Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Τρίτη 12 Ιουλίου 2016
Adherence to Hematologic Hold Parameters in Carboplatin and Dose-Dense Paclitaxel Chemotherapy for Ovarian Malignancies: A Survey of NCCN Member Institutions
Objective: To determine the adherence to hematologic chemotherapy hold parameters for the carboplatin and dose-dense paclitaxel chemotherapy regimen in patients with ovarian, fallopian tube, or primary peritoneal cancers. Methods: This is a quality assessment survey study. All 26 NCCN Member Institutions were contacted electronically. Hematologic chemotherapy hold parameter values (absolute neutrophil count [ANC] and platelet count) on days 1, 8, and 15 of each cycle were queried. These hold parameters were compared with published data supporting the use of dose-dense chemotherapy regimens in ovarian cancer. Results: The overall survey response rate was 85% (22/26 sites). Of responders, 27% (6 sites) were fully adherent with all hematologic hold parameters and 64% (14 sites) used hold parameters that differed from the published protocol. Specifically, all of these sites use hold parameters higher than those recommended in the literature. Two centers did not have center-specific hold parameters. Conclusions: Carboplatin and dose-dense paclitaxel chemotherapy has been shown to increase progression-free survival and overall survival in patients with stage II–IV ovarian, fallopian tube, or primary peritoneal cancers. However, our study found that two-thirds of queried sites had hold parameters higher than those in the published protocol. Using more stringent hold parameters may lead to compromised clinical outcomes. Further research is necessary to determine the optimal strategy to increase individual site adherence to chemotherapy hematologic hold parameters as specified in published trials.
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Whole-Exome Sequencing in Two Extreme Phenotypes of Response to VEGF-Targeted Therapies in Patients With Metastatic Clear Cell Renal Cell Carcinoma
Advances in next-generation sequencing have provided a unique opportunity to understand the biology of disease and mechanisms of sensitivity or resistance to specific agents. Renal cell carcinoma (RCC) is a heterogeneous disease and highly variable clinical responses have been observed with vascular endothelial growth factor (VEGF)–targeted therapy (VEGF-TT). We hypothesized that whole-exome sequencing analysis might identify genotypes associated with extreme response or resistance to VEGF-TT in metastatic (mRCC). Patients with mRCC who had received first-line sunitinib or pazopanib and were in 2 extreme phenotypes of response were identified. Extreme responders (ERs) were defined as those with partial response or complete response for 3 or more years (n=13) and primary refractory patients (PRPs) were defined as those with progressive disease within the first 3 months of therapy (n=14). International Metastatic RCC Database Consortium prognostic scores were not significantly different between the groups (P=.67). Considering the genes known to be mutated in RCC at significant frequency, PBRM1 mutations were identified in 7 ERs (54%) versus 1 PRP (7%) (P=.01). In addition, mutations in TP53 (n=4) were found only in PRPs (P=.09). Our data suggest that mutations in some genes in RCC may impact response to VEGF-TT.
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Care and Outcomes of Patients With Cancer Admitted to the Hospital on Weekends and Holidays: A Retrospective Cohort Study
Background: Patients admitted to the hospital on weekends experience worse outcomes than those admitted on weekdays. Patients with cancer may be especially vulnerable to the effects of weekend care. Our objective was to compare the care and outcomes of patients with cancer admitted urgently to the hospital on weekends and holidays versus those of patients with cancer admitted at other times. Materials and Methods: This was a retrospective study of all adult patients with cancer having an urgent hospitalization in Canada from 2010 to 2013. Patients admitted to hospital on weekends/holidays were compared with those admitted on weekdays. The primary outcome was 7-day in-hospital mortality. We also compared performance of procedures in the first 2 days of hospital admission and admission to critical care after the first 24 hours. Results: 290,471 hospital admissions were included. Patients admitted to hospital on weekends/holidays had an increased risk of 7-day in-hospital mortality (4.8% vs 4.3%; adjusted odds ratio [OR], 1.13; 95% CI, 1.08–1.17), corresponding to 137 excess deaths per year compared with the weekday group. This risk persisted after restricting the analysis to patients arriving by ambulance (7.1% vs 6.4%; adjusted OR, 1.11; 95% CI, 1.04–1.18). Among those who had procedures in the first 4 days of admission, fewer weekend/holiday-admitted patients had them performed in the first 2 days, for 8 of 9 common procedure groups. There was no difference in critical care admission risk after the first 24 hours. Conclusions: Patients with cancer admitted to the hospital on weekends/holidays experience higher mortality relative to patients admitted on weekdays. This may result from different care processes for weekend/holiday patients, including delayed procedures. Future research is needed to identify key outcome-driving procedures, and ensure timely access to these on all days of the week.
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NCCN Guidelines Insights: Malignant Pleural Mesothelioma, Version 3.2016
These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for Malignant Pleural Mesothelioma (MPM). These NCCN Guidelines Insights discuss systemic therapy regimens and surgical controversies for MPM. The NCCN panel recommends cisplatin/pemetrexed (category 1) for patients with MPM. The NCCN panel also now recommends bevacizumab/cisplatin/pemetrexed as a first-line therapy option for patients with unresectable MPM who are candidates for bevacizumab. The complete version of the NCCN Guidelines for MPM, available at NCCN.org, addresses all aspects of management for MPM including diagnosis, evaluation, staging, treatment, surveillance, and therapy for recurrence and metastasis; NCCN Guidelines are intended to assist with clinical decision-making.
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Prevention and Treatment of Cancer-Related Infections, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology
Infectious diseases are important causes of morbidity and mortality in patients with cancer. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prevention and Treatment of Cancer-Related Infections characterize the major pathogens to which patients with cancer are susceptible, with a focus on the prevention, diagnosis, and treatment of major common and opportunistic infections. This portion of the guidelines highlights the sections on antifungal and antiviral prophylaxis. Antifungal and antiviral prophylaxis recommendations have expanded over the past few years. New agents for the treatment of fungal infections and incorporation of therapeutic drug monitoring are presented. Antiviral prophylaxis for hepatitis B and management considerations for hepatitis C and HIV have been further developed.
