tbuckley/cabot-search huggingface dataset:
Weekly docetaxel-gemcitabine as first-line treatment in advanced non-small cell lung cancer: Preliminary results of a phase II study
Authors: S. R. Kalmadi, T. Mekhail, D. Adelstein, C. Giannini, D. Peereboom, T. Olencki, M. Davis, R. Bukowski
Journal: Journal of Clinical Oncology (2004)

7236 Background: Platinum based doublets are the standard of care for patients with advanced unresectable NSCLC and a good performance status. Non-platinum doublets have been investigated as an alternative to minimize toxicities. We report preliminary safety and efficacy results from a phase II study of weekly docetaxel and gemcitabine in such patients. Methods: Previously untreated patients with pathologically proven NSCLC and ECOG PS 0–1 and adequate organ functions were eligible. Docetaxel 36 mg/m2 IV and Gemcitabine 600 mg/m2IV were administered on D 1, 8, 15 of a 28 day cycle. Results: 26 patients were enrolled from December 2001 to date. Patients had a median age, 61 (Range 39–74); 13 were males; 2 had stage IIIB, 24 had stage IV. Of the 94 cycles (Median 3) administered, 40 were at full dose intensity, 51 required deletion of one week of treatment and 3 cycles required deletion of 2 weeks, mostly because of mylosuppresion. Treatment related grade 3 toxicities included: neutropenia in 34%, diarrhea in 15%, anemia in 4%, thrombocytopenia in 4% and mucositis in 4%. Atrial fibrillation and pulmonary embolism occurred in two patients each. There were no grade 4 hematological toxicities. There was 1 treatment related death due to pneumonia and 2 cases of hypersensitivity pneumonitis requiring hospitalization. Response rate was partial response 27 % (7/26), and stable disease 42% (11/26). Three patients (12%) were not evaluable for response. Median survival and progression free survival were not reached, but will be more than 8 months and 3.5 months respectively. Conclusions: Weekly docetaxel and gemcitabine is a well tolerated and active regimen in patients with advanced NSCLC, although this schedule was associated with frequent interruption secondary to myelosuppresion. Accrual to this study continues. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis; Eli Lilly Aventis
Prevalence of <i>PALB2</i> mutations in the Creighton University breast cancer family registry.
Authors: Carrie L. Snyder, Kelly A. Metcalfe, Victoria Sopik, Robert Royer, Dina Becirovic, Steven Narod, San Ming Wang, Mohammad R Akbari, Henry T. Lynch
Journal: Journal of Clinical Oncology (2015)

e12519 Background: PALB2 (i.e., the partner and localizer of BRCA2) plays an important role in double-strand DNA damage repair through interaction with BRCA1, BRCA2, and RAD51. Xia et al. (Nat Genet 2007;39:159-161) determined that homozygous mutations in PALB2 cause Fanconi’s anemia. Studies by Chen et al. (Clin Cancer Res 2008;14:5931-5937) and Janatova et al. (Cancer Epidemiol Biomarkers Prev 2013;22:2323-2332) found that, based on women with a family history of breast cancer, those who carried heterozygous mutations in PALB2 had an increased risk of developing hereditary breast cancer. Furthermore, a recent large-scale PALB2 predisposition study by Antoniou et al. (N Engl J Med 2014;371:497-506), indicates that the risk of breast cancer among PALB2 heterozygous mutation carriers is comparable to those of pathogenic BRCA2 mutation carriers, with a higher risk among those younger than 40 years of age; the breast cancer risk by age 70 is as high as 35%. According to Nguyen-Dumont et al. (Breast Cancer Res Treat 2015;149:547-554), germline heterozygous loss-of-function mutations in PALB2 are responsible for approximately 2.4% of familial breast cancer. Methods: The PALB2 gene was screened for mutations in 90 unrelated breast cancer families from Creighton’s Breast Cancer Family Registry who had previously tested negative for mutations in BRCA1 and BRCA2. All 13 coding exons of PALB2 plus 20 bp from both sides of each exon were amplified using Wafergene SmartChip Technology and sequenced by Illumina MiSeq next generation sequencer. Results: Two of 90 breast cancer probands (2.2%) were found to carry a truncating mutation in PALB2 (c.2411_2412delCT and c.2053delC). Both probands were diagnosed with breast cancer before the age of 35 and had three relatives with breast cancer. This early age of onset is consistent with findings by Nguyen-Dumont et al. (Breast Cancer Res Treat 2015;149:547-554). Also several missense variants with unknown clinical significance were identified among screened patients. Conclusions: Mutations of PALB2 are rare but testing for PALB2 mutations is a useful adjunct for patients undergoing testing for BRCA1 and BRCA2.
Pharmacogenetic analysis of <i>TS</i> and <i>UGT1A</i> polymorphisms predictive for response and toxicity in Spanish patients with advanced colorectal cancer treated with first-line irinotecan and 5-fluorouracil
Authors: E. Martinez-Balibrea, A. Abad, M. Valladares, M. Martinez-Villacampa, E. Aranda, E. Marcuello, M. Benavides, A. Martinez-Cardús, A. Ginés, J. L. Manzano
Journal: Journal of Clinical Oncology (2009)

