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Background: Fibroblast growth factor receptor 2 (FGFR2) fusions and rearrangements are clinically actionable genomic alterations in cholangiocarcinoma (CCA). Pemigatinib is a selective, potent, oral inhibitor of FGFR1-3 and demonstrated efficacy in patients with previously treated, advanced/metastatic CCA with FGFR2 alterations in FIGHT-202 (NCT02924376). We report final outcomes from the extended follow-up period., Patients and Methods: The multicenter, open-label, single-arm, phase II FIGHT-202 study enrolled patients ≥18 years old with previously treated advanced/metastatic CCA with FGFR2 fusions or rearrangements (cohort A), other FGF/FGFR alterations (cohort B), or no FGF/FGFR alterations (cohort C). Patients received once-daily oral pemigatinib 13.5 mg in 21-day cycles (2 weeks on, 1 week off) until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) in cohort A assessed as per RECIST v1.1 by an independent review committee; secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety., Results: FIGHT-202 enrolled 147 patients (cohort A, 108; cohort B, 20; cohort C, 17; unconfirmed FGF/FGFR alterations, 2). By final analysis, 145 (98.6%) had discontinued treatment due to progressive disease (71.4%), withdrawal by patient (8.2%), or adverse events (AEs; 6.8%). Median follow-up was 45.4 months. The ORR in cohort A was 37.0% (95% confidence interval 27.9% to 46.9%); complete and partial responses were observed in 3 and 37 patients, respectively. Median DOR was 9.1 (6.0-14.5) months; median PFS and OS were 7.0 (6.1-10.5) months and 17.5 (14.4-22.9) months, respectively. The most common treatment-emergent AEs (TEAEs) were hyperphosphatemia (58.5%), alopecia (49.7%), and diarrhea (47.6%). Overall, 15 (10.2%) patients experienced TEAEs leading to pemigatinib discontinuation; intestinal obstruction and acute kidney injury (n = 2 each) occurred most frequently., Conclusions: Pemigatinib demonstrated durable response and prolonged OS with manageable AEs in patients with previously treated, advanced/metastatic CCA with FGFR2 alterations in the extended follow-up period of FIGHT-202., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Skin-to-skin (STS) care effectively improves neonatal outcomes, particularly for preterm neonates. However, utilization of STS remains suboptimal for the most vulnerable preterm neonates in the first 4 weeks of life. This quality improvement (QI) project aimed to increase STS duration for neonates under 35 weeks gestation., Methods: The QI initiative was conducted in a 35-bed level IV NICU within a teaching hospital in New York City from July 2021 to January 2023. Six months of baseline data and a staff survey determined interventions across "Plan, Do, Study, Act" cycles. Interim analyses guided interventions using run charts. Interventions included parental counseling and information leaflets, discussion during rounds on STS eligibility, STS education for residents, nurses' feedback, and visual reminders. The primary outcome measure was the mean duration of STS per eligible patient day. The process measures were the age at first STS and documentation of eligibility for STS care in the electronic medical records. Balancing measures included adverse events such as apnea, bradycardia, desaturation, hypothermia, and inadvertent dislodgement of central lines and endotracheal tube., Results: The study included 185 infants with a mean gestational age of 29.1 weeks. The mean STS duration per eligible patient day increased from a baseline of 13.3 minutes to 32.4 minutes without significantly increasing adverse events., Conclusions: The QI interventions implemented have successfully increased the duration of STS in preterm infants. Our interventions combined into an STS bundle can be a potential model for other NICUs to improve STS practice., (Copyright © 2024 by the American Academy of Pediatrics.)

Background: Approximately 95% of advanced colorectal cancer patients (CRC) have mismatch repair MMR-proficient (MMRp) tumors, which do not respond to PD1 blockade alone. Preclinical studies have shown that combined histone deacetylases (HDAC) and/or DNA methyltransferases (DNMT) inhibition can induce susceptibility to immune checkpoint therapy and inhibit tumor growth. We conducted a pilot trial evaluating PD-1 immune checkpoint inhibitor therapy in combination with DNMT and HDAC inhibitors in MMRp CRC. The study was designed with a biological endpoint of change in immune cell infiltration, to determine the optimal epigenetic combination that optimizes the tumor microenvironment. This trial was designed to test that hypothesis., Results: From January 2016 to November 2018, 27 patients were enrolled with median age of 57 (range 40-69) years. Median progression-free survival and overall survival were 2.79 months and 9.17, respectively. One patient in Arm C achieved a durable partial response by RECIST criteria, lasting for approximately 19 months. The most common treatment-related hematological adverse events in all arms were anemia (62%), lymphopenia (54%) and thrombocytopenia (35%), and non-hematological AEs were anorexia (65%), nausea (77%), and vomiting (73%)., Conclusions: The combination of 5-azacitidine and romidepsin with pembrolizumab was safe and tolerable in patients with advanced MMRp CRC, but with a minimal activity. Further mechanistic investigations are needed to understand epigenetic-induced immunologic shift and to expand the potential applicability of checkpoint inhibitors in this setting., (© 2023. The Author(s).)