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Value, Access, and Cost of Cancer Care Delivery at Academic Cancer Centers
Key challenges facing the oncology community today include access to appropriate, high quality, patient-centered cancer care; defining and delivering high-value care; and rising costs. The National Comprehensive Cancer Network convened a Work Group composed of NCCN Member Institution cancer center directors and their delegates to examine the challenges of access, high costs, and defining and demonstrating value at the academic cancer centers. The group identified key challenges and possible solutions to addressing these issues. The findings and recommendations of the Work Group were then presented at the Value, Access, and Cost of Cancer Care Policy Summit in September 2015 and multi-stakeholder roundtable panel discussions explored these findings and recommendations along with additional items.
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A novel deleterious c.2656G>T MSH2 germline mutation in a Pakistani family with a phenotypic overlap of hereditary breast and ovarian cancer and Lynch syndrome
Abstract
Background
Hereditary breast and ovarian cancer syndrome (HBOC) and Lynch syndrome (LS) account for a significant proportion of inherited gynecologic malignancies, mainly caused by pathogenic germline mutations in the BRCA1 and BRCA2 genes or in mismatch repair (MMR) genes, such as MLH1 and MSH2. Women harboring deleterious mutations in these genes have increased life-time risks of developing a number of malignancies including ovarian cancer. Since there is a phenotypic overlap of HBOC and LS, timely identification of individuals at-risk of a particular syndrome is crucial in order to optimize cancer risk management.
Case presentation
We report a novel pathogenic MSH2 mutation, c.2656G > T, which was identified in a 67-year-old female patient with breast cancer, who had previously tested negative for a deleterious mutation in the breast cancer susceptibility genes BRCA1, BRCA2, CHEK2 or RAD51C. The patient reported a personal history of endometrial cancer diagnosed at age 48, and a strong family history of breast and ovarian cancer, as well as several other malignancies within the spectrum of LS. The novel mutation was also found in the index patient's daughter and a niece, who were diagnosed with endometrial and ovarian cancer, respectively. Breast and endometrial tumors from c.2656G > T mutation carriers showed loss of MSH2 and MSH6 protein expression. The mutation was absent in the control population.
Conclusions
Our finding suggests that testing for MMR genes may be of benefit to BRCA1/2 negative families with overlapping HBOC and LS phenotype in Pakistan. It is clinically significant to identify individuals harboring mutations in genes linked with a particular syndrome so that they can benefit from targeted life-saving cancer surveillance and preventive strategies.
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Are there biological differences between screen-detected and interval colorectal cancers in the English Bowel Cancer Screening Programme?
Are there biological differences between screen-detected and interval colorectal cancers in the English Bowel Cancer Screening Programme?
British Journal of Cancer 115, 261 (12 July 2016). doi:10.1038/bjc.2016.159
Authors: Elizabeth Walsh, Colin J Rees, Michael Gill, Clare E Parker, Roisin Bevan, Sarah L Perry, Yvonne Bury, Sarah Mills, D Michael Bradburn, Michael Bramble & Mark A Hull
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The relationship between tumour budding, the tumour microenvironment and survival in patients with primary operable colorectal cancer
The relationship between tumour budding, the tumour microenvironment and survival in patients with primary operable colorectal cancer
British Journal of Cancer 115, 156 (12 July 2016). doi:10.1038/bjc.2016.173
Authors: Hester C van Wyk, James H Park, Joanne Edwards, Paul G Horgan, Donald C McMillan & James J Going
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Overexpression of the oncostatin-M receptor in cervical squamous cell carcinoma is associated with epithelial–mesenchymal transition and poor overall survival
Overexpression of the oncostatin-M receptor in cervical squamous cell carcinoma is associated with epithelial–mesenchymal transition and poor overall survival
British Journal of Cancer 115, 212 (12 July 2016). doi:10.1038/bjc.2016.199
Authors: Justyna A Kucia-Tran, Valtteri Tulkki, Stephen Smith, Cinzia G Scarpini, Katherine Hughes, Angela M Araujo, Ka Yin Matthew Yan, Jan Botthof, Eduardo Pérez-Gómez, Miguel Quintanilla, Kate Cuschieri, Maria M Caffarel & Nicholas Coleman
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Adverse prognostic impact of the CpG island methylator phenotype in metastatic colorectal cancer
Adverse prognostic impact of the CpG island methylator phenotype in metastatic colorectal cancer
British Journal of Cancer 115, 164 (12 July 2016). doi:10.1038/bjc.2016.176
Authors: Yongjun Cha, Kyung-Ju Kim, Sae-Won Han, Ye Young Rhee, Jeong Mo Bae, Xianyu Wen, Nam-Yun Cho, Dae-Won Lee, Kyung-Hun Lee, Tae-Yong Kim, Do-Youn Oh, Seock-Ah Im, Yung-Jue Bang, Seung-Yong Jeong, Kyu Joo Park, Gyeong Hoon Kang & Tae-You Kim
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WW domain binding protein 5 induces multidrug resistance of small cell lung cancer under the regulation of miR-335 through the Hippo pathway
WW domain binding protein 5 induces multidrug resistance of small cell lung cancer under the regulation of miR-335 through the Hippo pathway
British Journal of Cancer 115, 243 (12 July 2016). doi:10.1038/bjc.2016.186
Authors: Ruixiang Tang, Yingying Lei, Bingshuang Hu, Jie Yang, Shun Fang, Qiongyao Wang, Man Li & Linlang Guo
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Role of nutritional status and intervention in oesophageal cancer treated with definitive chemoradiotherapy: outcomes from SCOPE1
Role of nutritional status and intervention in oesophageal cancer treated with definitive chemoradiotherapy: outcomes from SCOPE1
British Journal of Cancer 115, 172 (12 July 2016). doi:10.1038/bjc.2016.129
Authors: S Cox, C Powell, B Carter, C Hurt, Somnath Mukherjee & Thomas David Lewis Crosby
