0) and 9.2 months (95% CI, 5.0-15.9), respectively. The most common all-grade treatment-related adverse events were anemia (71%), hyperglycemia (71%), hypoalbuminemia (68%), and hypophosphatemia (61%). No correlation between molecular alterations and response was observed. Conclusion In patients with heavily pretreated advanced endometrial cancer prospectively selected for tumors with activating PI3K pathway mutations, LY3023414 demonstrated modest single-agent activity and a manageable safety profile.

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer worldwide. Mortality for CRC is improving in high income countries (HIC), but in low and middle income (LMIC) countries, rates of disease and death from disease are rising. In Sub-Saharan Africa, the ratio of CRC mortality to incidence is the highest in the world. This study investigated the nature of CRC treatment currently being offered and received in Nigeria. METHODS: Between April 2013 and October 2017, a prospective study of consecutively diagnosed cases of CRC was conducted. Patient demographics, clinical features, and treatment recommended and received was recorded for each case. Patients were followed during the study period every three months or until death. RESULTS: Three hundred patients were included in our analysis. Seventy-one percent of patients received a recommended surgical operation. Of those that didn’t undergo surgery as recommended, 37% cited cost as the main reason, 30% declined due to personal reasons, and

Background: Dilating eye drops are routinely used in pediatric retinoblastoma patients during anesthetized ophthalmologic exams. Information on the systemic effects of ocular mydriatics, especially in anesthetized pediatric patients, is limited. Objective: The primary aim of this study was to analyze hemodynamic changes during mydriatic eye drop administration in anesthetized pediatric patients. Methods: A retrospective chart review was performed for pediatric retinoblastoma patients who underwent MRI with anesthesia. Baseline blood pressure (BP) and heart rate (HR) were charted for each patient at induction. HR and mean arterial pressure (MAP) measurements were recorded at 5, 10, 15, 30, and 45 min after eye drop administration. Secondarily, we included data from 15 patients who received dilating eye drops while under sevoflurane general anesthetic. All patients were dilated with phenylephrine 2.5 or 10% (depending on age) and tropicamide 1%. Results: The final analysis included 176 anesthesia encounters. The results demonstrate no statistically significant deviation of more than 20% from baseline for either HR or MAP. Additionally, we did not detect any difference between patients who were anesthetized with propofol versus sevoflurane. Conclusions: We did not observe significant hemodynamic instability with administration of dilating eye drops during propofol anesthesia.

PURPOSE: The aim of this study was to investigate the relationship between CT imaging phenotypes and genetic and biological characteristics in pancreatic ductal adenocarcinoma (PDAC). METHODS: In this retrospective study, consecutive patients between April 2015 and June 2016 who underwent PDAC resection were included if previously consented to a targeted sequencing protocol. Mutation status of known PDAC driver genes (KRAS, TP53, CDKN2A, and SMAD4) in the primary tumor was determined by targeted DNA sequencing and results were validated by immunohistochemistry (IHC). Radiomic features of the tumor were extracted from the preoperative CT scan and used to predict genotype and stromal content. RESULTS: The cohort for analysis consisted of 35 patients. Genomic and IHC analysis revealed alterations in KRAS in 34 (97%) patients, and changes in expression of CDKN2A in 29 (83%), SMAD4 in 16 (46%), and in TP53 in 29 (83%) patients. Models created from radiomic features demonstrated associations with SMAD4 status and the number of genes altered. The number of genes altered was the only significant predictor of overall survival (p = 0.016). By linear regression analysis, a prediction model for stromal content achieved an R(2) value of 0.731 with a root mean square error of 19.5. CONCLUSIONS: In this study, we demonstrate that in PDAC SMAD4 status and tumor stromal content can be predicted using radiomic analysis of preoperative CT imaging. These data show an association between resectable PDAC imaging features and underlying tumor biology and their potential for future precision medicine.

BACKGROUND: Intraductal papillary mucinous neoplasms (IPMN) are cystic precursor lesions of pancreatic adenocarcinoma. Preoperative determination of the grade of dysplasia is difficult, yet necessary for optimal management. Previous data have suggested that serum Neutrophil-to-Lymphocyte Ratio (NLR) has an ability to predict invasive disease in patients with IPMN. METHODS: A prospectively maintained database was queried for consecutive patients who underwent resection of IPMN between 2000 and 2017. Exclusion criteria included recent diagnosis or treatment of non-pancreas associated cancer, immunosuppression, use of immunomodulatory mediations, and infection or jaundice within one month of operation. All patients had a complete blood count (CBC) with differential within 30 days of operation for calculation of NLR. RESULTS: Within the study period, 446 patients underwent resection for IPMN and 348 patients (78%) met inclusion criteria. Low-grade dysplasia was present in 60 patients (17%), 137 patients (39%) had intermediate-grade dysplasia, 76 (22%) had high-grade dysplasia and 75 (22%) had invasive carcinoma. NLR was associated with invasive carcinoma as compared to non-invasive disease (3.00 vs 2.68, p=0.039). There was no difference in NLR between patients with high-risk (invasive and high-grade) lesions and low-risk (low-grade and intermediate-grade) lesions (2.80 vs 2.71, p>0.95). There was also no difference between patients with high-grade dysplasia and those with less than high-grade dysplasia (2.80 vs 2.43, p=0.10). CONCLUSION: NLR was significantly higher in patients with IPMN-associated invasive carcinoma as compared to patients with non-invasive disease, however NLR was not helpful in differentiating between high-grade and low-grade lesions.