Background: Immunotherapy has demonstrated a limited clinical efficacy in approximately 5% of cholangiocarcinoma. The main challenges for an effective immunotherapy response in cholangiocarcinoma arise from the tumor microenvironment, which is poorly understood., Methods: For a comprehensive analysis of the tumor microenvironment in cholangiocarcinoma, we performed multiplex immunohistochemistry with two 15-marker immune panels and Nanostring assays for a comprehensive analysis of 104 surgically resected cholangiocarcinomas including intrahepatic, hilar, and distal cholangiocarcinoma. We also validated some key findings with a batch integration analysis of published single cell RNA sequencing data., Results: This study found that natural killer cells occupy the largest immune cell compartment in cholangiocarcinoma. Granzyme-B + CD8 + effector T cells are significantly associated with better overall survival in both intrahepatic and distal cholangiocarcinoma. Above 85% of intrahepatic cholangiocarcinomas with higher density of PD-1 - EOMES - CD8 + effector T cells are associated with long-term survival. However, only the density of PD-1 - EOMES - CD8 + T cells in the tumor areas, but not in the peripheries of the tumors, is prognostic. In all three cholangiocarcinoma subtypes, T regulator cells are significantly associated with a poor prognosis; however, M1 and M2 tumor-associated macrophages or PD-L1 + tumor-associated macrophage demonstrate different prognostic values. Combining PD-L1 + M1 or M2, PD-L1 - M1 or M2 tumor-associated macrophages, and T regulator cells to subgroup intrahepatic and distal cholangiocarcinoma, the prognosis is significantly better distinguished. Moreover, PD-L1 - M2 tumor-associated macrophages is associated with a good prognosis in intrahepatic and distal cholangiocarcinoma, suggesting this subtype of M2 tumor-associated macrophages may be antitumoral. Interestingly, lower densities of various types of immunosuppressive cells are associated with decreased infiltration of effector T cells in distal and hilar cholangiocarcinoma, but not in intrahepatic cholangiocarcinoma. In intrahepatic cholangiocarcinoma, PD-L1 + tumor-associated macrophages exert their immunosuppressive function likely through promoting T cell exhaustion., Conclusions: This study suggests that the densities of Granzyme-B + CD8 + effector T cells and non-exhausted PD-1 - EOMES - CD8 + T cells and the PD-L1 status in the tumor-associated macrophages are prognostic makers in cholangiocarcinomas. The study also supports targeting PD-L1 + tumor-associated macrophages as the immunotherapy for cholangiocarcinoma., (© 2022. The Author(s).)

Background: Survivorship care plans (SCP) should outline pertinent information about cancer treatment and follow-up., Methods: We descriptively analyzed the content of 74 colorectal cancer SCPs completed as part of a randomized, controlled trial of SCPs at an academic and community cancer center. Surveillance recommendations were compared with American Cancer Society, American Society of Clinical Oncology and National Comprehensive Cancer Network guidelines., Results: SCP information provided in >80% of the plans included participant age, cancer diagnosis, details, and side-effects of treatment (surgery, chemotherapy, radiation) and health promotion recommendations. SCP content documented less frequently included predisposing conditions, genetic counseling/testing information and staging. Posttreatment surveillance recommendations were documented in >90% SCPs. For stage 2-3 cancer, rates of guideline concordant recommendations were 100% for colonoscopy surveillance (Year 1 only), 87% for imaging surveillance, 65% for carcinoembryonic antigen surveillance, and 33% for follow-up visits. Excluding colonoscopy, >15 unique recommendations were listed for each modality across stages and sites, with more variation at the academic site., Conclusions: SCPs consistently recorded information about cancer diagnosis and treatment but omitted critical information about cancer-specific details denoting risk. Surveillance recommendations varied considerably between cancer centers. Future work to improve the consistency of surveillance recommendations documented in SCPs may be needed., (© 2021 Wiley Periodicals LLC.)

Importance: Isocitrate dehydrogenase 1 (IDH1) variations occur in up to approximately 20% of patients with intrahepatic cholangiocarcinoma. In the ClarIDHy trial, progression-free survival as determined by central review was significantly improved with ivosidenib vs placebo., Objective: To report the final overall survival (OS) results from the ClarIDHy trial, which aimed to demonstrate the efficacy of ivosidenib (AG-120)-a first-in-class, oral, small-molecule inhibitor of mutant IDH1-vs placebo for patients with unresectable or metastatic cholangiocarcinoma with IDH1 mutation., Design, Setting, and Participants: This multicenter, randomized, double-blind, placebo-controlled, clinical phase 3 trial was conducted from February 20, 2017, to May 31, 2020, at 49 hospitals across 6 countries among patients aged 18 years or older with cholangiocarcinoma with IDH1 mutation whose disease progressed with prior therapy., Interventions: Patients were randomized 2:1 to receive ivosidenib, 500 mg, once daily or matched placebo. Crossover from placebo to ivosidenib was permitted if patients had disease progression as determined by radiographic findings., Main Outcomes and Measures: The primary end point was progression-free survival as determined by blinded independent radiology center (reported previously). Overall survival was a key secondary end point. The primary analysis of OS followed the intent-to-treat principle. Other secondary end points included objective response rate, safety and tolerability, and quality of life., Results: Overall, 187 patients (median age, 62 years [range, 33-83 years]) were randomly assigned to receive ivosidenib (n = 126; 82 women [65%]; median age, 61 years [range, 33-80 years]) or placebo (n = 61; 37 women [61%]; median age, 63 years [range, 40-83 years]); 43 patients crossed over from placebo to ivosidenib. The primary end point of progression-free survival was reported elsewhere. Median OS was 10.3 months (95% CI, 7.8-12.4 months) with ivosidenib vs 7.5 months (95% CI, 4.8-11.1 months) with placebo (hazard ratio, 0.79 [95% CI, 0.56-1.12]; 1-sided P = .09). When adjusted for crossover, median OS with placebo was 5.1 months (95% CI, 3.8-7.6 months; hazard ratio, 0.49 [95% CI, 0.34-0.70]; 1-sided P < .001). The most common grade 3 or higher treatment-emergent adverse event (≥5%) reported in both groups was ascites (11 patients [9%] receiving ivosidenib and 4 patients [7%] receiving placebo). Serious treatment-emergent adverse events considered ivosidenib related were reported in 3 patients (2%). There were no treatment-related deaths. Patients receiving ivosidenib reported no apparent decline in quality of life compared with placebo., Conclusions and Relevance: This randomized clinical trial found that ivosidenib was well tolerated and resulted in a favorable OS benefit vs placebo, despite a high rate of crossover. These data, coupled with supportive quality of life data and a tolerable safety profile, demonstrate the clinical benefit of ivosidenib for patients with advanced cholangiocarcinoma with IDH1 mutation., Trial Registration: ClinicalTrials.gov Identifier: NCT02989857.

