Retraction

Abstract

This article has been retracted at the request of: Editor-in-Chief and Co-author

'Restoring sensitivity to oxaliplatin by a novel approach in gemcitabine-resistant pancreatic cancer cells in vitro and in vivo' by Banerjee, S., Kong, D., Azmi, A. S., Wang, Z., Ahmad, A., Sethi, S. and Sarkar, F. H.

The above article, published online on 16 November 2010, in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, the journal Editor-in-Chief, Professor Peter Lichter, and Wiley Periodicals, Inc. A university investigation involving the first and corresponding author determined that several figures in this paper were mislabeled, manipulated, or duplicated and relabeled while processing/compiling the final figures assembled from the original data sources. Therefore, the authors are retracting the paper in its entirety although they maintain that these issues did not affect the major conclusions. They apologize for any inconvenience this may have caused.

Reference

Banerjee, S., Kong, D., Azmi, A. S., Wang, Z., Ahmad, A., Sethi, S. and Sarkar, F. H. (2011), Restoring sensitivity to oxaliplatin by a novel approach in gemcitabine-resistant pancreatic cancer cells in vitro and in vivo. Int. J. Cancer, 128: 1240–1250. doi: 10.1002/ijc.25658

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Retraction

This article has been retracted at the request of: Editor-in-Chief and Author

'Inhibition of nuclear factor κb activity by genistein is mediated via Notch-1 signaling pathway in pancreatic cancer cells', by Wang, Z., Zhang, Y., Banerjee, S., Li, Y. and Sarkar, F. H.

The above article and associated erratum, published online on 11 November 2005 and 6 February 2014, respectively, in Wiley Online Library (wileyonlinelibrary.com), have been retracted by agreement between the authors, the journal Editor-in-Chief, Professor Peter Lichter, and Wiley Periodicals, Inc. In addition to what was corrected in the erratum, a university investigation involving the first and the corresponding author determined that several figures in this paper were re-used, mislabeled, manipulated, or duplicated while processing/compiling the final figures assembled from the original data sources. Therefore, the authors are retracting the paper in its entirety although they maintain that these issues did not affect the major conclusions. They apologize for any inconvenience this may have caused.

Reference

Wang, Z., Zhang, Y., Banerjee, S., Li, Y. and Sarkar, F. H. (2006), Inhibition of nuclear factor κb activity by genistein is mediated via Notch-1 signaling pathway in pancreatic cancer cells. Int. J. Cancer, 118:1930–1936. doi:10.1002/ijc.21589; corrected by Erratum: Inhibition of nuclear factor κb activity by genistein is mediated via Notch-1 signaling pathway in pancreatic cancer cells. Int. J. Cancer, 134: E3. doi: 10.1002/ijc.28709.

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Erratum

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Issue Information — Information for Authors

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Erratum

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Retraction

This article has been retracted at the request of: Editor-in-Chief and Author

'In vitro and in vivo molecular evidence of genistein action in augmenting the efficacy of cisplatin in pancreatic cancer' by Banerjee, S., Zhang, Y., Wang, Z., Che, M., Chiao, P. J., Abbruzzese, J. L. and Sarkar, F. H.

The above article and associated erratum, published online on 27 November 2006 and 6 February 2014, respectively, in Wiley Online Library (wileyonlinelibrary.com), have been retracted by agreement between the authors, the journal Editor-in-Chief, Professor Peter Lichter, and Wiley Periodicals, Inc. A university investigation involving the first and the corresponding author determined that several figures in this paper, including the b-actin bands in Fig. 1C in the erratum, were re-used, mislabeled, manipulated, or duplicated while processing/compiling the final figures assembled from the original data sources. Therefore, the authors are retracting the paper in its entirety although they maintain that these issues did not affect the major conclusions. They apologize for any inconvenience this may have caused.

ReferenceBanerjee, S., Zhang, Y., Wang, Z., Che, M., Chiao, P. J., Abbruzzese, J. L. and Sarkar, F. H. (2007), In vitro and in vivo molecular evidence of genistein action in augmenting the efficacy of cisplatin in pancreatic cancer. Int. J. Cancer, 120: 906–917. doi: 10.1002/ijc.22332; corrected by Erratum: In vitro and in vivo molecular evidence of genistein action in augmenting the efficacy of cisplatin in pancreatic cancer. Int. J. Cancer, 134: E4. doi: 10.1002/ijc.28710.

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Retraction

Abstract

This article has been retracted at the request of: Editor-in-Chief and Co-author

'Down-regulation of Jagged-1 induces cell growth inhibition and S phase arrest in prostate cancer cells' by Zhang, Y., Wang, Z., Ahmed, F., Banerjee, S., Li, Y. and Sarkar, F. H.

The above article, published online on 5 July 2006, in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, the journal Editor-in-Chief, Professor Peter Lichter, and Wiley Periodicals, Inc. A university investigation involving the second and the corresponding author determined that histone bands in Fig. 4 in this paper were manipulated and that β-actin bands in Fig. 1C were duplicated from another publication. Therefore, the authors are retracting the paper in its entirety although they maintain that these issues did not affect the major conclusions. They apologize for any inconvenience this may have caused.

Reference

Zhang, Y., Wang, Z., Ahmed, F., Banerjee, S., Li, Y. and Sarkar, F. H. (2006), Down-regulation of Jagged-1 induces cell growth inhibition and S phase arrest in prostate cancer cells. Int. J. Cancer, 119: 2071–2077. doi: 10.1002/ijc.22077

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Issue Information — Table of Contents

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Erratum

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Retraction

Abstract

This article has been retracted at the request of: Editor-in-Chief and Author

'TW-37, a small-molecule inhibitor of Bcl-2, inhibits cell growth and invasion in pancreatic cancer' by Wang, Z., Song, W., Aboukameel, A., Mohammad, M., Wang, G., Banerjee, S., Kong, D., Wang, S., Sarkar, F. H. and Mohammad, R. M.

The above article, published online on 4 June 2008, in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, the journal Editor-in-Chief, Professor Peter Lichter, and Wiley Periodicals, Inc. A university investigation involving the first and the second-to-last author determined that several figures from another published paper were manipulated or duplicated and re-used in this paper. Therefore, the authors are retracting the paper in its entirety although they maintain that these issues did not affect the major conclusions. They apologize for any inconvenience this may have caused.

Reference

Wang, Z., Song, W., Aboukameel, A., Mohammad, M., Wang, G., Banerjee, S., Kong, D., Wang, S., Sarkar, F. H. and Mohammad, R. M. (2008), TW-37, a small-molecule inhibitor of Bcl-2, inhibits cell growth and invasion in pancreatic cancer. Int. J. Cancer, 123: 958–966. doi: 10.1002/ijc.23610

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Issue Information — UICC

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Transient effects of tumor location on the functional architecture at rest in glioblastoma patients: three longitudinal case studies

The cognitive function of brain tumor patients is affected during the treatment. There is evidence that gliomas and surgery alter the functional brain connectivity but studies on the longitudinal effects are l...

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CAR T therapy against AFP for the treatment of liver cancer

Purpose: The majority of tumor-specific antigens are intracellular and/or secreted and therefore previously inaccessible by conventional chimeric antigen receptor (CAR) T cell therapy. Given that all intracellular/secreted proteins are processed into peptides and presented by class I major histocompatibility complexes (MHC) on the surface of tumor cells, we used alpha-fetoprotein (AFP), a specific liver cancer marker, as an example to determine whether peptide-MHC complexes can be targets for CAR T cell therapy against solid tumors. Experimental Design: We generated a fully human chimeric antigen receptor, ET1402L1-CAR (AFP-CAR), with exquisite selectivity and specificity for the AFP158-166 peptide complexed with human leukocyte antigen (HLA)-A*02:01. Results: We report that T cells expressing AFP-CAR selectively degranulated, released cytokines, and lysed liver cancer cells that were HLA-A*02:01+/AFP+ while sparing cells from multiple tissue types that were negative for either expressed proteins. In vivo, intratumoral injection of AFP-CAR T cells significantly regressed both Hep G2 and AFP-expressing SK-HEP-1 tumors in SCID-Beige mice (n=8 for each). Moreover, intravenous administration of AFP-CAR T cells in Hep G2 tumor-bearing NSG mice lead to rapid and profound tumor growth inhibition (n=6). Finally, in an established intraperitoneal liver cancer xenograft model, AFP-CAR T cells showed robust anti-tumor activity (n=6). Conclusions: This study demonstrates that CAR T cell immunotherapy targeting intracellular/secreted solid tumor antigens can elicit a potent anti-tumor response. Our approach expands the spectrum of antigens available for redirected T cell therapy against solid malignancies and offers a promising new avenue for liver cancer immunotherapy.

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FGFR1 is a therapeutic target in soft-tissue sarcoma

Purpose: Altered FGFR1 signaling has emerged as therapeutic target in epithelial malignancies. In contrast, the role of FGFR1 in soft-tissue sarcoma (STS) has not been established. Prompted by the detection and subsequent therapeutic inhibition of amplified FGFR1 in a patient with metastatic leiomyosarcoma, we investigated the oncogenic properties and potential as drug target of FGFR1 in STS. Experimental Design: The frequency of FGFR1 amplification and overexpression, as assessed by fluorescence in situ hybridization, microarray-based comparative genomic hybridization and mRNA expression profiling, SNP array profiling, and RNA sequencing, was determined in three patient cohorts. The sensitivity of STS cell lines with or without FGFR1 alterations to genetic and pharmacologic FGFR1 inhibition and the signaling pathways engaged by FGFR1 were investigated using viability assays, colony formation assays, and biochemical analysis. Results: Increased FGFR1 copy number was detected in 74 of 190 (38.9%; Cohort 1), 13 of 79 (16.5%; Cohort 2), and 80 of 254 (31.5%; Cohort 3) patients. FGFR1 overexpression occurred in 16 of 79 (20.2%, Cohort 2) and 39 of 254 (15.4%; Cohort 3) patients. Targeting of FGFR1 by RNA interference and small-molecule inhibitors (PD173074, AZD4547, BGJ398) revealed that the requirement for FGFR1 signaling in STS cells is dictated by FGFR1 expression levels, and identified the MAPK-ERK1/2 axis as critical FGFR1 effector pathway. Conclusions: These data identify FGFR1 as driver gene in multiple STS subtypes and support FGFR1 inhibition, guided by patient selection according to FGFR1 expression and monitoring of MAPK-ERK1/2 signaling, as therapeutic option in this challenging group of diseases.

