Hybrid minimally invasive Ivor Lewis esophagectomy after neoadjuvant chemoradiation yields excellent long-term survival outcomes with minimal morbidity

Background

There is a clear survival benefit to neoadjuvant chemoradiation prior to esophagectomy for patients with stages II–III esophageal cancer. A minimally invasive esophagectomy approach may decrease morbidity but is more challenging in a previously radiated field and therefore patients who undergo neoadjuvant chemoradiation may experience more postoperative complications.

Methods

A prospective database of all esophageal cancer patients who underwent attempted hybrid minimally invasive Ivor Lewis esophagectomy was maintained between 2006 and 2015. The clinical characteristics, neoadjuvant treatments, perioperative complications, and survival outcomes were reviewed.

Results

Overall 30- and 90-day mortality rates were 0.8% (1/131) and 2.3% (3/131), respectively. The majority of patients 58% (76/131) underwent induction treatment without significant adverse impact on mortality, major complications, or hospital stay. Overall survival at 1, 3, and 5 years was 85.9%, 65.3%, and 53.9%. Five-year survival by pathologic stage was stage I 68.9%, stage II 54.0%, and stage III 29.6%.

Conclusions

The hybrid minimally invasive Ivor Lewis esophagectomy approach results in low perioperative morbidity and mortality and is well tolerated after neoadjuvant chemoradiation. Good long-term overall survival rates likely resulted from combined concurrent neoadjuvant chemoradiation in the majority of patients, which did not impact the ability to safely perform the operation or postoperative complications rates. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

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Development and implementation of a comprehensive psychosocial screening program in a Brazilian cancer center

Abstract

Objective

International guidelines recommend routine screening for distress as part of care practices. Accordingly, a Brazilian cancer center developed and implemented a Distress Screening Program (DS) in 2007, which was enhanced in 2009 through the inclusion of a Psychosocial Care Meeting Group (DS + PCM) regarding patients' psychosocial needs. The current paper will provide an overview of the development and pilot implementation of this program, initial analyses to assess patient outcomes, and report initial results to extend international research on this key aspect of cancer care.

Method

Patients were assessed for distress, anxiety/depression, and in the DS + PCM phase for quality of life at the first day of chemotherapy infusion, at mid-point, and at treatment end. We compared data from program phases (DS vs. DS + PCM), with a sequential cohort design and mixed effects modeling.

Results

Clinical and demographic characteristics were similar between groups. Patients receiving DS + PCM showed significantly lower distress and depression/anxiety upon chemotherapy initiation (ps < .001). While both groups reported significantly lowered distress and total depression/anxiety scores across time (ps < .003), patients receiving DS + PCM maintained the lowest distress and total anxiety/depression at all assessments. Patients from DS + PCM group also reported improvements in quality of life over time.

Conclusions

The current study provides preliminary evidence that a multi-disciplinary structured screening program utilizing validated measures and team meetings is associated with reduced impairment in patients' psychological well-being. This program provided more opportunities for collaboration among providers with increased multi-disciplinary meetings, enabled patients to more easily report problems, and ensured rapid access to relevant resources. This article is protected by copyright. All rights reserved.

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Comment on: Contributing factors and outcomes of treatment refusal in pediatric oncology in Germany

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Isolated central nervous system primary acute monoblastic leukemia presenting as papilledema

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Risk-stratification management of febrile neutropenia in pediatric hematology-oncology patients: Results of a French nationwide survey

Abstract

Background

In 2012, new international guidelines for children with chemotherapy-induced febrile neutropenia (FN) were issued, recommending reduced-intensity management strategy based on stratification of infectious risks. Some studies have highlighted practice disparities in different countries and within the same country. Our aim was to assess the current management strategies for the treatment of chemotherapy-induced FN in children in France.

Procedure

This survey of all French pediatric oncology-hematology reference centers (n = 30) in late 2012 and early 2013 sent a standardized questionnaire to each center inquiring about their definition of an FN episode, its initial empiric treatment and ongoing management, use of management stratified by risk, and any criteria used for the risk assessment. Each center's management protocol was also analyzed.