4066 Background: The possible role of uridine diphosphate-glucuronosyltransferase 1A (UGT1A) and Thymidylate Synthase (TS) gene polymorphisms in predicting toxicity and outcomes in irinotecan/ 5-Fluorouracil (5FU)-treated patients is still controversial. The aim of this work was to determine whether UGT1A1, UGT1A7, and UGT1A9 as well as TS polymorphisms affect toxicities and/or outcomes of Spanish patients with advanced colorectal cancer (mCRC) Methods: A total of 149 patients with mCRC were treated either with weekly irinotecan plus high-dose 5FU (FUIRI) or biweekly irinotecan plus 5FU/Leucovorin (FOLFIRI) as first-line chemotherapy (Aranda E; Ann Oncol. 2008 Aug 20). Genomic DNA was extracted from peripheral blood and genotyped using allelic discrimination and direct sequencing. Chi-square test, Fisher's exact test and logistic regression were used to study the association of genotypes with toxicity and response. Log rank and cox regression were used in survival analysis. All statistical tests were two-sided. Results: According to TS 5’TRP genotypes, 79.3% of the 2R/2R patients responded to therapy while only 52.5% of 2R/3R or 3R/3R patients do so (HR=3.5; 95% CI=1.3- 9.1; p=0.009). TS genotypes were not associated with toxicity. UGT1A1*28 TA7/TA7 genotype was clearly associated with severe toxicity (HR=12.7; 95% CI=3.1–51.3; p=0.001) and diarrhea (HR=4; 95% CI=1.3–12; p=0.016) when compared to TA6/TA7 and TA6/TA6 genotypes. These patients also experienced more severe neutropenia (40% vs. 18.8%, p=0.087) and more frequent dose reductions (53.3% vs. 38.1%, p=ns). UGT1A7*3/*3 and UGT1A9–118(dT)9/9 were associated with severe diarrhea (50% vs. 27% p=0.032 and 43% vs. 23% p=0.012). When all non-favourable genotypes (TA7/TA7, *3/*3 and 9/9) were taken into account, there was a statistically significant association with severe diarrhea (HR=4.5; 95% CI 1.3–16.3; p=0.021), neutropenia (HR=3.5; 95% CI=1–12.7; p=0.047) and both (HR=12.4; 95% CI=2.8–54.2; p=0.001). Conclusions: Our data clearly link UGT1A genotypes with irinotecan-related severe toxicity. TS 5’TRP genotypes are predictive of response to irinotecan/5FU first-line chemotherapy. No significant financial relationships to disclose.
Response to the anti-EGFR antibody panitumumab combined with standard neoadjuvant chemotherapy in triple-negative breast cancer (TNBC): The immune and IGFR pathways.
Authors: Frederique Penault-Llorca, Marie-Melanie Dauplat, Catherine Abrial, Beatrice E. Weber, Marie-Ange Mouret-Reynier, Joseph Gligorov, Olivier Tredan, Maud Privat, Nancy Uhrhammer, Alexis Desrichard, Yannick Bidet, Nina Radosevic-Robin, Anne Cayre, Cécile Aubé, Pierre Charles Romero, Fabrice Kwiatkowski, Nassera Chalabi, Yves-Jean Bignon, Philippe Chollet, Jean-Marc Nabholtz
Journal: Journal of Clinical Oncology (2013)

