tbuckley/cabot-search huggingface dataset:
CD40/CD40L expression correlates with the survival of patients with glioblastomas and an augmentation in CD40 signaling enhances the efficacy of vaccinations against glioma models
Authors: Masashi Chonan, Ryuta Saito, Takuhiro Shoji, Ichiyo Shibahara, Masayuki Kanamori, Yukihiko Sonoda, Mika Watanabe, Toshiaki Kikuchi, Naoto Ishii, Teiji Tominaga
Journal: Neuro-Oncology (2015)

The prognosis of glioblastoma (GBM) remains poor; therefore, effective therapeutic strategies need to be developed. CD40 is a costimulatory molecule whose agonistic antibody has been shown to activate antitumor effects. Recently, CD40 has been extensively targeted for immunotherapeutic purposes. Expressions of CD40/CD40L mRNAs were examined in 86 cases of World Health Organization grade IV GBM and 36 cases of grade III gliomas and correlated with outcomes. CD40 signaling was employed to augment the efficacy of immunotherapy against gliomas. The efficacy of FGK45, an agonistic antibody for CD40, was examined by adding it to a tumor lysate–based subcutaneous vaccination against a GL261 glioma model and an NSCL61 glioma-initiating cell–like cell tumor model. We demonstrated for the first time using quantitative PCR that grade III gliomas express higher levels of CD40/CD40L than does grade IV GBM. The higher expression of CD40/CD40L was associated with good prognoses in patients with GBM. Addition of FGK45 to the subcutaneous tumor cell lysate–based vaccination significantly prolonged survival in both tumor models. However, the efficacy was modest in NSCL61-model mice. Therefore, we established combination immunotherapeutic strategies using FGK45 and OX86, an agonistic antibody for OX40. Combination immunotherapy significantly prolonged survival with synergistic effects. Apoptosis increased and proliferation decreased in tumors treated with combination immunotherapy. The high expression of CD40/CD40L can be used as a biomarker for better prognoses in patients with gliomas. Immunotherapy using FGK45 significantly prolonged survival and represents a potential therapeutic strategy for gliomas including glioma-initiating cells.
Continous low dose oral chemotherapy administration in heavily pretreated breast cancer patients
Authors: I. Pavese, M. Di Palma, G. Capuano, F. Satta
Journal: Journal of Clinical Oncology (2006)

10664 Background: The efficacy and the antiangiogenic effect of low dose continous (metronomic) administration of chemotherapy are well known. In thi study we tested the clinical activity of oral Ciclophosphamide (CTX) and Methotrexate (MTX) in advanced breast cancer (ABC). Methods: From november 2004 to september 2005 35 ABC patients were enrolled. Median age 59 (range 36–74), ECOG PS 0–2. All patients received at least two prior chemotherapeutic regimens (range 2–4). Metastatic sites were as follow: liver (16), lung (6), bone (9) and skin (4). patients with CNS involvement were excluded. All patients received CTX at the dose of 50 mg/die and MTX at the dose of 2.5 mg twice daily on days 3 and 4 of each week. After two months of treatment patients were re-evalated for disease response. Results: All patients were evaluable for response. After 2 months of treatment we observed 3 PR (8.5%) and 12 SD (34%), for an overall RR of 42%. 23 patients experienced PD. On the whole treatment was well tolerated, with mild toxicity; no patients discontinued treatment due to toxicity. Grade 2 or 3 neutropenia was observed in 14/35 patients and grade 2 trombocytopenia was observed in 9/35 patients. No grade 4 toxicity was observed. Conclusions: Metronomic administration of chemotherapy is well tolerated even in pretreated patients and shows moderate activity in advanced breast cancer No significant financial relationships to disclose.
Obesity and guideline-concordant systemic therapy for locoregional breast cancer.
Authors: Hollis Moore, Amy Trentham-Dietz, Caprice Christian Greenberg, David J. Vanness, John M Hampton, Xiao-cheng Wu, Roger T. Anderson, Joseph Lipscomb, Gretchen Genevieve Kimmick, Rosemary Donaldson Cress, Steven Fleming, J. Frank Wilson
Journal: Journal of Clinical Oncology (2014)