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Molecular characterisation of cutaneous melanoma: creating a framework for targeted and immune therapies
Molecular characterisation of cutaneous melanoma: creating a framework for targeted and immune therapies
British Journal of Cancer 115, 145 (12 July 2016). doi:10.1038/bjc.2016.195
Authors: Shivshankari Rajkumar & Ian R Watson
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Cardiorespiratory fitness in long-term lymphoma survivors after high-dose chemotherapy with autologous stem cell transplantation
Cardiorespiratory fitness in long-term lymphoma survivors after high-dose chemotherapy with autologous stem cell transplantation
British Journal of Cancer 115, 178 (12 July 2016). doi:10.1038/bjc.2016.180
Authors: Jo S Stenehjem, Knut B Smeland, Klaus Murbraech, Harald Holte, Stein Kvaløy, Lene Thorsen, Ingerid Arbo, Lee W Jones, Svend Aakhus, May Brit Lund & Cecilie E Kiserud
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A UK feasibility and validation study of the VE1 monoclonal antibody immunohistochemistry stain for BRAF-V600E mutations in metastatic melanoma
A UK feasibility and validation study of the VE1 monoclonal antibody immunohistochemistry stain for BRAF-V600E mutations in metastatic melanoma
British Journal of Cancer 115, 223 (12 July 2016). doi:10.1038/bjc.2016.106
Authors: Michelle Chin I Lo, Anna Paterson, Jane Maraka, Richard Clark, Joseph Goodwill, Jenny Nobes, Jennifer Garioch, Marc Moncrieff, Ed Rytina & Laszlo Igali
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Second-line therapy after nab-paclitaxel plus gemcitabine or after gemcitabine for patients with metastatic pancreatic cancer
Second-line therapy after nab-paclitaxel plus gemcitabine or after gemcitabine for patients with metastatic pancreatic cancer
British Journal of Cancer 115, 188 (12 July 2016). doi:10.1038/bjc.2016.185
Authors: E Gabriela Chiorean, Daniel D Von Hoff, Josep Tabernero, Robert El-Maraghi, Wen Wee Ma, Michele Reni, Marion Harris, Robert Whorf, Helen Liu, Jack Shiansong Li, Victoria Manax, Alfredo Romano, Brian Lu & David Goldstein
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KI67 and DLX2 predict increased risk of metastasis formation in prostate cancer–a targeted molecular approach
KI67 and DLX2 predict increased risk of metastasis formation in prostate cancer–a targeted molecular approach
British Journal of Cancer 115, 236 (12 July 2016). doi:10.1038/bjc.2016.169
Authors: William JF Green, Graham Ball, Geoffrey Hulman, Catherine Johnson, Gerry Van Schalwyk, Hari L Ratan, Daniel Soria, Jonathan M Garibaldi, Richard Parkinson, Joshua Hulman, Robert Rees & Desmond G Powe
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Tumour and immune cell dynamics explain the PSA bounce after prostate cancer brachytherapy
Tumour and immune cell dynamics explain the PSA bounce after prostate cancer brachytherapy
British Journal of Cancer 115, 195 (12 July 2016). doi:10.1038/bjc.2016.171
Authors: Yoichiro Yamamoto, Chetan P Offord, Go Kimura, Shigehiko Kuribayashi, Hayato Takeda, Shinichi Tsuchiya, Hisashi Shimojo, Hiroyuki Kanno, Ivana Bozic, Martin A Nowak, Željko Bajzer & David Dingli
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Definitive chemoradiation alters the immunologic landscape and immune checkpoints in head and neck cancer
Definitive chemoradiation alters the immunologic landscape and immune checkpoints in head and neck cancer
British Journal of Cancer 115, 252 (12 July 2016). doi:10.1038/bjc.2016.166
Authors: Vishwajith Sridharan, Danielle N Margalit, Stephanie A Lynch, Mariano Severgnini, Jun Zhou, Nicole G Chau, Guilherme Rabinowits, Jochen H Lorch, Peter S Hammerman, F Stephen Hodi, Robert I Haddad, Roy B Tishler & Jonathan D Schoenfeld
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Efficacy of focal adhesion kinase inhibition in non-small cell lung cancer with oncogenically activated MAPK pathways
Efficacy of focal adhesion kinase inhibition in non-small cell lung cancer with oncogenically activated MAPK pathways
British Journal of Cancer 115, 203 (12 July 2016). doi:10.1038/bjc.2016.190
Authors: Hao Zhang, Huanjie Shao, Vita M Golubovskaya, Hongbin Chen, William Cance, Alex A Adjei & Grace K Dy
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Mendelian randomisation analysis strongly implicates adiposity with risk of developing colorectal cancer
Mendelian randomisation analysis strongly implicates adiposity with risk of developing colorectal cancer
British Journal of Cancer 115, 266 (12 July 2016). doi:10.1038/bjc.2016.188
Authors: David Jarvis, Jonathan S Mitchell, Philip J Law, Kimmo Palin, Sari Tuupanen, Alexandra Gylfe, Ulrika A Hänninen, Tatiana Cajuso, Tomas Tanskanen, Johanna Kondelin, Eevi Kaasinen, Antti-Pekka Sarin, Jaakko Kaprio, Johan G Eriksson, Harri Rissanen, Paul Knekt, Eero Pukkala, Pekka Jousilahti, Veikko Salomaa, Samuli Ripatti, Aarno Palotie, Heikki Järvinen, Laura Renkonen-Sinisalo, Anna Lepistö, Jan Böhm, Jukka-Pekka Meklin, Nada A Al-Tassan, Claire Palles, Lynn Martin, Ella Barclay, Susan M Farrington, Maria N Timofeeva, Brian F Meyer, Salma M Wakil, Harry Campbell, Christopher G Smith, Shelley Idziaszczyk, Timothy S Maughan, Richard Kaplan, Rachel Kerr, David Kerr, Daniel D Buchanan, Aung K Win, John L Hopper, Mark A Jenkins, Noralane M Lindor, Polly A Newcomb, Steve Gallinger, David Conti, Fred Schumacher, Graham Casey, Jussi Taipale, Lauri A Aaltonen, Jeremy P Cheadle, Malcolm G Dunlop, Ian P Tomlinson & Richard S Houlston
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Combination of a third generation bisphosphonate and replication-competent adenoviruses augments the cytotoxicity on mesothelioma
Abstract
Background
Approximately 80 % of mesothelioma specimens have the wild-type p53 gene, whereas they contain homozygous deletions in the INK4A/ARF locus that encodes p14 ARF and the 16 INK4A genes. Consequently, the majority of mesothelioma is defective of the p53 pathways. We examined whether zoledronic acid (ZOL), a third generation bisphosphonate, and adenoviruses with a deletion of the E1B-55kD gene (Ad-delE1B55), which augments p53 levels in the infected tumors, could produce combinatory anti-tumor effects on human mesothelioma cells bearing the wild-type p53 gene.