Objective To characterize the results of surgery for gastrointestinal stromal tumor (GIST) in the pre and post-imatinib eras at a single institution and to identify current prognostic clinicopathologic factors. Background Imatinib has radically changed the management of GIST, yet the magnitude of impact on outcome across the spectrum of GIST presentation and relevance of historical prognostic factors are not well defined. Methods We retrospectively analyzed 1000 patients who underwent surgery for GIST at our institution from 1982 to 2016. Patients were stratified by presentation status as primary tumor only (PRIM), primary with synchronous metastasis (PRIM + MET), or metachronous recurrence/metastases (MET), and also imatinib era (before and after it became available). Cox proportional-hazard models and Kaplan-Meier methods were used to model and estimate overall survival (OS) and recurrence-free survival (RFS). Results OS was longer in the imatinib era compared with the pre-imatinib era in each presentation group, including in Miettinen high-risk primary tumors. Among PRIM patients from the pre-imatinib era, tumor site, size, and mitotic rate were independently associated with OS and RFS on multivariate analysis. PRIM patients in the imatinib era who received imatinib (neoadjuvant and/or adjuvant) had higher risk tumors, but after adjusting for treatment, only size >10 cm remained independently prognostic of RFS [hazard ratio (HR) 3.85, 95% confidence interval (CI) 2.00-7.40, P Conclusions Patients treated in the imatinib era had prolonged OS across all presentations. In the imatinib era, among site, size, and mitotic rate, high-risk features were associated with treatment with the drug, but only size >10 cm correlated with outcome. Imatinib should still be prescribed for patients with high-risk features.

Background Membrane heat shock protein 70 (mHsp70) is indicative of high-risk tumors and serves as a tumor-specific target for natural killer (NK) cells stimulated with Hsp70 peptide (TKD) and Interleukin(IL)-2. Radiochemotherapy (RCT), mHsp70-targeting NK cells, and programmed death(PD)-1 inhibition were combined to improve the efficacy of tumor-specific immune cells in a non-small cell lung carcinoma (NSCLC) patient. Patient Following simultaneous RCT (64.8 Gy), a patient with inoperable NSCLC (cT4, cN3, cM0, stage IIIb) was treated with 4 cycles of autologous ex vivo TKD/IL-2-activated NK cells and the PD-1 antibody nivolumab as a second-line therapy. Blood samples were taken for immunophenotyping during the course of therapy. Results Adoptive transfer of ex vivo TKD/IL-2-activated NK cells after RCT combined with PD-1 blockade is well tolerated and results in superior overall survival (OS). No viable tumor cells but a massive immune cell infiltration in fibrotic tissue was detected after therapy. Neither tumor progression nor distant metastases were detectable by CT scanning 33 months after diagnosis. Therapy response was associated with significantly increased CD3−/NKG2D+/CD94+ NK cell counts, elevated CD8+ to CD4+ T cell and CD3−/CD56bright to CD3−/CD56dim NK cell ratios, and significantly reduced regulatory T cells (Tregs) in the peripheral blood. Conclusion A combined therapy consisting of RCT, mHsp70-targeting NK cells, and PD-1 antibody inhibition is well tolerated, induces anti-tumor immunity, and results in long-term tumor control in one patient with advanced NSCLC. Further, randomized studies are necessary to confirm the efficacy of this combination therapy.

Purpose: The clinical behavior of ampullary adenocarcinoma varies widely. Targeted tumor sequencing may better define biologically distinct subtypes to improve diagnosis and management. Experimental Design: The hidden-genome algorithm, a multilevel meta-feature regression model, was trained on a prospectively sequenced cohort of 3,411 patients (1,001 pancreatic adenocarcinoma, 165 distal bile-duct adenocarcinoma, 2,245 colorectal adenocarcinoma) and subsequently applied to targeted panel DNA-sequencing data from ampullary adenocarcinomas. Genomic classification (i.e., colorectal vs. pancreatic) was correlated with standard histologic classification [i.e., intestinal (INT) vs. pancreatobiliary (PB)] and clinical outcome. Results: Colorectal genomic subtype prediction was primarily influenced by mutations in APC and PIK3CA, tumor mutational burden, and DNA mismatch repair (MMR)–deficiency signature. Pancreatic genomic-subtype prediction was dictated by KRAS gene alterations, particularly KRAS G12D, KRAS G12R, and KRAS G12V. Distal bile-duct adenocarcinoma genomic subtype was most influenced by copy-number gains in the MDM2 gene. Despite high (73%) concordance between immunomorphologic subtype and genomic category, there was significant genomic heterogeneity within both histologic subtypes. Genomic scores with higher colorectal probability were associated with greater survival compared with those with a higher pancreatic probability. Conclusions: The genomic classifier provides insight into the heterogeneity of ampullary adenocarcinoma and improves stratification, which is dictated by the proportion of colorectal and pancreatic genomic alterations. This approach is reproducible with available molecular testing and obviates subjective histologic interpretation.

Objectives Accurate detection of SARS-CoV-2 RNA is essential to stopping the spread of SARS-CoV-2. The aim of this study was to evaluate the performance of the recently introduced MassARRAY® SARS-CoV-2 Panel and to compare it to the cobas® SARS-CoV-2 Test. Methods The MassARRAY® SARS-CoV-2 Panel consists of five assays targeting different sequences of the SARS-CoV-2 genome. Accuracy was determined using national and international proficiency panels including 27 samples. For clinical evaluation, 101 residual clinical samples were analyzed and results compared. Samples had been tested for SARS-CoV-2 RNA with the cobas® SARS-CoV-2 Test. Results When accuracy was tested with the MassARRAY® SARS-CoV-2 Panel, 25 of 27 (92.6%) samples revealed correct results. When clinical samples were analyzed with the MassARRAY® SARS-CoV-2 Panel and compared to the cobas® SARS-CoV-2 Test, 100 samples showed concordant results. One sample was found to be inconclusive with the MassARRAY® SARS-CoV-2 Panel. When time-to-results were compared, the new assay showed longer total and hands-on times. Conclusions The MassARRAY® SARS-CoV-2 Panel showed a good performance and proved to be suitable for use in the routine diagnostic laboratory. Especially during phases of shortage of reagents and/or disposables, the new test system appears as beneficial alternative to standard assays used for detection of SARS-CoV-2 RNA.

