Cancer by Sfakianakis Alexandros: 07/02/18

Δευτέρα 2 Ιουλίου 2018

High-throughput functional evaluation of variants of unknown significance in ERBB2

Purpose: The advent of next-generation sequencing technologies has enabled the identification of several activating mutations of Erb-B2 receptor tyrosine kinase 2 (ERBB2) among various cancers. However, the significance of infrequent mutations has not been fully investigated. Herein, we comprehensively assessed the functional significance of the ERBB2 mutations in a high-throughput manner. Experimental Design: We evaluated the transforming activities and drug sensitivities of 55 nonsynonymous ERBB2 mutations using the mixed-all-nominated-in-one (MANO) method. Results: G776V, G778_S779insG, and L841V were newly revealed to be activating mutations. Although afatinib, neratinib and osimertinib were shown to be effective against most of the ERBB2 mutations, only osimertinib demonstrated good efficacy against L755P and L755S mutations, the most common mutations in breast cancer. In contrast, afatinib and neratinib were predicted to be more effective than other inhibitors for the A775_776insYVMA mutation, the most frequent ERBB2 mutation in lung cancer. We surveyed the prevalence of concurrent ERBB2 mutation with gene amplification and found that approximately 30% of ERBB2-amplified urothelial carcinomas simultaneously carried ERBB2 mutations, altering their sensitivity to trastuzumab, a monoclonal antibody against ERBB2. Furthermore, the MANO method was applied to evaluate the functional significance of 17 compound mutations within ERBB2 reported in the COSMIC database, revealing that compound mutations involving L755S were sensitive to osimertinib but insensitive to afatinib and neratinib. Conclusions: Several ERBB2 mutations showed varying sensitivities to ERBB2-targeted inhibitors. Our comprehensive assessment of ERBB2 mutations offers a fundamental database to help customize therapy for ERBB2-driven cancers.

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Oligosaccharyltransferase inhibition Reduces Receptor Tyrosine Kinase Activation and Enhances Glioma Radiosensitivity

Purpose: Parallel signaling reduces the effects of receptor tyrosine kinase (RTK) targeted therapies in glioma. We hypothesized that inhibition of protein N-linked glycosylation, an endoplasmic reticulum co- and post-translational modification crucial for RTK maturation and activation, could provide a new therapeutic approach for glioma radiosensitization. Experimental design: We investigated the effects of a small molecule inhibitor of the oligosaccharyltransferase (NGI-1) on EGFR family receptors, MET, PDGFR, and FGFR1. The influence of glycosylation state on tumor cell radiosensitivity, chemotherapy induced cell toxicity, DNA damage, and cell cycle arrest were determined and correlated with glioma cell receptor expression profiles. The effects of NGI-1 on xenograft tumor growth were tested using a nanoparticle formulation validated by in vivo molecular imaging. A mechanistic role for RTK signaling was evaluated through the expression of a glycosylation independent CD8-EGFR chimera. Results: NGI-1 reduced glycosylation, protein levels, and activation of most RTKs. NGI-1 also enhanced the radiosensitivity and cytotoxic effects of chemotherapy in those glioma cells with elevated ErbB family activation, but not in cells without high levels of RTK activation. NGI-1 radiosensitization was associated with increases in both DNA damage and G1 cell cycle arrest. Combined treatment of glioma xenografts with fractionated radiation and NGI-1 significantly reduced tumor growth compared to controls. Expression of the CD8-EGFR eliminated NGI-1's effects on G1 arrest, DNA damage, and cellular radiosensitivity, identifying RTK inhibition as the principal mechanism for the NGI-1 effect. Conclusion: This study suggests that OST inhibition with NGI-1 is a novel approach to radiosensitize malignant gliomas with enhanced RTK signaling.

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CD8+ T-cell density imaging with 64Cu-labeled cys-diabody informs immunotherapy protocols

Purpose: Noninvasive and quantitative tracking of CD8+ T-cells by positron emission tomography (PET) has emerged as a potential technique to gauge response to immunotherapy. We apply an anti-CD8 cys-diabody, labeled with 64Cu, to assess the sensitivity of PET imaging of normal and diseased tissue. Experimental Design Radiolabeling of an anti-CD8 cys-diabody (169cDb) with 64Cu was developed. The accumulation of 64Cu-169cDb was evaluated with PET/CT imaging (0, 5, and 24 hours) and biodistribution (24 hours) in wild-type mouse strains (n = 8 per group studied with imaging and immunohistochemistry or flow cytometry) after intravenous administration. Tumor-infiltrating CD8+ T-cells in tumor bearing mice treated with CpG and aPD-1 were quantified and mapped (n = 6-8 per group studied with imaging and immunohistochemistry or flow cytometry). Results We demonstrate the ability of immunoPET to detect small differences in CD8+ T-cell distribution between mouse strains and across lymphoid tissues, including the intestinal tract of normal mice. In FVB mice bearing a syngeneic HER2-driven model of mammary adenocarcinoma (NDL), 64Cu-169cDb PET imaging accurately visualized and quantified changes in tumor-infiltrating CD8+ T-cells in response to immunotherapy. A reduction in the circulation time of the imaging probe followed the development of treatment-related liver and splenic hypertrophy and provided an indication of off-target effects associated with immunotherapy protocols. Conclusion 64Cu-169cDb imaging can spatially map the distribution of CD8+ T-cells in normal organs and tumors. ImmunoPET imaging of tumor-infiltrating cytotoxic CD8+ T-cells detected changes in T-cell density resulting from adjuvant and checkpoint immunotherapy protocols in our pre-clinical evaluation.

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Dynamics of genome alterations in Crohn's disease associated colorectal carcinogenesis

Purpose: Patients with inflammatory bowel diseases, i.e., ulcerative colitis (UC) and Crohn's disease (CD), face an increased risk of developing colorectal cancer (CRC). Evidence, mainly from UC, suggests that TP53 mutations represent an initial step in the progression from inflamed colonic epithelium to CRC. However, the pathways involved in the evolution of CRC in CD patients are poorly characterized. Experimental Design: Here, we analyzed 73 tissue samples from 28 patients with CD-CRC, including precursor lesions, by targeted next generation sequencing of 563 cancer-related genes and array-based comparative genomic hybridization. The results were compared to 24 sporadic CRCs with similar histomorphology (i.e., mucinous adenocarcinomas), and to The Cancer Genome Atlas data. Results: CD-CRCs showed somatic copy number alterations (SCNAs) similar to sporadic CRCs with one notable exception: the gain of 5p was significantly more prevalent in CD-CRCs. CD-CRCs had a distinct mutation signature: TP53 (76% in CD-CRCs versus 33% in sporadic mucinous CRCs), KRAS (24% versus 50%), APC (17% versus 75%), and SMAD3 (3% versus 29%). TP53 mutations and SCNAs were early and frequent events in CD progression, while APC, KRAS and SMAD2/4 mutations occurred later. In four CD-CRC patients, at least one mutation and/or SCNAs were already present in non-dysplastic colonic mucosa, indicating occult tumor evolution. Conclusions: Molecular profiling of CD-CRCs and precursor lesions revealed an inflammation-associated landscape of genome alterations: 5p gains and TP53 mutations occurred early in tumor development. Detection of these aberrations in precursor lesions may help predicting disease progression and distinguishes CD-associated from sporadic colorectal neoplasia.