1058 Background: EGFR overexpression is one of the hallmarks of the “basal-like” TNBC definition by immunohistochemistry (IHC). In a phase II neoadjuvant clinical trial targeting EGFR in TNBC, we investigated various biomarkers to better identify an EGFR-sensitive population for potential further regimen development. Methods: Sixty patients (pts) with stage II-IIIA TNBC were prospectively included. Systemic treatment (ST) consisted of the anti-EGFR antibody panitumumab combined with FEC 100, followed by 4 cycles of docetaxel. All pts underwent surgery after ST completion. Patient characteristics: median tumor size: 40 mm (20-120); invasive ductal carcinoma: 96.7%; SBR grade III: 71.7%; complete pathological response (pCR) rate: 55.3% and 46.8% (according to Sataloff’s and Chevallier’s classifications, respectively). Paraffin-embedded and frozen tumor samples were collected before and after ST for biologic studies. Germinal BRCA1 mutations, and EGFR, KRAS, BRAF and PI3KCA somatic mutations were analyzed by NGS. EGFR, IGF-1R, MET, cytokeratins 5/6 and 8/18, PTEN, P-cadherin, ALDH1, Ki-67, p53, tumoral FOXP3 expression and the number of FOXP3+ or CD8+ tumor-infiltrating lymphocytes (TILs) were evaluated by IHC. Results: High CD8+ TILs was response-predictive (p=3.4.10 -6 ). Tumor FOXP3 expression and high FOXP3 TILs tended to be predictive. High IGF-1R expressors responded better than low expressors (p = 0.028). Comparison of EGFR, IGF-1R and Her3 in biopsies versus surgical samples showed reduced EGFR levels in non-responders (p = 0.037), while Her3 (p = 0.049) and IGF-1R (p = 0.08) increased. Sequencing revealed BRCA1 mutations in 10% of pts. No difference of response (pCR) was observed between mutated patients and others. Somatic mutations of PI3K were observed in 6 pts. No mutations were observed in BRAF, KRAS, or EGFR. Conclusions: The CD8+ TIL count seems to predict the response to panitumumab. Tumor FOXP3 expression and high FOXP3 TILs also tended to be predictive. Tumor levels of IGF-1R seem to play a determinant role in TNBC response to anti-EGFR antibodies, in concordance with our observations in a head-and-neck cancer cohort. Clinical trial information: NCT00933517.
Adoption of a regional physician peer review program for radiation oncology.
Authors: Eleanor Elizabeth Harris, Hyder Husain Arastu, Clinton Leinweber, Andrew Ju, Robert McLaurin, Randall Blackburn, Charles Shelton, Timothy Barnes, Michael Holloman
Journal: Journal of Clinical Oncology (2017)

67 Background: Physician peer review is an important component of patient quality and safety programs. In 2012, the American Society for Radiation Oncology (ASTRO) published a white paper on peer review standards with recommendations to evaluate quality standards and compliance. Methods: Per ASTRO guidelines, physician peer review policy was adopted in 2013 by the Radiation Oncologists at the medical school and health system regional network. Peer review was conducted via WebEx by 5 regional centers. Reviews were done prior to start of treatment for all but emergent cases. Data were collected prospectively on 25 quality metrics, and scored by pre-defined peer consensus as follows: no change, minor change, major change, refer to chair. A description of recommended change was notated. Major changes were required to be represented. Aggregate data for the group and per physician were analyzed quarterly and incorporated into annual performance evaluations. Results: Aggregate categorical scores were compared for time periods from June to December 2014 (N = 283 cases) and June to December 2015 (N = 352 cases), showing an overall improvement in average scores per physician from 1.150 to 1.001. There were 56 (19.7%) total variances in 2014 compared to 32 (9%) variances in 2015. Level 2 changes (“minor”) decreased from 15.5% in 2014 to 7.2% in 2015 (p = 0.001). Level 3 changes (“major”) decreased from 4.2% to 1.9%, respectively (NS). The most common minor and major changes recommended related to dose parameters and target volumes. Variance rates over 5% were addressed by the department chair with individual practitioners and improvement programs instituted as needed. Conclusions: Peer review among a geographically diffuse physician group including an academic group practice and solo community physicians was feasible using a telemedicine system. Acceptance by the peer group was high, and over time the conference was increasingly used by physicians to review cases prior to initiating treatment planning, resulting in overall improved quality of treatment plans presented. Improved quality of care for radiation patients’ was demonstrated by significant reductions in the number and severity level of changes to treatment plans recommended.
Abstract 428: DNA Methylation of ASC is Associated with Decreased ASC and IL-1β Expression in Heart Failure
Authors: Brittany Butts, Javed Butler
Journal: Circulation Research (2015)

