Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer.

Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies.

Direct engagement of the PI3K pathway by mutant KIT dominates oncogenic signaling in gastrointestinal stromal tumor.

Gastrointestinal stromal tumors (GISTs) predominantly harbor activating mutations in the receptor tyrosine kinase KIT. To genetically dissect in vivo the requirement of different signal transduction pathways emanating from KIT for tumorigenesis, the oncogenic KitV558Δ mutation was combined with point mutations abrogating specific phosphorylation sites on KIT. Compared with single-mutant KitV558Δ/+ mice, double-mutant KitV558Δ;Y567F/Y567F knock-in mice lacking the SRC family kinase-binding site on KIT (pY567) exhibited attenuated MAPK signaling and tumor growth. Surprisingly, abrogation of the PI3K-binding site (pY719) in KitV558Δ;Y719F/Y719F mice prevented GIST development, although the interstitial cells of Cajal (ICC), the cells of origin of GIST, were normal. Pharmacologic inhibition of the PI3K pathway in tumor-bearing KitV558Δ/+ mice with the dual PI3K/mTOR inhibitor voxtalisib, the pan-PI3K inhibitor pilaralisib, and the PI3K-alpha-restricted inhibitor alpelisib each diminished tumor proliferation. The addition of the MEK inhibitor PD-325901 or binimetinib further decreased downstream KIT signaling. Moreover, combining PI3K and MEK inhibition was effective against imatinib-resistant KitV558Δ;T669I/+ tumors.

Investigation of a Chlamydia pneumoniae outbreak in a Federal correctional facility in Texas.

BACKGROUND: Chlamydia pneumoniae illness is poorly characterized, particularly as a sole causative pathogen. We investigated a C. pneumoniae outbreak at a federal correctional facility. METHODS: We identified inmates with acute respiratory illness (ARI) from 1 November 2009 to 24 February 2010 through clinic self-referral and active case finding. We tested oropharyngeal and/or nasopharyngeal swabs for C. pneumoniae by real-time polymerase chain reaction (qPCR) and serum samples by microimmunofluorescence. Cases were inmates with ARI and radiologically confirmed pneumonia, positive qPCR, or serological evidence of recent infection. Swabs from 7 acutely ill inmates were tested for 18 respiratory pathogens using qPCR TaqMan Array Cards (TACs). Follow-up swabs from case patients were collected for up to 8 weeks. RESULTS: Among 33 self-referred and 226 randomly selected inmates, 52 (20.1%) met the case definition; pneumonia was confirmed in 4 by radiology only, in 9 by qPCR only, in 17 by serology only, and in 22 by both qPCR and serology. The prison attack rate was 10.4% (95% confidence interval, 7.0%-13.8%). White inmates and residents of housing unit Y were at highest risk. TAC testing detected C. pneumoniae in 4 (57%) inmates; no other causative pathogens were identified. Among 40 inmates followed prospectively, C. pneumoniae was detected for up to 8 weeks. Thirteen (52%) of 25 inmates treated with azithromycin continued to be qPCR positive >2 weeks after treatment. CONCLUSIONS: Chlamydia pneumoniae was the causative pathogen of this outbreak. Higher risk among certain groups suggests that social interaction contributed to transmission. Persistence of C. pneumoniae in the oropharynx creates challenges for outbreak control measures.

Serotype-specific changes in invasive pneumococcal disease after pneumococcal conjugate vaccine introduction: a pooled analysis of multiple surveillance sites.

