Immunotherapy in Pancreatic Ductal Adenocarcinoma: An Emerging Entity?

Abstract

The genomic-plasticity of the immune system creates a broad immune repertoire engaged to tackle cancer cells. Promising clinical activity has been observed with several immune therapy strategies in solid tumors including melanoma, lung, kidney and bladder cancers, albeit as yet immunotherapy-based treatment approaches in pancreatic ductal adenocarcinoma (PDAC) remain to have proven value. While translational and early clinical studies have demonstrated activation of antitumor immunity, most recent late-phase clinical trials have not confirmed the early promise in PDAC except in MSI-High PDAC patients. These results may in part be explained by multiple factors, including the poorly immunogenic nature of PDAC along with immune privilege, the complex tumor microenvironment and the genetic plasticity of PDAC cells. These challenges have led to disappointments in the field, nonetheless they have also advanced our understanding that may tailor the future steps for immunotherapy for PDAC. Therefore, there is significant hope that progress is on the horizon.

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Incorporating BEAMing technology as a liquid biopsy into clinical practice for the management of colorectal cancer patients: an expert taskforce review

Abstract

The importance of mutation identification for advanced colorectal cancer treatment with anti- epidermal growth factor receptor (EGFR) agents is well established. However, due to delays in turnaround time, low-quality tissue samples, and/or lack of standardization of testing methods a significant proportion of patients are being treated without the information that KRAS and NRAS testing can provide. The detection of mutated circulating tumor DNA by BEAMing technology addresses this gap in care and allows these patients to receive international guideline-recommended expanded RAS testing with rapid turnaround times. Furthermore, the overall concordance between OncoBEAM RAS CRC testing and standard of care tissue testing is very high (93.3%). This article presents an overview of the clinical utility and potential applications of this minimally-invasive method, such as early detection of emergent resistance to anti-EGFR therapy. If appropriately implemented, BEAMing technology holds considerable promise to enhance the quality of patient care and improve clinical outcomes.

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De-escalation strategies in HER2-positive early breast cancer (EBC): Final analysis of the WSG-ADAPT HER2+/HR- phase II trial: Efficacy, safety, and predictive markers for 12-weeks of neoadjuvant dual blockade with trastuzumab and pertuzumab ± weekly paclitaxel

Abstract

Background: Response rates in HER2-overexpressing EBC treated with neoadjuvant chemotherapy and trastuzumab (T) have been improved by addition of pertuzumab (P). The prospective, phase II, neoadjuvant WSG-ADAPT HER2+/HR- trial assessed whether patients with strong early response to dual blockade alone might achieve pathological complete response (pCR) comparable to that of patients receiving dual blockade and chemotherapy.Patients and Methods: Female patients with HER2+/HR- EBC (M0) were randomized (5:2) to 12 weeks of T+P ± weekly paclitaxel (pac) at 80 mg/m². Early response was defined as proliferation decrease ≥30% of Ki-67 (vs. baseline) or low cellularity (<500 invasive tumor cells) in the three-week biopsy. The trial was designed to test non-inferiority for pCR in early responding patients of the T+P arm versus all chemotherapy-treated patients. Results: From 2/2014 to 12/2015, 160 patients were screened; 92 were randomized to T+P and 42 to T+P+pac. Baseline characteristics were well balanced (median age 54 vs. 51.5 years, cT2 51.1 vs. 52.4%, cN0 54.3 vs. 61.9%); 91.3% of patients completed T+P per protocol and 92.9% T+P+pac. The pCR rate in the T+P+pac arm was 90.5%, compared to 36.3% in the T+P arm as a whole. In the T+P arm, 24/92 were classified as non-responders, and their pCR rate was only 8.3% compared to 44.7% in responders (38/92) and 42.9% in patients with unclassified early response (30/92).No new safety signals were observed in the study population.Conclusion: Addition of taxane monotherapy to dual HER2 blockade in a 12-week neoadjuvant setting substantially increases pCR rates in HER2+/HR- EBC compared to dual blockade alone, even within early responders to dual blockade. Early non-response under dual blockade strongly predicts failure to achieve pCR.