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A Combination Of Approved Antibodies Overcomes Resistance Of Lung Cancer To Osimertinib By Blocking Bypass Pathways

Purpose: Because of emergence of resistance to osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), no targeted treatments are available for patients with lung cancer who lose sensitivity due to new mutations or bypass mechanisms. We examined in animals and in vitro an alternative therapeutic approach making use of antibodies. Experimental Design: An osimertinib-sensitive animal model of lung cancer, which rapidly develops drug resistance, has been employed. To overcome compensatory hyper-activation of ERK, which we previously reported, an anti-EGFR antibody (cetuximab) was combined with other antibodies, as well as with a sub-therapeutic dose of osimertinib, and cancer cell apoptosis was assayed. Results: Our animal studies identified a combination of three clinically approved drugs, cetuximab, trastuzumab (an anti-HER2 mAb) and osimertinib (low dose), as an effective and long-lasting treatment, able to prevent onset of resistance to osimertinib. A continuous schedule of concurrent treatment was sufficient for effective tumor inhibition and for prevention of relapses. Studies employing cultured cells and analyses of tumor extracts indicated that the combination of two mAbs and a sub-therapeutic TKI dose sorted EGFR and HER2 for degradation, cooperatively enhanced apoptosis, inhibited activation of ERK, and reduced abundance of several bypass proteins, namely MET, AXL and HER3. Conclusions: Our in vitro assays and animal studies identified an effective combination of clinically approved drugs, which might overcome resistance to irreversible TKIs in clinical settings. The results we present attribute the long-lasting effect of the drug combination to simultaneous blockade of several well-characterized mechanisms of drug resistance.

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The anti-cancer activity of a first-in-class small molecule targeting PCNA

Purpose: Proliferating cell nuclear antigen (PCNA) plays an essential role in regulating DNA synthesis and repair and is indispensable to cancer cell growth and survival. We previously reported a novel cancer associated PCNA isoform (dubbed caPCNA), which was ubiquitously expressed in a broad range of cancer cells and tumor tissues, but not significantly in non-malignant cells. We found the L126-Y133 region of caPCNA is structurally altered and more accessible to protein-protein interaction. A cell permeable peptide harboring the L126-Y133 sequence blocked PCNA interaction in cancer cells and selectively kills cancer cells and xenograft tumors. Based on these findings, we sought small molecules targeting this peptide region as potential broad-spectrum anti-cancer agents. Experimental Design: By computer modeling and medicinal chemistry targeting a surface pocket partly delineated by the L126-Y133 region of PCNA, we identified a potent PCNA inhibitor (AOH1160) and characterized its therapeutic properties and potential toxicity. Results: AOH1160 selectively kills many types of cancer cells at below micromolar concentrations without causing significant toxicity to a broad range of non-malignant cells. Mechanistically, AOH1160 interferes with DNA replication, blocks homologous recombination-mediated DNA repair, and causes cell cycle arrest. It induces apoptosis in cancer cells and sensitizes them to cisplatin treatment. AOH1160 is orally available to animals and suppresses tumor growth in a dosage form compatible to clinical applications. Importantly, it doesn't cause significant toxicity at 2.5 times of an effective dose. Conclusion: These results demonstrated the favorable therapeutic properties and the potential of AOH1160 as a broad-spectrum therapeutic agent for cancer treatment.

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Inhibition of Rspo-Lgr4 facilitates checkpoint blockade therapy by switching macrophage polarization

Therapies targeting immune checkpoints have shown great clinical potential in a subset of cancer patients but may be hampered by a failiure to reverse the immunosuppressive tumor microenvironment (TME). As the most abundant immune cells in TME, tumor-associated macrophages (TAM) play non-redundant roles in restricting anti-tumor immunity. The leucine-rich repeat-containing G-protein-coupled receptor 4 (Lgr4, also known as Gpr48) has been associated with multiple physiological and pathological functions. Lgr4 and its ligands R-spondin 1-4 have been shown to promote the growth and metastasis of tumor cells. However, whether Lgr4 can promote tumor progression by regulating the function of immune cells in the tumor microenvironment remains largely unknown. Here we demonstrate that Lgr4 promotes macrophage M2 polarization through Rspo/Lgr4/Erk/Stat3 signaling. Notably, urethane-induced lung carcinogenesis, Lewis Lung carcinoma (LLC,) and B16F10 melanoma tumors were all markedly reduced in Lgr4fl/flLyz2cre/+ mice, characterized by fewer protumoral M2 TAM and increased CD8+ T lymphocyte infiltration in the TME. Furthermore, LLC tumor growth was greatly depressed when Rspo/Lgr4/Erk/Stat3 signaling was blocked with either the LGR4 extracellular domain or an anti-Rspo1 antibody. Importantly, blocking Rspo-Lgr4 signaling overcame LLC resistance to anti-PD-1 therapy and improved the efficacy of PD-1 immunotherapy against B16F10 melanoma, indicating vital roles of Rspo-Lgr4 in host anti-tumor immunity and a potential therapeutic target in cancer immunotherapy.

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High-throughput screening of combinatorial immunotherapies with patient-specific in silico models of metastatic colorectal cancer

Solid tumors are rich ecosystems of numerous different cell types whose interactions lead to immune escape and resistance to immunotherapy in virtually all patients with metastatic cancer. Here we have developed a 3D model of human solid tumor tissue that includes tumor cells, fibroblasts, and myeloid and lymphoid immune cells and can represent over a million cells over clinically relevant timeframes. This model accurately reproduced key features of the tissue architecture of human colorectal cancer (CRC) and could be informed by individual patient data, yielding in silico tumor explants. Stratification of growth kinetics of these explants corresponded to significantly different overall survival in a cohort of metastatic CRC patients. We used the model to simulate the effect of chemotherapy, immunotherapies, and cell migration inhibitors alone and in combination. We classified tumors according to tumor and host characteristics, showing that optimal treatment strategies markedly differed between these classes. This platform can complement other patient-specific ex vivo models and can be used for high-throughput screening of combinatorial immunotherapies.

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CTGF mediates tumor-stroma interactions between hepatoma cells and hepatic stellate cells to accelerate HCC progression.

Connective tissue growth factor (CTGF) is a matricellular protein related to hepatic fibrosis. This study aims to clarify the roles of CTGF in hepatocellular carcinoma (HCC), which usually develops from fibrotic liver. CTGF was overexpressed in 93 human HCC compared with non-tumorous tissues, primarily in tumor cells. Increased CTGF expression was associated with clinicopathological malignancy of HCC. CTGF was upregulated in hepatoma cells in hepatocyte-specific Kras-mutated mice (Alb-Cre KrasLSL-G12D/+). Hepatocyte-specific knockout of CTGF in these mice (Alb-Cre KrasLSL-G12D/+ CTGFfl/fl) decreased liver tumor number and size. Hepatic stellate cells (HSC) were present in both human and murine liver tumors, and α-SMA expression, a marker of HSC activation, positively correlated with CTGF expression. Forced expression of CTGF did not affect growth of PLC/PRF/5 cells, a hepatoma cell line with little CTGF expression, but facilitated their growth in the presence of LX-2 cells, a hepatic stellate cell line. The growth of HepG2 cells, which express high levels of CTGF, was promoted by co-culture with LX-2 cells compared with monoculture. Growth promotion by LX-2 cells was negated by an anti-CTGF antibody in both culture and xenografts. Co-culturing LX-2 cells with HepG2 cells drove LX-2-derived production of IL-6, which led to STAT-3 activation and proliferation of HepG2 cells. An anti-CTGF antibody reduced IL-6 production in LX-2 cells and suppressed STAT-3 activation in HepG2 cells. In conclusion, our data identify tumor cell-derived CTGF as a keystone in the HCC microenvironment, activating nearby HSC which transmit pro-growth signals to HCC cells, this interaction is susceptible to inhibition by an anti-CTGF antibody.