BACKGROUND: Vaccine-serotype (VT) invasive pneumococcal disease (IPD) rates declined substantially following introduction of 7-valent pneumococcal conjugate vaccine (PCV7) into national immunization programs. Increases in non-vaccine-serotype (NVT) IPD rates occurred in some sites, presumably representing serotype replacement. We used a standardized approach to describe serotype-specific IPD changes among multiple sites after PCV7 introduction. METHODS AND FINDINGS: Of 32 IPD surveillance datasets received, we identified 21 eligible databases with rate data ≥ 2 years before and ≥ 1 year after PCV7 introduction. Expected annual rates of IPD absent PCV7 introduction were estimated by extrapolation using either Poisson regression modeling of pre-PCV7 rates or averaging pre-PCV7 rates. To estimate whether changes in rates had occurred following PCV7 introduction, we calculated site specific rate ratios by dividing observed by expected IPD rates for each post-PCV7 year. We calculated summary rate ratios (RRs) using random effects meta-analysis. For children <5 years old, overall IPD decreased by year 1 post-PCV7 (RR 0.55, 95% CI 0.46-0.65) and remained relatively stable through year 7 (RR 0.49, 95% CI 0.35-0.68). Point estimates for VT IPD decreased annually through year 7 (RR 0.03, 95% CI 0.01-0.10), while NVT IPD increased (year 7 RR 2.81, 95% CI 2.12-3.71). Among adults, decreases in overall IPD also occurred but were smaller and more variable by site than among children. At year 7 after introduction, significant reductions were observed (18-49 year-olds [RR 0.52, 95% CI 0.29-0.91], 50-64 year-olds [RR 0.84, 95% CI 0.77-0.93], and ≥ 65 year-olds [RR 0.74, 95% CI 0.58-0.95]). CONCLUSIONS: Consistent and significant decreases in both overall and VT IPD in children occurred quickly and were sustained for 7 years after PCV7 introduction, supporting use of PCVs. Increases in NVT IPD occurred in most sites, with variable magnitude. These findings may not represent the experience in low-income countries or the effects after introduction of higher valency PCVs. High-quality, population-based surveillance of serotype-specific IPD rates is needed to monitor vaccine impact as more countries, including low-income countries, introduce PCVs and as higher valency PCVs are used. Please see later in the article for the Editors' Summary.

Multiple intratumoral sources of kit ligand promote gastrointestinal stromal tumor.

Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and is typically driven by a single mutation in the Kit or PDGFRA receptor. While highly effective, tyrosine kinase inhibitors (TKIs) are not curative. The natural ligand for the Kit receptor is Kit ligand (KitL), which exists in both soluble and membrane-bound forms. While KitL is known to stimulate human GIST cell lines in vitro, we used a genetically engineered mouse model of GIST containing a common human KIT mutation to investigate the intratumoral sources of KitL, importance of KitL during GIST oncogenesis, and contribution of soluble KitL to tumor growth in vivo. We discovered that in addition to tumor cells, endothelia and smooth muscle cells produced KitL in KitV558Δ/+ tumors, even after imatinib therapy. Genetic reduction of total KitL in tumor cells of KitV558Δ/+ mice impaired tumor growth in vivo. Similarly, genetic reduction of tumor cell soluble KitL in KitV558Δ/+ mice decreased tumor size. By RNA sequencing, quantitative PCR, and immunohistochemistry, KitL expression was heterogeneous in human GIST specimens. In particular, PDGFRA-mutant tumors had much higher KitL expression than Kit-mutant tumors, suggesting the benefit of Kit activation in the absence of mutant KIT. Serum KitL was higher in GIST patients with tumors resistant to imatinib and in those with tumors expressing more KitL RNA. Overall, KitL supports the growth of GIST at baseline and after imatinib therapy and remains a potential biomarker and therapeutic target.

A strategy to increase adoption of locally-produced, ceramic cookstoves in rural Kenyan households.