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HBV related acute hepatitis due to immune checkpoint inhibitors in a patient with malignant melanoma

Immune checkpoint inhibitorHepatitis BAcute HepatitisTenofovir

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Dynamic Molecular Analysis and Clinical Correlates of Tumor Evolution Within a Phase 2 Trial of Panitumumab-Based Therapy in Metastatic Colorectal Cancer

Abstract

Background: Mutations in rat sarcoma (RAS) genes may be a mechanism of secondary resistance in EGFR inhibitor−treated patients. Tumor-tissue biopsy testing has been the standard for evaluating mutational status; however, plasma testing of cell-free DNA has been shown to be a more sensitive method for detecting clonal evolution.Materials and Methods: Archival pre- and post-treatment tumor biopsy samples from a phase 2 study of panitumumab in combination with irinotecan in patients with metastatic colorectal cancer (mCRC) that also collected plasma samples before, during, and after treatment were analyzed for emergence of mutations during/post-treatment by next-generation sequencing (NGS) and BEAMing.Results: The rate of emergence of tumor tissue RAS mutations was 9.5% by NGS (n=21) and 6.3% by BEAMing (n=16). Plasma testing of cell-free DNA by BEAMing revealed a mutant RAS emergence rate of 36.7% (n=39). Exploratory outcomes analysis of plasma samples indicated that patients who had emergent RAS mutations at progression had similar median progression-free survival to those patients who remained wild type at progression. Serial analysis of plasma samples showed that the first detected emergence of RAS mutations preceded progression by a median of 3.6 months (range, –0.3 to 7.5 months) and that there did not appear to be a mutant RAS allele frequency threshold that could predict near-term outcomes.Conclusions: This first prospective analysis in mCRC showed that serial plasma biopsies are more inclusive than tissue biopsies for evaluating global tumor heterogeneity; however, the clinical utility of plasma testing in mCRC remains to be further explored.ClinicalTrials.gov Identifier: NCT00891930

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Of Mice and Men: patient-derived xenografts in cancer medicine

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Antigen Cross-Presentation and T-Cell Cross-Priming In Cancer Immunology And Immunotherapy

Abstract

Dendritic cells are the main professional antigen-presenting cells for induction of T cell adaptive responses. Cancer cells express tumor antigens, including neoantigens generated by non-synonymous mutations, but are poor for antigen presentation and for providing costimulatory signals for T-cell priming. Mounting evidence suggests that antigen transfer to dendritic cells (DCs) and their surrogate presentation on MHC class I and II molecules together with costimulatory signals is paramount for induction of viral and cancer immunity. Of the great diversity of DCs, BATF3/IRF8-dependent conventional DCs type 1 (cDC1) excel at cross-presentation of tumor cell-associated antigens. Location of cDC1s in the tumor correlates with improved infiltration by CD8⁺ T cells and tumor-specific T cell immunity. Indeed, cDC1s are crucial for antitumor efficacy using checkpoint inhibitors and anti-CD137 agonist monoclonal antibodies in mouse models. Enhancement and exploitation of T-cell cross-priming by cDC1s offer opportunities for improved cancer immunotherapy, including in vivo targeting of tumor antigens to internalizing receptors on cDC1s and strategies to increase their numbers, activation and priming capacity within tumors and tumor-draining lymph nodes.

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Tubal ligation and ovarian cancer risk in African American women

Abstract

Purpose

Tubal ligation has been associated with reduced risk of epithelial ovarian cancer (EOC) in studies of primarily white women, but less is known about the association in African American (AA) women. We sought to evaluate the associations among 597 invasive ovarian cancer cases and 742 controls of AA descent recruited from the African American Cancer Epidemiology Study, a population-based case–control study in 11 geographical areas in the US.

Methods

Multivariable logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusted for potentially confounding factors.