Methods
Cytotoxicity of ZOL and Ad-delE1B55 was assessed with a WST assay. Cell cycle changes were tested with flow cytometry. Expression levels of relevant molecules were examined with western blot analysis to investigate a possible mechanism of cytotoxicity. Furthermore, the expressions of Ad receptors on target cells and infectivity were estimated with flow cytometry. Viral replication was assayed with the tissue culture infection dose method.
Results
A combinatory use of ZOL and Ad-delE1B55 suppressed cell growth and increased sub-G1 or S-phase populations compared with a single agent, depending on cells tested. The combinatory treatment up-regulated p53 levels and subsequently enhanced the cleavage of caspase-3, 8, 9 and poly (ADP-ribose) polymerase, but expression of molecules involved in autophagy pathways were inconsistent. ZOL-treated cells also increased Ad infectivity with a dose-dependent manner and augmented Ad replication although the expression levels of integrin molecules, one of the Ad receptors, were down-regulated.
Conclusions
These findings indicated that ZOL and Ad-delE1B55 achieved combinatory anti-tumor effects through augmented apoptotic pathways or increased viral replication.
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Insulin-like growth factor-1 signaling in renal cell carcinoma
Abstract
Renal cell carcinoma (RCC) incidence is highest in highly developed countries and it is the seventh most common neoplasm diagnosed. RCC management include nephrectomy and targeted therapies. Type 1 insulin-like growth factor (IGF-1) pathway plays an important role in cell proliferation and apoptosis resistance. IGF-1 and insulin share overlapping downstream signaling pathways in normal and cancer cells. IGF-1 receptor (IGF1R) stimulation may promote malignant transformation promoting cell proliferation, dedifferentiation and inhibiting apoptosis. Clear cell renal cell carcinoma (ccRCC) patients with IGF1R overexpression have 70 % increased risk of death compared to patients who had tumors without IGF1R expression. IGF1R signaling deregulation may results in p53, WT, BRCA1, VHL loss of function. RCC cells with high expression of IGF1R are more resistant to chemotherapy than cells with low expression. Silencing of IGF1R increase the chemosensitivity of ccRCC cells and the effect is greater in VHL mutated cells. Understanding the role of IGF-1 signaling pathway in RCC may result in development of new targeted therapeutic interventions. First preclinical attempts with anti-IGF-1R monoclonal antibodies or fragment antigen-binding (Fab) fragments alone or in combination with an mTOR inhibitor were shown to inhibit in vitro growth and reduced the number of colonies formed by of RCC cells.
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A Posteriori Data-Derived Dietary Patterns and Incident Coronary Heart Disease: Making Sense of Inconsistent Findings
Abstract
Inconsistent findings have been reported from numerous prospective studies for the relations of the "Western" (unhealthy) and "Prudent" (healthy) diet patterns, derived using factor, principle components, or cluster analysis methods, with incident coronary heart disease (CHD). Among contemporary prospective studies, the Prudent diet pattern was inversely related to CHD risk in 7 of 12 studies, while the Western diet pattern positively related to risk in only 3 of 11 studies. To explain these inconsistent findings, we compared the methods and results from these prospective studies conducted in the USA, Europe, and Asia. A Prudent diet pattern was consistently related to 18–65 % lower risk of incident CHD in 7 studies conducted in the USA, Europe, and Asia. In 3 of 4 US studies, but not cohorts in Europe or Asia, the Western diet pattern was related to 37–64 % greater CHD risk. In Asian cohorts, the Western diet pattern was not related to increased CHD risk, which may be partially explained by the overall higher fish intake among Asians. The "a posteriori," or data driven, approach to diet patterns is based on reported dietary intake and we found the components of each dietary pattern differed by geographic location and diet assessment instrument. We discuss how the non-standardized methods used to discern diet patterns from the dietary data may contribute to discrepant results. Further, the disparate findings may also be explained by differing sample characteristics, follow-up period, and CHD ascertainment. In summary, a posteriori derived Prudent diet pattern was related to cardiovascular health.
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Toxicity-Related Factors Associated With Use of Services Among Community Oncology Patients [Focus on Quality]
Purpose:
Community oncology practices frequently manage chemotherapy-associated toxicities, which may disrupt treatment, impair quality of life, and induce unplanned service use. We sought to understand the patterns and correlates of unplanned health care service use among patients receiving first-cycle chemotherapy at five community-based ambulatory oncology practices.
