tbuckley/cabot-search huggingface dataset:
Personalized molecular testing for therapeutic guidance in Taiwan.
Authors: Kang-Yi Su, Sung-Liang Yu
Journal: Journal of Clinical Oncology (2013)

e22067 Background: Personalized cancer therapy is based on the precept that detail molecular characterization of tumors as well as tumor microenvironment will enable tailored therapies to improve outcomes and decrease toxicity. The goal of personalized therapy is to target aberrations driving tumor growth and prolongs survival, by administering the right drug combination for the right person. However, several practical and technological challenges including tumor heterogeneity, molecular evolution, costs and morbidity of biopsies as well as technical limitation critical for molecular testing. In addition, development of biomarkers should be considered all aspects of drug development, from discovery through to clinical trials. Methods: In Taiwan, we have established a well-qualified reference laboratory with ISO15189 certification for molecular testing of personalized therapy in clinical practice. Based on our innovation, we utilized DNA mass spectrometry platform to develop high sensitive EGFR mutation identification system. Recently, KRAS, BRAF, HER2 together with EGFR were also combined into multiplex gene testing for biomarker-assessed therapeutic decision. To this end, the National Science Council of Taiwan government had supported this project through NRPB (National Research Program of Biopharmaceutical) at the middle of 2011. This facility performed selected molecular tests for cancer patients from medical centers and regional hospitals. Results: A specific program had also been implemented to anticipate the launch of molecular targeting therapy (MTT) and reduce time-to-assess to MTT drugs and experimental therapies. From Jane 2011 to Dec 2012, more than 2,500 patients with lung cancer in Taiwan benefited from this facility. Conclusions: The Taiwan nationwide initiative for tumor molecular profiling is a tool to fight inequalities in access to molecular testing and target therapy, and demonstrates that molecular stratification of tumor for therapeutic decisions is a cost-effective strategy that can be integrated into the national health-care system.
Next-generation sequencing (NGS) to identify actionable genomic changes in common and rare solid tumors: The FMI experience with the initial 50 consecutive patients.
Authors: Gary A. Palmer, Vincent A. Miller, John Curran, Jeffrey S. Ross, Doron Lipson, Roman Yelensky, Philip Stephens, Mary Pat Lancelotta, Maureen T. Cronin
Journal: Journal of Clinical Oncology (2012)

10590 Background: Solid tumor (ST) oncology has been transformed by the linkage of genomic changes with targeted therapeutics. Unfortunately, most STs still have no alteration detected with currently available assays. Thus, more informative testing platforms are needed to analyze genomic changes in FFPE biopsy samples often limited by tumor size, heterogeneity and ploidy. Methods: We reviewed the genomic profiles of the first 50 clinical specimens received by our CLIA lab (Foundation Medicine) and analyzed by our NGS assay (Ross J. ASCO 2011). 182 genes known altered in STs and 14 genes known rearranged in STs were included. Genomic alterations were categorized as “actionable” if linked to an approved therapy in the ST under study or another ST (e.g. ALK rearrangement in lung or breast cancer, respectively), a known or suspected contraindication to a given therapy (e.g. KRAS G12D in colorectal cancer) or a clinical trial linked to the alteration (e.g. mTOR inhibition in a tumor with STK11 loss). Results: Fifty tumor specimens were received from 50 patients (median age 54, F/M=30/20) representing 35 sites. Two samples failed analysis and 6 had no detectable genomic alteration. Among 16 primary tumor types, lung (n=15), colorectal (n=7), sarcoma (n=5), breast and esophageal/gastric (n=4 each) were most common. We reported 135 genomic alterations (mean 2.8, range 0-6) unequivocally involved in oncogenesis and 69 actionable alterations. At most, 29 of these (42%) would have been detected by current assays (138% increase with NGS). Thirty seven patients had one or more actionable alterations (range 1-4) detected by NGS (74%, 95% CI 60-85%) versus only 21 (42%, 95% CI 28-57%) in whom changes would have been detected by current assays. Conclusions: Use of a broad, comprehensive NGS assay identifies an unprecedented number of actionable genomic alterations across a variety of STs from routine FFPE samples. This assay can serve as a paradigm for improving access to approved therapies in STs, minimizing use of ineffective therapies and enhancing enrollment in rationally chosen trials. Ongoing and planned trials will study the impact on several efficacy endpoints.
Evaluation of an instrument to assess the needs of cancer patients in an ambulatory chemotherapy unit
Authors: L. Bernal, A. Casas, A. Cayuela, J. Corral, M. Flor, J. Moreno, L. Iglesias, R. Puerto, P. Ramirez, F. Toscano
Journal: Journal of Clinical Oncology (2007)