Results

An inverse association between tubal ligation and EOC was observed that was not statistically significant (OR 0.88, 95% CI 0.68–1.14). However, an inverse association with EOC risk was observed among women who had a tubal ligation at age 35 years or older (OR 0.64; 95% CI 0.41–0.98), but not among those who had a tubal ligation before age 35 (OR 0.98; 95% CI 0.74–1.29) (p for interaction = 0.08). The association also varied considerably by tumor subtype. A strong inverse association was observed for endometrioid tumors (OR 0.31, 95% CI 0.14–0.70), whereas associations with mucinous (OR 0.87, 95% CI 0.36–2.12) and serous (OR 0.94, 95% CI 0.71–1.24) tumors were weaker and not statistically significant. A statistically non-significant positive association for clear cell tumors (OR 1.84, 95% CI 0.58–5.82) was based on a low number of cases.

Conclusions

Our findings show that tubal ligation may confer a reduced risk for EOC among AA women that is comparable to the associations that have been previously observed in primarily white populations.

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Diet, Gut Microbiota, and Colorectal Cancer Prevention: a Review of Potential Mechanisms and Promising Targets for Future Research

Abstract

Diet plays an important role in the development of colorectal cancer. Emerging data have implicated the gut microbiota in colorectal cancer. Diet is a major determinant for the gut microbial structure and function. Therefore, it has been hypothesized that alterations in gut microbes and their metabolites may contribute to the influence of diet on the development of colorectal cancer. We review several major dietary factors that have been linked to gut microbiota and colorectal cancer, including major dietary patterns, fiber, red meat and sulfur, and obesity. Most of the epidemiologic evidence derives from cross-sectional or short-term, highly controlled feeding studies that are limited in size. Therefore, high-quality large-scale prospective studies with dietary data collected over the life course and comprehensive gut microbial composition and function assessed well prior to neoplastic occurrence are critically needed to identify microbiome-based interventions that may complement or optimize current diet-based strategies for colorectal cancer prevention and management.

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Issue Information - Ed Board

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Phase I dose escalation and pharmacokinetic study on the nanoparticle formulation of polymeric micellar paclitaxel for injection in patients with advanced solid malignancies

Summary

Background Polymeric micellar paclitaxel (PM-paclitaxel) is a novel Cremophor EL-free, nanoparticle-encapsulated paclitaxel formulation administered through intravenous injection. The primary objective of this phase I trial was to determine the first cycle dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of PM-paclitaxel. Secondary objectives included the evaluation of the safety, antitumor activity, and pharmacokinetic (PK) profile of PM-paclitaxel in patients with advanced malignancies. Methods The PM-paclitaxel dose was escalated from 175 mg/m² (level 1) to 435 mg/m² (level 5). PM-paclitaxel was intravenously administered to patients for 3 h without premedication on day 1 of a 21-day cycle. Results Eighteen patients with confirmed advanced malignancies received PM-paclitaxel. DLT included grade 4 neutropenia (four patients) and grade 3 numbness (one patient), which occurred in one of the six patients who received 300 mg/m² (level 3) PM-paclitaxel and all three patients who were treated with 435 mg/m² PM-paclitaxel. Thus, the MTD of PM-paclitaxel was determined as 390 mg/m² (level 4). Acute hypersensitive reactions were not observed. Partial response was observed in six of 18 patients (33.3%), three of whom had prior exposure to paclitaxel chemotherapy. The peak concentration and area under the curve values of paclitaxel increased with increasing dosage, indicating that PM-paclitaxel exhibits linear PKs. Conclusions PM-paclitaxel showed high MTD without additional toxicity, and exhibited desirable antitumor activity. The recommended dose of PM paclitaxel for phase II study is 300 mg/m².

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Carpal spasm in a girl as initial presentation of celiac disease: a case report

Celiac disease is an immune-mediated disorder elicited by ingestion of gluten in genetically susceptible persons. This disorder is characterized by specific histological changes of the small intestine mucosa r...