Patients and Methods:A survey study examined the dichotomous outcome of unplanned service use, defined as oncologist visits, emergency department visits, and hospitalizations, resulting from toxicity-related factors. Newly diagnosed patients with breast, lung, head and neck, or colorectal cancer or non-Hodgkin lymphoma were recruited during the first chemotherapy cycle. Before beginning the second cycle of chemotherapy, patients completed a questionnaire that measured unplanned service use and overall distress, plus severity of nausea, vomiting, diarrhea, constipation, mouth sores, intravenous catheter problems, pain, fever and chills, extremity edema, and dyspnea on a 5-point scale (1, did not experience; 5, disabling). Medical record reviews captured chemotherapy doses, comorbid conditions, and supportive care interventions. Mixed-effects logistic regression was used to identify factors associated with unplanned service use, with random effects specified for each clinic.
Results:Among 106 patients (white, 98%; female, 74.5%; mean age ± standard deviation, 60 ± 11 years), frequently reported toxicities were pain, nausea, diarrhea, and constipation. Thirty-six patients (34%) reported unplanned service use: 29% reported oncologist visits, 14% reported emergency department visits, and 8% reported hospitalizations. Factors significantly associated with unplanned service use were high patient-reported distress and receipt of colony-stimulating factor.
Conclusion:Service use resulting from toxicity-related factors occurs frequently in community oncology settings. Monitoring toxicity patterns and outcomes can inform proactive symptom management approaches to reduce toxicity burden between scheduled visits.
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Survival and Toxicity After Cisplatin Plus Etoposide Versus Carboplatin Plus Etoposide for Extensive-Stage Small-Cell Lung Cancer in Elderly Patients [CARE DELIVERY]
Purpose:
Elderly patients with cancer are under-represented in clinical trials and risk greater toxicity from chemotherapy. These patients and their physicians need better evidence to decide among guideline-recommended regimens. We test whether patients with extensive-stage small-cell lung cancer (ES SCLC) have noninferior survival and less hospital-based health care after carboplatin/etoposide compared with cisplatin/etoposide.
Methods:We analyzed SEER-Medicare data for beneficiaries with ES SCLC diagnosed at age 67 years and older between 1995 and 2009. Among patients treated with first-line chemotherapy in the ambulatory setting, 831 received cisplatin/etoposide and 2,846 received carboplatin/etoposide. Propensity score matching (2:1 ratio) yielded 778 cisplatin/etoposide and 1,502 carboplatin/etoposide patients.
Results:Survival was nearly identical in the two groups: 35.7 weeks for cisplatin/etoposide and 35.9 weeks for carboplatin/etoposide. The hazard ratio of 1 (95% CI, 0.91 to 1.09) excluded our prespecified threshold, indicating noninferiority. Mortality at 6 months was indistinguishable: 35% for cisplatin/etoposide and 34% for carboplatin/etoposide. After carboplatin/etoposide, patients were less likely to be admitted to a hospital (80% v 86%, P < .001) and had fewer hospitalizations (median 1 v 2, odds ratio 0.76, 95% CI, 0.65 to 0.9), ED visits (median 1 v 2, odds ratio 0.82, 95% CI, 0.7 to 0.96), and ICU stays (median 0 v 0, odds ratio 0.82, 95% CI, 0.69 to 0.99).
Conclusion:First-line carboplatin/etoposide is associated with similar survival and less subsequent hospital-based health care use than cisplatin/etoposide among elderly patients with ES SCLC treated in ambulatory settings.
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Allogeneic Hematopoietic Stem-Cell Transplantation for Myelofibrosis: A Practical Review [Clinical Reviews]
Myelofibrosis is a myeloproliferative neoplasm with cardinal features of extramedullary hematopoiesis, hepatosplenomegaly, cytopenias, and constitutional symptoms that result in shortened survival and leukemic transformation. It is a disease predominantly of the elderly, and currently available therapies only offer symptom control without curative benefit or ability to alter disease progression. Allogeneic hematopoietic stem-cell transplant (HSCT) is the only potentially curative intervention; however, this is only feasible in younger and medically fit patients and selectively offered to those with high-risk disease. Despite ongoing advancements, HSCT is associated with substantial morbidity and mortality, and the determination of which patients with myelofibrosis are ideal candidates and the selection of the opportune moment to proceed with transplantation remains challenging. This review summarizes our current recommendations for the role of and indications for HSCT in myelofibrosis.
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Is FDA-Approved Bevacizumab Cost-Effective When Included in the Treatment of Platinum-Resistant Recurrent Ovarian Cancer? [FOCUS ON QUALITY]
Purpose:
Although the Food and Drug Administration has approved incorporation of bevacizumab (BEV) into the treatment of platinum-resistant ovarian cancer (PROC), cost-value measures are an essential consideration, as evidenced by the recent ASCO Value Framework initiative. We assessed the cost-effectiveness and reviewed the net health benefit (NHB) of this expensive treatment.
Methods:A cost-effectiveness decision model was constructed using results from a phase III trial comparing BEV plus cytotoxic chemotherapy with chemotherapy alone in patients with PROC. The Avastin Use in Platinum-Resistant Epithelial Ovarian Cancer (AURELIA) trial demonstrated improvement in progression-free survival and quality of life in patients receiving BEV. Costs, paracentesis rates, and adverse events were incorporated, including subgroup analysis of different partner chemotherapy agents.