Results

All French reference centers participated in this survey, completing 88% of the questionnaire items. Definitions of both fever and neutropenia varied between centers. Ten centers used a risk-stratification strategy for initial management. In all, 42 probabilistic first-line antibiotic treatments were identified. After 48 hr of apyrexia, 17 units applied different forms of step-down therapy.

Conclusions

Most French centers already offered some form of reduced-intensity or step-down therapy, although they differed substantially in their management of FN episodes. Risk stratification with validated tools is essential to facilitate the implementation of the international recommendations, which would ultimately help to standardize practices in France.

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mir-22 oncosuppressor network in Rhabdomyosarcoma

Current therapeutic options for the pediatric cancer rhabdomyosarcoma (RMS) have not improved significantly, especially for metastatic RMS. In the present work, we performed a deep microRNA profiling of the three major human RMS subtypes, along with cell lines and normal muscle, to identify novel molecular circuits with therapeutic potential. The signature we determined could discriminate RMS from muscle, revealing a subset of muscle-enriched microRNA (myomiR), including miR-22 which was strongly underexpressed in tumors. miR-22 was physiologically induced during normal myogenic differentiation and was transcriptionally regulated by MyoD, confirming its identity as a myomiR. Once introduced into RMS cells, miR-22 decreased cell proliferation, anchorage-independent growth, invasiveness and promoted apoptosis. Moreover, restoring miR-22 expression blocked tumor growth and prevented tumor dissemination in vivo. Gene expression profiling analysis of miR-22-expressing cells suggested TACC1 and RAB5B as possible direct miR-22 targets. Accordingly, loss and gain of function experiments defined the biological relevance of these genes in RMS pathogenesis. Finally, we demonstrated the ability of miR-22 to intercept and overcome the intrinsic resistance to MEK inhibition based on ERBB3 upregulation. Overall our results identified a novel miR-22 regulatory network with critical therapeutic implications in RMS.

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SOX9 and gastric cancer

Gastric cancer (GC) remains one of the leading causes of global cancer mortality due to therapy resistance, with H. pylori infection being a major risk factor. In this study, we report the significance of an elevation of the stem cell regulator SOX9 in bacteria-infected human gastritis and cancer samples, paralleling increased levels of TNFα. SOX9 elevation was more intense in specimens containing the pathogenically significant cagA+ strains of H. pylori. Notably, we found that SOX9 was required for bacteria-induced GC cell proliferation, increased levels of β-catenin and acquisition of stem cell-like properties. Analysis of three large clinical cohorts revealed elevated SOX9 levels in GC with advanced tumor stage and poor patient survival. Functionally, SOX9 silencing in GC cells enhanced apoptosis and senescence, concomitantly with a blockade to self-renewal and tumor initiating capability. Paralleling these effects, we also found SOX9 to mediate cisplatin chemoresistance associated with reduced disease-free survival. Mechanistic interactions between SOX9 and β-catenin expression suggested the existence a regulatory role for SOX9 targeting the WNT canonical pathway. Taken together, our findings establish the significance of SOX9 in gastric cancer pathobiology and heterogeneity, with implications for targeting WNT-SOX9 signaling as a rational therapeutic strategy.

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MSC Exosomes in Cancer Dormancy

Dormant breast cancers (BRCA) resurge as metastatic disease after a long dormancy period in the bone marrow where cancer cells interact with mesenchymal stem cells (MSC). However, the nature of early interactions between BRCA cells and MSC in the bone marrow microenvironment that facilitate adaptation to a quiescent state remain poorly understood. Here we report that BRCA cells prime MSC to release exosomes containing distinct miRNA contents such as miR-222/223, which in turn promotes quiescence in a subset of cancer cells and confers drug resistance. Building on these results, we developed a novel, non-toxic therapeutic strategy to target dormant BRCA cells based on systemic administration of MSC loaded with antagomiR-222/223. In an immune-deficient mouse model of dormant breast cancer, this therarpy sensitized BRCA cells to carboplatin-based therapy and increased host survival. Overall, our findings illuminate the nature of the regulatory interactions between BRCA cells and MSC in the evolution of tumor dormancy and resurgence in the micrometastatic microenvironment of the bone marrow.