Background Increased bone turnover is frequently observed in advanced cancer and predominantly related to bone metastases or therapy. Cachexia represents an important cause of morbidity and mortality in cancer patients. Key features are weight loss, muscle wasting and chronic inflammation, which induce profound metabolic changes in several organs, including the bone. However, whether cachexia contributes to abnormal bone metabolism in cancer patients is unknown. Aim of the present study was to determine the potential correlation of bone turnover markers with body composition and laboratory parameters in treatment-naïve cancer patients. Methods In this cross-sectional study we measured the levels of carboxy terminal telopeptide of collagen (CTX), an indicator of bone resorption, as well as osteocalcin (Ocn) and procollagen type I N-terminal propeptide (PINP), indicators of bone formation, in 52 cancer patients and correlated with body composition and laboratory parameters. Univariate and multivariate logistic analysis were performed to identify determinants of negative bone remodeling balance, estimated by CTX/Ocn and CTX/PINP ratio. Results Based on weight loss, body mass index and muscle mass, patients were divided into a cachectic (59.6%) and a control (40.4%) group. After correcting for the presence of bone metastases, our results showed a significant upregulation of CTX in cachectic patients compared to non-cachectic cancer patients (median 0.38 vs 0.27 ng/mL, p p = 0.2 and median 32 vs. 26 μg/L, p = 0.5, respectively). In addition, the CTX/Ocn and the CTX/PINP ratio were indicative of bone resorption in 68% and 60% of cachexia patients, respectively (vs. 20% and 31% in the control group, p = 0.002 and p = 0.06). The main determinants of the unbalanced bone turnover were hypoalbuminemia for the CTX/Ocn ratio (OR 19.8, p < 0.01) and high CRP for the CTX/PINP ratio (OR 5.3, p < 0.01) in the multivariate regression analysis. Conclusions CTX is substantially higher in cachectic patients compared to non-cachectic oncological patients and hypoalbuminemia as well as elevated CRP concentrations are independent predictors of a negative bone remodeling balance in cancer patients. These results strongly indicate that cachexia correlates with exacerbated bone turnover in cancer.

Background The aim of this study was to examine feasibility of trial processes and group-based, structured exercise training in patients with first-episode psychosis. Methods Twenty-five patients with first-episode psychosis took part in a two-arm randomised feasibility trial. They were individually randomised (1:1) via a computer-generated randomisation sequence and allocated to either an exercise intervention group (INT) or a control group (CON). Patients allocated to INT completed a physical exercise training programme at moderate-to-vigorous intensity, 1 h three times weekly for 8 weeks. CON patients were encouraged to continue their usual level of activity and were offered the training programme after 8 weeks. Primary outcomes included screening rate, recruitment rate, retention rate, attendance and adverse events. Secondary outcomes included heart rate response during training, cardiovascular health (VO2max, resting heart rate, blood pressure), body composition (muscle mass, fat percentage), muscle strength (sit-to-stand, grip strength, jump height) and balance. Results Recruitment lasted 6 weeks and 86 out of 324 patients (27%) were screened, 71 of whom (83%) were deemed eligible. Twenty-five (35%) accepted inclusion (mean age 25.5; mean body mass index 25.1) and were subsequently randomised (INT = 13, CON = 12). Retention of patients was 76% and 52% at the 8-week and 16-week follow-up, respectively. Attendance was 43% (min. 9%, max. 96%). No significant changes were observed between groups in secondary physiological outcome measures. Conclusions Feasibility was challenged by limited recruitment and retention rates, suggesting that modifications are required if a large-scale randomised controlled trial is to be conducted. Recommendations for modifications are presented and discussed. Trial registration Clinicaltrials.gov, NCT03409393. Retrospectively registered.

INTRODUCTION: Neoadjuvant imatinib (Neo-IM) therapy may facilitate R0 resection in primary gastrointestinal stromal tumors (GISTs) that are large or in difficult anatomic locations. While response to preoperative tyrosine kinase inhibitors is associated with better outcome in metastatic GIST, little is known about prognostic factors after Neo-IM in primary GIST. STUDY DESIGN: Patients with primary GIST with or without synchronous metastases who underwent Neo-IM were retrospectively analyzed from a prospective maintained institutional database for Response Evaluation Criteria in Solid Tumors (RECIST), tumor viability, and mitotic rate. Overall survival (OS) was estimated by Kaplan-Meier and compared by log-rank test. Cox proportionate hazard models were used for univariate and multivariate analysis. RESULTS: One hundred and fifty patients were treated for a median of 7.1 months (range 0.2–160). By RECIST, partial response, stable disease, and progressive disease were seen in 40%, 51%, and 9%, respectively. By pathologic analysis, ≤50% of the tumor was viable in 72%, and the mitotic rate was ≤5/50HPF in 74%. On multivariate analysis, RECIST response and tumor viability were not associated with OS, while post-treatment high mitotic rate (hazard ratio [HR] for death 5.3, CI 2.3–12.4), R2 margins (HR 6.0, CI 2.3–15.5), and adjuvant imatinib (HR 0.4, CI 0.2–0.9) were (p

