Cancers, Vol. 9, Pages 117: Reduced Cytokine Release in Ex Vivo Response to Cilengitide and Cetuximab Is a Marker for Improved Survival of Head and Neck Cancer Patients

Cancers, Vol. 9, Pages 117: Reduced Cytokine Release in Ex Vivo Response to Cilengitide and Cetuximab Is a Marker for Improved Survival of Head and Neck Cancer Patients

Cancers doi: 10.3390/cancers9090117

Authors: Susan Cedra Susanne Wiegand Marlen Kolb Andreas Dietz Gunnar Wichmann

Targeting of αVβ3 and αVβ5 integrins by cilengitide may reduce growth of solid tumors including head and neck squamous cell carcinoma (HNSCC). Preclinical investigations suggest increased activity of cilengitide in combination with other treatment modalities. The only published trial in HNSCC (ADVANTAGE) investigated cisplatin, 5-fluorouracil, and cetuximab (PFE) without or with once (PFE+CIL1W) or twice weekly cilengitide (PFE+CIL2W) in recurrent/metastatic HNSCC. ADVANTAGE showed good tolerability of the cilengitide arms and even lower adverse events (AEs) compared to PFE but not the benefit in overall survival expected based on preclinical data. As we found in the FLAVINO assay, a short-time ex vivo assay for prediction of chemosensitivity, only a subgroup of HNSCC had an increased suppressive effect of cilengitide containing combination therapies on colony formation of epithelial cells (CFec) and release of pro-angiogenetic and pro-inflammatory cytokines, whereas other HNSCC failed to respond. Response to αVβ3 and αVβ5 integrin targeting by cilengitide classifies HNSCC regarding outcome. We present FLAVINO data arguing for further development of cilengitide plus cetuximab in treatment of a subgroup of HNSCC potentially identified by the FLAVINO assay using a set of biomarkers for response evaluation.

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Cancers, Vol. 9, Pages 118: EML4-ALK Variants: Biological and Molecular Properties, and the Implications for Patients

Cancers, Vol. 9, Pages 118: EML4-ALK Variants: Biological and Molecular Properties, and the Implications for Patients

Cancers doi: 10.3390/cancers9090118

Authors: Sarah Sabir Sharon Yeoh George Jackson Richard Bayliss

Since the discovery of the fusion between EML4 (echinoderm microtubule associated protein-like 4) and ALK (anaplastic lymphoma kinase), EML4-ALK, in lung adenocarcinomas in 2007, and the subsequent identification of at least 15 different variants in lung cancers, there has been a revolution in molecular-targeted therapy that has transformed the outlook for these patients. Our recent focus has been on understanding how and why the expression of particular variants can affect biological and molecular properties of cancer cells, as well as identifying the key signalling pathways triggered, as a result. In the clinical setting, this understanding led to the discovery that the type of variant influences the response of patients to ALK therapy. Here, we discuss what we know so far about the EML4-ALK variants in molecular signalling pathways and what questions remain to be answered. In the longer term, this analysis may uncover ways to specifically treat patients for a better outcome.

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Early presence of anti-angiogenesis-related adverse events as a potential biomarker of antitumor efficacy in metastatic gastric cancer patients treated with apatinib: a cohort study

Abstract

Background

Reliable biomarkers of apatinib response in gastric cancer (GC) are lacking. We investigated the association between early presence of common adverse events (AEs) and clinical outcomes in metastatic GC patients.

Patients and methods

We conducted a retrospective cohort study using data on 269 apatinib-treated GC patients in two clinical trials. AEs were assessed at baseline until 28 days after the last dose of apatinib. Clinical outcomes were compared between patients with and without hypertension (HTN), proteinuria, or hand and foot syndrome (HFS) in the first 4 weeks. Time-to-event variables were assessed using Kaplan–Meier methods and Cox proportional hazard regression models. Binary endpoints were assessed using logistic regression models. Landmark analyses were performed as sensitivity analyses. Predictive model was analyzed, and risk scores were calculated to predict overall survival.

Results

Presence of AEs in the first 4 weeks was associated with prolonged median overall survival (169 vs. 103 days, log-rank p = 0.0039; adjusted hazard ratio (HR) 0.64, 95% confidence interval [CI] 0.64–0.84, p = 0.001), prolonged median progression-free survival (86.5 vs. 62 days, log-rank p = 0.0309; adjusted HR 0.69, 95% CI 0.53–0.91, p = 0.007), and increased disease control rate (54.67 vs. 32.77%; adjusted odds ratio 2.67, p < 0.001). Results remained significant in landmark analyses. The onset of any single AE or any combinations of the AEs were all statistically significantly associated with prolonged OS, except for the presence of proteinuria. An AE-based prediction model and subsequently derived scoring system showed high calibration and discrimination in predicting overall survival.

Conclusion

Presence of HTN, proteinuria, or HFS during the first cycle of apatinib treatment was a viable biomarker of antitumor efficacy in metastatic GC patients.

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Inhibition of Megakaryocyte Differentiation by Antibody-Drug Conjugates (ADCs) is Mediated by Macropinocytosis: Implications for ADC-induced Thrombocytopenia

Thrombocytopenia is a common adverse event in cancer patients treated with antibody–drug conjugates (ADC), including AGS-16C3F, an ADC targeting ENPP3 (ectonucleotide pyrophosphatase/phosphodiesterase-3) and trastuzumab emtansine (T-DM1). This study aims to elucidate the mechanism of action of ADC-induced thrombocytopenia. ENPP3 expression in platelets and megakaryocytes (MK) was investigated and shown to be negative. The direct effect of AGS-16C3F on platelets was evaluated using platelet rich plasma following the expression of platelet activation markers. Effects of AGS-16C3F, T-DM1, and control ADCs on maturing megakaryocytes were evaluated in an in vitro system in which human hematopoietic stem cells (HSC) were differentiated into MKs. AGS-16C3F, like T-DM1, did not affect platelets directly, but inhibited MK differentiation by the activity of Cys-mcMMAF, its active metabolite. FcRIIA did not appear to play an important role in ADC cytotoxicity to differentiating MKs. AGS-16C3F, cytotoxic to MKs, did not bind to FcRIIA on MKs. Blocking the interaction of T-DM1 with FcRIIA did not prevent the inhibition of MK differentiation and IgG1-mcMMAF was not as cytotoxic to MKs despite binding to FcRIIA. Several lines of evidence suggest that internalization of AGS-16C3F into MKs is mediated by macropinocytosis. Macropinocytosis activity of differentiating HSCs correlated with cell sensitivity to AGS-16C3F. AGS-16C3F was colocalized with a macropinocytosis marker, dextran-Texas Red in differentiating MKs. Ethyl isopropyl amiloride (EIPA), a macropinocytosis inhibitor, blocked internalization of dextran-Texas Red and AGS-16C3F. These data support the notion that inhibition of MK differentiation via macropinocytosis-mediated internalization plays a role in ADC-induced thrombocytopenia. Mol Cancer Ther; 16(9); 1877–86. ©2017 AACR.

See related article by Zhao et al., p. 1866

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Enzymatic Inactivation of Endogenous IgG by IdeS Enhances Therapeutic Antibody Efficacy

Endogenous plasma IgG sets an immunologic threshold that dictates the activity of tumor-directed therapeutic antibodies. Saturation of cellular antibody receptors by endogenous antibody limits antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Here, we show how enzymatic cleavage of IgG using the bacterial enzyme IdeS can be utilized to empty both high and low affinity Fc-receptors and clear the entire endogenous antibody pool. Using in vitro models, tumor animal models as well as ex vivo analysis of sera collected during a previous clinical trial with IdeS, we show how clearing of competing plasma antibody levels with IdeS unblocks cellular antibody receptors. We show that therapeutic antibodies against breast cancer (trastuzumab), colon cancer (cetuximab), and lymphomas (rituximab and alemtuzumab) can be potentiated when endogenous IgG is removed. Overall, IdeS is shown to be a potent tool to reboot the human antibody repertoire and to generate a window to preferentially load therapeutic antibodies onto effector cells and thereby create an armada of dedicated tumor-seeking immune cells. Mol Cancer Ther; 16(9); 1887–97. ©2017 AACR.

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Modeling Therapy Resistance in BRCA1/2-Mutant Cancers

Although PARP inhibitors target BRCA1- or BRCA2-mutant tumor cells, drug resistance is a problem. PARP inhibitor resistance is sometimes associated with the presence of secondary or "revertant" mutations in BRCA1 or BRCA2. Whether secondary mutant tumor cells are selected for in a Darwinian fashion by treatment is unclear. Furthermore, how PARP inhibitor resistance might be therapeutically targeted is also poorly understood. Using CRISPR mutagenesis, we generated isogenic tumor cell models with secondary BRCA1 or BRCA2 mutations. Using these in heterogeneous in vitro culture or in vivo xenograft experiments in which the clonal composition of tumor cell populations in response to therapy was monitored, we established that PARP inhibitor or platinum salt exposure selects for secondary mutant clones in a Darwinian fashion, with the periodicity of PARP inhibitor administration and the pretreatment frequency of secondary mutant tumor cells influencing the eventual clonal composition of the tumor cell population. In xenograft studies, the presence of secondary mutant cells in tumors impaired the therapeutic effect of a clinical PARP inhibitor. However, we found that both PARP inhibitor–sensitive and PARP inhibitor–resistant BRCA2 mutant tumor cells were sensitive to AZD-1775, a WEE1 kinase inhibitor. In mice carrying heterogeneous tumors, AZD-1775 delivered a greater therapeutic benefit than olaparib treatment. This suggests that despite the restoration of some BRCA1 or BRCA2 gene function in "revertant" tumor cells, vulnerabilities still exist that could be therapeutically exploited. Mol Cancer Ther; 16(9); 2022–34. ©2017 AACR.

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Cooperative Targets of Combined mTOR/HDAC Inhibition Promote MYC Degradation

Cancer treatments often require combinations of molecularly targeted agents to be effective. mTORi (rapamycin) and HDACi (MS-275/entinostat) inhibitors have been shown to be effective in limiting tumor growth, and here we define part of the cooperative action of this drug combination. More than 60 human cancer cell lines responded synergistically (CI<1) when treated with this drug combination compared with single agents. In addition, a breast cancer patient–derived xenograft, and a BCL-XL plasmacytoma mouse model both showed enhanced responses to the combination compared with single agents. Mice bearing plasma cell tumors lived an average of 70 days longer on combination treatment compared with single agents. A set of 37 genes cooperatively affected (34 downregulated; 3 upregulated) by the combination responded pharmacodynamically in human myeloma cell lines, xenografts, and a P493 model, and were both enriched in tumors, and correlated with prognostic markers in myeloma patient datasets. Genes downregulated by the combination were overexpressed in several untreated cancers (breast, lung, colon, sarcoma, head and neck, myeloma) compared with normal tissues. The MYC/E2F axis, identified by upstream regulator analyses and validated by immunoblots, was significantly inhibited by the drug combination in several myeloma cell lines. Furthermore, 88% of the 34 genes downregulated have MYC-binding sites in their promoters, and the drug combination cooperatively reduced MYC half-life by 55% and increased degradation. Cells with MYC mutations were refractory to the combination. Thus, integrative approaches to understand drug synergy identified a clinically actionable strategy to inhibit MYC/E2F activity and tumor cell growth in vivo. Mol Cancer Ther; 16(9); 2008–21. ©2017 AACR.