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CircNT5E acts as a sponge of microRNA-422a to promote glioblastoma tumorigenesis

Circular RNA and long noncoding RNA function as efficient microRNA sponges that regulate gene expression in eukaryotes. However, the sponges of functional miRNAs in glioblastoma remain largely unknown. Here we identify a subset of circRNAs and lncRNAs that are specifically increased in miR-422a-downregulated glioblastoma tissues. We characterized a novel circRNA derived from NT5E, named circNT5E, that is regulated by ADARB2 binding to sites flanking circRNA-forming introns. We hypothesized that circNT5E may serve as a sponge against miR-422a in glioblastoma tumorigenesis. circNT5E controlled multiple pathological processes, including cell proliferation, migration, and invasion. CircNT5E directly bound miR-422a and inhibited miR-422a activity. Furthermore, circNT5E was observed to sponge other miRNAs, exhibiting tumor suppressor-like features in glioblastoma. Taken together, these findings highlight a novel oncogenic function of circRNA in glioblastoma tumorigenesis.

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CRISPR/Cas9-mediated knockout of DGK improves anti-tumor activities of human T cells

The efficacy of T cell therapy is inhibited by various tumor-associated immunosuppressive ligands and soluble factors. Such inhibitory signals turn specific T cell signaling pathways on or off, impeding the anti-cancer functions of T cells. Many studies have focused on PD-1 or CTLA-4 blockade to invigorate T cell functions through CD28/B7 signaling, but obtaining robust clinical outcomes remains challenging. In this study, we use CRISPR/Cas9 to potentiate T cell function by increasing CD3 signaling via knockout of diacylglycerol kinase (DGK), an enzyme that metabolizes diacylglycerol to phosphatidic acid (PA). Knockout of DGK augmented the effector functions of CAR-T cells in vitro via increased TCR signaling. DGK knockout from CAR-T cells rendered them resistant to soluble immunosuppressive factors such as TGF-β and prostaglandin E2 and sustained effector functions under conditions of repeated tumor stimulation. Moreover, DGK knockout caused significant regression of U87MGvIII glioblastoma tumors through enhanced effector functions in a xenograft mouse model. Collectively, our study shows that knockout of DGK effectively enhances the effector functions of CAR-T cells, suggesting that CRISPR/Cas9-mediated knockout of DGK could be applicable as part of a multifaceted clinical strategy to treat solid cancers.

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Combined blockade of IL-6 and PD-1/PD-L1 signaling abrogates mutual regulation of their immunosuppressive effects in the tumor microenvironment

Recently emerging cancer immunotherapies combine the applications of therapeutics to disrupt the immunosuppressive conditions in tumor-bearing hosts. In this study, we found that targeting the pro-inflammatory cytokine interleukin (IL)-6 enhances tumor-specific Th1 responses and subsequent anti-tumor effects in tumor-bearing mice. IL-6 blockade upregulated expression of the immune checkpoint molecule programmed death-ligand 1 (PD-L1) on melanoma cells. This PD-L1 induction was canceled in IFN-gamma-deficient mice or CD4+ T cell-depleted mice, suggesting that CD4+ T cell-derived IFN-gamma is important for PD-L1 induction in tumor-bearing hosts. In some patients with melanoma, however, treatment with the anti-PD-1 antibody Nivolumab increased systemic levels of IL-6, which was associated with poor clinical responses. This PD-L1 blockade-evoked induction of IL-6 was reproducible in melanoma-bearing mice. We found that PD-1/PD-L1 blockade prompted PD-1+ macrophages to produce IL-6 in the tumor microenvironment. Depletion of macrophages in melanoma-bearing mice reduced the levels of IL-6 during PD-L1 blockade, suggesting macrophages are responsible for the defective CD4+ Th1 response. Combined blockade of the mutually regulated immunosuppressive activities of IL-6 and PD-1/PD-L1 signals enhanced expression of T cell-attracting chemokines and promoted infiltration of IFN-gamma-producing CD4+ T cells in tumor tissues, exerting a synergistic anti-tumor effect, while PD-L1 blockade alone did not promote Th1 response. Collectively, these findings suggest that IL-6 is a rational immunosuppressive target for overcoming the narrow therapeutic window of anti-PD-1/PD-L1 therapy.

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Microenvironmental Cues Determine Tumor Cell Susceptibility to Neutrophil Cytotoxicity

We have recently shown that neutrophil anti-tumor cytotoxicity is Ca2+-dependent and is mediated by TRPM2, an H2O2-dependent Ca2+ channel. However, neutrophil anti-tumor activity is dependent on context and is manifested in the premetastatic niche, but not at the primary site. We therefore hypothesized that expression of TRPM2 and the consequent susceptibility to neutrophil cytotoxicity may be associated with the epithelial/mesenchymal cellular state. We found that TRPM2 expression was upregulated during epithelial-to-mesenchymal transition (EMT), and mesenchymal cells were more susceptible to neutrophil cytotoxicity. Conversely, cells undergoing mesenchymal-to-epithelial transition (MET) expressed reduced levels of TRPM2, rendering them resistant to neutrophil cytotoxicity. Cells expressing reduced levels of TRPM2 were protected from neutrophil cytotoxicity and seeded more efficiently in the premetastatic lung. These data identify TRPM2 as the link between environmental cues at the primary tumor site, tumor cell susceptibility to neutrophil cytotoxicity, and disease progression. Furthermore, these data identify EMT as a process enhancing tumor-cell immune susceptibility and, by contrast, MET as a novel mode of immune evasion.

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Determination of Tumor Margins with Surgical Specimen Mapping Using Near-Infrared Fluorescence

For many solid tumors, surgical resection remains the gold standard and tumor-involved margins are associated with poor clinical outcomes. Near-infrared (NIR) fluorescence imaging using molecular agents has shown promise for in situ imaging during resection. However, for cancers with difficult imaging conditions, surgical value may lie in tumor-mapping of surgical specimens. We thus evaluated a novel approach for real-time, intraoperative tumor margin assessment. 21 adult patients with biopsy-confirmed squamous cell carcinoma arising from the head and neck (HNSCC) scheduled for standard-of-care surgery were enrolled. Cohort 1 (n=3) received panitumumab-IRDye800CW at an intravenous microdose of 0.06 mg/kg, cohort 2A (n=5) received 0.5mg/kg, cohort 2B (n=7) received 1mg/kg, and cohort 3 (n=6) received 50 mg. Patients were followed 30 days post-infusion and adverse events were recorded. Imaging was performed using several closed- and wide-field devices. Fluorescence was histologically correlated to determine sensitivity and specificity. In situ imaging demonstrated tumor-to-background ratio (TBR) of 2-3, compared to ex vivo specimen imaging TBR of 5-6. We obtained clear differentiation between tumor and normal tissue, with a three-fold signal difference between positive and negative specimens (p<0.05). We achieved high correlation of fluorescence intensity with tumor location with sensitivities and specificities >89%; fluorescence predicted distance of tumor tissue to the cut surface of the specimen. This novel method of detecting tumor-involved margins in surgical specimens using a cancer-specific agent provides highly sensitive and specific, real-time, intraoperative surgical navigation in resections with complex anatomy which are otherwise less amenable to image guidance.

