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Background/aim: Metastatic colorectal cancer (mCRC) is a heterogeneous disease with distinct molecular subtypes. The BRAF V600E -mutation found in approximately 8-12% of mCRC patients is associated with poor prognosis. Guideline recommendations for this population are mostly based on small cohorts due to lack of clinical data. This retrospective analysis was designed to evaluate (approved) therapeutic approaches and algorithms in BRAF V600E -mutant mCRC prior to approval of the targeted combination encorafenib plus cetuximab in Germany, Austria, and Switzerland., Patients and Methods: Anonymized data from BRAF V600E -mutant mCRC patients were analyzed retrospectively regarding 1 st -, 2 nd - and 3 rd -line treatment using descriptive statistics., Results: Forty-two patients were eligible for analysis (mean age 62.1 years, 47.6% female). At initial diagnosis, 20 patients (47.6%) were documented with right-sided tumors. Most patients (81.0%) were tested for BRAF before 1 st -line. Four patients (9.5%) showed high microsatellite instability (MSI-H). Based on 94 treatment lines, chemotherapy combined with targeted therapy (TT) was used mostly (61.7%), followed by chemotherapy alone (19.1%). Backbone therapies were most frequently FOLFOXIRI (27.7%), FOLFOX/CAPOX (22.3%), or FOLFIRI (20.2%). Anti-VEGF/VEGFR and anti-EGFR-treatments were used in 45.7% and 23.4% of patients, respectively. Across all treatment lines and types, the predominantly documented reason for discontinuation was lack of efficacy., Conclusion: Combined chemotherapy+TT (anti-VEGF/VEGFR and anti-EGFR) played a predominant role in BRAF V600E -mutated mCRC treatment prior to approval of the targeted combination encorafenib plus cetuximab. Since lack of efficacy was the major reason for treatment discontinuation, newly approved therapies including encorafenib plus cetuximab and - for MSI-H tumors - pembrolizumab represent urgently needed options for future mCRC patients., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: In Fontans, exercise tolerance is poorer compared to their healthy peers. Higher V ˙ O 2 p e a k represents a strong predictor for mortality and morbidity in these patients. Cardiac rehabilitation programs have been shown to improve cardiopulmonary function in Fontans. More habitual physical activity should therefore lead to a better exercise tolerance., Methods: We performed cardiopulmonary exercise testing in 24 Fontan patients who had engaged in physical activity for a minimum of 3 h per week over their lifetime. As a control we performed cardiopulmonary exercise testing in 20 Fontan patients who had undertaken no physical activity or <3 h per week in the past., Results: A total of 44 Fontan patients was included (mean age 18.1 years). The mean parameters measured at peak exercise differed significantly between the active and inactive group (peak oxygen uptake [ V ˙ O 2 p e a k ] of 34.0 vs. 25.0 ml/min/kg, peak heart rate (HR) of 169.8/min vs. 139.8/min). Even though the O 2 pulse and the EF did not differ significantly between both groups, N-Terminal-Pro-B-Type Natriuretic Peptide (NT-pro BNP) was significantly higher in the inactive group. The two groups did not differ with respect to their cardiac function determined by magnetic resonance imaging (MRI). V ˙ O 2 p e a k was positively correlated with hours of sports performed by Fontans., Conclusions: V ˙ O 2 p e a k and maximum HR were significantly higher in Fontans who had been physically active compared to those who had been inactive. The values reported in this study were higher than in other studies and reached normal values for V ˙ O 2 p e a k for most Fontans in the physically active group. The positive correlation between V ˙ O 2 p e a k and physical activity is an indicator of the importance of incorporating physical exercise programs into the treatment of Fontan patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Weigelt, Fritsch, Rottermann, Wällisch, Moosmann, Dittrich, Purbojo and Schöffl.)

Peritoneal cancer (PC) is a dire finding, yet in selected patients, long-term survival is possible. Complete cytoreductive surgery (CRS) together with combination immunochemotherapy is essential to achieve cure. Hyperthermic intraperitoneal chemotherapy (HIPEC) and pressurized intraperitoneal aerosol chemotherapy (PIPAC) are increasingly added to the multimodal treatment. The Swiss Peritoneal Cancer Group (SPCG) is an interdisciplinary group of expert clinicians. It has developed comprehensive treatment algorithms for patients with PC from pseudomyxoma peritonei, peritoneal mesothelioma, gastric, and colorectal origin. They include multimodal neoadjuvant treatment, surgical resection, and palliative care. The indication for and results of CRS HIPEC and PIPAC are discussed in light of the current literature. Institutional volume and clinical expertise required to achieve best outcomes are underlined, while inclusion of patients considered for CRS HIPEC and PIPAC in a clinical registry is strongly advised. The present recommendations are in line with current international guidelines and provide the first comprehensive treatment proposal for patients with PC including intraperitoneal chemotherapy. The SPCG comprehensive treatment algorithms provide evidence-based guidance for the multimodal care of patients with PC of gastrointestinal origin that were endorsed by all Swiss clinicians routinely involved in the multimodal care of these challenging patients.

This is a multicentre prospective randomised controlled trial for patients with 3 or more resectable pulmonary metastases from colorectal carcinoma. The study investigates the effects of pulmonary metastasectomy in addition to standard medical treatment in comparison to standard medical treatment plus possible local ablative measures such as SBRT. This trial is intended to demonstrate an overall survival difference in the group undergoing pulmonary metastasectomy. Further secondary and exploratory endpoints include quality of life (EORTC QLQ-C30, QLQ-CR29 and QLQ-LC29 questionnaires), progression-free survival and impact of mutational status. Due to the heterogeneity and complexity of the disease and treatment trajectories in metastasised colorectal cancer, well powered trials have been very challenging to design and execute. The goal of this study is to create a setting which allows treatment as close to the real life conditions as possible but under well standardised conditions. Based on previous trials, in which patient recruitment in the given setting hindered successful study completion, we decided to (1) restrict inclusion to patients with 3 or more metastases (since in case of lesser, surgery will probably be the preferred option) and (2) allow for real world standard of care (SOC) treatment options before and after randomisation including watchful waiting (as opposed to a predefined treatment protocol) and (3) possibility that patient can receive SOC externally (to reduce patient burden). Moreover, we chose to stipulate 12 weeks of systemic treatment prior to possible resection to further standardize treatment response and disease course over a certain period of time. Hence, included patients will be in the disease state of oligopersistence rather than primary oligometastatic. The trial was registered in the German Clinical Trials Register (DRKS-No.: DRKS00024727)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Schmid, Becker, Fritsch, Bausch, Hunter, Jenkner, Hassan and Passlick.)

Background: Anaplastic lymphoma kinase ( ALK ) rearrangements are known oncogenic drivers in non-small cell lung cancer (NSCLC). Few case reports described the occurrence of such rearrangements in large cell neuroendocrine carcinomas (LCNECs) of the lung without information on clinical responses to ALK tyrosine kinase inhibitors (TKIs) in these cases. Currently, neuroendocrine tumors of the lungs are not screened for ALK rearrangements., Methods: To illustrate the clinical impact of molecular characterization in LCNECs, we report the disease course in three patients with ALK -rearranged metastatic LCNEC from our clinical routine, as well as their treatment response to ALK TKIs (index cases). To gain insight into the prevalence of ALK rearrangements in neuroendocrine tumors of the lung, we analyzed a retrospective cohort of 436 tumor biopsies including LCNEC (n = 61), small cell lung cancer (SCLC) (n = 206), typical (n = 91) and atypical (n = 69) carcinoids, and mixed histology (n = 9) for the presence of ALK rearrangements using a sequential diagnostic algorithm. ALK immunohistochemistry (IHC) was evaluable in 362 cases; fluorescence in situ hybridization (FISH) was evaluable in 28 out of the 35 IHC-positive cases, followed by next-generation sequencing (NGS) that was available in 12 cases., Results: Within the retrospective cohort, ALK IHC was positive in 35 out of 362 (9.7%) evaluable samples. FISH was positive in 3 out of the 28 (10.7%) evaluable cases: 2 with atypical carcinoids and 1 with LCNEC. Additionally, the 3 index cases showed positive ALK IHC, which was confirmed by NGS. Within the retrospective cohort, NGS confirmed the presence of an ALK genomic rearrangement in one FISH-positive atypical carcinoid where material was sufficient for sequencing. Two out of three patients with metastatic ALK -rearranged LCNEC received up-front treatment with the ALK TKI alectinib and showed rapid tumor response at all metastatic sites, including multiple brain metastases., Conclusions: ALK rearrangements represent rare but targetable oncogenic driver alterations in LCNEC. Contrarily to NSCLC, the detection of ALK rearrangements in neuroendocrine tumors of the lung is challenging, since ALK IHC can lead to false-positive results and therefore needs confirmation by FISH or NGS. Up-front comprehensive molecular profiling with NGS should be performed in metastatic LCNEC in order not to miss actionable genomic alterations., Competing Interests: SH reports consulting and advisory fees from Bayer outside the submitted work. RF reports grants and consulting and advisory fees from Pierre Fabre, Bayer, Merck, MSD, Astra Zeneca, Novartis, and BMS outside the submitted work. MK reports ownership relationship with Novavax, Biontech, and Mol. Partners outside the submitted work. AC-F reports patent relationship with Astra Zeneca, Bristol Meyer Squibb, Boehringer Ingelheim, Pfizer, Roche, Takeda, MSD, and Janssen-Cilag outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Akhoundova, Haberecker, Fritsch, Höller, Kiessling, Rechsteiner, Rüschoff and Curioni-Fontecedro.)