Purpose: Non–small cell lung cancer (NSCLC) is a fatal disease with poor prognosis. A membrane-bound form of Hsp70 (mHsp70) which is selectively expressed on high-risk tumors serves as a target for mHsp70-targeting natural killer (NK) cells. Patients with advanced mHsp70-positive NSCLC may therefore benefit from a therapeutic intervention involving mHsp70-targeting NK cells. The randomized phase II clinical trial (EudraCT2008-002130-30) explores tolerability and efficacy of ex vivo–activated NK cells in patients with NSCLC after radiochemotherapy (RCT). Patients and Methods: Patients with unresectable, mHsp70-positive NSCLC (stage IIIa/b) received 4 cycles of autologous NK cells activated ex vivo with TKD/IL2 [interventional arm (INT)] after RCT (60–70 Gy, platinum-based chemotherapy) or RCT alone [control arm (CTRL)]. The primary objective was progression-free survival (PFS), and secondary objectives were the assessment of quality of life (QoL, QLQ-LC13), toxicity, and immunobiological responses. Results: The NK-cell therapy after RCT was well tolerated, and no differences in QoL parameters between the two study arms were detected. Estimated 1-year probabilities for PFS were 67% [95% confidence interval (CI), 19%–90%] for the INT arm and 33% (95% CI, 5%–68%) for the CTRL arm (P = 0.36, 1-sided log-rank test). Clinical responses in the INT group were associated with an increase in the prevalence of activated NK cells in their peripheral blood. Conclusions: Ex vivo TKD/IL2-activated, autologous NK cells are well tolerated and deliver positive clinical responses in patients with advanced NSCLC after RCT.

Objectives The objective of this study was to describe practice patterns of anesthetic management during pericardial window creation. Design Retrospective observational cohort study. Setting Single tertiary cancer center. Participants A total of 150 patients treated for cancer between 2011 and 2015 were included in the study. Measurements and Main Results The primary objective was to evaluate anesthetic management in pericardial window creation. Secondary outcomes were 30-day mortality and overall survival after pericardial window creation. Thirty-day mortality was 19.3%, and median survival was 5.84 months. Higher American Society of Anesthesiologists (ASA) physical status of patients was associated with preinduction arterial line placement (51% ASA 3 v 79% ASA 4; p = 0.002) and use of etomidate for anesthetic induction (34% ASA 3 v 60% ASA 4; p = 0.003). However, there was no association between anesthetic management and presence of tamponade in these patients. Cardiac aspirate volume (per 10 mL: odds ratio [OR], 1.02 [95% CI, 1.0-1.04]; p = 0.026) and intraoperative arrhythmia (atrial fibrillation: OR, 6.76 [95% CI, 1.2-37.49]; p = 0.029; sinus tachycardia: OR, 4.59 [95% CI, 1.25-16.90]; p = 0.022) were associated independently with increased 30-day mortality. High initial heart rate (per 10 beats per minute: hazard ratio [HR], 1.18 [95% CI, 1.05-1.33]; p = 0.005) in the operating room and intraoperative sinus tachycardia (HR, 1.86 [95% CI, 1.15-3.03]; p = 0.012) were associated independently with worse overall survival. Conclusion Risk of death after pericardial window creation remains high in patients with cancer. Variations in anesthetic management did not affect survival in oncologic patients with pericardial effusions.

Background DBS in the ventral intermediate nucleus (VIM) of the thalamus has been a revolutionary treatment for patients with essential tremor (ET) by reducing tremor. Unfortunately, some patients develop habituation to DBS and thus experience reduced efficacy and loss of tremor control. There are no standardized methods of addressing habituation to DBS. We propose alternating stimulation patterns as a way to reduce habituation. Methods This was a randomized, placebo-controlled trial for patients with VIM DBS for ET. Patients were randomized to either experimental treatment arm of alternating stimulation patterns on a weekly basis or standard care arm of continuous stimulation settings for 12 weeks. Primary outcome was change in the performance subscale of The Essential Tremor Rating Assessment Scale (TETRAS), which was performed at initial visit and 12-week follow-up. Secondary outcome included change in the activities of daily living subscale of TETRAS. Results Twenty-two patients were enrolled in the trial, and 16 were analyzed at follow-up. Experimental treatment subjects displayed sustained tremor control compared to standard care, as measured by the change in TETRAS performance subscale (-0.6 vs. 6.7 point change, respectively) with a 7.3 difference between the arms (P = 0.006). Conclusion Alternating stimulation patterns on a weekly basis for ET patients with VIM DBS reduced habituation in this pilot study. This study suggests that exposure to different stimulation groups may maintain better tremor control compared to constant stimulation parameters.

BACKGROUND Colorectal cancer (CRC) rates in low-resource countries, which typically lack CRC screening programs, are rising. This study determined whether a risk model for patients with rectal bleeding could identify patients with curable CRC. METHODS This prospective, cross-sectional study evaluated a model constructed from data from 1 hospital and validated at 2 other hospitals. The primary endpoint was the ability of the model to predict CRC, as diagnosed by colonoscopy, from clinical characteristics. The secondary endpoint was to determine the percentage of patients who had CRC. RESULTS Consecutive patients who were 45 years old or older and had self-reported rectal bleeding for more than 1 week were evaluated. From January 2014 to July 2016, 362 patients answered a questionnaire and underwent colonoscopy. In the validation cohort, 56% of patients with rectal bleeding, weight loss, and changes in bowel habits had CRC, whereas 2% of patients with bleeding alone did. Overall, 18.2% of the patients had CRC, and 8.6% had adenomas. The proportion of CRC patients with potentially curable stage II or III disease was 74%, whereas the historical rate was 36%. The combination of rectal bleeding with both symptoms significantly predicted CRC in the validation set (odds ratio, 12.8; 95% confidence interval, 4.6-35.4; P