Introduction: Heart failure (HF) is associated with formation and activation of inflammasome, a complex of intracellular interaction proteins that trigger maturation of inflammatory cytokines to initiate inflammatory response. ASC, a vital component of the inflammasome, is controlled through epigenetic modification via methylation of CpG islands surrounding exon 1. Methods: To assess the relationships between DNA methylation of ASC, ASC expression, and inflammatory cytokines IL-1β and IL-18 in HF, stored samples from 155 chronic HF patients (age 56.9±12.0 yr, 64% male, 47% black, and ejection fraction 29.9±14.9) were analyzed. DNA extracted from PMBCs were analyzed by pyrosequencing for percent methylation of seven CpG sites in the intron region preceding exon 1 of the ASC gene. ASC mRNA was quantified via real-time PCR and analyzed as the ratio ASC:GAPDH. Serum ASC, IL-1β, and IL-18 were measured by ELISA. Results: Higher ASC methylation was associated with lower ASC mRNA (r=0-.328, p&lt;0.001) and protein (r=-.464, p&lt;0.001) expression. Lower ASC mRNA expression was associated with lower ASC protein expression (r=0.494, p&lt;0.001). Decreased IL-1β expression was associated with higher ASC methylation (r=-.424, p=0.005) and lower ASC mRNA (r=.619, p&lt;0.001) and ASC protein (r=.433, p&lt;0.001). IL-18 expression was not significantly associated with ASC methylation or expression. Conclusions: Increased ASC methylation was associated with lower IL-1β, likely via decreased ASC gene expression. As ASC is required for inflammasome activation of IL-1β, this study implicates the inflammasome pathway as a driver of inflammation in HF, proving a potential target for novel interventions.
HIV Services Provided by STD Programs in State and Local Health Departments — United States, 2013–2014
Authors: Kendra M. Cuffe, Precious Esie, Jami S. Leichliter, Thomas L. Gift
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

The incidence of human immunodeficiency virus (HIV) infection in the United States is higher among persons with other sexually transmitted diseases (STDs), and the incidence of other STDs is increased among persons with HIV infection (1). Because infection with an STD increases the risk for HIV acquisition and transmission (1-4), successfully treating STDs might help reduce the spread of HIV among persons at high risk (1-4). Because health department STD programs provide services to populations who are at risk for HIV, ensuring service integration and coordination could potentially reduce the incidence of STDs and HIV. Program integration refers to the combining of STD and HIV prevention programs through structural, service, or policy-related changes such as combining funding streams, performing STD and HIV case matching, or integrating staff members (5). Some STD programs in U.S. health departments are partially or fully integrated with an HIV program (STD/HIV program), whereas other STD programs are completely separate. To assess the extent of provision of HIV services by state and local health department STD programs, CDC analyzed data from a sample of 311 local health departments and 56 state and directly funded city health departments derived from a national survey of STD programs. CDC found variation in the provision of HIV services by STD programs at the state and local levels. Overall, 73.1% of state health departments and 16.1% of local health departments matched STD case report data with HIV data to analyze possible syndemics (co-occurring epidemics that exacerbate the negative health effects of any of the diseases) and overlaps. Similarly, 94.1% of state health departments and 46.7% of local health departments performed site visits to HIV care providers to provide STD information or public health updates. One fourth of state health departments and 39.4% of local health departments provided HIV testing in nonclinical settings (field testing) for STD contacts, and all of these programs linked HIV cases to care. STD programs are providing some HIV services; however, delivery of certain specific services could be improved.
Factors affecting prognosis in stage II and III testicular non-seminomatous germ cell tumors
Authors: A. Ozet, S. Ataergin, F. Arpaci, M. Aliomeroglu, S. Komurcu, O. Gunhan, B. Ozturk, O. Kuzhan
Journal: Journal of Clinical Oncology (2004)