The combination of drugs targeting Ral and PI3K/AKT signaling has antitumor efficacy in preclinical models of pancreatic cancer. We combined dinaciclib (small molecule cyclin dependent kinase inhibitor with MK-2206 (Akt inhibitor) in patients with previously treated/metastatic pancreatic cancer. Patients were treated with dinaciclib (6-12 mg/m 2 i.v.) and MK-2206 (60-135 mg p.o.) weekly. Tumor biopsies were performed to measure pAKT, pERK, and Ki67 at baseline and after one completed cycle (dose level 2 and beyond). Thirty-nine patients participated in the study. The maximum tolerated doses were dinaciclib 9 mg/m 2 and MK-2206 135 mg. Treatment-related grade 3 and 4 toxicities included neutropenia, lymphopenia, anemia, hyperglycemia, hyponatremia, and leukopenia. No objectives responses were observed. Four patients (10%) had stable disease as their best response. At the recommended dose, median survival was 2.2 months. Survival rates at 6 and 12 months were 11% and 5%, respectively. There was a nonsignificant reduction in pAKT composite scores between pretreatment and post-treatment biopsies (mean 0.76 vs. 0.63; P = 0.635). The combination of dinaciclib and MK-2206 was a safe regimen in patients with metastatic pancreatic cancer, although without clinical benefit, possibly due to not attaining biologically effective doses. Given the strong preclinical evidence of Ral and AKT inhibition, further studies with better tolerated agents should be considered., (© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Background: Isocitrate dehydrogenase 1 (IDH1) mutations occur in approximately 13% of patients with intrahepatic cholangiocarcinoma, a relatively uncommon cancer with a poor clinical outcome. The aim of this international phase 3 study was to assess the efficacy and safety of ivosidenib (AG-120)-a small-molecule targeted inhibitor of mutated IDH1-in patients with previously treated IDH1-mutant cholangiocarcinoma., Methods: This multicentre, randomised, double-blind, placebo-controlled, phase 3 study included patients from 49 hospitals in six countries aged at least 18 years with histologically confirmed, advanced, IDH1-mutant cholangiocarcinoma who had progressed on previous therapy, and had up to two previous treatment regimens for advanced disease, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and a measurable lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (2:1) with a block size of 6 and stratified by number of previous systemic treatment regimens for advanced disease to oral ivosidenib 500 mg or matched placebo once daily in continuous 28-day cycles, by means of an interactive web-based response system. Placebo to ivosidenib crossover was permitted on radiological progression per investigator assessment. The primary endpoint was progression-free survival by independent central review. The intention-to-treat population was used for the primary efficacy analyses. Safety was assessed in all patients who had received at least one dose of ivosidenib or placebo. Enrolment is complete; this study is registered with ClinicalTrials.gov, NCT02989857., Findings: Between Feb 20, 2017, and Jan 31, 2019, 230 patients were assessed for eligibility, and as of the Jan 31, 2019 data cutoff date, 185 patients were randomly assigned to ivosidenib (n=124) or placebo (n=61). Median follow-up for progression-free survival was 6·9 months (IQR 2·8-10·9). Progression-free survival was significantly improved with ivosidenib compared with placebo (median 2·7 months [95% CI 1·6-4·2] vs 1·4 months [1·4-1·6]; hazard ratio 0·37; 95% CI 0·25-0·54; one-sided p<0·0001). The most common grade 3 or worse adverse event in both treatment groups was ascites (four [7%] of 59 patients receiving placebo and nine [7%] of 121 patients receiving ivosidenib). Serious adverse events were reported in 36 (30%) of 121 patients receiving ivosidenib and 13 (22%) of 59 patients receiving placebo. There were no treatment-related deaths., Interpretation: Progression-free survival was significantly improved with ivosidenib compared with placebo, and ivosidenib was well tolerated. This study shows the clinical benefit of targeting IDH1 mutations in advanced, IDH1-mutant cholangiocarcinoma., Funding: Agios Pharmaceuticals., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Fibroblast growth factor receptor (FGFR) 2 gene alterations are involved in the pathogenesis of cholangiocarcinoma. Pemigatinib is a selective, potent, oral inhibitor of FGFR1, 2, and 3. This study evaluated the safety and antitumour activity of pemigatinib in patients with previously treated, locally advanced or metastatic cholangiocarcinoma with and without FGFR2 fusions or rearrangements., Methods: In this multicentre, open-label, single-arm, multicohort, phase 2 study (FIGHT-202), patients aged 18 years or older with disease progression following at least one previous treatment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 recruited from 146 academic or community-based sites in the USA, Europe, the Middle East, and Asia were assigned to one of three cohorts: patients with FGFR2 fusions or rearrangements, patients with other FGF/FGFR alterations, or patients with no FGF/FGFR alterations. All enrolled patients received a starting dose of 13·5 mg oral pemigatinib once daily (21-day cycle; 2 weeks on, 1 week off) until disease progression, unacceptable toxicity, withdrawal of consent, or physician decision. The primary endpoint was the proportion of patients who achieved an objective response among those with FGFR2 fusions or rearrangements, assessed centrally in all patients who received at least one dose of pemigatinib. This study is registered with ClinicalTrials.gov, NCT02924376, and enrolment is completed., Findings: Between Jan 17, 2017, and March 22, 2019, 146 patients were enrolled: 107 with FGFR2 fusions or rearrangements, 20 with other FGF/FGFR alterations, 18 with no FGF/FGFR alterations, and one with an undetermined FGF/FGFR alteration. The median follow-up was 17·8 months (IQR 11·6-21·3). 38 (35·5% [95% CI 26·5-45·4]) patients with FGFR2 fusions or rearrangements achieved an objective response (three complete responses and 35 partial responses). Overall, hyperphosphataemia was the most common all-grade adverse event irrespective of cause (88 [60%] of 146 patients). 93 (64%) patients had a grade 3 or worse adverse event (irrespective of cause); the most frequent were hypophosphataemia (18 [12%]), arthralgia (nine [6%]), stomatitis (eight [5%]), hyponatraemia (eight [5%]), abdominal pain (seven [5%]), and fatigue (seven [5%]). 65 (45%) patients had serious adverse events; the most frequent were abdominal pain (seven [5%]), pyrexia (seven [5%]), cholangitis (five [3%]), and pleural effusion (five [3%]). Overall, 71 (49%) patients died during the study, most frequently because of disease progression (61 [42%]); no deaths were deemed to be treatment related., Interpretation: These data support the therapeutic potential of pemigatinib in previously treated patients with cholangiocarcinoma who have FGFR2 fusions or rearrangements., Funding: Incyte Corporation., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Mismatch repair proficient (MMRp) colorectal cancer (CRC) has been refractory to single-agent programmed cell death protein 1 (PD1) inhibitor therapy. Colon GVAX is an allogeneic, whole-cell, granulocyte-macrophage colony-stimulating factor -secreting cellular immunotherapy that induces T-cell immunity against tumor-associated antigens and has previously been studied in combination with low-dose cyclophosphamide (Cy) to inhibit regulatory T cells., Methods: We conducted a single-arm study of GVAX/Cy in combination with the PD1 inhibitor pembrolizumab in patients with advanced MMRp CRC. Patients received pembrolizumab plus Cy on day 1, GVAX on day 2, of a 21-day cycle. The primary endpoint was the objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary objectives included safety, overall survival, progression-free survival, changes in carcinoembryonic antigen (CEA) levels, and immune-related correlates., Results: Seventeen patients were enrolled. There were no objective responses, and the disease control rate was 18% by RECIST 1.1. The median progression-free survival was 82 days (95% confidence interval [CI], 48-97 days) and the median overall survival was 213 days (95% CI 179-441 days). Biochemical responses (≥30% decline in CEA) were observed in 7/17 (41%) of patients. Grade ≥ 3 treatment-related adverse events were observed in two patients (hemolytic anemia and corneal transplant rejection). Paired pre- and on-treatment biopsy specimens showed increases in programmed death-ligand 1 expression and tumor necrosis in a subset of patients., Conclusions: GVAX/Cy plus pembrolizumab failed to meet its primary objective in MMRp CRC. Biochemical responses were observed in a subset of patients and have not previously been observed with pembrolizumab monotherapy in MMRp CRC, indicating that GVAX may modulate the antitumor immune response., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Readmission has received attention as a potential healthcare quality metric. No studies have investigated the relationship between readmission and survival in patients undergoing rectal cancer surgery. The aims of this study were to identify factors associated with 30-day readmission after rectal cancer surgery and to determine the impact of readmission on overall survival (OS)., Methods: Patients who underwent surgical treatment for rectal/rectosigmoid adenocarcinoma stages I-IV were identified using the National Cancer Database (2004-2014). Multivariable logistic regression was used to identify factors for readmission. 2:1 nearest neighbor caliper matching without replacement was used to ensure similarity of patients being compared. Survival analyses were performed using Kaplan-Meier method along with log-rank test and Cox proportional hazards model., Results: Of 110,167 patients, 7045 (6.39%) were readmitted. Factors associated with readmission included higher Charlson comorbidity score, non-private or no insurance, procedure type, hospitals in the Northeast, South, and Midwest regions, and prolonged length of stay. Within the matched cohort (13,756 non-readmitted and 6878 readmitted), readmitted patients had worse 5- and 10-year OS regardless of cancer stage (p < 0.001) and procedure type. Five- and 10-year OS were 58.98% and 41.01% for readmitted patients, 64.96% and 43.50% for non-readmitted patients. Readmitted patients had shorter OS by 13.14 months and increased risk of mortality (HR 1.20, 95% CI 1.15-1.25, p < 0.001)., Conclusions: Thirty-day readmission after rectal cancer surgery is associated with decreased OS. Efforts to reduce readmissions should be considered to advance cancer care and enhance the potential for improved patient survival.