BACKGROUND: Exposure to household air pollutants released during cooking has been linked to numerous adverse health outcomes among residents of rural areas in low-income countries. Improved cookstoves are one of few available interventions, but achieving equity in cookstove access has been challenging. Therefore, innovative approaches are needed. To evaluate a project designed to motivate adoption of locally-produced, ceramic cookstoves (upesi jiko) in an impoverished, rural African population, we assessed the perceived benefits of the cookstoves (in monetary and time-savings terms), the rate of cookstove adoption, and the equity of adoption. METHODS: The project was conducted in 60 rural Kenyan villages in 2008 and 2009. Baseline (n = 1250) and follow-up (n = 293) surveys and a stove-tracking database were analyzed. RESULTS: At baseline, nearly all respondents used wood (95%) and firepits (99%) for cooking; 98% desired smoke reductions. Households with upesi jiko subsequently spent <100 Kenyan Shillings/week on firewood more often (40%) than households without upesi jiko (20%) (p = 0.0002). There were no significant differences in the presence of children <2 years of age in households using upesi jiko (48%) or three-stone stoves (49%) (p = 0.88); children 2-5 years of age were less common in households using upesi jiko versus three-stone stoves (46% and 69%, respectively) (p = 0.0001). Vendors installed 1,124 upesi jiko in 757 multi-family households in 18 months; 68% of these transactions involved incentives for vendors and purchasers. Relatively few (<10%) upesi jiko were installed in households of women in the youngest age quartile (<22 years) or among households in the poorest quintile. CONCLUSIONS: Our strategy of training of local vendors, appropriate incentives, and product integration effectively accelerated cookstove adoption into a large number of households. The strategy also created opportunities to reinforce health messages and promote cookstoves sales and installation. However, the project's overall success was diminished by inequitable and incomplete adoption by households with the lowest socioeconomic status and young children present. Additional evaluations of similar strategies will be needed to determine whether our strategy can be applied equitably elsewhere, and whether reductions in fuel use, household air pollution, and the incidence of respiratory diseases will follow adoption of improved cookstoves.

The V654A second-site KIT mutation increases tumor oncogenesis and STAT activation in a mouse model of gastrointestinal stromal tumor.

Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and arises in the gastrointestinal tract. Most GISTs are caused by activating mutations in the KIT receptor tyrosine kinase, such as the exon 11 KIT V559Δ mutation. The small molecule imatinib inhibits KIT and has been a mainstay of therapy in GIST. Unfortunately, imatinib-treated patients typically relapse, most often due to clonal emergence of the resistance-associated KIT V654A mutation. To determine the biologic impact of this second-site mutation in vivo, we created a mouse model with the corresponding V558Δ;V653A Kit double mutation restricted (a) spatially to ETV1+ cells, which include the interstitial cells of Cajal (ICCs) from which GISTs presumably originate, and (b) temporally through tamoxifen treatment after birth. This resulted in the first in vivo model of the most common second-site mutation associated with imatinib resistance in GIST and the first in vivo demonstration that cell-autonomous expression of mutant KIT in the ICC lineage leads to GIST. GISTs driven by the V558Δ;V653A Kit double mutation were resistant to imatinib, while cabozantinib was more effective in overcoming resistance than sunitinib. Compared to control mice with a single V558Δ Kit mutation, mice with a double V558Δ; V653A Kit mutation had increased tumor oncogenesis and associated KIT-dependent STAT activation. Our findings demonstrate that the biologic consequences of a second-site mutation in an oncogenic driver may include not only a mechanism for drug resistance, but changes in tumor oncogenic potential and differential activation of signaling pathways.

Oncogenic kinase inhibition limits Batf3-dependent dendritic cell development and antitumor immunity.

Gastrointestinal stromal tumor (GIST) is driven by an activating mutation in the KIT proto-oncogene. Using a mouse model of GIST and human specimens, we show that intratumoral murine CD103+CD11b- dendritic cells (DCs) and human CD141+ DCs are associated with CD8+ T cell infiltration and differentiation. In mice, the antitumor effect of the Kit inhibitor imatinib is partially mediated by CD103+CD11b- DCs, and effector CD8+ T cells initially proliferate. However, in both mice and humans, chronic imatinib therapy decreases intratumoral DCs and effector CD8+ T cells. The mechanism in our mouse model depends on Kit inhibition, which reduces intratumoral GM-CSF, leading to the accumulation of Batf3-lineage DC progenitors. GM-CSF is produced by γδ T cells via macrophage IL-1ß. Stimulants that expand and mature DCs during imatinib treatment improve antitumor immunity. Our findings identify the importance of tumor cell oncogene activity in modulating the Batf3-dependent DC lineage and reveal therapeutic limitations for combined checkpoint blockade and tyrosine kinase inhibition.

Differential immune profiles distinguish the mutational subtypes of gastrointestinal stromal tumor.