145 Background: Obese breast cancer patients tend to have higher mortality than non-obese patients. Hypothesizing that differences in receipt of adequate treatment may contribute to this mortality differential, we examined whether breast cancer patients with higher body mass index (BMI) received systemic adjuvant treatment consistent with National Comprehensive Cancer Network guidelines. Methods: Female adult stage I-III breast cancer cases diagnosed in 2004 were identified from population-based cancer registries in 7 states and supplemented with abstracted medical records. Differences in receipt of concordant treatment according to BMI were investigated using logistic regression models adjusted for age and other covariates. Results: Among all women, 57% (2,174 of 3,828) received overall guideline-concordant (GC) adjuvant systemic treatment, meaning treatment adherent in each of 3 defined domains: chemotherapy, chemotherapy regimen, and hormonal therapy. Within the domains, 82% of women received GC chemotherapy, and 93% of those received a GC regimen, and 80% received GC hormonal therapy. Women with higher BMI had greater odds of receiving GC systemic therapy (odds ratio for each 5 kg/m 2 increase in BMI 1.07, 95% CI 1.01 to 1.14; p value for trend = 0.04). No significant differences in guideline treatment according to BMI were found in the individual therapy domains (adjuvant chemotherapy, p = 0.18; chemotherapy regimen, p = 0.26), although a borderline significant, nonlinear pattern was seen for hormonal therapy, in which the highest odds of GC treatment were found in the lowest and highest BMI ranges (p = 0.07 from χ 2 test). Conclusions: Contrary to our hypothesis, odds of guideline concordant systemic therapy increased with higher BMI, and no significant differences were found within any specific treatment domain. Further research describing how multiple factors including treatment patterns influence outcomes for obese breast cancer patients may identify areas where changes in practice can reduce disease burden and mortality. Our research also suggests further investigation into patterns of care for underweight patients.
Excellent event-free survival (EFS) in newly diagnosed patients with supratentorial primitive neurectodermal tumors (SPNET) treated with risk-adapted craniospinal (CSI) radiation (RT) therapy followed by 4 cycles of high-dose chemotherapy and stem cell rescue
Authors: M. Chintagumpala, D. Ashley, T. Hassall, D. Wallace, T. E. Merchant, S. Woo, M. Sexton, R. Cheuk, A. Gajjar
Journal: Journal of Clinical Oncology (2005)

8553 Purpose: To estimate the EFS of average-risk (AR) and high-risk (HR) SPNET treated with risk-adapted CSI and conformal primary site boost followed by 4 cycles of high-dose chemotherapy supported by stem cell rescue. Patients and Methods: Between 1996 and 2003, 19 children with SPNET were enrolled. Patients with HR disease were differentiated from AR by the presence of residual tumor (M0 = 1.5 cm2) or disseminated neuraxis disease (M1–3) as defined by the Chang staging system. All patients received risk-adapted CSI (M0 with residual < 1.5 cm2, 23.4 Gy; M0 with residual tumor = 1.5 cm2 and M1, 36 Gy; M2-3, 36–39.6 Gy CSI). The tumor bed received 55.8 Gy using a 2 cm clinical target volume margin. Six weeks after RT, patients received chemotherapy consisting of 4 cycles of high-dose cyclophosphamide with cisplatin and vincristine. Results: The median age was 7.3 yrs (3.8–12.9). There were 8 females and 11 males, 4 patients with pineoblastoma, and 9 were classified as AR. 14 pts are alive at a median follow-up of 2.4 yrs (1.1–5.6). The 3 yr PFS for all patients with SPNET was 63%±16 and OS was 79%±12. The 3 yr PFS for AR patients was 61%±22. The 3 yr PFS for HR patients was 67% ± 19%. There were no toxic deaths on study. Conclusions: 4 cycles of high-dose cyclophosphamide based chemotherapy with stem cell support following risk-adapted CSI in patients with SPNET has resulted in excellent EFS with tolerable toxicity. Dose-intensive chemotherapy may allow for reduced CSI in AR patients with SPNET. No significant financial relationships to disclose.
Gemcitabine plus erlotinib (GE) followed by capecitabine (C) versus capecitabine plus erlotinib (CE) followed by gemcitabine (G) in advanced pancreatic cancer (APC): A randomized, cross-over phase III trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO).
Authors: S. H. Boeck, U. Vehling-Kaiser, D. Waldschmidt, E. Kettner, A. Märten, C. Winkelmann, S. Klein, G. Kojouharoff, A. Jung, V. Heinemann
Journal: Journal of Clinical Oncology (2010)