22q11.2 deletion syndrome (22q11.2DS) is a genetic neurodevelopmental disorder that represents one of the greatest known risk factors for psychosis. Previous studies in psychotic subjects without the deletion have identified a dopaminergic dysfunction in striatal regions, and dysconnectivity of striatocortical systems, as an important mechanism in the emergence of psychosis. Here, we used resting-state functional MRI to examine striatocortical functional connectivity in 22q11.2DS patients. We used a 2 × 2 factorial design including 125 subjects (55 healthy controls, 28 22q11.2DS patients without a history of psychosis, 10 22q11.2DS patients with a history of psychosis, and 32 subjects with a history of psychosis without the deletion), allowing us to identify network effects related to the deletion and to the presence of psychosis. In line with previous results from psychotic patients without 22q11.2DS, we found that there was a dorsal to ventral gradient of hypo- to hyperstriatocortical connectivity related to psychosis across both patient groups. The 22q11.2DS was additionally associated with abnormal functional connectivity in ventral striatocortical networks, with no significant differences identified in the dorsal system. Abnormalities in the ventral striatocortical system observed in these individuals with high genetic risk to psychosis may thus reflect a marker of illness risk., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Study Objectives: Our aim is to evaluate the presence of REM sleep without atonia (RWA), the objective hallmark of REM sleep Behaviour Disorder (RBD), as prodromal marker of Parkinson's disease (PD), in an adult cohort of 22q11.2 deletion syndrome (22qDS)., Methods: Sleep quality was assessed by means of Pittsburgh quality scale index (PSQI), and RBD symptoms by means of RBD questionnaire-Hong-Kong (RBDQ-HK). Attended domiciliary video-Polysomnography (v-PSG) were performed in 26 adults (18-51 years, 14 females) 22qDS patients. Electromyogram during REM sleep was analyzed by means of SINBAR procedure at 3-second time resolution (miniepochs)., Results: An overall poor sleep quality was observed in the cohort and high RBDQ-HK score in 7 of the 26 patients, two additional patients with positive dream enactment reported by close relatives had low score of RBDQ-HK. Nevertheless, SINBAR RWA scores were lower than cut-off threshold for RWA (mean 5.5%, range 0-12.2%). TST and the percentage of light sleep (N1) were increased, with preserved proportions of N2 and N3. Participants reported poor quality of sleep (mean PSQI > 5), with prolonged sleep latency in the v-PSG. No subjects exhibit evident dream enactment episodes during recording sessions., Conclusions: RWA was absent in the studied cohort of 22qDS adult volunteers according to validated polysomnographic criteria. High RBDQ-HK scores do not correlate with v-PSG results among 22qDS individuals., (© The Author(s) 2021. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The 22q11 deletion syndrome is a genetic disorder associated with a high risk of developing psychosis, and is therefore considered a neurodevelopmental model for studying the pathogenesis of schizophrenia. Studies have shown that localized abnormal functional brain connectivity is present in 22q11 deletion syndrome like in schizophrenia. However, it is less clear whether these abnormal cortical interactions lead to global or regional network disorganization as seen in schizophrenia. We analyzed from a graph-theory perspective fMRI data from 40 22q11 deletion syndrome patients and 67 healthy controls, and reconstructed functional networks from 105 brain regions. Between-group differences were examined by evaluating edge-wise strength and graph theoretical metrics of local (weighted degree, nodal efficiency, nodal local efficiency) and global topological properties (modularity, local and global efficiency). Connectivity strength was globally reduced in patients, driven by a large network comprising 147 reduced connections. The 22q11 deletion syndrome network presented with abnormal local topological properties, with decreased local efficiency and reductions in weighted degree particularly in hub nodes. We found evidence for abnormal integration but intact segregation of the 22q11 deletion syndrome network. Results suggest that 22q11 deletion syndrome patients present with similar aberrant local network organization as seen in schizophrenia, and this network configuration might represent a vulnerability factor to psychosis., (© 2021. The Author(s).)

Objective: The aim of this study was to pool data from randomized controlled trials (RCT) limited to resectable pancreatic ductal adenocarcinoma (PDAC) to determine whether a neoadjuvant therapy impacts on disease-free survival (DFS) and surgical outcome., Summary Background Data: Few underpowered studies have suggested benefits from neoadjuvant chemo (± radiation) for strictly resectable PDAC without offering conclusive recommendations., Methods: Three RCTs were identified comparing neoadjuvant chemo (± radio) therapy vs. upfront surgery followed by adjuvant therapy in all cases. Data were pooled targeting DFS as primary endpoint, whereas overall survival (OS), postoperative morbidity, and mortality were investigated as secondary endpoints. Survival endpoints DFS and OS were compared using Cox proportional hazards regression with study-specific baseline hazards., Results: A total of 130 patients were randomized (56 in the neoadjuvant and 74 in the control group). DFS was significantly longer in the neoadjuvant treatment group compared to surgery only [hazard ratio (HR) 0.6, 95% confidence interval (CI) 0.4-0.9] (P = 0.01). Furthermore, DFS for the subgroup of R0 resections was similarly longer in the neoadjuvant treated group (HR 0.6, 95% CI 0.35-0.9, P = 0.045). Although postoperative complications (Comprehensive Complication Index, CCI®) occurred less frequently (P = 0.008), patients after neoadjuvant therapy experienced a higher toxicity, but without negative impact on oncological or surgical outcome parameters., Conclusion: Neoadjuvant therapy can be offered as an acceptable standard of care for patients with purely resectable PDAC. Future research with the advances of precision oncology should now focus on the definition of the optimal regimen., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Despite overall success, T cell checkpoint inhibitors for cancer treatment are still only efficient in a minority of patients. Recently, intestinal microbiota was found to critically modulate anti-cancer immunity and therapy response. Here, we identify Clostridiales members of the gut microbiota associated with a lower tumor burden in mouse models of colorectal cancer (CRC). Interestingly, these commensal species are also significantly reduced in CRC patients compared with healthy controls. Oral application of a mix of four Clostridiales strains (CC4) in mice prevented and even successfully treated CRC as stand-alone therapy. This effect depended on intratumoral infiltration and activation of CD8 + T cells. Single application of Roseburia intestinalis or Anaerostipes caccae was even more effective than CC4. In a direct comparison, the CC4 mix supplementation outperformed anti-PD-1 therapy in mouse models of CRC and melanoma. Our findings provide a strong preclinical foundation for exploring gut bacteria as novel stand-alone therapy against solid tumors., Competing Interests: Declaration of interests M.S. and M.R.S. have shares in PharmaBiome. M.S. served as Advisor for Gilead, Fresenius, Topadur, Takeda, and Celltrion, and received speaker’s honoraria from Falk Pharma and Vifor Pharma. T.W. and L. Berchtold are employees of PharmaBiome. G.E.L. is also an employee of PharmaBiome. G.R. is member of the Board of Directors of PharmaBiome. A patent related to this work has been generated (PCT/EP2021/053390). This intellectual property is entirely owned by the University of Zürich., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Despite enormous efforts during the past decades, pancreatic adenocarcinoma (PAC) remains one of the most deleterious cancer entities. A useful biomarker for early detection or prognosis of PAC does not yet exist. The goal of our study was the characterization of β6-integrin (ITGB6) as a novel serum tumor marker for refined diagnosis and prognosis of PAC. Serum ITGB6 levels were analyzed in 3 independent PAC cohorts consisting of retrospectively and prospectively collected serum and/or (metastatic) PAC tissue specimens., Methods: Using 2 independent cohorts, we measured serum ITGB6 concentrations in 10 chronic pancreatitis patients, 10 controls, as well as in 27 (cohort 1) and 24 (cohort 2) patients with PAC, respectively. In these patients, we investigated whether ITGB6 serum levels correlate with known clinical and prognostic markers for PAC and whether they might differ between patients with PAC or benign inflammatory diseases of the pancreas., Results: We found that elevated serum ITGB6 levels (≥0.100 ng/mL) in patients suffering from metastasizing PAC presented an unfavorable prognostic outcome. By correlating the ITGB6 tissue expression in primary and metastatic PAC with clinical parameters, we found that positive ITGB6 expression in the tumor tissue is linked to increased serum ITGB6 levels in nonmetastatic PAC and correlates with carbohydrate antigen 19-9 and clinical outcome., Discussion: Our findings suggest that ITGB6 might serve as a novel serum biomarker for early diagnosis and prognosis of PAC. Given the limited specificity and sensitivity of currently used carbohydrate antigen 19-9-based assays, ITGB6 may have the potential to improve the diagnostic accuracy for PAC., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (p adj  = 6.73 × 10 -6 ). Novel reciprocal case-control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)

