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Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Δευτέρα 22 Αυγούστου 2016
PTD4-apoptin induces Bcl-2-insensitive apoptosis in human cervical carcinoma in vitro and in vivo.
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PRIMA-1 induces caspase-mediated apoptosis in acute promyelocytic leukemia NB4 cells by inhibition of nuclear factor-[kappa]B and downregulation of Bcl-2, XIAP, and c-Myc.
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Pharmacodynamic transcript biomarkers of FGFR inhibition
The challenge of developing effective pharmacodynamic biomarkers for pre-clinical and clinical testing of FGFR signalling inhibition is significant. Assays that rely on the measurement of phospho-protein epitopes can be limited by the availability of effective antibody detection reagents. Transcript profiling enables accurate quantification of many biomarkers and provides a broader representation of pathway modulation. To identify dynamic transcript biomarkers of FGFR signalling inhibition by AZD4547, a potent inhibitor of FGF receptor 1, 2 and 3, a gene expression profiling study was performed in FGFR2 amplified, drug sensitive tumour cell lines. Consistent with known signalling pathways activated by FGFR, we identified transcript biomarkers downstream of the RAS-MAPK and PI3K/AKT pathways. Using different tumour cell lines in vitro and xenografts in vivo we confirmed that some of these transcript biomarkers (DUSP6, ETV5, YPEL2) were modulated downstream of oncogenic FGFR1, 2, 3 whilst others showed selective modulation only by FGFR2 signalling (EGR1). These transcripts showed consistent time dependent modulation, corresponding to the plasma exposure of AZD4547 and inhibition of phosphorylation of the downstream signalling molecules FRS2 or ERK. Combination of FGFR and AKT inhibition in an FGFR2 mutated endometrial cancer xenograft model enhanced modulation of transcript biomarkers from the PI3K/AKT pathway and tumour growth inhibition. These biomarkers were detected on the clinically validated nanoString platform. Taken together, these data identified novel dynamic transcript biomarkers of FGFR inhibition that were validated in a number of in vivo models, and which are more robustly modulated by FGFR inhibition than some conventional downstream signalling protein biomarkers.
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TLR4-dependent tight junction regulation
We have previously shown increased intestinal permeability, to 4 kDa FITC-dextran, in BALB/c mice treated with irinotecan. Importantly, genetic deletion of Toll-like receptor 4 (TLR4; Tlr4-/-) protected against loss of barrier function indicating, TLR4 is critical in tight junction regulation. The current study aimed to (1) determine the molecular characteristics of intestinal tight junctions in wild-type and Tlr4-/- BALB/c mice, and (2) characterize the secretory profile of the distal colon. Forty-two female wild-type and 42 Tlr4-/- BALB/c mice weighing between 18-25 g received a single 270 mg/kg (i.p.) dose of irinotecan hydrochloride or vehicle control and were killed at 6, 24, 48, 72 and 96 h. The secretory profile of the distal colon, following carbachol and forksolin, was assessed using Ussing chambers at all time points. Tight junction integrity was assessed at 24 h, when peak intestinal permeability and diarrhea were reported, using immunofluorescence, western blotting and RT-PCR. Irinotecan caused internalization of claudin-1 with focal lesions of ZO-1 and occludin proteolysis in the ileum and colon of wild-type mice. Tlr4-/- mice maintained phenotypically normal tight junctions. Baseline conductance, a measure of paracellular permeability, was increased in irinotecan-treated wild-type mice at 24 h (53.19{plus minus}6.46 S/cm2; p=0.0008). No change was seen in Tlr4-/- mice. Increased carbachol-induced chloride secretion was seen in irinotecan-treated wild-type and Tlr4-/- mice at 24 h (wild-type 100.35{plus minus}18.37 μA/cm2; p=0.022; Tlr4-/- 102.72{plus minus}18.80 μA/cm2; p=0.023). Results suggest TLR4-dependent claudin-1 internalization and secondary anion secretion contribute to irinotecan-induced diarrhea.
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Dinaciclib Inhibits CDK1/2 Inducing Anaphase Catastrophe
Despite advances in targeted therapy, lung cancer remains the most common cause of cancer-related mortality in the United States. Chromosomal instability is a prominent feature in lung cancer and because it rarely occurs in normal cells, it represents a potential therapeutic target. Our prior work discovered that lung cancer cells undergo anaphase catastrophe in response to inhibition of cyclin-dependent kinase 2 (CDK2), followed by apoptosis and reduced tumor cell growth. In this study, the effects and mechanisms of the multi-CDK inhibitor dinaciclib on lung cancer cells were investigated. We sought to determine the specificity of CDK-dependent induction of anaphase catastrophe. Live cell imaging provided direct evidence that dinaciclib caused multipolar cell divisions resulting in extensive chromosome missegregation. Genetic knockdown of dinaciclib CDK targets revealed that repression of CDK2 and CDK1, but not CDK5 or CDK9 triggered anaphase catastrophe in lung cancer cells. Overexpression of CP110, which is a mediator of CDK2 inhibitor-induced anaphase catastrophe (and a CDK1 and 2 phosphorylation substrate), antagonized anaphase catastrophe and apoptosis following dinaciclib treatment. Consistent with our previous findings, acquisition of activated KRAS sensitized lung cancer cells to dinaciclib-mediated anaphase catastrophe and cell death. Combining dinaciclib with the mitotic inhibitor Taxol augmented anaphase catastrophe induction and reduced cell viability of lung cancer cells. Thus, the multi-CDK inhibitor dinaciclib causes anaphase catastrophe in lung cancer cells and should be investigated as a potential therapeutic for wild-type and KRAS mutant lung cancer, individually or in combination with taxanes.
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SLC44A4, an ADC target for pancreatic and prostate cancer
Here we report the development of an antibody-drug conjugate, ASG-5ME, which targets the solute carrier receptor SLC44A4. SLC44A4 is a member of a family of putative choline transporters which we show to be markedly upregulated in a variety of epithelial tumors, most notably prostate and pancreatic cancer. SLC44A4 is normally expressed on the apical surface of secretory epithelial cells but in cancer we show expression is not restricted to the luminal surface in advanced and undifferentiated tumors. ASG-5ME consists of a human IgG2 anti-SLC44A4 antibody conjugated through a cleavable linker to the microtubule-disrupting agent, monomethylauristatin E. It has potent anti-tumor activity in both cell line and patient-derived xenograft models of pancreatic and prostate cancers. Combination studies with ASG-5ME and nab-paclitaxel demonstrated combination effect in both pancreatic and prostate tumor models. Altogether, the data presented here suggests that ASG-5ME may have the potential to offer a new therapeutic option for the treatment of pancreatic and prostate cancer.
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DPP-23 treatment of cisplatin-resistant HNC
Many cancer cells show acquired resistance to chemotherapeutic agents such as cisplatin. This is a major cause of cancer treatment failure and novel agents to overcome resistance are thus urgently required. A novel synthetic polyphenol conjugate, (E)-3-(3,5-dimethoxyphenyl)-1-(2-methoxyphenyl)prop-2-en-1-one (DPP-23), selectively kills tumor cells via the reactive oxygen species (ROS)-mediated unfolded protein response. We investigated the ability of DPP-23 to overcome cisplatin resistance in head and neck cancer (HNC) cells nd further clarified its molecular mechanisms of action. Cisplatin-resistant HNC cell lines and their parental and other HNC cell lines were used. The effects of cisplatin and DPP-23 were assessed alone and in combination in HNC and normal cells using cell viability, cell cycle, and cell death assays, by measuring glutathione (GSH), ROS, and protein levels, and via preclinical mouse studies. DPP-23 induced selective cell death in HNC cells, including cisplatin-resistant HNC cells, but spared normal cells, via cellular GSH depletion and ROS accumulation. The effect was blocked by the antioxidant N-acetyl-L-cysteine. DPP-23 activated p53 and its related cell death pathways via a robust accumulation of cellular ROS that involved inhibition of nuclear factor erythroid 2-related factor 2 antioxidant defense mechanisms. Thus, DPP-23 significantly overcame cisplatin resistance in HNC cells in vitro and in vivo. As a promising anticancer strategy, ROS generation and subsequent selective cancer cell killing by DPP-23 might help to overcome cisplatin resistance in HNC.
