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Πέμπτη 4 Φεβρουαρίου 2021

Palpable head on digital rectal examination: a rare case of uterine incarceration causing obstruction and perforation of an ileal pouch in mid‐term pregnancy

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Extensive upper neck vascular lesion presenting as middle ear mass

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Clinical and biological subtypes of B-cell lymphoma revealed by microenvironmental signatures [Research Article]

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Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogenous disease. Transcriptomic and genetic characterization of DLBCL have increased the understanding of its intrinsic pathogenesis and provided potential therapeutic targets. However, the role of the microenvironment in DLBCL biology remains less understood. Here, we performed a transcriptomic analysis of the microenvironment of 4,655 DLBCLs from multiple independent cohorts and described four major lymphoma microenvironment categories that associate with distinct biological aberrations and clinical behavior. We also found evidence of genetic and epigenetic mechanisms deployed by cancer cells to evade microenvironmental constrains of lymphoma growth; supporting the rationale for implementing DNA hypomethylating agents in selected DLBCL patients. In addition, our work uncovered new therapeutic vulnerabilities in the biochemical composition of the extracellular matrix that were expl oited to decrease DLBCL proliferation in pre-clinical models. This novel classification provides a roadmap for the biological characterization and therapeutic exploitation of the DLBCL microenvironment.

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Benefit and danger from immunotherapy in myasthenia gravis

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Abstract

In the last years, significant advances have improved the knowledge of myasthenia gravis (MG) immunopathogenesis and have enabled to realize new molecules with a selective action targeting compounds of the immunological system. This review discusses emerging treatments for MG, including complement inhibitors, neonatal Fc receptor targeting agents, and B cell interfering drugs, focusing on benefit and danger. In the second section of the review, several related adverse events of immunotherapy, including MGonset, are debated.

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Preclinical modeling of surgery and steroid therapy for glioblastoma reveals changes in immunophenotype that are associated with tumor growth and outcome

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Purpose: Glioblastoma (GBM) immunotherapy clinical trials are generally initiated after standard-of-care treatment, including surgical resection, perioperative high-dose steroid therapy, chemotherapy, and radiation treatment, has either begun or failed. However, the impact of these interventions on the anti-tumoral immune response is not well studied. While discoveries regarding the impact of chemotherapy and radiation on immune response have been made and translated into clinical trial design, the impact of surgical resection and steroids on the anti-tumor immune response has yet to be determined. Experimental Design: We developed a murine model integrating tumor resection and steroid treatment and used flow cytometry to analyze systemic and local immune changes. These mouse model findings were validated in a cohort of 95 primary GBM patients. Results: Using our murine resection model, we observed a systemic reduction in lymphocytes corresponding to incre ased tumor volume and decreased circulating lymphocytes that was masked by dexamethasone treatment. The reduction in circulating T cells was due to reduced CCR7 expression, resulting in T-cell sequestration in lymphoid organs and the bone marrow. We confirmed these findings in a cohort of primary GBM patients and found that prior to steroid treatment, circulating lymphocytes inversely correlated with tumor volume. Lastly, we demonstrated that peripheral lymphocyte content varies with progression-free and overall survival, independent of tumor volume, steroid use, or molecular profiles. Conclusions: These data reveal that prior to intervention, increased tumor volume corresponds with reduced systemic immune function and that peripheral lymphocyte counts are prognostic when steroid treatment is taken into account.

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Gene expression-based prediction of neoadjuvant chemotherapy response in early breast cancer: results of the prospective multicenter EXPRESSION trial