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Determinants of Ibrutinib-induced apoptosis in CLL

Purpose: Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, is approved for the treatment of relapsed CLL and CLL with del17p. Mechanistically, ibrutinib interferes with BCR signaling as well as multiple CLL cell to microenvironment interactions. Given the importance of ibrutinib in the management of CLL, a deeper understanding of factors governing sensitivity and resistance is warranted. Experimental Design: We studied 48 longitudinally sampled paired CLL samples, 42 of which were procured before and after standard CLL chemotherapies, and characterized them for well-studied CLL molecular traits as well as by whole exome sequencing and SNP 6.0 array profiling. We exposed these samples to 0.25 µM - 5 µM of ibrutinib ex vivo and measured apoptosis fractions as well as BCR signaling by immunoblotting. We disrupted TP53 in HG3, PGA1 and PG-EBV cell lines and measured BCR signaling and ibrutinib responses. Results: CLL samples demonstrated a surprisingly wide range of ex vivo sensitivities to ibrutinib with IC50 values ranging from 0.4 µM - 9.7 µM. Unmutated IGVH status, elevated ZAP70 expression and trisomy 12 were associated with heightened sensitivity to ibrutinib treatment. Five CLL samples were substantially more resistant to ibrutinib following relapse from chemotherapy; of these, three had acquired a del17p/TP53 mutated status. A validation sample of 15 CLL carrying TP53 mutations, of which 13 carried both del17p and a TP53 mutation confirmed substantially less sensitivity to ibrutinib-induced apoptosis. Conclusions: This study identifies that CLL harboring del17p/TP53 mutated cells are substantially less sensitive to ibrutinib-induced apoptosis than del17p/TP53 wild type cells.

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PD-1 inhibitor-related pneumonitis in advanced cancer

Purpose: Investigate the clinical characteristics, radiographic patterns, and treatment course of PD-1 inhibitor-related pneumonitis in advanced cancer patients. Experimental Design: Among patients with advanced melanoma, lung cancer, or lymphoma treated in trials of nivolumab, we identified those who developed pneumonitis. Chest CT scans were reviewed to assess extent, distribution, and radiographic patterns of pneumonitis. Results: Among 170 patients treated in 10 different trials of nivolumab, 20 patients (10 melanoma, 6 lymphoma, 4 lung cancer) developed pneumonitis. Five patients received nivolumab monotherapy and 15 received combination therapy. Median time from therapy initiation to pneumonitis was 2.6 months. Radiographic pattern was cryptogenic organizing pneumonia (COP) in 13, nonspecific interstitial pneumonia (NSIP) in 3, hypersensitivity pneumonitis (HP) in 2, and acute interstitial pneumonia (AIP)/acute respiratory distress syndrome (ARDS) in 2 patients. AIP/ARDS pattern had the highest grade, followed by COP, while NSIP and HP had lower grade (median Grade: 3, 2, 1, 1, respectively; p=0.006). COP pattern was most common in all tumors and treatment regimens. Most patients (17/20;85%) received corticosteroids, and 3 (15%) also required infliximab. Seven patients restarted nivolumab therapy; two of them developed recurrent pneumonitis and were successfully retreated with corticosteroids. One of the patients experienced a pneumonitis flare after completion of corticosteroid taper without nivolumab retreatment. Conclusions: PD-1 inhibitor-related pneumonitis showed a spectrum of radiographic patterns, reflecting pneumonitis grades. COP was the most common pattern across tumor types and therapeutic regimens. Most patients were successfully treated with corticosteroids. Recurrent pneumonitis and pneumonitis flare were noted in a few patients.

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Circulating tumor DNA mutation detection

DNA extracted from cancer patients' whole blood may contain somatic mutations from circulating tumor DNA (ctDNA) fragments. In this study, we introduce cmDetect, a computational method for the systematic identification of ctDNA mutations using whole-exome sequencing of a cohort of tumor and corresponding peripheral whole-blood samples. Through the analysis of simulated data, we demonstrated an increase in sensitivity in calling somatic mutations by combining cmDetect to two widely used mutation callers. In a cohort of 93 breast cancer metastatic patients, cmDetect identified ctDNA mutations in 54% of the patients and recovered somatic mutations in cancer genes EGFR, PIK3CA and TP53. We further showed that cmDetect detected ctDNA in 89% of patients with confirmed mutated cell-free tumor DNA by plasma analyses (n=9) within 46 pan-cancer patients. Our results prompt immediate consideration of the use of this method as an additional step in somatic mutation calling using whole-exome sequencing data with blood samples as controls.

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Serum antibodies and HPV infection

Naturally induced serum antibodies against HPV may affect risks of subsequent incident genital infections by HPV 6, 11, 16, or 18 in men. In this study, we examined this hypothesis by following 4,123 healthy men every six months (median follow-up time 4.1 years). HPV antibodies were measured at baseline using a virus-like particle-based ELISA assay. Genital HPV genotypes were detected using the Roche Linear Array. Incidence proportions and six-month persistence proportions were calculated at six-month intervals. Kaplan-Meier curves and Cox models were used to assess genotype-specific cumulative incidence and hazard ratios (HR), respectively. HPV 6, 11, 16, and 18 seroprevalence was 8.1%, 13.9%, 12.7%, and 10.8%, respectively. Significantly higher rates of incident infections were observed for HPV 16 among baseline seropositive men (adjusted HR 1.37, 95% CI 1.01-1.86), with similar but non-significant HRs for six-month persistent infections. Risk of persistent HPV 18 infection was significantly lower among seropositive men in the unadjusted model (HR 0.22, 95% CI 0.06-0.91), but not in the adjusted model (HR 0.19, 95% CI 0.03-1.37). Incident and six-month persistent infections for HPV 6 and 11 did not differ by baseline serostatus. Baseline serostatus among men was not associated with a reduction in subsequent incident genital HPV 6, 11 and 16 infections. However, protection against persistent HPV 18 infections was observed in unadjusted models. Our results suggest a need of further studies to examine the potentially protective effects of naturally induced HPV18 antibodies in men.

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BCL2 Inhibitors as Anticancer Agents

Antiapoptotic BCL2 proteins play a major role in tumor cell survival. Hence, BCL2 inhibitors have been developed as direct inducers of apoptosis. ABT-199 (venetoclax) received breakthrough therapy designation from the FDA due to its apparent efficacy in CLL and AML. However, resistance to ABT-199 is mediated by other BCL2 proteins including BCLX_L and MCL1. Considerable effort has been expended seeking novel "BH3 mimetics" that inhibit all of these BCL2 proteins. While many BH3 mimetics inhibit BCL2 proteins in vitro, they fail to directly inhibit them in intact cells. Many BH3 mimetics induce the unfolded protein response culminating in induction of the proapoptotic protein NOXA, which in turn inhibits MCL1. We propose simple experiments to validate BH3 mimetics in cells. A true BCL2 inhibitor will rapidly induce apoptosis in chronic lymphocytic leukemia cells ex vivo. A BCLX_L inhibitor will rapidly induce apoptosis in platelets. Finally, a BH3 mimetic targeting MCL1 will inhibit its degradation thereby inducing rapid MCL1 accumulation. Compounds that fail these tests should no longer be called BH3 mimetics. We now have a toolbox of selective inhibitors for most of the BCL2 proteins, and we hope these new tools will lead to effective treatment options for many cancers. Mol Cancer Ther; 15(9); 1–7. ©2016 AACR.

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Expression of vascular morphogenesis genes and CLM

Angiogenesis-related gene expression is associated with the efficacy of anti-VEGF therapy. We tested whether intratumoral mRNA expression levels of genes involved in vascular morphogenesis and early vessel maturation predict response, recurrence-free survival (RFS), and overall survival (OS) in a unique cohort of patients with colorectal liver metastases (CLM) treated with bevacizumab-based chemotherapy followed by curative liver resection. Intratumoral mRNA was isolated from resected bevacizumab-pretreated CLM from 125 patients. In 42 patients, a matching primary tumor sample collected prior to bevacizumab treatment was available. Relative mRNA levels of 9 genes (ACVRL1, EGFL7, EPHB4, HIF1A, VEGFA, VEGFB, VEGFC, FLT1, KDR) were analyzed by RT-PCR and evaluated for associations with response, RFS, and OS. P values for the associations between the individual dichotomized expression level and RFS were adjusted for choosing the optimal cut-off value. In CLM, high expression of VEGFB, VEGFC, HIF1A, and KDR and low expression of EGFL7 were associated with favorable RFS in multivariable analysis (P<0.05). High ACVRL1 levels predicted favorable 3-year OS (P=0.041) and radiologic response (PR 1.093, SD 0.539, P=0.002). In primary tumors, low VEGFA and high EGFL7 were associated with radiologic and histologic response (P<0.05). High VEGFA expression predicted shorter RFS (10.1 vs. 22.6 mo; HR 2.83, P=0.038). High VEGFB (46% vs. 85%; HR 5.75, P=0.009) and low FLT1 (55% vs. 100%; P=0.031) predicted lower 3-year OS rates. Our data suggest that intratumoral mRNA expression of genes involved in vascular morphogenesis and early vessel maturation may be promising predictive and/or prognostic biomarkers.