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Greater Genomic Landscape: Heterogeneous Evolution of Cancer
Results have historically shown a broad plasticity in the origin of tumors and their functions, with significant heterogeneity observed in both morphologies and functional capabilities. Largely unknown, however, are the mechanisms by which these variations occur and how these events influence tumor formation and behavior. Contemporary views on the origin of tumors focus mainly on the role of particular sets of driver transformations, mutational or epigenetic, with the occurrence of the observed heterogeneity as an accidental byproduct of oncogenesis. As such, we present a hypothesis that tumors form due to heterogeneous adaptive selection in response to environmental stress through intrinsic genomic sampling mechanisms. Specifically, we propose that eukaryotic cells intrinsically explore their available genomic information, the greater genomic landscape (GGL), in response to stress under normal conditions, long before the formation of a cancerous lesion. Finally, considering the influence of chromatin heterogeneity on the GGL, we propose a new class of compounds, chromatin-protective therapies (CPT), which target the physical variations in chromatin topology. In this approach, CPTs reduce the overall information space available to limit the formation of tumors or the development of drug-resistant phenotypes. Cancer Res; 1–5. ©2016 AACR.
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An importance of IL-34 in cancer chemoresistance
The ability of tumor cells to escape immune destruction and their acquired resistance to chemotherapy are major obstacles to effective cancer therapy. Although immune checkpoint therapies such as anti-PD1 address these issues in part, clinical responses remain limited to a subpopulation of patients. In this report, we identified interleukin-34 (IL-34) produced by cancer cells as a driver of chemoresistance. In particular, we found that IL-34 modulated the functions of tumor-associated macrophages to enhance local immunosuppression and to promote the survival of chemoresistant cancer cells by activating AKT signaling. Targeting IL-34 in chemoresistant tumors resulted in a remarkable inhibition of tumor growth when accompanied with chemotherapy. Our results define a pathogenic role for IL-34 in mediating immunosuppression and chemoresistance and identify it as a tractable target for anticancer therapy.
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Unique mechanisms for an inhibitory MET IgG2 antibody
A sound rationale exists for antibody targeting of the MET receptor tyrosine kinase, but therapeutic agents that can broadly block HGF ligand binding and exon 14-mutated or amplified MET to induce receptor degradation have yet to be reported. Here we report the identification of several MET monoclonal antibodies (mAb) that block MET-dependent signaling and tumor growth. In particular, the MET mAb KTN0073 and KTN0074 bind the Sema/PSI domain, at overlapping but distinct epitopes, preventing HGF interaction with MET and triggering receptor ubiquitination and degradation. Notably, both mAb also triggered degradation of oncogenic MET exon 14 mutants, which propagate more durable MET signals due to a defect in receptor degradation. Mechanistic investigations showed that both mAb engaged a pathway distinct from HGF-induced receptor degradation and protease-mediated shedding, independently of signaling driven by the exon 14-encoded sequences in the intracellular juxtamembrane region of the MET receptor. Grafting the mAb variable regions onto the IgG2 constant region dramatically enhanced the tumor inhibitory activities of KTN0073 but not KTN0074, suggesting a specific influence of antibody isotype of the epitopes for these two MET mAb. Overall, our results highlight KTN0073 as a novel IgG2-based MET mAb that acts through exon 14-independent mechanisms to degrade the MET receptor, potentially offering a therapeutic tool to treat a broader range of human tumors where MET is exon 14 mutated or amplified.
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Interleukin-30 involvement in breast cancer
The inflammatory tissue microenvironment which promotes the development of breast cancer (BRCA) is not fully understood. Here we report a role for elevated IL-30 in supporting the BRCA cell viability and invasive migration. IL-30 was absent in normal mammary ducts, ductules and acini of histologically normal breast and scanty in the few stromal infiltrating leukocytes. In contrast, its IL-30 was expressed frequently in BRCA specimens where it was associated with triple-negative and HER2+ molecular subtypes. In stromal leukocytes found in primary tumors or tumor-draining lymph nodes, which included mainly CD14+ monocytes, CD68+ macrophages and CD33+/CD11b+ myeloid cells, IL-30 levels increased with disease stage and correlated with recurrence. A negative correlation was determined between IL-30 expression by nodal stromal leukocytes and overall survival. In vitro studies showed that human recombinant IL-30 upregulated expression of a pro-oncogenic program, including especially IL-6 in both triple-negative and HER2+ BRCA cells. In triple-negative BRCA cells, IL-30 boosted a broader program of proliferation, invasive migration and an inflammatory milieu associated with KISS1-dependent metastasis. Silencing of STAT1/STAT3 signaling hindered the regulation of the primary growth and progression factors in BRCA cells. IL-30 administration in vivo fostered the growth of triple-negative BRCA by promoting proliferation and vascular dissemination of cancer cells and the accumulation of intratumoral CD11b+/Gr1+myeloid cell infiltrates. Overall, our results show how IL-30 regulates BRCA cell viability, migration and gene expression to promote BRCA growth and progression and its impact on patient outcome.
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Role of INT6/EIF3E in DSB repair
Unrepaired DNA double-strand breaks (DSBs) are the most destructive chromosomal lesions driving genomic instability, a core hallmark of cancer. Here, we identify the anti-oncogenic breast cancer factor INT6/EIF3E as an essential regulator of DSB repair that promotes homologous recombination (HR)-mediated repair and, to a lesser extent, non-homologous end joining repair. INT6 silencing impaired the accrual of the ubiquitin ligase RNF8 at DSBs and the formation of ubiquitin conjugates at DSB sites, especially Lys63-linked polyubiquitin chains, resulting in impaired recruitment of BRCA1, BRCA2 and RAD51, which are all involved in HR repair. In contrast, INT6 deficiency did not affect the accumulation of RNF168, 53BP1, or RPA at DSBs. In INT6-silenced cells, there was also an alteration in DNA damage-induced localization of MDC1, a key target for ATM phosphorylation, which is a pre-requisite for RNF8 recruitment. The attenuated DNA damage-localization of RNF8 resulting from INT6 depletion could be attributed to the defective retention of ATM previously reported by us. Our findings deepen insights into how INT6 protects against breast cancer by showing how it functions in DSB repair, with potential clinical implications for cancer therapy.
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Characterization of the PARP inhibitor AZD2461
The PARP inhibitor AZD2461 was developed as a next generation agent following olaparib, the first PARP inhibitor approved for cancer therapy. In BRCA1-deficient mouse models, olaparib resistance predominantly involves overexpression of P-glycoprotein, so AZD2461 was developed as a poor substrate for drug transporters. Here we demonstrate the efficacy of this compound against olaparib-resistant tumors that overexpress P-glycoprotein. In addition, AZD2461 was better tolerated in combination with chemotherapy than olaparib in mice, suggesting AZD2461 could have significant advantages over olaparib in the clinic. However, this superior toxicity profile did not extend to rats. Investigations of this difference revealed a differential PARP3 inhibitory activity for each compound and a higher level of PARP3 expression in bone marrow cells from mice as compared to rats and humans. Our findings have implications for the use of mouse models to assess bone marrow toxicity for DNA-damaging agents and inhibitors of the DNA damage response. Finally, structural modelling of the PARP3 active site with different PARP inhibitors also highlights the potential to develop compounds with different PARP family member specificity profiles for optimal anti-tumor activity and tolerability.