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Mutation in the AGK gene in two siblings with unusual Sengers syndrome

Abstract

Sengers syndrome is a rare autosomal recessive metabolic disorder caused by lack of acylglycerol kinase due to mutations in the AGK gene. It is characterized by congenital cataract, hypertrophic cardiomyopathy, myopathy and lactic acidosis. Two clinical forms have been described: a severe neonatal form, and a more benign form displaying exercise intolerance. We describe two siblings with congenital cataract, cardiomyopathy, hypotonia, intellectual disability and lactic acidosis. Whole exome sequencing revealed a homozygous c.1035dup mutation in the two siblings, supporting a diagnosis of Sengers syndrome. Our patients presented an intermediate form with intellectual deficiency, an unusual feature in Sengers syndrome. This permitted a prenatal diagnosis for a following pregnancy.

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A Rare Presentation of Synovial Sarcoma as Cervical Lymphadenopathy in a Pediatric Patient—a Case Report

Abstract

Synovial sarcoma is the uncommon malignant tumor of children and adolescents. It usually involves the soft tissues of the upper and lower joints and most commonly affects adults in their fourth decade of life. We report a rare case of synovial sarcoma of the head and neck region in a five-year-old child who has presented with right side cervical lymphadenopathy associated with dysphagia and hoarseness of voice. Patient was managed by modified radical neck dissection followed by chemotherapy.

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Sclerosing angiomatoid nodular transformation of the spleen mimicking metastasis of melanoma: a case report and review of the literature

Sclerosing angiomatoid nodular transformation is a benign disorder of splenic tissue and is often mistaken as a potentially malignant entity in the diagnostic process. To the best of our knowledge, this is the...

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Upregulation of Treg-Related Genes in Addition with IL6 Showed the Significant Role for the Distant Metastasis in Colorectal Cancer

Abstract

T helper 17 (Th17) and T regulatory (Treg) cytokines appear to be contributing greatly to colorectal cancer (CRC) development and progression. The aim of the current study was to investigate the expression of Foxp3; IL10; TGFB1; IL17A; IL6 and NOS2 genes in tumor tissue, regional positive lymph nodes and distant metastasis obtained from 26 patients with advanced CRC. Quantitative real-time polymerase chain reaction (qPCR) was performed for mRNA detection by TaqMan gene expression assay. In distant metastasis, IL6 was strongly expressed, over 7.5 fold, followed by Treg-related genes Foxp3; IL10 and TGFB1 in contrast to IL17A and NOS2. The similar pattern of expression was observed in positive regional lymph node in addition to significant down-regulation of NOS2 (RQ = 0.287; p = 0.011) and a trend for the elevation of IL17A. In tumor tissue, Fopx3 was significantly upregulated and Foxp3 mRNA positively correlated with TGFB1 in all investigated tissue types. In tumor tissue, expression of IL17A was correlated with NOS2 (r = 0.68; p = 0.005), while in distant metastasis IL10 was in strong relation with TGFB1 and IL6. In addition, a reverse correlation between IL6 and NOS2 (r = −0.66; p = 0.009), was observed in distant metastasis. The simultaneous expression of given Treg and Th17-related genes found both in the primary tumor and in the regional lymph nodes appears to provide suitable microenvironment sufficient for promoting metastatic growth. The upregulation of Foxp3; IL10, TGFB1 and IL6 might be a transcriptional profile hallmark for colorectal metastases.

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In human brain ornithine transcarbamylase (OTC) immunoreactivity is strongly expressed in a small number of nitrergic neurons

Abstract

There is recent evidence for ornithine transcarbamylase (OTC) expression in adult human brain. We decided to immunocytochemically map OTC throughout brain, and to further characterize OTC-immunopositive neurons. By using double immunolabeling technique for OTC and neuronal nitric oxide synthase (nNOS) OTC protein expression was revealed in a small subset of nitrergic (nNOS) neurons. Since citrulline (the reaction product of OTC) enhances the bioavailability of L-arginine, the substrate of nNOS, it is conceivable that OTC activity supports NO production in nitrergic neurons.

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