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PDSS2 deficiency induces hepatocarcinogenesis by decreasing mitochondrial respiration and reprogramming glucose metabolism

Glucose metabolic reprogramming from oxidative phosphorylation to glycolysis is one of the hallmarks of cancer development. Coenzyme Q10 (CoQ10) is essential for electron transport in the mitochondrial respiratory chain and antioxidant defense. Here we investigated the role of a key factor in CoQ10 synthesis, prenyldiphosphate synthase subunit 2 (PDSS2), in hepatocellular carcinoma (HCC) tumorigenesis. PDSS2 was frequently downregulated in HCC tissues and was significantly associated with poorer HCC prognosis (P=0.027). PDSS2 downregulation was an independent prognostic factor independent of T status and staging (P=0.028). Downregulation of CoQ10 significantly correlated with downregulation of PDSS2 in HCC tumor tissues (R=0.414, P<0.001). Six different splicing isoforms of PDSS2 and five variants, except full-length PDSS2, showed loss of function in HCC. Reintroduction of full-length PDSS2 into HCC cells increased CoQ10 and mitochondrial electron transport complex I activity and subsequently induced a metabolic shift from aerobic glycolysis to mitochondrial respiration in cells. Reintroduction of PDSS2 also inhibited foci formation, colony formation in soft agar, and tumor formation in nude mice. Knockdown of PDSS2 induced chromosomal instability in the immortalized human liver cell line MIHA. Furthermore, knockdown of PDSS2 in MIHA induced malignant transformation. Overall, our findings indicate that PDSS2 deficiency might be a novel driving factor in HCC development.

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Expression of long non-coding RNA YIYA promotes glycolysis in breast cancer

Long non-coding RNA (lncRNA) have yet to be linked to cancer metabolism. Here we report that upregulation of the lncRNA LINC00538 (YIYA) promotes glycolysis, cell proliferation and tumor growth in in breast cancer. YIYA associated with the cytosolic cyclin-dependent kinase CDK6 and regulated CDK6-dependent phosphorylation of the fructose bisphosphatase PFK2 (PFKFB3) in a cell cycle-independent manner. In breast cancer cells, these events promoted catalysis of glucose 6-phosphate to fructose-2,6-bisphosphate/fructose-1,6-bisphosphate. CRISPR/Cas9-mediated deletion of YIYA or CDK6 silencing impaired glycolysis and tumor growth in vivo. In clinical specimens of breast cancer, YIYA was expressed in ~40% of cases where it correlated with CDK6 expression and unfavorable survival outcomes. Our results define a functional role for lncRNA in metabolic reprogramming in cancer, with potential clinical implications for its therapeutic targeting.

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Four Japanese Patients with Congenital Nephrogenic Diabetes Insipidus due to the AVPR2 Mutations

Almost 90% of nephrogenic diabetes insipidus (NDI) is caused by mutations in the arginine vasopressin receptor 2 gene (AVPR2) on the X chromosome. Herein, we reported clinical and biochemical parameters in four cases of three unrelated Japanese families and analyzed the status of the AVPR2. Two of the four patients had poor weight gain. However, in the male and female sibling cases, neither had poor weight gain while toddlers, but in the male sibling, episodes of recurrent fever, polyuria, and polydipsia led to the diagnosis of NDI at 4 years of age. Analysis of AVPR2 identified two nonsense mutations (c.299_300insA; p.K100KfsX91 and c.296G > A; p.W99X) and one missense mutation (c.316C > T; p.R106C). These mutations were previously reported. The patient with c.316C > T; p.R106C had milder symptoms consistent with previous reports. Of the familial cases, the sister was diagnosed as having NDI, but a skewed X-inactivation pattern in her peripheral blood lymphocytes was not identified. In conclusion, our study expands the spectrum of phenotypes and characterized mutations in AVPR2 in NDI.

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Within patients receiving chemotherapy for breast cancer, its receipt in the neoadjuvant setting has been increasing among all biologic subtypes. The highest use of NAC is in TNBC and HER2+ disease, with use in these subgroups being twice as frequent as in HR+/HER2− disease.

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Use of ADM reduced myofibroblasts, vascularity, fibroblasts, and EndoMT in capsule tissues. Moreover, ADM use decreased macrophages, a key regulator of tissue fibrosis, as well as TGF-β1 and PDGF-B expression. We hope that these results provide basic concepts important for prevention of capsular contracture.

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Minimally Invasive Surgery for Retroperitoneal Sarcoma: Just Because We Can Does Not Mean We Should

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Metastatic Melanoma to the Colon, Rectum, and Anus: A 50-Year Experience

Abstract

Strategic Delay: Histology- and Biology-Driven Decision-Making in Recurrent Retroperitoneal Sarcoma

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Evaluation of the Relationship Between Flap Tension and Tissue Perfusion in Implant-Based Breast Reconstruction Using Laser-Assisted Indocyanine Green Angiography

Abstract

Background

For implant-based breast reconstruction, inadequate tissue perfusion may cause devastating complications. Tissue tension by inadequate implant volume may reduce tissue perfusion by stretching and collapsing the capillaries. The SPY system is used to perform intraoperative fluorescence angiography with indocyanine green to assess visually the blood flow and evaluate tissue perfusion. However, there is no report yet about how mastectomy flap perfusion changes with the expander-filling volume. Therefore, to analyse the changes of tissue perfusion of the mastectomy flap according to the tension level, we used the SPY system and adjusted the filling volume of the tissue expander to change the tension on the skin flap.

Methods

Ten breasts of ten patients who underwent immediate two-stage, implant-based breast reconstructions were included. The expander-filling volume just before mastectomy flap blanching was set as 100%. Based on this, the expander-filling volume was reduced to 50% and increased to 150%. Ingress and egress rates were evaluated using the SPY system at each condition and analysed by a linear mixed model using least square means.

Results

The mean ingression rates were 138, 100, and 65%, and the mean egression rates were 145, 100, and 66% at 50, 100, and 150% inflation, respectively.

Conclusions

It was objectively proven that tissue perfusion deteriorates as the tension applied on the flap increases. On the basis of this finding, we can control the amount of inflation volume of the expander or remove the skin in the pre-ischaemic condition to reduce complications of implant-based breast reconstruction.

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Walking the Fine Line of Axillary Management in Mastectomy Patients

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Techniques for Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy

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Unusual case of primary spontaneous hemopneumothorax in a young man with atypical tension pneumothorax: a case report

Spontaneous life-threatening hemopneumothorax is an atypical but treatable entity of unexpected circulatory collapse in young patients, affecting 0.5–11.6% of patients with primary spontaneous pneumothorax. Sp...