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Functional association of WWOX and p53 in OS
Osteosarcoma (OS) is a highly metastatic and drug resistant bone cancer lacking an effective therapy, in part due to a lack of knowledge about its molecular pathogenesis. In this study, we illuminate the mechanistic underpinning of this aggressive disease through the use of mice that are genetically deficient in the tumor suppressor Wwox in either osteoblast progenitors or mature osteoblasts. Mice in which Wwox was deleted in pre-osteoblasts (Wwox(delta)osx1 mice) were defective in osteogenesis accompanied by p53 upregulation, effects that were not observed in mice lacking Wwox in mature osteoblasts. p53 deletion in WwoxΔosx1 mice rescued this osteogenic defect. In addition, doubly mutant Wwox;p53(delta)osx1 mice developed poorly differentiated osteosarcomas that resembled human OS in histology, location, metastatic behavior and gene expression. Strikingly, osteosarcoma development in these mice was accelerated greatly compared to mice deficient only in p53. In contrast, combined WWOX and p53 inactivation in mature osteoblasts did not accelerate OS development compared to p53 inactivation alone. Our findings define a WWOX-p53 genetic network that regulates normal bone formation with disruption of this network resulting in accelerated OS development. On the basis of our studies we propose the doubly mutant Wwox;p53Δosx1 mice as an improved model for human OS.
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Radioimmunotherapy and abscopal effects
Preclinical and clinical evidence indicate that the proimmune effects of radiotherapy can be synergistically augmented with immunostimulatory monoclonal antibodies (mAb) to act both on irradiated tumor lesions and on distant, non-irradiated tumor sites. The combination of radiotherapy with immunostimulatory anti-PD1 and anti-CD137 mAbs was conducive to favorable effects on distant non-irradiated tumor lesions as observed in transplanted MC38 (colorectal cancer), B16OVA (melanoma) and 4T1 (breast cancer) models. The therapeutic activity was crucially performed by CD8 T cells, as found in selective depletion experiments. Moreover, the integrities of BATF-3-dependent dendritic cells specialized in crosspresentation/crosspriming of antigens to CD8+ T cells and of the type I interferon system were absolute requirements for the antitumor effects to occur. The irradiation regimen induced immune infiltrate changes in the irradiated and non-irradiated lesions featured by reductions in the total content of effector T cells, Tregs, and myeloid-derived suppressor cells (MDSC), while effector T cells expressed more intracellular IFNy in both the irradiated and contralateral tumors. Importantly, 48h following irradiation CD8+ TILs showed brighter expression of CD137 and PD1, thereby displaying more target molecules for the corresponding mAbs. Likewise, PD1 and CD137 were induced on tumor-infiltrating lymphocytes from surgically excised human carcinomas that were irradiated ex-vivo. These mechanisms involving crosspriming and CD8 T cells advocate clinical development of immunotherapy combinations with anti-PD1 plus anti-CD137 mAbs that can be synergistically accompanied by radiotherapy strategies, even if disease is left outside the field of irradiation.
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Maximizing Clinical Relevance of Nonclinical Studies
Purpose: The translation of nonclinical oncology studies is a subject of continuous debate. We propose that translational oncology studies need to optimize both pharmacokinetic (drug exposure) and pharmacodynamic (xenograft model) aspects. While improvements in pharmacodynamic translatability can be obtained by choosing cell lines or patient-derived xenograft models closer to the clinical indication, significant ambiguity and variability exists when optimizing the pharmacokinetic translation of small molecule and biotherapeutic agents. Experimental Design and Results: In this work, we propose a pharmacokinetic-based strategy to select nonclinical doses for approved drug molecules. We define a clinically relevant dose (CRD) as the dosing regimen in mice that most closely approximates the relevant pharmacokinetic metric in humans. Such metrics include area under the time-concentration curve and maximal or minimal concentrations within the dosing interval. The methodology is applied to six drugs, including targeted agents and chemotherapeutics, small and large molecules (erlotinib, dasatinib, vismodegib, trastuzumab, irinotecan and capecitabine). The resulting efficacy response at the CRD is compared to clinical responses. Conclusion: We conclude that nonclinical studies designed with the appropriate CRDs of approved drug molecules will maximize the translatability of efficacy results, which is critical when testing approved and investigational agents in combination.
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MDM2 inhibition in adenoid cystic carcinoma
Purpose: Conventional chemotherapy has modest efficacy in advanced adenoid cystic carcinomas (ACC). Tumor recurrence is a major challenge in the management of ACC patients. Here, we evaluated the anti-tumor effect of a novel small molecule inhibitor of the MDM2-p53 interaction (MI-773) combined with Cisplatin in patient-derived xenograft (PDX) ACC tumors. Experimental design: Therapeutic strategies with MI-773 and/or Cisplatin were evaluated in SCID mice harboring PDX ACC tumors (UM-PDX-HACC-5) and in low passage primary human ACC cells (UM-HACC-2A, -2B, -5, -6) in vitro. The effect of therapy on the fraction of cancer stem cells was determined by flow cytometry for ALDH activity and CD44 expression. Results: Combined therapy with MI-773 with Cisplatin caused p53 activation, induction of apoptosis, and regression of ACC PDX tumors. Western blots revealed induction of MDM2, p53 and downstream p21 expression, and regulation of apoptosis-related proteins PUMA, BAX, Bcl-2, Bcl-xL and active Caspase-9 upon MI-773 treatment. Both, single-agent MI-773, and MI-773 combined with Cisplatin, decreased the fraction of cancer stem cells in PDX ACC tumors. Notably, neoadjuvant MI-773 and surgery eliminated tumor recurrences during a post-surgical follow-up of more than 300 days. In contrast, 62.5% of mice that received vehicle control presented with palpable tumor recurrences within this time period (p=0.0097). Conclusions: Collectively, these data demonstrate that therapeutic inhibition of MDM2-p53 interaction by MI-773 decreased the cancer stem cell fraction, sensitized ACC xenograft tumors to Cisplatin, and eliminated tumor recurrence. These results suggest that patients with ACC might benefit from the therapeutic inhibition of the MDM2-p53 interaction.
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Topotecan Carboplatin and PARPi Veliparib in Leukemia
Purpose: The poly(ADP-ribose) polymerase (PARP) inhibitor veliparib delays DNA repair and potentiates cytotoxicity of multiple classes of chemotherapy drugs, including topoisomerase I inhibitors and platinating agents. This study evaluated veliparib incorporation into leukemia induction therapy using a previously described topotecan/carboplatin backbone. Experimental Design: Employing a 3+3 trial design, we administered escalating doses of veliparib combined with topotecan + carboplatin in relapsed or refractory acute leukemias, aggressive myeloproliferative neoplasms (MPNs) and chronic myelomonocytic leukemia (CMML). Results: A total of 99 patients received veliparib 10-100 mg orally twice daily on Days 1-8, 1-14 or 1-21 along with continuous infusion topotecan 1.0-1.2 mg/m2/d + carboplatin 120-150 mg/m2/d on Days 3-7. The maximum tolerated dose was veliparib 80 mg twice daily for up to 21 days with topotecan 1.2 mg/m2/d + carboplatin 150 mg/m2/d. Mucositis was dose limiting and correlated with high veliparib concentrations. The response rate was 33% overall (33/99: 14 CR, 11 CRi, 8 PR) but was 64% (14/22) for patients with antecedent or associated aggressive MPNs or CMML. Leukemias with baseline DNA repair defects, as evidenced by impaired DNA damage-induced FANCD2 monoubiquitination, had improved survival (hazard ratio .56 (95% CI .27-.92)). A single 80 mg dose of veliparib, as well as veliparib in combination with topotecan + carboplatin, induced DNA damage as manifested by histone H2AX phosphorylation in CD34+ leukemia cells, with greater phosphorylation in cells from responders. Conclusions: The veliparib/topotecan/carboplatin combination warrants further investigation, particularly in patients with aggressive MPNs, CMML, and MPN- or CMML-related acute leukemias.