Hypoxia is prominent in solid tumors and a recognized driver of malignancy. Thus far, targeting tumor hypoxia has remained unsuccessful. Myo-inositol trispyrophosphate (ITPP) is a re-oxygenating compound without apparent toxicity. In preclinical models, ITPP potentiates the efficacy of subsequent chemotherapy through vascular normalization. Here, we report the results of an unrandomized, open-labeled, 3 + 3 dose-escalation phase Ib study (NCT02528526) including 28 patients with advanced primary hepatopancreatobiliary malignancies and liver metastases of colorectal cancer receiving nine 8h-infusions of ITPP over three weeks across eight dose levels (1'866-14'500 mg/m 2 /dose), followed by standard chemotherapy. Primary objectives are assessment of the safety and tolerability and establishment of the maximum tolerated dose, while secondary objectives include assessment of pharmacokinetics, antitumor activity via radiological evaluation and assessment of circulatory tumor-specific and angiogenic markers. The maximum tolerated dose is 12,390 mg/m 2 , and ITPP treatment results in 32 treatment-related toxicities (mostly hypercalcemia) that require little or no intervention. 52% of patients have morphological disease stabilization under ITPP monotherapy. Following subsequent chemotherapy, 10% show partial responses while 60% have stable disease. Decreases in angiogenic markers are noted in ∼60% of patients after ITPP and tend to correlate with responses and survival after chemotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive form of cancer with a dismal prognosis. The lack of symptoms in the early phase of the disease makes early diagnosis challenging, and about 80-85% of the patients are diagnosed only after the disease is locally advanced or metastatic. The current front-line treatment landscape in local stages comprises surgical resection and adjuvant chemotherapy. In Switzerland, although both FOLFIRINOX and gemcitabine plus nab-paclitaxel regimens are feasible and comparable in the first-line setting, FOLFIRINOX is preferred in the treatment of fit (Eastern Cooperative Oncology Group [ECOG] performance status [PS]: 0-1), young (<65 years old) patients with few comorbidities and normal liver function, while gemcitabine plus nab-paclitaxel is used to treat less fit (ECOG PS: 1-2) and more vulnerable patients. In the second-line setting of advanced PDAC, there is currently only one approved regimen, based on the phase III NAPOLI-1 trial. Furthermore, the use of liposomal-irinotecan in the second line is supported by real-world data. Beyond the standard of care, various alternative treatment modalities are being explored in clinical studies. Immunotherapy has demonstrated only limited benefits until now, and only in cases of high microsatellite instability (MSI-H). However, data on the benefit of poly (ADP-ribose) polymerase (PARP) inhibition as maintenance therapy in patients with germline BRCA-mutated tumors might signal of an advance in targeted therapy. Currently, there is a lack of molecular and genetic biomarkers for optimal stratification of patients and in guiding treatment decisions. Thus, identification of predictive and prognostic biomarkers and evaluating novel treatment strategies are equally relevant for improving the prognosis of metastatic pancreatic cancer patients., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Colorectal cancers (CRCs) remain one of the most common and challenging neoplasia in the Western world. The response rate of immunotherapeutic treatment approaches in a subset of advanced CRCs is remarkable and has sustainably changed treatment regimens. Unfortunately, currently available immunotherapeutics only displayed significant antitumoral activity - in terms of progression free survival (PFS) and objective response rate (ORR) - in microsatellite instability-high (MSI-H)/DNA mismatch repair deficient (dMMR) CRCs. Subsequently, these remarkable results had led to the US Food and Drug Administration's approval of both immune checkpoint inhibitors (ICIs) pembrolizumab and nivolumab in the treatment of advanced MSI-H/dMMR CRCs. However, in microsatellite stable (MSS)/DNA mismatch repair proficient (pMMR) CRCs, ICIs have clearly failed to meet their expectations and are therefore not considered effective. As the vast majority of CRCs display a molecular MSS/pMMR profile, current treatment approaches endeavor to improve tumor immunogenicity that consecutively leads to increased proinflammatory cytokine levels as well as tumor infiltrating T-cells, which in turn may be targeted by various immunotherapeutic agents. Therefore, ongoing studies are investigating novel synergistic therapy modalities and approaches to overcome a "cold" to "hot" tumor conversion in MSS/pMMR CRCs. In this review, we summarize the efficacy and possible immune-related adverse events as well as novel therapeutic approaches of ICIs in the treatment of MSI-H/dMMR and MSS/pMMR CRCs., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2021.)

Oncogenic mutations in RAS family genes arise frequently in metastatic human cancers. Here we developed new mouse and cellular models of oncogenic Hras G12V -driven undifferentiated pleomorphic sarcoma metastasis and of Kras G12D -driven pancreatic ductal adenocarcinoma metastasis. Through analyses of these cells and of human oncogenic KRAS-, NRAS- and BRAF-driven cancer cell lines we identified that resistance to single MEK inhibitor and ERK inhibitor treatments arise rapidly but combination therapy completely blocks the emergence of resistance. The prior evolution of resistance to either single agent frequently leads to resistance to dual treatment. Dual MEK inhibitor plus ERK inhibitor therapy shows anti-tumor efficacy in an Hras G12 V -driven autochthonous sarcoma model but features of drug resistance in vivo were also evident. Array-based kinome activity profiling revealed an absence of common patterns of signaling rewiring in single or double MEK and ERK inhibitor resistant cells, showing that the development of resistance to downstream signaling inhibition in oncogenic RAS-driven tumors represents a heterogeneous process. Nonetheless, in some single and double MEK and ERK inhibitor resistant cell lines we identified newly acquired drug sensitivities. These may represent additional therapeutic targets in oncogenic RAS-driven tumors and provide general proof-of-principle that therapeutic vulnerabilities of drug resistant cells can be identified.

Pancreatic ductal adenocarcinoma (PDAC) is a disease with a very unfavorable prognosis. Surgical resection represents the only potentially curative treatment option, but recurrence after complete resection is almost certain. In an exploratory attempt we here aimed at identifying preoperative plasma protein biomarkers with the potential to predict early recurrence after resection of PDAC. Peripheral blood samples from 14 PDAC patients divided into three groups according to their time to tumor recurrence after curatively intended resection (early: < 6 months, medium: 6-12 months, late: > 12 months) underwent targeted proteome analysis. Proteins most strongly discriminating early and late recurrence were then examined in a number of established PDAC cell lines and their culture supernatants. Finally, PDAC organoid lines from primary tumors of patients with early and late recurrence were analyzed for confirmation and validation of results. In total, 23 proteins showed differential abundance in perioperative plasma from PDAC patients with early recurrence when compared to patients with late recurrence. Following confirmation of expression on a transcriptional and translational level in PDAC cell lines we further focused on three upregulated (MAEA, NT5E, AZU1) and two downregulated proteins (ATP6AP2, MICA). Increased expression of NT5E was confirmed in a subset of PDAC organoid cultures from tumors with early recurrence. MICA expression was heterogeneous and ATP6AP2 levels were very similar in both organoids from early and late recurrent tumors. Most strikingly, we observed high MAEA expression in all tested PDAC (n = 7) compared to a non-cancer ductal organoid line. MAEA also demonstrated potential to discriminate early recurrence from late recurrence PDAC organoids. Our study suggests that identification of plasma protein biomarkers released by tumor cells may be feasible and of value to predict the clinical course of patients. Prediction of recurrence dynamics would help to stratify up-front resectable PDAC patients for neoadjuvant chemotherapy approaches in an individualized fashion. Here, MAEA and NT5E were the most promising candidates for further evaluation.

Molecular precision oncology faces two major challenges: first, to identify relevant and actionable molecular variants in a rapidly changing field and second, to provide access to a broad patient population. Here, we report a four-year experience of the Molecular Tumor Board (MTB) of the Comprehensive Cancer Center Freiburg (Germany) including workflows and process optimizations. This retrospective single-center study includes data on 488 patients enrolled in the MTB from February 2015 through December 2018. Recommendations include individual molecular diagnostics, molecular stratified therapies, assessment of treatment adherence and patient outcomes including overall survival. The majority of MTB patients presented with stage IV oncologic malignancies (90.6%) and underwent an average of 2.1 previous lines of therapy. Individual diagnostic recommendations were given to 487 patients (99.8%). A treatment recommendation was given in 264 of all cases (54.1%) which included a molecularly matched treatment in 212 patients (43.4%). The 264 treatment recommendations were implemented in 76 patients (28.8%). Stable disease was observed in 19 patients (25.0%), 17 had partial response (22.4%) and five showed a complete remission (6.6%). An objective response was achieved in 28.9% of cases with implemented recommendations and for 4.5% of the total population (22 of 488 patients). By optimizing the MTB workflow, case-discussions per session increased significantly while treatment adherence and outcome remained stable over time. Our data demonstrate the feasibility and effectiveness of molecular-guided personalized therapy for cancer patients in a clinical routine setting showing a low but robust and durable disease control rate over time.