Gastrointestinal stromal tumor (GIST) is the most common human sarcoma, frequently characterized by an oncogenic mutation in the KIT or platelet-derived growth factor receptor alpha (PDGFRA) genes. We performed RNA sequencing of 75 human GIST tumors from 75 patients, comprising the largest cohort of GISTs sequenced to date, in order to discover differences in the immune infiltrates of KIT and PDGFRA-mutant GIST. Through bioinformatics, immunohistochemistry, and flow cytometry, we found that PDGFRA-mutant GISTs harbored more immune cells with increased cytolytic activity when compared to KIT-mutant GISTs. PDGFRA-mutant GISTs expressed many chemokines, such as CXCL14, at a significantly higher level when compared to KIT-mutant GISTs and exhibited more diverse driver-derived neoepitope:HLA binding, both of which may contribute to PDGFRA-mutant GIST immunogenicity. Through machine learning, we generated gene expression-based immune profiles capable of differentiating KIT and PDGFRA-mutant GISTs, and also identified additional immune features of high PD-1 and PD-L1 expressing tumors across all GIST mutational subtypes, which may provide insight into immunotherapeutic opportunities and limitations in GIST.

Csf1r or Mer inhibition delays liver regeneration via suppression of Kupffer cells.

INTRODUCTION: Murine Kupffer cells (KCs) comprise CD11bhi and F4/80hi subsets. Tissue-resident macrophages are known to express the tyrosine kinase receptors colony-stimulating factor 1 receptor (Csf1r) and Mer. However, the expression of Csf1r and Mer on KC subsets and the importance of these tyrosine kinases during liver regeneration (LR) are unknown. METHODS: KCs from wild-type and Csf1r-GFP mice were characterized by flow cytometry. Partial hepatectomy (PH) was performed in mice treated with clodronate liposomes, a Csf1r small molecule inhibitor or depleting antibody, or a small molecule Mer inhibitor. Sera and livers were analyzed. The function of sorted KC subsets was tested in vitro. RESULTS: Mer was specifically expressed on tissue-resident F4/80hi KCs, 55% of which also expressed Csf1r. Mer+Csf1r+ and Mer+Csf1r- KCs had distinct expression of macrophage markers. Csf1r inhibition in mice reduced F4/80hi KCs by approximately 50%, but did not affect CD11bhi KCs. Clodronate liposomes depleted F4/80hi KCs, but also altered levels of other intrahepatic leukocytes. Csf1r inhibition delayed LR, as demonstrated by a 20% reduction in liver-to-body weight ratios 7 days after PH. At 36h after PH, Csf1r inhibition increased serum ALT and histological liver injury, and decreased liver cell proliferation. A small molecule inhibitor of Mer did not alter the percentage of KCs or their proliferation and just modestly delayed LR. In vitro, Csf1r or Mer inhibition did not decrease KC viability, but did attenuate their cytokine response to stimulation. CONCLUSIONS: F4/80hi KCs are Mer+ and can be subdivided based on Csf1r expression. Csf1r or Mer inhibition each reduces KC cytokine production and delays LR.

Macrophages and CD8+ T Cells Mediate the Antitumor Efficacy of Combined CD40 Ligation and Imatinib Therapy in Gastrointestinal Stromal Tumors.

Tyrosine kinase inhibition of gastrointestinal stromal tumors (GIST) is effective but typically culminates in resistance and is rarely curative. Immunotherapy has potential application to GIST, as we previously showed that T-cell checkpoint blockade increases the antitumor effects of imatinib. Here, we showed that ligation of CD40 using an agonistic antibody (anti-CD40) activated tumor-associated macrophages (TAMs) in vivo in a knock-in mouse model of GIST harboring a germline mutation in Kit exon 11. Activated TAMs had greater TNFα production and NFκB signaling and directly inhibited tumor cells in vitro Anti-CD40 required concomitant therapy with imatinib for efficacy and depended on TAMs, and to a lesser extent CD8+ T cells, but not on CD4+ T cells or B cells. In an analysis of 50 human GIST specimens by flow cytometry, we found that CD40 was expressed on human TAMs and tumor cells yet was downregulated after response to imatinib. CD40 ligation did not have a direct inhibitory effect on human GIST cells. Our findings provide the rationale for combining anti-CD40 and tyrosine kinase inhibition to treat human GIST. Cancer Immunol Res; 6(4); 434-47. ©2018 AACR.