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Biospecimen complexity
Purpose: Biospecimens (e.g. tissues, bloods, fluids) are critical for translational cancer research to generate the necessary knowledge to guide implementation of precision medicine. Rising demand and the need for higher quality biospecimens are already evident. Methods: The recent increase in requirement for biospecimen complexity in terms of linked biospecimen types, multiple preservation formats, and longitudinal data was explored by assessing trends in cancer research publications from 2000 to 2014. Results: A Pubmed search shows that there has been an increase in both raw numbers and the relative proportion (adjusted for total numbers of papers in each period) of the subgroups of papers typically associated with the use of biospecimens and both dense treatment and/or outcomes data and multiple biospecimen formats. Conclusions: Increasing biospecimen complexity is a largely unrecognized and new pressure on cancer research biobanks. New approaches to cancer biospecimen resources are needed such as the implementation of more efficient and dynamic consent mechanisms, stronger participant involvement in biobank governance, development of requirements for registration of collections, and models to establish stock targets for biobanks. In particular, the latter two approaches would enable funders to establish a better balance between biospecimen supply and research demand, reduce expenditure on duplicate collections, and encourage increased efficiency of biobanks to respond to the research need for more complex cases. This in turn would also enable biobanks to focus more on quality and standardization that are surely factors in the even more important arena of research reproducibility.
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Corrigendum
Future Oncology Ahead of Print.
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Is it best to expect the worst? Influence of patients' side-effect expectations on endocrine treatment outcome in a 2-year prospective clinical cohort study
Breast cancer patients' side-effect expectations prospectively influenced the incidence of side-effects, quality of life, and adherence during 2 years of endocrine treatment. The unique impact of expectations on long-term tolerability is important, because expectations can be psychologically modified and become a therapeutic target to prevent nocebo-related effects and non-adherence.
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Nanoparticle that Mimics Salmonella Counteracts Chemotherapy Resistance
Researchers at the University of Massachusetts Medical School have designed a nanoparticle that mimics the bacterium Salmonella and may help to counteract a major mechanism of chemotherapy resistance.
Working with mouse models of colon and breast cancer, Beth McCormick, Ph.D., and her colleagues demonstrated that when combined with chemotherapy, the nanoparticle reduced tumor growth substantially more than chemotherapy alone.
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Metachronous bladder metastases of a type 2 papillary renal cell carcinoma: a case report and review of the literature
Abstract
Background
Renal cell carcinoma developing metastases in the bladder is rare. Bladder metastasis due to a papillary type of renal cell carcinoma is rarer. Such metastases could be synchronous or metachronous.
Case presentation
Here we present a 55-year-old female patient with haematuria who underwent left nephro-ureterectomy for a suspected urothelial tumour. Histopathology revealed it to be a type 2 papillary renal cell carcinoma. Eighteen months later, she developed metachronous bladder metastasis of the papillary renal cell carcinoma which was treated with total cystectomy. Currently, she is on interferon therapy.
Conclusions
These bladder metastases from renal cell carcinoma could be due to drop metastases, lymphatic spread or haematogenous spread. The exact mechanism in a given case appears to be unpredictable.
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The comparison of perioperative outcomes of robot-assisted and open partial nephrectomy: a systematic review and meta-analysis
Abstract
Background
Robot-assisted partial nephrectomy (RAPN) has been widely used worldwide, to determine whether RAPN is a safe and effective alternative to open partial nephrectomy (OPN) via the comparison of RANP and OPN.
Methods
A comprehensive literature search was performed within the databases including PubMed, Cochrane Library, and Embase updated on 30 September 2015. Summary data with their corresponding 95 % confidence intervals (CIs) were calculated using a random effects or fixed effects model. Heterogeneity and publication bias were also evaluated.
Results
A total of 16 comparative studies including 3024 cases were used for this meta-analysis. There are no significant differences in the demographic characteristic between the two groups, but the age was lower and the tumor size was smaller for the RAPN group. RAPN had a longer operative time and warm ischemia time but which showed less estimated blood loss, hospital stay, and perioperative complications. No differences existed in the margin status, the change of glomerular filtration rate, transfusion rate, and conversion rate between the two groups. There was no significant publication bias.
Conclusions
RAPN offered a lower rate of perioperative complications, less estimated blood loss, and shorter length of hospital stay than OPN, suggesting that RAPN can be an effective alternative to OPN. Well-designed prospective randomized controlled trials will be helpful in validating our findings.
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Immunological evaluation of personalized peptide vaccination for patients with histologically unfavorable carcinoma of unknown primary site
Abstract
The immunological characteristics of carcinoma of unknown primary site (CUP) are not well established due to inclusion of heterogeneous types of metastatic tumors with the absence of any detectable primary site. We evaluated the immune responses in patients with histologically unfavorable CUP during personalized peptide vaccination (PPV). Ten patients with histologically unfavorable CUP who had been treated by PPV after chemotherapy failure were analyzed. In PPV treatment, up to four human leukocyte antigen-matched peptides of a total 31 peptides were selected according to preexisting host immunity before vaccination and administered subcutaneously. Peptides derived from the Lck antigen were most often chosen for use among all patients. CTL responses were increased in 8 of the 10 and 5 of the five patients tested at the end of the first and second PPV cycles, respectively. Increases in humoral responses after vaccination, including IgG, IgG1, IgG3, IgA, and IgM, were observed against not only the vaccinated peptides but also the non-vaccinated peptides. Severe adverse events due to PPV were not observed. Median overall survival was 13.9 months (95 % CI 4.0–22.5 months). PPV activated both cellular and humoral immune responses to short peptides derived from CTL epitopes in the majority of CUP patients. PPV with Lck-derived peptides may be a feasible, new treatment modality for histologically unfavorable CUP patients due to its safety and strong ability to boost immune responses, although its clinical efficacy remains to be investigated in larger-scale trials.
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Stage-Specific Embryonic Antigen-1 (SSEA-1) Expression in Thyroid Tissues
Abstract
Stage-specific embryonic antigen-1 (SSEA-1), also known as CD15, is a member of a cluster of differentiation antigens that have been identified in various normal tissues and in different types of cancers including papillary and medullary thyroid carcinoma. SSEA-1 may be expressed in normal stem cells and cancer stem-like cells. To evaluate the potential diagnostic and prognostic utility of SSEA-1 in thyroid tumors, we analyzed the expression of SSEA-1 in normal and neoplastic thyroid tissues by immunohistochemistry (IHC) using a tissue microarray with 158 different tissue cores. To evaluate the potential utility of SSEA-1 as a surface marker, we also assessed the expression of SSEA-1 in thyroid cell lines by flow cytometric analysis. SSEA-1 immunoreactivity was identified in malignant thyroid follicular epithelial cancers but not in the benign thyroid tissues. Anaplastic thyroid (ATC) (80 %) and conventional papillary thyroid carcinoma (PTC) (60.7 %) showed significantly higher percentage of cases that were SSEA-1 immunoreactive than follicular variant of papillary thyroid carcinoma (FVPTC) (20.6 %) and follicular carcinoma (FCA) (32.1 %). Flow cytometric analysis of cultured thyroid cell lines showed that a small subpopulation of ATC and PTC thyroid tumor cells had SSEA-1 immunoreactivity which may represent thyroid cancer stem-like cells. The ATC cells expressed more SSEA-1 immunoreactive cells than the PTC cell lines. Our findings suggest that expression of SSEA-1 immunoreactivity in thyroid neoplasms was associated with more aggressive thyroid carcinomas. SSEA-1 is a marker that detects malignant thyroid neoplasms in formalin-fixed paraffin-embedded thyroid tissue sections and may be a useful marker for thyroid cancer stem-like cells.