Results:Inclusion of BEV in the treatment of platinum-resistant recurrent ovarian cancer meets the common willingness-to-pay incremental cost-effectiveness ratio (ICER) threshold of $100,000 per progression-free life-year saved (LYS) for 15-mg/kg dosing and approaches this threshold for 10-mg/kg dosing, with an ICER of $160,000. In sensitivity analysis, reducing the cost of BEV by 13% (from $9,338 to $8,100 per cycle) allows 10-mg/kg dosing to reach a $100,000 ICER. Exploratory analysis of different BEV chemotherapy partners showed an ICER of $76,000 per progression-free LYS (6.5-month progression-free survival improvement) and $54,000 per LYS (9.1-month overall survival improvement) for the addition of BEV to paclitaxel once per week. Using the ASCO framework for value assessment, the NHB score for BEV plus paclitaxel once per week is 48.
Conclusion:Using a willingness-to-pay threshold of $100,000 ICER, the addition of BEV to chemotherapy either demonstrates or approaches cost-effectiveness and NHB when added to the treatment of patients with PROC.
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Variations in Oncologist Recommendations for Chemotherapy for Stage IV Lung Cancer: What Is the Role of Performance Status? [CARE DELIVERY]
Purpose:
Chemotherapy prolongs survival in patients with advanced non–small-cell lung cancer. However, few studies have included patients with poor performance status. This study examined rates of oncologists' recommendations for chemotherapy by patient performance status and symptoms and how physician characteristics influence chemotherapy recommendations.
Methods:We surveyed medical oncologists involved in the care of a population-based cohort of patients with lung cancer from the CanCORS (Cancer Care Outcomes Research and Surveillance) study. Physicians were queried about their likelihood to recommend chemotherapy to patients with stage IV lung cancer with varying performance status (Eastern Cooperative Oncology Group performance status 0 [good] v 3 [poor]) and presence or absence of tumor-related pain. Repeated measures logistic regression was used to estimate the independent associations of patients' performance status and symptoms and physicians' demographic and practice characteristics with chemotherapy recommendations.
Results:Nearly all physicians (adjusted rate, 97% to 99%) recommended chemotherapy for patients with good performance status, and approximately half (adjusted rate, 38% to 53%) recommended chemotherapy for patients with poor performance status (P < .001). Compared with patient factors, physician and practice characteristics were less strongly associated with chemotherapy recommendations in adjusted analyses.
Conclusion:Strong consensus among oncologists exists for chemotherapy in patients with advanced non–small-cell lung cancer and good performance status. However, the relatively high rate of chemotherapy recommendations for patients with poor performance status despite the unfavorable risk–benefit profile highlights the need for ongoing work to define high-value care in oncology and to implement and evaluate strategies to align incentives for such care.
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E-Mail Communication Practices and Preferences Among Patients and Providers in a Large Comprehensive Cancer Center [CARE DELIVERY]
Purpose:
Little is known about how electronic mail (e-mail) is currently used in oncology practice to facilitate patient care. The objective of our study was to understand the current e-mail practices and preferences of patients and physicians in a large comprehensive cancer center.
Methods:Separate cross-sectional surveys were administered to patients and physicians (staff physicians and clinical fellows) at the Princess Margaret Cancer Centre. Logistic regression was used to identify factors associated with current e-mail use. Record review was performed to assess the impact of e-mail communication on care.
Results:The survey was completed by 833 patients. E-mail contact with a member of the health care team was reported by 41% of respondents. The team members contacted included administrative assistants (52%), nurses (45%), specialist physicians (36%), and family physicians (18%). Patient factors associated with a higher likelihood of e-mail contact with the health care team included younger age, higher education, higher income, enrollment in a clinical trial, and receipt of multiple treatments. Eighty percent of physicians (n = 63 of 79) reported previous contact with a patient via e-mail. Physician factors associated with a greater likelihood of e-mail contact with patients included older age, more senior clinical position, and higher patient volume. Nine hundred sixty-two patient records were reviewed, with e-mail correspondence documented in only 9% of cases.
Conclusion:E-mail is commonly used for patient care but is poorly documented. The use of e-mail in this setting can be developed with appropriate guidance; however, there may be concerns about widening the gap between certain groups of patients.
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Recent Insights and Advances in the Management of Merkel Cell Carcinoma [Clinical Reviews]
Merkel cell carcinoma (MCC) is a rare and highly aggressive neuroendocrine malignancy with a propensity for recurrence and a poor prognosis. Incidence of MCC is on the rise and is known to increase with advanced age, immunosuppression, and UV exposure. Merkel cell polyomavirus is implicated in the pathogenesis of virus-positive MCC and accounts for 80% of MCCs in the northern hemisphere and 25% in southern latitudes. In contrast, tumorigenesis of virus-negative MCC is linked to UV-induced DNA damage. Interplay between ubiquitous Merkel cell polyomavirus skin infections that commonly occur in healthy skin and other established risk factors, such as immunosuppression and UV exposure, remains poorly understood. Surgery and radiotherapy achieves excellent locoregional control; however, invariably, a significant proportion of patients develop disseminated disease that is incurable. Chemotherapy offers a high response rate for metastatic disease, but responses are short-lived and the impact on survival is not established. Recent advances in our understanding of the genetic landscape and immunobiology of MCC has led to investigation of novel treatments, including immune checkpoint inhibitors, which are likely to rapidly transform the way we manage these patients. We review epidemiologic, clinical, and histopathologic features of MCC; describe recent insights in MCC biology; and discuss novel therapeutic approaches.
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Positron Emission Tomography-Computed Tomography (PET-CT) Versus No PET-CT in the Management of Potentially Resectable Colorectal Cancer Liver Metastases: Cost Implications of a Randomized Controlled Trial [BUSINESS OF ONCOLOGY]
Purpose:
To evaluate whether positron emission tomography (PET) combined with computed tomography (PET-CT) is cost saving, or cost neutral, compared with conventional imaging in management of patients with resectable colorectal cancer liver metastases.