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HPV OPSCC in the UK

A rising incidence of oropharyngeal squamous cell carcinoma (OPSCC) incidence has occurred throughout the developed world, where it has been attributed to an increasing impact of human papillomavirus (HPV) on disease etiology. This report presents the findings of a multicenter cross-sectional retrospective study aimed at determining the proportion of HPV-positive and HPV-negative OPSCC within the United Kingdom (UK). Archival tumor tissue blocks from 1602 patients previously diagnosed with OPSCC (2002-2011) were collated from 11 centers. HPV status was determined with 3 validated commercial tests to provide valid data for 1474 cases in total. Corresponding national incidence data from the same decade were obtained from UK Cancer registries.The overall proportion of HPV+ OPSCC between 2002-2011 was 51.8% (95% CI:49.3, 54.4) and this remained unchanged throughout the decade (unadjusted risk ratio:1.00 (95% CI:0.99, 1.02). However, over the same period, the incidence of OPSCC in the broader UK population underwent a 2-fold increase (age standardised rate (ASR) 2002:2.1 (95% CI:1.9, 2.2); 2011:4.1(95% CI:4.0, 4.3)). Although the number of OPSCC diagnosed within the UK from 2002-2011 nearly doubled, the proportion of HPV+ cases remained static at ~50%. Our results argue that the rapidly increasing incidence of OPSCC in the UK cannot be solely attributable to the influence of HPV. The parallel increase in HPV+ and HPV- cases we documented warrants further investigation, so that appropriate future prevention strategies for both types of disease can be implemented.

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Genetic Dissection of miR-10b and Breast Cancer

The invasive and metastatic properties of many human tumors have been associated with upregulation of the microRNA miR-10b, but its functional contributions in this setting have not been fully unraveled. Here we report the generation of miR-10b-deficient mice in which miR-10b is shown to be largely dispensable for normal development but critical to tumorigenesis. Loss of miR-10b delays oncogene-induced mammary tumorigenesis and suppresses epithelial-mesenchymal transition, intravasation, and metastasis in a mouse model of metastatic breast cancer. Among the target genes of miR-10b, the tumor suppressor genes Tbx5 and Pten and the metastasis suppressor gene Hoxd10 are significantly upregulated by miR-10b deletion. Mechanistically, miR-10b promotes breast cancer cell proliferation, migration, and invasion through inhibition of the expression of the transcription factor TBX5, leading to repression of the tumor suppressor genes DYRK1A and PTEN. In clinical specimens of breast cancer, the expression of TBX5, HOXD10, and DYRK1A correlates with relapse-free survival and overall survival outcomes in patients. Our results establish miR-10b as an oncomiR that drives metastasis, termed a metastamiR, and define the set of critical tumor suppressor mechanisms it overcomes to drive breast cancer progression.

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Cancer chemotherapy requires T cell costimulation

Certain cytotoxic chemotherapeutic drugs are immunogenic, stimulating tumor immunity through mechanisms that are not completely understood. Here we show how the DNA damaging drug cisplatin modulates tumor immunity. At the maximum tolerated dose (MTD), cisplatin cured 50% of mice with established murine TC-1 or C3 tumors, which are preclinical models of human papilloma virus (HPV)-associated cancer. Notably, the curative benefit of cisplatin relied entirely upon induction of tumor-specific CD8+ T cells. Mechanistic investigations showed that cisplatin stimulated tumor infiltration of inflammatory antigen-presenting cells (APCs) expressing relatively higher levels of the T-cell costimulatory ligands CD70, CD80 and CD86. Cell death triggered by cisplatin was associated with the release of at least 19 proteins in the tumor environment that could act as damage-related molecular patterns (DAMPs) and upregulate costimulatory molecules, either alone or in concert, but the responsible proteins remain unknown. Essentially, the curative effect of cisplatin was abrogated in mice lacking expression of CD80 and CD86 on APCs. Further, cisplatin treatment was improved by CTLA-4 blockade, which increases the availability of CD80/86 to bind to CD28. In contrast, there was no effect of CD27 stimulation, which replaces CD70 interaction. At the cisplatin MTD, cure rates could also be increased by vaccination with synthetic long peptides, whereas cures could also be achieved at similar rates at 80% of the MTD with reduced side effects. Our findings reveal an essential basis for the immunogenic properties of cisplatin, which are mediated by induction of costimulatory signals for CD8+ T cell-dependent tumor destruction.