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Retinoblastoma-binding protein 2 (RBP2) is frequently expressed in neuroendocrine tumors and promotes the neoplastic phenotype
Retinoblastoma-binding protein 2 (RBP2) is frequently expressed in neuroendocrine tumors and promotes the neoplastic phenotype
Oncogenesis 5, e257 (August 2016). doi:10.1038/oncsis.2016.58
Authors: E C Maggi, J Trillo-Tinoco, A P Struckhoff, J Vijayaraghavan, L Del Valle & J S Crabtree
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Qigong/tai chi for sleep and fatigue in prostate cancer patients undergoing radiotherapy: A randomized controlled trial
Abstract
Objectives
Sleep disturbances and fatigue are common in prostate cancer patients undergoing radiotherapy. Prior research suggests mind-body techniques may improve these outcomes. We conducted a randomized-controlled trial of qigong/tai chi (QGTC) in men with prostate cancer undergoing radiotherapy.
Methods
Men with prostate cancer starting definitive radiation were randomized to one of three groups: (1) QGTC; (2) light exercise (LE); or (3) wait list control (WLC). Sleep disturbances (PSQI) and fatigue (BFI) were assessed at baseline, mid-radiotherapy (T2), during the last week of radiotherapy (T3) and at 1 (T4) and 3 months (T5) after the end of radiotherapy. Patients in the QGTC and LE groups attended three 40-minute classes per week throughout radiotherapy.
Results
Ninety patients were randomized to the three groups (QGTC = 26; LE = 26; WLC = 24). QGTC group reported longer sleep duration at mid-XRT (QGTC = 7.01 hours; LE = 6.42; WL = 6.50; p = 0.05) but this difference did not persist over time. There were no group differences in other domains of sleep or fatigue. Exploratory analyses conducted to examine the effect of health-related QOL (EPIC and AUA score) on sleep and fatigue showed significant correlations across multiple domains.
Conclusions
QGTC during radiation for prostate cancer resulted in superior sleep duration midway through radiation, but this effect was not durable and there were no differences in other domains of sleep or fatigue. Exploratory analysis demonstrated that both sleep and fatigue were highly correlated with prostate cancer related physical symptoms. Future mind-body intervention studies should incorporate multi-modal therapy focused on improving physical symptoms in this population.
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Prospective Validation of A High Dimensional Shape Model for Organ Motion in Intact Cervical Cancer
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Casey W. Williamson, Garrett Green, Sonal S. Noticewala, Nan Li, Hanjie Shen, Florin Vaida, Loren K. Mell
Purpose/Objective(s)Validated models are needed to justify strategies to define planning target volumes (PTVs) for intact cervical cancer used in clinical practice. Our objective was to independently validate a previously published shape model, using data collected prospectively from clinical trials.Materials/MethodsWe analyzed 42 patients with intact cervical cancer treated with daily fractionated pelvic IMRT and concurrent chemotherapy on one of two prospective clinical trials. We collected on-line cone beam computed tomography (CBCT) scans before each fraction. Clinical target volume (CTV) structures from the planning CT were cast onto each CBCT after rigid registration and manually redrawn to account for organ motion and deformation. We applied the 95% isodose cloud from the planning CT to each CBCT and computed any CTV volume outside the 95% isodose cloud. The primary aim was to determine the proportion of CTVs that were encompassed within the 95% isodose volume. A one-sample t-test was used to test the hypothesis that the probability of complete coverage was different than 95%. We used mixed-effects logistic regression to assess effects of time and patient variability.ResultsThe 95% isodose line completely encompassed 92.3% of all CTVs (95% CI 88.3-96.4), not significantly different from the 95% probability anticipated a priori (p=0.19). The overall proportion of missed CTV was small: the grand mean of covered CTV was 99.9%, and 95.2% of misses were located in the anterior body of the uterus. Time did not affect coverage probability (p=0.71).ConclusionWith the clinical implementation of a previously proposed PTV definition strategy based on a shape model for intact cervical cancer, the probability of CTV coverage was high and the volume of CTV missed was low. This PTV expansion strategy is acceptable for clinical trials and practice; however, we recommend daily image guidance to avoid systematic large misses in select patients.
Teaser
We sought to validate a strategy for planning target volume definition in patients with intact cervical cancer, based on a previously published shape model. Using daily cone-beam computed tomography imaging from patients treated with intensity modulated radiation therapy, we found that 92.3% of target volumes were entirely encompassed within the 95% isodose structure, which was not significantly lower than our hypothesized probability of 95.0% (p=0.19). Therefore, we consider this expansion strategy to be valid.from Cancer via ola Kala on Inoreader http://ift.tt/2bc6jgX
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Androgen Deprivation Therapy Use in the Setting of High-Dose Radiation Therapy and the Risk of Prostate Cancer-Specific Mortality Stratified by the Extent of Competing Mortality
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Brent S. Rose, Ming-Hui Chen, Jing Wu, Michelle H. Braccioforte, Brian J. Moran, Daniel E. Doseretz, Michael J. Katin, Rudolf H. Ross, Sharon A. Salenius, Anthony V. D'Amico
PurposeThe addition of androgen deprivation therapy (ADT) to radiation therapy (RT) is standard of care for men with intermediate and high-risk prostate cancer (PC). However, whether competing mortality impacts the ability of ADT to improve survival remains unanswered.Methods and MaterialsWe calculated a competing mortality (CM) risk score using a Fine-Gray semi-parametric model including age and cardiometabolic comorbidities from a cohort of 17,669 men treated with high-dose RT with or without supplemental ADT for non-metastatic PC. Fine and Gray competing risk regression was used to assess whether ADT reduced the risk of prostate cancer-specific mortality (PCSM) for men with low vs. high risk of CM amongst the 4,550 patients within the intermediate and high-risk cohort adjusted for established PC prognostic factors, year of treatment, site, and ADT treatment propensity score.ResultsAfter a median follow-up of 8.4 years 1,065 men died; 89 (8.36%) from PC. Among men with a low CM score, ADT use was associated with a significant reduction in the risk of PCSM (adjusted HR (AHR): 0.35, 95% CI: 0.14 to 0.87, p = 0.02) but not in men with a high CM score (AHR: 1.33, 95% CI: 0.77 to 2.30, p = 0.30).ConclusionsAdding ADT to high-dose RT appears to be associated with decreased PCSM-risk in men with low but not high CM. These data should serve to heighten awareness about the importance of considering competing risks when determining whether or not to add ADT to RT to treat older men with intermediate or high-risk PC.
Teaser
Adding androgen deprivation therapy (ADT) to high-dose radiation therapy (RT) appears to be associated with decreased prostate cancer-specific mortality (PCSM) risk in men with low but not high competing mortality (CM). These data should serve to heighten awareness about the importance of considering competing risks when determining whether or not to add ADT to RT to treat older men with intermediate or high-risk PC.from Cancer via ola Kala on Inoreader http://ift.tt/2bcKDh9
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Does Bleomycin lung toxicity increase the risk of radiation pneumonitis in Hodgkin Lymphoma?