Colorectal cancer is the third most common cancer worldwide. Half of CRC patients develop liver metastases during the course of the disease, with a 5-year survival rate close to zero in the absence of therapy. Surgical resection remains the only possible curative option, and current guidelines recommend adjuvant chemotherapy, resulting in a 5-year survival rate exceeding 50%. Neoadjuvant systemic therapy is not indicated in cases with simple resection but should be offered to all patients with extensive bilobar disease. Personalised systemic treatment is essential to convert upfront non-resectable lesions to resectable ones. Anatomical resections, non-anatomical resections and two-stage hepatectomies can be performed though open or minimally invasive (laparoscopic or robotic) surgery. The extent of a hepatic resection is limited by the risk of postoperative liver failure due to a too small liver remnant, inflow or outflow obstruction or insufficient biliary drainage. About 75% of patients are diagnosed with non-resectable liver metastases not amenable to a standard upfront resection. In recent years, effective therapeutic approaches have revolutionised liver surgery and new strategies have enabled the conversion of primarily non-resectable metastatic disease for resection. These strategies include oncological and surgical therapies, as well as combinations of the two. From an oncological perspective, colorectal liver metastases&nbsp; may be treated by systemic chemotherapy or immunotherapy, or selective intra-hepatic arterial infusion chemotherapy, depending on the extent of the disease and the mutational status. In surgery, we often apply two-stage strategies using portal vein occlusion, such as portal vein embolisation or ligation, or complex two-stage hepatectomy such as associating liver partition and portal vein ligation for staged hepatectomy. Other additive tools to reach curative resection are tumour ablations (electroporation, microwave or radiofrequency). The role of stereotactic radiation of liver metastases is not yet well defined. Modern radiation techniques, including image guidance, breath hold and gating, were only introduced for a larger patient population in recent years. Therefore, prospective studies with larger patient cohorts are still pending. Over the last decade, liver transplantation has gained increasing attention in selective cases of non-resectable colorectal liver metastases, with promising cohort studies, but definitive recommendations must await the results of ongoing randomised controlled trials. The optimal treatment of patients with colorectal liver metastases requires the timely association of various strategies, and all cases must be discussed at multidisciplinary team conferences. While colorectal liver metastases was a uniformly lethal condition a few decades ago, it has become amenable to curative therapies, with excellent quality of life in many scenarios. This review reports on up-to-date treatment modalities and their combinations in the treatment algorithm of colorectal liver metastases. &nbsp; &nbsp.

Malignant liver tumours include a wide range of primary and secondary tumours. Although surgery remains the mainstay of curative treatment, modern therapies integrate a variety of neoadjuvant and adjuvant strategies and have achieved dramatic improvements in survival. Extensive tumour loads, which have traditionally been considered unresectable, are now amenable to curative treatment through systemic conversion chemotherapies followed by a variety of interventions such as augmentation of the healthy liver through portal vein occlusion, staged surgeries or ablation modalities. Liver transplantation is established in selected patients with hepatocellular carcinoma but is now emerging as a promising option in many other types of tumour such as perihilar cholangiocarcinomas, neuroendocrine or colorectal liver metastases. In this Review, we summarize the available therapies for the treatment of malignant liver tumours, with an emphasis on surgical and ablative approaches and how they align with other therapies such as modern anticancer drugs or radiotherapy. In addition, we describe three complex case studies of patients with malignant liver tumours. Finally, we discuss the outlook for future treatment, including personalized approaches based on molecular tumour subtyping, response to targeted drugs, novel biomarkers and precision surgery adapted to the specific tumour.

Objectives: To analyze long-term oncological outcome along with prognostic risk factors in a large cohort of patients with colorectal liver metastases (CRLM) undergoing ALPPS., Background: ALPPS is a two-stage hepatectomy variant that increases resection rates and R0 resection rates in patients with primarily unresectable CRLM as evidenced in a recent randomized controlled trial. Long-term oncologic results, however, are lacking., Methods: Cases in- and outside the International ALPPS Registry were collected and completed by direct contacts to ALPPS centers to secure a comprehensive cohort. Overall, cancer-specific (CSS), and recurrence-free (RFS) survivals were analyzed along with independent risk factors using Cox-regression analysis., Results: The cohort included 510 patients from 22 ALPPS centers over a 10-year period. Ninety-day mortality was 4.9% and median overall survival, CSS, and RFS were 39, 42, and 15 months, respectively. The median follow-up time was 38 months (95% confidence interval 32-43 months). Multivariate analysis identified tumor-characteristics (primary T4, right colon), biological features (K/N-RAS status), and response to chemotherapy (Response Evaluation Criteria in Solid Tumors) as independent predictors of CSS. Traditional factors such as size of metastases, uni versus bilobar involvement, and liver-first approach were not predictive. When hepatic recurrences after ALPPS was amenable to surgical/ablative treatment, median CSS was significantly superior compared to chemotherapy alone (56 vs 30 months, P < 0.001)., Conclusions: This large cohort provides the first evidence that patients with primarily unresectable CRLM treated by ALPPS have not only low perioperative mortality, but achieve appealing long-term oncologic outcome especially those with favorable tumor biology and good response to chemotherapy.

Purpose: We evaluated circulating tumor DNA (ctDNA) for detecting tumor burden in melanoma and examined whether early changes in the number of ctDNA copies predict response to treatment., Patients and Methods: We included 12 patients with stage III and 50 patients with stage IV melanoma with BRAF exon 15 or NRAS exon 3 mutations in tumor tissue. We used droplet digital polymerase chain reaction to retrospectively analyze serial plasma samples for mutation-positive ctDNA., Results: Matched plasma and serum samples were positive for ctDNA, lactate dehydrogenase, and S100 in 113 (45.8%), 108 (43.7%; not significant), and 58 (23.5%; P < .0001) of 247 samples from 50 patients with stage IV melanoma, and in 17 (63%), eight (29.6%; P = .014), and five (18.5%; P < .0001) of 27 samples from 12 patients with stage III melanoma. The number of mutant ctDNA copies correlated with concentrations of lactate dehydrogenase ( r = 0.50) and S100 ( r = 0.64), tumor volume ( r 2 = 0.58), and tumor metabolic activity ( r 2 = 0.83). Within 30 days before surgery, initiation of treatment, or change in treatment, ctDNA, LDH, and S100 were positive in 76.8%, 53.6% ( P = .01), and 46.4% ( P < .001) of patients, respectively. In patients with stage III or IV melanoma, early changes in ctDNA within 1 month after initiation of treatment correctly predicted RECIST response categories in 19 of 20 patients. Detectable ctDNA within 30 days after surgery or initiation of systemic treatment predicted inferior progression-free survival in patients with stage III disease ( P = .018). In patients with stage IV disease, 10 or more copies of ctDNA per mL at first follow-up indicated shorter progression-free survival (3.8 v 9 months; hazard ratio, 4.05; 95% CI, 1.56 to 10.53)., Conclusion: ctDNA indicated active tumor and was an adverse prognostic marker for tumor progression. Dynamic changes in ctDNA allowed prediction of response early after initiation of treatment. These data support the use of ctDNA to guide treatment in melanoma.

Time-resolved temperature-jump infrared absorption spectroscopy at a 0.5 to 1 kHz repetition rate is presented. A 1 kHz neodymium-doped yttrium aluminum garnet (Nd:YAG) laser pumping an optical parametric oscillator provided >70 µJ, 3.75 µm pump pulses, which delivered a temperature jump via excitation of the O-D stretch of a D 2 O solution. A 10 kHz train of mid-infrared probe pulses was used to monitor spectral changes following the temperature jump. Calibration with trifluoroacetic acid solution showed that a temperature jump of 10 K lasting for tens of microseconds was achieved, sufficient to observe fast processes in functionally relevant biomolecular mechanisms. Modeling of heating profiles across ≤10 µm path length cells and subsequent cooling dynamics are used to describe the initial <100 ns cooling at the window surface and subsequent, >10 µs cooling dynamics of the bulk solution.

Cases where animals use controlled illumination to improve vision are rare and thus far limited to chemiluminescence, which only functions in darkness. This constraint was recently relaxed by studies on Tripterygion delaisi , a small triplefin that redirects sunlight instead. By reflecting light sideways with its iris, it has been suggested to induce and detect eyeshine in nearby micro-prey. Here, we test whether 'diurnal active photolocation' also improves T. delaisi 's ability to detect the cryptobenthic sit-and-wait predator Scorpaena porcus, a scorpionfish with strong daytime retroreflective eyeshine. Three independent experiments revealed that triplefins in which light redirection was artificially suppressed approached scorpionfish significantly closer than two control treatments before moving away to a safer distance. Visual modelling confirmed that ocular light redirection by a triplefin is sufficiently strong to generate a luminance increase in scorpionfish eyeshine that can be perceived by the triplefin over 6-8 cm under average conditions. These distances coincide well with the closest approaches observed. We conclude that light redirection by small, diurnal fish significantly contributes to their ability to visually detect cryptic predators, strongly widening the conditions under which active sensing with light is feasible. We discuss the consequences for fish eye evolution.