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Metformin Inhibits Cellular Proliferation and Bioenergetics in Colorectal Cancer Patient-Derived Xenografts

There is increasing preclinical evidence suggesting that metformin, an antidiabetic drug, has anticancer properties against various malignancies, including colorectal cancer. However, the majority of evidence, which was derived from cancer cell lines and xenografts, was likely to overestimate the benefit of metformin because these models are inadequate and require supraphysiologic levels of metformin. Here, we generated patient-derived xenograft (PDX) lines from 2 colorectal cancer patients to assess the properties of metformin and 5-fluorouracil (5-FU), the first-line drug treatment for colorectal cancer. Metformin (150 mg/kg) as a single agent inhibits the growth of both PDX tumors by at least 50% (P < 0.05) when administered orally for 24 days. In one of the PDX models, metformin given concurrently with 5-FU (25 mg/kg) leads to an 85% (P = 0.054) growth inhibition. Ex vivo culture of organoids generated from PDX demonstrates that metformin inhibits growth by executing metabolic changes to decrease oxygen consumption and activating AMPK-mediated pathways. In addition, we also performed genetic characterizations of serial PDX samples with corresponding parental tissues from patients using next-generation sequencing (NGS). Our pilot NGS study demonstrates that PDX represents a useful platform for analysis in cancer research because it demonstrates high fidelity with parental tumor. Furthermore, NGS analysis of PDX may be useful to determine genetic identifiers of drug response. This is the first preclinical study using PDX and PDX-derived organoids to investigate the efficacy of metformin in colorectal cancer. Mol Cancer Ther; 16(9); 2035–44. ©2017 AACR.

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Tyrosine Kinase Inhibitors Protect the Salivary Gland from Radiation Damage by Inhibiting Activation of Protein Kinase C-{delta}

In patients undergoing irradiation (IR) therapy, injury to nontumor tissues can result in debilitating, and sometimes permanent, side effects. We have defined protein kinase C- (PKC) as a regulator of DNA damage–induced apoptosis and have shown that phosphorylation of PKC by c-Abl and c-Src activates its proapoptotic function. Here, we have explored the use of tyrosine kinase inhibitors (TKI) of c-Src and c-Abl to block activation of PKC for radioprotection of the salivary gland. Dasatinib, imatinib, and bosutinib all suppressed tyrosine phosphorylation of PKC and inhibited IR-induced apoptosis in vitro. To determine whether TKIs can provide radioprotection of salivary gland function in vivo, mice were treated with TKIs and a single or fractionated doses of irradiation. Delivery of dasatinib or imatinib within 3 hours of a single or fractionated dose of irradiation resulted in >75% protection of salivary gland function at 60 days. Continuous dosing with dasatinib extended protection to at least 5 months and correlated with histologic evidence of salivary gland acinar cell regeneration. Pretreatment with TKIs had no impact on clonogenic survival of head and neck squamous cell carcinoma (HNSCC) cells, and in mice harboring HNSCC cell–derived xenografts, combining dasatinib or imatinib with fractionated irradiation did not enhance tumor growth. Our studies indicate that TKIs may be useful clinically to protect nontumor tissue in HNC patients undergoing radiotherapy, without negatively impacting cancer treatment. Mol Cancer Ther; 16(9); 1989–98. ©2017 AACR.

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A Potential Mechanism for ADC-Induced Neutropenia: Role of Neutrophils in Their Own Demise

Neutropenia is a common adverse event in cancer patients treated with antibody–drug conjugates (ADC) and we aimed to elucidate the potential mechanism of this toxicity. To investigate whether ADCs affect neutrophil production from bone marrow, an in vitro assay was developed in which hematopoietic stem cells (HSC) were differentiated to neutrophils. Several antibodies against targets absent in HSCs and neutrophils were conjugated to MMAE via a cleavable valine-citrulline linker (vcMMAE-ADC) or MMAF via a noncleavable maleimidocaproyl linker (mcMMAF-ADC), and their cytotoxicity was tested in the neutrophil differentiation assay. Results showed that HSCs had similar sensitivity to vcMMAE-ADCs and mcMMAF-ADCs; however, vcMMAE-ADCs were more cytotoxic to differentiating neutrophils than the same antibody conjugated to mcMMAF. This inhibitory effect was not mediated by internalization of ADC either by macropinocytosis or FcRs. Our results suggested that extracellular proteolysis of the cleavable valine-citrulline linker is responsible for the cytotoxicity to differentiating neutrophils. Mass spectrometry analyses indicated that free MMAE was released from vcMMAE-ADCs in the extracellular compartment when they were incubated with differentiating neutrophils or neutrophil conditioned medium, but not with HSC-conditioned medium. Using different protease inhibitors, our data suggested that serine, but not cysteine proteases, were responsible for the cleavage. In vitro experiments demonstrated that the purified serine protease, elastase, was capable of releasing free MMAE from a vcMMAE-ADC. Here we propose that ADCs containing protease cleavable linkers can contribute to neutropenia via extracellular cleavage mediated by serine proteases secreted by differentiating neutrophils in bone marrow. Mol Cancer Ther; 16(9); 1866–76. ©2017 AACR.

See related article by Zhao et al., p. 1877

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ADA-07 Suppresses Solar Ultraviolet-Induced Skin Carcinogenesis by Directly Inhibiting TOPK

Cumulative exposure to solar ultraviolet (SUV) irradiation is regarded as the major etiologic factor in the development of skin cancer. The activation of the MAPK cascades occurs rapidly and is vital in the regulation of SUV-induced cellular responses. The T-LAK cell–originated protein kinase (TOPK), an upstream activator of MAPKs, is heavily involved in inflammation, DNA damage, and tumor development. However, the chemopreventive and therapeutic effects of specific TOPK inhibitors in SUV-induced skin cancer have not yet been elucidated. In the current study, ADA-07, a novel TOPK inhibitor, was synthesized and characterized. Pull-down assay results, ATP competition, and in vitro kinase assay data revealed that ADA-07 interacted with TOPK at the ATP-binding pocket and inhibited its kinase activity. Western blot analysis showed that ADA-07 suppressed SUV-induced phosphorylation of ERK1/2, p38, and JNKs and subsequently inhibited AP-1 activity. Importantly, topical treatment with ADA-07 dramatically attenuated tumor incidence, multiplicity, and volume in SKH-1 hairless mice exposed to chronic SUV. Our findings suggest that ADA-07 is a promising chemopreventive or potential therapeutic agent against SUV-induced skin carcinogenesis that acts by specifically targeting TOPK. Mol Cancer Ther; 16(9); 1843–54. ©2017 AACR.

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Metformin Synergizes with BCL-XL/BCL-2 Inhibitor ABT-263 to Induce Apoptosis Specifically in p53-Defective Cancer Cells

p53 deficiency, a frequent event in multiple kinds of malignancies, decreases the sensitivity of diverse targeted chemotherapeutics including the BCL-XL/BCL-2 inhibitor ABT-263. Loss of p53 function can activate mTOR complex 1 (mTORC1), which may make it a vulnerable target. Metformin has shown anti-neoplastic efficiency partially through suppressing mTORC1. However, it remains unknown whether mTORC1 activation confers ABT-263 resistance and whether metformin can overcome it in the p53-defective contexts. In this study, we for the first time demonstrated that metformin and ABT-263 synergistically elicited remarkable apoptosis through orchestrating the proapoptotic machineries in various p53-defective cancer cells. Mechanistic studies revealed that metformin sensitized ABT-263 via attenuating mTORC1-mediated cap-dependent translation of MCL-1 and survivin and weakening internal ribosome entry site (IRES)-dependent translation of XIAP. Meanwhile, ABT-263 sensitized metformin through disrupting the BCL-XL/BIM complex. However, metformin and ABT-263 had no synergistic killing effect in p53 wild-type (p53-WT) cancer cells because the cotreatment dramatically induced the senescence-associated secretory phenotype (SASP) in the presence of wild type p53, and SASP could aberrantly activate the AKT/ERK–mTORC1–4EBP1–MCL-1/survivin signaling axis. Blocking the axis using corresponding kinase inhibitors or neutralizing antibodies against different SASP components sensitized the cotreatment effect of metformin and ABT-263 in p53-WT cancer cells. The in vivo experiments showed that metformin and ABT-263 synergistically inhibited the growth of p53-defective (but not p53-WT) cancer cells in tumor xenograft nude mice. These results suggest that the combination of metformin and ABT-263 may be a novel targeted therapeutic strategy for p53-defective cancers. Mol Cancer Ther; 16(9); 1806–18. ©2017 AACR.

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Synthesis and Profiling of a Novel Potent Selective Inhibitor of CHK1 Kinase Possessing Unusual N-trifluoromethylpyrazole Pharmacophore Resistant to Metabolic N-dealkylation

Checkpoint-mediated dependency of tumor cells can be deployed to selectively kill them without substantial toxicity to normal cells. Specifically, loss of CHK1, a serine threonine kinase involved in the surveillance of the G₂–M checkpoint in the presence of replication stress inflicted by DNA-damaging drugs, has been reported to dramatically influence the viability of tumor cells. CHK1's pivotal role in maintaining genomic stability offers attractive opportunity for increasing the selectivity, effectivity, and reduced toxicity of chemotherapy. Some recently identified CHK1 inhibitors entered clinical trials in combination with DNA antimetabolites. Herein, we report synthesis and profiling of MU380, a nontrivial analogue of clinically profiled compound SCH900776 possessing the highly unusual N-trifluoromethylpyrazole motif, which was envisioned not to undergo metabolic oxidative dealkylation and thereby provide greater robustness to the compound. MU380 is a selective and potent inhibitor of CHK1 which sensitizes a variety of tumor cell lines to hydroxyurea or gemcitabine up to 10 times. MU380 shows extended inhibitory effects in cells, and unlike SCH900776, does not undergo in vivo N-dealkylation to the significantly less selective metabolite. Compared with SCH900776, MU380 in combination with GEM causes higher accumulation of DNA damage in tumor cells and subsequent enhanced cell death, and is more efficacious in the A2780 xenograft mouse model. Overall, MU380 represents a novel state-of-the-art CHK1 inhibitor with high potency, selectivity, and improved metabolic robustness to oxidative N-dealkylation. Mol Cancer Ther; 16(9); 1831–42. ©2017 AACR.

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Combination Treatment with Orlistat-Containing Nanoparticles and Taxanes Is Synergistic and Enhances Microtubule Stability in Taxane-Resistant Prostate Cancer Cells

Taxane-based therapy provides a survival benefit in patients with metastatic prostate cancer, yet the median survival is less than 20 months in this setting due in part to taxane-associated resistance. Innovative strategies are required to overcome chemoresistance for improved patient survival. Here, NanoOrl, a new experimental nanoparticle formulation of the FDA-approved drug, orlistat, was investigated for its cytotoxicity in taxane-resistant prostate cancer utilizing two established taxane-resistant (TxR) cell lines. Orlistat is a weight loss drug that inhibits gastric lipases, but is also a potent inhibitor of fatty acid synthase (FASN), which is overexpressed in many types of cancer. NanoOrl was also investigated for its potential to synergize with taxanes in TxR cell lines. Both orlistat and NanoOrl synergistically inhibited cell viability when combined with paclitaxel, docetaxel, and cabazitaxel in PC3-TxR and DU145-TxR cells, yet these combinations were also additive in parental lines. We observed synergistic levels of apoptosis in TxR cells treated with NanoOrl and docetaxel in combination. Mechanistically, the synergy between orlistat and taxanes was independent of effects on the P-glycoprotein multidrug resistance protein, as determined by an efflux activity assay. On the other hand, immunoblot and immunofluorescence staining with an anti-detyrosinated tubulin antibody demonstrated that enhanced microtubule stability was induced by combined NanoOrl and docetaxel treatment in TxR cells. Furthermore, TxR cells exhibited higher lipid synthesis, as demonstrated by ¹⁴C-choline incorporation that was abrogated by NanoOrl. These results provide a strong rationale to assess the translational potential of NanoOrl to overcome taxane resistance. Mol Cancer Ther; 16(9); 1819–30. ©2017 AACR.