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Z. A. Abou Yehia, N.G. Mikhaeel, G. Smith, C.C. Pinnix, S.A. Milgrom, C. Tang, W. Jiang, M. Fanale, Y. Oki, J. Shank, P. Horace, J. Reddy, M. Akhtari, J.R. Gunther, O. Mawlawi, P.K. Allen, B.S. Dabaja
PurposeBleomycin pulmonary toxicity (BPT) is a well-known complication of treatment in HL patients. We undertook this study to investigate the risk of radiation pneumonitis (RP) in the setting of BPT and to determine the need for delay or omission of radiation in these patients.MethodsWe identified 123 HL patients treated with ABVD followed by radiation therapy (RT) to the chest between January 2009 and December 2014. Medical records were reviewed for clinical, pathologic, and treatment information as well as toxicities. Our primary outcome was RP of any grade. Univariate and multivariate analysis were used to assess the association of BPT, baseline patient characteristics and treatment variables to the incidence of RP.Results123 patients were included of which 99 patients (80%) received consolidation IMRT after ABVD treatment. We identified 31 patients (25.2%) with BPT following frontline ABVD. Seventeen patients (13.8%) developed RP at a median of 8 weeks after completion of RT (range: 1-39 weeks). BPT did not correlate with the risk of developing RP (p= 0.36). We evaluated RP outcomes with respect to B-RT interval (≤6 weeks vs. > 6 weeks) and we found that this interval did not predict for RP risk (P=0.60). Dosimetric parameters such as V5 and MLD were analyzed; V5 > 55% and MLD > 13.5 Gy were found to increase the risk of RP by 1.14 fold (p= 0.002) and 4.24 fold (P=0.007), respectively.ConclusionOur study suggested that BPT doesn't increase the risk of developing RP. Furthermore, time to RT initiation does not need to be delayed following chemotherapy except to allow for the completion of steroids or clinical recovery from BPT.
Teaser
Bleomycin pulmonary toxicity (BPT) is a well-known complication of treatment in HL patients. We reviewed HL patients treated with ABVD and Mediastinal RT and we compared the risk of RP in patients who developed BPT versus those who didn't. Patients with BPT who received standard RT had no excess risk of subsequent RP; moreover, time to RT initiation did not influence the risk of developing RP.from Cancer via ola Kala on Inoreader http://ift.tt/2bc7ddn
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Functional data analysis applied to modeling of severe acute mucositis and dysphagia resulting from head and neck radiation therapy
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Jamie A. Dean, Kee H. Wong, Hiram Gay, Liam C. Welsh, Ann-Britt Jones, Ulrike Schick, Jung Hun Oh, Aditya Apte, Kate L. Newbold, Shreerang A. Bhide, Kevin J. Harrington, Joseph O. Deasy, Christopher M. Nutting, Sarah L. Gulliford
PurposeCurrent normal tissue complication probability (NTCP) modeling using logistic regression suffers from bias and high uncertainty in the presence of highly correlated radiation therapy (RT) dose data. This hinders robust estimates of dose-response associations and, hence, optimal normal tissue-sparing strategies from being elucidated. Using functional data analysis (FDA) to reduce the dimensionality of the dose data could overcome this limitation.Methods and MaterialsFDA was applied to modeling of severe acute mucositis and dysphagia resulting from head and neck RT. Functional partial least squares regression (FPLS) and functional principal component analysis (FPCA) were used for dimensionality reduction of the dose-volume histogram data. The reduced dose data were input into functional logistic regression models (FPLS-LR and FPC-LR) along with clinical data. This approach was compared with penalized logistic regression (PLR) in terms of predictive performance and the significance of treatment covariate-response associations, assessed using bootstrapping.ResultsThe area under the receiver operating characteristic curves (AUC) for the PLR, FPC-LR and FPLS-LR models were 0.65, 0.69 and 0.67 for mucositis (internal validation) and 0.81, 0.83 and 0.83 for dysphagia (external validation), respectively. The calibration slopes/intercepts for the PLR, FPC-LR and FPLS-LR models were 1.6/-0.67, 0.45/0.47 and 0.40/0.49 for mucositis (internal validation) and 2.5/-0.96, 0.79/-0.04 and 0.79/0.00 for dysphagia (external validation). The bootstrapped odds ratios indicated significant associations between RT dose and severe toxicity in the mucositis and dysphagia FDA models. Cisplatin was significantly associated with severe dysphagia in the FDA models. None of the covariates was significantly associated with severe toxicity in the PLR models. Dose levels greater than approximately 1.0 Gy/fraction were most strongly associated with severe acute mucositis and dysphagia in the FDA models.ConclusionsFPLS and FPCA marginally improved predictive performance compared with PLR and provided robust dose-response associations. FDA is recommended for use in NTCP modeling.
Teaser
Normal tissue complication probability modeling using logistic regression (LR) suffers from bias and uncertainty in the presence of highly correlated radiation therapy dose data. Consequently robust estimates of the dose levels most strongly associated with toxicity and, potentially, predictive performance are limited. To overcome this limitation, functional data analysis (FDA), which describes the dose-volume histogram as a continuous curve, was applied to modeling of severe acute mucositis and dysphagia and compared with LR. FDA models demonstrated slightly better predictive performance and more robust dose-response estimates than LR.from Cancer via ola Kala on Inoreader http://ift.tt/2bcJWol
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Bruceantin inhibits multiple myeloma cancer stem cell proliferation
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Necroptosis: A new way of dying?
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NDRG1 overexpression promotes the progression of esophageal squamous cell carcinoma through modulating Wnt signaling pathway
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Isolated splenic metastasis from a thymic carcinoma: A case report
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Berberine reverses lapatinib resistance of HER2-positive breast cancer cells by increasing the level of ROS
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Retinoic acid-pretreated Wharton’s jelly mesenchymal stem cells in combination with triiodothyronine improve expression of neurotrophic factors in the subventricular zone of the rat ischemic brain injury
Abstract
Stroke is the consequence of limited blood flow to the brain with no established treatment to reduce the neurological deficits. Focusing on therapeutic protocols in targeting subventricular zone (SVZ) neurogenesis has been investigated recently. This study was designed to evaluate the effects of retinoic acid (RA)-pretreated Wharton's jelly mesenchymal stem cells (WJ-MSCs) in combination with triiodothyronine (T3) in the ischemia stroke model. Male Wistar rats were used to induce focal cerebral ischemia by middle cerebral artery occlusion (MCAO). There were seven groups of six animals: Sham, Ischemic, WJ-MSCs, RA-pretreated WJ-MSCs, T3, WJ-MSCs +T3, and RA-pretreated WJ-MSCs + T3. The treatment was performed at 24 h after ischemia, and animals were sacrificed one week later for assessments of retinoid X receptor β (RXRβ), brain-derived neurotrophic factor (BDNF), Sox2 and nestin in the SVZ. Pro-inflammatory cytokines in sera were measured at days four and seven after ischemia. RXRβ, BDNF, Sox2 and nestin had the significant expressions in gene and protein levels in the treatment groups, compared with the ischemic group, which were more vivid in the RA-pretreated WJ-MSCs + T3 (p ≤ 0.05). The same trend was also resulted for the levels of TNF-α and IL-6 at four days after ischemia (p ≤ 0.05). In conclusion, application of RA-pretreated WJ-MSCs + T3 could be beneficial in exerting better neurotrophic function probably via modulation of pro-inflammatory cytokines.
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Laparoscopic proximal gastrectomy for early gastric cancer
Abstract
The incidence of proximal early gastric cancer (EGC) is increasing, and while laparoscopic proximal gastrectomy (LPG) has been performed as a surgical option, it is not yet the standard treatment, because there is no established common reconstruction method following proximal gastrectomy (PG). We reviewed the English-language literature to clarify the current status and problems associated with LPG in treating proximal EGC. This procedure is considered indicated for EGC located in the upper third of the stomach with clinical T1N0, but not when it can be treated endoscopically. No operative mortality or conversion to open surgery was reported in our review, suggesting that this procedure is technically feasible. The most frequent postoperative complication involved problems with anastomoses, possibly caused by the technical complexity of the reconstruction. Although various reconstruction methods following open PG (OPG) and LPG have been reported, there is no standard reconstruction method. Well-designed multicenter, randomized, controlled, prospective trials to evaluate the various reconstruction methods are necessary.