Objective: The role of innate lymphoid cells (ILCs) in the pathophysiology of rheumatic diseases is emerging. Evidence from animal studies implicate type I IFN, produced by plasmacytoid dendritic cells, to be involved in regulating the survival of group 2 and group 3 ILCs (ILC2s and ILC3s) via the upregulation of Fas (CD95) expression. For the first time, we explored the frequency and phenotype of circulating ILCs in SLE and primary Sjögren's syndrome (pSS) in relationship to the IFN signature., Methods: Frequencies and phenotypes of ILC subsets and plasmacytoid dendritic cells were assessed by flow cytometry in peripheral blood of patients with SLE (n = 20), pSS (n = 20) and healthy controls (n = 17). Patients were stratified by the presence or absence of an IFN signature as assessed by RT-qPCR on circulating mononuclear cells., Results: ILC1 frequencies were increased in peripheral blood of patients with SLE as compared with healthy controls and correlate with disease activity in pSS patients. Overall, the frequencies of ILC2s or ILC3s did not differ between patients with SLE, pSS and healthy controls. However, patients with a high type I IFN signature expressed elevated levels of Fas on ILC2s and ILC3s, which coincided with decreased frequencies of these cells in blood., Conclusion: The presence of a type I IFN signature is related to Fas expression and frequencies of circulating ILC2s and ILC3s in patients with SLE and pSS, potentially altering the homeostatic balance of ILCs., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

RAC1 P29 is the third most commonly mutated codon in human cutaneous melanoma, after BRAF V600 and NRAS Q61. Here, we study the role of RAC1 P29S in melanoma development and reveal that RAC1 P29S activates PAK, AKT, and a gene expression program initiated by the SRF/MRTF transcriptional pathway, which results in a melanocytic to mesenchymal phenotypic switch. Mice with ubiquitous expression of RAC1 P29S from the endogenous locus develop lymphoma. When expressed only in melanocytes, RAC1 P29S cooperates with oncogenic BRAF or with NF1-loss to promote tumorigenesis. RAC1 P29S also drives resistance to BRAF inhibitors, which is reversed by SRF/MRTF inhibitors. These findings establish RAC1 P29S as a promoter of melanoma initiation and mediator of therapy resistance, while identifying SRF/MRTF as a potential therapeutic target., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Platinum-based chemotherapy remains standard-of-care for gastric and gastroesophageal junction (GEJ) adenocarcinoma. For locally advanced resectable disease, perioperative treatment with cisplatin-based doublet or triplet chemotherapy regimens had been the predominant approach in Europe and the US, based on pivotal phase III trials including the MAGIC study. Results from more recent landmark studies including the German FLOT4 and the Asian CLASSIC trials have, however, triggered a shift from cisplatin towards oxaliplatin-based chemotherapy protocols in the perioperative setting. Areas covered: This drug profile summarizes current state-of-the-art of perioperative and adjuvant treatment for locally advanced resectable gastric/GEJ cancers with a special focus on the increasingly predominant role of oxaliplatin over cisplatin in this setting. We review pharmacology, clinical efficacy, and safety profile of oxaliplatin and oxaliplatin combination regimens. We highlight recent advances and ongoing developments in the field. Expert opinion: While the adoption of oxaliplatin-containing combination regimens for perioperative therapy of gastric/GEJ cancers represents a significant step ahead, many pivotal questions remain unanswered. At the sample time, the evolution of molecular subtyping and immunotherapy is likely to dramatically change clinical practice in the foreseeable future.

Background: Data on the course of mental disorders during imprisonment are scarce. Longitudinal studies from high-income Western countries point to improvements of symptoms over time. The aim of the present study was to assess mental disorders and symptoms three years after baseline evaluation at imprisonment and to determine predictors of change in a South American prison context., Methods: Consecutively admitted prisoners in Santiago de Chile were assessed at intake and reassessed after three years using the Mini International Neuropsychiatric Interview and the Symptom-Check-List 90 Revised (SCL-90-R). The global severity index (GSI) was calculated with standard deviations (SD) and compared using paired t-tests. The prevalence of mental disorders at baseline and at follow-up were compared using McNemar tests. Analyses of variance were conducted to evaluate whether prespecified socio-demographic variables and disorders at baseline predicted symptom change at follow-up., Results: 73 (94%) out of 78 prisoners participated. The prevalence of major mental illnesses was lower at follow-up: 47 (64%) at intake vs. 23 (32%) at follow-up had major depression (p<0.001); 22 (30%) at intake vs. 10 (14%) at follow-up had psychosis (p = 0.008). The mean GSI improved from 1.97 (SD 0.65) at intake to 1.16 (SD 0.82) at follow-up (p<0.001). Depression at baseline (F = 9.39; [Formula: see text] = 0.137; β = -0.67; p = 0.003) and working or studying during imprisonment (F = 10.61; [Formula: see text] = 0.152; β = -0.71; p = 0.002) were associated with strong improvement of the GSI at follow-up, whereas psychosis at intake was associated with relatively small symptom improvement (F = 12.11; [Formula: see text] = 0.17; β = 0.81; p = 0.001)., Conclusions: In a resource poor prison context in South America, mental health symptoms and disorders improve considerably over three years during imprisonment. This applies especially to people with depression at intake. Offers to work or study during imprisonment may improve mental health outcomes., Competing Interests: The authors have declared that no competing interests exist.

Purpose: To evaluate the feasibility and toxicity profile of repeated stereotactic body radiotherapy (SBRT) for recurrent primary or secondary liver tumors., Methods: Consecutive patients with primary (hepatocellular carcinoma [HCC] or cholangiocarcinoma [CCC]) or secondary liver cancer (LM), with intrahepatic recurrence or progression after SBRT, underwent re-SBRT in 3 to 12 fractions with a median time of 15 (range 2-66) months between treatments., Results: In all, 24 patients which were previously treated with SBRT (30 lesions) were retreated with SBRT for "in- and out-of-field" recurrences (2nd SBRT: n = 28, 3rd SBRT: n = 2). The median follow-up after re-irradiation was 14 months. The median prescribed dose for the first SBRT was 46.5 (range 33-66 Gy, EQD2 10  = 70.5) Gy and 48 (range 27-66 Gy, EQD2 10  = 71) Gy for the re-SBRT. The median mean liver dose (D mean, liver ) was 6 Gy (range 1-25, EQD2 2  = 7 Gy) for the first SBRT and 10 Gy (range 1-63 Gy, EQD2 2  = 9 Gy) for the re-SBRT. Of the 30 re-irradiated lesions 6 were re-irradiated in-field resulting in a median EQD2 2, maximum of 359 (range 120-500) Gy for both treatments, with an α/β = 2 to account for liver parenchyma. Treatment was well tolerated. Two patients with stent placement before SBRT developed cholangitis 4 and 14 months after re-SBRT. There were no elevations of the serum liver parameters after re-SBRT. One patient developed a grade 3 gastrointestinal bleeding. There was no radiation induced liver disease (RILD) observed., Conclusions: Repeated liver SBRT is feasible, without excessive liver toxicity, when there is no considerable overlapping with pre-irradiated portions of the stomach or bowel and enough time for the liver to regenerate.

Background: Postpartum depression (PPD) is a public health issue, and appropriate screening may lead to clinical gains., Aim: To describe the screening for PPD, its relationship with the use of health care services, and treatment access barriers in Chilean public primary health care (PHC) centers., Material and Methods: Puerperal women attending PHC centers for a well-child check-up were assessed for the presence of PPD using the Edinburgh Postnatal Depression Scale and a structured psychiatric interview. PPD cases were assessed by telephone three months later. Also, women with PPD and PHC workers were interviewed to explore treatment barriers., Results: Of the 305 women assessed, 21% met diagnostic criteria for PPD. Sixty five percent of assessed women were previously screened for PPD while attending well-child check-ups. The results of the screening were communicated to 60% of them and 28% received some management indication. After three months of follow up, 70% of PPD cases continued to be depressed, and two thirds of them did not consult a health care provider and most of them rejected psychotherapy or medical treatment., Conclusions: Management of postpartum depression should be substantially improved in public PHC from screening to treatment.