Guidelines recommend vaccination starting 12 months after autologous hematopoietic stem cell transplant (aHCT), but there is varying practice for patients on maintenance therapy, with some centers not immunizing at all. Because of decreased vaccine rates among the general population causing loss of herd immunity, we aimed to establish the safety and efficacy of revaccinating multiple myeloma patients on lenalidomide maintenance (LM). Of the 122 patients who were vaccinated after aHCT between 2010 and 2014 at Memorial Sloan Kettering Cancer Center, 91 (75%) were on LM. Vaccine responses were defined by increases between pre- and postvaccination titers. Reponses varied by vaccine type with 76% responding to pertussis, 70% diphtheria, 60% tetanus, 71% Haemophilus influenzae, and 58% pneumococcal. All patients retained minimal levels of polio immunity, but 27% responded with increased titers. Fewer patients received hepatitis A and B, but of those who did, 30% responded to hepatitis A and 40% to hepatitis B. No differences were seen in rates of response for those on LM at time of vaccination compared with those who were not. There were no vaccine-related adverse effects. Reimmunization with inactivated vaccines in patients on LM is therefore both safe and effective, offering this population immunity to vaccine-preventable diseases.

Introduction Trastuzumab with systemic chemotherapy has shown an improvement in outcomes for patients (pts) with HER2 amplified/overexpressed (HER2+) breast cancer. Pts enrolled onto trials were young with a minority of pts at ≥65 years (yrs) of age. Herein, we report the administration of systemic treatment (ST) (chemotherapy and/or trastuzumab) verus no treatment in elderly pts at a single center. Methods Patients ≥65 yrs with stage I-III HER2+ (defined as IHC 3+ or FISH >2.0) breast cancer, treated at Memorial Sloan Kettering Cancer Center between 2000-2012, were retrospectively identified from our database. Clinicopathologic features were retrieved and co-morbidity indexes (CI) were calculated. Pts were divided by hormone receptor (HR) (defined as ER >10% and/or PR >10%) status into HER2+HR- and HER2+HR+. Each group was further divided by use of ST into: chemotherapy and trastuzumab (CT+T), chemotherapy alone (CT) or no systemic treatment (No Rx). Patients receiving neoadjuvant ST or trastuzumab only as ST were excluded from the KM analysis. Primary objective was to identify patterns of treatment recommendation in the elderly population. We explored disease-free survival (DFS) as estimated using the Kaplan-Meier (KM) method. Results We identified 300 pts ≥65 yrs with HER2+ tumors. 128 (42.7%) were HER2+HR- and 172 (57.3%) were HER2+HR+. The median follow-up for all patients was 6.1 years (range, 0.07-16.7). In the HER2+HR- group, 63 (49.2%) patients received CT+T, 25 (19.5%) CT alone, and 40 (31.3%) had no Rx. Anthracycline based chemotherapy was administered to 57/88 (65%) of patients on CT. Women receiving chemotherapy with or without trastuzumab were younger (65-70 vs >70 years of age) (p=.002) and had more advanced tumor stages (p=.003). Their respective 5-yr DFS KM estimates were 0.84, 0.80, and 0.61 (logrank p=0.06). In the HER2+HR+ group, 77 (44.8%) patients received CT+T, 22 (12.8%) CT alone, and 73 (42.2%) had no Rx. Anthracycline based chemotherapy was administered to 51/99 (51%) of patients on CT. Endocrine therapy was given to 153/172 (89%) of the total cohort. Women receiving chemotherapy with or without trastuzumab were younger (p Conclusions At a single center, in the elderly populations at ≥65 years of age with HER2+ HR- and HER2+HR+ breast cancer, pts who received systemic treatment were younger and had higher stage of disease than those who received no treatment. In an exploratory analysis, there appeared to be a benefit of systemic treatment in pts in the HER+HR- group. Citation Format: Muhsen S, Dang C, Plitas G, Seier K, Stempel M, Patil S, Morrow M, El-Tamer M. Chemotherapy with and without trastuzumab or no treatment in elderly patients with HER2 amplified breast cancer at a single center [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-13-07.

Background: Cyclooxygenase (COX) activity is increased in endoscopic normal colonic mucosa from patients with colorectal neoplasia (CRN). COX-2 is thought to be the predominant COX isozyme involved in neoplasia. Meanwhile, relative contributions of COX-1 and COX-2 isoforms are unknown. Knowledge about their mutual activity in colonic mucosa is important for diagnostics and targeted therapy for CRN. The aim of this study was to assess the relative function, expression and localization of COX-1 and COX-2 enzymes in colonic non-neoplastic human mucosa and thereby to potentially reveal a mucosal disease predisposition for better treatment. Methods: Biopsies were pinched from normal appearing colonic mucosa in patients undergoing endoscopy. Ussing chamber technique was applied for an indirect assessment of epithelial activity, RT-qPCR for expression and immunohistochemistry for localization of COX-1 and COX-2 enzymes in patients without (ctrls) and with a history of CRN (CRN-pts). Results: Combined COX-1 and COX-2 activity was higher in CRN-pts, p=0.036. COX-2 was primarily localized in absorptive cells, while COX-1 appeared to be restricted to nonenteroendocrine tuft cells of the colonic epithelium. Conclusions: In biopsies from endoscopic normal appearing colonic mucosa, combined activity of COX-1 and COX-2 enzymes is increased in CRN-pts compared with ctrls. This indicates that COX-1 and COX-2 together contribute to an increased proliferation process. Of note, in colonic epithelial cell lining, the COX-1 enzyme seems localized in tuft cells.