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ADCT-301 targets CD25-expressing hematological malignancies

Despite the many advances in the treatment of hematological malignancies over the past decade, outcomes in refractory lymphomas remain poor. One potential strategy in this patient population is the specific targeting of IL-2R-α (CD25), which is over-expressed on many lymphoma and leukemic cells, using antibody drug conjugates (ADCs). ADCT-301 is an ADC composed of human IgG1 HuMax®-TAC against CD25, stochastically conjugated through a dipeptide cleavable linker to a pyrrolobenzodiazepine (PBD) dimer warhead with a drug-antibody ratio (DAR) of 2.3. ADCT-301 binds human CD25 with picomolar affinity. ADCT-301 has highly potent and selective cytotoxicity against a panel of CD25-expressing human lymphoma cell lines. Once internalized, the released warhead binds in the DNA minor groove and exerts its potent cytotoxic action via the formation of DNA interstrand cross-links. A strong correlation between loss of viability and DNA cross-link formation is demonstrated. DNA damage persists, resulting in phosphorylation of histone H2AX, cell cycle arrest in G2/M and apoptosis. Bystander killing of CD25-negative cells by ADCT-301 is also observed. In vivo, a single-dose of ADCT-301 results in dose-dependent and targeted antitumor activity against both subcutaneous and disseminated CD25-positive lymphoma models. In xenografts of Karpas 299, which expressed both CD25 and CD30, marked superiority over brentuximab vedotin (Adcetris®) is observed. Dose-dependent increases in DNA cross-linking, -H2AX and PBD payload staining were observed in tumors in vivo indicating a role as relevant pharmacodynamic assays. Together these data support the clinical testing of this novel ADC in patients with CD25-expressing tumors.

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CD33- targeted thorium-227 conjugate

The clinical efficacy of the first approved alpha pharmaceutical Xofigo (radium-223 dichloride, 223RaCl2), has stimulated significant interest in the development of new alpha-particle emitting drugs in oncology. Unlike radium-223 (223Ra), the parent radionuclide thorium-227 (227Th) is able to form highly stable chelator complexes and is therefore amenable to targeted radioimmunotherapy (RIT). We describe the preparation and use of a CD33 targeted thorium-227 conjugate (CD33-TTC) which binds to the sialic-acid receptor CD33 for the treatment of acute myeloid leukemia (AML). A chelator was conjugated to the CD33-targeting antibody lintuzumab via amide bonds, enabling radiolabeling with the alpha-emitter 227Th. The CD33-TTC induced in vitro cytotoxicity on CD33-positive cells, independent of multiple drug resistance (MDR) phenotype. After exposure to CD33-TTC, cells accumulated DNA double strand breaks and were arrested in the G2 phase of the cell cycle. In vivo, the CD33-TTC demonstrated anti-tumor activity in a subcutaneous xenograft mouse model using HL-60 cells at a single dose regimen. Dose dependent significant survival benefit was further demonstrated in a disseminated mouse tumor model after single dose injection or administered as a fractionated dose. The data presented support the further development of the CD33-TTC as a novel alpha pharmaceutical for the treatment of AML.

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E7090, a novel selective inhibitor of FGFR

The fibroblast growth factor receptor (FGFR) signaling pathway has a crucial role in proliferation, survival, and migration of cancer cells, tumor angiogenesis, and drug resistance. FGFR genetic abnormalities, such as gene fusion, mutation, and amplification, have been implicated in several types of cancer. Therefore, FGFRs are considered potential targets for cancer therapy. E7090 is an orally available and selective inhibitor of the tyrosine kinase activities of FGFR1, -2, and -3. In kinetic analyses of the interaction between E7090 and FGFR1 tyrosine kinase, E7090 associated more rapidly with FGFR1 than did the type II FGFR1 inhibitor ponatinib, and E7090 dissociated more slowly from FGFR1, with a relatively longer residence time, than did the type I FGFR1 inhibitor AZD4547, suggesting that its kinetics are more similar to the type V inhibitors, such as lenvatinib. E7090 showed selective anti-proliferative activity against cancer cell lines harboring FGFR genetic abnormalities and decreased tumor size in a mouse xenograft model using cell lines with dysregulated FGFR. Furthermore, E7090 administration significantly prolonged the survival of mice with metastasized tumors in the lung. Our results suggest that E7090 is a promising candidate as a therapeutic agent for the treatment of tumors harboring FGFR genetic abnormalities. It is currently being investigated in a Phase 1 clinical trial.

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Dual-targeting APE1/Ref-1 and CA9 in hypoxic PDAC cells

Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related mortality in the United States. Aggressive treatment regimens have not changed the disease course, and the median survival has just recently reached a year. Several mechanisms are proposed to play a role in PDAC therapeutic resistance, including hypoxia, which creates a more aggressive phenotype with increased metastatic potential and impaired therapeutic efficacy. AP Endonuclease-1/ Redox Effector Factor 1 (APE1/Ref-1) is a multi-functional protein possessing a DNA repair function in base excision repair and the ability to reduce oxidized transcription factors, enabling them to bind to their DNA target sequences. APE1/Ref-1 regulates several transcription factors involved in survival mechanisms, tumor growth, and hypoxia signaling. Here, we explore the mechanisms underlying PDAC cell responses to hypoxia and modulation of APE1/Ref-1 redox signaling activity, which regulates the transcriptional activation of hypoxia inducible factor 1 alpha (HIF1α). Carbonic anhydrase IX (CA9) is regulated by HIF1α and functions as part of the cellular response to hypoxia to regulate intracellular pH, thereby promoting cell survival. We hypothesized that modulating APE1/Ref-1 function will block activation of downstream transcription factors, STAT3 and HIF1α, interfering with hypoxia-induced gene expression. We demonstrate APE1/Ref-1 inhibition in patient-derived and established PDAC cells results in decreased HIF1α–mediated induction of CA9. Furthermore, an ex vivo 3D tumor co-culture model demonstrates dramatic enhancement of APE1/Ref-1-induced cell killing upon dual-targeting of APE1/Ref-1 and CA9. Both APE1/Ref-1 and CA9 are under clinical development, therefore these studies have the potential to direct novel PDAC therapeutic treatment.

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Bazedoxifene as a novel GP130 signaling inhibitor

The IL-6/GP130/STAT3 pathway is crucial for tumorigenesis in multiple cancer types, including pancreatic cancer and presents as a viable target for cancer therapy. We reported Bazedoxifene, which is approved as a selective estrogen modulator by FDA, as a novel inhibitor of IL-6/GP130 protein–protein interactions using multiple ligand simultaneous docking and drug repositioning approaches. STAT3 is one of the major downstream effectors of IL-6/GP130. Here, we observed Bazedoxifene inhibited STAT3 phosphorylation and STAT3 DNA binding, induced apoptosis, and suppressed tumor growth in pancreatic cancer cells with persistent IL-6/GP130/STAT3 signaling in vitro and in vivo. In addition, IL-6 but not INF- rescued Bazedoxifene-mediated reduction of cell viability. Bazedoxifene also inhibited STAT3 phosphorylation induced by IL-6 and IL-11, but not by OSM or STAT1 phosphorylation induced by INF- in pancreatic cancer cells, suggesting that Bazedoxifene inhibits GP130/STAT3 pathway mediated by IL-6 and IL-11. Furthermore, Bazedoxifene combined with paclitaxel or gemcitabine synergistically inhibited cell viability and cell migration in pancreatic cancer cells. These results indicate that Bazedoxifene is a potential agent and can generate synergism when combined with conventional chemotherapy in human pancreatic cancer cells and tumor Xenograft in mice. Therefore, our results support that Bazedoxifene as a novel inhibitor of GP130 signaling and may be a potential and safe therapeutic agent for human pancreatic cancer therapy.

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Oncofertility in Japan: advances in research and the roles of oncofertility consortia

Future Oncology Ahead of Print.


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Multiparametric MRI of the prostate gland: technical aspects

Future Oncology Ahead of Print.


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Late recurrence of gastric cancer in the ovary and uterine cervix

Abstract

Uterine cervical metastasis from gastric cancer is relatively rare. This is a report of an extremely rare instance of concurrent late gastric-cancer recurrence to the left ovary and the uterine cervix, 11 years after initial treatment. A 53-year-old woman was referred to our hospital with continuous abdominal pain and genital bleeding. Eleven years prior, she had been treated for gastric cancer, pathologically confirmed as stage II poorly differentiated adenocarcinoma with signet-ring cell carcinoma (pT2N1M0). Magnetic resonance imaging results showed a solid mass in the left ovary, about 8 cm in diameter, fixed to the enlarged uterus and displaying slightly high intensity on T1-weighted images and uneven low intensity and enhanced hypervascular areas on T2-weighted images. Cervical biopsy revealed small, round, spindle-shaped tumor cells beneath a normal cervical epithelium. When we did the immunohistochemistry tests, the tumor cells were positive for cytokeratin 5.2, cytokeratin anion exchange protein 1/3, and cytokeratin 7; the cells were negative for cytokeratin 20 and paired-box gene (PAX) 8. This marker pattern was the same as that of her previous gastric cancer; therefore, the tumors of the cervix and left ovary were diagnosed as metastatic gastric cancer. After obtaining informed consent, the patient received transarterial chemoembolization using cisplatin and, subsequently, underwent a modified radical hysterectomy, bilateral salpingo-oophorectomy. Pathological examination revealed an infiltrative pattern with poorly differentiated adenocarcinoma and signet-ring cell carcinoma. The patient received combination chemotherapy with cisplatin and S-1, and she is currently alive 12 months after surgery with no evidence of recurrence. Late recurrence more than 10 years after treatment for primary gastric cancer is extremely rare. Clinicians should be aware of the possibility of metastasis from extrapelvic carcinomas, even in patients treated many years prior to presentation.