19593 Background: The physical deterioration, suffering and proximity of death associated with cancer dramatically affect the patient. Knowing about their perception of the circumstances that influence quality of life and adaptation to the disease, allows us to take appropriate medical action to satisfy their needs and improve the quality of patient care. Patients and Methods: The aim of this study was to evaluate treatment-related symptoms, information access, patient-doctor relationships, health service management, confidence, waiting time and financial needs of patients receiving ambulatory chemotherapy, through an “ad hoc” questionnaire. Different samples of patients were used to design the questionnaire: 141 patients for item identification, and completeness and acceptability evaluation; 47 patients for construct validity and prevalence of needs. The construct validity of the questionnaire was tested via analysis of the principal components, while reliability was evaluated in terms of the internal consistency of dimensions and test-retest scores. Results: The principal components found through factor analysis with Varimax rotation identified seven dimensions with Cronbrach′s a coefficients &gt;0.70, which accounted for 64.3% of the variance. Internal consistency was high: Cronbrach′s a coefficients were 0.82. Test-retest reliability was acceptable with intraclass correlation coefficients ranging from 0.60 to 0.83. The most common needs were more information about diagnosis and prognosis (63%); over 50% of patients perceived shortcomings in communication with their doctors; 85% perceived sufficient intimacy in doctors‘ offices; 76% perceived that they had waited too long before being seen by doctors and given treatment. Conclusions: The validation analysis showed rather good reliability, structure validity and internal consistency. The needs expressed by patients are related to objective aspects of the disease, to time spent in contact with the service, to disease duration and to treatment lines. More vulnerable patients (elderly, low education level, more advanced treatment lines) express less needs, which is why they need an individualized analysis of their circumstances and greater attention from the professionals who take care of them. No significant financial relationships to disclose.
The zinc-finger protein ZFYVE1 modulates TLR3-mediated signaling by facilitating TLR3 ligand binding
Authors: Xuan Zhong, Lu Feng, Wen-Hua Xu, Xin Wu, Yi-Di Ding, Yan Zhou, Cao-Qi Lei, Hong-Bing Shu
Journal: Cellular and Molecular Immunology (2019)
Clinicopathological Study of Methotrexate-Associated Lymphoproliferative Disorders in Rheumatoid Arthritis Patients: Histological Classification and Predictive Factors for Disease Progression
Authors: Daisuke Kurita, Hiroaki Miyoshi, Ayako Ichikawa, Yuya Sasaki, Keisuke Kawamoto, Joji Shimono, Masao Matsuoka, Masahiro Kizaki, Masao Seto, Jun-ichi Tamaru, Michihide Tokuhira, Koichi Ohshima
Journal: Blood (2017)
Biochemical and immunologic markers in patients with metastatic melanoma treated with chemotherapy and dendritic cell vaccine.
Authors: Igor Samoylenko, Tatiana Zabotina, Irina N. Mikhaylova, George Z. Chkadua, Olga V. Korotkova, Anastasia S Vikhrova, Valery V Nazarova, Galina Kharkevich, Lev V. Demidov
Journal: Journal of Clinical Oncology (2013)