Background The reversal agent sugammadex has been shown to be more efficacious at reversal from neuromuscular blockade (NMB) induced by the aminosteroid class of non-depolarizing muscle relaxants than the traditionally used medication neostigmine. However, whether these differences lead to significantly faster PACU discharge readiness remains unknown. Given the increased acquisition cost of sugammadex as compared to neostigmine we compared these two reversal agents in our surgical population to determine if its pharmacokinetic superiority warranted a change in current practice. Methods We conducted a single-center randomized patient and assessor blinded clinical trial. A total of 201 patients presenting for surgery requiring NMB with an estimated duration of ≤ 6 hours were included in the intention-to-treat (ITT) analysis. The primary outcome was time from reversal agent administration to PACU discharge readiness, measured by either the institutional discharge scoring tool or bedside clinical assessment by a PACU physician or advanced practice provider. Secondary outcomes included subjective assessment of recovery by the patient (pain, visual changes, speaking difficulty, swallowing difficulty, PONV, anxiety) and a simple strength assessment. Results Median time from reversal administration to PACU discharge readiness was 3.59 hours (IQR 2.49-5.09) in the neostigmine group and 3.62 hours (IQR 2.70-5.87) in the sugammadex group. Patients who received sugammadex had 8% longer reversal to PACU discharge times (exp(estimate) 1.08, 95% CI [0.87-1.34], p=0.499). Patients age 70 or older had 28% longer reversal to PACU discharge times (exp(estimate) of 1.28, 95% CI [0.91-1.80], P=0.158). In the a modified ITT analysis, sugammadex patients were estimated to be in PACU 13% longer than neostigmine arm patients (exp(estimate) 1.13, 95% CI [0.91-1.40], p=0.265) and patients older than or equal to 70 years 31% longer than patients less than 70 years old (exp(estimate) 1.31, 95% CI [0.93-1.84], p=0.121). Treatment arm was not associated with any of the secondary outcomes. Conclusion There was no significant difference in time to readiness to discharge from PACU, and there were no subjective or objective clinically relevant differences in recovery from neuromuscular blockade between the groups. Findings of this study support continued use of either agent at the anesthesiologist's discretion.

PURPOSE: Clinician gestalt may hold unexplored information that can be capitalized upon to improve existing nomograms. The study objective was to evaluate physician ability to predict 2-year overall survival (OS) in resected pancreatic ductal adenocarcinoma (PDAC) patients based on preoperative clinical characteristics and routine CT imaging. METHODS: Ten surgeons and two radiologists were provided with a clinical vignette (including age, gender, presenting symptoms, and pre-operative CA19-9 when available) and preoperative CT scan for 20 resected PDAC patients and asked to predict the probability of each patient reaching 2-year OS. Receiver operating characteristic curves were used to assess agreement and to compare performance with an established institutional nomogram. RESULTS: Ten surgeons and 2 radiologists participated in this study. The area under the curve (AUC) for all physicians was 0.707 (95%CI 0.642–0.772). Attending physicians with >5 years experience performed better than physicians with

Energy systems with a high share of renewable electricity generation face a challenge associated with surplus electricity generation. Flexibility options may help to integrate renewable electricity and reduce the need for electricity from fossil fuels. Load shifting is one of the flexibility options that lead to residual load smoothing in energy systems. In this paper, the effects of load shifting by dynamic electricity purchase on future residual load smoothing was assessed using wastewater treatment plants (WWTPs) in Germany as a case study. As dynamic electricity purchase is motivated economically, a consumer’s demand for supplying flexibility options needs a price signal. Therefore, electricity wholesale prices on an hourly basis were modeled for 2030 using a merit order simulation for two scenarios. Relevant data for WWTPs was obtained from primary data suppliers, which was then aggregated. The effects on residual load smoothing were assessed by optimizing WWTPs electricity purchase costs on a daily basis. Our results show that German WWTPs have a potential to integrate 120 MWel of surplus electric power. The developed methodology has a high potential to be applied to other potential load shifting actors when assessing the potential of residual load smoothing and renewable electricity integration. This can be achieved by adapting boundary constraints to other electricity consumers.

Objective:To compare motor and nonmotor outcomes at 6 months of asleep deep brain stimulation (DBS) for Parkinson disease (PD) using intraoperative imaging guidance to confirm electrode placement vs awake DBS using microelectrode recording to confirm electrode placement.Methods:DBS candidates with PD referred to Oregon Health & Science University underwent asleep DBS with imaging guidance. Six-month outcomes were compared to those of patients who previously underwent awake DBS by the same surgeon and center. Assessments included an “off”-levodopa Unified Parkinson’s Disease Rating Scale (UPDRS) II and III, the 39-item Parkinson's Disease Questionnaire, motor diaries, and speech fluency.Results:Thirty participants underwent asleep DBS and 39 underwent awake DBS. No difference was observed in improvement of UPDRS III (+14.8 ± 8.9 vs +17.6 ± 12.3 points, p = 0.19) or UPDRS II (+9.3 ± 2.7 vs +7.4 ± 5.8 points, p = 0.16). Improvement in “on” time without dyskinesia was superior in asleep DBS (+6.4 ± 3.0 h/d vs +1.7 ± 1.2 h/d, p = 0.002). Quality of life scores improved in both groups (+18.8 ± 9.4 in awake, +8.9 ± 11.5 in asleep). Improvement in summary index (p = 0.004) and subscores for cognition (p = 0.011) and communication (p < 0.001) were superior in asleep DBS. Speech outcomes were superior in asleep DBS, both in category (+2.77 ± 4.3 points vs −6.31 ± 9.7 points (p = 0.0012) and phonemic fluency (+1.0 ± 8.2 points vs −5.5 ± 9.6 points, p = 0.038).Conclusions:Asleep DBS for PD improved motor outcomes over 6 months on par with or better than awake DBS, was superior with regard to speech fluency and quality of life, and should be an option considered for all patients who are candidates for this treatment.Clinicaltrials.gov identifier:NCT01703598.Classification of evidence:This study provides Class III evidence that for patients with PD undergoing DBS, asleep intraoperative CT imaging–guided implantation is not significantly different from awake microelectrode recording–guided implantation in improving motor outcomes at 6 months.