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Gender specific association of TP53 polymorphisms (EX4 215G > C Arg72Pro, IVS3 + 40-41ins16 and IVS6 + 62G > A), with risk of oral cancer subtypes and overall survival of the patients

Abstract

Reports on the association of TP53 polymorphisms with oral cancer are not only limited but also not specific to site and/or gender. Hence, we examined the effect of TP53 polymorphisms (EX4 215G > C, IVS3 + 40-41ins16 and IVS6 + 62G > A) on buccal mucosa cancer (BMC) and tongue cancer (TC) risk, survival of patients in relation to risk and clinical factors, gender wise [excepting for estimating hazards ratio (HR)], using Fisher's Exact Test, Kaplan-Meier analysis and Cox-proportional hazards models. The exonic polymorphism increased BMC and TC risk in males by 2-4 fold. The IVS3 + 40-41ins16 was protective against BMC and TC in both genders, whereas IVS6 + 62G > A protected only males against TC. Genotype combinations and haplotypes which altered the risk of cancers in males and females were different. TC males, aged 40-44 years and females, aged 55-59 years survived better than BMC patients. The IVS3 + 40-41ins16 polymorphism differentially impacted survival of female patients exposed to tobacco. TC patients with EX4 215GC with lymphovascular spread (LVS) and metastasis exhibited higher HR while, patients with EX4 215CC and perineural invasion (PNI) showed lower HR. Impact of the intronic variants along with clinical parameters on survival and HR estimates varied between BMC and TC. Our bioinformatics analysis revealed the presence of CTCF binding site within TP53 gene. In conclusion, the polymorphisms altered risk and survival of BMC and TC in a gender specific manner, which varied with mode of tobacco and/or alcohol use. The current study, therefore underscores strong need for research, stratified by tumor site and gender. This article is protected by copyright. All rights reserved

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TWIST1 up-regulates the MAGEA4 oncogene

Abstract

Background

Overexpression of MAGEA4 oncogene has been demonstrated in different malignancies; however, little is known about its exact mechanism for overexpression. TWIST1, as a bHLH transcription factor, activates a cell migration-invasion program involved in both embryonic and tumor development. Since MAGEA4 overexpression was statistically correlated to TWIST1, we aimed to elucidate the probable regulatory role of TWIST1 on MAGEA4 expression in KYSE30 cells.

Methods

Expression pattern of MAGEA4 and TWIST1 was analyzed in 55 ESCC patients using relative comparative Real-time PCR. In silico analysis of the MAGEA4 gene was performed. Methylation status of MAGEA4 promoter was determined by quantitative methylation specific PCR (qMSP). Using a retroviral system, KYSE30 cells were transduced to ectopically express TWIST1, followed by qRT-PCR, western blot analysis, Chromatin Immuno-Precipitation (ChIP) and luciferase assays to elucidate the regulatory role of TWIST1 on MAGEA4 gene expression.

Results

Concomitant overexpression of MAGEA4 and TWIST1 was detected in ESCC in significant correlation with each other in different clinicopathological indices of poor prognosis (p < 0.05). The TWIST1 expressing cells showed significantly higher MAGEA4 expression compared to control cells. ChIP and luciferase assays results confirmed indirect binding of TWIST1 to the E-boxes of MAGEA4 promoter sequence and revealed a novel regulatory role of TWIST1 in MAGEA4 up-regulation.

Conclusion

Since MAGEA4 is a highly expressed oncogene in a variety of malignancies in significant correlation with tumor cell invasiveness and aggressiveness, our finding may help to understand one regulatory mechanism of increased expression in tumor cells. This article is protected by copyright. All rights reserved

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MicroRNA-21 regulates the ERK/NF-κB signaling pathway to affect the proliferation, migration and apoptosis of human melanoma A375 cells by targeting SPRY1, PDCD4 and PTEN

ABSTRACT

Objective

To explore the effects of microRNA-21 (miR-21) and ERK/NF-κB signaling pathway on human melanoma A375 cells.

Methods

The melanoma tissues and adjacent normal tissues were obtained from 45 melanoma patients. qRT-PCR was conducted to quantify the expression of miR-21 and the gene mRNA expressions. Human melanoma A375 cells were divided into the Mock, negative control (NC), miR-21 inhibitors, miR-21 inhibitors + siRNA-SPRY1, miR-21 inhibitors + siRNA-PDCD4 and miR-21 inhibitors + siRNA-PTEN groups. Western blotting was used to determine protein expressions. CCK8 assay and Transwell assay were performed to evaluate the proliferation, migration and invasion of A375 cells. Annexin V/propidium iodide double staining and flow cytometry were adopted to detect cell apoptosis.

Results

MiR-21 expression was higher in melanoma tissues than in adjacent tissues, while the mRNA and protein expressions of SPRY1, PDCD4 and PTEN were lower in melanoma tissues than in adjacent tissues. Compared with the Mock and NC groups, the miR-21 inhibitors group exhibited increased expressions of SPRY1, PDCD4 and PTEN and decreased expressions of ERK, p-ERK, NF-κB p65 and p-NF-κB p65. After transfection of miR-21 inhibitors, the proliferation, migration and invasion of A375 cells were inhibited, while the apoptosis of A375 cells was promoted. However, the effects of miR-21 inhibitors on the growth, migration, invasion and apoptosis of A375 cells were reversed after transfection of siRNA-SPRY1, siRNA-PDCD4 or siRNA-PTEN.

Conclusion

MiR-21 can promote the proliferation, migration and inhibit the apoptosis of human melanoma A375 cells by inhibiting SPRY1, PDCD4 and PTEN via ERK/NF-κB signaling pathway. This article is protected by copyright. All rights reserved

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Oroxylin A reverses the drug resistance of chronic myelogenous leukemia cells to imatinib through CXCL12/CXCR7 axis in bone marrow microenvironment

Abstract

Imatinib (IM), a tyrosine-kinase inhibitor, is used in treatment of multiple cancers, most notably Philadelphia chromosome-positive (Ph⁺) chronic myelogenous leukemia (CML). However, the majority of patients continue to present with minimal residual disease occurred in the bone marrow (BM) microenvironment. One of the key factors that contribute to leukemia cell drug resistance is chemokine CXCL12. In the current study, co-culturing CML cell K562 and KU812 with BM stromal cell M2-10B4 attenuated IM-induced apoptosis. CXCL12/CXCR7 pathway was activated in co-culture models, which was further proved to be related to drug resistance by silencing CXCR7. ERK phosphorylation and downstream apoptosis related proteins' activation were also observed in co-culture group after the activation of CXCR7. Moreover, oroxylin A, a bioactive flavonoid isolated from the root of Scutellaria baicalensis Georgi, was found to be effective in reversing BM stroma induced CML resistance to IM. After cells were treated with weakly toxic concentration of oroxylin A, cell apoptosis induced by IM in co-culture model was enhanced. And the activated CXCL12/CXCR7 pathway, the expression of p-ERK and downstream apoptosis related proteins were suppressed. The in vivo study also showed that oroxylin A increased apoptosis of CML cells with low systemic toxicity, and the mechanism was consistent with the in vitro study. In conclusion, oroxylin A improved sensitivity of CML cells to IM treatment in BM microenvironment through regulating CXCL12/CXCR7 pathway. This article is protected by copyright. All rights reserved

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Alcohol promotes migration and invasion of triple-negative breast cancer cells through activation of p38 MAPK and JNK

Abstract

Although alcohol is an established breast cancer risk factor, the underlying mechanisms remain unclear. Previous studies examined the general association between alcohol consumption and breast cancer risk; however the risk for different breast cancer subtypes has been rarely reported. Triple-negative breast cancer (TNBC) is a subtype of breast cancer lacking hormone receptors and HER2 expression, and having poor prognosis. Understanding the molecular mechanisms of TNBC etiology remains a significant challenge. In this study, we investigated cellular responses to alcohol in two TNBC cell lines, MDA-MB-231 and MDA-MB-468. Our results showed that alcohol at low concentrations (0.025%-0.1% v/v) induced cell proliferation, migration, and invasion in 1% FBS-containing medium. Molecular analysis indicated that these phenotypic changes were associated with alcohol-induced reactive oxygen species production and increased p38 and JNK phosphorylation. Likewise, p38 or JNK inhibition attenuated alcohol-induced cell migration and invasion. We revealed that alcohol treatment activated/phosphorylated NF-κB regulators and increased transcription of NF-κB-targeted genes. While examining the role of acetaldehyde, the major alcohol metabolite, in alcohol-associated responses in TNBC cells, we saw that acetaldehyde induced cell migration, invasion, and increased phospho-p38, phospho-JNK, and phospho-IκBα in a pattern similar to alcohol treatment. Taken together, we established that alcohol promotes TNBC cell proliferation, migration, and invasion in vitro. The underlying mechanisms involve the induction of oxidative stress and the activation of NF-κB signaling. In particular, the activation of p38 and JNK plays a pivotal role in alcohol-induced cellular responses. These results will advance our understanding of alcohol-mediated development and promotion of TNBC. This article is protected by copyright. All rights reserved

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Silibinin inhibits hypoxia-induced HIF-1α-mediated signaling, angiogenesis and lipogenesis in prostate cancer cells: In vitro evidence and in vivo functional imaging and metabolomics