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Necessity for autologous blood storage and transfusion in patients undergoing pancreatoduodenectomy
Abstract
Purpose
To establish which patients undergoing pancreaticoduodenectomy (PD) need autologous blood storage and transfusion.
Methods
Autologous blood was collected and stored for 69 patients scheduled to undergo PD, and not used in 50 patients. Based on the use of the deposited autologous blood and the estimated postoperative hemoglobin (Hb) level when blood was not deposited, we divided the patients into a "transfusion necessary" group and a "transfusion unnecessary" group. By comparing the two groups, we proposed a method of scoring to predict the necessity for storing autologous blood.
Results
The "transfusion necessary" group comprised 6 patients (2 who received homologous blood transfusion and 4 with an estimated postoperative Hb of <8.0 g/dL) and the "transfusion unnecessary" group comprised 63 patients (24 whose autologous blood was discarded and 39 with an estimated Hb ≥8.0 g/dL). By analyzing the differences between the groups, including the preoperative hemoglobin level and the need for portal vein resection, we devised a scoring system to predict the necessity of collecting autologous blood. The scoring significantly correlated with the proportion of patients who did not require autologous blood storage and transfusion.
Conclusions
Not all patients benefited from autologous blood storage and transfusion. Our scoring system proved useful for identifying which patients required autologous blood storage and transfusion during PD.
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High serum levels of interleukin-6 in patients with advanced or metastatic colorectal cancer: the effect on the outcome and the response to chemotherapy plus bevacizumab
Abstract
Purpose
We evaluated the relationship of the pretreatment serum IL-6 levels with the outcome and treatment response in patients with advanced or metastatic colorectal cancer (CRC) who underwent bevacizumab-containing chemotherapy.
Methods
In this retrospective study, the pretreatment serum IL-6 and plasma vascular endothelial growth factor (VEGF) levels were measured in 113 patients with metastatic CRC. The cut-off values for these measurements, as determined by a receiver operating characteristic curve analysis, were 4.3 and 66 pg/mL, respectively. The median follow-up period was 19 months (range 1–40 months). Sixty-three patients had primary cancer, and 38 had a metachronous recurrence. Thirty patients underwent curative resection, and 71 underwent chemotherapy, 53 of whom received bevacizumab-containing chemotherapy. Overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan–Meier and multivariate Cox proportional hazards regression analyses.
Results
The plasma VEGF levels and positive KRAS mutation status were not associated with the outcomes. However, high serum IL-6 levels were significantly associated with poorer OS and PFS in comparison to low serum IL-6 levels. A Cox proportional hazards regression analysis showed that high serum IL-6 levels were an independent risk factor for a poor outcome.
Conclusion
In patients with metastatic CRC, high pretreatment serum IL-6 levels were associated with a poor outcome and bevacizumab resistance.
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Palliative surgery for colorectal cancer with peritoneal metastasis: a propensity-score matching analysis
Abstract
Purpose
Peritoneal metastasis (PM) in patients with colorectal cancer (CRC) is associated with poor prognosis. We conducted this study to assess whether palliative resection (PR) of the primary tumor improved the overall survival (OS) of patients with PM-CRC.
Methods
We analyzed retrospectively, data collected prospectively from patients with CRC. PM was categorized into three subgroups according to the Japanese classification of PM. A propensity‐score model was used to compare the outcomes of patients who underwent PR (PR group) and those who did not [non‐resection (NR) group].
Results
Among 1909 patients with metastatic CRC, 309 (16 %) had only peritoneal metastases and 255 of these patients who underwent palliative surgery (R2) were the subjects of our analysis: 161 in the PR group and 94 in the NR group. Median OS was significantly longer in the PR group than in the NR group (23 vs. 11 months, P < 0.001). Patients in the PR group had less extensive PM and a higher rate of receiving palliative chemotherapy than those in the NR group (P < 0.001). In a Cox multivariate analysis of 69 propensity‐score matched pairs, PR resulted in significantly longer OS than NR (hazard ratio 0.496, 95 % confidence interval 0.268–0.919, P = 0.025).
Conclusions
Our results show that PR resulted in better OS than NR for patients with PM-CRC, when their overall condition permitted a more aggressive approach.
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Pre-treatment double- or triple-positive tumor markers are predictive of a poor outcome for patients undergoing radiofrequency ablation for hepatocellular carcinoma
Abstract
Purposes
We evaluated the therapeutic effect of radiofrequency ablation (RFA) on hepatocellular carcinoma (HCC) according to the number of positive tumor markers.
Methods
The subjects of this study were 160 patients who underwent percutaneous and surgical RFA for HCC. Patients were divided into negative (n = 51), single- (n = 69), double- (n = 31), and triple-positive (n = 9) tumor marker groups according to the pre-treatment expression of these markers. We looked for any relationships among clinical parameters, outcomes, and tumor markers.
Results
The 3-year recurrence-free and overall survival rates of the negative, single-, double-, and triple-positive groups were 30, 19, 16, and 11 % (P = 0.02), and 94, 88, 67, and 37 % (P < 0.001), respectively. The 2-year local recurrence rates were 6.5, 0, 41.2, and 61.9 %, respectively (P < 0.001). Multivariate analysis revealed that a double- or triple-positive pre-treatment tumor marker profile was independently associated with local recurrence [hazard ratio (HR) 5.48, 95 % confidence interval (CI) 2.44–12.33, P < 0.001] and overall survival (HR 4.21, 95 % CI 1.89–9.37, P < 0.001).
Conclusion
RFA may not be suitable for patients with HCC who have pre-treatment expression of ≥two of these tumor markers.
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Misoprostol Vaginal Insert in Labor Induction: A Cost–Consequences Model for 5 European Countries—An Economic Evaluation Supported with Literature Review and Retrospective Data Collection
Abstract
Introduction
The present study aimed to assess the costs and consequences of using an innovative medical technology, misoprostol vaginal insert (MVI), for the induction of labor (IOL), in place of alternative technologies used as a standard of care.
Methods
This was a retrospective study on cost and resource utilization connected with economic model development. Target population were women with an unfavorable cervix, from 36 weeks of gestation, for whom IOL is clinically indicated. Data on costs and resources was gathered via a dedicated questionnaire, delivered to clinical experts in five EU countries. The five countries participating in the project and providing completed questionnaires were Austria, Poland, Romania, Russia and Slovakia. A targeted literature review in Medline and Cochrane was conducted to identify randomized clinical trials meeting inclusion criteria and to obtain relative effectiveness data on MVI and the alternative technologies. A hospital perspective was considered as most relevant for the study. The economic model was developed to connect data on clinical effectiveness and safety from randomized clinical trials with real life data from local clinical practice.
Results
The use of MVI in most scenarios was related to a reduced consumption of hospital staff time and reduced length of patients' stay in hospital wards, leading to lower total costs with MVI when compared to local comparators.
Conclusions
IOL with the use of MVI generated savings from a hospital perspective in most countries and scenarios, in comparison to alternative technologies.
Funding
Sponsorship, article processing charges, and the open access charge for this study were funded by Ferring Pharmaceuticals Poland.
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Impact of marital status, insurance status, income, and race/ethnicity on the survival of younger patients diagnosed with multiple myeloma in the United States
BACKGROUND
Recent advances in the treatment of multiple myeloma (MM) have been associated with improved survival, predominantly among young and white patients. The authors hypothesized that sociodemographic factors, adjusted for race/ethnicity, influence the survival of younger patients with MM.
METHODS
Overall survival (OS) data were obtained for individuals included in the Surveillance, Epidemiology, and End Results (SEER-18) program who were diagnosed with MM before the age of 65 years between 2007 and 2012. The sociodemographic variables addressed were marital status, insurance status, median household income, and educational achievement in the county of residence. Race/ethnicity was defined as a self-reported construct including Hispanic (regardless of race), non-Hispanic black, non-Hispanic white, and other.