Objective To investigate hepatic and adipose tissue macrophage content in subjects with obesity and the role of adipose tissue macrophages in weight loss-induced improved insulin sensitivity (IS). Methods A cross-sectional and a longitudinal study were combined to investigate the role of macrophages in subcutaneous (SAT) and visceral (VAT) adipose tissue and the liver in obesity-induced impaired IS and improvements with weight loss. Macrophage markers (CD68, CD163, and CD206) in SAT, VAT, and the liver from patients with obesity were investigated. The same macrophage markers were investigated in SAT from 18 patients with obesity before and ∼18 months after a diet- and Roux-en-Y gastric bypass-induced weight loss. Results SAT macrophage markers did not decrease with weight loss, but macrophage concentration may have increased, concomitant with improved IS. Hepatic macrophage markers did not correlate to VAT mass or macrophage markers, but they were higher in patients with obesity compared with patients without obesity. Hepatic anti-inflammatory macrophage markers correlated positively with hepatic IS. VAT and SAT macrophage markers did not correlate. Conclusions The results indicate that decreased SAT macrophage content is not a primary driver for weight loss-induced IS improvements, but a better hepatic CD163 and CD206 macrophage profile may contribute to improved glycemic control. SAT macrophage markers were not predictive for VAT macrophage markers.

In 2015, the American Gastroenterological Association recommended the discontinuation of radiographic surveillance after 5 years for patients with stable pancreatic cysts. The current study evaluated the yield of continued surveillance of pancreatic cysts up to and after 5 years of follow up.A prospectively maintained registry of patients evaluated for pancreatic cysts was queried (1995-2016). Patients who initially underwent radiographic surveillance were divided into those with5 years and ≥5 years of follow up. Analyses for the presence of cyst growth (5 mm increase in diameter), cross-over to resection, and development of carcinoma were performed.A total of 3024 patients were identified, with 2472 (82%) undergoing initial surveillance. The ≥5 year group (n = 596) experienced a greater frequency of cyst growth (44% vs. 20%; P0.0001), a lower rate of cross-over to resection (8% vs 11%; P = 0.02), and a similar frequency of progression to carcinoma (2% vs 3%; P = 0.07) compared with the5 year group (n = 1876). Within the ≥5 year group, 412 patients (69%) had demonstrated radiographic stability at the 5-year time point. This subgroup, when compared with the5 year group, experienced similar rates of cyst growth (19% vs. 20%; P= 0.95) and lower rates of cross-over to resection (5% vs 11%; P0.0001) and development of carcinoma (1% vs 3%; P= 0.008). The observed rate of developing cancer in the group that was stable at the 5-year time point was 31.3 per 100,000 per year, whereas the expected national age-adjusted incidence rate for this same group was 7.04 per 100,000 per year.Cyst size stability at the 5-year time point did not preclude future growth, cross-over to resection, or carcinoma development. Patients who were stable at 5 years had a nearly 3-fold higher risk of developing cancer compared with the general population and should continue long-term surveillance.

Following the acute phase of a myocardial infarction, a set of structural and functional changes evolves in the myocardium, collectively referred to as cardiac remodeling. This complex set of processes, including interstitial fibrosis, inflammation, myocyte hypertrophy and apoptosis may progress to heart failure. Analogs of the incretin hormone glucagon-like peptide 1 (GLP-1) have shown some promise as cardioprotective agents. We hypothesized that a long-acting GLP-1 analog liraglutide would ameliorate cardiac remodeling over the course of 4 weeks in a rat model of non-reperfused myocardial infarction. In 134 male Sprague Dawley rats myocardial infarctions were induced by ligation of the left anterior descending coronary artery. Rats were randomized to either subcutaneous injection of placebo or 0.3mg liraglutide once daily. Cardiac magnetic resonance imaging was performed after 4 weeks. Histology of the infarcted and remote non-infarcted myocardium, selected molecular remodeling markers and mitochondrial respiration in fibers of remote non-infarcted myocardium were analyzed. Left ventricular end diastolic volume increased in the infarcted hearts by 62% (from 0.58±0.03mL to 0.95±0.07mL, P

Background Low central venous pressure (LCVP) anesthesia reduces blood loss during hepatic resection and historically has required a central venous catheter (CVC) for intra-operative monitoring. The aim of this study was to assess the effect of an evolution of practice to CVP monitoring without CVC on the perioperative outcomes after liver resection. Methods A retrospective study of partial hepatectomy patients from 2007 to 2016 who were over 18 years of age was performed. Results Of 3903 patients having partial hepatectomy, 2445 (62%) met inclusion criteria, and 404 (16%) had a CVC. Overall morbidity (33% non-CVC vs 38% CVC P = 0.076), major morbidity (16% vs 20% P = 0.067), and infective complications (superficial wound infection) 3% vs 4% P = 0.429; deep wound infection (5% vs 6% P = 0.720) did not differ between the two groups. In multivariate analysis, superficial wound infection, deep wound infection, and major complications were not associated with the presence of a CVC. All-cause mortality at 90 days was associated with CVC presence (OR 3.45, CI 1.74–6.85, P = 0.001) and age (OR 1.05, CI 1.02–1.08, P Conclusion Since the adoption of non-invasive CVP monitoring, there has been no increase in adverse peri-operative outcomes.

