tbuckley/cabot-search huggingface dataset:
A phase II study of pemetrexed in patients (pts) with advanced neuroendocrine tumors (NETs)
Authors: P. Bhargava, C. C. Earle, A. X. Zhu, J. W. Clark, M. Vincitore, S. Battu, E. Regan, C. Lawrence, M. H. Kulke
Journal: Journal of Clinical Oncology (2007)

15149 Background: Traditional antifolates such as 5-florouracil have been associated with only modest activity in NETs. Pemetrexed is a multitargeted antifolate active in diseases not known to be responsive to other antifolates. We performed a prospective phase II study of pemetrexed in pts with advanced NETs to assess response, toxicity, and survival. Methods: Pts were treated with Pemetrexed administered intravenously at a dose of 500 mg/m 2 every 21 days. To reduce toxicity, folic acid and vitamin B12 supplementation were mandatory. Pts were also treated with oral dexamethasone 4 mg twice daily the day prior to, day of, and day after pemetrexed administration. The study utilized a two-step design, with an initial accrual phase of 17. Pts were required to have metastatic neuroendocrine tumors (excluding small cell carcinoma), and preserved hematologic, renal, and hepatic function. Treatment with prior chemotherapy was allowed; pts receiving octreotide remained on octreotide at a stable dose level during study therapy. Results: 17 pts were enrolled with the following characteristics: M: F=4:13. median age 56 (range 38 to 72); ECOG Performance Status 0/1/2=4/12/1. Tumor types included carcinoid n=12(71%) and islet cell n=5(29%). 17 pts received treatment for a median of three, 21-day cycles; the median time on study was 10 weeks. Grade 3–4 toxicities included: fatigue n=8(47%), leukopenia n=7 (41%), neutropenia n=6 (35%), elevated alkaline phosphatase n=4 (23%), thrombocytopenia n=3 (17%), lymphopenia n=3 (17%), pneumonitis n=2 (11%), hyponatremia n=2 (11%), dyspnea n=1 (5%), hyperbilirubinemia n=1 (5%), weight loss n=1 (5%), diarrhea n=1 (5%), elevated ALT/SGPT n=1 (5%), edema n=1 (5%), weakness n=1 (5%), grade 4 proteinuria n=1 (5%). 15 pts were evaluable for response; the best treatment response was stable disease (n=9;), the remaining 6 pts experienced progressive disease as their best response to therapy. Accrual to the study was halted due to lack of observed antitumor activity. Conclusions: Pemetrexed does not have significant antitumor activity in pts with advanced NET. No significant financial relationships to disclose.
Disability-Free Life-Years Lost Among Adults Aged ≥50 Years With and Without Diabetes
Authors: Barbara H. Bardenheier, Ji Lin, Xiaohui Zhuo, Mohammed K. Ali, Theodore J. Thompson, Yiling J. Cheng, Edward W. Gregg
Journal: Diabetes Care (2015)

To quantify the impact of diabetes status on healthy and disabled years of life for older adults in the U.S. and provide a baseline from which to evaluate ongoing national public health efforts to prevent and control diabetes and disability.Adults (n = 20,008) aged 50 years and older were followed from 1998 to 2012 in the Health and Retirement Study, a prospective biannual survey of a nationally representative sample of adults. Diabetes and disability status (defined by mobility loss, difficulty with instrumental activities of daily living [IADL], and/or difficulty with activities of daily living [ADL]) were self-reported. We estimated incidence of disability, remission to nondisability, and mortality. We developed a discrete-time Markov simulation model with a 1-year transition cycle to predict and compare lifetime disability-related outcomes between people with and without diabetes. Data represent the U.S. population in 1998.From age 50 years, adults with diabetes died 4.6 years earlier, developed disability 6-7 years earlier, and spent about 1-2 more years in a disabled state than adults without diabetes. With increasing baseline age, diabetes was associated with significant (P < 0.05) reductions in the number of total and disability-free life-years, but the absolute difference in years between those with and without diabetes was less than at younger baseline age. Men with diabetes spent about twice as many of their remaining years disabled (20-24% of remaining life across the three disability definitions) as men without diabetes (12-16% of remaining life across the three disability definitions). Similar associations between diabetes status and disability-free and disabled years were observed among women.Diabetes is associated with a substantial reduction in nondisabled years, to a greater extent than the reduction of longevity.