e20042 Background: The purpose of this sub study was to identify peripheral blood biomarkers associated with the therapeutic effect of immunotherapy with dendritic cell vaccine in patients with metastatic melanoma (MM). Methods: Patients (pts) with low disease burden achieved disease control after two cycles of chemo (cisplatine, vinbalstie, DTIC) were randomized dendritic cell vaccine (DC) or three cycles of chemo. Vaccination schedule consisted of 5 subcutaneous injections of dendritic cell (DC) vaccine (2×10 6 cells pulsed with autologous lysate) with 14 days intervals. S100B level, LDH level, and peripheral blood lymphocytes immune phenotype were assessed before treatment, after two cycles of chemo and after each vaccination cycle. Results: 104 pts were included in the study, 30 pts were randomized to DC arm, 29 pts were randomized to continue chemo. In pts with rapid disease progression baseline serum S100b level was significantly higher compared to patients with objective response or stable disease (0.874±1.15 mcg/L vs. 0.361±0.66 mcg/L, P=0.002). Similar results were found for baseline serum LDH level (559.8±469.7 U/L vs. 412.5±184.4 U/L, P=0.005) and serum S100b level after 2 cycles of chemo (0.688±0.855 mcg/L vs. 0.187±0,29 mcg/L, P&lt;0.001). Contrary, baseline CD3 + HLA-DR + and CD4 + CD25 + lymphocytes levels after 2 cycles of chemo were significantly higher in pts with disease control (11.9±8.9% vs. 8.9±5.3%, P=0.047 and 14.4±8.3% vs. 11.3±5.5%, P=0.036 respectively).In pts randomized to DC arm following markers were associated with long lasting objective response or stable disease course (&gt;6 months): lower baseline S100b level (0.133±0.120 mcg/L vs. 0.445±0.406 mcg/L, P=0.014), lower S100b level after 2 cycles of chemo (0.105±0.095 mcg/L vs. 0.255±0.154 mcg/L, P=0.048), higher proportion of active CD8 + lymphocytes prior to vaccination (74.7±3.6% vs. 51.7±14.2%, P=0.05); and more prominent increase of NK-cells CD3 - CD16 + CD56 + from baseline (increase in 76.5%±41.12% vs. 4.5±28.8%, P=0.01). Conclusions: Biochemical and immunological markers may be helpful when selecting patients with metastatic melanoma for immunotherapy with dendritic cell vaccine.
Abstract 13032: Dimethlyguanidino Valeric Acid Predicts Partial Resistance to the Metabolic Health Benefits of Regular Exercise
Authors: Jeremy M Robbins, Matthew Herzig, Jordan Morningstar, Mark A Sarzynski, Claude Bouchard, Tuomo Rankinen, Robert E Gerszten
Journal: Circulation (2018)

Background: Substantial heterogeneity exists in the individual response to physical activity, and identifying biomarkers that predict clinical responsiveness to exercise remains an unmet clinical n...
Impact of news drugs in the median overall survival of patients with metastatic castration resistant prostate cancer (mCRPC).
Authors: Natacha Chaumard-Billotey, Sylvie Chabaud, Helen Jane Boyle, Bertrand Favier, Yves Devaux, Jean-Pierre Droz, Aude Flechon
Journal: Journal of Clinical Oncology (2013)

e16096 Background: In the past 3 years new therapies, such as cabazitaxel (C): a novel taxane, enzulatamide (E): a new androgen receptor signaling inhibitor and abiraterone acetate (A): an inhibitor of androgen synthesis, have been developed in the treatment of post-docetaxel metastatic CRPC patients. This study assessed the clinical impact of these new drugs, comparing the outcomes of two historical cohorts of patients with mCRPC. Methods: We retrospectively reviewed the data of all patients with mCRPC treated by first line chemotherapy with docetaxel (D) at the Centre Léon Bérard. Based on the timing of the development of new drugs, we defined two cohorts based on two time periods depending on drugs available on the market: group 1: 2006-2009 corresponding to the period when only conventional drugs (D, mitoxantrone) were available; group 2: 2009-2012 corresponding to the period when new drugs like C, E, A could be used post docetaxel. Outcome evaluated was overall survival (OS). OS was defined as the time from date of D introduction to date of death or date of last follow-up for patients alive at last contact. Survival distributions were estimated by the Kaplan-Meier method and compared between groups using Log-Rank test. Results: One-hundred and thirty five patients were included: 66 patients in group 1 and 69 patients in group 2. Median age was 64 years in both groups. Karnofsky score was ≥ 80% for 67.7% of patients in group 1 and 81.8% in group 2. Gleason score was ≥ 9 for 38.7% and 31.4% of patients, respectively. In group 1, 47% of patients had visceral metastases when started on chemotherapy vs 40.6% in group 2. The weekly schedule of D (25mg/m 2 ) was significantly more frequently used in group 1 than in group 2 (53% vs 15%, p&lt;0.001). Median cumulative doses of D at first line treatment were significantly higher in group 2: 643 mg/m 2 vs 454 mg/m 2 (p&lt;0.001). Median overall survival was 10.6 months (95% CI 7.8–15.7) in group 1 vs 32.5 months (95% CI 25–42.4) in group 2 (p&lt;0·0001). Conclusions: This study reflects how the management of mCRPC patients has evolved over the last 7 years. Survival has improved especially through an earlier management, a more intensive schedule of D and the impact of these new drugs.
DNMT3b polymorphism and age of onset of Hereditary Nonpolyposis Colorectal Cancer in a Caucasian population
Authors: J. Shawn Jones, Christopher I. Amos, Imelda M. Campos, Xiangjun Gu, Qingyi Wei, Patrick M. Lynch, Miguel Rodriguez-Bigas, Marsha L. Frazier
Journal: Cancer Research (2005)

1314  Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant syndrome of familial malignancies resulting from germline mutations in DNA mismatch repair (MMR) genes. Colorectal and endometrial cancers are most frequently observed. A polymorphic C-to-T change in the promoter region of the DNMT3b gene, -149 bp from the transcription start site, greatly increases promoter activity and is associated with increased risk for lung cancer. We studied the influence of this DNMT3b polymorphism on HNPCC age of onset. We determined the DNMT3b genotype of 122 Caucasian MMR mutation carriers from 60 families, of whom 58 had colorectal cancer. The subjects were genotyped by single-strand conformational polymorphism (SSCP) analysis and DNA sequencing. We tested the association between age of onset and the DNMT3b genotypes by comparing Kaplan-Meier survival curves, evaluating the homogeneity of the curves using the log-rank test and Wilcoxon’s test, and estimating the association using the Cox proportional hazards regression model to adjust for potential demographic confounding factors. The HNPCC patients who were heterozygous developed their colorectal cancer 21 years earlier than HNPCC patients who were homozygous for the wild-type allele. Combining knowledge of an individual’s DNMT3b genotype with information on other genetic and environmental risk factors may improve risk estimates and help to identify individuals who are genetically susceptible to developing HNPCC at an earlier age.
Prediction of tumor recurrence by tumor location in stage II and III colon cancer patients through common germ-line variants of genes involved in wnt signaling pathway.
Authors: Wu Zhang, Yan Ning, Dongyun Yang, Takeru Wakatsuki, Sebastian Stintzing, Nico Benjamin Volz, Joseph Ethan Li, Melissa Janae Labonte, Rita Elie El-Khoueiry, Afsaneh Barzi, Anthony B. El-Khoueiry, Michael Kahn, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2013)

e14714 Background: Wnt signaling is essential for embryonic development, stem cells and tissue regeneration. The Wnt signaling pathway was found to be deregulated in 93% of colorectal cancer (CRC). Tumor recurrence after curative resection is still a major problem in the management of adjuvant CRC, with recurrence rate approximately 30-40%. Identifying molecular markers for tumor recurrence is critical for successfully selecting patients who are more likely to benefit from adjuvant chemotherapy. In this study, our group tested whether gene polymorphisms [TCF7L2 rs7903146, AXIN2 (rs2240308, rs3923087) and P300 (rs7286979, rs220551 and rs5782022)] involved in Wnt signaling pathway could predict the risk of tumor recurrence in stage II and III CRC patients. Methods: Either blood or FFPE tissue specimens were obtained from 234 patients (107 females and 127 males; median age 59 years (range 22–78 years)) with stage II (105 patients) or III (129 patients) colon cancer at the University of Southern California/Norris Comprehensive Cancer Center. The median follow-up was 4.4 years. TCF7L2, AXIN2 and p300 SNPs were determined by PCR-RFLP or PCR-based direct sequence. The primary endpoint of the study was time to tumor recurrence (TTR). Results: In univariate analysis, patients with TCF7L2 rs7903146 TT genotype had significantly longer TTR (median=10.7 months, 95%CI 4.9,10.7 +) compared with those harboring CT (median=3.9months, 95% CI 2.4, 10.7) or CC genotype (median=5.9months, 95% CI 2.8, 11.4+) patients (p=0.042, log-rank test). In multivariate analysis, left-side tumor patients with p300 rs7286979 AA genotype had highest risk of TTR (HR=2.85, 95% CI 1.03,7.89) compared to those carring GA (HR=0.81, 95% CI 0.35,1.84) or AA genotype (p=0.048, Wald test). Conclusions: Our results show that germline polymorphisms profiling of Wnt signaling pathway TCF7L2 rs7903146, p300 rs7286979 may predict tumor recurrence risk in adjuvant colon cancer patients, and may dependent on tumor location. Our exploratory data warrants further validation.
Topoisomerase II alpha gene status, HER2, and microtubule-associated protein tau as predictors of pathologic complete response after neoadjuvant chemotherapy.
Authors: Agust Barnadas, Ariadna Tibau Martorell, Laura Lopez Vilaro, Daniel Escuin, M Carmen Alonso, Belen Ojeda, Teresa Ramon y Cajal, M Josefa Fuentes, Jose Ignacio Perez Garcia, Barbara Garcia Valdecasas, Montserrat Clotet, M Sofia Torrubia, Ignasi Gich, Enrique Lerma
Journal: Journal of Clinical Oncology (2012)

10555 Background: There is growing evidence that topoisomerase II-alpha (TOPOIIα) is a marker for anthracycline-, and microtubule-associated protein tau (MAPT) for taxane sensitivity. HER2 has been described as a marker of both anthracycline and taxane sensitivity.The goal of our study was to examine the predictive and prognostic value of TOPOIIα, MAPT and HER2 expression in breast cancer patients (pts) who received neoadjuvant chemotherapy (NAC) based on anthracycline-taxane regimens. We analyzed the relationship between these biomarkers and pathological complete response (pCR), disease-free survival (DFS) and overall survival (OS). Methods: Between November 1993-2009, 140 pts (mean age 52 years) with locally advanced breast cancer (T1-4, N0-3, M0) were retrospectively studied. The study contained 2 groups: group A included 85 pts who received NAC with an anthracycline-taxane regimen and group B included the last 55 pts who received NAC with only an anthracycline-based regimen. HER2 was tested by immunohistochemistry (IH) or FISH, TOPOIIα by CISH and MAPT by IH. Expression of these proteins was evaluated in core needle breast biopsy. Results: Overall, 12 pts (8.5%) had a pCR. TOPOIIα was amplified in 6 (4%) of the tumors. Among pts without amplification, 6 (4%) had deletion of the TOPOIIα, and 10 (7%) polysomia of chromosome 17. TOPOIIα gene aberrations (amplification, deletion, polysomia), which was present in 22 (25%) of the tumors, was a strong predictive factor for pCR (p=0.018) but showed no direct association with prognostic outcome in multivariate analysis. HER2 amplification, which was present in 16% (21) of the tumors, show no direct association with pCR, DFS or OS. Finally, differences by treatment arm or pCR in low versus high MAPT expression groups were not observed, indicating that MAPT is not a useful predictive marker for taxane-based chemotherapy. In multivariate analysis high MAPT expression was associated with longer DFS (p=0.002). Conclusions: TOPOIIα gene aberrations but not HER2 are highly predictive of pCR for anthracycline-based regimen. MAPT is not associated with response to taxanes but has a prognostic value.
Second-year results of the first large-scale, multistate BCBS clinical oncology pathway program.
Authors: Jim M. Koeller, Eugene Kreys
Journal: Journal of Clinical Oncology (2012)

e16522 Background: Clinical pathways (CP) are viewed as valuable practice tools leading to presumed cost savings, however none have been fully implemented on a state-wide scale. CareFirst BCBS partnering with P4 Pathways implemented a multi-state oncology CP program in Aug., 2008. The CP included both chemotherapy (chemo) and supportive care (SC). Our study goals were to determine year (yr) 2 physician (MD) compliance (compl) to CP, their effects on drug and hospitalization (hosp) cost, and their ability to curb projected cost increases. Methods: This study used a retrospective single-group, pretest-posttest design. Data representing pre-CP yr -1 (2007-08) and two years after CP initiation, yr +1 and +2 (08-10) were obtained from claims data. The dataset contained breast, colorectal and lung cancer. One claim from each of the 3 yrs was needed for site eligibility. First and 2 nd yr compl was defined as 65% and 80%, respectively, use of chemo regimens according to CP by site. Compl for SC was defined as 80% use of agents per CP for each year. Drug and hosp (occurring within 30 days of chemo regimen) cost were calculated. Savings were determined by extrapolating results on a per patient basis and comparing them to projections cost increases for yr +2. Results: Overall, 46 sites representing 193 MD’s, 4713 pts and 110,203 claims met inclusion criteria. The uncorrected site compl rate for chemo was 83% and 54% for yrs +1 and +2 respectively, while SC site compl was 74% for both yrs. Compared to yr -1, per patient drug expenditures ↑ by 5.8% in yr +1 and 2.7% in yr +2. Per patient hosp costs ↓ by 4.2% in yr +1 and 8.3% in yr +2 compared to yr -1. Total hosp costs ↓ by 28.4% in yr +1 and 63.4% in yr +2 compared to yr -1. Using national data to project drug cost ↑ of 14.5% and hosp cost ↑ of 9.5% yearly over yrs +1 and +2, the CP provided an estimated $36 million in savings by yr +2, with $23 million due to drug and $13 million due to hosp. An absolute $7+ million savings for yr +2 would still have been seen if we assume no ↑ in drug &amp; hosp spending over the 2 yr period. Conclusions: Reasonable MD compliance can be achieved on broad scale use of CP. CP reduce chemotherapy and hosp expenditures, although an increase use in supportive care was seen. Total costs savings can be substantial.