Immunotherapy has led to a paradigm shift in the treatment of many advanced malignancies. Despite the success in treatment of tumors like non-small cell lung cancer (NSCLC) and melanoma, checkpoint inhibition-based immunotherapy has limitations. Many tumors, such as pancreatic cancer, are less responsive to checkpoint inhibitors, where patients tend to have a limited duration of benefit and where clinical responses are more robust in patients who are positive for predictive biomarkers. One of the critical factors that influence the efficacy of immunotherapy is the tumor microenvironment (TME), which contains a heterogeneous composition of immunosuppressive cells. Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) alter the immune landscape of the TME and serve as facilitators of tumor proliferation, metastatic growth and immunotherapy resistance. Small molecule inhibitors that target these components of the TME have been developed. This special issue review focuses on two promising classes of immunomodulatory small molecule inhibitors: colony stimulating factor-1 receptor (CSF-1R) and focal adhesion kinase (FAK). Small molecule inhibitors of CSF-1R reprogram the TME and TAMs, and lead to enhanced T-cell-mediated tumor eradication. FAK small molecule inhibitors decrease the infiltration MDSCs, TAMs and regulatory T-cells. Additionally, FAK inhibitors are implicated as modulators of stromal density and cancer stem cells, leading to a TME more conducive to an anti-tumor immune response. Immunomodulatory small molecule inhibitors present a unique opportunity to attenuate immune escape of tumors and potentiate the effectiveness of immunotherapy and traditional cytotoxic therapy.

Pancreatic ductal adenocarcinoma (PDAC) represents an immune quiescent tumor that is resistant to immune checkpoint inhibitors. Previously, our group has shown that a GM-CSF-secreting allogenic pancreatic tumor cell vaccine (GVAX) may prime the tumor microenvironment by inducing intratumoral T cell infiltration. Here, we show that untreated PDACs express minimal indoleamine-2,3-dioxygenase (IDO1); however, GVAX therapy induced IDO1 expression on tumor epithelia as well as vaccine-induced tertiary lymphoid aggregates. IDO1 expression plays a role in regulating the polarization of Th1, Th17, and possibly T regulatory cells in PDAC tumors. IDO1 inhibitor enhanced antitumor efficacy of GVAX in a murine model of PDACs. The combination of vaccine and IDO1 inhibitor enhanced intratumoral T cell infiltration and function, but adding anti-PD-L1 antibody to the combination did not offer further synergy and in fact may have had a negative interaction, decreasing the number of intratumoral effector T cells. Additionally, IDO1 inhibitor in the presence of vaccine therapy did not significantly modulate intratumoral myeloid-derived suppressor cells quantitatively, but diminished their suppressive effect on CD8+ proliferation. Our study supports the combination of IDO1 inhibitor and vaccine therapy; however, it does not support the combination of IDO1 inhibitor and anti-PD-1/PD-L1 antibody for T cell-inflamed tumors such as PDACs treated with vaccine therapy.