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Rapamycin promotes human and murine anti-cancer {gamma}{delta} T cells

The FDA approved mTOR inhibitor rapamycin mediates important immune effects, but their contributions to the drug's anti-cancer effects are unclear. Here we report evidence that rapamycin-mediated cancer protection relies upon stimulation of γδ T cells. In a well-established mouse model of carcinogen and inflammation-driven skin carcinogenesis, interferon-γ recruited γδ TCRmid T cells to the epidermis where rapamycin boosted their perforin-dependent antitumor properties. These antitumor cells were mostly Vγ5-Vγ4-Vγ1- in phenotype. Interferon-γ signals were required in both hematopoietic and non-hematopoietic cells for rapamycin to optimally promote epidermal infiltration of γδ TCRmid T cells, as mediated by CXCR3-CXCL10 interactions, along with the antitumor effects of these cells. In mouse xenograft models of human squamous cell carcinoma, rapamycin improved human γδ T cell-mediated cancer cell killing. Our results identify immune mechanisms for the cancer prevention and treatment properties of rapamycin, challenging the paradigm that mTOR inhibition acts primarily by direct action on tumor cells.

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SMYD3-methylated H2A.Z.1 up-regulates cyclin A1

SMYD3 methyltransferase is nearly undetectable in normal human tissues but highly expressed in several cancers, including breast cancer, although its contributions to pathogenesis in this setting are unclear. Here we report that histone H2A.Z.1 is a substrate of SMYD3 that supports malignancy. SMYD3-mediated dimethylation of H2A.Z.1 at lysine 101 (H2A.Z.1K101me2) increased stability by preventing binding to the removal chaperon ANP32E and facilitating its interaction with histone H3. Moreover, a microarray analysis identified cyclin A1 as a target co-regulated by SMYD3 and H2A.Z.1K101me2. The co-localization of SMYD3 and H2A.Z.1K101me2 at the promoter of cyclin A1 activated its expression and G1/S progression. Enforced expression of cyclin A1 in cells containing mutant H2A.Z.1 rescued tumor formation in a mouse model. Our findings suggest that SMYD3-mediated H2A.Z.1K101 dimethylation activates cyclin A1 expression and contributes to driving the proliferation of breast cancer cells.

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Therapeutic outcomes of MTD vs. LDM therapy regimens

Conventional chemotherapy drugs administered at a maximum tolerated dose (MTD) remains the backbone for treating most cancers. Low-dose metronomic (LDM) chemotherapy, which utilizes lower, less toxic, doses given on a close regular basis over prolonged periods, is an alternative and better tolerated potential strategy to improve chemotherapy. LDM chemotherapy has been evaluated preclinically and clinically and has shown therapeutic benefit, in both early and advanced stage metastatic disease, especially when used as a maintenance therapy. However, knowledge about the anti-tumor mechanisms by which LDM chemotherapy acts remain limited. Here we characterized the effects of LDM and MTD capecitabine therapy on tumor and host cells using high-throughput systems approaches involving mass spectrometry flow cytometry and automated cell imaging followed by in vivo analyses of such therapies. An increase in myeloid and T regulatory cells and a decrease in NK and T cytotoxic cells were found in MTD-capecitabine-treated tumors compared to LDM-capecitbine-treated tumors. Plasma from MTD capecitabine-treated mice induced a more tumorigenic and metastatic profile in both breast and colon carcinoma cells than plasma from mice treated with LDM capecitabine. These results correlated, in part, with in vivo studies using models of human or mouse advanced metastatic disease, where the therapeutic advantage of MTD capecitabine was limited despite a substantial initial anti-tumor activity found in the primary tumor setting. Overall these results implicate a possible contribution of immunological host effects in accounting for the therapeutic limitations of MTD compared to LDM capecitabine.