Abstract 286: Coordinated activation of TLR8 and NLRP3 by VTX-2337 (motolimod) ignites tumoricidal NK cell activity
Authors: Greg Dietsch, Haling Lu, Yi Yang, Chihiro Morishima, Laura Q. Chow, Mary L. Disis, Robert Hershberg
Journal: Cancer Research (2015)

Abstract VTX-2337 (motolimod) is a selective toll-like receptor 8 (TLR8) agonist in clinical development as an immunotherapy for multiple oncology indications, including squamous cell carcinomas of the head and neck (SCCHN). Activation of TLR8 has been found to enhance natural killer (NK) cell activation, increase antibody-dependent cell-mediated cytotoxicity (ADCC), and induce Th1 polarizing cytokines. Further characterization of VTX-2337 reveals the release of mature IL-1β and IL-18 from monocyte cell populations through coordinated actions on both TLR8 and NLRP3. In vitro, VTX-2337 primes monocytes to produce pro-IL-1β, pro-IL-18 and caspase 1, while activating the NLRP3 inflammasome, leading to the release of mature IL-1 family cytokines. Inflammasome activation by VTX-2337 is blocked by inhibiting caspase 1, with little impact on the production of other TLR8 induced mediators such as TNFα. The release of IL-18 stimulates NK cells, and augments other activation pathways including: FcγRIII and NKG2D receptors, resulting in IFNγ production and induction of CD107α. NLRP3 activation in vivo was confirmed by a dose-related increase in plasma levels of IL-1β and IL-18 in cynomolgus monkeys administered VTX-2337. This pathway for NK activation was subsequently assessed in SCCHN patients treated with VTX-2337 in combination with cetuximab, a clinically approved epidermal growth factor receptor (EGFR) specific monoclonal antibody (mAb). Cetuximab can activate NK cells through an interaction with FcγRIII, and facilitate ADCC of tumor cells. Preliminary data from a Phase I clinical trial found that prior to treatment, patient NK cells did not effectively activate in response to ex vivo stimulation by NKG2D or FcγRIII. However, following VTX-2337 treatment, patient NK cells become more responsive to these activating signals. These results show that TLR8 stimulation and inflammasome activation by VTX-2337, can complement FcγRIII engagement, and may augment clinical responses in SCCHN patients treated with cetuximab. Citation Format: Greg Dietsch, Haling Lu, Yi Yang, Chihiro Morishima, Laura Q. Chow, Mary L. Disis, Robert Hershberg. Coordinated activation of TLR8 and NLRP3 by VTX-2337 (motolimod) ignites tumoricidal NK cell activity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 286. doi:10.1158/1538-7445.AM2015-286
Effect of tumor necrosis factor-alpha on the proliferation of leukemic cells from children with B-cell precursor-acute lymphoblastic leukemia (BCP-ALL): studies of primary leukemic cells and BCP-ALL cell lines
Authors: MX Zhou, HW Findley, LH Ma, SR Zaki, T Hill, M Hamid, WC Hooper, AH Ragab
Journal: Blood (1991)
Association of Polymorphisms of Cytochrome P450 2D6 With Blood Hydroxychloroquine Levels in Patients With Systemic Lupus Erythematosus
Authors: Ji Yeon Lee, Nadimuthu Vinayagamoorthy, Kyungdo Han, Seung Ki Kwok, Ji Hyeon Ju, Kyung Su Park, Seung‐Hyun Jung, Sung‐Won Park, Yeun‐Jun Chung, Sung‐Hwan Park
Journal: Arthritis & Rheumatology (2015)