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Chimeric Antigen Receptor Therapy

The aim of cancer immunotherapy is to enhance the immune response against tumor cells. The emergence of immuno-oncology as the first broadly successful strategy to treat metastatic cancer will require clinicians to integrate this new type of medicine with chemotherapy, surgery, radiation therapy,…

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Chimeric Antigen Receptor Therapy

Clinical outcomes of brain metastases from hepatocellular carcinoma: a multicenter retrospective study and a literature review

Abstract

Introduction

The introduction of systemic chemotherapy for advanced hepatocellular carcinoma in recent years has led to the prediction that cases of brain metastases from hepatocellular carcinoma will increase. However, because brain metastases from hepatocellular carcinoma are relatively rare, the characteristics of this pathology are poorly understood.

Methods

We carried out a multicenter retrospective study to verify the characteristics of brain metastases from hepatocellular carcinoma in Japan.

Results

A total of 38 patients were enrolled and patient characteristics were poor general condition in many patients due to the progression of primary cancers. Stereotactic radiosurgery/stereotactic radiotherapy alone was the most common treatment (39.5%), with best supportive care provided for 10.5%. Median survival was 6 months, the neurological death rate was 28%, and the rate of brain hemorrhage was high (39.5%). Overall survival was analyzed for correlations with age, etiology of chronic liver disease, albumin–bilirubin (ALBI) grade, RPA classification, control of the primary tumor, number of brain metastases, brain hemorrhage, surgical resection, and radiotherapy. In multivariate analysis, ALBI grade, number of brain metastases and brain hemorrhage showed statistically significant correlation.

Conclusions

A multivariate analysis extracted three items—ALBI grade, number of brain metastases, and brain hemorrhage—as prognostic factors for survival of brain metastases from hepatocellular carcinoma.

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Einsatz alternativer Behandlungsmethoden bei Krebserkrankungen und Auswirkungen auf das Überleben

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Radiobiological considerations in combining doses from external beam radiotherapy and brachytherapy for cervical cancer

Publication date: Available online 2 July 2018
Source:Reports of Practical Oncology & Radiotherapy
Author(s): Ana M. Tornero-López, Damián Guirado
The recommended radio-therapeutic treatment for cervix cancer consists of a first phase of external beam radiotherapy (EBRT) plus a second phase of brachytherapy (BT), the combined treatment being delivered within 8 weeks.In order to assess a comprehensive dosimetry of the whole treatment, it is necessary to take into account that these two phases are characterized by different spatial and temporal dosimetric distributions, which complicates the task of the summation of the two contributions, EBRT and BT. Radiobiology allows to tackle this issue pragmatically by means of the LQ model and, in fact, this is the usual tool currently in use for this matter.In this work, we describe the rationale behind the summation of the dosimetric contributions of the two phases of the treatment, EBRT and BT, for cervix cancer, as carried out with the LQ model.Besides, we address, from a radiobiological point of view, several important considerations regarding the use of the LQ model for this task. One of them is the analysis of the effect of the overall treatment time in the result of the global treatment. Another important question considered is related to the fact that the capacity of LQ to predict the treatment outcomes is deteriorated when the dose per fraction of the radiotherapic scheme exceeds 6–10Gy, which is a typical brachytherapy fractionation. Finally, we analyze the influence of the uncertainty and the variability of the main parameters utilized in the LQ model formulation in the assessment of the global dosimetry.

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Nab-paclitaxel in combination with gemcitabine for the treatment of metastatic pancreas cancer: the South Wales experience

Abstract

The prognosis of pancreatic cancer remains very poor, with a 5-year survival rate of around 3%. There has been little impact from various chemotherapy regimens on improving outcome for several decades. Gemcitabine has been the mainstay chemotherapy for around two decades with little improvement in overall survival (OS) for patients with advanced disease. However, more recently, there has been a paradigm shift in treatment options for these patients. Reported in 2011, combination therapy with FOLFIRINOX (oxaliplatin, irinotecan, leucovorin, and fluorouracil) showed a long awaited but modest improvement in survival, but is reserved only for a small proportion of very fit patients due to concerns over its toxicities. In 2013, the landmark phase III international study MPACT demonstrated an improvement in OS with the combination of nab-paclitaxel and gemcitabine (GEMBRAX) for the treatment of patients more akin to the real-world population. In the United Kingdom (UK), it was first made widely available on the National Health Service (NHS) in Wales in September 2014 and only recently received a final positive appraisal by NICE (National Institute of Clinical Excellence) for England in 2017. In this paper, we present our data on the use of this treatment for patients in South Wales and compare real-life practical experience with the MPACT data and reflecting the impact of this paradigm shift.

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Clinical features, treatments and long-term follow-up outcomes of spinal chondroblastoma: report of 13 clinical cases in a single center

Abstract

Purpose

Chondroblastoma (CB) in the spine is extremely rare and there is little published information regarding this subject. We attempt to explore the clinical features of spinal CB and address the importance of total resection, especially total en bloc spondylectomy (TES) for the treatment of spinal CB.

Methods

Clinical data of 13 consecutive CB patients who received surgical treatment in our center between January 2006 and December 2016 were reviewed retrospectively. Recurrence-free survival (RFS) was estimated by Kaplan–Meier method and Log-rank test.

Results

The 13 CB patients included 9 men and 4 women with a mean age of 32 years. The lesions were located in the cervical spine in 2 cases, thoracic spine in 5 cases, and lumbar spine in 6 cases. All the patients were treated surgically using either curettage, piecemeal total resection, or TES. Postoperative radiotherapy was administered in 2 cases. The mean follow-up period was 41.6 months. Relapse occurred in 3 (23.1%) cases, resulting in one death in 60 months. The mean RFS duration was 28.7 months.

Conclusions

CB predominantly affects males and various age groups. Spinal CB more commonly involves the thoracic and lumbar segments. Spinal CB usually appears as an aggressive and destructive bony lesion with a soft tissue mass on imaging, forming compression on the spinal cord in some cases. Recurrence is not uncommon for spinal CB. Total resection, especially TES, has been confirmed as a powerful method to control the disease, while curettage is more likely to associate with local recurrence. Radiotherapy does not seem to reduce local recurrence.

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Risk of Different Cancers Among First-degree Relatives of Pancreatic Cancer Patients: Influence of Probands’ Susceptibility Gene Mutation Status

Abstract

Background

Increased risk of malignancies other than pancreatic cancer (PC) has been reported among first-degree relatives (FDRs) of PC patients; however, the roles of susceptibility gene mutations are unclear. We assessed risk for 15 cancers among FDRs of unselected PC probands.

Methods

Data on 17 162 FDRs, with more than 336 000 person-years at risk, identified through 2305 sequential PC probands enrolled at Mayo Clinic (2000–2016) were analyzed. Family history data were provided by the probands. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated, comparing malignancies observed among the FDRs with that expected using Surveillance, Epidemiology, and End Results (SEER) data. Genetic testing was performed among a subset of probands (n = 2094), enabling stratified analyses among FDRs based on whether the related proband tested positive or negative for inherited mutation in 22 sequenced cancer susceptibility genes. All statistical tests were two-sided.