Mitochondrial Inhibition Augments the Efficacy of Imatinib by Resetting the Metabolic Phenotype of Gastrointestinal Stromal Tumor.

Purpose: Imatinib dramatically reduces gastrointestinal stromal tumor (GIST) 18F-FDG uptake, providing an early indicator of treatment response. Despite decreased glucose internalization, many GIST cells persist, suggesting that alternative metabolic pathways are used for survival. The role of mitochondria in imatinib-treated GIST is largely unknown.Experimental Design: We quantified the metabolic activity of several human GIST cell lines. We treated human GIST xenografts and genetically engineered KitV558del/+ mice with the mitochondrial oxidative phosphorylation inhibitor VLX600 in combination with imatinib and analyzed tumor volume, weight, histology, molecular signaling, and cell cycle activity. In vitro assays on human GIST cell lines were also performed.Results: Imatinib therapy decreased glucose uptake and downstream glycolytic activity in GIST-T1 and HG129 cells by approximately half and upregulated mitochondrial enzymes and improved mitochondrial respiratory capacity. Mitochondrial inhibition with VLX600 had a direct antitumor effect in vitro while appearing to promote glycolysis through increased AKT signaling and glucose transporter expression. When combined with imatinib, VLX600 prevented imatinib-induced cell cycle escape and reduced p27 expression, leading to increased apoptosis when compared to imatinib alone. In KitV558del/+ mice, VLX600 alone did not induce tumor cell death, but had a profound antitumor effect when combined with imatinib.Conclusions: Our findings show that imatinib alters the metabolic phenotype of GIST, and this may contribute to imatinib resistance. Our work offers preclinical proof of concept of metabolic targeting as an effective strategy for the treatment of GIST. Clin Cancer Res; 24(4); 972-84. ©2017 AACR.

ETV4 collaborates with Wnt/ß-catenin signaling to alter cell cycle activity and promote tumor aggressiveness in gastrointestinal stromal tumor.

Gastrointestinal stromal tumor (GIST) is the most common sarcoma, often resulting from a KIT or platelet-derived growth factor receptor alpha (PDGFRA) mutation. The lineage transcription factor ETV1 is expressed similarly in GISTs regardless of malignant potential. Although the related transcription factor ETV4 has been associated with metastasis and tumor progression in other cancers, its role in GIST is unknown. In this study, we found that ETV4 levels were high in a subset of human GISTs and correlated with high mitotic rate. Through Gene Set Enrichment Analysis in selected human GISTs, we identified a relationship between ETV4 levels and ß-catenin signaling, especially in advanced GISTs. GIST specimens with high ETV4 levels overexpressed cell cycle regulating genes and had aberrant activation of the canonical Wnt pathway. In human GIST cell lines, ETV4 RNA interference suppressed cell cycle genes and Wnt/ß-catenin signaling. ETV4 knockdown also reduced tumor cell proliferation, invasion, and tumor growth in vivo. Conversely, ETV4 overexpression increased cyclin D1 expression and Wnt/ß-catenin signaling. Moreover, we determined that ETV4 knockdown destabilized nuclear ß-catenin and increased its degradation via COP1, an E3 ligase involved in both ETV4 and ß-catenin turnover. Aberrant accumulation of ETV4 and nuclear ß-catenin was found in patient derived xenografts created from metastatic GISTs that became resistant to tyrosine kinase inhibitors. Collectively, our findings highlight the significance of ETV4 expression in GIST and identify ETV4 as a biomarker in human GISTs.

Wnt/ß-catenin Signaling Contributes to Tumor Malignancy and Is Targetable in Gastrointestinal Stromal Tumor.