To evaluate associations of genetic polymorphisms in cytochrome P450 (CYP) isoforms 2D6, 3A5, and 3A4 with blood concentrations of hydroxychloroquine (HCQ) and its metabolite, N-desethyl HCQ (DHCQ), in patients with systemic lupus erythematosus (SLE).SLE patients taking HCQ for >3 months were recruited and were genotyped for 4 single-nucleotide polymorphisms in CYP2D6*10, CYP3A5*3, and CYP3A4*18B. Blood HCQ and DHCQ concentrations ([HCQ] and [DHCQ]) were measured and their association with corresponding genotypes was investigated.A total of 194 patients were included in the analysis. CYP2D6*10 polymorphisms (rs1065852 and rs1135840) were significantly associated with the [DHCQ]:[HCQ] ratio after adjustment for age, sex, dose per weight per day, and SLE Disease Activity Index score (P = 0.03 and P < 0.01, respectively). In adjusted models, the [DHCQ]:[HCQ] ratio was highest in patients with the G/G genotype of the CYP2D6*10 (rs1065852) polymorphism and lowest in those with the A/A genotype (P = 0.03). Similarly, the [DHCQ]:[HCQ] ratio was highest in patients with the C/C genotype of the CYP2D6*10 (rs1135840) polymorphism and lowest in those with the G/G genotype (P < 0.01). The CYP2D6*10 (rs1065852) polymorphism was significantly related to the [DHCQ] (P = 0.01). However, the polymorphisms of CYP3A5*3 and CYP3A4*18B did not show any significant association with the [HCQ], [DHCQ], or [DHCQ]:[HCQ] ratio.Our study showed that the [DHCQ]:[HCQ] ratio was related to CYP2D6 polymorphisms in Korean lupus patients taking oral HCQ. CYP polymorphisms may explain why there is wide variation in blood HCQ concentrations. The role of an individual's CYP polymorphisms should be considered when prescribing oral HCQ.
<i>EGFR</i> and <i>KRAS</i> mutations in patients with bronchioloalveolar carcinoma treated with erlotinib in a phase II multicenter trial
Authors: M. G. Kris, A. Sandler, V. A. Miller, M. F. Zakowski, W. Pao, A. Tsao, J. D. Patel, D. H. Johnson, D. P. Carbone
Journal: Journal of Clinical Oncology (2005)

7029 Background: Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene have been associated with sensitivity to erlotinib (Tarceva™). Virtually all patients whose tumors harbor these mutations respond. Mutations in KRAS, which encodes a signaling protein downstream of EGFR, appear to be mutually exclusive of EGFR mutations (Shigematsu H. JNCI 2004) and are associated with sensitivity and resistance to erlotinib (Pao W. PLoS Medicine 2005). We now report the association of EGFR and KRAS mutations with partial radiographic response, BAC histologic types, and smoking history in patients with BAC treated with erlotinib in this ongoing phase II trial. Methods: Patients with stage IIIB/IV BAC received erlotinib 150 mg PO daily. We performed standard PCR-based sequencing using tumor-extracted genomic DNA to detect mutations in EGFR (exons 18–21) and KRAS (exon2) on the first 37 specimens available from this trial planned to enroll 100. The analysis includes 36 specimens previously reported by Pao cited above. Results: We found mutations in EGFR in 9 of 37 (24%) and KRAS in 4 of 34 (12%). In the 11 patients with partial responses, mutations in EGFR were found in 9 (82%) and in KRAS in none. Two patients with partial response had neither mutation. EGFR mutations were found in 1/8 (13%) with “pure BAC” (WHO defined) and 8/29 (28%) with AdenoCa with BAC features. All 4 KRAS mutations were found in the latter group. EGFR mutations were found in 0/5, 4/25 and 5/7 current, former and never smokers, respectively. KRAS mutations were detected in 1/5, 2/24 and 1/5 current, former and never smokers. Conclusions: In these patients with BAC: 1) All 9 tumors with EGFR mutations and 2 without showed partial responses. None of the 4 tumors with KRAS responded. 2) EGFR mutations are more common in AdenoCa with BAC features than “pure” BAC. 3) EGFR mutations were most frequent in never smokers. 4) Since EGFR and KRAS mutations are associated with sensitivity and resistance to erlotinib, these data may help decide when to prescribe it and may define the biological basis of clinical observations. We plan to study additional tumors from the 89 patients accrued. Support: P50 CA90949, Genentech, Inc. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech
Abstract 13614: Atrial Fibrillation Increases Adverse Cardiac Events in Hypertrophic Cardiomyopathy With Moderate Tissue Fibrosis
Authors: Yuko Wada, Takeshi Aiba, Taka-aki Matsuyama, Kohei Ishibashi, Ikutaro Nakajima, Koji Miyamoto, Yuko Yamada, Hideo Okamura, Takashi Noda, Kazuhiro Satomi, Yoshiaki Morita, Hideaki Kanzaki, Toshihisa Anzai, Masaharu Ishihara, Kengo F. Kusano, Satoshi Yasuda, Shiro Kamakura, Hatsue Ishibashi-Ueda, Wataru Shimizu, Hisao Ogawa
Journal: Circulation (2013)
Left Main Dissection and Pseudoaneurysm Formation After a Road Traffic Accident
Authors: Carolina Granda Nistal, Belén Rubio Alonso, Elena Mejía Martínez, Leticia Blázquez Arroyo, Blanca Coto Morales, Juan José Parra Fuertes, Julio García Tejada, Felipe Hernández Hernández, María Teresa Velázquez Martín, Agustín Albarrán González-Trevilla
Journal: Circulation (2015)
Internal tandem duplication of FLT3 associated with leukocytosis in acute promyelocytic leukemia
Authors: H Kiyoi, T Naoe, S Yokota, M Nakao, S Minami, K Kuriyama, A Takeshita, K Saito, S Hasegawa, S Shimodaira, J Tamura, C Shimazaki, K Matsue, H Kobayashi, N Arima, R Suzuki, H Morishita, H Saito, R Ueda, R Ohno
Journal: Leukemia (1997)
Initial results of LC-MAP: An institutional program to routinely profile tumor specimens for the presence of mutations in targetable pathways in all patients with lung adenocarcinoma.
Authors: M. G. Kris, C. Y. Lau, D. Ang, E. Brzostowski, G. J. Riely, V. W. Rusch, S. Jhanwar, A. Lash, M. F. Zakowski, M. Ladanyi
Journal: Journal of Clinical Oncology (2010)

7009 Background: Mutated oncogenes underlie the behavior of lung adenocarcinomas and can serve as targets for therapy. Determining the presence of these molecular abnormalities can direct the care of individual patients, qualify them for clinical trials, and aid research. To acquire this information on as many patients as feasible, in JAN 2009 our multidisciplinary Disease Management Team began a program (the Lung Cancer Mutation Analysis Project - LC-MAP), to prospectively detect all recurrent mutations in EGFR, KRAS, BRAF, HER2, PIK3CA, MEK1 and AKT1 and the EML4-ALK fusion gene in all patients diagnosed with lung adenocarcinoma with sufficient tissue. Methods: Patients sign an institutional consent to permit the use of previously obtained ("leftover") tissue for mutation profiling after standard morphologic and molecular diagnostic studies are complete. After PCR-based testing for EGFR exon 19 deletions and L858R, KRAS mutations are determined by direct sequencing, then remaining DNA is studied in a multiplexed mass-spectrometry-based system (Sequenom) to study 40 additional mutations in 7 genes. The EML4-ALK translocation is assayed by ALK FISH. Results: In the first six months, 301 patients entered the program. We completed all proposed testing in 92%. Mutations detected include 72 KRAS, 63 EGFR, 22 EML4-ALK, 1 BRAF, 4 PIK3CA, 0 HER2, 0 AKT1, and 0 MEK1. Based on this information, 27 patients with EGFR mutations received an EGFR tyrosine kinase inhibitor. No patient with wild type EGFR or a KRAS mutation received an EGFR TKI. 24 patients were entered on clinical trials testing agents targeting the specific molecular abnormality detected. Conclusions: (1) The presence of relevant mutations can be routinely determined in patients with adenocarcinoma of the lung. (2) The mutational data obtained can be used to select erlotinib or gefitinib for individuals with EGFR mutations and to identify patients appropriate for clinical trials of targeted therapies. (3) This effort supports making upfront genotyping of lung adenocarcinomas part of routine care. Support: P01 CA129243, Chandler Fund. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Boehringer Ingelheim, Merck, Pfizer