LBA4011 Background: Gemcitabine plus erlotinib (GE) is regarded as one standard of care for patients (pts) with APC and CE as an all-oral regimen could be a feasible option in this population. To date, the value of a prospectively defined second-line treatment is unclear in APC. Methods: Within a prospective multicenter phase III trial, 281 pts with histologically confirmed APC and adequate organ function were randomly assigned to first-line treatment with either C (2,000 mg/m 2 /d, d1-14 q3w) plus E (150 mg/d, arm A) or G (1,000 mg/m 2 over 30 min weekly x 7, then d1, 8, 15 q4w) plus E (150 mg/d, arm B). In case of treatment-failure (e.g. disease progression or toxicity, TTF1), pts were "crossed-over" to second-line treatment with the comparator cytostatic drug without E. The primary study endpoint was time to treatment failure of second-line therapy (TTF2); secondary endpoints included TTF1, objective response, overall survival (OS) and toxicity. Results: Of 279 eligible pts, 60% were male and median age was 64 years; 47 pts had locally advanced and 232 metastatic disease, 141 pts (51%) received second-line chemotherapy. Objective response rate (CR+PR, ITT) to first-line treatment was 5% (A) vs. 13% (B). Currently, TTF2 is estimated with 4.4 months (mo) in arm A and 4.2 mo in arm B (HR 0.98, p=0.43), median OS is 6.9 mo (A) and 6.6 mo (B), respectively (HR 0.96, p=0.78). TTF1 was significantly prolonged in arm B (2.4 mo vs 3.4 mo; HR 0.69, p=0.0036). Hematological toxicity was more frequent with G-containing regimens, skin rash &gt; grade 1 during E treatment occurred in 31% pts in arm A and in 43% pts in arm B. Tissue tumor samples are available from 204 pts; 123 tumors (70%) harboured a somatic KRAS mutation (mut). Pts with KRAS wildtype (wt, n=53) had an improved OS (wt: 8.0 mo vs. mut: 6.6 mo; HR 1.62, p=0.011). Conclusions: TTF2 and OS were comparable in both arms; GE was superior compared to CE with regard to TTF1. Wt KRAS status was associated with an imprved OS in pts with APC. [Table: see text]
EGFR GENOTYPING AND EPIDEMIOLOGY, CLINICAL AND PATHOLOGICAL FEATURES IN 191 PATIENTS WITH METASTATIC PULMONARY ADENOCARCINOMA IN SAO PAULO - BRAZIL.
Authors: Gilberto Castro Jr., Tiago K. Takahashi, Rafael Caires-Lima, Bruno M. Protasio, Manuel C. D. F. Maia, Ibere C. Soares, Felipe S. R. Roitberg, Andrea M. Marini, Renata E. Martins, Teresa Y. Takagaki, Pedro H. X. N. Araujo, Ricardo M. Terra, Christina Shiang, Sheila A. C. Siqueira, Evandro S. Mello, Venancio A. Alves, Paulo M. Hoff
Journal: Journal of Thoracic Oncology (2013)
Chemotherapy for squamous cell carcinoma of the penis: An 8-year, single-institution experience.
Authors: B. Y. Kularatne, B. E. Ayres, D. Mukherji, N. Watkin, W. Lam, M. Perry, L. M. Pickering
Journal: Journal of Clinical Oncology (2011)