Gastrointestinal stromal tumor (GIST) is the most common type of sarcoma and usually harbors either a KIT or PDGFRA mutation. However, the molecular basis for tumor malignancy is not well defined. Although the Wnt/ß-catenin signaling pathway is important in a variety of cancers, its role in GIST is uncertain. Through analysis of nearly 150 human GIST specimens, we found that some human GISTs expressed ß-catenin and contained active, dephosphorylated nuclear ß-catenin. Furthermore, advanced human GISTs expressed reduced levels of the Wnt antagonist DKK4. Accordingly, in human GIST T1 cells, Wnt stimulation increased ß-catenin-mediated transcriptional activity in a reporter assay as well as transcription of the downstream target genes Axin2 and CCND1 In contrast, DKK4 overexpression in GIST T1 cells reduced Wnt/ß-catenin signaling. In addition, we showed that nuclear ß-catenin stability was partially regulated by the E3 ligase COP1, as demonstrated with coimmunoprecipitation and COP1 knockdown. Three molecular inhibitors of the Wnt/ß-catenin pathway demonstrated antitumor efficacy in various GIST models, both in vitro and in vivo Notably, the tankyrase inhibitor G007-LK alone had substantial activity against tumors of genetically engineered KitV558Δ/+ mice, and the effect was increased by the addition of the Kit inhibitor imatinib mesylate. Collectively, our findings demonstrate that Wnt/ß-catenin signaling is a novel therapeutic target for selected untreated or imatinib-resistant GISTs. Mol Cancer Ther; 16(9); 1954-66. ©2017 AACR.

PD-1/PD-L1 Blockade Enhances T-cell Activity and Antitumor Efficacy of Imatinib in Gastrointestinal Stromal Tumors.

PURPOSE: Tyrosine kinase inhibitors are effective in gastrointestinal stromal tumors (GISTs) but often are of transient benefit as resistance commonly develops. Immunotherapy, particularly blockade of the inhibitory receptor programmed death 1 (PD-1) or the ligand programmed death ligand 1 (PD-L1), has shown effectiveness in a variety of cancers. The functional effects of PD-1/PD-L1 blockade are unknown in GISTs. EXPERIMENTAL DESIGN: We analyzed tumor and matched blood samples from 85 patients with GISTs and determined the expression of immune checkpoint molecules using flow cytometry. We investigated the combination of imatinib with PD-1/PD-L1 blockade in KitV558Δ/+ mice that develop GISTs. RESULTS: The inhibitory receptors PD-1, lymphocyte activation gene 3, and T-cell immunoglobulin mucin-3 were upregulated on tumor-infiltrating T cells compared with T cells from matched blood. PD-1 expression on T cells was highest in imatinib-treated human GISTs. Meanwhile, intratumoral PD-L1 expression was variable. In human GIST cell lines, treatment with imatinib abrogated the IFNγ-induced upregulation of PD-L1 via STAT1 inhibition. In KitV558Δ/+ mice, imatinib downregulated IFNγ-related genes and reduced PD-L1 expression on tumor cells. PD-1 and PD-L1 blockade in vivo each had no efficacy alone but enhanced the antitumor effects of imatinib by increasing T-cell effector function in the presence of KIT and IDO inhibition. CONCLUSIONS: PD-1/PD-L1 blockade is a promising strategy to improve the effects of targeted therapy in GISTs. Collectively, our results provide the rationale to combine these agents in human GISTs. Clin Cancer Res; 23(2); 454-65. ©2016 AACR.

Combined KIT and CTLA-4 Blockade in Patients with Refractory GIST and Other Advanced Sarcomas: A Phase Ib Study of Dasatinib plus Ipilimumab.

Purpose: A phase Ib study of dasatinib plus ipilimumab in patients with gastrointestinal stromal tumor (GIST) and other sarcomas was performed on the basis of preclinical data demonstrating that combined KIT and CTLA-4 blockade is synergistic.Experimental Design: A standard 3 + 3 design was used to evaluate the safety, efficacy, and immune correlates of treatment. Dose escalation cohorts received ipilimumab 10 or 3 mg/kg every 3 weeks, followed by maintenance every 12 weeks with escalating doses of dasatinib (70 mg daily, 100 mg daily, or 70 mg twice daily). Response was assessed by RECIST 1.1, Choi, and immune-related RECIST criteria (irRC).Results: A total of 28 patients (17 male) were enrolled. Histologic subtypes included GISTs (n = 20) and other sarcomas (n = 8.) Dasatinib 70 mg/day with ipilimumab 10 mg/kg or dasatinib 140 mg/day with ipilimumab 3 mg/kg can be safely administered. Dose-limiting toxicities included grade 3 gastric hemorrhage and anemia. No partial or complete responses were noted by RECIST or irRC. There were 7 of 13 partial responses in the GIST patients by Choi criteria, and 3 of 13 patients each had stable and progressive disease, respectively.Conclusions: Dasatinib and ipilimumab can be safely administered to GIST and sarcoma patients. However, dasatinib was not synergistic with ipilimumab, as there was limited clinical efficacy with the combination. This limited cohort provides prospective data that indoleamine-2,3-dioxygenase (IDO) suppression may potentially correlate with antitumor efficacy in GIST. Given the small cohort, it is only hypothesis generating and additional data would be required. In the era of more modern and effective checkpoint inhibitors, next steps could be consideration of tyrosine kinase inhibitors or IDO inhibitors in combination with anti-PD-1 therapy. Clin Cancer Res; 23(12); 2972-80. ©2016 AACR.

Effectiveness of Six Improved Cookstoves in Reducing Household Air Pollution and Their Acceptability in Rural Western Kenya.

BACKGROUND: Household air pollution (HAP) from biomass fuel burning is linked to poor health outcomes. Improved biomass cookstoves (ICS) have the potential to improve HAP. OBJECTIVES: A pre-/post- intervention study assessed the impact of six ICS on indoor air quality and acceptability of ICS to local users in rural Western Kenya. METHODS: We measured mean personal and kitchen level concentrations of particulate matter <2.5µm in diameter (PM2.5, µg/m3) and carbon monoxide (CO, ppm) during the 48-hour period of each ICS use in 45 households. We compared these levels to those observed with traditional 3-stone fire (TSF) use. We assessed ICS acceptability through interviews and focus groups. We evaluated association of stove type, fuel use, and factors related to cooking practices with mean kitchen PM2.5 and CO using multivariable regression. RESULTS: Stove type, exclusive ICS use (vs. concurrent TSF use), and the amount of fuel used were independently associated with kitchen PM2.5 and CO levels. Reductions (95%CI) in mean PM2.5 compared to TSF, ranged by ICS from 11.9% (-2.8-24.5) to 42.3% (32.3-50.8). Reductions in kitchen CO compared to TSF, ranged by ICS from -5.8% (-21.9-8.2) to 34.5% (23.2-44.1). Mean kitchen PM2.5 ranged from 319µg/m3 to 518µg/m3 by ICS. Women thought ICS were easy to use, more efficient, produced less smoke, and cooked faster, compared to TSF. Women also reported limitations for each ICS. CONCLUSIONS: We documented reductions in HAP from ICS compared to TSF. The PM2.5 levels with ICS use were still considerably higher than WHO indoor air quality guidelines. Achieving maximal potential of ICS requires adherence to more exclusive use and addressing user reported ICS limitations.

User Perspectives of Characteristics of Improved Cookstoves from a Field Evaluation in Western Kenya.

Over half of the world's population uses biomass fuels; these households cook on open fires indoors, increasing their risk of adverse health effects due to household air pollution (HAP) from biomass combustion. This study evaluated six improved cookstoves (ICS) for effectiveness and acceptability in a rural community in Western Kenya. This paper describes women's views on each ICS compared to the traditional three-stone fire. Views on stove characteristics, fuel consumption, health effects and acceptability were assessed through structured interviews and focus group discussions. Data were coded and analyzed using a thematic approach. In total, 262 interviews and 11 focus groups were conducted from 43 women. Overall, women preferred the ICS over the traditional three-stone fire for various reasons including ease of use, efficiency, fuel efficiency and perceived reduction in smoke and improved health. However, there were clear preferences for specific ICS with almost half of women preferring a Philips stove. Despite acceptance and use of ICS, women used multiple stoves to meet their daily needs. Qualitative studies are essential to field evaluations to provide insight into user perspectives and acceptability of ICS and to inform research and development of technologies that are both effective in reducing HAP and practical in use.