Carcinogenicity of Proposed Cancer Chemotherapeutic Agents With Stilbene-Arylnitrosamine Structures
Authors: Richard S. Yamamoto, Howard L. Richardson, Elizabeth K. Weisburger, John H. Weisburger, Timothy Benjamin, Carl Tabb Bahner
Journal: JNCI Journal of the National Cancer Institute (1973)

Two compounds, 1-(4-N-methyl-N- nitrosaminobenzylidene)indene and 4-(4-N- methyl-N-nitrosaminostyryl)quinoline, originally synthesized for a cancer chemotherapy study, were carcinogenic in Fischer rats.
Predicting response to second-line trastuzumab-based therapy in patients (pts) with HER2-positive advanced breast cancer (ABC)
Authors: R. Bartsch, C. Wenzel, U. Pluschnig, P. Dubsky, S. P. Gampenrieder, M. Rudas, R. Mader, M. Gnant, C. C. Zielinski, G. G. Steger
Journal: Journal of Clinical Oncology (2009)

1090 Background: In HER2-positive ABC, the upfront use of trastuzumab (T) is well established. Following progression upon first-line therapy, pts may be switched to lapatinib. Others however may be candidates for continued antibody therapy. Finding the optimal treatment approach therefore is pertinent. Here, we aimed to identify factors predicting response to second-line T-based therapy. Methods: 80 pts (median age 50.5 years) with ABC treated with &gt;1 line of T-containing therapy were identified from a breast cancer database. HER-2-status was determined by immunohistochemistry (HercepTest) and re-analyzed by FISH if a score of 2+ was gained. Response rate (RR; CR+PR), clinical benefit rate (CBR; CR+PR+SD &gt;6 months), time to progression (TTP), overall survival (OS), and cardiac toxicity were recorded. Response was evaluated every three months (m) using UICC criteria. TTP and OS were estimated using the Kaplan-Meier product limit method. In order to identify factors associated with TTP, the following variables were included in a Cox regression model: age (≤65 y/&gt;65 y), initial tumor stage (&lt;IV/IV), grading, ductal/lobular carcinoma, endocrine receptor status, prior non T-containing palliative chemotherapy, metastatic sites (visceral/non-visceral only), and clinical benefit (CB) from T-based first-line therapy. The same variables were used in a multinomial logistic regression model to evaluate their influence on treatment response. P values &lt;0.05 were considered to indicate statistical significance. Results: Median time of observation was 28 m. TTP was median 9.3 m (95% CI 7.73–10.96) in the first-line and 7.5 m (95% CI 6.14–8.82) in the second-line setting (n.s.). First-line treatment yielded an 83% CBR, as compared to 54% in second-line. None of the factors included in the multivariate model independently predicted outcome. A significant deterioration of cardiac function was observed in a single patient; 22.5% developed brain metastases. Conclusions: T in multiple lines showed considerable activity. None of the variables investigated could independently predict response to second-line therapy. In order to reliably predict activity of second-line T-based therapy evaluation of other factors such as truncated HER2 or PTEN-loss appears necessary. [Table: see text]
Drug delivery analysis of the Canadian multicenter trial in non-small-cell lung cancer.