ABSTRACT

Hypoxia is associated with aggressive phenotype and poor prognosis in prostate cancer (PCa) patients suggesting that PCa growth and progression could be controlled via targeting hypoxia-induced signaling and biological effects. Here, we analyzed silibinin (a natural flavonoid) efficacy to target cell growth, angiogenesis and metabolic changes in human PCa, LNCaP and 22Rv1 cells under hypoxic condition. Silibinin treatment inhibited the proliferation, clonogenicity and endothelial cells tube formation by hypoxic (1% O₂) PCa cells. Interestingly, hypoxia promoted a lipogenic phenotype in PCa cells via activating acetyl-Co A carboxylase (ACC) and fatty acid synthase (FASN) that was inhibited by silibinin treatment. Importantly, silibinin treatment strongly decreased hypoxia-induced HIF-1α expression in PCa cells together with a strong reduction in hypoxia-induced NADPH oxidase (NOX) activity. HIF-1α overexpression in LNCaP cells significantly increased the lipid accumulation and NOX activity; however, silibinin treatment reduced HIF-1α expression, lipid levels, clonogenicity and NOX activity even in HIF-1α overexpressing LNCaP cells. In vivo, silibinin feeding (200 mg/kg body weight) to male nude mice with 22Rv1 tumors, specifically inhibited tumor vascularity (measured by dynamic contrast-enhanced MRI) resulting in tumor growth inhibition without directly inducing necrosis (as revealed by diffusion-weighted MRI). Silibinin feeding did not significantly affect tumor glucose uptake measured by FDG-PET; however, reduced the lipid synthesis measured by quantitative ¹H-NMR metabolomics. IHC analyses of tumor tissues confirmed that silibinin feeding decreased proliferation and angiogenesis as well as reduced HIF-1α, FASN and ACC levels. Together, these findings further support silibinin usefulness against PCa through inhibiting hypoxia-induced signaling. This article is protected by copyright. All rights reserved

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Emerging links among Chromosome Instability (CIN), cancer, and aging

Abstract

Aneuploidy was predicted to cause cancer. To test the prediction, various Chromosome Instability (CIN) mice models that carry transgenic mutations in mitotic regulators have been created. The availability of these mice has aided researchers in discovering connections between CIN, cancer, and aging. This review will focus on recent interdisciplinary findings regarding how CIN and aneuploidy affect carcinogenesis, immune dysfunction, and aging. High CIN can be generated in vivo by various intrinsic alterations (e.g., gene mutation, epigenetic modification) and extrinsic/environmental challenges (e.g., biological, chemical, biophysical), while immune surveillance, cell death, and natural turnover can remove cells with CIN. CIN itself is mutagenic and may cause further cellular mutations, which can be carcinogenic. Mitotically damaged cells can activate senescence-related tumor suppressors (e.g., p21^WAF1, p27^KIP1, p16^INK4A), which may lead to tissue-level senescence/aging through inflammatory paracrine mechanisms called Senescence-Associated Secretory Phenotype (SASP) and Senescence Inflammatory Response (SIR). Organs with high CIN show altered gene expressions in both organ-specific and non-specific manners. Organ-specific gene expression signatures include activation of oncogenic pathways. Non-organ-specific gene expression signatures include metabolic changes and downregulations in immune functions. Immune surveillance normally targets senescent cells and tetraploid cells, a form of aneuploidy, for elimination. However, with partial immune dysfunction, immune surveillance is weakened with systemic CIN. In this case, more senescent cells and aneuploid cells survive, which further leads to an inflammatory, pro-tumorigenic, and senescent/aging microenvironment. We also discuss how we may intervene in this sequence of events to prevent CIN- or age-related carcinogenesis and/or some aspects of tissue aging. This article is protected by copyright. All rights reserved

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Transient effects of tumor location on the functional architecture at rest in glioblastoma patients: three longitudinal case studies

Abstract

Background

The cognitive function of brain tumor patients is affected during the treatment. There is evidence that gliomas and surgery alter the functional brain connectivity but studies on the longitudinal effects are lacking.

Methods

We acquired longitudinal (pre- and post-radiotherapy) resting-state functional magnetic resonance imaging on three selected glioblastoma patients. These cases were selected to study three models: a lesion involving a functional hub within a central system, a lesion involving a peripheral node within a central system and a lesion involving a peripheral node of a non-central system.

Results

We found that, as expected, the tumor lesion affects connections in close vicinity, but when the lesion relates to a functional hub, these changes involve long-range connections leading to diverse connectivity profiles pre- and post-radiotherapy. In particular, a global but temporary improvement in the post-radiotherapy connectivity was obtained when treating a lesion close to a network hub, such as the posterior Cingulate Cortex.

Conclusions

This suggests that this node re-establishes communication to nodes further away in the network. Eventually, these observed effects seem to be transient and on the long-term the tumor burden leads to an overall decline of connectivity following the course of the pathology. Furthermore, we obtained that the link between hubs, such as the Supplementary Motor Area and posterior Cingulate Cortex represents an important backbone by means of which within and across network communication is handled: the disruption of this connection seems to imply a strong decrease in the overall connectivity.

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Proton beam therapy with concurrent chemotherapy for glioblastoma multiforme: comparison of nimustine hydrochloride and temozolomide

Abstract

To evaluate the safety and efficacy of postoperative proton beam therapy (PBT) combined with nimustine hydrochloride (ACNU) or temozolomide (TMZ) for glioblastoma multiforme (GBM). The subjects were 46 patients with GBM who were treated with high dose (96.6 GyE) PBT. There were 24 males and 22 females, and the median age was 58 years old (range 24–76). The Karnofsky performance status was 60, 70, 80, 90 and 100 in 5, 10, 12, 11 and 8 patients, respectively. Total resection, partial resection, and biopsy were performed for 31, 14 and 1 patients, respectively. Photon beams were delivered to high intensity areas on T2-weighted magnetic resonance imaging (MRI) in the morning (50.4 Gy in 28 fractions). More than 6 h later, PBT was delivered to the enhanced area plus a 10 mm margin in the first half of the protocol (23.1 GyE in 14 fractions) and to the enhanced volume in the second half (23.1 GyE in 14 fraction). Concurrent chemotherapy with ACNU during weeks 1 and 4 or daily TMZ was administered in 23 and 23 patients, respectively. The overall 1 and 2 year survival rates were 82.6 and 47.6 %, respectively. Median survival was 21.1 months (95 % CI 13.1–29.2), with no significant difference in survival between the ACNU and TMZ groups. The patient characteristics were similar in the two groups. Late radiation necrosis occurred in 11 patients (six ACNU, five TMZ), but was controlled by necrotomy and therapy including bevacizumab. PBT concurrent with ACNU or TMZ was tolerable and beneficial for carefully selected patients with GBM.

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Serial analysis of 3D H-1 MRSI for patients with newly diagnosed GBM treated with combination therapy that includes bevacizumab

Abstract

Interpretation of changes in the T1- and T2-weighted MR images from patients with newly diagnosed glioblastoma (GBM) treated with standard of care in conjunction with anti-angiogenic agents is complicated by pseudoprogression and pseudoresponse. The hypothesis being tested in this study was that 3D H-1 magnetic resonance spectroscopic imaging (MRSI) provides estimates of levels of choline, creatine, N-acetylaspartate (NAA), lactate and lipid that change in response to treatment and that metrics describing these characteristics are associated with survival. Thirty-one patients with newly diagnosed GBM and being treated with radiation therapy (RT), temozolomide, erlotinib and bevacizumab were recruited to receive serial MR scans that included 3-D lactate edited MRSI at baseline, mid-RT, post-RT and at specific follow-up time points. The data were processed to provide estimates of metrics representing changes in metabolite levels relative to normal appearing brain. Cox proportional hazards analysis was applied to examine the relationship of these parameters with progression free survival (PFS) and overall survival (OS). There were significant reductions in parameters that describe relative levels of choline to NAA and creatine, indicating that the treatment caused a decrease in tumor cellularity. Changes in the levels of lactate and lipid relative to the NAA from contralateral brain were consistent with vascular normalization. Metabolic parameters from the first serial follow-up scan were associated with PFS and OS, when accounting for age and extent of resection. Integrating metabolic parameters into the assessment of patients with newly diagnosed GBM receiving therapies that include anti-angiogenic agents may be helpful for tracking changes in tumor burden, resolving ambiguities in anatomic images caused by non-specific treatment effects and for predicting outcome.

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Type 2 diabetes mellitus and risk of colorectal adenoma: a meta-analysis of observational studies

Abstract

Background

To summarize the relationship between type 2 diabetes mellitus (T2DM) and risk of colorectal adenomas (CRA), we performed a meta-analysis of observational studies.

Methods

To find studies, we searched PubMed, Embase, the Cochrane Library, Web of Science and conference abstracts and related publications for American Society of Clinical Oncology and the European Society of Medical Oncology. Studies that reported relative risks (RRs) or odds ratios (ORs) with 95 % confidence intervals (CIs) for the association between T2DM and risk of CRA were included. The meta-analysis assessed the relationships between T2DM and risk of CRA. Sensitivity analyses were performed in two ways: (1) by omitting each study iteratively and (2) by keeping high-quality studies only. Publication bias was detected by Egger's and Begg's tests and corrected using the trim and fill method.

Results

This meta-analysis included 17 studies with 28,999 participants and 6798 CRA cases. We found that T2DM was a risk factor for CRA (RR: 1.52; 95 % CI: 1.29–1.80), and also for the advanced adenoma (RR: 1.41; 95 % CI: 1.06–1.87). Patients with existing T2DM (RR: 1.56; 95 % CI: 1.16–2.08) or newly diagnosed T2DM (RR: 1.51; 95 % CI: 1.16–1.97) have a risk of CRA. Similar significant results were found in retrospective studies (RR: 1.57; 95 % CI: 1.30–1.89) and population based cross-sectional studies (RR: 1.46; 95 % CI: 1.21–1.89), but not in prospective studies (RR: 1.27; 95 % CI: 0.77–2.10).

Conclusions

Our results suggested that T2DM plays a risk role in the risk of developing CRA. Consequently, medical workers should increase the rate of CRA screening for T2DM patients so that they can benefit from behavioural interventions that can help prevent the development of colorectal cancer. Additional, large prospective cohort studies are needed to make a more convincing case for these associations.

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Cholesterol and prostate cancer risk: a long-term prospective cohort study

Abstract

Background

Few studies have taken risk of competing events into account when examining the relationship between cholesterol and prostate cancer incidence, and few studies have a follow-up over several decades. We aimed to use these approaches to examine the relationship between cholesterol and prostate cancer.