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FOXD1-ALDH1A3 Axis in Mesenchymal Glioma Stem-like Cells

Glioma stem-like cells (GSC) with tumor initiating activity orchestrate the cellular hierarchy in glioblastoma (GBM) and engender therapeutic resistance. Recent work has divided GSC into two subtypes with a mesenchymal (MES) GSC population as the more malignant subtype. In this study, we identify the FOXD1-ALDH1A3 signaling axis as a determinant of the MES GSC phenotype. The transcription factor FOXD1 is expressed predominantly in patient-derived cultures enriched with MES, but not with the proneural (PN) GSC subtype. shRNA-mediated attenuation of FOXD1 in MES GSC ablates their clonogenicity in vitro and in vivo. Mechanistically, FOXD1 regulates the transcriptional activity of ALDH1A3, an established functional marker for MES GSC. Indeed, the functional roles of FOXD1 and ALDH1A3 are likely evolutionally conserved, insofar as RNAi-mediated attenuation of their orthologous genes in Drosophila blocks formation of brain tumors engineered in that species. In clinical specimens of high-grade glioma, the levels of expression of both FOXD1 and ALDH1A3 are inversely correlated with patient prognosis. Lastly, a novel small molecule inhibitor of ALDH we developed, termed GA11, displays potent in vivo efficacy when administered systemically in a murine GSC-derived xenograft model of GBM. Collectively, our findings define a FOXD1-ALDH1A3 pathway in controlling the clonogenic and tumorigenic potential of MES GSC in GBM tumors.

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Lung tumor angiogenesis

Angiogenesis is vital for tumor growth but in well-vascularized organs such as the lung its importance is unclear. This situation is complicated by the fact that the lung has two separate circulations, the pulmonary and the systemic bronchial circulation. There are few relevant animal models of non-small cell lung cancer, which can be used to study the lung's complex circulations, and mice, lacking a systemic bronchial circulation cannot be used. We report here a novel orthotopic model of non-small cell lung cancer in rats, where we have studied the separate contributions of each of the two circulations for lung tumor growth. Results show that bronchial artery perfusion, quantified by fluorescent microspheres (206% increase in large tumors) or HRCT scans (276% increase in large tumors), parallels the growth in tumor volume, while pulmonary artery perfusion remained unchanged. Ablation of the bronchial artery after the initiation of tumor growth resulted in a decrease in tumor volume over a subsequent course of 4 weeks. These results demonstrate that while the existing pulmonary circulation can supply the metabolic needs for tumor initiation, further growth of the tumor requires angiogenesis from the highly proliferative bronchial circulation. This model may be useful to investigate new therapeutic approaches that target specifically the bronchial circulation.

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EpCAM-Regulated Transcription Promotes EMT

Overexpression of epithelial cell adhesion molecule (EpCAM) has been implicated in advanced endometrial cancer, but its roles in this progression remain to be elucidated. In addition to its structural role in modulating cell-surface adhesion, here we demonstrate that EpCAM is a regulatory molecule in which its internalization into the nucleus turns on a transcription program. Activation of EGF/EGFR signal transduction triggered cell-surface cleavage of EpCAM, leading to nuclear internalization of its cytoplasmic domain EpICD. ChIP-seq analysis identified target genes that are co-regulated by EpICD and its transcription partner, LEF-1. Network enrichment analysis further uncovered a group of 105 genes encoding functions for tight junction, adherent and cell migration. Furthermore, nanomechanical analysis by atomic force microscope (AFM) revealed increased softness and decreased adhesiveness of EGF-stimulated cancer cells, implicating acquisition of an epithelial-mesenchymal transition (EMT) phenotype. Thus, genome editing of EpCAM could be associated with altering these nanomechanical properties towards a less aggressive phenotype. Using this integrative genomic-biophysical approach, we demonstrate for the first time an intricate relationship between EpCAM-regulated transcription and altered biophysical properties of cells that promote EMT in advanced endometrial cancer.

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Rare Case Report of Alveolar Soft Part Sarcoma of the Orbit

Abstract

Alveolar soft part sarcoma (ASPS) is a rare but distinct soft tissue tumor with unique histopathological and electron microscopic features. Orbital involvement is rare with only few reports published in the literature. ASPS have an indolent clinical course, but it is known to metastasize. Primary modality of treatment is surgery followed by adjuvant treatment. This case is a unique presentation with orbital mass with on and off bleeding. This is the largest orbital ASPS for which orbital exenteration was performed.

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