222 Background: Penile cancer is a rare malignancy affecting approximately 400 men per year in the United Kingdom. There are relatively limited data regarding the role of chemotherapy, although it may be considered in the adjuvant setting for high-risk disease and for palliation of metastatic disease. Methods: Patients treated with chemotherapy between June 2002 and March 2010 were identified from our prospectively maintained institutional database. Regimens were recorded and toxicity documented according to the Common Toxicity Criteria version 4.0. Response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 until 2009 and then version 1.1. Results: Twenty patients received chemotherapy either for adjuvant treatment (n=6) or for metastatic disease (n=14). Median age was 59 (range 33-80). Different regimens were used over the time period. In the adjuvant setting 4-6 cycles of chemotherapy were planned and all patients received cisplatin in combination with 5-FU or capecitabine. Five (83%) completed planned treatment with no grade 3 or 4 toxicities. One patient stopped after 2 cycles due to deteriorating renal function. Patients remained disease free at up to 22 months follow-up. In the metastatic setting, 10 patients received cisplatin and capecitabine, 1 cisplatin and 5-FU and 1 carboplatin and capecitabine. Of these 12 patients, 2 (17%) had partial response as their best response, 4 (33%) had stable disease (SD) and 6 (50%) had progressive disease (PD). Three patients (25%) experienced pulmonary embolism, 1 of whom died. Two (17%) developed grade 3 neutropenia. One patient received carboplatin, methotrexate and bleomycin with PD after 3 cycles and developed grade 3 neutropenia, stomatitis, and diarrhea. One patient received 3 cycles of paclitaxel, ifosfamide, and cisplatin with SD and no grade 3 or 4 toxicities. Conclusions: Combination chemotherapy can be delivered with acceptable toxicity in the adjuvant setting. In the metastatic setting response rates were disappointing and treatments were associated with greater toxicity. New treatments are urgently required to improve outcomes in this difficult malignancy. [Table: see text]
Detection of new mutations in patients (pts) with imatinib-resistant chronic myeloid leukemia in chronic phase (CML-CP) treated with nilotinib.
Authors: A. Hochhaus, G. Saglio, H. Kantarjian, A. Haque, Y. Shou, R. C. Woodman, T. P. Hughes, J. P. Radich, G. Martinelli, D. Kim
Journal: Journal of Clinical Oncology (2010)

6516 Background: BCR-ABL transcript levels have been reported to be a predictor of response outcomes, including the detection of new mutations, in pts with imatinib resistance. In this posthoc analysis of the nilotinib phase II study we examined the association between newly detectable BCR-ABL mutations, baseline mutations (BL), resistance, and intolerance to imatinib, and initial molecular response to nilotinib. Methods: CML-CP pts (n = 321) with imatinib resistance (78%) or intolerance (22%) were analyzed. All pts had at least 24 mo follow-up. BCR-ABL transcript levels at 3 mo (≤1%, >1-≤10%, and >10% BCR-ABL [International Scale, IS]) were used to perform a landmark analysis. Results: Newly detectable mutations were observed in 56 of 290 (19%) pts with available BL mutation data, including 51 of 200 (26%) imatinib-resistant and 5 of 90 (6%) imatinib-intolerant pts. Pts with BL mutations and resistance to prior imatinib had a higher probability of detecting new mutations compared with pts without BL mutations (p < 0.0001) and imatinib-intolerant pts (p = 0.0002). BCR-ABL% (IS) at 3 mo did not predict for newly detectable mutations, including less sensitive mutations (Y253H, E255K/V, F359C/V, T315I), in pts with BL mutations or those resistant to imatinib therapy (Table), Molecular response to nilotinib at 3 mo did not predict for newly detectable mutations in pts without BL mutation and those intolerant of imatinib. Conclusions: In this analysis pts with BL mutations and imatinib resistance had a higher probability of detecting new mutations. Molecular response to nilotinib at 3 mo did not correlate with detection of new mutations within 24 mo of nilotinib therapy. Other correlative factors need to be evaluated. Occurrence of newly detectable mutations by 24 mo by BCR-ABL% (IS) at 3 mo on nilotinib BCR-ABL% (IS) at 3 mo p value ≤ 1 > 1 – ≤ 10 > 10 Occurrence of newly detectable mutations by 24 mo (%) Pts with BL mutations, n = 79 21 17 45 0.258a, 0.983b Resistant pts, n = 158 21 14 28 0.146a, 0.532b Occurrence of less sensitive mutations by 24 mo (%) Pts with BL mutations, n = 79 21 17 21 0.983a, 0.919b Resistant pts, n = 158 11 10 16 0.556a, 0.858b a Comparison of > 1 – ≤10 vs > 10. b Comparison of ≤ 1 vs > 1 – ≤ 10. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Bristol-Myers Squibb, Merck, Novartis, Wyeth Novartis Bristol-Myers Squibb, Celgene, Merck, Novartis Bristol-Myers Squibb, Genzyme, Novartis, Wyeth
Endothelin synthesis by rat inner medullary collecting duct cells.
Authors: D E Kohan, F T Fiedorek
Journal: Journal of the American Society of Nephrology (1991)