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Purpose: Expression-based classifiers to predict complete pathological response (pCR) after neoadjuvant chemotherapy (NACT) are not routinely used in the clinic. We aimed to build and validate a classifier for pCR after NACT. Experimental Design: We performed a prospective multicenter study (EXPRESSION) including 114 patients treated with anthracycline/taxane-based NACT. Pretreatment core-needle biopsies from 91 patients were used for gene expression analysis and classifier construction, followed by validation in five external cohorts (n=619). Results: A 20-gene classifier established in the EXPRESSION cohort using a Youden's index-based cutpoint predicted pCR in the validation cohorts with an accuracy, area under the curve (AUC), negative predictive value (NPV), positive predictive value (PPV), sensitivity and specificity of 0.811, 0.768, 0.829, 0.587, 0.216 and 0.962, respectively. Alternatively, aiming for a high NPV by defining the cutpoint for classi fication based on the complete responder with the lowest predicted probability of pCR in the EXPRESSION cohort led to an NPV of 0.960 upon external validation. With this extreme-low cutpoint, a recommendation to not treat with anthracycline/taxane-based NACT would be possible for 121 of 619 unselected patients (19.5%) and 112 of 322 luminal breast cancer patients (34.8%). The analysis of the molecular subtypes showed that the identification of patients who do not achieve a pCR by the 20 gene classifier was particularly relevant in luminal breast cancer. Conclusions: The novel 20 gene classifier reliably identifies patients who do not achieve a pCR in about one third of luminal breast cancer in both the EXPRESSION and the combined validation cohort.

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Safety, anti-tumor activity and T-cell responses in a dose-ranging phase 1 trial of the oncolytic peptide LTX-315 in patients with solid tumors

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Purpose: LTX-315 is a first in class, 9-mer membranolytic peptide that has shown potent immunomodulatory properties in preclinical models. We conducted a phase 1 dose-escalating study of intratumoral LTX-315 administration in patients with advanced solid tumors. Patient and methods: Thirty-nine patients were enrolled, receiving LTX-315 injections into accessible tumors. The primary objective was to assess the safety and tolerability of this approach, with anti-tumor and immunomodulatory activity as secondary objectives. Tumor biopsies were collected at baseline and post-treatment for analysis of immunological parameters. Results: The most common treatment-related grade 1-2 adverse events were vascular disorders including transient hypotension (18 patients, 46%), flushing (11 patients, 28%), and injection site reactions in 38% of patients. The most common grade 3 LTX-315-related toxicities were hypersensitivity or anaphylaxis (4 patients, 10%). Analysis of im mune endpoints in serial biopsies indicated that LTX-315 induces necrosis and CD8+ T cell infiltration into the tumor microenvironment. Sequencing of the TCR repertoire in peripheral blood identified significant expansion of T-cell clones after treatment, of which 49% were present in available tumor biopsies after treatment, suggesting that they were tumor-associated. Substantial volume reduction ({greater than or equal to}30%) of injected tumors occurred in 29% of the patients, and 86% (12 out of 14 biopsies) had an increase in intralesional CD8+ T cells post-treatment. No partial responses by immune-related response criteria were seen, but evidence of abscopal effect was demonstrated following treatment with LTX-315. Conclusions: LTX-315 has an acceptable safety profile, is clinically active, induces changes in the tumor microenvironment and contributes to immune-mediated anticancer activity.

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Emergence of Enzalutamide resistance in prostate cancer is associated with BCL-2 and IKKB dependencies

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Purpose:Although enzalutamide (ENZ) has been widely used to treat de novo or castration-resistant metastatic prostate cancer, resistance develops, and disease progression is ultimately inevitable. There are currently no approved targeted drugs to specifically delay or overcome ENZ-resistance. Experimental Design:We selected several ENZ-resistant cell lines that replicated clinical characteristics of the majority of patients with ENZ-resistant disease. A high- throughput pharmacological screen was utilized to identify compounds with greater cytotoxic effect for ENZ-resistant cell lines, compared to parental ENZ-sensitive cells. We validated the potential hits in vitro and in vivo, and used knock-down and over- expression assays to study the dependencies in ENZ-resistant prostate cancer. Results:ABT199 (BCL-2 inhibitor) and IMD0354 (IKKB inhibitor), were identified as potent and selective inhibitors of cell viability in ENZ-resistant cell lines in vitro and in vivo which were further validated using loss-of-function assays of BCL-2 and IKKB. Notably, we observed that overexpression of BCL-2 and IKKB in ENZ-sensitive cell lines was sufficient for the emergence of ENZ resistance. In addition, we confirmed that BCL-2 or IKKB inhibitors suppressed the development of ENZ resistance in xenografts. However, validation of both BCL-2 and IKKB in matched castration-sensitive/resistant clinical samples showed that, concurrent with the development of enzalutamide/abiraterone resistance in patients, only the protein levels of IKKB were increased. Conclusions:Our findings identify BCL-2 and IKKB dependencies in clinically relevant ENZ-resistant prostate cancer cells in vitro and in vivo but indicate that IKKB upregulation appears to have greater relevance to the progression of human castrate resistant prostate cancer.