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Antitumor Synergism and Enhanced Survival with a Tumor Vasculature-Targeted Enzyme Prodrug System, Rapamycin, and Cyclophosphamide

Mutant cystathionine gamma-lyase was targeted to phosphatidylserine exposed on tumor vasculature through fusion with Annexin A1 or Annexin A5. Cystathionine gamma-lyase E58N, R118L, and E338N mutations impart nonnative methionine gamma-lyase activity, resulting in tumor-localized generation of highly toxic methylselenol upon systemic administration of nontoxic selenomethionine. The described therapeutic system circumvents systemic toxicity issues using a novel drug delivery/generation approach and avoids the administration of nonnative proteins and/or DNA required with other enzyme prodrug systems. The enzyme fusion exhibits strong and stable in vitro binding with dissociation constants in the nanomolar range for both human and mouse breast cancer cells and in a cell model of tumor vascular endothelium. Daily administration of the therapy suppressed growth of highly aggressive triple-negative murine 4T1 mammary tumors in immunocompetent BALB/cJ mice and MDA-MB-231 tumors in SCID mice. Treatment did not result in the occurrence of negative side effects or the elicitation of neutralizing antibodies. On the basis of the vasculature-targeted nature of the therapy, combinations with rapamycin and cyclophosphamide were evaluated. Rapamycin, an mTOR inhibitor, reduces the prosurvival signaling of cells in a hypoxic environment potentially exacerbated by a vasculature-targeted therapy. IHC revealed, unsurprisingly, a significant hypoxic response (increase in hypoxia-inducible factor 1 α subunit, HIF1A) in the enzyme prodrug–treated tumors and a dramatic reduction of HIF1A upon rapamycin treatment. Cyclophosphamide, an immunomodulator at low doses, was combined with the enzyme prodrug therapy and rapamycin; this combination synergistically reduced tumor volumes, inhibited metastatic progression, and enhanced survival. Mol Cancer Ther; 16(9); 1855–65. ©2017 AACR.

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FBW7-Dependent Mcl-1 Degradation Mediates the Anticancer Effect of Hsp90 Inhibitors

Heat shock protein 90 (Hsp90) is widely overexpressed in cancer cells and necessary for maintenance of malignant phenotypes. Hsp90 inhibition induces tumor cell death through degradation of its client oncoproteins and has shown promises in preclinical studies. However, the mechanism by which Hsp90 inhibitors kill tumor cells is not well-understood. Biomarkers associated with differential sensitivity and resistance to Hsp90 inhibitors remain to be identified. In this study, we found that colorectal cancer cells containing inactivating mutations of FBW7, a tumor suppressor and E3 ubiquitin ligase, are intrinsically insensitive to Hsp90 inhibitors. The insensitive colorectal cancer cells lack degradation of Mcl-1, a prosurvival Bcl-2 family protein. Hsp90 inhibition promotes GSK3β-dependent phosphorylation of Mcl-1, which subsequently binds to FBW7 and undergoes ubiquitination and proteasomal degradation. Specifically blocking Mcl-1 phosphorylation by genetic knock-in abrogates its degradation and renders in vitro and in vivo resistance to Hsp90 inhibitors, which can be overcame by Mcl-1–selective small-molecule inhibitors. Collectively, our findings demonstrate a key role of GSK3β/FBW7-dependent Mcl-1 degradation in killing of colorectal cancer cells by Hsp90 inhibitors and suggest FBW7 mutational status as a biomarker for Hsp90-targeted therapy. Mol Cancer Ther; 16(9); 1979–88. ©2017 AACR.

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A Novel Theranostic Strategy for MMP-14-Expressing Glioblastomas Impacts Survival

Glioblastoma (GBM) has a dismal prognosis. Evidence from preclinical tumor models and human trials indicates the role of GBM-initiating cells (GIC) in GBM drug resistance. Here, we propose a new treatment option with tumor enzyme-activatable, combined therapeutic and diagnostic (theranostic) nanoparticles, which caused specific toxicity against GBM tumor cells and GICs. The theranostic cross-linked iron oxide nanoparticles (CLIO) were conjugated to a highly potent vascular disrupting agent (ICT) and secured with a matrix-metalloproteinase (MMP-14) cleavable peptide. Treatment with CLIO-ICT disrupted tumor vasculature of MMP-14–expressing GBM, induced GIC apoptosis, and significantly impaired tumor growth. In addition, the iron core of CLIO-ICT enabled in vivo drug tracking with MR imaging. Treatment with CLIO-ICT plus temozolomide achieved tumor remission and significantly increased survival of human GBM-bearing mice by more than 2-fold compared with treatment with temozolomide alone. Thus, we present a novel therapeutic strategy with significant impact on survival and great potential for clinical translation. Mol Cancer Ther; 16(9); 1909–21. ©2017 AACR.

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Optimization of RAS/BRAF Mutational Analysis Confirms Improvement in Patient Selection for Clinical Benefit to Anti-EGFR Treatment in Metastatic Colorectal Cancer

In metastatic colorectal cancer (mCRC), recent studies have shown the importance to accurately quantify low-abundance mutations of the RAS pathway because anti-EGFR therapy may depend on certain mutation thresholds. We aimed to evaluate the added predictive value of an extended RAS panel testing using two commercial assays and a highly sensitive and quantitative digital PCR (dPCR). Tumor samples from 583 mCRC patients treated with anti–EGFR- (n = 255) or bevacizumab- (n = 328) based therapies from several clinical trials and retrospective series from the TTD/RTICC Spanish network were analyzed by cobas, therascreen, and dPCR. We evaluated concordance between techniques using the Cohen kappa index. Response rate, progression-free survival (PFS), and overall survival (OS) were correlated to the mutational status and the mutant allele fraction (MAF). Concordance between techniques was high when analyzing RAS and BRAF (Cohen kappa index around 0.75). We observed an inverse correlation between MAF and response in the anti-EGFR cohort (P < 0.001). Likelihood ratio analysis showed that a fraction of 1% or higher of any mutated alleles offered the best predictive value. PFS and OS were significantly longer in RAS/BRAF wild-type patients, independently of the technique. However, the predictability of both PFS and OS were higher when we considered a threshold of 1% in the RAS scenario (HR = 1.53; CI 95%, 1.12–2.09 for PFS, and HR = 1.9; CI 95%, 1.33–2.72 for OS). Although the rate of mutations observed among techniques is different, RAS and BRAF mutational analysis improved prediction of response to anti-EGFR therapy. Additionally, dPCR with a threshold of 1% outperformed the other platforms. Mol Cancer Ther; 16(9); 1999–2007. ©2017 AACR.

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IL6 Receptor Blockade Enhances Chemotherapy Efficacy in Pancreatic Ductal Adenocarcinoma

Inflammation mediated by activation of JAK/STAT signaling is a major cause of chemotherapy resistance in cancer. We studied the impact of selectively blocking the IL6 receptor (IL6R) as a strategy to inhibit IL6-induced STAT activation and to overcome chemoresistance in pancreatic ductal adenocarcinoma (PDAC). To do this, STAT activation was investigated in tumors arising spontaneously in LSL-Kras^G12D/+;LSL-Trp53^R172H/+;Pdx-1Cre (KPC) mice. Plasma from patients with PDAC was assessed for its ability to activate STAT3/SOCS3 in human monocytes using immunofluorescence microscopy and quantitative gene expression assays. KPC mice and syngeneic mice (wild type and IL6^–/–) implanted with KPC-derived cell lines were treated with an IL6R-blocking antibody (anti-IL6R). The impact of treatment on tumor growth in KPC mice and mice with KPC-derived tumor implants was monitored using ultrasonography and calipers, respectively. Tumors were analyzed by IHC to detect changes in STAT activation, tumor viability, and proliferation. We found that STAT3 was the most activated STAT protein in PDAC tumors from KPC mice. Plasma from patients with advanced PDAC stimulated STAT3/SOCS3 activation in human monocytes. In mice, anti-IL6R antibodies targeted Ly6C^hi monocytes, inhibited STAT3 activation in tumor cells, and decreased tumor cell proliferation in vivo. IL6R blockade in combination with chemotherapy induced tumor cell apoptosis, tumor regressions, and improved overall survival. Overall, we show that IL6 signaling drives STAT3 activation in tumor cells and mediates chemoresistance in PDAC. Thus, disrupting IL6 signaling using anti-IL6R antibodies holds promise for improving chemotherapy efficacy in PDAC. Mol Cancer Ther; 16(9); 1898–908. ©2017 AACR.

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Herpes Simplex Virus Glycoprotein D Targets a Specific Dendritic Cell Subset and Improves the Performance of Vaccines to Human Papillomavirus-Associated Tumors

Cervical cancer is a major public health problem and one of the leading causes of cancer deaths in women. Virtually all cases of cervical cancer, as well as a growing share of anal and head/neck tumors, are associated with human papillomavirus (HPV) infection. Despite the effectiveness, the available prophylactic vaccines do not benefit women with cervical lesions or cancer. Therefore, the search of new immunotherapeutic approaches to treat HPV-induced tumors is still a priority. The present study characterizes a therapeutic antitumor vaccine based on the genetic fusion of the Herpes simplex virus-1 (HSV-1) glycoprotein D (gD) with the E7 oncoprotein from HPV-16 (gDE7). Two subcutaneous doses of gDE7, admixed with poly (I:C), conferred complete and long-lasting therapeutic antitumor protection on mice previously challenged with tumor cells expressing the HPV-16 oncoproteins. The vaccine induced multifunctional E7-specific CD8⁺ T cells with cytotoxic activity and effector memory phenotype (CD44⁺ CD62L^low). In addition, gDE7 admixed with poly (I:C) vaccination controlled the expansion of tumor-induced regulatory T cells and myeloid-derived suppressor cells. More importantly, gDE7 activated mouse CD11c⁺ CD8α⁺ and human BDCA3⁺ dendritic cells (DC), specialized in antigen cross-presentation to CD8⁺ T cells, under in vitro conditions. These results indicated that the activation of a specific DC population, mediated by gD, improved the antigen-specific immune responses and the therapeutic performance induced by antitumor vaccines. These results open perspectives for the clinical testing of gDE7-based vaccines under the concept of active immunization as a tool for the therapeutic control of cancer. Mol Cancer Ther; 16(9); 1922–33. ©2017 AACR.

http://ift.tt/2wzTJm3

Inhibition of Aurora A and Aurora B Is Required for the Sensitivity of HPV-Driven Cervical Cancers to Aurora Kinase Inhibitors

The activity and efficacy of Aurora inhibitors have been reported in a wide range of cancer types. The most prominent Aurora inhibitor is alisertib, an investigational Aurora inhibitor that has been the subject of more than 30 clinical trials. Alisertib has inhibitory activity against both Aurora A and B, although it is considered to be primarily an Aurora A inhibitor in vivo. Here, we show that alisertib inhibits both Aurora A and B in vivo in preclinical models of HPV-driven cervical cancer, and that it is the inhibition of Aurora A and B that provides the selectivity and efficacy of this drug in vivo in this disease setting. We also present formal evidence that alisertib requires progression through mitosis for its efficacy, and that it is unlikely to combine with drugs that promote a G₂ DNA damage checkpoint response. This work demonstrates that inhibition of Aurora A and B is required for effective control of HPV-driven cancers by Aurora kinase inhibitors. Mol Cancer Ther; 16(9); 1934–41. ©2017 AACR.

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mTORC1 Inhibition Induces Resistance to Methotrexate and 6-Mercaptopurine in Ph+ and Ph-like B-ALL

Elevated activity of mTOR is associated with poor prognosis and higher incidence of relapse in B-cell acute lymphoblastic leukemia (B-ALL). Thus, ongoing clinical trials are testing mTOR inhibitors in combination with chemotherapy in B-ALL. However, the combination of mTOR inhibitors with standard of care chemotherapy drugs has not been studied extensively in high-risk B-ALL subtypes. Therefore, we tested whether mTOR inhibition can augment the efficacy of current chemotherapy agents in Ph⁺ and Ph-like B-ALL models. Surprisingly, inhibiting mTOR complex 1 (mTORC1) protected B-ALL cells from killing by methotrexate and 6-mercaptopurine, two antimetabolite drugs used in maintenance chemotherapy. The cytoprotective effects correlated with decreased cell-cycle progression and were recapitulated using cell-cycle inhibitors, palbociclib or aphidicolin. Dasatinib, a tyrosine kinase inhibitor currently used in Ph⁺ patients, inhibits ABL kinase upstream of mTOR. Dasatinib resistance is mainly caused by ABL kinase mutations, but is also observed in a subset of ABL unmutated cases. We identified dasatinib-resistant Ph+ cell lines and patient samples in which dasatinib can effectively reduce ABL kinase activity and mTORC1 signaling without causing cell death. In these cases, dasatinib protected leukemia cells from killing by 6-mercaptopurine. Using xenograft models, we observed that mTOR inhibition or dasatinib increased the numbers of leukemia cells that emerge after cessation of chemotherapy treatment. These results demonstrate that inhibitors targeting mTOR or upstream signaling nodes should be used with caution when combined with chemotherapeutic agents that rely on cell-cycle progression to kill B-ALL cells. Mol Cancer Ther; 16(9); 1942–53. ©2017 AACR.

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Wnt/{beta}-catenin Signaling Contributes to Tumor Malignancy and Is Targetable in Gastrointestinal Stromal Tumor

Gastrointestinal stromal tumor (GIST) is the most common type of sarcoma and usually harbors either a KIT or PDGFRA mutation. However, the molecular basis for tumor malignancy is not well defined. Although the Wnt/β-catenin signaling pathway is important in a variety of cancers, its role in GIST is uncertain. Through analysis of nearly 150 human GIST specimens, we found that some human GISTs expressed β-catenin and contained active, dephosphorylated nuclear β-catenin. Furthermore, advanced human GISTs expressed reduced levels of the Wnt antagonist DKK4. Accordingly, in human GIST T1 cells, Wnt stimulation increased β-catenin–mediated transcriptional activity in a reporter assay as well as transcription of the downstream target genes Axin2 and CCND1. In contrast, DKK4 overexpression in GIST T1 cells reduced Wnt/β-catenin signaling. In addition, we showed that nuclear β-catenin stability was partially regulated by the E3 ligase COP1, as demonstrated with coimmunoprecipitation and COP1 knockdown. Three molecular inhibitors of the Wnt/β-catenin pathway demonstrated antitumor efficacy in various GIST models, both in vitro and in vivo. Notably, the tankyrase inhibitor G007-LK alone had substantial activity against tumors of genetically engineered Kit^V558/+ mice, and the effect was increased by the addition of the Kit inhibitor imatinib mesylate. Collectively, our findings demonstrate that Wnt/β-catenin signaling is a novel therapeutic target for selected untreated or imatinib-resistant GISTs. Mol Cancer Ther; 16(9); 1954–66. ©2017 AACR.

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Re-irradiation for oligo-recurrence from esophageal cancer with radiotherapy history: a multi-institutional study

Abstract

Background

Neoadjuvant chemoradiotherapy following surgery has recently become a standard therapy. The purpose of the present study was to determine the effectiveness and toxicity of re-irradiation for oligo-recurrence in lymph nodes from esophageal cancer treated by definitive radiotherapy or by surgery with additional radiotherapy.

Methods

We reviewed retrospectively 248 patients treated with (chemo)radiotherapy for oligo-recurrence in lymph nodes from esophageal cancer in five Japanese high-volume centers between 2000 and 2015. Thirty-three patients in whom re-irradiation was performed were enrolled in this study, and the results for patients in whom re-irradiation was performed were compared with the results for other patients.

Results

Median maximum lymph node diameter was 22 mm. Median total radiation dose was 60 Gy. The median calculated biological effective dose using the LQ model with α/β = 10 Gy (BED10) in patients in whom re-irradiation was performed was significantly lower than the median BED10 in others. There was no different factor except for BED10, histology and irradiation field between patients with a past irradiation history and patients without a past irradiation history. The median observation period in surviving patients in whom re-irradiation was performed was 21.7 months. The 3-year overall survival rate in the 33 patients with a past irradiation history was 17.9%, with a median survival period of 16.0 months. Overall survival rate and local control rate in patients with a past irradiation history were significantly worse than those in patients without a past irradiation history (log-rank test, p = 0.016 and p = 0.0007, respectively). One patient in whom re-irradiation was performed died from treatment-related gastric hemorrhage.

Conclusions

Results in the present study suggested that re-irradiation for oligo-recurrence in lymph nodes from esophageal cancer treated by definitive radiotherapy or by surgery with additional radiotherapy might be acceptable but unsatisfactory.

http://ift.tt/2x73Y2I

Soy isoflavones inducing overt hypothyroidism in a patient with chronic lymphocytic thyroiditis: a case report

Many people have thyroid conditions that make them susceptible to hypothyroidism. If the foods they eat may interfere with the production of thyroid hormone, which can lead to development of serious hypothyroi...

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Role of Densitometric Criteria in Evaluation of Effectiveness of Antiangiogenic Therapies in Metastatic Colorectal Cancer: An Italian Clinical Experience

Background/Aim: To evaluate the role of densitometric criterion using the Choi Criteria in the assessment of the response to antiangiogenic treatments of metastatic colorectal cancer (mCRC) compared to the RECIST criteria. Patients and Methods: Fifty-four patients (mean age=50.6 years) affected by advanced colorectal cancer and with hepatic and possibly peritoneal and pulmonary metastases, that can be treated with bevacizumab, were prospectively evaluated by computerized tomography (CT) scan. Metastases were also evaluated by CT in one-dimensional form according to RECIST. Results: Results show that in 58% of analyzed cases, stable disease according to RECIST coincided with stable disease according to the CHOI criteria, whereas in 42% of analyzed cases disease progression according to RECIST corresponded to stable disease or even partial response according to CHOI criteria. Conclusion: By using the densitometric criterion with CHOI criteria, the evaluation of the response to antiangiogenic treatment of mCRC is partially different compared to RECIST criteria.

http://ift.tt/2eFekzk

Lidocaine Stimulates the Function of Natural Killer Cells in Different Experimental Settings

Background: One of the functions of natural killer (NK) cells is to eliminate cancer cells. The cytolytic activity of NK cells is tightly regulated by inhibitory and activation receptors located in the surface membrane. Lidocaine stimulates the function of NK cells at clinically relevant concentrations. It remains unknown whether this effect of lidocaine has an impact on the expression of surface receptors of NK cells, can uniformly stimulate across different cancer cell lines, and enhances the function of cells obtained during oncological surgery. Materials and Methods: NK cells from healthy donors and 43 patients who had undergone surgery for cancer were isolated. The function of NK cells was measured by lactate dehydrogenase release assay. NK cells were incubated with clinically relevant concentrations of lidocaine. By flow cytometry, we determined the impact of lidocaine on the expression of galactosylgalactosylxylosylprotein3-beta-glucuronosytranferase 1, marker of cell maturation (CD57), killer cell lectin like receptor A, inhibitory (NKG2A) receptors and killer cell lectin like receptor D, activation (NKG2D) receptors of NK cells. Differences in expression at p<0.05 were considered statistically significant. Results: Lidocaine increased the expression of NKG2D receptors and stimulated the function of NK cells against ovarian, pancreatic and ovarian cancer cell lines. Lidocaine also increased the cytolytic activity of NK cells from patients who underwent oncological surgery, except for those who had orthopedic procedures. Conclusion: Lidocaine showed an important stimulatory activity on NK cells. Our findings suggest that lidocaine might be used perioperatively to minimize the impact of surgery on NK cells.

http://ift.tt/2gAJViz

MRI and Ultrasound Fusion Imaging for Cervical Cancer

Background: Evaluating locoregional extension of cervical cancer is a key step in patient management. This study evaluated the feasibility of fusion imaging – a combination of magnetic resonance imaging (MRI) with real-time high-resolution ultrasound (US) – to diagnose cervical cancer and its extension. Patients and Methods: This prospective bi-center study included 13 women who underwent a 1.5-T MRI protocol including at least one T2-weighted plane. The results of imaging fusion were then compared with US and MRI results alone. Results: Cervical cancer was detected as a hyperechogenic hypervascularized lesion. Parametrial extension was detected by exploration of the stromal ring and the use of color Doppler mode in fusion imaging, and characterized by visualization of a vascular bridge. Conclusion: Fusion imaging could be used as a complementary technique for MRI to enhance diagnostic performance for cervical cancer lesions. While MRI remains the reference, real-time fusion imaging could improve its characterization and detect parametrial infiltration.

http://ift.tt/2eFkQ9b

Physical Needs of Long-term Cancer Patients

The enormous success in the therapeutic area of oncology has allowed achieving a number of long-term survival patients unthinkable until a few decades ago. The number of cancer survivors in the world has, in fact, almost tripled in the last decade alone. Anticancer therapies, including those of the latest generation, aimed at targeting also the chronicity of the disease, are not free from side-effects, especially when used in the long term. This scenario should lead to development of follow-up programs with the purpose of assessing long-term effects related to cancer treatments, in addition to the early detection of any relapse or a second tumor. Oncologists who take care of cancer survivors cannot ignore these effects; it is, therefore, essential to start a program of prevention and treatment of these sequelae, to meet patients' health needs.

http://ift.tt/2eFwzop

Study on the Validity of Pancreaticoduodenectomy in the Elderly

Aim: Pancreaticoduodenectomy (PD) is still the only curative treatment for periampullary cancer. Confirming the outcomes of PD in elderly patients is important as the aging population continues to grow. Patients and Methods: We analyzed 340 patients with periampullary cancer who underwent PD, dividing them into three groups by age: group A: aged 64 years or younger, n=115; group B: 65-74 years, n=144; and group C: 75 years or older, n=81. Results: Group C had a significantly higher 60-day mortality of 6.3% (p=0.04), the lowest 5-year overall survival rate of 9.9% (p=0.02), and there was no impact of staging of the Union for International Cancer Control classification on overall survival of patients with pancreatic cancer. Independent prognostic factors of group C in the multivariate analysis were pancreatic cancer and reoperation. Conclusion: For elderly patients aged 75 years or over, caution should be exercised in selecting PD for patients with pancreatic cancer.

http://ift.tt/2gAFrZw

Deepening a Simple Question: Can MSCs Be Used to Treat Cancer?

In cancer, mesenchymal stem/stromal cells (MSCs) have been considered as vehicles for targeted delivery of drugs due to their inherent tropism toward primary and metastatic tumors. However, it is still unclear whether MSCs could be therapeutically explored without significant harm, since a great amound of evidence indicates that MSCs are able to exert both tumor-suppressive and pro-oncogenic effects. Here, we discuss how MSCs might adopt a pro- or anti-inflammatory profile in response to changes within the tumor microenvironment and how these features may lead to opposite outcomes in tumor development. Additionally, we address how differences in experimental design might impact interpretation and consistency of the current literature in this specific field. Finally, we point-out critical issues to be addressed at a pre-clinical stage, regarding safety and therapeutic effectiveness of MSCs application in cancer treatment.

http://ift.tt/2eFwwsJ

Flattening Filter Free vs. Flattened Beams for Lung Stereotactic Body Radiation Therapy

Background/Aim: To assess the clinical impact of high dose rate stereotactic body radiation therapy (SBRT) in patients with lung neoplastic lesions. Patients and Methods: From January 2014 to June 2016, a single-center retrospective analysis was performed including all patients treated by either flattening filter free (FFF) beams or flattening filter beams (FF) three-dimensional (3D) SBRT for lung neoplastic lesions. Results: A total of 99 SBRT were performed on 75 patients. Among these, 29 SBRT were performed using a FFF technique while 70 other SBRT were done using a FF technique. Median follow-up time was 12.9 months. Overall, no difference between the two groups was found except for the mean beam on time which was reduced by 3.3 to 0.9 minutes in the FFF group (p<0.001). Conclusion: We report a low toxicity rate and a shortened beam on time in patients treated with 3D FFF SBRT for lung neoplastic lesions.

http://ift.tt/2gAJnsX

Colorectal Carcinogenesis: Role of Oxidative Stress and Antioxidants

One of the contributory causes of colon cancer is the negative effect of reactive oxygen species on DNA repair mechanisms. Currently, there is a growing support for the concept that oxidative stress may be an important etiological factor for carcinogenesis. The purpose of this review is to elucidate the role of oxidative stress in promoting colorectal carcinogenesis and to highlight the potential protective role of antioxidants. Several studies have documented the importance of antioxidants in countering oxidative stress and preventing colorectal carcinogenesis. However, there are conflicting data in the literature concerning its proper use in humans, since these studies did not yield definitive results and were performed mostly in vitro on cell populations, or in vivo in experimental animal models.

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The Local Recurrence of Breast Cancer with Squamous Metaplasia and Obvious Histological Heterogeneity

Case Report: We herein report a case of local recurrence of breast cancer with squamous metaplasia and obvious intratumoral and intertumoral heterogeneity. A 39-year-old female patient was diagnosed with T3N2M0 stage IIIB right breast cancer and underwent right total mastectomy and axillar lymph node dissection. At four years after surgery, she became aware of chest wall pain and diagnostic imaging revealed recurrence in the lung, right thoracic wall and sternum. The recurrent lesions remained stable for 18 months with endocrine therapy. Thereafter, the lesion in the right thoracic wall suddenly became enlarged. Moreover, liver metastasis was confirmed on FDG-PET/CT. She underwent right thoracic wall tumor resection. A biopsy was simultaneously performed to obtain a specimen from the site of liver metastasis. Postoperatively, the right chest wall mass showed obvious intratumoral heterogeneity; squamous differentiation with aggressive features and a papillotubular component similar to the primary tumor. The metastatic liver tumor showed similar pathological features to the primary tumor. Conclusion: Intratumoral and intertumoral heterogeneity within primary tumors and associated metastatic sites may contribute to treatment failure and drug resistance.

http://ift.tt/2gAJ9SD

Fluoride Induces Apoptosis in Mammalian Cells: In Vitro and In Vivo Studies

Apoptosis is genetically programmed cell death, an irreversible process of cell senescence with characteristic features different from other cellular mechanisms of death such as necrosis. In the last years, apoptosis has been extensively studied in the scientific literature, because it has been established that apoptosis plays a crucial role following the time course of chronic degenerative diseases, such as cancer. Thus, several researchers have strugged to detect what chemical agents are able to inter fere with the apoptotic process. Thus, the purpose of this literature review is to assess if fluoride induces apoptosis in mammalian cells using in vivo and in vitro test systems. Certain mammalian cell types such as oral cells, blood and brain were exetensively investigated; the results showed that fluoride is able to induce apoptosis in both intrinsinc and extrinsic pathways. Moreover, other cells types have been poorly investigated such as bone, kidney and reproductive cells with conflicting results so far. Therefore, this area needs further investigation for the safety of human populations exposed to fluoride in a chronic way, as for example in developing countries.

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Thrombocytosis Portends Adverse Prognosis in Colorectal Cancer: A Meta-Analysis of 5,619 Patients in 16 Individual Studies

Aim: The current study aimed to determine the prognostic significance of thrombocytosis in patients with colorectal cancer (CRC) by a meta-analysis of the literature. Patients and Methods: The meta-analysis followed the 2009 guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses. A systematic literature review was conducted from PubMed and Web of Science for articles published up to May 15, 2015. Sixteen studies with a total of 5,619 patients met the inclusion criteria. Hazard ratios and 95% confidence intervals were retrieved from the original articles, calculated from the published Kaplan–Meier survival curves, or the corresponding authors were contacted for additional information. Heterogeneity was assessed using the I² statistic and Chi-square tests. Publication bias was assessed by Begg's funnel plot, Egger's linear regression test and trim-and-fill method. Sensitivity analysis was performed to validate the reliability. Results: Thrombocytosis is associated with shorter overall, disease-free and cancer-specific survival. Overall survival is reduced in patients with thrombocytosis regardless of their clinical tumor stage, and ethnicity. Shortened disease-free survival is associated with elevated platelet count in the non-specific stage (I-IV), localized tumor (stage I-III), and in the Asian patient population. Thrombocytosis is further associated with reduced cancer-specific survival in the non-specific stage and in Asian patients. Finally, thrombocytosis is significantly related to female patients, colon tumor location, T3-4 stage, lymph node positivity, metastasis, undifferentiated histology and lymphatic involvement. Conclusion: Thrombocytosis portends adverse prognosis in CRC, and may serve as a clinically useful marker to facilitate risk stratification and guide postoperative management.

http://ift.tt/2gAFCDW

Gefitinib Enhances Mitochondrial Biological Functions in NSCLCs with EGFR Mutations at a High Cell Density

Background/Aim: Gefitinib is a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and has been approved for the treatment of non-small cell lung cancers (NSCLCs) with EGFR mutations. Here we demonstrated that gefitinib induced a significantly enhanced biological activity of succinate-tetrazolium reductase (STR) in mitochondria and mitochondrial membrane potential in HCC827 cells (EGFR mutation NSCLCs, sensitive to gefitinib) at a high cell density. Materials and Methods: We assessed the biological activity (STR, mitochondrial membrane potential, expression level of Bcl-2 family proteins) of gefitinib on NSCLCs at different cell densities. Results: The 3D cell culture experiments showed the enhanced mitochondrial biological activity in clustered cell culture treated with gefitinib. Interestingly, the expression levels of Bcl-x_L and Bax, were affected by the cellular number and gefitinib treatment. We also found that gefitinib prevented additive anticancer activity in the combinational treatment with doxorubicin, which induces mitochondria-dependent apoptotic cell death. Conclusion: Our results indicate that gefitinib may work as a mitochondrial protector against combinational treatment with mitochondria-dependent anticancer agents in high-cell-density.

http://ift.tt/2eFwiBT

Metastatic Microcystic Adnexal Carcinoma with DNA Sequencing Results and Response to Systemic Antineoplastic Chemotherapy

Microcystic adnexal carcinoma (MAC) is a rare cutaneous malignancy. Due to its rarity, the molecular characteristics and treatment for metastatic MAC remain undefined. Here we present, as far as we are aware, the first case of metastatic MAC with DNA sequencing results indicating a mutation in TP53 and chromosomal losses in cyclin dependent kinase inhibitor 2A (CDKN2A) and cyclin dependent kinase inhibitor 2B (CDKN2B). In addition, this is the first case of metastatic MAC with a documented objective response to systemic antineoplastic chemotherapy (carboplatin and paclitaxel) confirmed by positron emission tomography/computed tomography. Our case increases the very limited medical knowledge of this rare disease.

http://ift.tt/2gAm5nj

Phosphoproteomic Analysis Identifies Signaling Pathways Regulated by Curcumin in Human Colon Cancer Cells

Background: Curcumin, a major polyphenol of the spice turmeric, acts as a potent chemopreventive and chemotherapeutic agent in several cancer types, including colon cancer. Although various proteins have been shown to be affected by curcumin, how curcumin exerts its anticancer activity is not fully understood. Materials and Methods: Phosphoproteomic analyses were performed using SW480 and SW620 human colon cancer cells to identify curcumin-affected signaling pathways. Results: Curcumin inhibited the growth of the two cell lines in a dose-dependent manner. Thirty-nine curcumin-regulated phosphoproteins were identified, five of which are involved in cancer signaling pathways. Detailed analyses revealed that the mTORC1 and p53 signaling pathways are main targets of curcumin. Conclusion: Our results provide insight into the molecular mechanisms of the anticancer activities of curcumin and future molecular targets for its clinical application.

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Prognostic Significance of Serum CEA for Non-small Cell Lung Cancer Patients Receiving Stereotactic Body Radiotherapy

Background/Aim: To examine the prognostic significance of serum carcinoembryonic antigen (CEA) for stage I non-small cell lung cancer (NSCLC) treated with stereotactic body radiotherapy (SBRT). Patients and Methods: In total, 129 stage I NSCLC patients were analyzed and divided into two groups: CEA-High (CEA>5 ng/ml) and CEA-Low (CEA≤5 ng/ml). Results: Median follow-up time was 38 months. Overall survival was not significantly different between CEA-High (n=47) and CEA-Low (n=82) patients (57% vs. 63% at 3 years; p=0.39), although progression-free survival (PFS) was significantly worse in CEA-High patients (31% vs. 51% at 3 years; p=0.01). Larger tumor size and high CEA level were independent prognostic factors for worse PFS. Failure pattern analysis showed that regional node or distant recurrence was more common in CEA-High patients (47%) than in CEA-Low patients (29%). Conclusion: Patients with CEA-High stage I NSCLC have a higher risk of regional or systemic relapse and should be followed-up carefully.

http://ift.tt/2gAlMJb

Inhibitory Activity of Iron Chelators ATA and DFO on MCF-7 Breast Cancer Cells and Phosphatases PTP1B and SHP2

Background: Rapidly-dividing cancer cells have higher requirement for iron compared to non-transformed cells, making iron chelating a potential anticancer strategy. In the present study we compared the anticancer activity of uncommon iron chelator aurintricarboxylic acid (ATA) with the known deferoxamine (DFO). Materials and Methods: We investigated the impact of ATA and DFO on the viability and proliferation of MCF-7 cancer cells. Moreover we performed enzymatic activity assays and computational analysis of the ATA and DFO effects on pro-oncogenic phosphatases PTP1B and SHP2. Results: ATA and DFO decrease the viability and proliferation of breast cancer cells, but only ATA considerably reduces the activity of PTP1B and SHP2 phosphatases. Our studies indicated that ATA strongly inactivates and binds in the PTP1B and SHP2 active site, interacting with arginine residue essential for enzyme activity. Conclusion: We confirmed that iron chelating can be considered as a potential strategy for the adjunctive treatment of breast cancer.

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Comparing the Efficacy of DeVIC Therapy and High-dose Methotrexate Monotherapy with Whole-brain Radiation Therapy for Newly-diagnosed Primary Central Nervous System Lymphoma: A Single Institution Study

Background/Aim: In the current study, we aimed to compare DeVIC (dexamethasone, etoposide, ifosfamide and carboplatin) chemotherapy with high-dose methotrexate (HD-MTX) monotherapy plus whole-brain radiation therapy (WBRT) for newly-diagnosed primary central nervous system lymphoma (PCNSL), in terms of their efficacies and tolerability. Patients and Methods: A total of 21 consecutive patients with PCNSL were treated with DeVIC therapy and WBRT, between 2002 and 2010. From 2010 to 2014, 14 consecutive patients with PCNSL were treated with HD-MTX followed by WBRT. Results: Overall response rates of complete and partial response for initial chemotherapy were significantly better with DeVIC therapy (95.2%) than with HD-MTX monotherapy (50%). Furthermore, one-year and two-year progression-free survival (PFS) rates were better in the DeVIC cohort than in the HD-MTX cohort. DeVIC therapy yielded higher early response rates, longer PFS, and manageable adverse events, and may be potentially better for the treatment of cases that are refractory to MTX-based therapy. Conclusion: Our retrospective clinical study revealed that DeVIC therapy is comparable with that of HD-MTX monotherapy plus WBRT, for newly diagnosed PCNSL.

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Effective Metabolic Targeting of Human Osteosarcoma Cells In Vitro and in Orthotopic Nude-mouse Models with Recombinant Methioninase

Background: Methionine dependence may be the only known general metabolic defect in cancer. In order to exploit methionine dependence for therapy, our laboratory previously cloned L-methionine α-deamino--mercaptomethane lyase [EC 4.4.1.11]) (recombinant methioninase [rMETase]), which was subsequently tested in mouse models of various types of human tumors. The present study aimed to investigate the efficacy of rMETase on human osteosarcoma cells in vitro and in vivo. Materials and Methods: Human osteosarcoma cell lines 143B, HOS and SOSN2 were tested in vitro for survival during a 72-h exposure to rMETase using the WST-8 assay. Half-maximal inhibitory concentrations were calculated for in vitro efficacy experiments. 143B cells were orthotopically transplanted into the tibia of nude mice. Mouse models were randomized into the following groups 1 week after transplantation: Group 1, untreated control; Group 2, cisplatinum (CDDP) [intraperitoneal (i.p.) injection at 6 mg/kg weekly, for 3 weeks], positive control; Group 3, rMETase, 100 units/mouse i.p. daily, for 21 days. Tumor sizes and body weight were measured with calipers and a digital balance once per week, respectively. Results: rMETase significantly inhibited osteosarcoma cell growth, in a dose-dependent manner, in vitro. Both CDDP and rMETase treatment significantly inhibited tumor volume compared to untreated control mice at 5 weeks after initiation. Tumor volumes were as follows: Group 1, untreated, control: 1808.2 ± 344 mm³; Group 2, CDDP: 1102.2 ± 316 mm³, p=0.0008 compared to untreated control; Group 3, rMETase: 884.8 ± 361 mm³, p=0.0001 compared to untreated control. There were no animal deaths in any group. The body weight of mice was not significantly different between any group. Conclusion: rMETase showed promising efficacy against osteosarcoma, a recalcitrant tumor type. Future studies will investigate the efficacy of rMETase on patient-derived orthotopic xenograft (PDOX) models of osteosarcoma as a bridge to testing rMETase in the clinic.

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Surgical Strategy for T1 Duodenal or Ampullary Carcinoma According to the Depth of Tumor Invasion

Aim: To investigate the utility of local resection (LR) for T1 duodenal carcinoma and T1 ampullary carcinoma. Patients and Methods: Between June 2002 and November 2014, a total of 64 patients with pathological T1 (pT1) ampullary carcinoma (25 patients) and pT1 duodenal carcinoma (39 patients) were treated. Of these, 33 patients underwent local resection (LR group), while the other 31 patients underwent pancreatoduodenectomy (PD group). Results: The LR group had 31 patients with pT1a and 2 patients with pT1b. PD group had 18 patients with pT1a and 13 patients with pT1b. One patient with pT1b duodenal carcinoma (20.0%) and one patient with pT1b ampullary carcinoma (10.0%) developed lymph node metastasis, while none of the patients with pT1a disease developed metastases. Conclusion: LR may be considered in the patients preoperatively diagnosed with T1a duodenal carcinoma and T1a ampullary carcinoma.

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Probing the Molecular Mechanisms Governing the Oncolytic Activity of Paeonia suffruticosa on Triple-negative Breast Cancer Cells In Vitro

Background/Aim: Extracts of Paeonia suffruticosa are traditionally used in Chinese medicine to increase blood flow. Recently, this extract has been shown to possess anti-tumor and anti-inflammatory properties, though this mechanism remains unknown. In the current work, we prepared extracts of P. suffruticosa and analyzed their effects on MDA-MB-231 triple-negative breast cancer cells. Materials and Methods: Varying concentrations of an aqueous extract of P. suffruticosa was administered to MDA-MB-231. An MTS assay was used to determine the cell viability. Cytokine production was investigated through enzyme-linked immunosorbent assay (ELISA). Caspase-Glo assays were performed to measure caspase 3/7, 8 and 9 to analyze anti-apoptotic effects. Results: MTS assay for cell viability revealed that the extract increased viability at low concentrations (0.6 mg/ml) and decreased viability observed at concentrations ≥2.5 mg/ml (p<0.01). ELISA for IL-6, IL-2, and TNF-alpha revealed a biphasic dose-response inversely related to viability (p<0.05). IL-24 expression also increased at 2.5 mg/ml and 4.0 mg/ml (p<0.05). Bax levels remained relatively constant while Bcl-2 decreased significantly in all concentrations (p<0.01). Small decreases in Fas ligand levels was observed in parallel with a lack of increase in caspase-8 activity. Most notable was that while 4mg/ml of P. suffruticosa extract reduced MDA-MB-231 viability by >60% (p<0.01), the same concentration reduced the viability of non-transformed HaCat cells by ~8% (p>0.05), suggesting a selective oncolytic effect. Conclusion: P. suffruticosa extract has the ability to modulate the production of several tumor suppressive cytokines, induce intrinsic apoptosis and has the capability of reducing cancer burden while sparing healthy tissue.

http://ift.tt/2eFvMUt

3,6-Dihydroxyflavone regulates microRNA-34a through DNA methylation

Abstract

Background

Breast cancer is the common cancer in China. In previous study, we determined that 3,6-dihydroxyflavone (3,6-DHF) increases miR-34a significantly in breast carcinogenesis, but the mechanism remains unclear.

Methods

We used qRT-PCR to analyze miR-34a and ten-eleven translocation (TET)1, TET2, TET3 levels in breast cancer cells. With a cellular breast carcinogenesis model and an experimental model of carcinogenesis in rats, TET1 levels were evaluated by western blot analysis and immunofluorescence. TET1 and 5hmC (5-hydroxymethylcytosine) levels were evaluated by immunofluorescence in nude mouse xenografts of MDA-MB-231 cells. Chromatin immunoprecipitation(ChIP) assayed for TET1 on the TET1 promoter, and dot blot analysis of DNA 5hmC was performed in MDA-MB-231 cells. We evaluated the mechanism of 3,6-DHF on the expression of tumor suppressor miR-34a by transfecting them with DNA methyltransferase (DNMT)1 plasmid and TET1 siRNA in breast cancer cells. Methylation-specific PCR detected methylation of the miR-34a promoter.

Results

First, we found that 3,6-DHF promotes the expression of TET1 during carcinogen-induced breast carcinogenesis in MCF10A cells and in rats. 3,6-DHF also increased TET1 and 5hmC levels in MDA-MB-231 cells. Further study indicated that TET1 siRNA and pcDNA3/Myc-DNMT1 inhibited the 3,6-DHF reactivation effect on expression of miR-34a in breast cancer cells. Methylation-specific PCR assays indicated that TET1 siRNA and pcDNA3/Myc-DNMT1 inhibit the effect of 3,6-DHF on the demethylation of the miR-34a promoter.

Conclusions

Our study showed that 3,6-DHF effectively increases TET1 expression by inhibiting DNMT1 and DNA hypermethylation, and consequently up-regulates miR-34a in breast carcinogenesis.

http://ift.tt/2ezSHNk

Programmed cell death ligand 1 cut-point is associated with reduced disease specific survival in resected pancreatic ductal adenocarcinoma

Abstract

Background

Programmed cell death 1 (PD1) inhibitors have recently shown promising anti-cancer effects in a number of solid tumor types. A predictive biomarker to this class of drugs has not been clearly identified; however, overexpression of the PD1 ligand (PD-L1) has shown particular promise in lung adenocarcinoma. In this study, we explore the staining characteristics, prevalence, and clinico-molecular correlates of PD-L1 overexpression in pancreatic ductal adenocarcinoma (PDAC).

Methods

A tissue microarray (TMA) was constructed from cases of resected PDAC. PD-L1 immunohistochemistry (IHC) was performed using the SP142 primary antibody. Immunohistochemical assessment for deficient mismatch repair status (MMRd), CD3 and CD8 were performed. All biomarkers were assessed independently by two anatomical pathologists and consensus achieved on all cases. Survival analysis was performed using three thresholds (> = 1%, >5% and >10%) for tumor cell membrane staining.

Results

Two-hundred fifty-two cases were included in the TMA and evaluable by IHC. Thirty-one (12%), 17 (7%), 12(5%) cases were positive at percentage cut offs of >0, >5, and >10% respectively. Increased PD-L1 expression was associated with inferior prognosis (p = 0.0367). No statistically significant association was identified between PD-L1 status and MMR status or tumor infiltrating lymphocytes.

Conclusions

This data suggests that there is an inverse relationship between PD-L1 expression and disease specific survival times in resected PDAC. Consequently, this association may represent a phenotype where increased PD-L1 expression has an effect on tumor biology and could therefore identify a subgroup where PD1 blockade could have enhanced effectiveness.

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Trifluoperazine, a novel autophagy inhibitor, increases radiosensitivity in glioblastoma by impairing homologous recombination

Abstract

Background

Resistance to adjuvant radiotherapy is a major cause of treatment failure in patients with glioblastoma (GBM). Autophagy inhibitors have been shown to enhance the efficacy of radiotherapy for certain solid tumors. However, current inhibitors do not penetrate the blood-brain-barrier (BBB). Here, we assessed the radiosensitivity effects of the antipsychotic drug trifluoperazine (TFP) on GBM in vitro and in vivo.

Methods

U251 and U87 GBM cell lines as well as GBM cells from a primary human biopsy (P3), were used in vitro and in vivo to evaluate the efficacy of TFP treatment. Viability and cytotoxicity was evaluated by CCK-8 and clonogenic formation assays. Molecular studies using immunohistochemistry, western blots, immunofluorescence and qPCR were used to gain mechanistic insight into the biological activity of TFP. Preclinical therapeutic efficacy was evaluated in orthotopic xenograft mouse models.

Results

IC50 values of U251, U87 and P3 cells treated with TFP were 16, 15 and 15.5 μM, respectively. TFP increased the expression of LC3B-II and p62, indicating a potential disruption of autophagy flux. These results were further substantiated by a decreased Lysotracker Red uptake, indicating impaired acidification of the lysosomes. We show that TFP and radiation had an additive effect when combined. This effect was in part due to impaired TFP-induced homologous recombination. Mechanistically we show that down-regulation of cathepsin L might explain the radiosensitivity effect of TFP. Finally, combining TFP and radiation resulted in a significant antitumor effect in orthotopic GBM xenograft models.

Conclusions

This study provides a strong rationale for further clinical studies exploring the combination therapy of TFP and radiation to treat GBM patients.

http://ift.tt/2eEV4SI

Redefining the Positive Margin in Pancreatic Cancer: Impact on Patterns of Failure, Long-Term Survival and Adjuvant Therapy

Abstract

Purpose

There is debate regarding the definition and clinical significance of margin clearance in pancreatic ductal adenocarcinoma (PDA). A comprehensive archival analysis of surgical resection margins was performed to determine the effect on locoregional recurrence and survival, and the impact of adjuvant therapy in PDA.

Methods

We identified 105 patients with resected PDA. Pancreatic, anterior, bile duct, and posterior surgical resection margins (PM; posterior surface, uncinate and vascular groove) were identified. Three pathologists reviewed all archival surgical specimens and recategorized each margin as tumor at ink/transected, <0.5, 0.5–1, >1–2, or >2 mm from the inked surface. The impact of these and other clinical variables was assessed on local control, disease-free survival (DFS), and overall survival (OS).

Results

Among all margins, PM clearance up to 2 mm was prognostic of DFS (p = 0.01) and OS (p = 0.01). Dichotomizing the PM at 2 mm revealed it to be an independent predictor of local recurrence-free survival [hazard ratio HR] 0.20, 95% confidence interval [CI] 0.048–0.881, p = 0.033), DFS (HR 0.46, 95% CI 0.22–0.96, p = 0.03), and OS (HR 0.31, 95% CI 0.14–0.74, p = 0.008). A margin status of >2 mm was also prognostic of OS in patients who received adjuvant chemotherapy (HR 0.31, 95% CI 0.11–0.89, p = 0.03), however this difference was mitigated in patients receiving adjuvant chemoradiotherapy (HR 0.40, 95% CI 0.10–1.58, p = 0.19).

Conclusion

These data highlight the clinical significance of the PM and the lack of significance of other resection margins. Clearance in excess of 2 mm should be considered to improve long-term clinical outcomes. The use of adjuvant radiotherapy should be strongly considered in patients with PMs <2 mm.

http://ift.tt/2x67wSZ

Prognostic Value of the Age-Adjusted Charlson Comorbidity Index (ACCI) on Short- and Long-Term Outcome in Patients with Advanced Primary Epithelial Ovarian Cancer

Abstract

Background

We evaluated the prognostic impact of the age-adjusted Charlson Comorbidity Index (ACCI) on both postoperative morbidity and overall survival (OS) in patients with advanced epithelial ovarian cancer (EOC) treated at a tertiary gynecologic cancer center.

Patients and Methods

Exploratory analysis of our prospectively documented tumor registry was performed. Data of all consecutive patients with stage IIIB–IV ovarian cancer who underwent primary cytoreductive surgery (PDS) from January 2000 to June 2016 were analyzed. Patients were divided into three groups, based on their ACCI: low (0–1), intermediate (2–3), and high (≥4), and postoperative surgical complications were graded according to the Clavien–Dindo classification (CDC). The Fisher's exact test, log-rank test, and Cox regression models were used to investigate the predictive value of the ACCI on postoperative complications and OS.

Results

Overall, 793 consecutive patients were identified; 328 (41.4%) patients were categorized as low ACCI, 342 (43.1%) as intermediate ACCI, and 123 (15.5%) as high ACCI. A high ACCI was significantly associated with severe postoperative complications (CDC 3–5; odds ratio 3.27, 95% confidence interval 1.97–5.43, p < 0.001). Median OS for patients with a low, intermediate, or high ACCI was 50, 40, and 23 months, respectively (p < 0.001), and the ACCI remained a significant prognostic factor for OS in multivariate analysis (p = 0.001). The same impact was observed in a sensitivity analysis including only those patients with complete tumor resection.

Conclusion

The ACCI is associated with perioperative morbidity in patients undergoing PDS for EOC, and also has a prognostic impact on OS. The potential role of the ACCI as a selection criteria for different therapy strategies is currently under investigation in the ongoing, prospective, multicenter AGO-OVAR 19 trial.

http://ift.tt/2w0FQK4

Visceral Adiposity and Sarcopenic Visceral Obesity are Associated with Poor Prognosis After Resection of Pancreatic Cancer

Abstract

Background

Visceral fat accumulation and muscle depletion have been identified as poor prognostic factors for various cancers. However, the significance of visceral adiposity and sarcopenic visceral obesity on outcomes after resection of pancreatic cancer remains unclear.

Methods

A retrospective analysis of 301 patients who underwent resection for localized pancreatic cancer between 2004 and 2015 was performed. The extent of visceral adiposity [visceral to subcutaneous adipose tissue area ratio (VSR)] and visceral obesity [visceral fat area (VFA)] were measured on preoperative computed tomography images, together with skeletal muscle index (SMI) and muscle attenuation (MA). The impacts of these body composition parameters on outcomes after pancreatic resection were investigated.

Results

The overall survival (OS) and recurrence-free survival (RFS) rates in patients with high VSR were significantly lower than those in patients with low VSR (P = 0.001, P = 0.007, respectively). There were no differences in OS and RFS between high VFA and low VFA group; however, when analyzed together with sarcopenic factors, OS and RFS rates of the patients with sarcopenic visceral obesity were significantly lower compared with those of the others. Multivariate analyses revealed that high VSR was an independent risk factor for mortality (hazard ratio (HR) 1.58, P = 0.009) and recurrence (HR 1.41, P = 0.026) together with low SMI, low MA, high CA19-9, microvascular invasion, and nodal metastasis.

Conclusions

Visceral adiposity and sarcopenic visceral obesity, as well as low muscle mass and quality, were closely associated with mortality and recurrence after resection of pancreatic cancer.

http://ift.tt/2x5QQei

Anatomy of the Transverse Mesocolon Based on Embryology for Laparoscopic Complete Mesocolic Excision of Right-Sided Colon Cancer

Abstract

Background

To treat colon cancer via complete mesocolic excision (CME) with central vascular ligation (CVL), dissection along the embryologic fusion planes is required. However, this surgery is difficult, especially for right-sided colon cancer, because the anatomy and embryology of the transverse mesocolon are not familiar to gastrointestinal surgeons.

Methods

In this video article, the anatomic details of the transverse mesocolon based on embryology are illustrated with a focus on the venous anatomy. Dissection of the transverse mesocolon along the embryologic planes using a cranial approach during laparoscopic right hemicolectomy also is presented.

Results

During the development of the primitive gastrointestinal tract, the transverse mesocolon locates between the terminal portion of the midgut and the beginning of the hindgut. After 270° counterclockwise rotation of the primary intestinal loop, the transverse mesocolon fuses with the frontal surface of the duodenum and pancreas. Simultaneously, the greater omentum hangs down from the greater curvature of the stomach in front of the transverse colon and fuses with the transverse mesocolon. Moreover, the drainage vein of the right colon sometimes joins the right gastroepiploic vein, and the gastrocolic trunk is formed. Anatomic complexity of the transverse mesocolon is caused by rotation and fusion of the gastrointestinal tract during embryologic development.

Conclusions

Knowledge concerning these embryologic peculiarities of the transverse mesocolon should be useful in the performance of laparoscopic CME with CVL for right-sided colon cancer.

http://ift.tt/2vFtwE9

Alcohol Consumption and Breast Cancer Risk in Younger Women According to Family History of Breast Cancer and Folate Intake

Abstract

To evaluate the association between alcohol consumption and breast cancer risk in younger women, overall and by family history of breast cancer and folate intake, we prospectively followed 93,835 US women aged 27–44 years in Nurses' Health Study II who had alcohol consumption data in 1991. Alcohol consumption and folate intake were measured by food frequency questionnaire every 4 years. We documented 2,866 incident cases of invasive breast cancer between 1991 and 2011. Alcohol consumption was not associated with breast cancer risk overall (for intake of ≥10 g/day vs. nondrinking, multivariate hazard ratio = 1.07, 95% confidence interval: 0.94, 1.22). When the association was stratified by family history and folate intake, a positive association between alcohol consumption and breast cancer was found among women with a family history and folate intake less than 400 μg/day (multivariate hazard ratio = 1.82, 95% confidence interval: 1.06, 3.12; P-trend = 0.08). Alcohol consumption was not associated with breast cancer in other categories of family history and folate intake (P-interaction = 0.55). In conclusion, in this population of younger women, higher alcohol consumption was associated with increased risk of breast cancer among those with both a family history of breast cancer and lower folate intake.

http://ift.tt/2iXZfdE

RE: “SMOKELESS TOBACCO USE AND THE RISK OF HEAD AND NECK CANCER: POOLED ANALYSIS OF US STUDIES IN THE INHANCE CONSORTIUM”

http://ift.tt/2iXZdT4

Maternal Dietary L-Arginine and Adverse Birth Outcomes in Dar es Salaam, Tanzania

Abstract

The amino acid arginine is a physiological precursor to nitric oxide, which is a key mediator of embryonic survival, fetal growth, and pregnancy maintenance. We evaluated the association between consumption of the amino acid arginine and the rate of adverse birth outcomes using data from a double-blind, randomized, placebo-controlled micronutrient supplementation trial among pregnant women in Dar es Salaam, Tanzania (2001–2004). Dietary intakes of arginine were assessed using repeated 24-hour recalls that were administered throughout pregnancy. Participants (n = 7,591) were monitored by research midwives throughout follow-up to assess pregnancy outcomes. Cubic-restricted splines and multivariable log-Poisson regression with empirical standard errors were used to estimate the continuous and categorical associations between arginine intake and adverse birth outcomes. Compared with women within the lowest quintile of arginine intake, those within the highest quintile had 0.79 times the risk of preterm birth before 37 weeks (95% confidence interval: 0.63, 1.00; P = 0.03). The continuous associations of arginine intake with preterm birth before 37 weeks and with preterm birth before 34 weeks were characterized by an initial rapid decrease in risk with increasing intake (P for nonlinearity < 0.01). Arginine intake was not associated with fetal loss or giving birth to infants who were born small for their gestational ages. This data suggest that the association between dietary arginine intake and preterm birth warrants further investigation.

http://ift.tt/2wzYZpM

THE AUTHORS REPLY

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Particulate Matter and Risk of Hospital Admission in the Kathmandu Valley, Nepal: A Case-Crossover Study

Abstract

Air pollution is known to lead to a substantial health burden, but the majority of evidence is based on data from North America and Europe. Despite rising pollution levels, very limited information is available for South Asia. We investigated the impact of particulate matter with an aerodynamic diameter less than or equal to 10 μm (PM₁₀) on hospitalization, by cause and subpopulation, in the Kathmandu Valley, an understudied and rapidly urbanizing region in Nepal. Individual-level daily inpatient hospitalization data (2004–2007) were collected from each of 6 major hospitals, as Nepal has no central data collection system. Time-stratified case-crossover analysis was used with interaction terms for potential effect modifiers (e.g., age, sex, and socioeconomic status), with adjustment for day of the week and weather. Daily PM₁₀ concentrations averaged 120 μg/m³, with the daily maximum reaching 403 μg/m³. A 10-μg/m³ increase in PM₁₀ level was associated with increased risks of hospitalization of 1.00% (95% confidence interval (CI): 0.62, 1.38), 1.70% (95% CI: 0.18, 3.25), and 2.29% (95% CI: 0.18, 4.43) for total, respiratory, and cardiovascular admissions, respectively. We did not find strong evidence of effect modification by age, sex, or socioeconomic status. These results, in combination with the high levels of exposure, indicate a potentially serious human health burden from air pollution in the Kathmandu Valley.

http://ift.tt/2iXNvYv

Evaluating the Effectiveness of New York City Health Policy Initiatives in Reducing Cardiovascular Disease Mortality, 1990–2011

Abstract

Beginning in 2002, New York City (NYC) implemented numerous policies and programs targeting cardiovascular disease (CVD) risk factors. Using death certificates, we analyzed trends in NYC-specific and US mortality rates from 1990 to 2011 for all causes, any CVD, atherosclerotic CVD (ACVD), coronary artery disease (CAD), and stroke. Joinpoint analyses quantified annual percent change (APC) and evaluated whether decreases in CVD mortality accelerated after 2002 in either NYC or the total US population. Our analyses included 1,149,217 NYC decedents. The rates of decline in mortality from all causes, any CVD, and stroke in NYC did not change after 2002. Among men, the decline in ACVD mortality accelerated during 2002–2011 (APC = −4.8%, 95% confidence interval (CI): −6.1, −3.4) relative to 1990–2001 (APC = −2.3%, 95% CI: −3.1, −1.5). Among women, ACVD rates began declining more rapidly in 1993 (APC = −3.2%, 95% CI: −3.8, −2.7) and again in 2006 (APC = −6.6%, 95% CI: −8.9, −4.3) as compared with 1990–1992 (APC = 1.6%, 95% CI: −2.7, 6.0). In the US population, no acceleration of mortality decline was observed in either ACVD or CAD mortality rates after 2002. Relative to 1990–2001, atherosclerotic CVD and CAD rates began to decline more rapidly during the 2002–2011 period in both men and women—a pattern not observed in the total US population, suggesting that NYC initiatives might have had a measurable influence on delaying or reducing ACVD mortality.

http://ift.tt/2wzgsPc

Prediction of Multiple Recurrent Events: A Comparison of Extended Cox Models in Bladder Cancer

Abstract

Recurrence of bladder cancer can occur repeatedly in the same patient after treatment of the primary tumor. Models predicting the risk of a next recurrence may inform individualized decision-making on surveillance frequency. We aimed to assess the usefulness of extensions of the Cox proportional hazards model for repeated events in this context. We analyzed 531 Dutch patients with bladder cancer (1990–2012) with information on 7 prespecified predictors at the time of diagnosis of the primary and recurrent tumors. We considered 3 aspects of model variants: how to model time to the repeated events (calendar time, gap time, elapsed time); the number of preceding events (predictor, stratum variable); and the within-subject correlation (ignored in a simple Cox model, robust standard errors in a variance-correction model, random effect in a frailty model). First to fourth recurrences of bladder cancer occurred in 313, 174, 103, and 66 patients, respectively, with median calendar follow-up times of 1.1, 2.5, 3.8, and 4.5 years, respectively. We focused on gap time in the detailed analyses, allowing for clinically meaningful predictions. Variance-correction models may be useful if predictor selection is part of the model development. Frailty models may be useful when within-subject correlation is strong.

http://ift.tt/2iY5wpG

Rotating Night-Shift Work and the Risk of Breast Cancer in the Nurses' Health Studies

Abstract

In 2007, the International Agency for Research on Cancer declared shift work that involved circadian disruption to be a "probable" carcinogen (group 2A), noting that human evidence was limited. Using data from 2 prospective cohort studies, the Nurses' Health Study (1988–2012; n = 78,516) and Nurses' Health Study II (1989–2013; n = 114,559), we examined associations between rotating night-shift work and breast cancer risk. In the 2 cohorts, there were a total of 9,541 incident invasive breast malignancies and 24 years of follow-up. In the Nurses' Health Study, women with 30 years or more of shift work did not have a higher risk of breast cancer (hazard ratio (HR) = 0.95, 95% confidence interval (95% CI): 0.77, 1.17; P for trend = 0.63) compared with those who never did shift work, although follow-up occurred primarily after retirement from shift work. Among participants in the Nurses' Health Study II, who were younger than participants in the other cohort, the risk of breast cancer was significantly higher in women with 20 years or more of shift work at baseline, reflecting young-adult exposure (HR = 2.15, 95% CI: 1.23, 3.73; P for trend = 0.23), and was marginally significantly higher for women with 20 years or more of cumulative shift work when we used updated exposure information (HR = 1.40, 95% CI: 1.00, 1.97; P for trend = 0.74). In conclusion, long-term rotating night-shift work was associated with a higher risk of breast cancer, particularly among women who performed shift work during young adulthood. Further studies should explore the role of shift work timing on breast cancer risk.

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Invited Commentary: Integrating Genomics and Social Epidemiology—Analysis of Late-Life Low Socioeconomic Status and the Conserved Transcriptional Response to Adversity

Abstract

Socially disadvantaged children face increased morbidity and mortality as they age. Understanding mechanisms through which social disadvantage becomes biologically embedded and devising measurements that can track this embedding are critical priorities for research to address social gradients in health. The analysis by Levine et al. (Am J Epidemiol. 2017;186(5):503–509) of genome-wide gene expression in a subsample of US Health and Retirement Study participants suggests important new directions for the field. Specifically, findings suggest promise in integrating gene expression data into population studies and provide further evidence for the conserved transcriptional response to adversity as a marker of biological embedding of social disadvantage. The study also highlights methodological issues related to the analysis of gene expression data and social gradients in health and a need to examine the conserved transcriptional response to adversity alongside other proposed measurements of biological embedding. Looking to the future, advances in genome science are opening new opportunities for sociogenomic epidemiology.

http://ift.tt/2iYxVf5

Contemporaneous Social Environment and the Architecture of Late-Life Gene Expression Profiles

Abstract

Environmental or social challenges can stimulate a cascade of coordinated physiological changes in stress response systems. Unfortunately, chronic activation of these adaptations under conditions such as low socioeconomic status (SES) can have negative consequences for long-term health. While there is substantial evidence tying low SES to increased disease risk and reduced life expectancy, the underlying biology remains poorly understood. Using pilot data on 120 older adults from the Health and Retirement Study (United States, 2002–2010), we examined the associations between SES and gene expression levels in adulthood, with particular focus on a gene expression program known as the conserved transcriptional response to adversity. We also used a bioinformatics-based approach to assess the activity of specific gene regulation pathways involved in inflammation, antiviral responses, and stress-related neuroendocrine signaling. We found that low SES was related to increased expression of conserved transcriptional response to adversity genes and distinct patterns of proinflammatory, antiviral, and stress signaling (e.g., sympathetic nervous system and hypothalamic-pituitary-adrenal axis) transcription factor activation.

http://ift.tt/2wzVdNd

Phenol Concentrations During Childhood and Subsequent Measures of Adiposity Among Young Girls

Abstract

Phenolic compounds represent a class of environmental chemicals with potentially endocrine-disrupting capabilities. We investigated longitudinal associations between childhood exposure to phenols, from both manmade and natural sources, and subsequent measures of adiposity among girls enrolled in the Breast Cancer and the Environment Research Program between 2004 and 2007. Baseline (ages 6–8 years) urinary concentrations were obtained for creatinine and phenol metabolites: enterolactone, genistein, daidzein, benzophenone-3, bisphenol A, the sum of parabens (methyl, ethyl, and propyl parabens), 2,5-dichlorophenol, and triclosan. Body mass index (weight (kg)/height (m)²), waist circumference, and percent body fat were measured at annual or semiannual examinations through 2015 (n = 1,017). Linear mixed-effects regression was used to estimate how baseline concentrations of phenols (tertile groups) were related to changes in girls' adiposity measurements from ages 7 through 15 years. Enterolactone was inversely associated with body mass index, waist circumference, and percent body fat, while 2,5-dichlorophenol was positively associated with these measurements. A nonmonotonic association was observed for triclosan and girls' adiposity; however, it was due to effect modification by baseline overweight status. Triclosan was positively associated with adiposity only among overweight girls. These results suggest that exposure to specific phenols during childhood may influence adiposity through adolescence.

http://ift.tt/2iYxBwT

Changes in the Inflammatory Potential of Diet Over Time and Risk of Colorectal Cancer in Postmenopausal Women

Abstract

We examined the associations between changes in dietary inflammatory potential and risk of colorectal cancer (CRC) in 87,042 postmenopausal women recruited from 1993–1998 by the Women's Health Initiative, conducted in the United States. Food frequency questionnaire data were used to compute patterns of change in dietary inflammatory index (DII) scores and cumulative average DII scores over 3 years. Cox regression models were used to estimate hazard ratios for CRC risk. After a median of 16.2 years of follow-up, 1,038 CRC cases were diagnosed. DII changes were not substantially associated with overall CRC, but proximal colon cancer risk was higher in the proinflammatory-change DII group than in the antiinflammatory-stable DII group (hazard ratio = 1.32, 95% confidence interval: 1.01, 1.74). Among nonusers of nonsteroidal antiinflammatory drugs (NSAIDs) (P_interaction = 0.055), the proinflammatory-stable DII group was at increased risk of overall CRC and proximal colon cancer. Also among nonusers of NSAIDs, risks of overall CRC, colon cancer, and proximal colon cancer were higher in the highest quintile compared with the lowest cumulative average DII quintile (65%, 61%, and 91% higher risk, respectively). Dietary changes toward, or a history of, proinflammatory diets are associated with an elevated risk of colon cancer, particularly for proximal colon cancer and among nonusers of NSAIDs.

http://ift.tt/2wzkvuQ

Traffic Congestion as a Risk Factor for Mortality in Near-Road Communities: A Case-Crossover Study

Abstract

Existing epidemiologic research on traffic largely neglects localized fluctuations. We leveraged finely resolved congestion data to investigate short-term associations with mortality in communities near roadways. We identified all nonaccidental, cardiovascular, cerebrovascular, and respiratory deaths (2009–2013) within 1 km of a highway in the Puget Sound region of Washington State. Using a case-crossover design, we examined the association of congestion 0–150 m, 151–300 m, and 301–1,000 m upwind of a decedent's home with mortality, adjusting for meteorology, holidays, and influenza activity. Among 9,449 deaths, we observed higher odds of cerebrovascular and respiratory mortality with greater upwind congestion, especially congestion near the decedent's home. For each 10-minute-km increase in upwind congestion within 150 m, the odds of cerebrovascular mortality were 1.08 (95% confidence interval (CI): 0.88, 1.33); within 151–300 m, the odds of cerebrovascular mortality were 1.05 (95% CI: 0.98, 1.12) times higher. We observed similar patterns for respiratory mortality, with 1.06 (95% CI: 0.76, 1.50) times higher odds of death with greater upwind congestion within 150 m and 1.02 (95% CI: 0.95, 1.10) times higher odds within 151–300 m. No increased odds of mortality were observed at greater distances, for overall mortality, or with downwind congestion. Unexpectedly, lower odds of cardiovascular mortality were suggested with greater congestion. This work demonstrates the use of nontraditional data to characterize the impacts of near-road exposures.

http://ift.tt/2iXz4np

Evaluating the Relationship Between Birth Weight for Gestational Age and Adult Blood Pressure Using Participants From a Cohort of Same-Sex Siblings, Discordant on Birth Weight Percentile

Abstract

Many studies have described an inverse relationship between birth weight and blood pressure (BP). Debate continues, however, over the magnitude and validity of the association. This analysis draws on the Early Determinants of Adult Health study (2005–2008), a cohort of 393 US adults (mean age 43 years; 47% male), including 114 same-sex sibling pairs deliberately sampled to be discordant on sex-specific birth weight for gestational age (BW/GA) in order to minimize confounding in studies of fetal growth and midlife health outcomes. Every quintile increment in BW/GA percentile was associated with a 1.04−mm Hg decrement in adult systolic BP (95% confidence interval (CI): −2.14, 0.06) and a 0.63−mm Hg decrement in diastolic BP (95% CI: −1.35, 0.09), controlling for sex, age, site, smoking, and race/ethnicity. The relationship was strongest among those in the lowest decile of BW/GA. Adding adult body mass index to the models attenuated the estimates (e.g., to −0.90 mm Hg (95% CI: −1.94, 0.14) for systolic BP). In the sibling-pair subgroup, associations were slightly stronger but with wider confidence intervals (e.g., −1.22 mm Hg (95% CI: −5.20, 2.75) for systolic BP). In conclusion, we found a small inverse relationship between BW/GA and BP in cohort and sibling-pair analyses, but the clinical or public health significance is likely limited.

http://ift.tt/2wzpags

Lifetime Alcohol Intake, Binge Drinking Behaviors, and Breast Cancer Risk

Abstract

The prevalence of binge drinking in the United States is rising. While alcohol is a risk factor for breast cancer, less is known about the impact of episodic heavy drinking. In 2003–2009, women aged 35–74 years who were free of breast cancer were enrolled in the Sister Study (n = 50,884). Residents of the United States or Puerto Rico who had a sister with breast cancer were eligible. Multivariable Cox regression was used to estimate adjusted hazard ratios and 95% confidence intervals for breast cancer. During follow-up (mean = 6.4 years), 1,843 invasive breast cancers were diagnosed. Increased breast cancer risk was observed for higher lifetime alcohol intake (for ≥230 drinks/year vs. <60 drinks/year, hazard ratio (HR) = 1.35, 95% confidence interval (CI): 1.15, 1.58). Relative to low-level drinkers (<60 drinks/year), hazard ratios were increased for ever binge drinking (HR = 1.29, 95% CI: 1.15, 1.45) or blacking out (HR = 1.39, 95% CI: 1.17, 1.64). Compared with low-level drinkers who never binged, moderate drinkers (60–229 drinks/year) who binged had a higher risk (HR = 1.25, 95% CI: 1.08, 1.44). There was evidence of effect modification between moderate lifetime drinking and binging (relative excess risk due to interaction = 0.33, 95% CI: 0.10, 0.57). Our findings support the established association between lifetime alcohol intake and breast cancer and provide evidence for an increased risk associated with heavy episodic drinking, especially among moderate lifetime drinkers.

http://ift.tt/2iWJSSH

Parental Body Mass Index and Behavioral Problems in Their Offspring: A Danish National Birth Cohort Study

Abstract

Maternal obesity has been associated with increased risk of offspring behavioral problems. We examined whether this association could be explained by familial factors by comparing associations for maternal body mass index (BMI) with associations for paternal BMI. We studied 38,314 children born to mothers enrolled in the Danish National Birth Cohort during 1996–2002. Data on maternal BMI was collected at 15 weeks of gestation, and paternal BMI was assessed when the child was 18 months old. When the child was 7 years old, the Strengths and Difficulties Questionnaire was completed by the parents. We estimated odds ratios for behavioral problems in offspring born to overweight/obese parents, and we found that maternal BMI was associated with offspring behavioral problems. Maternal BMI of 25.0–29.9 was associated with a 33% (odds ratio = 1.33, 95% confidence interval: 1.13, 1.57) higher risk of total difficulties in offspring, and maternal BMI of ≥30.0 was associated with an 83% (odds ratio = 1.83, 95% confidence interval: 1.49, 2.25) higher risk. Paternal obesity was also associated with higher risk of offspring behavioral problems, but stronger associations were observed with maternal prepregnancy obesity. Our results suggest that part of the association between maternal BMI and behavioral problems can be accounted for by genetic and social factors, but environmental risk factors may also contribute to the etiology of behavioral problems.

http://ift.tt/2wA8CoK