Shigella pathogenesis has confounded researchers for years because of its narrow host selectivity and extraordinary infectious capability. In this issue of Immunity, Xu et al. (2018) identify a cunning mechanism whereby Shigella hijacks human α-defensin 5 to enhance its adhesion and subsequent invasion., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Primary schools in Kenya provide a promising venue for widespread delivery of HIV prevention interventions. This article describes the development and evaluation of Making Life's Responsible Choices (MLRC), a school-based HIV prevention intervention for primary school children developed through a collaborative global partnership involving multiple community stakeholders. Intervention development was informed by extensive reviews of youth-focused evidence-based HIV prevention interventions, and was rooted in both the Theory of Planned Behavior and Social Cognitive Theory. MLRC includes six modules: 1) self-awareness, 2) human sexuality, 3) healthy relationships, 4) drug/alcohol abuse, 5) HIV/AIDS and other sexually transmitted infections, and 6) behavior change. Class 5 pupils (N=1846; 52.1% girls, 47.9% boys; mean age = 12) attending 46 different Catholic-sponsored public and private primary schools throughout Kenya participated in the evaluation of the intervention program which was delivered in the classroom and occurred over the course of 40 weeks (one academic term). Changes in knowledge and behavioral intentions were assessed using a one-group pre-test post-test experimental design. Pupils completed module-specific assessment measures, and paired samples t-tests were used to compare changes in knowledge and behavioral intentions at the classroom level. Gender-specific analyses were also conducted. All six modules displayed statistically significant positive changes in the mean percentage of knowledge items answered correctly for the full sample, with marginal gender differences revealed. Statistically significant health-promoting changes were seen in 11 of the 18 behavioral intention items (3 per module), with gender differences also revealed. Findings suggest that implementing interventions such as MLRC has the potential to thwart the spread of HIV among youth in Kenya, and equip youth with health-promoting skills. In addition, school-based programs have the potential to become institutionalized in school settings in order to maintain their long-term sustainability.

Pancreatic ductal adenocarcinoma (PDA) is renowned for high rates of metastasis and poor survival. Its notoriously dense fibrotic stroma contributes to chemoresistance. Stromal signaling in PDA is recognized for its multiple roles in regulating tumor invasion and metastasis. However, no stromal biomarker which can predict survival in PDA exists. Annexin A2 (AnxA2) was formerly identified as a metastasis-associated protein in PDA and tumoral overexpression is associated with poor survival. In this study, we examined AnxA2 expression in the tumor microenvironment in a preclinical model of PDA which suggests its role in tumor colonization. We injected wild-type (KPC) and AnxA2 knockout (KPCA) pancreatic cells into C57BL/GJ (B6) and AnxA2 knockout (KO) mice using the hemi-spleen model and observed their survival. We performed quantitative immunohistochemistry examining stromal AnxA2 expression in 56 patients who had surgically resected PDA and correlated expression with clinical outcomes. B6 mice injected with KPC cells demonstrated decreased median survival compared to those injected with KPCA cells (90 days vs. not reached, p < 0.0001) whereas there was no survival difference in the AnxA2 KO mice ( p = 0.63). In patient specimens, we found that high stromal AnxA2 expression (≥80th percentile) was associated with significantly reduced disease-free survival ( p = 0.002) and overall survival ( p < 0.001). Using multivariate Cox models, there were no significant associations between other clinical covariates apart from high stromal AnxA2 expression. This study highlights the role that stromal AnxA2 expression plays as a prognostic marker in PDA and its potential as a predictive biomarker for survival outcomes in PDA., Competing Interests: CONFLICTS OF INTEREST The authors declare that they have no competing interests.

Pattern recognition receptors (PRR), such as NOD-like receptors (NLRs), sense conserved microbial signatures, and host danger signals leading to the coordination of appropriate immune responses. Upon activation, a subset of NLR initiate the assembly of a multimeric protein complex known as the inflammasome, which processes pro-inflammatory cytokines and mediates a specialized form of cell death known as pyroptosis. The identification of inflammasome-associated genes as inflammatory bowel disease susceptibility genes implicates a role for the inflammasome in intestinal inflammation. Despite the fact that the functional importance of inflammasomes within immune cells has been well established, the contribution of inflammasome expression in non-hematopoietic cells remains comparatively understudied. Given that intestinal epithelial cells (IEC) act as a barrier between the host and the intestinal microbiota, inflammasome expression by these cells is likely important for intestinal immune homeostasis. Accumulating evidence suggests that the inflammasome plays a key role in shaping epithelial responses at the host-lumen interface with many inflammasome components highly expressed by IEC. Recent studies have exposed functional roles of IEC inflammasomes in mucosal immune defense, inflammation, and tumorigenesis. In this review, we present the main features of the predominant inflammasomes and their effector mechanisms contributing to intestinal homeostasis and inflammation. We also discuss existing controversies in the field and open questions related to their implications in disease. A comprehensive understanding of the molecular basis of intestinal inflammasome signaling could hold therapeutic potential for clinical translation.

The connection between inflammation and malignancy has long been recognized in gastric and esophageal cancers. Given the considerable success of immune checkpoint inhibitors in other tumor types, for example, lung cancer and melanoma, much attention is being paid to furthering their role in gastric and esophageal cancers. The Cancer Genome Atlas has provided further details of the molecular heterogeneity of these tumors, which may help predict responsiveness to immune checkpoint inhibitors. This article discusses the rationale for investigating these agents in gastroesophageal cancer and summarizes the relevant clinical trial data and ongoing studies., (Copyright © 2017 Elsevier Inc. All rights reserved.)