Results

Compared with SEER, PC risk was twofold higher among FDRs of PC probands (SIR = 2.04, 95% CI = 1.78 to 2.31, P < .001). Primary liver cancer risk was elevated among female FDRs (SIR = 2.10, 95% CI = 1.34 to 3.12, P < .001). PC risk was more elevated among FDRs of mutation-positive probands (SIR = 4.32, 95% CI = 3.10 to 5.86) than FDRs of mutation-negative probands (SIR = 1.77, 95% CI = 1.51 to 2.05, between-group P < .001). FDR PC risk was higher when the related proband was younger than age 60 years at diagnosis and mutation-positive (SIR = 5.24, 95% CI = 2.93 to 8.64) than when the proband was younger than age 60 years but mutation-negative (SIR = 1.76, 95% CI = 1.21 to 2.47, between-group P < .001). Breast (SIR = 1.29, 95% CI = 1.01 to 1.63) and ovarian (SIR = 2.38, 95% CI = 1.30 to 4.00) cancers were elevated among FDRs of mutation-positive probands.

Conclusions

Our study substantiates twofold risk of PC among FDRs of PC patients and suggests increased risk for primary liver cancer among female FDRs. FDRs of susceptibility mutation carriers had substantially increased risk for PC and increased risk for breast and ovarian cancers.

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BCL2 expression is associated with a poor prognosis independent of cellular origin in primary central nervous system diffuse large B-cell lymphoma

Abstract

Purpose

Primary central nervous system diffuse large B-cell lymphoma (CNS-DLBCL) is a distinct clinicopathological entity with a poor prognosis. Concurrent MYC and BCL2 overexpression predicts inferior prognosis in systemic DLBCL, although their prognostic significance remains unclear in primary CNS-DLBCL.

Methods

Pretreatment diagnostic biopsy samples were retrospectively evaluated for 79 patients with primary CNS-DLBCL who were treated between January 2001 and December 2017. Histological and immunohistochemical testing were performed to evaluate the patients' statuses for various markers, which were also evaluated for associations with survival outcomes.

Results

According to the Hans criteria, 26 patients (32.9%) had the germinal center B-cell subtype and 53 patients (67.1%) had the activated B-cell subtype. Forty-one cases (51.9%) were positive for MYC (expression of ≥ 40%), 33 cases (41.8%) were positive for BCL2 (expression of ≥ 70%), 22 patients (27.8%) were positive for both MYC and BCL2, and 27 patients (34.2%) were negative for both MYC and BCL2. There were no significant differences in survival between the germinal center and activated B-cell subtypes. Furthermore, MYC positivity was not associated with overall survival (p = 0.369) or progression-free survival (PFS) (p = 0.253). However, BCL2 positivity was significantly associated with poor overall survival (p = 0.039) and PFS (p = 0.036). Co-expression of MYC and BCL2 was not associated with survival.

Conclusion

Our data suggest that evaluating BCL2 expression may help predict the prognosis in cases of primary CNS-DLBCL.

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Peripheral monocytes and neutrophils predict response to immune checkpoint inhibitors in patients with metastatic non-small cell lung cancer

Abstract

We carried out a retrospective cohort study on patients with metastatic non-small cell lung cancer (mNSCLC) to identify the peripheral blood count parameters associated with response to immune checkpoint inhibitors (ICIs). There were 17 males and 15 females. Their median age was 64.5 years (range 20–84). History of smoking was present in 25/32 (78%) patients. Twelve patients received pembrolizumab, 19 patients nivolumab, and one patient nivolumab followed by pembrolizumab. Responses were observed in 19/32 (59%) patients, all partial responses. There was no difference in the distribution of sex, age, and smoking status between responders and non-responders. The median time to response (TTR) was 12 weeks (range 6–24) and the median duration of response (DoR) was 24 weeks (range 7–112). Higher pre-therapy absolute monocyte counts (AMCs) correlated to shorter TTR (p = 0.03), but not to response rate or DoR. Within the group of responders, those with AMCs > 700/mm³ had a significantly shorter median TTR than those with AMCs ≤ 700/mm³ (8 weeks vs 12 weeks; p = 0.048). Although baseline absolute neutrophil counts (ANCs) did not have any prognostic value, ANCs after first dose predicted response to ICI (p = 0.02). Patients with ANCs ≤ 4200/mm³ after first dose were more likely to respond than those with ANCs > 4200/mm³ (OR = 6.8; 95% CI 1.1–41.8; p = 0.05). Analysis of AMC and ANC before and during therapy may, therefore, provide an easy method to identify those mNSCLC patients most likely to benefit from ICI therapy.

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Stereotactic Body Radiation Therapy (SBRT) for Early-stage Lung Cancer in the Elderly

Publication date: Available online 1 July 2018
Source:Seminars in Oncology
Author(s): Ashwin Shinde, Richard Li, Jae Kim, Ravi Salgia, Arti Hurria, Arya Amini
Early-stage non-small cell lung cancer (NSCLC) is on the rise due to the implementation of screening guidelines for patients at risk for developing lung cancer. It is anticipated that as the United States population continues to age, there will be a higher percentage of medically inoperable early-stage lung cancer patients. For this reason, non-invasive ablative therapies are necessary. Stereotactic body radiation therapy (SBRT) is an effective modality in addressing early-stage NSCLC. SBRT consists of high-dose radiation delivered over three to five treatments. Several randomized trials comparing surgery to SBRT in early-stage operable patients have unfortunately closed early due to poor accrual. However, a recent pooled analysis from two randomized trials (STARS and ROSEL) comparing surgery to SBRT did show comparable local control and overall survival rates between surgery and SBRT, offering a very effective, non-invasive modality for older adult patients with early-stage NSCLC. In this review, we summarize the role of SBRT in early-stage NSCLC, in particularly applying it to the older adult population.

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Oncocytoma managed by active surveillance in a transplant allograft kidney: a case report

Abstract

Background

The ethical implications of the utilization of kidneys with solid renal masses (SRMs) in transplantation are the subject of lively debate in the transplantation community and beyond. One of such implications is that as the life expectancy of renal transplant patients improve, the prevalence of SRMs in donors is likely to increase. We report a case of an oncocytoma in a renal allograft complicating a deceased-donor kidney transplant.

Case presentation

A 60-year-old woman received and underwent deceased-donor renal transplantation for end-stage renal disease after a waiting-list period of 11 years. Kidney Doppler ultrasound (DUS) of the deceased donor was negative for any nodular lesion. The finding of the DUS, done on postoperative day 1, to assess the patency of the graft, was suspicious for an acute arterial thrombosis but did not reveal any focal irregularities. An ensuing computed tomography (CT) scan did not show any arterial complications but serendipitously revealed a 2.4-cm lesion on the upper pole of the renal allograft, which was not detected during the back-table or ultrasonography monitoring. Histology of the biopsied lesion was consistent with oncocytoma. However, because the eosinophilic variant of chromophobe renal cell carcinoma may morphologically resemble renal oncocytoma, immunohistochemical staining was performed. The results were negative, ruling out chromophobe RCC. After discussing the therapeutic options and potential related outcomes with the patient, we found no reason for resection of the lesion or an allograft nephrectomy, given the low risk of malignant transformation in an oncocytoma. Active surveillance of the benign tumor was done with ultrasonography, every 2 months, for the first year and, then, with magnetic resonance imaging, every year. The patient received mycophenolate-mofetil, tacrolimus, and prednisone throughout the 5-year follow-up period, and the regimen for immunosuppression was not changed despite the presence of the renal mass. After 60 months, we report that none of the radiological findings have shown any morphological changes of the lesion, and the patient is well.

