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Background The incidence of fatal and near-fatal outcomes after perioperative anaphylaxis is unknown in the USA. Previously identified risk factors of neuromuscular-blocker-induced fatal perioperative anaphylaxis include male sex, obesity, and use of beta blockers. We examined the incidence of fatal and near-fatal outcomes after perioperative anaphylaxis in the USA and the underlying risk factors using a large national database. Methods Using the Nationwide Inpatient Sample from 2005 to 2014, we identified cases of fatal and near-fatal perioperative anaphylaxis, defined as perioperative anaphylaxis cases complicated by respiratory or cardiac arrest, using the International Classification of Diseases, Ninth Revision, Clinical Modification codes. Results Amongst 5223 perioperative anaphylaxis cases, the proportion of near-fatal or fatal cases attributable to perioperative anaphylaxis was 7.0% (95% confidence interval [CI]: 6.2–7.7), with near-fatal perioperative anaphylaxis cases accounting for 5.0% (95% CI: 4.4–5.6%) and fatal cases accounting for 2.0% (95% CI: 1.5–2.5%) of cases overall. Thus, the incidence of fatal or near-fatal perioperative anaphylaxis is 1.26 in 100 000 procedures. Risk factors for fatal or near-fatal perioperative anaphylaxis include age (≥65 yr); undergoing a cardiac procedure; and comorbid conditions of weight loss, non-metastatic solid tumours, metastatic cancer, paralysis, coagulopathy, renal failure, congestive heart failure, fluid and electrolyte disorder, and neurological disorders. Individuals with near-fatal or fatal perioperative anaphylaxis reactions had increased lengths of stay and hospital costs compared with controls. Conclusions The incidence of fatal or near-fatal perioperative anaphylaxis in the USA was 1.26 in 100 000 procedures. Risk factors for fatal or near-fatal outcomes include older age, cardiac procedures, and specific comorbidities.

Objective: Pancreatic cancer activates coagulation and increases risk of venous thromboembolism (VTE). We aimed at characterizing the association of hemostatic biomarkers and VTE with mortality and chemotherapy response. Approach and Results: Pancreatic cancer patients (N=145) were included in a prospective, observational cohort study (CATS [Vienna Cancer and Thrombosis Study]). Hemostatic biomarkers (D-dimer, extracellular vesicle–tissue factor activity, prothrombin fragment 1+2, fibrinogen, factor VIII, PAI-1 [plasminogen activator inhibitor 1], sP-selectin [soluble P-selectin], thrombin generation assay) were measured at inclusion. The impact of VTE on overall survival/progression-free survival (OS/PFS) was evaluated by multistate modeling. The association of biomarkers with OS was analyzed by Cox-regression and with PFS and disease control rate in patients initiating palliative chemotherapy (n=95) by Cox-regression and logistic regression. Multivariable analysis included stage, grade, sex, age, performance status, VTE (time-dependent), vascular infiltration/compression, and tumor marker levels (carbohydrate-antigen 19-9, carcinoembryonic antigen). VTE occurrence was associated with shorter OS (transition hazard ratio, 3.40 [95% CI, 2.05–5.64]) and shorter PFS (transition hazard ratio, 2.10 [1.16–3.79]). Median post-VTE OS/PFS in months was 5.5 [2.2–6.5] and 3.0 [1.5–3.9], compared with 13.4 [9.7–16.6] and 7.5 [5.9–9.8] in patients without VTE (both P Conclusions: VTE diagnosis is associated with shorter OS and PFS. Higher baseline levels of D-dimer, extracellular vesicle–tissue factor activity, PAI-1, and sP-selectin were independently prognostic for increased mortality, and D-dimer predicted response to palliative chemotherapy. Graphic Abstract: A graphic abstract is available for this article.

Personalized medicine aims to match the right drug with the right patient by using specific features of the individual patient's tumor. However, current strategies of personalized therapy matching provide treatment opportunities for less than 10% of patients with cancer. A promising method may be drug profiling of patient biopsy specimens with single-cell resolution to directly quantify drug effects. We prospectively tested an image-based single-cell functional precision medicine (scFPM) approach to guide treatments in 143 patients with advanced aggressive hematologic cancers. Fifty-six patients (39%) were treated according to scFPM results. At a median follow-up of 23.9 months, 30 patients (54%) demonstrated a clinical benefit of more than 1.3-fold enhanced progression-free survival compared with their previous therapy. Twelve patients (40% of responders) experienced exceptional responses lasting three times longer than expected for their respective disease. We conclude that therapy matching by scFPM is clinically feasible and effective in advanced aggressive hematologic cancers. Significance: This is the first precision medicine trial using a functional assay to instruct n-of-one therapies in oncology. It illustrates that for patients lacking standard therapies, high-content assay-based scFPM can have a significant value in clinical therapy guidance based on functional dependencies of each patient's cancer. See related commentary by Letai, p. 290. This article is highlighted in the In This Issue feature, p. 275

Male hypogonadism is defined as an abnormally low serum testosterone concentration or sperm count. As men age, often in the context of obesity and other comorbid conditions, serum testosterone levels may decrease. Normalizing serum testosterone levels in male adults with hypogonadism may improve symptoms related to androgen deficiency, but controversies exist regarding the long-term benefits and risks of hormone supplementation in this setting. In 2020, the American College of Physicians published a clinical guideline for the use of testosterone supplementation in adult men based on a systematic review of available evidence. Among their recommendations were that clinicians discuss whether to initiate testosterone treatment in men with age-related low testosterone with sexual dysfunction who want to improve sexual function and not initiate testosterone treatment in men with age-related low testosterone to improve energy, vitality, physical function, or cognition. Here, two clinicians with expertise in this area, one a generalist and the other an endocrinologist, debate the management of a patient with sexual symptoms and a low serum testosterone level. They discuss the diagnosis of male hypogonadism, the indications for testosterone therapy, its potential benefits and risks, how it should be monitored, and how long it should be continued.

Perioperative anaphylaxis (PA) is a rare but life-threatening condition that poses diagnostic and management challenges in the operating room. The incidence of severe perioperative reactions is estimated to be approximately 1:7000-10,000. Management involves both immediate stabilization of the patient and identifying the culprit agent. Identification is essential to prevent recurrence of the event in subsequent surgeries and to avoid unnecessary labeling of drug allergy. Identifying all possible exposures including medications, disinfectants, latex, and dyes and choosing the appropriate tests are essential for proper evaluation. To identify the culprit, primary testing modalities include tryptase at the time of the reaction with subsequent levels and skin testing with nonirritating concentrations to the medications and substances utilized during the procedure and those potentially used as alternates. This strategy provides guidance for future surgeries and procedures. Close collaboration between the allergy, anesthesiology, and surgery teams is essential for appropriate management of these patients at the time of the reaction, during the post event evaluation and in preparation for subsequent surgeries.

Aim: To survey European physicians managing patients with metastatic pancreatic ductal adenocarcinoma (PDAC) and understand differences in baseline characteristics, diagnostic methods, symptoms and co-morbidities. Materials & methods: Patient record inclusion criteria were: ≥18 years old, metastatic PDAC diagnosis and completion of first-line treatment between July 2014 and January 2016. Records were grouped by patient age, gender and primary tumor location. Results: Records (n = 2565) were collected from nine countries. Baseline characteristics varied between subgroups. Computed tomography was the most frequently used diagnostic technique. Symptoms at diagnosis included abdominal and/or mid-back pain (72% of patients) and weight loss (61.5%). Co-morbidities varied with patient age. Conclusion: Greater awareness of symptoms, diagnostic methods and co-morbidities present at PDAC diagnosis may support better patient management decisions.