Systematic review of the effect of pneumococcal conjugate vaccine dosing schedules on vaccine-type invasive pneumococcal disease among young children.

BACKGROUND: Pneumococcal conjugate vaccines (PCV) are being implemented globally using a variety of different schedules. The optimal schedule to maximize protection of vaccinated children against vaccine-type invasive pneumococcal disease (VT-IPD) is not known. METHODS: To assess the relative benefit of various PCV dosing schedules, we conducted a systematic review of studies published in English from 1994 to 2010 (supplemented post hoc with studies from 2011) on PCV effectiveness against VT-IPD among children targeted to receive vaccine. Data on 2-dose and 3-dose primary series, both with and without a booster ("2+0," "2+1," "3+0" and "3+1"), were included. For observational studies using surveillance data or case counts, we calculated percentage reduction in VT-IPD before and after PCV introduction. RESULTS: Of 4 randomized controlled trials and 31 observational studies reporting VT-IPD among young children, none evaluated a 2+0 complete series, 7 (19%) evaluated 2+1, 4 (11%) 3+0 and 27 (75%) 3+1. Most (86%) studies were from North America or Europe. Only 1 study (observational) directly compared 2 schedules (3+0 vs. 3+1); results supported the use of a booster dose. In clinical trials, vaccine efficacy ranged from 65% to 71% with 3+0 and 83% to 94% with 3+1. Surveillance data and case counts demonstrate reductions in VT-IPD of up to 100% with 2+1 (6 studies) or 3+1 (17 studies) schedules and up to 90% with 3+0 (2 studies). Reductions were observed as early as 1 year after PCV introduction. CONCLUSIONS: These data support the use of 2+1, 3+0 and 3+1 schedules, although most data of PCV impact on VT-IPD among young children are from high-income countries using 3+1. Differences between schedules for impact on VT-IPD are difficult to discern based on available data.

Systematic review of the effect of pneumococcal conjugate vaccine dosing schedules on prevention of pneumonia.

BACKGROUND: Pneumonia is the leading cause of morbidity and mortality among children <5 years of age globally. Pneumococcal conjugate vaccines (PCVs) are known to provide protection against vaccine serotype pneumococcal pneumonia; uncertainty exists regarding the optimum PCV dosing schedule. METHODS: We conducted a systematic review of studies published from 1994 to 2010 (supplemented post hoc with studies from 2011) documenting the effect of PCV dosing schedules on clinical and radiologically confirmed pneumonia, pneumococcal pneumonia and empyema among children of ages targeted to receive vaccine. Data on 2- and 3-dose schedules were included. Percent change of pneumonia incidence rates from baseline to most recent year post-PCV introduction was calculated. RESULTS: We identified 42 primary citations that evaluated PCV schedules and pneumonia. Thirty-seven (88%) were from North America, Europe or Australia; 37 (88%) evaluated PCV7 and 1 (2%) PCV10. Two studies (both observational) compared multiple schedules within the study. We found evidence of reduced clinical and radiologically confirmed pneumonia incidence for all schedules, including 2+1 (1 nonrandomized trial, 5 observational studies), 3+0 (5 randomized trials, 2 observational studies) and 3+1 (5 clinical trials, 24 observational studies) schedules. The magnitude of disease impact did not differ among schedules. Evidence for impact on pneumococcal pneumonia and empyema varied. CONCLUSIONS: All schedules (2+1, 3+0 and 3+1) reduced clinical and radiologically confirmed pneumonia. Quantifying differences in pneumonia disease impact between schedules was difficult due to heterogeneity among studies in design, case definition and population. These findings support World Health Organization recommendations for 3-dose schedules administered as either 3+0 or 2+1 regimens. Pneumonia impact data are still needed on expanded serotype PCV products, developing country settings and the role for a booster dose.