9701 Background: Some patients in advanced stage of testicular germ cell cancers die due to unresponsiveness to treatment or disease progression. Many prognostic factors have been investigated up to date. Results apropos MIB-1 and HER-2/neu are still conflicting. Methods: 58 cases were enrolled in the study. Initial serum AFP and βHCG, histopathology, relapse sites, persistent tumor marker elevation and tumor sites were noted. Cases were classified according to International germ cell consensus as good, intermediate and poor prognosis. Cross sections were obtained retrospectively from tissue blocks and MIB-1, HER-2/neu, vascular density were evaluated by immunohistochemical method. Vascular invasion was identified for all specimen. Results were analysed with uni and multivariate analysis. Results: 22% were primary refractory (100% died) and 20% were later-relapsed cases (33% died). 57%, 9% and 27% of the cases were classified as good, intermediate and poor risk groups, respectively. 31% in good, 11% in intermediate and 0% in poor risk groups could achieve remission after relapse. Most important prognostic factors were found tumor site, vascular density, initial serum tumor marker level, existance of yolk sac and choriocarcinoma components, relapse sites (lung vs other than lung), persistent tumor marker elevation in univariate analysis (p: 0.0001, p: 0.0005, p: 0.008, p: 0.0007, p: 0.0034, p: 0.0039, p: 0.0032, and p < 0.001). Tumor site, choriocarcinoma component and initial serum AFP level were most expressive prognostic factors in multivariate analysis (p: 0.0017, p: 0.049 and p: 0.0009). MIB-1 and HER-2/neu were not found prognosticator for survival neither for relapse. Survival was affected mainly by prognosis level (p<0.001). Vascular density and MIB-1 were different between never-relapsed, later-relapsed and primary refractory cases. Vascular invasion nor her-2/neu were different between the three groups. Conclusions: Although MIB-1 level was different in all prognostic groups, it was not significant as prognostic factor as her-2/neu in this study. Vascular density may be a good prognosticator as well as other known predictors. No significant financial relationships to disclose.
Gefitinib phase II study in second-line treatment of advanced esophageal cancer
Authors: C. Van Groeningen, D. Richel, G. Giaccone
Journal: Journal of Clinical Oncology (2004)

4022 Background: Patients with advanced esophageal cancer have a poor prognosis. Although chemotherapy is often employed as first-line treatment there is no standard therapy for second-line intervention. Methods: Gefitinib (Iressa, ZD1839), an orally active EGFR-TKI (epidermal growth factor receptor tyrosine kinase inhibitor), was given at a dose of 500 mg/day to patients with histologically verified advanced esophageal cancer (patients with gastroesophageal cancer were eligible if >50% of the tumor involved the esophagus) after failure of one prior chemotherapy regimen. Patients were aged >18 years, with a WHO performance status (PS) <3, good organ function status, and measurable disease. Tumor biopsies were taken prior to starting treatment and thereafter every 28 days. A total of 38 patients were to be recruited with selection independent of EGFR expression and histologic status. Assessment of response was performed every 2 months using RECIST. Results: Of the 34 patients enrolled thus far, 26 have been fully evaluated: median age (range) was 57 (36–75) years, 20 were male, 22 had a PS <2, and 24 had metastatic disease. Treatment continued for >56 days in 15/26 patients (58%). Therapy was relatively well tolerated and there were no deaths due to toxicity. The most common drug-related adverse events were: diarrhea (58%), skin toxicity (42%), vomiting (12%), and elevated transaminases (12%). Dose reductions were recorded in 3 patients and interruptions in 4, of whom 2 had both reduction and interruption. Response was assessed in 34 patients: 3 had a partial response (duration: 154, 280, and 121 days), 6 had stable disease, 15 had disease progression, and 10 were non-eligible, not evaluable, or too early to be evaluated. Immunohistochemistry and comparative genomic hybridization of initial and serial biopsies is currently being performed. Accrual up to 38 patients is ongoing. Conclusions: Gefitinib is a promising agent for second-line treatment of advanced esophageal cancer. Iressa is a trademark of the AstraZeneca group of companies. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca