Plasticity-induced repression of Irf6 underlies acquired resistance to cancer immunotherapy in pancreatic ductal adenocarcinoma.

Acquired resistance to immunotherapy remains a critical yet incompletely understood biological mechanism. Here, using a mouse model of pancreatic ductal adenocarcinoma (PDAC) to study tumor relapse following immunotherapy-induced responses, we find that resistance is reproducibly associated with an epithelial-to-mesenchymal transition (EMT), with EMT-transcription factors ZEB1 and SNAIL functioning as master genetic and epigenetic regulators of this effect. Acquired resistance in this model is not due to immunosuppression in the tumor immune microenvironment, disruptions in the antigen presentation machinery, or altered expression of immune checkpoints. Rather, resistance is due to a tumor cell-intrinsic defect in T-cell killing. Molecularly, EMT leads to the epigenetic and transcriptional silencing of interferon regulatory factor 6 (Irf6), rendering tumor cells less sensitive to the pro-apoptotic effects of TNF-α. These findings indicate that acquired resistance to immunotherapy may be mediated by programs distinct from those governing primary resistance, including plasticity programs that render tumor cells impervious to T-cell killing.

Semiquantitative Tissue Perfusion Assessment Using Indocyanine Green in Complex Open Urethral Reconstruction.

OBJECTIVE: Current assessment of critical tissue in genitourinary reconstruction, including graft beds and tissue flaps, primarily relies upon qualitative visual and tactile assessment by experienced surgeons. Here we explore the feasibility of using intravenous indocyanine green (ICG) for semiquantitative assessment of perfusion in complex open urethral reconstruction. METHODS: A standardized protocol for intravenous use of ICG and near-infrared fluorescence was established. Black and white mode was used for qualitative assessment of perfusion based on signal brightness. Quantitative perfusion mode was used to assess relative perfusion to tissue of interest compared to a control area with similar tissue type outside of the studied area. Real-time perfusion was visualized as percentage of perfusion relative to control. RESULTS: In case 1, the graft bed was assessed during dorsal onlay graft substitution urethroplasty. Perfusion to graft bed was compared to that of erectile bodies proximally. A proposed perfusion cutoff of 60% was noted to correlate with clinical judgment of graft bed quality. In case 2, tissue perfusion of Blandy flap in perineal urethrostomy was assessed before and after mobilization. A cutoff of 40% was proposed based on existing flap-based reconstruction literature with the goal to tailor flap and ultimately avoid tissue ischemia and necrosis. In case 3, in a complex staged substitution urethroplasty after hypospadias repair, the use of ICG facilitated a limited excision and shorter graft inlay in this staged reconstruction. CONCLUSION: The application of near-infrared fluorescence tools in open genitourinary reconstruction has the potential to advance quantitative assessment of graft, flaps, and other critical tissue planes, and help establish meaningful perfusion threshold and correlate with clinical outcomes.

Hyperinsulinemia acts via acinar insulin receptors to initiate pancreatic cancer by increasing digestive enzyme production and inflammation.

The rising pancreatic cancer incidence due to obesity and type 2 diabetes is closely tied to hyperinsulinemia, an independent cancer risk factor. Previous studies demonstrated reducing insulin production suppressed pancreatic intraepithelial neoplasia (PanIN) pre-cancerous lesions in Kras-mutant mice. However, the pathophysiological and molecular mechanisms remained unknown, and in particular it was unclear whether hyperinsulinemia affected PanIN precursor cells directly or indirectly. Here, we demonstrate that insulin receptors (Insr) in KrasG12D-expressing pancreatic acinar cells are dispensable for glucose homeostasis but necessary for hyperinsulinemia-driven PanIN formation in the context of diet-induced hyperinsulinemia and obesity. Mechanistically, this was attributed to amplified digestive enzyme protein translation, triggering of local inflammation, and PanIN metaplasia in vivo. In vitro, insulin dose-dependently increased acinar-to-ductal metaplasia formation in a trypsin- and Insr-dependent manner. Collectively, our data shed light on the mechanisms connecting obesity-driven hyperinsulinemia and pancreatic cancer development.

Plasticity-induced repression of Irf6 underlies acquired resistance to cancer immunotherapy.

Acquired resistance to immune checkpoint immunotherapy remains a critical yet incompletely understood biological mechanism. Here, using a mouse model of pancreatic ductal adenocarcinoma (PDAC) to study tumor relapse following immunotherapy-induced responses, we found that tumors underwent an epithelial-to-mesenchymal transition (EMT) that resulted in reduced sensitivity to T cell-mediated killing. EMT-transcription factors (EMT-TFs) ZEB1 and SNAIL function as master genetic and epigenetic regulators of this tumor-intrinsic effect. Acquired resistance was not due to immunosuppression in the tumor immune microenvironment, disruptions in the antigen presentation machinery, or altered expression of immune checkpoints. Rather, EMT was associated with epigenetic and transcriptional silencing of interferon regulatory factor 6 (Irf6), which renders tumor cells less sensitive to the pro-apoptotic effects of TNF-α. These findings show how resistance to immunotherapy in PDAC can be acquired through plasticity programs that render tumor cells impervious to T cell killing.

Emerging Therapies for Transthyretin Amyloidosis.

PURPOSE OF REVIEW: This review provides an overview of the available therapies for treating neuropathic and/or cardiac manifestations of transthyretin amyloidosis (ATTR), as well as investigational therapeutic agents in ongoing clinical trials. We discuss additional emergent approaches towards thwarting this life-threatening disease that until recently was considered virtually untreatable. RECENT FINDINGS: Advances in noninvasive diagnostic methods for detecting ATTR have facilitated easier diagnosis and detection at an earlier stage of disease when therapeutic interventions are likely to be more effective. There are now several ATTR-directed treatments that are clinically available, as well as investigational agents that are being studied in clinical trials. Therapeutic strategies include tetramer stabilization, gene silencing, and fibril disruption. ATTR has been historically underdiagnosed. With advances in diagnostic methods and the advent of disease-modifying treatments, early diagnosis and initiation of treatment is revolutionizing management of this disease.

Mesonephric Adenomyofibroma: A Biphasic Vaginal Mass of Mesonephric Type With Molecular Analysis: A Case Report of a Rare Entity.

Mesonephric neoplasms of the lower female genital tract are rare. To date, there are scarce reports of benign biphasic vaginal mesonephric lesions, and none have included immunohistochemical and/or molecular analysis. A biphasic neoplasm of mesonephric-type was incidentally identified in the vaginal submucosal tissue of a 55-yr-old woman who underwent a right salpingo-oophorectomy for an ovarian cyst. The well-circumscribed, 5 mm nodule exhibited white-tan, firm homogenous cut surfaces. Microscopic examination showed a lobular arrangement of glands with columnar to the cuboidal epithelium and intraluminal eosinophilic secretions, embedded within a myofibromatous stroma. Cytologic atypia and mitotic activity were absent. Immunohistochemical staining for PAX8 and GATA3 demonstrated diffuse expression in the glandular epithelium, CD10 exhibited a patchy luminal expression pattern, while TTF1, ER, PR, p16, and NKX3.1 were negative. Desmin highlighted a subset of the stromal cells, but myogenin was negative. Whole exome sequencing demonstrated variants of unknown significance in multiple genes including PIK3R1 and NFIA . The morphologic and immunohistochemical profiles are consistent with a benign mesonephric neoplasm. This is the first report describing the immunohistochemical and whole exome sequencing results for a benign biphasic vaginal mesonephric neoplasm. To the best of our knowledge, benign mesonephric adenomyofibroma has not been previously reported in this anatomic location.

PRO score: predictive scoring system for visual outcomes after rhegmatogenous retinal detachment repair.

BACKGROUND/AIMS: To compare risk factors for poor visual outcomes in patients undergoing primary rhegmatogenous retinal detachment (RRD) repair and to develop a scoring system. METHODS: Analysis of the Primary Retinal detachment Outcomes (PRO) study, a multicentre interventional cohort of consecutive primary RRD surgeries performed in 2015. The main outcome measure was a poor visual outcome (Snellen VA ≤20/200). RESULTS: A total of 1178 cases were included. The mean preoperative and postoperative logMARs were 1.1±1.1 (20/250) and 0.5±0.7 (20/63), respectively. Multivariable logistic regression identified preoperative risk factors predictive of poor visual outcomes (≤20/200), including proliferative vitreoretinopathy (PVR) (OR 1.26; 95% CI 1.13 to 1.40), history of antivascular endothelial growth factor (VEGF) injections (1.38; 1.11 to 1.71), >1-week vision loss (1.17; 1.08 to 1.27), ocular comorbidities (1.18; 1.00 to 1.38), poor presenting VA (1.06 per initial logMAR unit; 1.02 to 1.10) and age >70 (1.13; 1.04 to 1.23). The data were split into training (75%) and validation (25%) and a scoring system was developed and validated. The risk for poor visual outcomes was 8% with a total score of 0, 17% with 1, 29% with 2, 47% with 3, and 71% with 4 or higher. CONCLUSIONS: Independent risk factors were compared for poor visual outcomes after RRD surgery, which included PVR, anti-VEGF injections, vision loss >1 week, ocular comorbidities, presenting VA and older age. The PRO score was developed to provide a scoring system that may be useful in clinical practice.

Serial 7-Day Electrocardiogram Patch Screening for AF in High-Risk Older Women by the CHARGE-AF Score.

BACKGROUND: Asymptomatic atrial fibrillation (AF) is associated with an increased risk of stroke. The yield of serial electrocardiographic (ECG) screening for AF is unknown. OBJECTIVES: The aim of this study was to determine the frequency of AF detected by serial, 7-day ECG patch screenings in older women identified as having an elevated risk of AF according to the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology)-AF clinical prediction score. METHODS: Postmenopausal women with a 5-year predicted risk of new-onset AF ≥5% according to CHARGE-AF were recruited from the ongoing WHISH (Women's Health Initiative Strong and Healthy) randomized trial of a physical activity intervention. Participants with AF at baseline by self-report or medical records review were excluded. Screening with 7-day ECG patch monitors was performed at baseline, 6 months, and 12 months from study enrollment. RESULTS: On baseline monitoring, 2.5% of the cohort had AF detected, increasing to 3.7% by 6 months and 4.9% cumulatively by 12 months. Yield of patch screening was higher among participants with a higher (≥10%) CHARGE-AF score: 4.2% had AF detected at baseline, 5.9% at 6 months, and 7.2% at 12 months. Most participants with patch-identified AF never had a clinical diagnosis of AF (36 of 46 [78%]). CONCLUSIONS: Older women with an elevated CHARGE-AF score had a high prevalence of AF on 7-day ECG patch screening. Serial screening over 12 months substantially increased the detection of AF. These data can be useful in helping identify high-risk participants for enrollment in future studies of the management of asymptomatic AF.(Women's Health Initiative Silent Atrial Fibrillation Recording Study [WHISH STAR]; NCT05366803.).

Molecular Analysis of HPV-independent Primary Endometrial Squamous Cell Carcinoma Reveals TP53 and CDKN2A Comutations : A Clinicopathologic Analysis With Re-evaluation of Diagnostic Criteria.

Human papillomavirus (HPV)-independent primary endometrial squamous cell carcinoma (PESCC) is a rare but aggressive subtype of endometrial carcinoma for which little is known about the genomic characteristics. Traditional criteria have restricted the diagnosis of PESCC to cases without any cervical involvement. However, given that modern ancillary techniques can detect HPV and characteristic genetic alterations that should identify the more common mimics in the differential diagnosis, including endometrial endometrioid carcinoma with extensive squamous differentiation and HPV-associated primary cervical squamous cell carcinoma, those criteria may benefit from revision. To further characterize PESCC, we identified 5 cases of pure squamous cell carcinoma dominantly involving the endometrium that had the potential to be PESCC: 1 case involving only the endometrium and 4 cases with some involvement of the cervix. Clinicopathologic features were assessed and immunohistochemical analysis (p16, estrogen receptor, progesterone receptor, and p53), HPV RNA in situ hybridization (high-risk and low-risk cocktails and targeted probes for 16 and 18), and molecular studies were performed. All tumors showed aberrant/mutation-type p53 expression, were negative for estrogen receptor, progesterone receptor, and p16, and had no detectable HPV. Per whole-exome sequencing, 4 of the 5 tumors demonstrated comutations in TP53 and CDKN2A (p16). Four patients died of disease within 20 months (range, 1 to 20 mo; mean, 9 mo), and 1 patient had no evidence of disease at 38 months. PESCC represents a unique, clinically aggressive subtype of endometrial cancer with TP53 and CDKN2A comutations. This characteristic profile, which is similar to HPV-independent squamous cell carcinoma of the vulva, is distinct from endometrioid carcinoma with extensive squamous differentiation and HPV-associated primary cervical squamous cell carcinoma and can be used to distinguish PESCC from those mimics even when cervical involvement is present. Diagnostic criteria for PESCC should be relaxed to allow for cervical involvement when other pathologic features are consistent with, and ancillary techniques are supportive of classification as such.

Site-Dependent Immune Escape Due to Impaired Dendritic Cell Cross-Priming.

T-cell recognition of tumor neoantigens is critical for cancer immune surveillance and the efficacy of immunotherapy. Tumors can evade host immunity by altering their antigenicity or orchestrating an immunosuppressive microenvironment, leading to outgrowth of poorly immunogenic tumors through the well-established process of cancer immunoediting. Whether cancer immune surveillance and immunoediting depend on the tissue site of origin, however, is poorly understood. Herein, we studied T-cell-mediated surveillance of antigenic, clonal murine pancreatic adenocarcinoma cells expressing neoantigen. Whereas such tumors are robustly eliminated after subcutaneous or intravenous challenge, we observed selective immune escape within the pancreas and peritoneum. Tumor outgrowth occurred in the absence of immunoediting, and antitumor immunity could not be rescued by PD-1 or CTLA-4 checkpoint blockade. Instead, tumor escape was associated with diminished CD8+ T-cell priming by type I conventional dendritic cells (cDC1). Enhancing cDC1 cross-presentation by CD40 agonist treatment restored immunologic control by promoting T-cell priming and broadening T-cell responses through epitope spread. These findings demonstrate that immune escape of highly antigenic tumors can occur without immunoediting in a tissue-restricted manner and highlight barriers to cDC1-mediated T-cell priming imposed by certain microenvironments that must be addressed for successful combination immunotherapies.

Clinical value of 18FDG PET/MRI in muscle-invasive, locally advanced, and metastatic bladder cancer.

OBJECTIVE: Metastatic bladder cancer is an aggressive disease that can often be difficult to diagnose and stage with conventional cross-sectional imaging. The primary objective of this study was to determine the clinical value of fluorine-18 2-fluoro-2-deoxy-D-glucose (18F-FDG) PET/MRI for surveillance and restaging of patients with muscle-invasive, locally advanced, and metastatic bladder cancer compared to conventional imaging methods. MATERIALS AND METHODS: This retrospective study enrolled patients with muscle-invasive, locally advanced and metastatic bladder cancer in a single institute evaluated with 18F-FDG PET/MRI. All patients also underwent conventional imaging with CT. Additional imaging may also have included 18F-FDG PET/CT (18F-FDG PET), or sodium fluoride (NaF) PET/CT in some patients. Images were reviewed by a diagnostic radiologist/nuclear medicine physician. Number of lesions and sites of disease were captured and compared between 18F-FDG PET/MRI and conventional imaging. Lesions were confirmed by sequential imaging or lesion biopsy. All patients were followed for survival. RESULTS: Fifteen patients (4 for surveillance; 11 for restaging) underwent 34 18F-FDG PET/MRI scans. Each patient received a corresponding conventional CT around the time of the 18F-FDG PET/MRI (median 6 days). The 15 patients (11 male; 4 female) had a median age of 61.5 years (range 37-73) and histologies of urothelial carcinoma (n = 13) and small-cell carcinoma of the bladder (n = 2) diagnosed as stage 4 (n = 13), stage 3 (n = 1), or stage 2 (n = 1). 18F-FDG PET/MRI detected 82 metastatic malignant lesions involving lymph nodes (n = 22), liver (n = 10), lung (n = 34), soft tissue (n = 12), adrenal glands (n = 1), prostate (n = 1), and bone (n = 2) with a resultant advantage of 36% for lesion visibility in comparison with CT. Serial imaging or biopsy confirmed these lesions as malignant. CONCLUSION: 18F-FDG PET/MRI can detect metastatic lesions which cannot be identified on conventional CT, and this can allow for better treatment planning and improved disease monitoring during therapy.

Cabozantinib in patients with platinum-refractory metastatic urothelial carcinoma: an open-label, single-centre, phase 2 trial.

BACKGROUND: Cabozantinib is a multikinase inhibitor of MET, VEGFR, AXL, and RET, which also has an effect on the tumour immune microenvironment by decreasing regulatory T cells and myeloid-derived suppressor cells. In this study, we examined the activity of cabozantinib in patients with metastatic platinum-refractory urothelial carcinoma. METHODS: This study was an open-label, single-arm, three-cohort phase 2 trial done at the National Cancer Institute (Bethesda, MD, USA). Eligible patients were 18 years or older, had histologically confirmed urothelial carcinoma or rare genitourinary tract histologies, Karnofsky performance scale index of 60% or higher, and documented disease progression after at least one previous line of platinum-based chemotherapy (platinum-refractory). Cohort one included patients with metastatic urothelial carcinoma with measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Two additional cohorts that enrolled in parallel (patients with bone-only urothelial carcinoma metastases and patients with rare histologies of the genitourinary tract) were exploratory. Patients received cabozantinib 60 mg orally once daily in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate by RECIST in cohort one. Response was assessed in all patients who met the eligibility criteria and who received at least 8 weeks of therapy. All patients who received at least one dose of cabozantinib were included in the safety analysis. This completed study is registered with ClinicalTrials.gov, NCT01688999. FINDINGS: Between Sept 28, 2012, and Oct, 20, 2015, 68 patients were enrolled on the study (49 in cohort one, six in cohort two, and 13 in cohort three). All patients received at least one dose of cabozantinib. The median follow-up was 61·2 months (IQR 53·8-70·0) for the 57 patients evaluable for response. In the 42 evaluable patients in cohort one, there was one complete response and seven partial responses (objective response rate 19%, 95% CI 9-34). The most common grade 3-4 adverse events were fatigue (six [9%] patients), hypertension (five [7%]), proteinuria (four [6%]), and hypophosphataemia (four [6%]). There were no treatment-related deaths. INTERPRETATION: Cabozantinib has single-agent clinical activity in patients with heavily pretreated, platinum-refractory metastatic urothelial carcinoma with measurable disease and bone metastases and is generally well tolerated. Cabozantinib has innate and adaptive immunomodulatory properties providing a rationale for combining cabozantinib with immunotherapeutic strategies. FUNDING: National Cancer Institute Intramural Program and the Cancer Therapy Evaluation Program.

Type 1 conventional dendritic cells are systemically dysregulated early in pancreatic carcinogenesis.

Type 1 conventional dendritic cells (cDC1s) are typically thought to be dysregulated secondarily to invasive cancer. Here, we report that cDC1 dysfunction instead develops in the earliest stages of preinvasive pancreatic intraepithelial neoplasia (PanIN) in the KrasLSL-G12D/+ Trp53LSL-R172H/+ Pdx1-Cre-driven (KPC) mouse model of pancreatic cancer. cDC1 dysfunction is systemic and progressive, driven by increased apoptosis, and results in suboptimal up-regulation of T cell-polarizing cytokines during cDC1 maturation. The underlying mechanism is linked to elevated IL-6 concomitant with neoplasia. Neutralization of IL-6 in vivo ameliorates cDC1 apoptosis, rescuing cDC1 abundance in tumor-bearing mice. CD8+ T cell response to vaccination is impaired as a result of cDC1 dysregulation. Yet, combination therapy with CD40 agonist and Flt3 ligand restores cDC1 abundance to normal levels, decreases cDC1 apoptosis, and repairs cDC1 maturation to drive superior control of tumor outgrowth. Our study therefore reveals the unexpectedly early and systemic onset of cDC1 dysregulation during pancreatic carcinogenesis and suggests therapeutically tractable strategies toward cDC1 repair.

CCL5 mediates CD40-driven CD4+ T cell tumor infiltration and immunity.

The role CD4+ T cells play in tumor immunity is less well appreciated than the cytotoxic role of CD8+ T cells. Despite clear evidence for CD4+ T cell dependency across multiple immunotherapies, the mechanisms by which CD4+ T cells infiltrate tumors remain poorly understood. Prior studies by our group have shown in a mouse model of pancreatic cancer that systemic activation of the cell surface TNF superfamily member CD40 drives T cell infiltration into tumors and, in combination with immune checkpoint blockade, leads to durable tumor regressions and cures that depend on both CD8+ and CD4+ T cells. Here, we used single-cell transcriptomics to examine the tumor microenvironment following treatment with agonist CD40 antibody with or without immune checkpoint blockade. We show that intratumor myeloid cells produce the chemokine CCL5 in response to CD40 agonist and that CCL5 mediates an influx of CD4+ T cells into the tumor microenvironment. Disruption of CCL5 genetically or pharmacologically mitigates the influx of CD4+ but not CD8+ T cells into tumors and blunts the therapeutic efficacy of immunotherapy. These findings highlight a previously unappreciated role for CCL5 in selectively mediating CD4+ T cell tumor infiltration in response to effective immunotherapy.

Global Regulation of the Histone Mark H3K36me2 Underlies Epithelial Plasticity and Metastatic Progression.

Epithelial plasticity, reversible modulation of a cell's epithelial and mesenchymal features, is associated with tumor metastasis and chemoresistance, leading causes of cancer mortality. Although different master transcription factors and epigenetic modifiers have been implicated in this process in various contexts, the extent to which a unifying, generalized mechanism of transcriptional regulation underlies epithelial plasticity remains largely unknown. Here, through targeted CRISPR/Cas9 screening, we discovered two histone-modifying enzymes involved in the writing and erasing of H3K36me2 that act reciprocally to regulate epithelial-to-mesenchymal identity, tumor differentiation, and metastasis. Using a lysine-to-methionine histone mutant to directly inhibit H3K36me2, we found that global modulation of the mark is a conserved mechanism underlying the mesenchymal state in various contexts. Mechanistically, regulation of H3K36me2 reprograms enhancers associated with master regulators of epithelial-to-mesenchymal state. Our results thus outline a unifying epigenome-scale mechanism by which a specific histone modification regulates cellular plasticity and metastasis in cancer. SIGNIFICANCE: Although epithelial plasticity contributes to cancer metastasis and chemoresistance, no strategies exist for pharmacologically inhibiting the process. Here, we show that global regulation of a specific histone mark, H3K36me2, is a universal epigenome-wide mechanism that underlies epithelial-to-mesenchymal transition and mesenchymal-to-epithelial transition in carcinoma cells. These results offer a new strategy for targeting epithelial plasticity in cancer.This article is highlighted in the In This Issue feature, p. 747.

18F-Sodium fluoride PET/CT predicts overall survival in patients with advanced genitourinary malignancies treated with cabozantinib and nivolumab with or without ipilimumab.

PURPOSE: We evaluated the prognostic value of 18F-sodium fluoride (NaF) PET/CT in patients with urological malignancies treated with cabozantinib and nivolumab with or without ipilimumab. METHODS: We prospectively recruited patients with advanced urological malignancies into a phase I trial of cabozantinib plus nivolumab with or without ipilimumab. NaF PET/CT scans were performed pre- and 8 weeks post-treatment. We measured the total volume of fluoride avid bone (FTV) using a standardized uptake value (SUV) threshold of 10. We used Kaplan-Meier analysis to predict the overall survival (OS) of patients in terms of SUVmax, FTV, total lesion fluoride (TLF) uptake at baseline and 8 weeks post-treatment, and percent change in FTV and TLF. RESULT: Of 111 patients who underwent NaF PET/CT, 30 had bone metastases at baseline. Four of the 30 patients survived for the duration of the study period. OS ranged from 0.23 to 34 months (m) (median 6.0 m). The baseline FTV of all 30 patients ranged from 9.6 to 1570 ml (median 439 ml). The FTV 8 weeks post-treatment was 56-6296 ml (median 448 ml) from 19 available patients. Patients with higher TLF at baseline had shorter OS than patients with lower TLF (3.4 vs 14 m; p = 0.022). Patients with higher SUVmax at follow-up had shorter OS than patients with lower SUVmax (5.6 vs 24 m; p = 0.010). However, FTV and TLF 8 weeks post-treatment did not show a significant difference between groups (5.6 vs 17 m; p = 0.49), and the percent changes in FTV (12 vs 14 m; p = 0.49) and TLF (5.6 vs 17 m; p = 0.54) also were not significant. CONCLUSION: Higher TLF at baseline and higher SUVmax at follow-up NaF PET/CT corresponded with shorter survival in patients with bone metastases from urological malignancies who underwent treatment. NaF PET/CT may be a useful predictor of OS in this population.

Tumor cell-intrinsic EPHA2 suppresses anti-tumor immunity by regulating PTGS2 (COX-2).

Resistance to immunotherapy is one of the biggest problems of current oncotherapeutics. WhileT cell abundance is essential for tumor responsiveness to immunotherapy, factors that define the T cell inflamed tumor microenvironment are not fully understood. We conducted an unbiased approach to identify tumor-intrinsic mechanisms shaping the immune tumor microenvironment(TME), focusing on pancreatic adenocarcinoma because it is refractory to immunotherapy and excludes T cells from the TME. From human tumors, we identified EPHA2 as a candidate tumor intrinsic driver of immunosuppression. Epha2 deletion reversed T cell exclusion and sensitized tumors to immunotherapy. We found that PTGS2, the gene encoding cyclooxygenase-2, lies downstream of EPHA2 signaling through TGFß and is associated with poor patient survival. Ptgs2 deletion reversed T cell exclusion and sensitized tumors to immunotherapy; pharmacological inhibition of PTGS2 was similarly effective. Thus, EPHA2-PTGS2 signaling in tumor cells regulates tumor immune phenotypes; blockade may represent a novel therapeutic avenue for immunotherapy-refractory cancers. Our findings warrant clinical trials testing the effectiveness of therapies combining EPHA2-TGFß-PTGS2 pathway inhibitors with anti-tumor immunotherapy, and may change the treatment of notoriously therapy-resistant pancreatic adenocarcinoma.

The effects of physical activity on cancer prevention, treatment and prognosis: A review of the literature.

INTRODUCTION: The World Health Organization has reported that approximately 35% of cancer-related deaths are attributed to modifiable risk factors. Among the most important risk factors amenable to modification are obesity and lack of physical activity. The purpose of this article is to review the current evidence of the benefits of physical activity in various types of cancer. METHODS: A PubMed search for the key words "physical activity and cancer" as well as "exercise and cancer" was used to identify all indexed publications on this topic for potential utilization in this review. One MET was defined as the amount of oxygen consumed while a person is sitting quietly and is about 3.5 mL O2/kg body weight/min. MET represents the ratio of the working metabolic rate to the resting metabolic rate. RESULTS: Routine physical activity was found to be associated with a reduced incidence of several of the most common malignancies, including colon, breast, lung, and endometrial cancer as well as many others. Physical activity also appears to reduce all-cause mortality and cancer-related mortality among patients with breast and colon cancer, and may improve the functional status and quality of life for these patients during cancer therapy. CONCLUSIONS: The benefits of physical activity in the prevention and progression of cancer patients are multiple. However, the strength of the available evidence is limited by the observational nature of most studies. Given the probable improvement in prevention, mortality, and quality of life with structured physical activity in different malignancies, it is important that healthcare providers discuss physical activity programs with their cancer patients. Larger randomized trials are recommended.

Adjuvant therapy after radical trachelectomy for stage I cervical cancer.

•Radical trachelectomy is a fertility sparing option for select stage I cervical patients.•Indications for adjuvant treatment following trachelectomy are based on standard recommendations following hysterectomy.•Case report outlining specifics of imaged-guided brachytherapy as part of the adjuvant treatment after trachelectomy.

Tumor Cell-Intrinsic Factors Underlie Heterogeneity of Immune Cell Infiltration and Response to Immunotherapy.

The biological and functional heterogeneity between tumors-both across and within cancer types-poses a challenge for immunotherapy. To understand the factors underlying tumor immune heterogeneity and immunotherapy sensitivity, we established a library of congenic tumor cell clones from an autochthonous mouse model of pancreatic adenocarcinoma. These clones generated tumors that recapitulated T cell-inflamed and non-T-cell-inflamed tumor microenvironments upon implantation in immunocompetent mice, with distinct patterns of infiltration by immune cell subsets. Co-injecting tumor cell clones revealed the non-T-cell-inflamed phenotype is dominant and that both quantitative and qualitative features of intratumoral CD8+ T cells determine response to therapy. Transcriptomic and epigenetic analyses revealed tumor-cell-intrinsic production of the chemokine CXCL1 as a determinant of the non-T-cell-inflamed microenvironment, and ablation of CXCL1 promoted T cell infiltration and sensitivity to a combination immunotherapy regimen. Thus, tumor cell-intrinsic factors shape the tumor immune microenvironment and influence the outcome of immunotherapy.