This article examines the discursive construction of female same-sex sexual identities in Nairobi. We identify the discursive forces of "choice," devaluation, and invisibility as influential within Kenyan media representations of lesbian, gay, bisexual, transgender, and intersex citizens. Using creative focus groups and participant observation, we demonstrate how same-sex attracted women in Nairobi resist and rearticulate these discursive forces to assert their identity and agency as individuals and as a queer community.

Colorectal cancer (CRC) is a leading cause of cancer deaths. Molecularly targeted therapies (e.g. bevacizumab) have improved survival rates but drug resistance ultimately develops and newer therapies are required. We identified quininib as a small molecule drug with anti-angiogenic activity using in vitro, ex vivo and in vivo screening models. Quininib (2-[(E)-2-(Quinolin-2-yl) vinyl] phenol), is a small molecule drug (molecular weight 283.75 g/mol), which significantly inhibited blood vessel development in zebrafish embryos (p < 0.001). In vitro, quininib reduced endothelial tubule formation (p < 0.001), cell migration was unaffected by quininib and cell survival was reduced by quininib (p < 0.001). Using ex vivo human CRC explants, quininib significantly reduced the secretions of IL-6, IL-8, VEGF, ENA-78, GRO-α, TNF, IL-1β and MCP-1 ex vivo (all values p < 0.01). Quininib is well tolerated in mice when administered at 50 mg/kg intraperitoneally every 3 days and significantly reduced tumour growth of HT-29-luc2 CRC tumour xenografts compared to vehicle control. In addition, quininib reduced the signal from a α v β 3 integrin fluorescence probe in tumours 10 days after treatment initiation, indicative of angiogenic inhibition. Furthermore, quininib reduced the expression of angiogenic genes in xenografted tumours. Collectively, these findings support further development of quininib as a novel therapeutic agent for CRC., Competing Interests: Quininib is the subject of the patent: Anti-Angiogenic compounds. WO 2012/095836 A1, granted Dec 2014.

We describe a 62-year-old of Egyptian origin who presented with sudden, severe and symptomatic anemia requiring hospitalization shortly after beginning concurrent radiation and temozolomide for his newly diagnosed glioblastoma. He had also recently been started on steroids, anticonvulsants and Pneumocystis jirovecii prophylaxis. He was ultimately diagnosed with G6PD deficiency with an acute hemolytic anemia precipitated by dapsone. Screening for G6PD deficiency should be considered in high-risk patient populations where P. jirovecii prophylaxis is planned.

In many countries where HIV/AIDS is prevalent, social, cultural, and economic factors often mitigate the adoption of healthy reproductive behaviors and practices. One group that is particularly susceptible to mitigating influences is women who work in the sex trade. In this article, we utilize a culture-centered approach to determine how a population of sex workers in Nairobi, Kenya, perceives their individual, social, and structural needs and resources in relation to the public, their families, friends, and peers. We conclude the article with next steps regarding collaboration with media representatives and policymakers.

Mechanisms of protective immunity to Staphylococcus aureus infection in humans remain elusive. While the importance of cellular immunity has been shown in mice, T cell responses in humans have not been characterised. Using a murine model of recurrent S. aureus peritonitis, we demonstrated that prior exposure to S. aureus enhanced IFNγ responses upon subsequent infection, while adoptive transfer of S. aureus antigen-specific Th1 cells was protective in naïve mice. Translating these findings, we found that S. aureus antigen-specific Th1 cells were also significantly expanded during human S. aureus bloodstream infection (BSI). These Th1 cells were CD45RO+, indicative of a memory phenotype. Thus, exposure to S. aureus induces memory Th1 cells in mice and humans, identifying Th1 cells as potential S. aureus vaccine targets. Consequently, we developed a model vaccine comprising staphylococcal clumping factor A, which we demonstrate to be an effective human T cell antigen, combined with the Th1-driving adjuvant CpG. This novel Th1-inducing vaccine conferred significant protection during S. aureus infection in mice. This study notably advances our understanding of S. aureus cellular immunity, and demonstrates for the first time that a correlate of S. aureus protective immunity identified in mice may be relevant in humans.

The anatomical locations of upper gastrointestinal (GI) tumors have changed remarkably in the western world and reflect the increasing impact of obesity and gastroesophageal (GE) reflux rather than infectious etiologies. Incidence rates of GE tumors are rising rapidly and survival rates for patients with metastatic disease remain poor. Traditionally, cytotoxic chemotherapy has had some survival advantages but increasingly complex combination regimens are limited by toxicities. The advent of molecularly targeted therapy has provided additional options for patients with advanced disease including trastuzumab and ramucirumab. There has also been detailed molecular characterization of upper GI tumors which hopefully will result in improved tailoring of clinical trial design accounting for the heterogeneity inherent in GE tumors. While numerous targeted therapies are currently being studied in clinical trials, there is much excitement regarding the role of immunotherapy in GE cancers. Although further investigation is warranted, it represents a promising avenue for patients with advanced GE tumors.

The capacity for intracellular survival within phagocytes is likely a critical factor facilitating the dissemination of Staphylococcus aureus in the host. To date, the majority of work on S. aureus-phagocyte interactions has focused on neutrophils and, to a lesser extent, macrophages, yet we understand little about the role played by dendritic cells (DCs) in the direct killing of this bacterium. Using bone marrow-derived DCs (BMDCs), we demonstrate for the first time that DCs can effectively kill S. aureus but that certain strains of S. aureus have the capacity to evade DC (and macrophage) killing by manipulation of autophagic pathways. Strains with high levels of Agr activity were capable of causing autophagosome accumulation, were not killed by BMDCs, and subsequently escaped from the phagocyte, exerting significant cytotoxic effects. Conversely, strains that exhibited low levels of Agr activity failed to accumulate autophagosomes and were killed by BMDCs. Inhibition of the autophagic pathway by treatment with 3-methyladenine restored the bactericidal effects of BMDCs. Using an in vivo model of systemic infection, we demonstrated that the ability of S. aureus strains to evade phagocytic cell killing and to survive temporarily within phagocytes correlated with persistence in the periphery and that this effect is critically Agr dependent. Taken together, our data suggest that strains of S. aureus exhibiting high levels of Agr activity are capable of blocking autophagic flux, leading to the accumulation of autophagosomes. Within these autophagosomes, the bacteria are protected from phagocytic killing, thus providing an intracellular survival niche within professional phagocytes, which ultimately facilitates dissemination., (Copyright © 2015 O'Keeffe et al.)

We summarize results of two independent studies on plastic pollution in the marine environment that overlap in time and space. One study evaluated the abundance of anthropogenic debris on 37 sandy beaches bordering the Salish Sea in Washington State while the other characterized plastic debris in surface waters of the Salish Sea and the Inside Passage to Skagway, Alaska. Both studies concluded that foam, primarily expanded polystyrene was the dominant pollutant. Plastic was found in surface waters the full length of the Inside Passage but was concentrated near harbors. At the wrack line, an average square meter of Washington's 1180km of sandy beaches in the Salish Sea had 61 pieces of anthropogenic debris weighing approximately 5g. The total loading for the entire 1m wide band is estimated to be 72,000,000 pieces and 5.8metric tons. Most anthropogenic debris on beaches is generated within the region., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Immunotherapy shows promise for positively changing the landscape of the management of many advanced solid tumors, including gastrointestinal (GI) malignancies. Many of these developments have been focused on vaccine-based, monoclonal antibody therapies and more recently, checkpoint inhibitors, although many small molecule inhibitors can function as immunomodulators. Small molecule compounds have several advantages over conventional immunotherapeutic agents including: ease of production and the potential for oral administration. There is a potential niche for small molecule immunomodulators to enhance the efficacy of existing immunotherapeutic and cytotoxic agents. This article focuses on two categories of small molecule compounds with immunomodulatory effects: IDO and MEK inhibitors. Indoleamine -2, 3- dioxygenase (IDO) is known for its effects in tumor immunity. IDO inhibitors are generally well-tolerated and have the potential to enhance anti-tumor responses when combined with checkpoint inhibitors. MEK inhibitors affect signal transduction of the RAS-RAF-MEK pathway and numerous MEK inhibitors are currently being investigated in solid tumors. Small molecule immunomodulators are currently being investigated for their potential role in augmenting the effects of conventional immunotherapeutic agents although further research is required to identify those patients most likely to respond to combination therapy.

Despite showing promise in preclinical models, anti-Staphylococcus aureus vaccines have failed in clinical trials. To date, approaches have focused on neutralizing/opsonizing antibodies; however, vaccines exclusively inducing cellular immunity have not been studied to formally test whether a cellular-only response can protect against infection. We demonstrate that nasal vaccination with targeted nanoparticles loaded with Staphylococcus aureus antigen protects against acute systemic S. aureus infection in the absence of any antigen-specific antibodies. These findings can help inform future developments in staphylococcal vaccine development and studies into the requirements for protective immunity against S. aureus.

The development of vaccines against Staphylococcus aureus has consistently failed in clinical trials, likely due to inefficient induction of cellular immunity. T cell-derived IL-17 is one of the few known correlates of antistaphylococcoal immunity, conferring protection against S. aureus infections through its ability to promote phagocytic cell effector functions. A comprehensive understanding of the discrete T cell subsets critical for site-specific IL-17-mediated bacterial clearance will therefore be necessary to inform the development of vaccines that efficiently target cellular immunity. In this study, we have identified a population of CD44+ CD27- memory γδ T cells, expanded upon infection of C57BL/6 mice with S. aureus, which produce high levels of IL-17 and mediate enhanced bacterial clearance upon reinfection with the bacterium. These cells are comprised largely of the Vγ4+ subset and accumulate at the site of infection subsequent to an initial Vγ1.1+ and Vγ2+ T cell response. Moreover, these Vγ4+ T cells are retained in the peritoneum and draining mediastinal lymph nodes for a prolonged period following bacterial clearance. In contrast to its critical requirement for γδ T cell activation during the primary infection, IL-1 signaling was dispensable for activation and expansion of memory γδ T cells upon re-exposure to S. aureus. Our findings demonstrate that a γδ T cell memory response can be induced upon exposure to S. aureus, in a fashion analogous to that associated with classical αβ T cells, and suggest that induction of IL-17-expressing γδ T cells may be an important property of a protective vaccine against S. aureus.

Most new HIV infections in Kenya occur among young people. The purpose of this study was to understand ecological factors that influence HIV-related sexual risk and resilience among young people in rural Kenya and to elicit their ideas for HIV prevention interventions. Nine focus groups (N = 199) were conducted with both female (55%) and male (45%) participants (ages 14-24 years) living in rural communities in Kenya. Findings were organized into thematic areas related to the following systems of influence: (i) intrapersonal (substance use, HIV knowledge), (ii) interpersonal (peer pressure, lack of parent-child communication, interpersonal sexual violence), (iii) institutional/community (pornography, transactional sex, 'idleness', lack of role models) and (iv) socio-cultural/policy (Kikuyu culture, Western influence, religious beliefs, HIV-related stigma and gendered sexual scripts). Results regarding the types of HIV prevention programs that participants believed should be developed for young people in rural Kenya revealed seven primary themes, including (i) HIV prevention community/group workshops, (ii) condom distribution, (iii) job skills trainings, (iv) athletic and social clubs, (v) HIV-related stigma reduction campaigns, (vi) community-wide demonstrations and (vii) other HIV/AIDS activities led by young people. Implications for the development of culturally and developmentally appropriate HIV prevention interventions for young people in rural Kenya are discussed.

Recent work has identified T cells and the cytokines they produce as important correlates of immune protection during Staphylococcus aureus infections through the ability of these T cells to regulate local neutrophil responses. However, the specific T-cell subsets that are involved in coordinating protection at distinct sites of infection remains to be established. In this study, we identify for the first time an important role for γδT cells in controlling S. aureus surgical site infection (SSI). γδT cells are recruited to the wound site following S. aureus challenge, where they represent the primary source of interleukin 17 (IL-17), with a small contribution from other non-γδT cells. The IL-17 response is entirely dependent upon IL-1 receptor signaling. Using IL-17 receptor-deficient mice, we demonstrate that IL-17 is required to control bacterial clearance during S. aureus SSI. However, we demonstrate a strain-dependent requirement for γδT cells in this process due to the differential abilities of individual strains to activate IL-1β production. IL-1β processing relies upon activation of the Nlrp3 inflammasome complex, and we demonstrate that Nlrp3-deficient and IL-1 receptor-deficient mice have an impaired ability to control S. aureus SSI due to reduced production of IL-17 by γδT cells at the site of infection. Given that IL-17 has been identified as an important correlate of immune protection during S. aureus infection, it is vital that the unique cellular sources of this cytokine and mechanisms inducing its activation are identified at distinct sites of infection. Our study demonstrates that while IL-17 may be critically important for mediating immune protection during S. aureus SSI, the relative contribution of γδT cells to these protective effects may be strain dependent.

The nucleoside analogue Ribavirin significantly increases patient response to IFN-α treatment of HCV, by directly inhibiting viral replication. Recent studies indicate that Ribavirin also regulates immunity and we propose that Ribavirin enhances specific interferon sensitive gene (ISG) expression by amplifying the IFN-α-JAK/STAT pathway. We found that IFN-α-induced STAT1 and STAT3 phosphorylation was increased in hepatocytes co-treated with Ribavirin and IFN-α, compared to IFN-α alone. Ribavirin specifically enhanced IFN-α induced mRNA and protein of the anti-viral mediator MxA, which co-localised with HCV core protein. These novel findings indicate for the first time that Ribavirin, in addition to its viral incorporation, also enhances IFN-α-JAK/STAT signalling, leading to a novel MxA-mediated immuno-modulatory mechanism that may enhance IFN-α anti-viral activity against HCV.

Objective: Our purpose was to investigate the efficacy and safety of 0.1% topical tacrolimus in erosive or ulcerative oral lichen planus., Methods: This was an open-label, noncomparative study conducted in an outpatient oral medicine unit in London, United Kingdom. The study covered an 8-week period with a 22-week follow-up after cessation of therapy. Nineteen patients, aged 28 to 87 years with biopsy-proven oral lichen planus refractory to, or dependent on, systemic immunosuppressive agents, were enrolled. Seventeen patients (89%) completed the study. Application of 0.1% tacrolimus was administered to all symptomatic oral mucosal lesions. Clinical review took place 1, 3, 5, 7, and 8 weeks after commencing therapy. Alleviation of symptoms was evaluated by using a visual analogue scale as well as the McGill Pain and Oral Health Impact profile questionnaires. The extent of the oral mucosal erosion or ulceration was directly measured by the same clinician at all visits. Safety assessments included monitoring of adverse events, complete blood cell count, renal and hepatic clinical chemistry, and tacrolimus blood concentrations., Results: Tacrolimus caused a statistically significant improvement in symptoms within 1 week of commencement of therapy. A mean decrease of 73.3% occurred in the area of ulceration over the 8-week study period. Local irritation (in 6 subjects, 35%) was the most commonly reported adverse effect. Laboratory values showed no significant changes with time. Therapeutic levels of tacrolimus were demonstrated in 8 subjects but were unrelated to the extent of oral mucosal involvement. Thirteen of 17 patients suffered a relapse of oral lichen planus within 2 to 15 weeks of cessation of tacrolimus therapy., Conclusion: Topical tacrolimus is effective therapy for erosive or ulcerative oral lichen planus.

Objective: Previous randomized controlled trials for treatment of rheumatoid arthritis (RA) with acid-soluble chicken and bovine type II collagen (CII) have produced conflicting results. This randomized, double-blind, controlled trial examined the therapeutic effect of bovine CII tablets in RA., Methods: CII tablets were prepared by adsorption onto a lactose base. Patients with a duration of RA of > or = 2 years and who had failed treatment with at least 1 slow-acting drug were recruited, provided that they had active arthritis. Patients were randomly assigned to receive either 0.05 mg, 0.5 mg, or 5 mg of CII or placebo daily for 6 months. All slow-acting drugs were stopped at least 4 weeks before starting CII, although prednisolone was permitted at dosages < 10 mg/day. Clinical assessments were performed at screening and at 0, 1, 4, 8, 12, 16, 20, and 24 weeks of treatment., Results: Fifty-five patients were recruited. Initially, there were no significant differences in mean Disease Activity Scores between groups. At 24 weeks, there was a significant difference (P = 0.041, by Kruskal-Wallis analysis of variance); the major components of this difference were attributable to relatively large decreases in the 0.5 mg CII group (19% of initial values) and to minimal decreases in patients receiving placebo (3% of initial values). Twenty patients had American College of Rheumatology 20% responses; 11 of these were in the 0.5 mg CII group and 3 were in each of the other groups, a significant difference (chi2 = 14.6, P = 0.002). There was no significant difference in any clinical measure between the placebo, 0.05 mg CII, and 5 mg CII groups. There were no side effects associated with CII treatment., Conclusion: Treatment with 0.5 mg/day of bovine CII is well tolerated and produces small, but significant, disease improvement in RA. However, the therapeutic window is narrow. The difference between our results and those of other trials may relate to the dose, species, and formulation of the CII.

A 15% aminosidine sulphate (AS)/10% urea/white soft paraffin (WSP) ointment cured all Leishmania major lesions on Balb/C mice following topical application for 10 d. Some relapses were observed 10 weeks after treatment. AS alone in WSP ointment was also highly effective. The ointment containing urea was non-irritant to mice, whereas ointments containing quaternary ammonium compounds were irritant. The 15% AS/10% urea/WSP ointment was not effective in the treatment of L. mexicana or L. panamensis lesions on Balb/C mice, no cure being observed.