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Cancers, Vol. 13, Pages 626: Emerging Trends in Neoadjuvant Chemotherapy for Ovarian Cancer

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cancers-13-00626-g001-550.jpg

Cancers, Vol. 13, Pages 626: Emerging Trends in Neoadjuvant Chemotherapy for Ovarian Cancer

Cancers doi: 10.3390/cancers13040626

Authors: Ami Patel Puja Iyer Shinya Matsuzaki Koji Matsuo Anil K. Sood Nicole D. Fleming

Epithelial ovarian cancer remains a leading cause of death amongst all gynecologic cancers despite advances in surgical and medical therapy. Historically, patients with ovarian cancer underwent primary tumor reductive surgery followed by postoperative chemotherapy; however, neoadjuvant chemotherapy followed by interval tumor reductive surgery has gradually become an alternative approach for patients with advanced-stage ovarian cancer for whom primary tumor reductive surgery is not feasible. Decision-making about the use of these approaches has not been uniform. Hence, it is essential to identify patients who can benefit most from neoadjuvant chemotherapy followed by interval tumor reductive surgery. Several prospective and retrospective studies have proposed potential models to guide upfront decision-making for patients with advanced ovarian cancer. In this review, we summarize important decision-making models that can improve patient selection for personalized treatment. Models based on clinical factors (clinical parameters, radiology studies and laparoscopy scoring) and molecular markers (circulating and tumor-based) are useful, but laparoscopic staging is among the most informative diagnostic methods for upfront decision-making in patients medically fit for surgery. Further research is needed to explore more reliable models to determine personalized treatment for advanced epithelial ovarian cancer.

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Targeting DNA damage repair functions of two histone deacetylases, HDAC8 and SIRT6, sensitizes acute myeloid leukemia to NAMPT inhibition

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Purpose: Nicotinamide phosphoribosyltransferase (NAMPT) inhibitors are currently in development, but may be limited as a single agent therapy due to compound-specific toxicity and cancer metabolic plasticity allowing resistance development. To potentially lower the doses of NAMPT inhibitors required for therapeutic benefit against acute myeloid leukemia (AML), we performed a genome-wide CRISPRi screen to identify rational disease-specific partners for a novel NAMPT inhibitor, KPT-2974. Experimental Design: Cell lines and primary cells were analyzed for cell viability, self-renewal and responses at RNA and protein levels with loss-of-function approaches and pharmacologic treatments. In vivo efficacy of combination therapy was evaluated with a xenograft model. Results: We identified two histone deacetylases, HDAC8 and SIRT6, whose knockout conferred synthetic lethality with KPT-9274 in AML. Furthermore, HDAC8-specific inhibitor, PCI-34051, or clinical Class I HDAC inhibitor, AR-42, in combination with KPT-9274, synergistically decreased the survival of AML cells in a dose-dependent manner. AR-42/KPT-9274 co-treatment attenuated colony-forming potentials of patient cells while sparing healthy hematopoietic cells. Importantly, combined therapy demonstrated promising in vivo efficacy compared with KPT-9274 or AR-42 monotherapy. Mechanistically, genetic inhibition of SIRT6 potentiated the effect of KPT-9274 on PARP-1 suppression by abolishing mono-ADP ribosylation. AR-42/KPT-9274 co-treatment resulted in synergistic attenuation of homologous recombination (HR) and nonhomologous end joining (NHEJ) pathways in cell lines and leukemia initiating cells (LICs). Conclusions: Our findings provide evidence that HDAC8 inhibition- or shSIRT6-induced DNA repair deficiencies are potently synergistic with NAMPT targeting, with minimal toxicity towards normal cells, providing a rationale for a novel-novel combination-based trea tment for AML.