Methods

A cohort of 1997 healthy Norwegian men aged 40–59 years in 1972–75 was followed throughout 2012. Cancer data were extracted from the Cancer Registry of Norway. The association between cholesterol and prostate cancer incidence was assessed using competing risk regression analysis, with adjustment for potential confounders. Date and cause of death was obtained from the Cause of Death Registry of Norway.

Results

The study cohort had a cancer risk similar to the general Norwegian population. Prostate cancer was registered in 213 men (11 %), including 62 (3 %) with advanced stage at diagnosis. For overall and advanced stage prostate cancer, the incidence was twice as high in the lowest quartile of cholesterol compared to the highest quartile. These associations remained significant after adjustment for age, smoking, physical fitness, BMI, and systolic blood pressure. Furthermore, high physical fitness and low BMI were associated with increased prostate cancer incidence. Sensitivity analyses excluding events during the first 20 years of observation revealed similar results.

Conclusion

Low cholesterol, as well as high physical fitness and low BMI, may be associated with increased risk of prostate cancer. These findings conflict with current prostate cancer prevention recommendations.

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A phase 1 ‘window-of-opportunity’ trial testing evofosfamide (TH-302), a tumour-selective hypoxia-activated cytotoxic prodrug, with preoperative chemoradiotherapy in oesophageal adenocarcinoma patients

Abstract

Background

Neo-adjuvant chemoradiotherapy followed by surgery is the standard treatment with curative intent for oesophageal cancer patients, with 5-year overall survival rates up to 50 %. However, patients' quality of life is severely compromised by oesophagectomy, and eventually many patients die due to metastatic disease.

Most solid tumours, including oesophageal cancer, contain hypoxic regions that are more resistant to chemoradiotherapy. The hypoxia-activated prodrug evofosfamide works as a DNA-alkylating agent under these hypoxic conditions, which directly kills hypoxic cancer cells and potentially minimizes resistance to conventional therapy. This drug has shown promising results in several clinical studies when combined with chemotherapy. Therefore, in this phase I study we investigate the safety of evofosfamide added to the chemoradiotherapy treatment of oesophageal cancer.

Methods/Design

A phase I, non-randomized, single-centre, open-label, 3 + 3 trial with repeated hypoxia PET imaging, will test the safety of evofosfamide in combination with neo-adjuvant chemoradiotherapy in potentially resectable oesophageal adenocarcinoma patients. Investigated dose levels range from 120 mg/m2 to 340 mg/m2. Evofosfamide will be administered one week before the start of chemoradiotherapy (CROSS-regimen) and repeated weekly up to a total of six doses. PET/CT acquisitions with hypoxia tracer ¹⁸F-HX4 will be made before and after the first administration of evofosfamide, allowing early assessment of changes in hypoxia, accompanied with blood sampling to measure hypoxia blood biomarkers. Oesophagectomy will be performed according to standard clinical practice.

Higher grade and uncommon non-haematological, haematological, and post-operative toxicities are the primary endpoints according to the CTCAEv4.0 and Clavien-Dindo classifications. Secondary endpoints are reduction in hypoxic fraction based on ¹⁸F-HX4 imaging, pathological complete response, histopathological negative circumferential resection margin (R0) rate, local and distant recurrence rate, and progression free and overall survival.

Discussion

This is the first clinical trial testing evofosfamide in combination with chemoradiotherapy. The primary objective is to determine the dose limiting toxicity of this combined treatment and herewith to define the maximum tolerated dose and recommended phase 2 dose for future clinical studies. The addition of non-invasive repeated hypoxia imaging ('window-of-opportunity') enables us to identify the biologically effective dose. We believe this approach could also be used for other hypoxia targeted drugs.

Trial registration

ClinicalTrials.gov Identifier: NCT02598687.

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Experiences of “openness” between mothers & daughters during breast cancer: implications for coping and healthy outcomes

Abstract

Objective

Mother-daughter communication is central to how women adjust to breast cancer. They may be aided by models of healthy communication that take illustrate both women's perspectives. Families establish normative communication patterns that inform how they cope. We used Family Communication Patterns theory to examine correlations between openness/avoidance and health. We extended this by capturing mother-daughter open/avoidant narratives to illustrate how these behaviors function in helpful (health-promoting) and unhelpful ways.

Methods

Phase 1 of this mixed-method study involved 41 patients and 37 mothers/daughters (N = 78) completing surveys on mother-daughter openness, avoidant coping, and quality of life. Phase 2 involved interviews with 40 patients and 38 mothers/daughters (N = 78) to ascertain what diagnosed women share (or don't) with their mother/daughter and their reasons.

Results

Diagnosed women reporting high levels of mother-daughter openness had better relational health (r = .730, p < .001). Those who engaged in more avoidant coping reported poorer physical health (r = -.431, p = .01). Mothers and daughters talked about treatment side effects and procedures, disease risk and prevention, and medical decisions. They avoided discussions about distressing emotions and topics and uncertainty about the future. Motivations to disclose/avoid centered on protecting themselves and/or their mother/daughter. Qualitative findings illustrate the tension between openness and avoidance. Developmental differences and relational role perspectives illustrate women's diverse needs.

Conclusions

A history of openness is linked with relational health, but coping is not as simple as "be open." Both openness/avoidance are helpful and unhelpful depending on age, topic, and responses. This article is protected by copyright. All rights reserved.

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Successful management of esophageal perforation using a removable self-expanding covered metallic stent after endoscopic submucosal dissection for a patient with a history of gastrectomy

Abstract

An 81-year-old man with esophageal perforation after endoscopic submucosal dissection, who had a history of distal gastrectomy and had undergone endoscopic submucosal dissection for high-grade intraepithelial dysplasia at another hospital, suddenly developed epigastric pain at night after vomiting. Computed tomography showed pneumomediastinum and bilateral pleural effusions indicating esophageal perforation. The initial doctor referred the patient to our department. On arrival, the patient was in septic shock with acute respiratory failure. It was considered that he was unable to undergo aggressive surgical treatment safely, and a stent with a silicone cover and check valve was placed. Drainage tubes were then inserted into the mediastinum and each thoracic cavity, and a double elementary diet tube was inserted for nutrition and decompression of the stomach. The stent was removed on the 26th day, and the perforation was cured. Stent insertion is a useful treatment for the patient with serious esophageal perforation after ESD with a history of gastrectomy.

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Characterization of VHL missense mutations in sporadic clear cell renal cell carcinoma: hotspots, affected binding domains, functional impact on pVHL and therapeutic relevance

Abstract

Background

The VHL protein (pVHL) is a multiadaptor protein that interacts with more than 30 different binding partners involved in many oncogenic processes. About 70 % of clear cell renal cell carcinoma (ccRCC) have VHL mutations with varying impact on pVHL function. Loss of pVHL function leads to the accumulation of Hypoxia Inducible Factor (HIF), which is targeted by current targeted treatments. In contrast to nonsense and frameshift mutations that highly likely nullify pVHL multipurpose functions, missense mutations may rather specifically influence the binding capability of pVHL to its partners. The affected pathways may offer predictive clues to therapy and response to treatment. In this study we focused on the VHL missense mutation pattern in ccRCC, and studied their potential effects on pVHL protein stability and binding partners and discussed treatment options.

Methods

We sequenced VHL in 360 sporadic ccRCC FFPE samples and compared observed and expected frequency of missense mutations in 32 different binding domains. The prediction of the impact of those mutations on protein stability and function was assessed in silico. The response to HIF-related, anti-angiogenic treatment of 30 patients with known VHL mutation status was also investigated.

Results

We identified 254 VHL mutations (68.3 % of the cases) including 89 missense mutations (35 %). Codons Ser65, Asn78, Ser80, Trp117 and Leu184 represented hotspots and missense mutations in Trp117 and Leu 184 were predicted to highly destabilize pVHL. About 40 % of VHL missense mutations were predicted to cause severe protein malfunction. The pVHL binding domains for HIF1AN, BCL2L11, HIF1/2α, RPB1, PRKCZ, aPKC-λ/ι, EEF1A1, CCT-ζ-2, and Cullin2 were preferentially affected. These binding partners are mainly acting in transcriptional regulation, apoptosis and ubiquitin ligation. There was no correlation between VHL mutation status and response to treatment.

Conclusions

VHL missense mutations may exert mild, moderate or strong impact on pVHL stability. Besides the HIF binding domain, other pVHL binding sites seem to be non-randomly altered by missense mutations. In contrast to LOF mutations that affect all the different pathways normally controlled by pVHL, missense mutations may be rather appropriate for designing tailor-made treatment strategies for ccRCC.

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A phase I/II clinical trial for the hybrid of intracavitary and interstitial brachytherapy for locally advanced cervical cancer

Abstract

Background

This paper describes about a study protocol of phase I/II multicenter prospective clinical trial evaluating the feasibility and efficacy of the hybrid of intracavitary and interstitial brachytherapy (HBT) for locally advanced uterine cervical cancer patients.

Methods and design

Patients with histologically confirmed FIGO stage IB2, IIA2, IIB, and IIIB uterine cervical carcinoma width of which is larger than 5 cm assessed by MRI will be entered to this clinical trial. Protocol therapy is 30-30.6 Gy in 15-17 fractions of whole pelvic radiotherapy concurrent with weekly CDDP (40 mg/m²), followed by 24 Gy in 4 fractions of HBT and central shield EBRT up to 50-50.4 Gy in 25-28 fractions. Tumor width is assessed again within one week before the first HBT and if the tumor width is larger than 4 cm, patients proceed to the secondary registration. In phase I section, feasibility of this will be investigated. If less than 10 % out of 20 patients experienced greater than grade 3 acute non-hematologic adverse effects, the study proceeds to phase II part. In phase II part a total of 55 patients will be accrued and the efficacy of the HBT will be investigated comparing with historical control data. If the lower margin of 90 % confidence interval of the 2-year pelvic progression-free survival of the HBT trial is higher than 64 %, the HBT is considered to be more effective than conventional ICBT.