Purpose: Dramatic advances in our understanding of the molecular pathophysiology of cancer, along with a rapidly expanding portfolio of molecular targeted drugs, have led to a paradigm shift toward personalized, biomarker-driven cancer treatment. Here, we report the 2-year experience of the Comprehensive Cancer Center Freiburg Molecular Tumor Board (MTB), one of the first interdisciplinary molecular tumor conferences established in Europe. The role of the MTB is to recommend personalized therapy for patients with cancer beyond standard-of-care treatment., Methods: This retrospective case series includes 198 patients discussed from March 2015 through February 2017. The MTB guided individual molecular diagnostics, assessed evidence of actionability of molecular alterations, and provided therapy recommendations, including approved and off-label treatments as well as available matched clinical trials., Results: The majority of patients had metastatic solid tumors (73.7%), mostly progressive (77.3%) after a mean of 2.0 lines of standard treatment. Diagnostic recommendations resulted in 867 molecular diagnostic tests for 172 patients (five per case), including exome analysis in 36 cases (18.2%). With a median turnaround time of 28 days, treatment recommendations were given to 104 patients (52.5%). These included single-agent targeted therapies (42.3%), checkpoint inhibitors (37.5%), and combination therapies (18.3%). Treatment recommendations were implemented in 33 of 104 patients (31.7%), of whom 19 (57.6%) showed stable disease or partial response, including 14 patients (7.1% of the entire population) receiving off-label treatments., Conclusion: Personalized extended molecular-guided patient care is effective for a small but clinically meaningful proportion of patients in challenging clinical situations. Limited access to targeted drugs, lack of trials, and submission at late disease stage prevents broader applicability, whereas genome-wide analyses are not a strict requirement for predictive molecular testing., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Rouven HoefflinEmployment: Roche Pharma AG (I)Anna-Lena GeißlerNo relationship to discloseRalph FritschHonoraria: Genentech, Servier, Merck, Amgen Consulting or Advisory Role: Genentech Travel, Accommodations, Expenses: Amgen, Celgene, Servier, MerckRainer ClausStock and Other Ownership Interests: Medigene, Evotec Honoraria: Roche, Abbvie, Novartis, Janssen Oncology, Gilead Sciences Consulting or Advisory Role: Abbvie, Roche, Janssen Oncology Speakers' Bureau: Janssen Oncology, Roche Travel, Accommodations, Expenses: Janssen Oncology, AbbvieJulius WehrleTravel, Accommodations, Expenses: PharmaMar, NovartisPatrick MetzgerNo relationship to discloseMeike ReiserTravel, Accommodations, Expenses: AstraZenecaLeman MehmedNo relationship to discloseLisa FauthNo relationship to discloseDieter Henrik HeilandNo relationship to discloseThalia ErbesHonoraria: Roche, Novartis, Teva, Pfizer, AstraZeneca, EisaiFriedrich StockNo relationship to discloseAgnes CsanadiNo relationship to discloseCornelius MiethingConsulting or Advisory Role: Roche Pharma AG, Novartis Travel, Accommodations, Expenses: CelgeneBritta WeddelingNo relationship to discloseFrank MeissHonoraria: Bristol-Myers Squibb, Novartis, MSD Oncology Consulting or Advisory Role: Bristol-Myers Squibb, Novartis Travel, Accommodations, Expenses: Novartis, Bristol-Myers SquibbDagmar von BubnoffHonoraria: Roche, iOMEDICO AG Travel, Accommodations, Expenses: Bristol-Myers SquibbChristine DierksNo relationship to discloseIsabell GeNo relationship to discloseVolker BrassNo relationship to discloseSteffen HeegNo relationship to discloseHenning SchäferHonoraria: Genentech Consulting or Advisory Role: Bristol-Myers Squibb Travel, Accommodations, Expenses: Bristol-Myers SquibbMartin BoekerNo relationship to discloseJustyna RawlukConsulting or Advisory Role: Roche Pharma AG, Takeda, Boehringer Ingelheim, MSD, Bristol-Myers Squibb, Chugai Pharma, AstraZenecaElke Maria BotzenhartNo relationship to discloseGian KayserNo relationship to discloseSimone HettmerNo relationship to discloseHauke BuschNo relationship to discloseChristoph PetersLeadership: University Medical Center Freiburg Honoraria: University Medical Center Freiburg Travel, Accommodations, Expenses: NovartisMartin WernerHonoraria: Diakovere Consulting or Advisory Role: Roche, Novartis, Johnson & Johnson Research Funding: Agilent (Inst), Novartis (Inst), Roche (Inst)Justus DuysterHonoraria: Novartis, Genentech, Pfizer Consulting or Advisory Role: Novartis, Roche Travel, Accommodations, Expenses: NovartisTilman BrummerNo relationship to discloseMelanie BoerriesNo relationship to discloseSilke LassmannHonoraria: Novartis, AstraZeneca Travel, Accommodations, Expenses: Novartis, AstraZenecaNikolas von BubnoffHonoraria: AstraZeneca, Amgen, Bristol-Myers Squibb Consulting or Advisory Role: Novartis Research Funding: Novartis Travel, Accommodations, Expenses: Novartis, (© 2018 by American Society of Clinical Oncology.)

Objective: To compare dyadic (marital) functioning between users of natural family planning (NFP) and users of artificial methods of contraception (AMC)., Method: A cross-sectional study was conducted in healthy, over eighteen-year-old couples living in stable relationships recruited from primary and secondary health centers in Santiago, Chile. Participants were assessed using a structured interview on sociodemographic and sexual aspects. Primary outcome, marital functioning, was studied using the Dyadic Adjustment Scale (DAS)., Results: One hundred and thirty-eight couples were studied, sixty-nine in each user group. Both groups had a similar average time living together (124.3 vs. 126.9 months). DAS results were consistent with functional couples in both groups, but on average, the NFP group had a significantly higher DAS score than AMC. After controlling for age, socioeconomic status, time in the relationship, and religious commitment in multivariable analysis, the NFP group had a 47 percent (odds ratio = 1.47) greater possibility of having a functional marital score above the cutoff (DAS > 114) when compared with the AMC group. The AMC group reported more frequency of sexual intercourse but similar sexual satisfaction. Most (>60 percent) of the NFP couples mentioned that their methods improved their relationship., Conclusion: There are sociodemographic differences between both groups, explained partly by unequal access to NFP centers. Both groups have DAS scores within functional range, but NFP users have a higher probability of being in that functional range. This study of mentally and emotionally healthy couples highlights the importance of family planning methods on intimate relationships. Summary Marital functioning is affected by family planning methods. A structured interview and a specific inventory to address conjugal functioning were applied to a group of healthy couples who live in stable relationships and are users of natural family planning (NFP) or artificial methods of contraception (AMC). The results were consistent with functional couples in both groups, but on average, the NFP group had a significantly higher score than the AMC group. The use of NFP explained this difference. This study of mentally and emotionally healthy couples highlights the importance of family planning methods on intimate relationships., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: In the treatment of depression, primary care teams have an essential role, but they are most effective when inserted into a collaborative care model for disease management. In rural areas, the shortage of specialized mental health resources may hamper management of depressed patients., Objective: The aim was to test the feasibility, acceptability, and effectiveness of a remote collaborative care program for patients with depression living in rural areas., Methods: In a nonrandomized, open-label (blinded outcome assessor), two-arm clinical trial, physicians from 15 rural community hospitals recruited 250 patients aged 18 to 70 years with a major depressive episode (DSM-IV criteria). Patients were assigned to the remote collaborative care program (n=111) or to usual care (n=139). The remote collaborative care program used Web-based shared clinical records between rural primary care teams and a specialized/centralized mental health team, telephone monitoring of patients, and remote supervision by psychiatrists through the Web-based shared clinical records and/or telephone. Depressive symptoms, health-related quality of life, service use, and patient satisfaction were measured 3 and 6 months after baseline assessment., Results: Six-month follow-up assessments were completed by 84.4% (221/250) of patients. The remote collaborative care program achieved higher user satisfaction (odds ratio [OR] 1.94, 95% CI 1.25-3.00) and better treatment adherence rates (OR 1.81, 95% CI 1.02-3.19) at 6 months compared to usual care. There were no statically significant differences in depressive symptoms between the remote collaborative care program and usual care. Significant differences between groups in favor of remote collaborative care program were observed at 3 months for mental health-related quality of life (beta 3.11, 95% CI 0.19-6.02)., Conclusions: Higher rates of treatment adherence in the remote collaborative care program suggest that technology-assisted interventions may help rural primary care teams in the management of depressive patients. Future cost-effectiveness studies are needed., Trial Registration: Clinicaltrials.gov NCT02200367; https://clinicaltrials.gov/ct2/show/NCT02200367 (Archived by WebCite at http://www.webcitation.org/6xtZ7OijZ)., (©Graciela Rojas, Viviana Guajardo, Pablo Martínez, Ariel Castro, Rosemarie Fritsch, Markus Moessner, Stephanie Bauer. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 30.04.2018.)

Late diagnosis and systemic dissemination essentially contribute to the invariably poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Therefore, the development of diagnostic biomarkers for PDAC are urgently needed to improve patient stratification and outcome in the clinic. By studying the transcriptomes of independent PDAC patient cohorts of tumor and non-tumor tissues, we identified 81 robustly regulated genes, through a novel, generally applicable meta-analysis. Using consensus clustering on co-expression values revealed four distinct clusters with genes originating from exocrine/endocrine pancreas, stromal and tumor cells. Three clusters were strongly associated with survival of PDAC patients based on TCGA database underlining the prognostic potential of the identified genes. With the added information of impact of survival and the robustness within the meta-analysis, we extracted a 17-gene subset for further validation. We show that it did not only discriminate PDAC from non-tumor tissue and stroma in fresh-frozen as well as formalin-fixed paraffin embedded samples, but also detected pancreatic precursor lesions and singled out pancreatitis samples. Moreover, the classifier discriminated PDAC from other cancers in the TCGA database. In addition, we experimentally validated the classifier in PDAC patients on transcript level using qPCR and exemplify the usage on protein level for three proteins (AHNAK2, LAMC2, TFF1) using immunohistochemistry and for two secreted proteins (TFF1, SERPINB5) using ELISA-based protein detection in blood-plasma. In conclusion, we present a novel robust diagnostic and prognostic gene signature for PDAC with future potential applicability in the clinic.