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A novel mouse model of radiation-induced cardiac injury reveals biological and radiological biomarkers of cardiac dysfunction with potential clinical relevance

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Purpose: Radiation-induced cardiotoxicity is a significant concern in thoracic oncology patients. However, the basis for this disease pathology is not well-characterized. We developed a novel mouse model of radiation-induced cardiotoxicity to investigate pathophysiologic mechanisms and identify clinically targetable biomarkers of cardiac injury. Experimental Design: Single radiation doses of 20, 40, or 60 Gy were delivered to the cardiac apex of female C57BL/6 mice aged 9-11 weeks, with or without adjacent lung tissue, using conformal radiation therapy (RT). Cardiac tissue was harvested up to 24 weeks post-RT for histologic analysis. Echocardiography and Technetium-99 sestamibi single photon emission computed tomography (SPECT) at 8 and 16 weeks post-RT were implemented to evaluate myocardial function and perfusion. Mouse cardiac tissue and mouse and human plasma were harvested for biochemical studies. Results: Histopathologically, RT resulted in perivascu lar fibrosis 8 and 24 (p<0.05) weeks post-RT. Apical perfusion deficits on SPECT and systolic and diastolic dysfunction on echocardiography 8 and 16 weeks post-RT were also observed (p<0.05). Irradiated cardiac tissue and plasma showed significant increases in placental growth factor (PlGF), interleukin-6, and tumor necrosis factor-alpha (TNFa) compared to non-radiated matched controls, with greater increases in cardiac cytokine levels when RT involved lung. Human plasma showed increased PlGF (p=0.021) and TNFa (p=0.036) levels post-thoracic RT. Conclusions: We developed and characterized a pathophysiologically relevant mouse model of radiation-induced cardiotoxicity involving in situ irradiation of the cardiac apex. The model can be used to integrate radiomic and biochemical markers of cardiotoxicity to inform early therapeutic intervention and human translational studies.

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Therapeutic targeting of nemo-like kinase in primary and acquired endocrine-resistant breast cancer

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Purpose: Endocrine resistance remains a major clinical challenge in estrogen-receptor (ER) positive breast cancer. Despite the encouraging results from clinical trials for the drugs targeting known survival signaling, relapse is still inevitable. There is an unmet need to discover new drug targets in the unknown escape pathways. Here we report Nemo-Like Kinase (NLK) as a new actionable kinase target that endows previously uncharacterized survival signaling in endocrine resistant breast cancer. Experimental Design: The effects of NLK inhibition on the viability of endocrine resistant breast cancer cell lines were examined by MTS assay. The effect of VX-702 on NLK activity was verified by kinase assay. The modulation of ER and its coactivator SRC-3 by NLK were examined by immunoprecipitation, kinase assay, luciferase assay, and RNAseq. The therapeutic effects of VX-702 and Everolimus were tested on cell line- and patient-derived xenograft tumor models. Resul ts: NLK overexpression endow reduced endocrine responsiveness and is associated with worse outcome of tamoxifen-treated patients. Mechanistically, NLK may function at last in part via enhancing the phosphorylation of ERα and its key coactivator SRC-3 to modulate ERα transcriptional activity. Through interrogation of a kinase-profiling database, we uncovered and verified a highly selective dual p38/NLK inhibitor, VX-702. Co-administration of VX-702 with the mTOR inhibitor Everolimus demonstrated a significant therapeutic effect in cell line- and patient-derived xenograft tumor models of acquired or de novo endocrine resistance. Conclusions: Together, this study reveals the potential of therapeutic modulation of NLK for the management of the endocrine-resistant breast cancers with active NLK signaling.

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