RESULTS
There were 10,161 cases of MM included with a median follow-up of 27 months (range, 0-71 months; 22,179 person-years). Using multivariable Cox proportional hazards analysis, SEER registry; age; male sex; and 3 sociodemographic factors including marital status (other than married), insurance status (uninsured or Medicaid), and county-level income (lowest 2 quartiles), but not race/ethnicity, were found to be associated with an increased risk of death. The 4-year estimated OS rate was 71.1%, 63.2%, 53.4%, and 46.5% (P<.001), respectively, for patients with 0, 1, 2, or 3 adverse sociodemographic factors. Hispanic and non-Hispanic black individuals were found to have more adverse sociodemographic factors and worse OS. However, when the population was stratified by the cumulative number of sociodemographic factors, no consistent association between race/ethnicity and OS was observed after adjustment for confounders.
CONCLUSIONS
Sociodemographic factors that potentially affect care, but not race/ethnicity, were found to influence the survival of younger patients with MM. Cancer 2016. © 2016 American Cancer Society.
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Endometriosis and mammographic density measurements in the Nurses’ Health Study II
Abstract
Purpose
Endometriosis and mammographic density have been hypothesized to be influenced by sex steroid hormonal exposures in adolescence and early adulthood. We investigated the association between endometriosis and mammographic density, a consistent and independent risk factor for breast cancer.
Methods
We conducted a cross-sectional analysis among 1,581 pre- and postmenopausal women not previously diagnosed with breast cancer in the Nurses' Health Study II cohort. We measured average percent mammographic density and absolute dense and non-dense breast area using a validated computer-assisted method. Multivariable linear regression was used to estimate the association between endometriosis and mammographic density among pre- and postmenopausal women separately.
Results
Among premenopausal women, average percent mammographic density was 43.1 % among women with endometriosis (n = 91) and 40.5 % among women without endometriosis (n = 1,150). Endometriosis was not associated significantly with mammographic density among premenopausal (% difference = 2.00 percentage points 95 % CI −1.33, 5.33) or among postmenopausal women (% difference = −0.89 percentage points 95 % CI −5.10, 3.33). Among premenopausal women, there was heterogeneity by BMI at age 18 (p value = 0.003), with a suggested association among those who were lean at age 18 (BMI < 20.6 kg/m2) (% difference = 3.74 percentage points 95 % CI −0.29, 7.78).
Conclusion
Endometriosis was not found to be associated with overall measurements of mammographic density.
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Effect of the timing of best tumor shrinkage on survival of patients with metastatic renal cell carcinoma who received first-line tyrosine kinase inhibitor therapy
Abstract
Background
To evaluate the association between the timing of best tumor shrinkage (bTS) and metastatic renal cell carcinoma (mRCC) patient survival after first-line tyrosine kinase inhibitor (TKI) therapy.
Methods
The tumors of 91 patients with mRCC showed a response to TKIs. None of the patients had received prior cytokine therapy. The magnitude of bTS was categorized according to the Response Evaluation Criteria in Solid Tumors v. 1.1. The patients were divided into two subgroups according to the timing of bTS: early responders (≤3 months) and late responders (>3 months). Overall survival (OS) and progression-free survival (PFS) after first-line TKI therapy were evaluated, and factors predicting survival were examined.
Results
Sunitinib, sorafenib, and pazopanib were used in 62, 25, and 4 responders, respectively. In total, 52 (57.1 %) and 39 (42.9 %) patients were early and late responders, respectively. Early responders had significantly lower PFS compared to late responders (median survival, 11.4 vs. 19.1 months; log-rank test, p = 0.0263), although there were no significant differences in the OS of early and late responders (27.0 vs. 30.1 months, p = 0.306). Multivariate analyses revealed that the timing of bTS was an independent predictor of PFS and OS (PFS, hazard ratio 4.09, p < 0.0001; OS, hazard ratio 2.32, p = 0.0107).
Conclusion
The timing of bTS was an independent predictor of survival in patients with mRCC who received first-line TKIs.
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One-step nucleic acid amplification (OSNA): where do we go with it?
Abstract
The one-step nucleic acid amplification (OSNA) assay was initially developed for the intraoperative assessment of sentinel lymph node metastases in breast cancer. This assay measures cytokeratin 19 (CK19) mRNA copy number and is widely used in hospitals. The results of the IBCSG 23-01, ACOSOG Z0011, and AMAROS trials demonstrated that no further axillary dissection is required for patients with sentinel lymph nodes that tested positive for cancer, which has led to a decreasing trend in the need for intraoperative assessment of lymph nodes. Here, I review studies relevant to OSNA and discuss perspectives on future applications of OSNA in cancer surgery. The studies reviewed were identified by carrying out a search on PubMed for all articles pertaining to OSNA and published prior to the end of June 2016 using the keywords "OSNA" or "one-step nucleic acid amplification" in the title or abstract. Method comparison studies between OSNA and pathological assessment for the detection of lymph node metastasis in breast cancer revealed that in a pooled assessment OSNA had a high specificity (94.8 %), high concordant rate (93.8 %), and a negative predictive value (97.6 %). Similar results have been found for gastric, colorectal, and lung cancers in multicenter studies. These results demonstrate that OSNA can serve as an alternative method to pathological assessment for examining lymph node metastasis. Multicenter prospective studies with a large sample size are needed to definitively reveal the superiority of OSNA over pathological assessment to predict prognosis. Technical refinements to improve the assay are essential to its further development as a new standard for testing in place of pathological examination.
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Fulminant anaplastic large cell lymphoma (ALCL) concomitant with primary cytomegalovirus (CMV) infection, and human herpes virus 8 (HHV-8) infection together with Epstein-Barr-virus (EBV) reactivation in a patient with asymptomatic HIV-infection
Abstract
Background
Most malignant lymphomas in HIV-patients are caused by reactivation of EBV-infection. Some lymphomas have a very rapid fulminant course. HHV-8 has also been reported to be a cause of lymphoma. The role of CMV in the development of lymphoma is not clear, though both CMV and HHV-8 have been reported in tissues adjacent to the tumour in Burkitt lymphoma patients. Here we present a patient with asymptomatic HIV infection, that contracted a primary cytomegalovirus (CMV) infection and human herpes virus 8 (HHV-8) infection. Three weeks before onset of symptoms the patient had unprotected sex which could be possible source of his CMV and also HHV-8 infection He deteriorated rapidly and died with a generalized anaplastic large cell lymphoma (ALCL).
Methods
A Caucasian homosexual male with asymptomatic human immunodeficiency virus (HIV) infection contracted a primary cytomegalovirus (CMV) infection and human herpes virus 8 (HHV-8) infection. He deteriorated rapidly and died with a generalized anaplastic large cell lymphoma (ALCL). Clinical and laboratory records were compiled. Immunohistochemistry was performed on lymphoid tissues, a liver biopsy, a bone marrow aspirate and the spleen during the illness and at autopsy. Serology and PCR for HIV, CMV, EBV, HHV-1–3 and 6–8 was performed on blood drawn during the course of disease.
Results
The patient presented with an acute primary CMV infection. Biopsies taken 2 weeks before death showed a small focus of ALCL in one lymph node of the neck. Autopsy demonstrated a massive infiltration of ALCL in lymph nodes, liver, spleen and bone marrow. Blood samples confirmed primary CMV- infection, a HHV-8 infection together with reactivation of Epstein- Barr-virus (EBV).
Conclusion
Primary CMV-infection and concomitant HHV-8 infection correlated with reactivation of EBV. We propose that these two viruses influenced the development and progression of the lymphoma. Quantitative PCR blood analysis for EBV, CMV and HHV-8 could be valuable in diagnosis and treatment of this type of very rapidly developing lymphoma. It is also a reminder of the importance of prevention and prophylaxis of several infections by having protected sex.
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