Discussion

The aim of this study is to demonstrate the feasibility and efficacy of the HBT for locally advanced cervical cancer. This trial will clarify the indication, feasibility, and efficacy of this new technique.

Trial registration

UMIN000019081; Registration date: 2015/9/30

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MPO density in primary cancer biopsies of ovarian carcinoma enhances the indicative value of IL-17 for chemosensitivity

Abstract

Background

Cancer of the ovary is mostly discovered at a late stage and cannot be removed by surgery alone. Therefore surgery is usually followed by adjuvant chemotherapy. However, few reliable biomarkers exist to predict response to chemotherapy of ovarian cancer. Previously, we could demonstrate that IL-17 density is indicative for chemosensitivity. This study focuses on the predictive value of myeloperoxidase (MPO) concerning response to chemotherapy of ovarian cancer.

Methods

Biopsies of mostly high-grade primary serous ovarian carcinomas and their matched recurrences were stained with MPO after fixation in formalin and embedding in paraffin. For this staining the technique of tissue-microarray was used. Recurrence within 6 months of the completion of platinum-based chemotherapy was defined as chemoresistance as previously publised. Data for MPO could be analyzed in 92 biopsies.

Results

MPO and IL-17 positive immune cells correlated significantly in biopsies of primary and recurrent carcinomas (r _s = 0.41; p = 0.004 and r _s = 0.40; p = 0.007, respectively). MPO expression alone did not predict response to chemotherapy, but in multivariate cox regression analysis including age, residual disease, number of chemotherapy cycles, FIGO classification and combined categorized MPO and IL-17 cell densities of primary cancer biopsies, the combination of both immune markers was an independent prognostic factor for recurrence-free survival (p = 0.013, HR = .23, 95CI = 0.07–0.73). There was no chemoresistant patient in the subgroup of MPO + IL-17+, neither in primary nor in recurrent cancer biopsies.

Conclusions

High MPO positive cell density enhances the indicative value of IL-17 for response to chemotherapy in ovarian carcinoma. Although, these results have to be validated in a larger cohort.

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Heterogeneity of ERG expression in prostate cancer: a large section mapping study of entire prostatectomy specimens from 125 patients

Abstract

Background

TMPRSS2:ERG fusions are frequent in prostate cancer, and occur predominantly in young patients. Several studies had proposed intratumoral heterogeneity of these fusions. This study was designed to determine frequency and extent of ERG fusion heterogeneity in early-onset prostate cancer (EO-PCA, <50 years) and in elderly patients.

Methods

The prostates from 63 EO-PCA and 62 elderly prostate cancer patients were thoroughly reviewed for presence of cancer foci. All 1592 tumor-containing sections were analyzed by immunohistochemistry for ERG expression.

Results

The prostates included in this study contained one tumor focus in 44, two tumor foci in 21, three tumor foci in 32, four tumor foci in 15, and five or more tumor foci in 13 patients. Among 59 cancer foci with ≤3 mm, 19 (32.2 %) were homogeneously ERG positive, 39 66.1 %) were homogeneously ERG negative, and one case (1.7 %) showed a heterogeneous ERG status. The fraction of homogeneously ERG positive cancer foci remained largely constant (14–37 %) with increasing tumor focus diameter but the fraction of heterogeneous ERG findings continuously increased with tumor size and reached 39 % in cancer foci larger than 22 mm. On a patient level, ERG expression was markedly more frequent in EO-PCA than in elderly patients: 13 % of EO-PCA were homogeneously and 62 % were heterogeneously ERG positive. In elderly patients, 3 % of cancers were homogeneously and 57 % were heterogeneously ERG positive (p = 0.0721).

Conclusion

These data show that about 20–30 % of prostate cancer foci have early ERG fusions. ERG fusions further occur in about 50 % of initially ERG negative cancer foci during cancer progression. The vast majority of cancers are heterogeneous for TMPRSS2:ERG fusions on a patient level, challenging the concept of classifying prostate cancer patients into "fusion type" and "non-fusion type" prostate cancer.

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Psychosocial outcomes of an electronic self-report assessment and self-care intervention for patients with cancer: randomized controlled trial

Abstract

Objective

The use of Web-based technology to facilitate self-care and communication with healthcare providers has the potential to improve psychosocial outcomes for patients undergoing cancer treatment. This study reports an analysis of psychosocial outcomes of the Electronic Self-Report Assessment for Cancer (ESRA-C-II) study.

Methods

Adult patients starting cancer therapy were randomized to receive usual education about symptoms and quality of life (SxQOL) topics (control) or usual education plus self-care instruction for SxQOL issues, communication coaching, and the opportunity to track SxQOL between clinic visits (intervention). Depression (Patient Health Questionnaire-9) and social, emotional, and role functioning (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 subscales) were measured before treatment (T1), 3-6 weeks after starting treatment (T2), 2 weeks later (T3), and 2-4 weeks after treatment ended or at the next restaging visit for participants who continued to receive treatment (T4). Clinicians received summaries of participant reports at each time point in both groups.

Results

In multivariable analysis, the depression scores were significantly lower (p = 0.04) and there was a trend to higher social and role functioning (p = 0.07) in the intervention group compared to the control. Working status was significantly associated with lower depression and better social and role functioning.

Conclusions

A patient-centered, Web-based intervention that facilitates self-care and communication can improve psychosocial outcomes in the cancer setting. This article is protected by copyright. All rights reserved.

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Negative trials in ovarian cancer: Is there such a thing as too much optimism?

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Caregiving and Social Support for Gay and Bisexual Men with Prostate Cancer

Abstract

Objective:

Prostate cancer, the second most common cancer among men, typically onsets in middle or older age. Gay/bisexual men have different social networks and unique social support needs, particularly as it pertains to health care access and prostate side effects. Few studies have investigated the availability and provision of social support for gay and bisexual men with prostate cancer (GBMPCa).

Methods

This study used qualitative data from in-depth, semi-structured, one-on-one telephone interviews with 30 GBMPCa recruited from a national cancer support group network, Malecare. Inductive and deductive coding were used to identify themes about social support provided to GBMPCa during diagnosis and treatment.

Results

GBMPCa reported help from friends, family (parents, siblings), ex-partners, and paid caregivers. Men in relationships reported varying levels of reliance on their partners for support, in part due to relationship dynamics and living arrangements. Single men showed a theme of independence ("I turned down all help", "my friends don't want to be bothered"). After diagnosis, many men reported seeking informational and emotional support from prostate cancer support groups; most expressed wanting more support groups specifically for GBMPCa. During or after treatment, men reported receiving a range of instrumental support, largely a function of relationship status and treatment type.

Conclusions

GBMPCa received variable, but generally low, social support during diagnosis and treatment and from a diverse social network, including a prominence of friends and family. Clinicians should be aware of GBMPCa's distinct patterns of social support needs and providers.

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2015 President's Plenary International Psycho-oncology Society: psychosocial care as a human rights issue—challenges and opportunities

Abstract

The International Psycho-Oncology Society (IPOS) Human Rights Task Force has been working since 2008 to raise awareness and support, for the relevance of psychosocial cancer care as a human rights issue. In 2014 the "Lisbon Declaration: Psychosocial Cancer Care as a Universal Human Right" was fully endorsed by IPOS. Subsequently, the IPOS Standard on Quality Cancer Care, endorsed by 75 cancer organizations worldwide, has been updated and now includes 3 core principles: Psychosocial cancer care should be recognised as a universal human right; Quality cancer care must integrate the psychosocial domain into routine care; Distress should be measured as the 6th vital sign. The President's plenary held at the 2015 World Congress of Psycho-Oncology in Washington DC was devoted to discussing psychosocial care as a human rights issue. Many challenges and opportunities are illustrated in different continents and contexts: from Africa where resources for basic cancer treatment are scarce and children and their parents face significant difficulties with hospital detention practices; to Europe where for many countries psychosocial care is still seen as a luxury; and the Middle East where Muslim women face stigma and a culture of silence over cancer. We further discuss how to move the Lisbon Declaration forward towards its implementation into clinical practice globally, using the successful example of the World Health Assembly resolution supporting palliative care as a human right which has achieved widespread approval, and identifying the vital role the IPOS Federation of National Psychoncology Societies plays worldwide to move this agenda forward. Copyright © 2016 John Wiley & Sons, Ltd.

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Spirituality is Associated with Less Treatment Regret in Men with Localized Prostate Cancer

Abstract

Objective:

Some prostate cancer patients go on to regret their treatment choice. Treatment regret is associated with lower physical and mental quality of life. We investigated whether, in men with prostate cancer, spirituality is associated with lower decisional regret 6 months after treatment and whether this is, in part, because men with stronger spiritual beliefs experience lower decisional conflict when they are deciding how to treat their cancer.

Methods

1093 prostate cancer patients (84% white, 10% black, 6% Hispanic; mean age = 63.18 (SD = 7.75)) completed measures of spiritual beliefs and decisional conflict after diagnosis and decisional regret 6 months after treatment. We used multivariable linear regression to test whether there is an association between spirituality and decisional regret, and structural equation modeling to test whether decisional conflict mediated this relationship.

Results

Stronger spiritual beliefs were associated with less decisional regret (b = -0.40, 95% CI = -0.55, -0.26, p < .001, partial η² = 0.03), after controlling for covariates. Decisional conflict partially (38%) mediated the effect of spirituality on regret; (indirect effect: b = -0.15, 95% CI = -0.20,-0.10, p < .001).

Conclusions

Spirituality may help men feel less conflicted about their cancer treatment decisions and ultimately experience less decisional regret. Psychosocial support post-diagnosis could include clarification of spiritual values and opportunities to reappraise the treatment decision-making challenge in light of these beliefs.