Methods:Cost evaluation of a randomized trial that compared the effect of PET-CT on surgical management of patients with resectable colorectal cancer liver metastases. Health care use data ≤ 1 year after random assignment was obtained from administrative databases. Cost analysis was undertaken from the perspective of a third-party payer (ie, Ministry of Health). Mean costs with 95% credible intervals (CrI) were estimated by using a Bayesian approach.
Results:The estimated mean cost per patient in the 263 patients who underwent PET-CT was $45,454 CAD (range, $1,340 to $181,420) and in the 134 control patients, $40,859 CAD (range, $279 to $293,558), with a net difference of $4,327 CAD (95% CrI, –$2,207 to $10,614). The primary cost driver was hospitalization for liver surgery (difference of $2,997 CAD for PET-CT; 95% CrI, –$2,144 to $8,010), which was mainly a result of a longer length of hospital stay for the PET-CT arm (median, 7 v 6 days; P = .03) and a higher postoperative complication rate (20% v 10%; P = .01). Baseline characteristics were similar between groups, including the number of liver segments involved with cancer, number of segments resected, and type of liver resection performed. No difference in survival was detected between arms.
Conclusion:PET-CT was associated with limited clinical benefit and a nonsignificant increased cost. Universal funding of PET-CT in the management of patients with resectable colorectal cancer liver metastases does not seem justified.
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Accuracy of pre-contrast imaging in abdominal magnetic resonance imaging of pediatric oncology patients
Abstract
Background
Safety concerns are increasingly raised regarding the use of gadolinium-based contrast media for MR imaging.
Objective
To determine the accuracy of pre-contrast abdominal MR imaging for lesion detection and characterization in pediatric oncology patients.
Materials and methods
We included 120 children (37 boys and 83 girls; mean age 8.94 years) referred by oncology services. Twenty-five had MRI for the first time and 95 were follow-up scans. Two authors independently reviewed pre-contrast MR images to note the following information about the lesions: location, number, solid vs. cystic and likely nature. Pre- and post-contrast imaging reviewed together served as the reference standard.
Results
The overall sensitivity was 88% for the first reader and 90% for the second; specificity was 94% and 91%; positive predictive value was 96% and 94%; negative predictive value was 82% and 84%; accuracy of pre-contrast imaging for lesion detection as compared to the reference standard was 90% for both readers. The difference between mean number of lesions detected on pre-contrast imaging and reference standard was not significant for either reader (reader 1, P = 0.072; reader 2, P = 0.071). There was substantial agreement (kappa values of 0.76 and 0.72 for readers 1 and 2) between pre-contrast imaging and reference standard for determining solid vs. cystic lesion and likely nature of the lesion. The addition of post-contrast imaging increased confidence of both readers significantly (P < 0.0001), but the interobserver agreement for the change in confidence was poor (kappa 0.12).
Conclusion
Pre-contrast abdominal MR imaging has high accuracy in lesion detection in pediatric oncology patients and shows substantial agreement with the reference standard for characterization of lesions. Gadolinium-based contrast media administration cannot be completely eliminated but can be avoided in many cases, with the decision made on a case-by-case basis, taking into consideration location and type of tumor.
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Seven-year follow-up for energy/vitality outcomes in early stage Hodgkin’s disease patients treated with subtotal lymphoid irradiation versus chemotherapy plus radiation: SWOG S9133 and its QOL companion study, S9208
Abstract
Purpose
We describe 7 years of follow-up for the energy/vitality outcome in early-stage Hodgkin's disease patients treated on a randomized clinical trial that compared subtotal lymphoid irradiation (STLI) with combined modality treatment (CMT) (SWOG 9133). Survivorship research questions involved the extent to which symptoms/side effects endured over a follow-up period of 7 years for this early-stage patient group.
Methods
Two hundred thirty-nine patients participated in the quality of life (QOL) companion study (SWOG 9208) and completed the SF-36 vitality scale, SF-36 health perception item, Cancer Rehabilitation Evaluation System-Short Form (CARES-SF), and symptom distress scale. This paper reports vitality outcome results obtained from randomization, 6 months, and annually for 7 years. To assess changes in vitality over time, we used linear mixed models with patient as a random effect.
Results
Patients receiving CMT had lower observed vitality at 6 months than did the STLI patients (p < .0001). However, beginning at year 1, vitality results did not differ significantly by treatment over the 5-year (p = .13) and 7-year (p = .16) follow-up periods. Vitality only slightly improved over baseline in either group after treatment. The results were similar after accounting for patterns of recurrence and missing data.
Conclusions
This study demonstrated that patients with early-stage Hodgkin's disease experience a short-term (at 6 months) decrease in vitality with treatment, which is more severe with CMT, but that after the first year, vitality scores were similar between the two treatment groups. Enduring fatigue results for patients receiving these therapies were not observed.
Implications for cancer survivors
These data provide comprehensive 7-year follow-up vitality information, an important symptom for early-stage lymphoma survivors.
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Validation study of HPV DNA detection from stained FNA smears by polymerase chain reaction: Improving the diagnostic workup of patients with a tumor on the neck
BACKGROUND
Human papillomavirus (HPV)–related oropharyngeal squamous cell carcinoma (OPSCC) often presents with cystic cervical metastasis and a small primary tumor localized in the palatine tonsils or base of the tongue, which is diagnostically challenging. Testing for HPV DNA in fine-needle aspiration (FNA) smears from metastases may facilitate a targeted diagnostic workup for identifying the primary tumor. This study was designed to assess the ability to detect HPV DNA in FNA smears with polymerase chain reaction (PCR).
METHODS
May-Grünvald-Giemsa (MGG)–stained FNA smears from metastases and corresponding surgical specimens were collected from 71 patients with known HPV-positive OPSCC, 12 patients with oral squamous cell carcinoma (OSCC), 20 patients with branchial cleft cysts, and 20 patients with Warthin tumors. Thirty-eight patients with OPSCC and 7 patients with OSCC had FNA smears available from metastases and also surgical specimens from the primary tumor and the metastases. The scraped cell material from FNA smears and corresponding surgical specimens were analyzed for HPV DNA by PCR. p16 immunohistochemistry was performed on surgical specimens from the carcinomas.