Conclusion

To the best of our knowledge, we report the first case of an oncocytoma in a renal allograft complicating a deceased-donor kidney transplant, which was successfully managed by active surveillance.

https://ift.tt/2KrpPJp

A TCP-based early regression index predicts the pathological response in neo-adjuvant radio-chemotherapy of rectal cancer

Introducing a radiobiological index based on early tumor regression during neo-adjuvant radio-chemotherapy (RCT, including oxaliplatin) of rectal adenocarcinoma and testing its discriminative power in predicting the tumor response.

https://ift.tt/2tNKUn3

UV scintillating particles as radiosensitizer enhance cell killing after X-ray excitation

Radiation therapy is the gold standard treatment for inoperable malignant tumors. However, due to the heterogeneity of the tumor, some regions are more radio resistant and can lead to metastasis and tumor recurrence. In this study, we propose combining traditional X-ray treatment with UVC-emitting LuPO4:Pr3+ nanoparticles (NPs) to increase the tumor control as well as to reduce tumor recurrence and metastasis. These NPs convert ionizing radiation into UVC-photons (UVC range: 200–280 nm) locally at the tumor site.

https://ift.tt/2IJ9YQT

Fully automated, multi-criterial planning for Volumetric Modulated Arc Therapy – An international multi-center validation for prostate cancer

Reported plan quality improvements with autoplanning of radiotherapy of the prostate and seminal vesicles are poor. A system for automated multi-criterial planning has been validated for this treatment in a large international multi-center study. The system is configured with training plans using a mechanism that strives for quality improvements relative to those plans.

https://ift.tt/2lMwSh5

Prognostic analysis of stage III gastric cancer after curative surgery according to the newest TNM classification

Abstract

Aim

To study the prognostic factors of gastric cancer (GC) patients who were classified with stage III disease according to the newest TNM classification.

Methods

This study retrospectively enrolled 279 patients who underwent radical gastrectomy from January 2012 to December 2014 at our hospital and who were diagnosed with stage III GC according to the new 8th edition of the TNM classification. The patient data that were collected included age, sex, pathological parameters, survival, lymph node ratio, neo-adjuvant chemotherapy with oxaliplatin and S-1, and operation type. The characteristics, survival, and prognostic factors of the patients were analyzed by univariate and multivariate analyses.

Results

The median OS of the patients after curative surgery was 19 months, and the 3-year survival rate (3-YSR) was 25.3%. A univariate analysis showed that tumor location (P = 0.01), neo-adjuvant chemotherapy (P = 0.005), pathological T stage (P = 0.002), pathological N stage (P < 0.001), lymph node ratio (LNR) (P < 0.001), and operation type (P = 0.032) were significantly associated with overall survival. A multivariate analysis revealed that neo-adjuvant chemotherapy (P = 0.009), pathological T stage (P = 0.012), and LNR (P < 0.001) were independent prognostic factors.

Conclusions

Neo-adjuvant chemotherapy, pathological T stage, and LNR were independent prognostic factors for the overall survival of patients with stage III GC. The neo-adjuvant chemotherapy with oxaliplatin and S-1 can be used for the patients to improve their survival.

https://ift.tt/2KFvjQ3

mTOR-mediated glycolysis contributes to the enhanced suppressive function of murine tumor-infiltrating monocytic myeloid-derived suppressor cells

Abstract

Immune cell activation occurs concurrently with metabolic reprogramming. As important components of the tumor microenvironment, monocytic myeloid-derived suppressor cells (M-MDSCs) are featured by their potent immunosuppressive abilities on anti-tumor effector cells. However, little is known about the contribution of metabolic adaptations to their suppressive roles. In this study, we found that tumor-infiltrating M-MDSCs had the same phenotype with splenic M-MDSCs. Compared with splenic M-MDSCs, tumor-infiltrating M-MDSCs exhibited stronger suppressive activities which was accompanied by higher glycolysis. Inhibition of glycolysis impaired the suppressive function of tumor M-MDSCs. Meanwhile, the results demonstrated that mTOR was responsible for this function regulation. mTOR inhibition by rapamycin decreased the glycolysis and reduced the suppressive activities of these cells. Furthermore, rapamycin treatment inhibited the tumor growth and reduced the percentage of M-MDSCs in 3LL tumor bearing mice. These results demonstrated that modulation of metabolism in immune cells can be an effective way to enhance anti-tumor effects.

https://ift.tt/2KCyzIQ

Colorectal neoplasia differentially expressed: a long noncoding RNA with an imperative role in cancer

https://ift.tt/2MImySv

Making a Difference by Addressing Social Determinants of Health

"Social Determinants of Health (SDH) are the conditions in which people are born, grow, work, live, and age, and the waiter set of forces and systems shaping the conditions of daily life. These forces and systems include economic policies and systems, development agendas, Social norms, social policies and political systems."¹

SDH have a profound impact on our patients. "[T]hey are violent because they cause injury to people…. [C]linicians are not trained to understand such social forces, nor are we trained to alter them. Yet it has long been clear that many medical and public health interventions will fail if we are unable to understand the social determinants of disease."² These determinants can be addressed at many different levels, helpfully classified as upstream, midstream, and downstream (Figure 1). Downstream determinants after temporally and spatially close to health efffects, upstream determinants are fundamental causes that set in motion causal pathways leading to health effects.³

In the case, "Childhood obesity in Mexico: social determinants of health and other risk factors" by Rodriguez et al, the most obvious aspects are the downstream effects of social determinants of health. A child is diagnosed with gastro-oesophageal reflux (GORD) and obesity. The downstream social determinants are the obvious presentation, and the first priority of the treating clinician. In this case, that can be seen with the lifestyle modifications recommended including changes in diet, exercise and sleeping habits and pharmacological treatment. As noted, these interventions were not very effective, and "The aim of this case report is to demonstrate how childhood obesity is rooted since pregnancy… and how the social determinants of health, like unsafe outdoor conditions, lack of infrastructure to exercise and suboptimal physical activity curriculum in government schools strongly influence the development and maintenance of childhood obesity and complicate management." (Figure 2)

The midstream effects are also easily seen. Regarding the physical environment, "the family avoids going to the park because of the unsafe outdoor and poor park conditions…. This family lives in a small apartment with a small patio (3x4m), so how much can the patient effectively exercise?" The case is no better when it comes to health behavior, "[T]he total daily caloric intake surpassed her daily caloric requirements by approximately 500 kcal/day…. [And] [i]n the case of our patient, 5 hours of screen use per day clearly exceed the recommended daily screen use hours…which affects the duration of sleep and contribute to the patient's sedentary lifestyle."

Finally, the upstream SDH are evident in the "suboptimal physical activity curriculum in government schools." The authors also note that "[M]ost community parks have been built in popular areas that are located far away from the most vulnerable." The authors also mention the social inequalities, "Women and children in low socioeconomic groups are the most vulnerable…. [B]eing a lower middle class family in Mexico and the inequalities this implies clearly affects management."

According to the WHO, "Obesity prevention and treatment requires a whole-of-government approach in which policies across all sectors systematically take health into account, avoid harmful health impacts, and thus improve population health and health equity."⁴ As clinicians, we see the full weight of SDH on the health of individuals. It is our duty and privilege to report on the harmful effects of policies and infrastructure that wreak havoc on the lives of the vulnerable. Healthcare professionals see the weakest at their most vulnerable, and the authors of this case are examples in not only reporting the facts but offering interventions. In their "Learning points" they include, "Schools must offer more than 60 min of physical activity per week to achieve a negative caloric balance in children. Construction of new parks in vulnerable neighborhoods and tackling crime are priorities to promote outdoor physical activity in Mexico."