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CCL2 in Treg and MDSC trafficking to glioma

In many aggressive cancers, such as glioblastoma multiforme (GBM), progression is enabled by local immunosuppression driven by the accumulation of regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC). However, the mechanistic details of how Treg and MDSC are recruited in various tumors is not yet well understood. Here we report that macrophages and microglia within the glioma microenvironment produce CCL2, a chemokine that is critical for recruiting both CCR4+ Treg and CCR2+Ly-6C+ monocytic MDSC in this disease setting. In murine gliomas, we established novel roles for tumor-derived CCL20 and osteoprotegerin in inducing CCL2 production from macrophages and microglia. Tumors grown in CCL2 deficient mice failed to maximally accrue Treg and monocytic MDSC. In mixed-bone marrow chimera assays, we found that CCR4-deficient Treg and CCR2-deficient monocytic MDSC were defective in glioma accumulation. Further, administration of a small molecule antagonist of CCR4 improved median survival in the model. In clinical specimens of GBM, elevated levels of CCL2 expression correlated with reduced overall survival of patients. Lastly, we found that CD163-positive infiltrating macrophages were a major source of CCL2 in GBM patients. Collectively, our findings show how glioma cells influence the tumor microenvironment to recruit potent effectors of immunosuppression that drive progression.

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Inflammation triggers escape from latency

The emergence of metastatic disease in cancer patients many years or decades after initial successful treatment of primary tumors is well documented but poorly understood at the molecular level. Recent studies have begun exploring the cell-intrinsic programs causing disseminated tumor cells to enter latency and the cellular signals in the surrounding non-permissive tissue microenvironment that maintain the latent state. However, relatively little is known about the mechanisms that enable disseminated tumor cells to escape cancer dormancy or tumor latency. We describe here an in vivo model of solitary metastatic latency in the lung parenchyma. The induction of a localized inflammation in the lungs, initiated by lipopolysaccharide (LPS) treatment, triggers the awakening of these cells, which develop into macroscopic metastases. The escape from latency is dependent on the expression of Zeb1, a key regulator of the epithelial-to-mesenchymal transition (EMT). Furthermore, activation of the EMT program on its own, as orchestrated by Zeb1, is sufficient to incite metastatic outgrowth by causing carcinoma cells to enter stably into a metastasis-initiating cell state.

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Targeting DEPTOR in myeloma

DEPTOR is a 48kDa protein that binds to mTOR and inhibits this kinase in TORC1 and TORC2 complexes. Over-expression of DEPTOR specifically occurs in a model of multiple myeloma (MM). Its silencing in MM cells is sufficient to induce cytotoxicity, suggesting DEPTOR is a potential therapeutic target. mTORC1 paralysis protects MM cells against DEPTOR silencing, implicating mTORC1 in DEPTOR's critical role in MM cell viability. Building on this foundation, we interrogated a small molecule library for compounds that prevent DEPTOR binding to mTOR in a yeast-two-hybrid assay. One compound was identified that also prevented DEPTOR-mTOR binding in human myeloma cells with subsequent activation of mTORC1 and mTORC2. In a surface plasmon resonance (SPR) assay, the compound bound to recombinant DEPTOR but not to mTOR. The drug also prevented binding of recombinant DEPTOR to mTOR in the SPR assay. Remarkably, although activating TORC1 and TORC2, the compound induced apoptosis and cell cycle arrest in MM cell lines and prevented outgrowth of human MM cells in immunodeficient mice. In vitro cytotoxicity against MM cell lines was directly correlated with DEPTOR protein expression and was mediated, in part, by the activation of TORC1 and induction of p21 expression. Additional cytotoxicity was seen against primary MM cells while normal hematopoietic colony formation was unaffected. These results further support DEPTOR as a viable therapeutic target in MM and suggest an effective strategy of preventing binding of DEPTOR to mTOR.

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NUDT15 mediates 6-thioguanine efficacy in cells

Thiopurines are a standard treatment for childhood leukemia, but like all chemotherapeutics their use is limited by inherent or acquired resistance in patients. Recently, the nucleoside diphosphate hydrolase NUDT15 has received attention based on its ability to hydrolyze the thiopurine effector metabolites 6-thio-deoxy-GTP (dGTP) and 6-thio-GTP, thereby limiting the efficacy of thiopurines. In particular, increasing evidence suggests an association between the NUDT15 missense variant, R139C and thiopurine sensitivity. In this study, we elucidated the role of NUDT15 and NUDT15 R139C in thiopurine metabolism. In vitro and cellular results argued that 6-thio-dGTP and 6-thio-GTP are favored substrates for NUDT15, a finding supported by a crystallographic determination of NUDT15 in complex with 6-thio-GMP. We found that NUDT15 R139C mutation did not affect enzymatic activity but instead negatively influenced protein stability, likely due to a loss of supportive intramolecular bonds that caused rapid proteasomal degradation in cells. Mechanistic investigations in cells indicated that NUDT15 ablation potentiated induction of the DNA damage checkpoint and cancer cell death by 6-thioguanine. Taken together, our results defined how NUDT15 limits thiopurine efficacy and how genetic ablation via the R139C missense mutation confers sensitivity to thiopurine treatment in patients.

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Novel murine models of ovarian high grade serous carcinoma

There is a need for transplantable murine models of ovarian high grade serous carcinoma (HGSC) with regard to mutations in the human disease, to assist investigations of the relationships between tumor genotype, chemotherapy response and immune microenvironment. In addressing this need, we performed whole exome sequencing of ID8, the most widely-used transplantable model of ovarian cancer, covering 194,000 exomes at a mean depth of 400x with 90% exons sequenced >50x. We found no functional mutations in genes characteristic of HGSC (Trp53, Brca1, Brca2, Nf1, Rb1) and p53 remained transcriptionally active. Homologous recombination in ID8 remained intact in functional assays. Further, we found no mutations typical of clear cell carcinoma (Arid1A, Pik3ca), low grade serous carcinoma (Braf), endometrioid (Ctnnb1) or mucinous (Kras) carcinomas. Using CRISPR/Cas9 gene editing, we modeled HGSC by generating novel ID8 derivatives that harbored single (Trp53-/-) or double (Trp53-/-;Brca2-/-) suppressor gene deletions. In these mutants, loss of p53 alone was sufficient to increase the growth rate of orthotopic tumors with significant effects observed on the immune microenvironment. Specifically, p53 loss increased expression of the myeloid attractant CCL and promoted the infiltration of immunosuppressive myeloid cell populations into primary tumors and their ascites. In Trp53-/-;Brca2-/- mutant cells, we documented a relative increase in sensitivity to the PARP inhibitor rucaparib and slower orthotopic tumor growth compared to Trp53-/- cells, with an appearance of intra-tumoral tertiary lymphoid structures rich in CD3+ T cells. This work validates new CRISPR-generated models of HGSC to investigate its biology and promote mechanism-based therapeutics discovery.

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Water concentration analysis of the surgical margin

Adequate resection of oral cavity squamous cell carcinoma (OCSCC) means complete tumor removal with a clear margin of more than 5 mm. For OCSCC 85% of the surgical resections appear inadequate. Raman spectroscopy is an objective and fast tool that can provide real-time information about the molecular composition of tissue and has the potential to provide an objective and fast intraoperative assessment of the entire resection surface. A previous study demonstrated that OCSCC can be discriminated from healthy surrounding tissue based on the higher water concentration in tumor. In this study we investigated how the water concentration changes across the tumor border towards the healthy surrounding tissue on freshly excised specimens from the oral cavity. Experiments were performed on tissue sections from 20 patients undergoing surgery for OCSCC. A transition from a high to a lower water concentration, from tumor (76% {plus minus} 8% of water) towards healthy surrounding tissue (54% {plus minus} 24% of water), takes place over a distance of ≈ 4 to 6 mm across the tumor border. This was accompanied by an increase of the heterogeneity of the water concentration in the surrounding healthy tissue. The water concentration distributions between the regions were significantly different (p-values<0.0001). This new finding highlights the potential of Raman spectroscopy for objective intraoperative assessment of the resection margins.

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Plasma 25-hydroxyvitamin D and breast cancer risk

Experimental evidence supports a protective role of 25-hydroxyvitamin D (25(OH)D) in breast carcinogenesis, but epidemiologic evidence is inconsistent. Whether plasma 25(OH)D interacts with breast tumor expression of vitamin D receptor (VDR) and retinoid X receptor-alpha (RXR) has not been investigated. We conducted a nested case-control study in the Nurses' Health Study, with 1,506 invasive breast cancer cases diagnosed after blood donation in 1989-90, 417 of whom donated a second sample in 2000-02. VDR and RXR expression were assessed by immunohistochemical staining of tumor microarrays (n=669 cases). Multivariate relative risks (RRs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression. Results: Plasma 25(OH)D levels were not associated with breast cancer risk overall (top ({greater than or equal to}32.7ng/mL) vs. bottom (<17.2ng/mL) quintile RR=0.87, 95% CI (0.67-1.13), p-trend=0.21). 25(OH)D measured in summer (May-October) was significantly inversely associated with risk (top vs. bottom quintile RR=0.66, 95% CI (0.46-0.94), p-trend=0.01); winter levels (November-April) were not (RR=1.10, 95% CI (0.75-1.60), p-trend=0.64; p-interaction=0.03). 25(OH)D levels were inversely associated with risk of tumors with high expression of stromal nuclear VDR ({greater than or equal to}30ng/mL vs. <30ng/mL RR (95% CI): VDR{greater than or equal to}median=0.67 (0.48-0.93); VDR<median=0.98 (0.72-1.35), p-heterogeneity=0.12), and significantly stronger for summer measures (p-heterogeneity=0.01). Associations were not significantly different by RXR expression. No overall association was observed between plasma 25(OH)D and breast cancer risk. However, our results suggest women with high, compared with low, plasma 25(OH)D levels in the summer have a reduced breast cancer risk, and plasma 25(OH)D may be inversely associated with risk of tumors expressing high levels of VDR.

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