RESULTS
HPV DNA was detected in 68 of the 71 FNA smears from OPSCC metastases. All corresponding surgical specimens from primary tumors (n = 71) and metastases (n = 38) were p16- and HPV DNA–positive. All the surgical specimens and corresponding FNA smears from OSCCs, Warthin tumors, and branchial cleft cysts were HPV DNA–negative. The sensitivity and specificity were 94.7% and 100%, respectively.
CONCLUSIONS
The detection of HPV DNA in MGG-stained FNA smears by PCR is a valid method that could be implemented in routine clinical practice. Cancer Cytopathol 2016. © 2016 American Cancer Society.
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RPL23-MDM2-p53 pathway response to oncogenic RAS
The ribosomal protein (RP)-MDM2 interaction is a p53 response pathway critical for preventing oncogenic c-MYC-induced tumorigenesis. To investigate whether the RP-MDM2-p53 pathway is a broad anti-oncogenic mechanism, we crossed mice bearing an MDM2C305F mutation, which disrupts RPL11 binding to MDM2, with mice expressing an oncogenic HrasG12V transgene. Interestingly, the MDM2C305F mutant mice, which are hypersensitive to c-MYC-induced tumorigenesis, are not hypersensitive to oncogenic HrasG12V-induced tumorigenesis. Unlike c-MYC, which induces expression of RPL11, RAS overexpression leads to an increase in RPL23 mRNA and protein while RPL11 expression remains unchanged. The induction of RPL23 involves both MEK and PI3K signaling pathways and requires mTOR function. Increased expression of RPL23, which maintains binding to MDM2C305F mutant, correlates with increased p53 expression in MDM2C305F cells. Furthermore, RAS overexpression can induce p53 in the absence of p19ARF, and the induction can be abolished by down-regulation of RPL23. Thus, while the RPL11-MDM2-p53 pathway coordinates with the p19ARF-MDM2-p53 pathway against oncogenic c-MYC-induced tumorigenesis, the RPL23-MDM2-p53 pathway coordinates with the p19ARF-MDM2-p53 pathway against oncogenic RAS-induced tumorigenesis.
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miRNAs in PDGFR{beta}-mediated vasculogenesis of TNBC
Organization of cancer cells into endothelial-like cell lined structures to support neovascularization and fuel solid tumors is a hallmark of progression and poor outcome. In triple negative breast cancer (TNBC), PDGFRβ has been identified as a key player of this process and is considered a promising target for breast cancer therapy. Thus, we aimed at investigating the role of microRNAs as therapeutic approach to inhibit PDGFRβ-mediated vasculogenic properties of TNBC, focusing on miR-9 and miR-200. In MDA-MB-231 and MDA-MB-157 TNBC cell lines, miR-9 and miR-200 promoted or inhibited, respectively, the formation of vascular-like structures in vitro. Induction of endogenous miR-9 expression, upon ligand-dependent stimulation of PDGFRβ signaling, promoted significant vascular-sprouting of TNBC cells in part by direct repression of STARD13. Conversely, ectopic expression of miR-200 inhibited this sprouting by indirectly reducing the protein levels of PDGFRβ through the direct suppression of ZEB1. Notably, in vivo miR-9 inhibition or miR-200c restoration, through either the generation of MDA-MB-231 stable clones or peritumoral delivery in MDA-MB-231 xenografted mice, strongly decreased the number of vascular lacunae. Finally, immunohistochemistry and immunofluorescence analyses in TNBC specimens indicated that PDGFRβ expression marked tumor cells engaged in vascular lacunae. In conclusion, our results demonstrate that miR-9 and miR-200 play opposite roles in the regulation of the vasculogenic ability of TNBC, acting as facilitator and suppressor of PDGFRβ, respectively. Moreover, our data support the possibility to therapeutically exploit miR-9 and miR-200 to inhibit the process of vascular lacunae formation in TNBC.
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Cost-Effectiveness of Pharmacogenomic and Pharmacogenetic Test-Guided Personalized Therapies: A Systematic Review of the Approved Active Substances for Personalized Medicine in Germany
Abstract
Background
The use of targeted therapies has recently increased. Pharmacogenetic tests are a useful tool to guide patient treatment and to test a response before administering medicines. Pharmacogenetic tests can predict potential drug resistance and may be used for determining genotype-based drug dosage. However, their cost-effectiveness as a diagnostic tool is often debatable. In Germany, 47 active ingredients are currently approved. A prior predictive test is required for 39 of these and is recommended for eight. The objective of this study was to review the cost-effectiveness (CE) of pharmacogenetic test-guided drug therapy and compare the application of drugs with and without prior genetic testing.
Methods
A systematic literature review was conducted to identify the CE and cost-utility of genetic tests. Studies from January 2000 until November 2015 were searched in 16 databases including Medline, Embase, and Cochrane. A quality assessment of the full-text publications was performed using the validated Quality of Health Economic Studies (QHES) instrument.
Results
In the majority of the included studies, the pharmacogenetic test-guided therapy represents a cost-effective/cost-saving treatment option. Only seven studies lacked a clear statement of CE or cost-savings, because of uncertainty, restriction to specific patient populations, or assumptions for comparative therapy. Moreover, the high quality of the available evidence was evaluated.
Conclusion
Pharmacogenetic testing constitutes an opportunity to improve the CE of pharmacotherapy. The CE of targeted therapies depends on various factors including costs, prevalence of biomarkers, and test sensitivity and specificity. To guarantee the CE comparability of stratified drug therapies, national and international standards for evaluation studies should be defined.
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