BMJ Case Reports invites authors to submit global health case reports that describe the effects of SDH on vulnerable patients and ways to mitigate these effects. These cases could focus on:

Upstream and midstream interventions and their impact on individual lives
Downstream effects of SDH on individual patients
Challenges to instituting SDH interventions as a healthcare professional

Manuscripts may be submitted by students, physicians, nurses and allied health professionals to BMJ Case Reports at www.bmjcasereports.com. For more information, review our guidance on how to write a global health case report and look through our online collection

To read more about SDH at BMJ Case Reports, please review:

To read more about SDH, please review:

^[1] World Health Organization. Social determinants of health. What are social determinants of health [internet] available from http://www.who.int/social_determinants/en/ accessed 6/26/2018

^[2] Farmer PE, Nizeye B, Stulac S, Keshavjee. Structural violence and clinical medicine. PLoS Med (2006) 3(10):e449

^[3] BMJ Case Reports Global Health Curriculum (Available at casereports.BMJ.com/site/about/Global_health_curriculum_slides.pptx

^[4] World Health Organization. Report of the commission on ending childhood obesity. World Health Organization; 2016. Geneva, Switzerland

The post Making a Difference by Addressing Social Determinants of Health appeared first on BMJ Case Reports blog.

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Outcomes of esophagectomy after chemotherapy with biweekly docetaxel plus cisplatin and fluorouracil for advanced esophageal cancer: a retrospective cohort analysis

Abstract

Background

Docetaxel, cisplatin, and 5-fluorouracil (DCF) therapy can cause severe adverse events, including neutropenia and febrile neutropenia. The feasibility of DCF therapy is a concern, particularly for elderly patients, patients with moderate organ disorders, and patients suffering from malnutrition caused by dysphagia or insufficient oral intake. We introduced a biweekly DCF therapy (bDCF) for the purpose of reducing severe adverse events for these fragile patients. This study investigated the feasibility and outcome of an esophagectomy after bDCF therapy for patients with advanced esophageal squamous cell carcinoma.

Methods

Fifty-nine patients with esophageal carcinoma underwent an esophagectomy after DCF or bDCF therapy as primary chemotherapy. DCF was administered to 37 patients in the DCF group, whereas bDCF was administered to 22 patients in the bDCF group.

Results

Patients in the bDCF group were significantly older than those in the DCF group (p = 0.016). Heart and pulmonary comorbidities were significantly more common in the bDCF than in the DCF group (p < 0.001 and p = 0.039, respectively). Grade 3 or 4 neutropenia was less frequent in the bDCF than in the DCF group (40.9 vs. 81.1%, p = 0.002). Anorexia was more frequent in the DCF group than in the bDCF group (18.9 vs. 0%, p = 0.030). The clinical response rate of the bDCF group was significantly higher than that of the DCF group (86.4 vs. 62.2%, p = 0.047). There was no significant between-group difference in the postoperative morbidity rate (bDCF 45.5% vs. DCF 32.4%) or in the histological therapeutic effect.

Conclusion

The results demonstrate that primary bDCF therapy for high-risk patients with advanced esophageal cancer is feasible and safe in both chemotherapeutic and perioperative periods without a reduction in the efficacy of DCF therapy.

https://ift.tt/2IJEk5A

Genomic characterization of colitis-associated colorectal cancer

Abstract

Background

Inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD), is a chronic, idiopathic, repeated inflammatory disease. Colorectal cancer (CRC) that develops in patients with IBD is known as colitis-associated colorectal cancer (CAC), but the underlying carcinogenic mechanism remains unclear. Genomic analysis of sporadic CRC has been well described based on next-generation sequencing (NGS) data. Using NGS, we compared all exons of 415 cancer-associated genes in patients in Japan and the USA who had CRC and found similar genomic alteration patterns among the two populations. However, genomic analysis of CAC has not been thoroughly investigated.

Main body

The molecular pathogenesis of CAC shares many features with sporadic CRC, but there are distinct variations in the time and frequency of some alterations. Gene alterations in CAC are gradually being elucidated using genomic sequencing analyses. Some studies have shown that gene alteration patterns differ between UC and CD. The carcinogenesis of CAC depends on unique environmental, genetic, and immunological factors.

Conclusions

In this review, we have discussed the differences in genomic alterations between sporadic CRC and CAC. NGS in patients with IBD has the potential to detect early CAC and to suggest therapeutic targets.

https://ift.tt/2NfF6eh

Angiolymphoid hyperplasia with eosinophilia (epithelioid hemangioma) of the external auditory canal, an unusual presentation in an adult female: a case report

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Abstract

Introduction: Angiolymphoid hyperplasia with eosinophilia (ALHE) is a rare entity that usually occurs as 0.5–3 cm, pink-to-brown nodules on the skin surface and subcutaneous tissues of the head and neck (Al-Muharraqi MA, Faqi MK, Uddin F, Ladak K, Darwish A. Angiolymphoid hyperplasia with eosinophilia (epithelioid hemangioma) of the face: an unusual presentation. Int J Surg Case Rep 2011;2:258–60.; Suzuki H, Hatamochi A, Horie M, Suzuki T, Yamazaki S. A case of angiolymphoid hyperplasia with eosinophilia (ALHE) of the upper lip. J Dermatol 2005; 32:991–5.). Case presentation: A 29-year-old woman presented to our ENT (ear-nose-throat) clinic with multiple, small reddish to pinkish nodules of approximately 1 × 2 cm² in dimension. A biopsy from the surface of the left external auditory canal skin, where she had severe itching, showed features consistent with Angiolymphoid hyperplasia with eosinophilia ALHE. Discussion: Whether angiolymphoid hyperplasia with an eosinophilia etiology is a neoplastic or atopic hypersensitivity reaction (unusual reactive process) is controversial. The definitive treatment is surgical excision and follow-up (Al-Muharraqi MA, Faqi MK, Uddin F, Ladak K, Darwish A Angiolymphoid hyperplasia with eosinophilia (epithelioid hemangioma) of the face: An unusual presentation. Int J Surg Case Rep 2011;2:258–60.; Barnes L, editor. Surgical Pathology of the Head and Neck. 3rd edn. New York: Marcel Decker; 2001.). Conclusion: Although ALHE of <3 cm has been rarely reported in the literature, it should be considered in the differential diagnosis of large subcutaneous tumors of the head and neck.

https://ift.tt/2KEp7Ys

Complete small bowel obstruction without intussusception due to a submucosal lipoma

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Abstract

Submucosal lipomas of the small bowel are rare, often asymptomatic, benign tumors. Large lesions may present with acute symptoms such as a bowel obstruction from an intussusception or acute hemorrhage. Acute findings such as these require operative intervention. In this case, we present a 53-year-old female with a complete small bowel obstruction secondary to a submucosal lipoma without signs of an intussusception.

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Gallstone ileus 1 year after cholecystectomy

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Abstract

Post-cholecystectomy gallstone ileus (GSI) is very rare with only 16 cases reported in the literature. This condition poses diagnostic challenges both because of its rarity and since the gallbladder had been previously removed. A high index of suspicion is needed for diagnosis. We report a case of a 37-year-old female who presented with GSI 12 months post-cholecystectomy.

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