Authors: N Murray, C Coppin, A Coldman, J Pater, E Rapp
Journal: Journal of Clinical Oncology (1994)

PURPOSE The Canadian multicenter trial for advanced non-small-cell lung cancer (NSCLC) reported survival benefit for chemotherapy when best supportive care was compared with vindesine-cisplatin (VP) and the combination of cyclophosphamide, doxorubicin, and cisplatin (CAP). We examined received drug delivery to document dose-intensity (DI) and total dose of drugs given to various groups in this patient population. PATIENTS AND METHODS Plots of cumulatively received chemotherapy against time were used to evaluate drug delivery by regimen, major prognostic factors, and response status. RESULTS Individual CAP patients show a narrow range of received DI, with the median similar to protocol. Drug delivery analysis exposed a wide range of received DI for both drugs in the more intensive VP regimen, and the median received DI was below protocol. The median received DI for cisplatin was still higher for VP than CAP, but only during the first 8 weeks of protocol treatment (20 v 10 mg/m2/wk); thereafter, the ongoing received cisplatin DI was the same (10 mg/m2/wk). The median received DI for cisplatin in each regimen was not influenced by stage, performance status, prior weight loss, sex, or response status. VP-treated patients received a higher total dose of cisplatin than CAP patients (median, 255 mg/m2 v 112.5 mg/m2; P &lt; .0001). Median cisplatin total dose was similar for patients with a chemotherapy response or stable disease and threefold greater than for patients with progressive disease for both regimens. Although patients with chemotherapy response and stable disease had similar survival outcomes for both CAP and VP, the VP regimen had a higher proportion of patients without progressive disease (P = .004), which resulted in an overall survival advantage (P = .01). CONCLUSION The major prognostic factors for advanced NSCLC do not exert their influence on outcome by affecting deliverable chemotherapy DI. Regimen and treatment response determined total dose. Because stable disease patients usually outnumber responding patients in advanced NSCLC trials, controlled studies should be performed that allow assessment of the impact of total received dose on outcome according to response status.
Acute radiotherapy toxicity in breast cancer patients
Authors: M. Rucinska, S. T. Langkjer
Journal: Journal of Clinical Oncology (2008)

20592 Background: Radiotherapy is associated with several side effects, which adversely affect the quality of life. The aim of the study was to estimate the level of fatigue and radiation induced skin reaction after adjuvant postoperative radiotherapy of breast cancer patients after breast-conserving surgery. Methods: 50 patients (age 33–72 years, mean 56 years) with early breast cancer after breast- conserving surgery were treated with adjuvant radiotherapy between February 2006 and February 2007. RTOG Acute Radiation Morbidity Scoring Criteria (0–4) were used for the estimation of acute skin reaction. For quantitative evaluation of the erythema a reflectance spectrophotometr (Derma Spectrometr, Corex) with digital read-out was used. The subjective feeling of fatigue intensity was measured according to 10-score visual analog scale (VAS). Examinations were done before and weekly during radiotherapy, as well as 1 and 3 months after it. Results: Fatigue intensity increased gradually during radiotherapy (mean fatigue-VAS before and in the last week of treatment was 1.44 and 3.38 respectively; p=0.004). 1 month after the end of radiotherapy, fatigue intensity was still higher than before treatment (1.92; p=0.04), but 3 months after radiotherapy, fatigue relapsed to the pretreatment level. On the last day of radiotherapy patients estimated acute skin reaction according to RTOG scale on mean 1.52 (median 2), nurses on mean 1.16 (median 1). The objective measurments of erythema by the reflectance spectrophotometr were compatible with nurses‘ RTOG scale results. There was a correlation between fatigue level and intensity of skin reaction. Mean fatigue VAS was 2.75 and 4.76 for patients who estimated skin reaction on 0–1 and 2–4, respectively. Conclusions: Fatigue increased over the course of adjuvant radiotherapy in breast cancer patients. There was a positive correlation between fatigue level and intensity of skin reaction. Patients estimate radiation-induced skin side effects on higher level than nurses. RTOG scale was equivalent to the reflectance spectrophotometr. No significant financial relationships to disclose.