Background: Heart failure is a leading cause of death worldwide and is associated with the rising prevalence of obesity, hypertension, and diabetes. O -GlcNAcylation (the attachment of O -linked β-N-acetylglucosamine [ O -GlcNAc] moieties to cytoplasmic, nuclear, and mitochondrial proteins) is a posttranslational modification of intracellular proteins and serves as a metabolic rheostat for cellular stress. Total levels of O -GlcNAcylation are determined by nutrient and metabolic flux, in addition to the net activity of 2 enzymes: O -GlcNAc transferase (OGT) and O -GlcNAcase (OGA). Failing myocardium is marked by increased O -GlcNAcylation, but whether excessive O -GlcNAcylation contributes to cardiomyopathy and heart failure is unknown. Methods: We developed 2 new transgenic mouse models with myocardial overexpression of OGT and OGA to control O -GlcNAcylation independent of pathologic stress. Results: We found that OGT transgenic hearts showed increased O -GlcNAcylation and developed severe dilated cardiomyopathy, ventricular arrhythmias, and premature death. In contrast, OGA transgenic hearts had lower O -GlcNAcylation but identical cardiac function to wild-type littermate controls. OGA transgenic hearts were resistant to pathologic stress induced by pressure overload with attenuated myocardial O -GlcNAcylation levels after stress and decreased pathologic hypertrophy compared with wild-type controls. Interbreeding OGT with OGA transgenic mice rescued cardiomyopathy and premature death, despite persistent elevation of myocardial OGT. Transcriptomic and functional studies revealed disrupted mitochondrial energetics with impairment of complex I activity in hearts from OGT transgenic mice. Complex I activity was rescued by OGA transgenic interbreeding, suggesting an important role for mitochondrial complex I in O -GlcNAc–mediated cardiac pathology. Conclusions: Our data provide evidence that excessive O -GlcNAcylation causes cardiomyopathy, at least in part, attributable to defective energetics. Enhanced OGA activity is well tolerated and attenuation of O -GlcNAcylation is beneficial against pressure overload–induced pathologic remodeling and heart failure. These findings suggest that attenuation of excessive O -GlcNAcylation may represent a novel therapeutic approach for cardiomyopathy.

Hereditary angioedema (HAE) is a disease manifested by repeated episodes of localized submucosal or subcutaneous edematous episodes, potentially triggered by emotional stress, mechanical trauma, or intake of estrogens. We present our experience managing two parturients with HAE. Multidisciplinary care is essential for planning and executing the specialized care of these patients, and management included extensive planning among obstetric, anesthesiology, and allergy and immunology teams. Pregnancy has been shown to have a variable effect on triggering HAE episodes. First-line treatment includes C1 esterase inhibitor concentrate, which can also be used for prophylaxis in high-risk patients. Neuraxial analgesia is recommended to avoid general anesthesia and was established early in both individuals. Vaginal delivery was well tolerated without need for emergent treatment for angioedema symptoms.

Cannabis includes 140 active cannabinoid compounds, the most important of which are tetrahydrocannabinol and cannabidiol (CBD). Tetrahydrocannabinol is primarily responsible for the intoxicating effects of cannabis; CBD has potential therapeutic effects, including reduction in chronic pain. Recent legislative changes have resulted in the legal availability of cannabinoids in all 50 states, as well as a marked increase in patients' interest in their use. Despite an abundance of data, albeit of varied quality, clinicians may feel poorly prepared to counsel patients seeking advice on the suitability of CBD products for various indications, particularly chronic neuropathic pain. In 2018, on the basis of a systematic review of the literature, a Canadian Evidence Review Group published a guideline with recommendations for clinicians on prescribing cannabinoids in primary care practice. The overall quality of evidence was low to very low. In a meta-analysis of 15 randomized trials of medical cannabis for treating chronic pain, 39% of patients achieved at least a 30% reduction in pain. The corresponding value for placebo-treated patients was 30%; the number needed to treat was 11. More evidence exists for neuropathic pain than for other types of noncancer pain. Here, a general internist with a focus on addiction medicine and an addiction psychiatrist discuss how they would apply the literature to make recommendations for a patient with painful diabetic neuropathy, including counseling on both potential benefits and harms.

Background The prevalence of burnout and depressive symptoms is high among physician trainees. Research Question What is the burden of burnout and depressive symptoms among fellows training in pulmonary and critical care medicine (PCCM) and what are associated individual fellow, program, and institutional characteristics? Study Design and Methods We conducted a cross-sectional electronic survey of fellows enrolled in pulmonary, PCCM, and critical care medicine training programs in the United States to assess burnout and depressive symptoms. Burnout symptoms were measured using the Maslach Burnout Index two-item measure. The two-item Primary Care Evaluation of Mental Disorders Procedure was used to screen for depressive symptoms. For each of the two outcomes (burnout and depressive symptoms), we constructed three multivariate logistic regression models to assess individual fellow characteristics, program structure, and institutional polices associated with either burnout or depressive symptoms. Results Five hundred two of the 976 fellows who received the survey completed it—including both outcome measures—giving a response rate of 51%. Fifty percent of fellows showed positive results for either burnout or depressive symptoms, with 41% showing positive results for depressive symptoms, 32% showing positive results for burnout, and 23% showing positive results for both. Reporting a coverage system in the case of personal illness or emergency (adjusted OR [aOR], 0.44; 95% CI, 0.26-0.73) and access to mental health services (aOR, 0.14; 95% CI, 0.04-0.47) were associated with lower odds of burnout. Financial concern was associated with higher odds of depressive symptoms (aOR, 1.13; 95% CI, 1.05-1.22). Working more than 70 hours in an average clinical week and the burdens of electronic health record (EHR) documentation were associated with a higher odds of both burnout and depressive symptoms. Interpretation Given the high prevalence of burnout and depressive symptoms among fellows training in PCCM, an urgent need exists to identify solutions that address this public health crisis. Strategies such as providing an easily accessible coverage system, access to mental health resources, reducing EHR burden, addressing work hours, and addressing financial concerns among trainees may help to reduce burnout or depressive symptoms and should be studied further by the graduate medical education community.

Homocysteinemia is a metabolic condition characterized by abnormally high level of homocysteine in the blood and is considered to be a risk factor for peripheral neuropathy. However, the cellular mechanisms underlying toxic effects of homocysteine on the processing of peripheral nociception have not yet been investigated comprehensively. Here, using a rodent model of experimental homocysteinemia, we report the causal association between homocysteine and the development of mechanical allodynia. Homocysteinemia-induced mechanical allodynia was reversed on pharmacological inhibition of T-type calcium channels. In addition, our in vitro studies indicate that homocysteine enhances recombinant T-type calcium currents by promoting the recycling of Cav3.2 channels back to the plasma membrane through a protein kinase C–dependent signaling pathway that requires the direct phosphorylation of Cav3.2 at specific loci. Altogether, these results reveal an unrecognized signaling pathway that modulates the expression of T-type calcium channels, and may potentially contribute to the development of peripheral neuropathy associated with homocysteinemia. Refereed/Peer-reviewed

Summary Background Advanced therapy-refractory parotid gland carcinomas have a poor prognosis with limited therapy options. We used molecular profiling to offer molecular guided therapies to patients with advanced metastatic parotid gland malignancies. Methods In this retrospective analysis we describe the molecular profiling of ten patients diagnosed with therapy-refractory metastatic parotid gland malignancies. Results We identified seven genetic aberrations in five patients: two mutations in CDKN2A and one mutation in APC, ATM, TP53, SMARCB1 and FGFR1, respectively. No mutations were detected in five patients. The IHC demonstrated frequent expressions of EGFR and p‑mTOR, as well as PTEN in eight patients. For four fifths (n = 8) of the patients, a targeted therapy was suggested. Eventually, three patients received the targeted therapy recommendation and one patient achieved stable disease for 14 months. Conclusion A total of eight therapy recommendations were provided. Based on our observations, molecular-guided therapies may be a feasible treatment approach for this rare disease entity.

For years, experts have warned that a global pandemic was only a matter of time. Indeed, over the past two decades, several outbreaks and pandemics, from SARS to Ebola, have tested our ability to respond to a disease threat and provided the opportunity to refine our preparedness systems. However, when a novel coronavirus with human-to-human transmissibility emerged in China in 2019, many of these systems were found lacking. From international disputes over data and resources to individual disagreements over the effectiveness of facemasks, the COVID-19 pandemic has revealed several vulnerabilities. As of early November 2020, the WHO has confirmed over 46 million cases and 1.2 million deaths worldwide. While the world will likely be reeling from the effects of COVID-19 for months, and perhaps years, to come, one key question must be asked, How can we do better next time? This report summarizes views of experts from around the world on how lessons from past pandemics have shaped our current disease preparedness and response efforts, and how the COVID-19 pandemic may offer an opportunity to reinvent public health and healthcare systems to be more robust the next time a major challenge appears.

Objectives Heavy alcohol use is a particular problem in the US military, prompting the Institute of Medicine to identify it as a public health crisis. Developing prevention programs aimed at reducing problematic drinking during military service would be useful. Thus, the purpose of the current study, was to broadly disseminate and assess the effectiveness of a brief alcohol intervention (BAI) + random breathalyzer (RB) intervention to reduce alcohol related incidents (ARIs), to all incoming Air Force trainees. Methods The BAI was administered to all incoming Airmen (N = 15,898) across 4 major training Air Force bases. Additionally, underage Airmen were subject to RB tests. A quasi-experimental pre-test post-test design compared the rate of ARIs, per 100,000 training days, during the year prior and the year after the intervention was delivered. Results A Poisson model indicated that the BAI + RB intervention was associated with a decrease in ARIs across all bases. Overall, the intervention lowered the ARI rate by 16% (β = -0.178, standard error = 0.0742, P = 0.016). For every 100,000 training days, annual ARIs decreased from 30.8 to 25.5 after implementation. Conclusions A universally administered brief alcohol intervention, coupled with RB targeting underage drinkers, was associated with a reduction in the rate of ARIs. Results of this large-scale prevention study indicate that a brief alcohol intervention can be widely disseminated during US Air Force training and can perhaps reduce costs and make a public health contribution by decreasing alcohol related incidents.

Background The proposition that a pregnancy is 40 weeks or 280 days in duration is attributed to the German obstetrician Franz Naegele (1778-1851). His rule adds nine months and seven days to the first day of the last menstrual period. The expected date of confinement from this formula is approximately right in the majority of cases. However, the idea that this rule can apply to every pregnant female - young or old, nulliparous or multigravida, Caucasian, Asian, African, or Indigenous - stretches credulity. In addition, many women regard the 40-week date as a deadline, which if crossed, may then place the baby under stress. Forty weeks is such a simple, round, convenient figure that it has proved difficult to challenge, despite criticism. Nonetheless, what might have been an appropriate formula in Germany in the 19th century deserves to be revisited in the 21st. Aims To review the length of pregnancy, in the light of current technology, in particular ultrasound scanning, and assisted reproductive techniques. Material and methods A Medline search was performed for variables on the length of pregnancy, the expected date of confinement, and prolonged pregnancy. Results A number of factors were found to significantly influence the length of a pregnancy, including ethnicity, height, variations in the menstrual cycle, the timing of ovulation, parity and maternal weight. Conclusions Naegele's rule should be considered as a guideline for the expected date of confinement, and not a definite date.

In recent years, the number of patients choosing to have direct-to-consumer (DTC) genetic testing without involving their clinicians has increased substantially. For example, the number of subscribers to a commonly used testing site has grown to more than 10 million. These services have been heavily marketed in the United States and often include information about ancestry; genetic traits; and, increasingly, disease risk. In clinical care, genetic testing by a physician is accompanied by both pre- and posttest counseling by a trained genetic counselor. However, there are not enough genetic counselors to meet the needs of all persons contemplating DTC genetic testing. Formal genetic counseling includes preparation of a family pedigree; a discussion about potential benefits, the possibility that some information might be stressful to receive or difficult to understand, and the potential for disclosure of genetic information; and a detailed informed consent process. Some DTC tests for genetic susceptibilities look for only a few known mutations in a particular gene (such as BRCA1); a negative test result does not exclude the possibility of a clinically important mutation. A positive DTC genetic test result that might change clinical management should be followed by a confirmatory test through a genetics laboratory. Here, 2 expert physicians-a general internist and a medical oncologist with genetics experience-discuss an approach to counseling a patient who is considering DTC testing to learn more about his ancestry and his risk for metabolic syndrome.

Summary Background Effective treatments for patients with cholangiocarcinoma after progression on gemcitabine-based chemotherapy are urgently needed. Mutations in the BRAF gene have been found in 5% of biliary tract tumours. The combination of dabrafenib and trametinib has shown activity in several BRAFV600E-mutated cancers. We aimed to assess the activity and safety of dabrafenib and trametinib combination therapy in patients with BRAFV600E-mutated biliary tract cancer. Methods This study is part of an ongoing, phase 2, open-label, single-arm, multicentre, Rare Oncology Agnostic Research (ROAR) basket trial in patients with BRAFV600E-mutated rare cancers. Patients were eligible for the biliary tract cancer cohort if they were aged 18 years or older, had BRAFV600E-mutated, unresectable, metastatic, locally advanced, or recurrent biliary tract cancer, an Eastern Cooperative Oncology Group performance status of 0–2, and had received previous systemic treatment. All patients were treated with oral dabrafenib 150 mg twice daily and oral trametinib 2 mg once daily until disease progression or intolerance of treatment. The primary endpoint was the overall response rate, which was determined by Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat evaluable population, which comprised all enrolled patients regardless of receiving treatment who were evaluable (ie, had progression, began a new anticancer treatment, withdrew consent, died, had stable disease for 6 weeks or longer, or had two or more post-baseline assessments). The ROAR trial is registered with ClinicalTrials.gov , NCT02034110 . These results are based on an interim analysis; the study is active but not recruiting. Findings Between March 12, 2014, and July 18, 2018, 43 patients with BRAFV600E-mutated biliary tract cancer were enrolled to the study and were evaluable. Median follow-up was 10 months (IQR 6–15). An investigator-assessed overall response was achieved by 22 (51%, 95% CI 36–67) of 43 patients. An independent reviewer-assessed overall response was achieved by 20 (47%, 95% CI 31–62) of 43 patients. The most common grade 3 or worse adverse event was increased γ-glutamyltransferase in five (12%) patients. 17 (40%) patients had serious adverse events and nine (21%) had treatment-related serious adverse events, the most frequent of which was pyrexia (eight [19%]). No treatment-related deaths were reported. Interpretation Dabrafenib plus trametinib combination treatment showed promising activity in patients with BRAFV600E-mutated biliary tract cancer, with a manageable safety profile. Routine testing for BRAFV600E mutations should be considered in patients with biliary tract cancer. Funding GlaxoSmithKline and Novartis.

Background Therapeutic options are limited for advanced, metastatic biliary tract cancer. The pivotal NAPOLI-1 trial demonstrated the superior clinical benefit of nanoliposomal irinotecan (Nal-IRI) in gemcitabine-pretreated patients with metastatic pancreatic ductal adenocarcinoma; however, the antitumor activity of Nal-IRI in biliary tract cancer is unknown. This is the first report describing the efficacy of Nal-IRI in biliary tract cancer. Methods In this multicenter retrospective cohort analysis, we identified patients with metastatic biliary tract adenocarcinoma who were treated with Nal-IRI in combination with 5-fluorouracil and folinic acid following tumor progression under standard therapy at one of the study centers between May 2016 and January 2019. We assessed disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Results There were 14 patients; the median age at the time of diagnosis and the median age at the initiation of Nal-IRI were 59.3 and 60.0 years, respectively. Nal-IRI in combination with 5-fluorouracil and folinic acid was administered as second-, third-, fourth-, and fifth-line treatment in 6 (43%), 5 (36%), 2 (14%), and 1 (7%) patient with metastatic disease, respectively. The objective DCR with Nal-IRI was 50% (7/14 patients). Six patients (43%) had partial response, and one patient (7%) had stable disease. Progressive disease was observed in seven patients. The median PFS and median OS following Nal-IRI initiation were 10.6 and 24.1 months, respectively. Conclusions This retrospective analysis provides the first evidence that Nal-IRI might exhibit a clinical meaningful antitumor activity in metastatic biliary tract cancer.

Approximately 12 million adults in the United States receive a diagnosis of chronic obstructive pulmonary disease (COPD) each year, and it is the fourth leading cause of death. Chronic obstructive pulmonary disease refers to a group of diseases that cause airflow obstruction and a constellation of symptoms, including cough, sputum production, and shortness of breath. The main risk factor for COPD is tobacco smoke, but other environmental exposures also may contribute. The GOLD (Global Initiative for Chronic Obstructive Lung Disease) 2020 Report aims to provide a nonbiased review of the current evidence for the assessment, diagnosis, and treatment of patients with COPD. To date, no conclusive evidence exists that any existing medications for COPD modify mortality. The mainstay of treatment for COPD is inhaled bronchodilators, whereas the role of inhaled corticosteroids is less clear. Inhaled corticosteroids have substantial risks, including an increased risk for pneumonia. Here, 2 experts, both pulmonologists, reflect on the care of a woman with severe COPD, a 50-pack-year smoking history, frequent COPD exacerbations, and recurrent pneumonia. They consider the indications for inhaled corticosteroids in COPD, when inhaled corticosteroids should be withdrawn, and what other treatments are available.

Background Malignant mesothelioma is an aggressive cancer and has a poor prognosis. Here, we analyzed the feasibility, molecular and gender aspects of targeted therapy recommendations for malignant mesothelioma based on the individual molecular tumor profile. Methods In this single‐center, real‐world retrospective analysis of our platform for precision medicine, we evaluated the molecular profiling of malignant mesothelioma in 14 patients, including nine men and five women. Tumor samples of the patients were examined with a 50 gene next‐generation sequencing (NGS) panel, immunohistochemistry, and fluorescence in situ hybridization, to detect possible molecular aberrations which may be targeted by off‐label therapy custom‐tailored to the individual patient. Results In total, we identified 11 mutations in six of the 14 patients, including BAP1, FANCA, NF1, NF2, PD‐L1, RAD52D, SETD2, SRC, and TP53. No mutation was detected in eight of the 14 patients. Targeted therapy was recommended for 11 out of the 14 patients. All recommendations were mainly based on the molecular characteristics determined by immunohistochemistry. Targeted therapy recommendations were significantly more often for men than women due to gender‐specific differences in PDGFRα expression. Eventually, four patients received the targeted therapy, of whom one patient subsequently achieved stable disease. Conclusions Our observations suggest that a molecular‐guided treatment approach is feasible for the management of advanced malignant mesothelioma. Our analysis revealed gender specific differences in PDGFRα expression that should be further evaluated in clinical trials.

Both lipid oversupply and poor mitochondrial function (low respiration and elevated H(2)O(2) emission) have been implicated in the development of hepatic steatosis and liver injury. Mitophagy, the targeted degradation of low-functioning mitochondria, is critical for maintaining mitochondrial quality control. Here, we used intralipid injection combined with acute (4 day) and chronic (4–7wk) high-fat diets (HFD) to examine whether hepatic mitochondrial respiration would decrease and H(2)O(2) emission would increase with lipid overload. We tested these effects in male and female wild type (WT) mice and mice null for a critical mediator of mitophagy, BCL-2/adenovirus EIB 19-kDa interacting protein knockout (BNIP3 KO) housed at thermoneutral temperatures. Intralipid injection was successful in elevating serum triglycerides and nonesterified fatty acids but had no impact on hepatic mitochondrial respiratory function or H(2)O(2) emission. However, female mice had greater mitochondrial respiration on the acute HFD and lower H(2)O(2) emission across both HFD durations and were protected against hepatic steatosis. Unexpectedly, BNIP3 KO animals had greater hepatic mitochondrial respiration, better coupled respiration, and increased electron chain protein content after the 4-day HFD, compared with WT animals. Altogether, these data suggest that acute lipid overload delivered by a single intralipid bolus does not alter hepatic mitochondrial outcomes, but rather sex and genotype profoundly impact hepatic mitochondrial respiration and H(2)O(2) emission. NEW & NOTEWORTHY This is the first study focusing on hepatic mitochondrial respiratory outcomes in response to lipid overload via a high-fat diet (HFD) combined with intralipid injection. Novel findings include no effect of intralipid injection on mitochondrial outcomes of interest despite increased circulating lipid concentrations. However, we report pronounced differences in hepatic mitochondrial respiration, complex protein expression, and H(2)O(2) production by sex and BCL-2/adenovirus EIB 19-kDa interacting protein (BNIP3) genotype. Specifically, female mice had lower H(2)O(2) emission globally and on an acute HFD, females had greater hepatic mitochondrial respiration than males while BNIP3 knockout (KO) animals had greater mitochondrial coupling and complex protein expression than wild-type (WT) animals.

Introduction Advanced gynecologic cancers have a poor prognosis and constitute a major challenge for adequate treatment strategies. By analyzing and targeting molecular alterations, molecular guided treatments may be a viable option for the treatment of advanced gynecologic cancers. Patients and Methods In this single‐center, real‐world retrospective analysis of our platform for precision cancer medicine (PCM), we describe the molecular profiling of 72 patients diagnosed with different types of advanced gynecologic malignancies. Tumor samples of the patients were examined by next‐generation sequencing panel and immunohistochemistry (IHC). Results In total, we identified 209 genetic aberrations in 72 patients. The ten most frequent alterations were TP53 (n = 42, 20%), KRAS (n = 14, 6.6%), PIK3CA (n = 11, 5.2%), PIK3R1 (n = 9, 4.3%), ATR (n = 8, 3.8%), PTEN (n = 8, 3.8%), BRCA1 (n = 6, 2.8%), NF1 (n = 4, 1.9%), NOTCH1 (n = 4, 1.9%), and POLE (n = 4, 1.9%), which account for more than half of all molecular alterations (52.6%). In 21 (29.1%) patients only one mutation could be detected, and 44 (61.1%) patients had more than one mutation. No molecular alterations were detected in seven (9.7%) patients. IHC detected expression of phosphorylated mammalian target of rapamycin and epidermal growth factor receptor in 58 (80.6%) and 53 (73.6%) patients, respectively. In over two thirds (n = 49, 68.1%), a targeted therapy was suggested, based on the identified genetic aberrations. The most frequently recommended specific treatment was the combination of everolimus with exemestane (n = 18, 25 %). Conclusion Based on our observations, it seems that PCM might be a feasible approach for advanced gynecologic cancers with limited treatment options. Implications for Practice Nowadays molecular profiling of advanced gynecologic malignancies is feasible in the clinical routine. A molecular portrait should be done for every patient with an advanced therapy‐refractory gynecologic malignancy to offer molecular‐based treatment concepts., To determine the feasibility of precision cancer medicine (PCM) in gynecologic cancers, this retrospective study analyzed patients with advanced gynecologic cancers enrolled and profiled in a PCM platform, MONDTI, focusing on the technical feasibility to map the molecular profiles of advanced, pretreated, and mainly relapsed gynecologic cancers and to subsequently target the detected molecular alterations

Stricture formation is a common complication of Crohn's disease, resulting from the disease process, surgery, or drugs. Endoscopic balloon dilation has an important role in the management of strictures, with emerging techniques, such as endoscopic electroincision and stenting, showing promising results. The underlying disease process, altered bowel anatomy from disease or surgery, and concurrent use of immunosuppressive drugs can make endoscopic procedures more challenging. There is an urgent need for the standardisation of endoscopic procedures and peri-procedural management strategies. On the basis of an extensive literature review and the clinical experience of the consensus group, which consisted of representatives from the Interventional Inflammatory Bowel Disease Group, we propose detailed guidance on all aspects of the principles and techniques for endoscopic procedures in the treatment of inflammatory bowel disease-associated strictures.

Introduction Advanced therapy-refractory biliary tract cancer (BTC) has poor prognosis and constitutes a major challenge for adequate treatment strategies. By mapping the molecular profiles of advanced BTC patients, precision cancer medicine may provide targeted therapies for these patients. Objective In this analysis, we aimed to show the potential of PCM in metastatic BTC. Methods In this single-center, real-world retrospective analysis of our PCM platform, we describe the molecular profiling of 30 patients diagnosed with different types of metastatic BTC. Tumor samples of the patients were examined using a 161-gene next-generation sequencing panel, immunohistochemistry (IHC), and fluorescence in situ hybridization for chromosomal translocations. Results In total, we identified 35 molecular aberrations in 30 patients. The predominant mutations were KRAS (n = 8), TP53 (n = 7), IDH2 (n = 4), and IDH1 (n = 3) that accounted for the majority of all molecular alterations (62.86%). BRAF mutations were observed in two patients. Less frequent alterations were noted in ARID1A, CTNNB1, ESR1, FBXW7, FGFR2, MET, NOTCH2, PIK3CA, PTCH1, SMAD4, and SRC1, each in one case. FGFR fusion gene was detected in one patient. No mutations were detected in eight patients. IHC revealed EGFR and p-mTOR expression in 28 patients. Applying these results to our patients, targeted therapy was recommended for 60% of the patients (n = 18). One patient achieved stable disease. Conclusions PCM is a feasible treatment approach and may provide molecular-guided therapy recommendations for metastatic BTC.

Background: Effective treatments are needed to improve outcomes for high-grade glioma and low-grade glioma. The activity and safety of dabrafenib plus trametinib were evaluated in adult patients with recurrent or progressive BRAFV600E mutation-positive high-grade glioma and low-grade glioma. Methods: This study is part of an ongoing open-label, single-arm, phase 2 Rare Oncology Agnostic Research (ROAR) basket trial at 27 community and academic cancer centres in 13 countries (Austria, Belgium, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, South Korea, Spain, Sweden, and the USA). The study enrolled patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2. Patients with BRAFV600E mutation-positive high-grade glioma and low-grade glioma received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily orally until unacceptable toxicity, disease progression, or death. In the high-grade glioma cohort, patients were required to have measurable disease at baseline using the Response Assessment in Neuro-Oncology high-grade glioma response criteria and have been treated previously with radiotherapy and first-line chemotherapy or concurrent chemoradiotherapy. Patients with low-grade glioma were required to have measurable non-enhancing disease (except pilocytic astrocytoma) at baseline using the Response Assessment in Neuro-Oncology low-grade glioma criteria. The primary endpoint, in the evaluable intention-to-treat population, was investigator-assessed objective response rate (complete response plus partial response for high-grade glioma and complete response plus partial response plus minor response for low-grade glioma). This trial is ongoing, but is closed for enrolment, NCT02034110. Findings: Between April 17, 2014, and July 25, 2018, 45 patients (31 with glioblastoma) were enrolled into the high-grade glioma cohort and 13 patients were enrolled into the low-grade glioma cohort. The results presented here are based on interim analysis 16 (data cutoff Sept 14, 2020). In the high-grade glioma cohort, median follow-up was 12·7 months (IQR 5·4–32·3) and 15 (33%; 95% CI 20–49) of 45 patients had an objective response by investigator assessment, including three complete responses and 12 partial responses. In the low-grade glioma cohort, median follow-up was 32·2 months (IQR 25·1–47·8). Nine (69%; 95% CI 39–91) of 13 patients had an objective response by investigator assessment, including one complete response, six partial responses, and two minor responses. Grade 3 or worse adverse events were reported in 31 (53%) patients, the most common being fatigue (five [9%]), decreased neutrophil count (five [9%]), headache (three [5%]), and neutropenia (three [5%]). Interpretation: Dabrafenib plus trametinib showed clinically meaningful activity in patients with BRAFV600E mutation-positive recurrent or refractory high-grade glioma and low-grade glioma, with a safety profile consistent with that in other indications. BRAFV600E testing could potentially be adopted in clinical practice for patients with glioma. Funding: Novartis.

Background: Non-muscle-invasive bladder cancer (NMIBC) is characterized by frequent recurrences and a risk of progression in stage and grade. Increased knowledge of underlying biological mechanisms is needed.Objective: To identify single nucleotide polymorphisms (SNPs) associated with recurrence-free (RFS) and progression-free (PFS) survival in NMIBC.Design, setting, and participants: We analyzed outcome data from 3400 newly diagnosed NMIBC patients from the Netherlands, the UK, Canada, and Spain. We generated genome-wide germline SNP data using Illumina OmniExpress and Infinium Global Screening Array in combination with genotype imputation.Outcome measurements and statistical analysis: Cohort-specific genome-wide association studies (GWASs) for RFS and PFS were performed using a Cox proportional hazard model. Results were combined in a fixed-effect inverse-variance weighted meta-analysis. Candidate genes for the identified SNP associations were prioritized using functional annotation, gene-based analysis, expression quantitative trait locus analysis, and transcription factor binding site databases. Tumor expression levels of prioritized genes were tested for association with RFS and PFS in an independent NMIBC cohort.Results and limitations: This meta-analysis revealed a genome-wide significant locus for RFS on chromosome 14 (lead SNP rs12885353, hazard ratio [HR] C vs T allele 1.55, 95% confidence interval [CI] 1.33-1.82, p = 4.0 x 10(-8)), containing genes G2E3 and SCFD1. Higher expression of SCFD1 was associated with increased RFS (HR 0.70, 95% CI 0.59-0.84, p(FDR) = 0.003). Twelve other loci were suggestively associated with RFS (p < 10(-5)), pointing toward 18 additional candidate genes. For PFS, ten loci showed suggestive evidence of association, indicating 36 candidate genes. Expression levels of ten of these genes were statistically significantly associated with PFS, of which four (IFT140, UBE2I, FAHD1, and NME3) showed directional consistency with our meta-analysis results and published literature.Conclusions: In this first prognostic GWAS in NMIBC, we identified several novel candidate loci and five genes that showed convincing associations with recurrence or progression.Patient summary: In this study, we searched for inherited DNA changes that affect the outcome of non-muscle-invasive bladder cancer (NMIBC). We identified several genes that are associated with disease recurrence and progression. The roles and mechanisms of these genes in NMIBC prognosis should be investigated in future studies. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology.

Long-term photophobia in children that has no obvious cause is uncommon and presents a diagnostic dilemma. It may produce significant discomfort and result in social isolation and school absence. We present the case of a 5-year-old boy who presented with chronic photophobia due to interstitial keratitis that was the result of Lyme disease.

Background Treatment sequencing for patients with refractory metastatic colorectal cancer (mCRC) has been highly debated. The thymidine-based nucleoside trifluridine/tipiracil (TAS-102) and the multikinase inhibitor regorafenib have demonstrated clinical benefits in randomized phase III trials compared with placebo. However, limited data are available on the most optimal therapy sequence involving TAS-102 and regorafenib. Patients and Methods In the present retrospective, observational, real-life study, clinical data on mCRC patients treated with TAS-102 or an alternative salvage treatment at the Medical University of Vienna and University Hospital Zurich were collected from January 2013 to December 2016. Results A total of 85 patients whose disease had progressed during fluoropyrimidine-based therapy (FBT) with or without an antibody were included. The disease control rate in patients treated with TAS-102 after FBT-based treatment was 24% compared with 35% in patients treated with regorafenib after FBT-based treatment (adjusted odds ratio, 1.75; 95% confidence interval, 0.41-7.47; P = .449). The progression-free survival (PFS) and overall survival (OS) for patients treated with TAS-102 was 2.8 months (quartile, 2.0-4.8 months) and 15.9 months, respectively. When the data were analyzed according to the subgroups of patients with or without an FBT-free period, the TAS-102–treated patients with a previous FBT-free interval had a PFS of 3.1 months and OS of 17.7 months compared with a PFS of 2.2 months and OS of 8.1 months for patients who received TAS-102 immediately after FBT. Conclusion Our results have confirmed the efficacy of TAS-102 and regorafenib in the real-life setting. The treatment sequence analysis showed a tendency for longer PFS and OS for TAS-102–treated patients after an FBT-free interval. Prospective randomized data are needed to gain more information about the most beneficial therapy sequence in the salvage treatment of mCRC.

There are two categories of pulmonary edema: edema caused by increased capillary pressure (hydrostatic or cardiogenic edema) and edema caused by increased capillary permeability (noncardiogenic pulmonary edema, or acute respiratory distress syndrome). This review focuses on cardiogenic pulmonary edema and describes the general approach to patients with suspected cardiogenic pulmonary edema. The pathogenesis, diagnosis, treatment, and outcome of cardiogenic pulmonary edema are reviewed. Figures include chest scans showing pulmonary edema and noncardiogenic pulmonary edema, an illustration of the differences between cardiogenic and noncardiogenic edema, and a chart comparing lung mechanics and other variables in experimental models of cardiogenic pulmonary edema and noncardiogenic edema. Tables show clinical characteristics of patients with cardiogenic pulmonary edema and treatment options. This review contains 3 figures, 4 tables, and 29 references Keywords: cardiogenic pulmonary edema, congestive heart failure, pulmonary edema, Starling’s law

The Austrian Society for Hematology and Medical Oncology (OeGHO) aimed to define a clear position on the importance of molecular diagnostics in solid tumors. This position covers the following four points: the indication for the assessment of a molecular profile has to be given by the treating medical oncologist depending on the course of the patient’s disease; the requirement that the molecular profile might lead to a therapeutic intervention in the individual patient; quality control of the molecular analysis through proficiency testing and/or accreditation of the method used; and adherence to patient’s data safety according to data protection regulation. The present position paper does not cover the topic of germline mutations and other assessments in human genetics. Due to the fact that clinically relevant information on germline mutations may appear during the diagnostic processing we strongly recommend thorough patient education and documentation of patient consent.

Background: Aggressive hematological malignancies in relapsed/refractory setting bear a dire prognosis with low cure rates and short survival. Matching these patients to therapies is challenged by complexity due to spatial and temporal tumor evolution and incomplete understanding of genotype to phenotype correlations. Direct functional testing could address these impediments. The EXALT trial is an interventional, one-arm study designed to assess the clinical value of next generation functional drug screening (ngFDS). An interim analysis on 17 patients suggested a clinical benefit (Snijder et al., Lancet Hematol. 2017). Methods: We applied image-based ngFDS to quantify differential ex-vivo sensitivity of primary patient tumor cells to respective non-tumor cells towards 136 small molecule drugs, including EMA approved for any indication or experimental. We screened bone marrow, peripheral blood or lymph node material from 143 patients who suffered from late stage aggressive hematological malignancies (acute leukemias, aggressive B- and T-cell lymphomas) , discussed the results in a multidisciplinary tumor board and recommended treatments to physicians (A). The primary endpoint of this study was the percentage of patients reaching a PFS-ratio (PFS(ngFDS treatment)/PFS(previous treatment)) of ≥1.3 with an H0 hypothesis < 15% patients. The secondary endpoint was overall response rate (ORR) defined as proportion of patients reaching complete remission (CR) or partial remission (PR). Additionally, we performed a post hoc analysis to evaluate the matching of ngFDS to drugs used in actual treatment (matching score of received treatment). Results: 56 (39%) patients were evaluable and treated according to ngFDS based recommendations. With 30 of 56 (54%) ngFDS guided patients experiencing a PFS ratio of ≥1.3, the primary study endpoint was reached. 11 patients (37%) had ongoing response at censoring date (B). The median follow-up was 718 days. The median number of days from sampling to treatment was 21 (range 4-77). The ngFDS treatment regimens consisted of a median of 2 drugs (range: 1-6). ORR was 55% for all evaluable ngFDS treated patients, 60% for the lymphoid subgroup and 41% for the myeloid subgroup. Patients on ngFDS guided treatment with performance status ECOG ≤ 1 had a median PFS of 207 days compared to a median PFS of 29 days for patients with higher ECOG (p < 0.001, C). 24 of 39 (62%) patients with ECOG ≤ 1 had a PFS ratio of ≥1.3 (D). In disease specific subgroup analysis median PFS of T-cell lymphoma patients was 235 days versus 60 days for B-cell lymphoma patients (p = 0.018, E). Age (≤60 vs. >60), sex, lineage (myeloid vs. lymphoid), number of previous treatment lines (≤2 vs. >2), and clinical presentation (leukemia vs. lymphoma) did not have an impact on PFS of ngFDS guided treatment. Post hoc analysis including additional 17 non-ngFDS treated patients demonstrated that only patients receiving treatment with a positive ngFDS matching score demonstrated clinical benefit (HR: 0.53, p=0.005; vs. HR: 1.4, p=0.4). ngFDS matched treatments resulted in higher PFS for patients with tumor samples that had a cancer cell fraction of 10-50% in comparison to patients with samples of lower or higher cancer cell percentage (HR:0.35, p=0.01). Conclusion: ngFDS could be integrated in the routine clinical work flow. ngFDS guided treatments led to high rates of PFS prolongation compared to previous treatments of individual patients. ngFDS guided treatment is feasible and effective in patients with late stage aggressive hematological malignancies. These results prompted a prospective randomized trial comparing treatment guidance based on ngFDS or comprehensive genomic profiling or physician's choice (EXALT-2 trial, NCT04470947). Figure Disclosures Vladimer: Allcyte GmbH: Current Employment, Current equity holder in private company, Other: Founder. Jaeger:Karyopharm: Honoraria; Amgen: Honoraria; Gilead: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; True North: Honoraria, Research Funding; Miltenyi: Consultancy, Honoraria; CDR Life AG: Consultancy, Research Funding; F. Hoffmann-La Roche: Honoraria, Research Funding; Infinity: Honoraria; Takeda: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria. Krall:Allcyte GmbH: Current Employment, Current equity holder in private company, Other: Founder. Valent:Allcyte GmbH: Research Funding; Cellgene: Honoraria, Research Funding; Pfizer: Honoraria. Wolf:Celgene: Honoraria, Research Funding. Zielinski:MSD: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Imugene: Consultancy, Honoraria, Speakers Bureau; Ariad: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Merrimack: Consultancy, Honoraria, Speakers Bureau; Merck KGaA: Consultancy, Honoraria, Speakers Bureau; Fibrogen: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Tesaro: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Speakers Bureau; Shire: Consultancy, Honoraria, Speakers Bureau; Eli Lilly: Consultancy, Honoraria, Speakers Bureau; Athenex: Consultancy, Honoraria, Speakers Bureau. Superti-Furga:Allcyte GmbH: Current equity holder in private company, Other: Founder. Snijder:Allcyte GmbH: Current equity holder in private company, Other: Founder. Staber:Roche: Consultancy, Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria; Celgene/ BMS: Consultancy, Honoraria; msd: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria.

Rituximab (RTX) treatment is used for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, but its benefits in eosinophilic granulomatosis with polyangiitis (EGPA) are unclear. Our aim was to characterize asthma control and glucocorticoid (GC) sparing after RTX treatment.A retrospective, computer-assisted search was performed to identify patients with EGPA and GC-dependent asthma diagnosed between 2000 and 2017 who received RTX for remission induction. Demographic and clinical features were analyzed.Of the 17 patients included, the majority were myeloperoxidase-ANCA positive (n = 13, 76.5%). Uncontrolled asthma symptoms and atopy were present in 13 patients (76.5%). RTX was used for initial remission induction in patients with new onset of severe disease (n = 5, 29.4%) and after failed remission induction with other immunosuppression (n = 12, 70.6%). It was used for remission maintenance in nine patients (52.9%). GCs were used for maintenance at a median dose of 25 mg/day (interquartile range, 16.25-37.5). At the end of follow-up, 13 patients (76.5%) had non-severe or controlled asthma, and remission was achieved in 12 (70.6%). Median serum eosinophil and C-reactive protein values decreased (1.06 vs 0.10 × 10RTX seems to be safe and have GC-sparing efficacy for asthma control in EGPA. Randomized controlled trials are needed for detailed study of RTX for treating EGPA.Key Points• In this retrospective study we have concluded that rituximab (RTX) might be considered for the control of severe corticosteroid-dependent asthma in eosinophilic granulomatosis polyangiitis (EGPA) patients especially when myeloperoxidase antibodies are positive.• Rituximab has not been studied particularly for asthma control in EGPA patients.• The most noticeable effect of RTX was the decrease in the use of corticosteroids for the control of asthma.

Brain tumours that are refractory to treatment have a poor prognosis and constitute a major challenge in offering effective treatment strategies. By targeting molecular alterations, precision cancer medicine may be a viable option for the treatment of brain tumours. In this retrospective analysis of our PCM platform, we describe the molecular profiling of primary brain tumours from 50 patients. Tumour samples of the patients were examined by a 161-gene next-generation sequencing panel, immunohistochemistry, and fluorescence in situ hybridization (FISH). We identified 103 molecular aberrations in 36 (72%) of the 50 patients. The predominant mutations were TP53 (14.6%), IDH1 (9.7%) and PIK3CA (6.8%). No mutations were detected in 14 (28%) of the 50 patients. IHC demonstrated frequent overexpression of EGFR and mTOR, in 38 (76%) and 35 (70%) patients, respectively. Overexpression of PDGFRa and PDGFRb were less common and detected in 16 and four patients, respectively. For 35 patients a targeted therapy was recommended. In our database, the majority of patients displayed mutations, against which targeted therapy could be offered. Based on our observations, PCM may be a feasible novel treatment approach in neuro-oncology.

Objective Post‐traumatic stress disorder (PTSD) is a severe psychiatric disorder, which might develop after a traumatic event, like cancer diagnosis, and threatens the patient's psychological and/or physiological integrity. Anxiety, depression, and mental distress are known to be common in cancer patients; however, the frequency of PTSD was not investigated thoroughly in this patient group so far. Here, we aim to screen cancer patients for PTSD symptoms and determine a possible correlation with anxiety, depression, and distress. Methods The study was performed at the Divisions of Hematology and Oncology of the Medical University of Vienna from 2010 to 2018. Following written consent, patients were asked to fill out the validated self‐assessment questionnaire for PTSS‐10 and HADS. The study was approved by the institutional ethics committee of the Medical University of Vienna (EC Nr: 2255/2016). Results A total of 1017 adult cancer patients (513 male, 504 female) were included in a cross‐sectional single‐center study. Mean age was 57.6 years (SD 14.4 years); 31.7%, 14.6%, 13.2%, and 27.4% of patients outscored the predefined thresholds for self‐assessed cases of PTSD, anxiety, depression, and distress, respectively. Compared with men, women showed a higher prevalence of symptoms for PTSD (38.9% vs 24.5%; P

Despite recent advances in the treatment of gastric cancer, mortality related to this disease is still substantial. Surgery and chemotherapy represent the cornerstones of patient management. Targeted treatments that include anti-angiogenic agents and the advent of immunotherapies can contribute to improved patient prognosis. Herein, we present an Austrian consensus on the systemic treatment of patients with gastric adenocarcinoma and lower gastroesophageal junction, including those with human epidermal growth factor receptor 2 (HER2)-positive disease. The consensus considers the curative setting, as well as first-line to late-line systemic treatment options in the palliative setting. For HER2-positive disease, first-line and second-line therapies are discussed, as well as HER2 testing. Potential future therapies are also listed, with a focus on anti-angiogenic treatments and checkpoint inhibition, that might provide a further step forward in the management of patients with gastric cancer.

The impact of sexual dimorphism and mitophagy on hepatic mitochondrial adaptations during the treatment of steatosis with physical activity are largely unknown. Here, we tested if deficiencies in liver-specific peroxisome proliferative activated-receptor-γ coactivator-1α (PGC-1α), a transcriptional coactivator of biogenesis, and BCL-2/ADENOVIRUS EIB 19-kDa interacting protein (BNIP3), a mitophagy regulator, would impact hepatic mitochondrial adaptations (respiratory capacity, H2O2production, mitophagy) to a high-fat diet (HFD) and HFD plus physical activity via voluntary wheel running (VWR) in both sexes. Male and female wild-type (WT), liver-specific PGC-1α heterozygote (LPGC-1α), and BNIP3 null mice were thermoneutral housed (29–31°C) and divided into three groups: sedentary-low-fat diet (LFD), 16 wk of (HFD), or 16 wk of HFD with VWR for the final 8 wk (HFD + VWR) ( n = 5–7/sex/group). HFD did not impair mitochondrial respiratory capacity or coupling in any group; however, HFD + VWR significantly increased maximal respiratory capacity only in WT and PGC-1α females. Males required VWR to elicit mitochondrial adaptations that were inherently present in sedentary females including greater mitochondrial coupling control and reduced H2O2production. Females had overall reduced markers of mitophagy, steatosis, and liver damage. Steatosis and markers of liver injury were present in sedentary male mice on the HFD and were effectively reduced with VWR despite no resolution of steatosis. Overall, reductions in PGC-1α and loss of BNIP3 only modestly impacted mitochondrial adaptations to HFD and HFD + VWR with the biggest effect seen in BNIP3 females. In conclusion, hepatic mitochondrial adaptations to HFD and treatment of HFD-induced steatosis with VWR are more dependent on sex than PGC-1α or BNIP3.

Substantial improvements have been made in the systemic treatment of colorectal cancer over the last two decades. Median overall survival (OS) of patients with metastatic colorectal cancer (mCRC) has been constantly increased and the most recent first-line studies exceeded the 30-month median overall survival. The standard first-line regimen for mCRC is a combination of chemotherapy plus a biological agent either targeting the main angiogenic growth factor vascular endothelial growth factor (VEGF) via Bevacizumab or by antibodies targeting the epidermal growth factor receptor (EGRF) via Panitumumab or Cetuximab. Recent improvements have been shown in the efficacy of the biological agent by stratifying these agents according to the primary tumor location. In this context EGFR-inhibitors showed improved OS when used first-line in tumors derived from the left-sided colon or rectum, while tumor sidedness was not predictive for anti-VEGF-antibodies. Furthermore, the biological activity of anti-EGFR antibodies is restricted to tumors with a rat sarcoma virus (RAS)-wild-type genotype but not RAS-mutated tumors. The RAS-mutation status is not predictive for VEGF-inhibitors. Recent developments in the molecular characterisation of tumor cells led to the development of specific so called targeted therapies in colorectal cancer.

Suspected perioperative allergic reactions are often severe. To avoid potentially life-threatening re-exposure to the culprit drug, establishing a firm diagnosis and identifying the culprit is crucial. Drug provocation tests are considered the gold standard in drug allergy investigation but have not been recommended in the investigation of perioperative allergy, mainly because of the pharmacological effects of drugs such as induction agents and neuromuscular blocking agents. Some specialised centres have reported benefits of provocation testing in perioperative allergy investigation, but the literature on the subject is limited. Here we provide a status update on the use of drug provocation testing in perioperative allergy, including its use in specific drug groups. This review is based on a literature search and experiences of the authors comprising anaesthesiologists and allergists with experience in perioperative allergy investigation. In addition, 19 participating centres in the International Suspected Perioperative Allergic Reaction Group were surveyed on the use of provocation testing in perioperative allergy investigation. A response was received from 13 centres in eight European countries, New Zealand, and the USA. Also, 21 centres from the Australian and New Zealand Anaesthetic Allergy Group were surveyed. Two centres performed provocation routinely and seven centres performed no provocations at all. Nearly half of the centres reported performing provocations with induction agents and neuromuscular blocking agents. Drug provocation testing is being used in perioperative allergy investigation in specialised centres, but collaborations between relevant specialties and multi-centre studies are necessary to determine indications and establish common testing protocols.

An increasing number of patients with metastatic colorectal cancer (mCRC) are able to receive 3 or more lines of therapy. Treatments in this setting can include regorafenib (an oral multikinase inhibitor), trifluridine/tipiracil hydrochloride (TAS-102), antibodies that target epidermal growth factor receptor for patients with RAS wild-type tumors (if no prior exposure), and, where approved, anti-programmed cell death protein 1 inhibitors for patients with microsatellite instability-high mCRC. Although guidelines describe the available treatment options, few insights are provided to guide selection and sequencing. In this article, we share expert opinion from diverse geographic regions, to offer guidance for best practice when selecting and managing third-line treatment for mCRC. Various factors, including performance status, age, and tumor sidedness, can be used to guide treatment selection. Biomarkers, such as RAS, BRAF, and microsatellite instability, can be useful for treatment stratification. Management of adverse events, to maintain quality of life, is a key consideration and is crucial to best practice in this setting. Common toxicities associated with third-line treatments are hand-foot skin reaction, fatigue, diarrhea, and cytopenias. Patients who receive third-line and later-line treatments should be monitored for these events, especially during the first 2 cycles. Dose modifications can also be used to manage toxicities and to minimize the effect on quality of life, while maximizing treatment benefit. Clinical trials of emerging agents, new treatment combinations, and novel therapies continue the efforts to improve outcomes for patients with mCRC. Sharing expert opinions on best practice for treatment selection and management can ultimately improve outcomes for patients with mCRC.

Type I hypersensitivity reactions (HSR) to dabrafenib are rare but have been previously described. We present a case where a 72-year-old woman with recurrent, metastatic BRAF-mutated melanoma developed a type I HSR to dabrafenib. We, therefore, developed a desensitization protocol with encorafenib, a similar class agent, to allow the patient to continue with treatment. Patients with a history of HSR to dabrafenib may be considered for encorafenib desensitization when other therapeutic options are limited.

The SCOPE project aimed to better understand practice patterns, identify drivers for treatment goals, and determine third- and fourth-line treatment choices for patients with metastatic colorectal cancer (mCRC). The survey was developed by an expert panel of gastrointestinal oncologists. Questions concerned general practice patterns, and treatment decisions for three hypothetical patient case scenarios. Participants had to routinely manage patients with mCRC. We present results from 629 participants who provided input on patient treatment scenarios (data cutoff: 17/01/2020). Prolonging overall survival (OS, 51%) was the main aim in first line. In third line, quality of life (QOL) was the primary goal (34%). Forty-three percent also cited efficacy-focused goals, 18% and 13% noted prolonging OS and improving progression-free survival as main aims, respectively. For fit and active patients, 89% of respondents considered trifluridine-tipiracil an appropriate third-line treatment, regorafenib (31%) or clinical trial enrollment (29%) were the fourth-line options. For patients with comorbidities and limited caregiver support, trifluridine-tipiracil was the preferred third-line treatment (70%). For KRAS-mutated patients with comorbidities and adverse events who received prior oxaliplatin, 90% considered oxaliplatin rechallenge an unsuitable third-line treatment, mainly due to the risk of cumulative toxicity (75%). In the third/fourth-line settings, trifluridine-tipiracil followed by regorafenib was the most common option (54%), 17% chose regorafenib followed by trifluridine-tipiracil. Efficacy coupled with QOL are important goals in third-line treatment. Daily practice patterns reflect the guideline recommendations in third- and fourth-line settings, with a trend toward using trifluridine-tipiracil versus regorafenib in KRAS-wildtype and KRAS-mutant tumors.

Background Brain metastases (BM) are a rare complication in colorectal cancer (CRC) patients and associated with an unfavorable survival prognosis. Primary tumor side (PTS) was shown to act as a prognostic and predictive biomarker in several trials including metastatic CRC (mCRC) patients. Here, we aim to investigate whether PTS is also associated with the outcome of CRC patients with BM. Methods Patients treated for CRC BM between 1988 and 2017 at an academic care center were included. Right-sided CRC was defined as located in the appendix, cecum and ascending colon and left-sided CRC was defined as located in the descending colon, sigma and rectum. Results Two hundred and eighty-one CRC BM patients were available for this analysis with 239/281 patients (85.1%) presenting with a left-sided and 42/281 patients (14.9%) with a right-sided primary CRC. BM-free survival (BMFS) was significantly longer in left-sided compared with right-sided CRC patients (33 versus 20 months, P = 0.009). Overall survival from CRC diagnosis as well as from diagnosis of BM was significantly longer in patients with a left-sided primary (42 versus 25 months, P = 0.002 and 5 versus 4 months, P = 0.005, respectively). In a multivariate analysis including graded prognostic assessment, PTS remained significantly associated with prognosis after BM (hazard ratio 0.65; 95% confidence interval: 0.46-0.92 months, P = 0.0016). Conclusions PTS was associated with survival times after the rare event of BM development in CRC patients. Therefore, its prognostic value remains significant even thereafter., Highlights • Primary tumor side is a relevant and independent prognostic factor in mCRC. • Left-sided CRC was associated with a significantly longer BMFS compared with right-sided CRC. • OS from initial diagnosis of CRC as well as from BM was significantly longer in patients with left-sided primaries.

Background In preclinical studies trifluridine/tipiracil (FTD/TPI) plus oxaliplatin (Industriestrasse, Holzkirchen, Germany) sensitised microsatellite stable (MSS) metastatic colorectal cancer (mCRC) to anti-programmed cell death protein-1; the addition of oxaliplatin or bevacizumab (F Hoffmann- la ROCHE AG, Kaiseraugst, Switzerland) enhanced the antitumour effects of FTD/TPI. This study aimed to investigate the safety and efficacy of FTD/TPI plus oxaliplatin and either bevacizumab or nivolumab (Uxbridge business Park, Uxbridge, United Kingdom) in patients with mCRC who had progressed after at least one prior line of treatment. Patients and methods In 14-day cycles, patients received FTD/TPI 35 mg/m2 (twice daily, days 1-5) plus oxaliplatin 85 mg/m2 (day 1), and, on day 1, either bevacizumab 5 mg/kg (cohort A) or nivolumab 3 mg/kg (cohort B). Patients in Cohort B had confirmed MSS status. Results In total, 54 patients were enrolled: 37 in cohort A and 17 in cohort B. Recruitment in cohort B was stopped early due to the low response rate (RR) observed at interim analyses of efficacy. The most common adverse events (AEs) in cohort A were neutropenia/decreased neutrophils (75.7%), nausea (59.5%), vomiting (40.5%), diarrhoea (37.8%), peripheral sensory neuropathy (37.8%), fatigue (35.1%) and decreased appetite (35.1%). In cohort B, the most common AEs were neutropenia/decreased neutrophils (70.6%), diarrhoea (58.8%), nausea (47.1%), vomiting (47.1%), fatigue (47.1%), asthenia (41.2%), paraesthesia (41.2%), thrombocytopenia/decreased platelets (35.3%) and decreased appetite (35.3%). Confirmed objective RR was 17.1% in cohort A and 7.1% in cohort B; the corresponding values for median progression-free survival in the two cohorts were 6.3 and 6.0 months. Conclusion FTD/TPI plus oxaliplatin and bevacizumab or nivolumab had an acceptable safety profile and demonstrated antitumour activity in previously treated patients with mCRC., Highlights • This study evaluated the safety and efficacy of FTD/TPI plus oxaliplatin and either bevacizumab or nivolumab in mCRC patients. • FTD/TPI plus oxaliplatin in combination with bevacizumab or nivolumab had an acceptable and manageable safety profile. • Antitumour activity was observed following treatment with FTD/TPI plus oxaliplatin and bevacizumab. • Despite a modest RR with the addition of nivolumab, survival data were promising in these poor-prognosis patients.

Background Feedback for participants’ self-monitoring is a crucial and costly component of technology-based weight loss interventions. Detailed examination of interventionist time when reviewing and providing feedback for online self-monitoring data is lacking. Objective The aim of this study was to longitudinally examine the time counselors spent providing feedback on participant self-monitoring data (ie, diet, physical activity, weight) in a 12-month technology-based weight loss intervention. We hypothesized that counselors would compose feedback for participants more quickly over time. Methods The time the lay counselors (N=10) spent reviewing self-monitoring records and providing feedback to participants via email was longitudinally examined for all counselors across the three years of study implementation. Descriptives were observed for counselor feedback duration across counselors by 12 annual quarters (ie, 3-month periods). Differences in overall duration times by each consecutive annual quarter were analyzed using Wilcoxon-Mann-Whitney tests. Results There was a decrease in counselor feedback duration from the first to second quarter (mean 53 to 46 minutes; P Conclusions Counselors used increasingly less time to review online self-monitoring data and compose feedback after the initial 9 months of study implementation. Results inform counselor costs for future technology-based behavioral weight loss interventions. For example, regardless of increasing counselor efficiency, 25-30 minutes per feedback message is a high cost for interventions. One possibility for reducing costs would be generating computer-automated feedback. Trial Registration ClinicalTrials.gov NCT02063178; https://clinicaltrials.gov/ct2/show/NCT02063178