Background: Substance use among adolescents is a major problem worldwide, producing many health and economic consequences. Even though there are well-known personal, familial, and social factors associated with drug use, less is known about the effect of school-related factors. School membership is a recognized variable affecting academic performance among students; however, its effect on substance use is less understood., Aims: The primary aim of this study was to explore the association between school membership and cigarette, alcohol, and cannabis use among a representative sample of secondary students from municipal state-funded schools in Santiago of Chile, and secondly, to test the hypothesis that depressive or anxiety symptoms mediate this association., Methods: A total of 2,508 students from 22 state-funded schools in Santiago, Chile, answered a questionnaire. This instrument included an abbreviated version of the psychological sense of school membership (PSSM), questions regarding the use of alcohol, tobacco, and cannabis and scales of psychological functioning (depression, anxiety, self-concept, and problem-solving). The association analyses were performed using adjusted regression models for each outcome using all independent variables while controlling for gender and age. For the mediation effect, a combination of ordinary least square and logistic regression analyses was conducted., Results: There was an association between a strong PSSM and low risk for smoking (OR 0.57; 95% CI 0.46-0.72), drinking (0.65; 95% CI: 0.51-0.83), and cannabis use (0.52; 95% CI 0.37-0.74). We also found that depressive and anxiety symptoms do not fully mediate the association between school membership and any substance use, and 73% of this effect in the case of smoking, 80% in the case of drinking, and 78.5% in the case of cannabis use, was direct., Conclusion: This is the first study in Latin America exploring the association between school membership and substance use among secondary students. School membership seems to be an important and independent factor to be included in preventive interventions. Therefore, these results support future research aiming to test interventions at increasing the sense of school membership to prevent substance use among adolescents., Clinical Trial Registration: ISRCTN19466209. Retrospectively registered.

The environment and lifestyle of a species are known to exert selective pressure on the visual system, often demonstrating a tight link between visual morphology and ecology. Many studies have predicted the visual requirements of a species by examining the anatomical features of the eye. However, among the vast number of studies on visual specializations in aquatic animals, only a few have focused on small benthic fishes that occupy a heterogeneous and spatially complex visual environment. This study investigates the general retinal anatomy including the topography of both the photoreceptor and ganglion cell populations and estimates the spatial resolving power (SRP) of the eye of the Mediterranean triplefin Tripterygion delaisi . Retinal wholemounts were prepared to systematically and quantitatively analyze photoreceptor and retinal ganglion cell (RGC) densities using design-based stereology. To further examine the retinal structure, we also used magnetic resonance imaging (MRI) and histological examination of retinal cross sections. Observations of the triplefin's eyes revealed them to be highly mobile, allowing them to view the surroundings without body movements. A rostral aphakic gap and the elliptical shape of the eye extend its visual field rostrally and allow for a rostro-caudal accommodatory axis, enabling this species to focus on prey at close range. Single and twin cones dominate the retina and are consistently arranged in one of two regular patterns, which may enhance motion detection and color vision. The retina features a prominent, dorso-temporal, convexiclivate fovea with an average density of 104,400 double and 30,800 single cones per mm 2 , and 81,000 RGCs per mm 2 . Based on photoreceptor spacing, SRP was calculated to be between 6.7 and 9.0 cycles per degree. Location and resolving power of the fovea would benefit the detection and identification of small prey in the lower frontal region of the visual field.

Background: To evaluate the role of ablative radiotherapy doses in the treatment of hilar or intrahepatic cholangiocarcinoma (CCC) using stereotactic body radiotherapy (SBRT)., Methods: Consecutive patients treated from 2007 to 2016 with CCC were evaluated. Local control and toxicities were assessed every 3 months according to the Response Evaluation Criteria In Solid Tumors (RECIST) and the Common Terminology Criteria for Adverse Events v4.0, respectively. Overall survival (OS), local control (LC) and progression free survival were calculated from SBRT., Results: Thirty seven patients with 43 lesions were retrospectively evaluated. The median dose delivered was 45 Gy (range 25-66 Gy) in 3-12 fractions, corresponding to a median equivalent dose in 2 Gy fractions (EQD2 10 ) of 56 (range 25-85) Gy. The median follow up was 24 months. The OS at 1 year was 56% with a median OS of 14 (95% CI: 7.8-20.2) months from start of SBRT and 22 (95% CI: 17.5-26.5) months from diagnosis. Eight lesions progressed locally. The local control rate (LC) at 1 year was 78%. The median progression free survival was 9 months (95% CI 2.8-15.2) 21 patients progressed in the liver but out of field and 15 progressed distantly. SBRT was well tolerated. Three patients (9%) developed a Grade III bleeding. Seven patients developed a cholangitis, one due to progression and the other because of a stent dysfunction 2-21(median 8) months from SBRT., Conclusion: In patients with locally advanced cholangiocarcinoma, SBRT is a local treatment option with an acceptable toxicity profile which warrants further investigation in prospective trials.

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Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease. Circulating tumor cells (CTC) in the blood are hypothesized as the means of systemic tumor spread. Blood obtained from healthy donors and patients with PDAC was therefore subject to size-based CTC-isolation. We additionally compared Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in pancreatic CTC and corresponding tumors, and evaluated their significance as prognostic markers. Samples from 68 individuals (58 PDAC patients, 10 healthy donors) were analyzed; CTCs were present in patients with UICC stage IA-IV tumors and none of the controls (p < 0.001). Patients with >3 CTC/ml had a trend for worse median overall survival (OS) than patients with 0.3–3 CTC/ml (P = 0.12). Surprisingly, CTCs harbored various KRAS mutations in codon 12 and 13. Patients with a KRAS G12V mutation in their CTC (n = 14) had a trend to better median OS (24.5 months) compared to patients with other (10 months), or no detectable KRAS mutations (8 months; P = 0.04). KRAS mutations in CTC and corresponding tumor were discordant in 11 of 26 “tumor-CTC-pairs” (42%), while 15 (58%) had a matching mutation; survival was similar in both groups (P = 0.36). Genetic characterization, including mutations such as KRAS, may prove useful for prognosis and understanding of tumor biology.

The present study aimed to explore the burden of separation from children and its relationship with suicide risk in prisoners with minor children at the moment of admission into the penal justice system. Suicide risk was assessed using the Mini International Neuropsychiatric Interview in newly admitted female (n=198) and male (n=229) prisoners in Santiago de Chile. The burden of separation from minor children was rated on a numeric rating scale. Both genders showed high burden of separation from children at imprisonment. Mothers had significantly lower suicide risk than women without children. The relative risk was 0.31 (95% CI [0.16-0.6], p<0.001) to show 'high suicide risk'. There was no difference of suicide risk between imprisoned fathers and male prisoners without children. Within the group of fathers, the suicide risk associated with the burden of separation. Our study indicates that strengthening the parent role and facilitating parent-child contacts during imprisonment could be an important element of suicide prevention interventions., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The recurrent 22q11.2 deletion is a genetic risk factor for early-onset Parkinson's disease. Adults with the associated 22q11.2 deletion syndrome (22q11.2DS) may exhibit phenotypes that could help identify those at highest risk and reveal disease trajectories. We investigated clinical and neuroimaging features relevant to Parkinson's disease in 26 adults: 13 with 22q11.2DS at genetic risk of Parkinson's disease (mean age = 41.5 years, standard deviation = 9.7), 12 healthy age and sex-matched controls, and a 22q11.2DS patient with l-DOPA-responsive early-onset Parkinson's disease. Neuroimaging included transcranial sonography and positron emission tomography using 11C-dihydrotetrabenazine (11C-DTBZ), a radioligand that binds to the presynaptic vesicular monoamine transporter. The 22q11.2DS group without Parkinson's disease demonstrated significant motor and olfactory deficits relative to controls. Eight (61.5%) were clinically classified with parkinsonism. Transcranial sonography showed a significantly larger mean area of substantia nigra echogenicity in the 22q11.2DS risk group compared with controls (P = 0.03). The 22q11.2DS patient with Parkinson's disease showed the expected pattern of severely reduced striatal 11C-DTBZ binding. The 22q11.2DS group without Parkinson's disease however showed significantly elevated striatal 11C-DTBZ binding relative to controls (∼33%; P < 0.01). Results were similar within the 22q11.2DS group for those with (n = 7) and without (n = 6) psychotic illness. These findings suggest that manifestations of parkinsonism and/or evolution to Parkinson's disease in this genetic at-risk population may include a hyperdopaminergic mechanism. Adequately powered longitudinal studies and animal models are needed to evaluate the relevance of the observed clinical and imaging phenotypes to Parkinson's disease and other disorders that are more prevalent in 22q11.2DS, such as schizophrenia., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The light environment in water bodies changes with depth due to the absorption of short and long wavelengths. Below 10 m depth, red wavelengths are almost completely absent rendering any red-reflecting animal dark and achromatic. However, fluorescence may produce red coloration even when red light is not available for reflection. A large number of marine taxa including over 270 fish species are known to produce red fluorescence, yet it is unclear under which natural light environment fluorescence contributes perceptively to their colours. To address this question we: (i) characterized the visual system of Tripterygion delaisi, which possesses fluorescent irides, (ii) separated the colour of the irides into its reflectance and fluorescence components and (iii) combined these data with field measurements of the ambient light environment to calculate depth-dependent perceptual chromatic and achromatic contrasts using visual modelling. We found that triplefins have cones with at least three different spectral sensitivities, including differences between the two members of the double cones, giving them the potential for trichromatic colour vision. We also show that fluorescence contributes increasingly to the radiance of the irides with increasing depth. Our results support the potential functionality of red fluorescence, including communicative roles such as species and sex identity, and non-communicative roles such as camouflage.

EGFR-targeted therapy is a key treatment approach in patients with RAS wildtype metastatic colorectal cancers (CRC). Still, also RAS wildtype CRC may be resistant to EGFR-targeted therapy, with few predictive markers available for improved stratification of patients. Here, we investigated response of 7 CRC cell lines (Caco-2, DLD1, HCT116, HT29, LS174T, RKO, SW480) to Cetuximab and correlated this to NGS-based mutation profiles, EGFR promoter methylation and EGFR expression status as well as to E-cadherin expression. Moreover, tissue specimens of primary and/or recurrent tumors as well as liver and/or lung metastases of 25 CRC patients having received Cetuximab and/or Panitumumab were examined for the same molecular markers. In vitro and in situ analyses showed that EGFR promoter methylation and EGFR expression as well as the MSI and or CIMP-type status did not guide treatment responses. In fact, EGFR-targeted treatment responses were also observed in RAS exon 2 p.G13 mutated CRC cell lines or CRC cases and were further linked to PIK3CA exon 9 mutations. In contrast, non-response to EGFR-targeted treatment was associated with ATM mutations and low E-cadherin expression. Moreover, down-regulation of E-cadherin by siRNA in otherwise Cetuximab responding E-cadherin positive cells abrogated their response. Hence, we here identify ATM and E-cadherin expression as potential novel supportive predictive markers for EGFR-targeted therapy.

Background: Most animal eyes feature an opaque pigmented eyecup to assure that light can enter from one direction only. We challenge this dogma by describing a previously unknown form of eyeshine resulting from light that enters the eye through the top of the head and optic nerve, eventually emanating through the pupil as a narrow beam: the Optic-Nerve-Transmitted (ONT) eyeshine. We characterize ONT eyeshine in the triplefin blenny Tripterygion delaisi (Tripterygiidae) in comparison to three other teleost species, using behavioural and anatomical observations, spectrophotometry, histology, and magnetic resonance imaging. The study's aim is to identify the factors that determine ONT eyeshine occurrence and intensity, and whether these are specifically adapted for that purpose., Results: ONT eyeshine intensity benefits from locally reduced head pigmentation, a thin skull, the gap between eyes and forebrain, the potential light-guiding properties of the optic nerve, and, most importantly, a short distance between the head surface and the optic nerves., Conclusions: The generality of these factors and the lack of specifically adapted features implies that ONT eyeshine is widespread among small fish species. Nevertheless, its intensity varies considerably, depending on the specific combination and varying expression of common anatomical features. We discuss whether ONT eyeshine might affect visual performance, and speculate about possible functions such as predator detection, camouflage, and intraspecific communication.

Background: International evidence has shown the complex interaction between depression and chronic physical diseases. Depression in scenarios involving multiple comorbidities has not received enough attention in Chile., Aim: To characterize the depressed people who consult at Primary Health Care Centers (PHCCs), taking into account the presence of chronic physical or psychiatric comorbidity., Materials and Methods: A secondary analysis of databases used in a clinical trial. Two hundred fifty six adults seeking professional help were recruited in four PHCCs located in the Metropolitan Region. These people had a major depressive episode, identified with a structured psychiatric interview (MINI), and gave their informed consent to participate. Socio-demographic information was collected, depressive symptomatology was measured with the patient health questionnaire 9 (PHQ-9), psychiatric morbidity was assessed using the Mini International Neuropsychiatric Interview (MINI), and chronic physical diseases were self-reported by the patients. Descriptive analyses of all the variables were conducted., Results: Seventy percent of patients had a history of depression, with a median of two prior depressive episodes. Depressive symptoms were mostly considered as moderate to severe and severe and 31% of the patients had high suicide risk. Seventy eight percent displayed a physical or psychiatric comorbidity. Of these patients, 29% only had a chronic physical comorbidity, while 46% suffered from an additional psychiatric disorder., Conclusions: Depressed individuals who seek help at PHCCs constitute an especially complex population that must be treated taking into account multiple comorbidities.

Background: Targeted next generation sequencing (tNGS) has become part of molecular pathology diagnostics for determining RAS mutation status in colorectal cancer (CRC) patients as predictive tool for decision on EGFR-targeted therapy. Here, we investigated mutation profiles of case-matched tissue specimens throughout the disease course of CRC, to further specify RAS-status dynamics and to identify de novo mutations associated with distant metastases., Methods: Case-matched formalin-fixed and paraffin-embedded (FFPE) resection specimens (n = 70; primary tumours, synchronous and/or metachronous liver and/or lung metastases) of 14 CRC cases were subjected to microdissection of normal colonic epithelial, primary and metastatic tumour cells, their DNA extraction and an adapted library protocol for limited DNA using the 48 gene TruSeq Amplicon Cancer Panel TM , MiSeq sequencing and data analyses (Illumina)., Results: By tNGS primary tumours were RAS wildtype in 5/14 and mutated in 9/14 (8/9 KRAS exon 2; 1/9 NRAS Exon 3) of cases. RAS mutation status was maintained in case-matched metastases throughout the disease course, albeit with altered allele frequencies. Case-matched analyses further identified a maximum of three sequence variants (mainly in APC, KRAS, NRAS, TP53) shared by all tumour specimens throughout the disease course per individual case. In addition, further case-matched de novo mutations were detected in synchronous and/or metachronous liver and/or lung metastases (e.g. in APC, ATM, FBXW7, FGFR3, GNAQ, KIT, PIK3CA, PTEN, SMAD4, SMO, STK11, TP53, VHL). Moreover, several de novo mutations were more frequent in synchronous (e.g. ATM, KIT, PIK3CA, SMAD4) or metachronous (e.g. FBXW7, SMO, STK11) lung metastases. Finally, some de novo mutations occurred only in metachronous lung metastases (CDKN2A, FGFR2, GNAS, JAK3, SRC)., Conclusion: Together, this study employs an adapted FFPE-based tNGS approach to confirm conservation of RAS mutation status in primary and metastatic tissue specimens of CRC patients. Moreover, it identifies genes preferentially mutated de novo in late disease stages of metachronous CRC lung metastases, several of which might be actionable by targeted therapies.

Background: Previous mental health surveys conducted in prisons within emerging countries recruited samples of all prisoners at any single point in time. However, this sampling strategy results in an overrepresentation of long-term prisoners as compared with those studies recruiting from all admissions over time. This study aimed to assess mental disorders in consecutively admitted prisoners soon after admission, in order to address service needs of people with short-term imprisonments and people at early stages of imprisonment., Method: Disorders were assessed in a sample of 229 male and 198 female prisoners, consecutively committed to the penal justice system in Santiago de Chile, using the structured Mini-Neuropsychiatric interview. Prevalence rates were calculated as per cent values. Ninety-five per cent confidence intervals were calculated for the proportions., Results: Illicit drug and/or alcohol use disorders in the year prior to admission were present in 173 (76%) male and 64 (32%) female prisoners. The substances most frequently causing addiction were cocaine-based products in 108 (47%) male and 42 (21%) female prisoners. Current major depression was present in 124 (54%) male and 86 (43%) female prisoners, and current non-affective psychotic disorders in 18 (8%) male and in 10 (5%) female prisoners. High suicidal risk was present in 64 (28%) male prisoners and in 29 (15%) female prisoners., Conclusion: When consecutive prisoners are assessed at admission, rates of mental health and substance use disorders were higher than in previous studies in emerging countries that had sampled from all existing prisoners at a time. Affective disorders and suicide risk appear more prevalent than in admission studies conducted in Western high-income countries. Previous research may have systematically underestimated the extent of mental health problems in prisoners, which poses a major public health challenge in emerging countries.

Class I phosphoinositide 3-kinases (PI3Ks) catalyze production of the lipid messenger phosphatidylinositol 3,4,5-trisphosphate (PIP3), which plays a central role in a complex signaling network regulating cell growth, survival, and movement. This network is overactivated in cancer and inflammation, and there is interest in determining the PI3K catalytic subunit (p110α, p110β, p110γ, or p110δ) that should be targeted in different therapeutic contexts. Previous studies have defined unique regulatory inputs for p110β, including direct interaction with Gβγ subunits, Rac, and Rab5. We generated mice with knock-in mutations of p110β that selectively blocked the interaction with Gβγ and investigated its contribution to the PI3K isoform dependency of receptor tyrosine kinase (RTK) and G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor (GPCR) responses in primary macrophages and neutrophils. We discovered a unique role for p110β in supporting synergistic PIP3 formation in response to the coactivation of macrophages by macrophage colony-stimulating factor (M-CSF) and the complement protein C5a. In contrast, we found partially redundant roles for p110α, p110β, and p110δ downstream of M-CSF alone and a nonredundant role for p110γ downstream of C5a alone. This role for p110β completely depended on direct interaction with Gβγ, suggesting that p110β transduces GPCR signals in the context of coincident activation by an RTK. The p110β-Gβγ interaction was also required for neutrophils to generate reactive oxygen species in response to the Fcγ receptor-dependent recognition of immune complexes and for their β2 integrin-mediated adhesion to fibrinogen or poly-RGD+, directly implicating heterotrimeric G proteins in these two responses., (Copyright © 2016, American Association for the Advancement of Science.)