Objectives To assess public perceptions regarding ovarian cancer (OC) care delivery. Methods The 2018 Empire State Poll, conducted by the Survey Research Institute of Cornell University (February-April/2018), was the 16th annual survey of New York State residents. We contributed questions regarding OC care delivery. Results 800 residents were surveyed: median age 48 years (range 18–94), 50% female, 47% married, 64% White. 55% of respondents with an OC diagnosis would seek evaluation by an oncologist first. Those with household incomes >$75,000 were more likely to do so (OR=1.43, 95% CI1.04–1.95); those who identified as ‘Other’ race (OR=0.48, 95%CI 0.32–0.73) or unmarried (OR=0.73, 95%CI 0.54–1.0) were less likely. 81% were willing to travel >2 hours for surgery, 55% >4 hours. Older (OR=1.67, 95%CI 1.13–2.46) and unemployed (OR=1.58, 95%CI 1.07–2.34) respondents were less willing to travel. 46% relied on referral from primary care physicians (PCPs) in choosing an OC doctor; 21% relied on internet research. Females (OR 0.61, 95%CI 0.46–0.81) and those with some college education (OR 0.65, 95%CI 0.47–0.88) were less likely to depend on physician referral; respondents >48 years of age (OR 1.49, 95%CI 1.12–1.98) were more likely. Conclusions Despite data demonstrating improved outcomes for women with OC seeking treatment with high-volume providers, only half of respondents recognize the importance of subspecialty care. Historically disenfranchised populations are less likely to seek subspecialty care and are less likely to travel. PCPs significantly influence patient decision-making. These data identify vulnerable populations, providing a springboard for public awareness and access initiatives.

OBJECTIVE: We sought to define the prognostic significance of histologic subtype for extremity/truncal liposarcoma (LPS). SUMMARY OF BACKGROUND DATA: LPS, the most common sarcoma, is comprised of five histologic subtypes. Despite their distinct behaviors, LPS outcomes are frequently reported as a single entity. METHODS: We analyzed data on all patients from a single-institution prospective database treated from July 1982 to September 2017 for primary, non-metastatic, extremity or truncal LPS of known subtype. Clinicopathologic variables were tested using competing risk analyses for association with disease-specific death (DSD), distant recurrence (DR), and local recurrence (LR). RESULTS: Among 1001 patients, median follow-up in survivors was 5.4 years. Tumor size and subtype were independently associated with DSD and DR. Size, subtype, and R1 resection were independently associated with LR. DR was most frequent among pleomorphic and round cell LPS; the former recurred early (43% by 3 years), and the latter over a longer period (23%, 3 years; 37%, 10 years). LR was most common in dedifferentiated LPS, in which it occurred early (24%, 3 years; 33%, 5 years), followed by pleomorphic LPS (18%, 3 years; 25%, 10 years). CONCLUSIONS: Histologic subtype is the factor most strongly associated with DSD, DR, and LR in extremity/truncal LPS. Both risk and timing of adverse outcomes vary by subtype. These data may guide selective use of systemic therapy for patients with round cell and pleomorphic LPS, which carry a high risk of DR, and radiotherapy for LPS subtypes at high risk of LR when treated with surgery alone.

We have previously shown that totally pancreatectomized patients (PX) and patients with type 2 diabetes (T2D) exhibit hypersecretion of glucagon in response to oral glucose stimulation whereas intravenous glucose suppresses plasma concentrations of glucagon. Here, we evaluated the expression of the gene encoding glucagon (GCG), glucagon peptide content and density of glucagon-positive cells in mucosal biopsies from the upper gastrointestinal tract of PX patients, patients with T2D and nondiabetic controls. Eight PX patients, eight patients with T2D and eight sex, age and BMI-matched healthy controls underwent upper enteroscopy with intestinal biopsy sampling followed by an intraluminal infusion of 100 ml 50% (w/v) glucose solution with frequent blood sampling. The mucosal biopsies were subjected to mRNA sequencing, immunohistochemistry using a new glucagon-directed C-terminal monoclonal antibody, peptide extraction and subsequent measurements of tissue concentrations of glucagon and other proglucagon-derived peptides. GCG expression in the small intestine was 3 to 4-fold higher in PX and T2D patients compared to controls (P Disclosure M. Baekdal: None. A.B. Lund: None. N.J. Wewer Albrechtsen: Research Support; Self; Mercodia, Novo Nordisk A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp. J.I. Egholk: None. T. Jorsal: None. C.T. Juel: None. K.D. Galsgaard: None. J. Hunt: None. J.F. Rehfeld: None. K. Rigbolt: Employee; Self; Gubra. Stock/Shareholder; Self; Gubra. S.U. Friis: Stock/Shareholder; Self; Alk-Abello B, Bavarian Nordic, H. Lundbeck A/S, Lundbeck, Novo Nordisk A/S. C. Orskov: None. S.S. Poulsen: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. T. Vilsbøll: None. F.K. Knop: Advisory Panel; Self; AstraZeneca, MedImmune, Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk A/S, Sanofi. Consultant; Self; Amgen Inc., Carmot Therapeutics, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, MedImmune, Merck Sharp & Dohme Corp., Mundipharma, Norgine, Novo Nordisk A/S. Funding European Foundation for the Study of Diabetes; Novo Nordisk Foundation; Aase og Ejnar Danielsens Foundation; A.P. Møller Foundation

Testosterone has in recent years been proven essential for normal growth and maturation of small growing follicles. Concomitantly, low functional ovarian reserve (LFOR), characterized by a small growing follicle pool, has been associated with low testosterone levels, which can be of ovarian and/or adrenal origin. In this study we, therefore, investigated whether peripheral sex steroid precursors and testosterone levels potentially reflect on adrenal function. In a retrospective cohort study of 355 consecutive infertile women, who presented to an academically affiliated fertility center in New York City, we investigated in a series of statistical models whether low peripheral sex steroid precursors and testosterone are associated with peripheral cortisol (C) levels, reflecting adrenal function. To determine potential correlations, we investigated the dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), androstenedione (AD), total testosterone (TT), free testosterone (FT); sex hormone binding globulin (SHBG), anti-Mullerian hormone (AMH), thyroid stimulating hormone (TSH) and C in a series of multivariate and logistic regression analyses, utilizing C either as a continuous variable or with cut off