Endothelin has been shown to affect a broad range of renal functions, including rat inner medullary collecting duct Na/K ATPase activity, renin release, renal blood flow, and glomerular filtration rate. The source of endothelin in the kidney has been assumed to be endothelial cells. However, the inner medulla contains the highest concentration of immunoreactive endothelin in the kidney. Additionally, MDCK cells, a distal tubule-like cell line, synthesize endothelin. In order to determine if primary renal tubule cells release endothelin, supernatants collected from rat inner medullary collecting duct cells in culture were tested for endothelin-1 detected by specific radioimmunoassay. Inner medullary collecting duct cells produced endothelin-1 in a time-dependent manner, releasing 1,016.7 +/- 60.1 pg of endothelin-1 per mg/cell protein/24 h. Inner medullary collecting duct cells expressed a 2.2-kilobase mRNA on blot hybridization with rat prepro endothelin-1 cDNA. Vasopressin, thrombin, bradykinin, and epinephrine did not affect endothelin-1 release. These data demonstrate endothelin-1 production by inner medullary collecting duct cells and suggest a possible autocrine role for the peptide.
Modeling the cost-effectiveness of granulocyte colony-stimulating factor use in early-stage breast cancer.
Authors: J H Silber, M Fridman, A Shpilsky, O Even-Shoshan, D S Smink, J Jayaraman, K R Fox, M V Pauly
Journal: Journal of Clinical Oncology (1998)

PURPOSE To model the cost-effectiveness (CE) of granulocyte colony-stimulating factor (G-CSF) in early-stage breast cancer when its use is directed to those most in need of the medication. METHODS A conditional CE model was developed for the use of G-CSF based on a ranking of patient need as determined by patient blood counts during the first cycle of chemotherapy. In the base case, no G-CSF was used. In the alternative case, G-CSF was used in the following manner. If the risk of a neutropenic event (as defined by a predictive model based on nadir absolute neutrophil count [ANC] and hemoglobin decrease in cycle 1) was equal to or exceeded a predetermined critical value "T," then patients would receive G-CSF in cycles 2 through 6 of chemotherapy. If the risk of an event was less than T, patients would not use G-CSF unless an event occurred, at which time G-CSF would be administered with every subsequent cycle. RESULTS A decision rule (T) that would allow the most needy 50% of early-stage breast cancer patients to receive G-CSF after the first cycle of chemotherapy resulted in a CE ratio of $34,297 dollars per life-year saved (LYS). If only the most needy 10% of patients received G-CSF, then the associated CE ratio was $23,748/LYS; if 90% of patients could receive the medication, the CE ratio would be $76,487/LYS. These estimates were relatively insensitive to inpatient hospital cost estimates (inpatient costs for fever and neutropenia of $3,090 to $7,726 per admission produced dollar per LYS figures of $34,297 to $32,415, respectively). However, the model was sensitive to assumptions about the shape of the relationship between dose reduction and disease-free survival (DFS) at 3 years. CONCLUSION Providing G-CSF to the neediest 50% of early-stage breast cancer patients (as defined by first-cycle blood counts) starting after the first cycle of chemotherapy is associated with a CE ratio of $34,297/LYS, which is well in the range of CE ratios for treatment of other common medical conditions. Furthermore, conditional CE studies, based on predictive models that incorporate individual patient risk, allow one to define populations for which therapy is, or is not, cost-effective. Limitations of our present understanding of the shape of the chemotherapy dose-response curve, especially at low levels of dose reductions, affect these results. Further work is required to define the shape of the dose-response curve in early-stage breast cancer.
Abstract 17695: Transsulfuration Pathway is Essential for Fasting-Induced Cardioprotection Against Ischemic/Reperfusion Injury
Authors: Shintaro Nakano, Isao Ishii, Noriyuki Akahoshi, Kayoko Tamaki, Nobuyuki Komiyama, Shigeyuki Nishimura, Ken Shinmura
Journal: Circulation (2011)

&lt;Background&gt;: Hydrogen sulfide (H 2 S), a gaseous mediator that is endogenously produced by two transsulfuration enzymes, cystathionine β-synthase (CBS) and cystathionine gamma-lyase (CTH), is known to act against myocardial ischemia/reperfusion (I/R) injury. However, the roles of the transsulfuration that is also essential for cysteine/glutathione biosynthesis remain to be clarified. We investigated the role of transsulfuration pathway in myocardial I/R injury and fasting-induced cardioprotection using mice lacking CBS (CBS -/- ) or CTH (CTH -/- ). &lt;Methods and results&gt;: Ad libitum (AL) fed wild-type mice (Wt), CBS -/- and CTH -/- displayed no alteration in basal cardiac functions when evaluated by echocardiography. The Langendorff experiment, in which isolated perfused hearts were subjected to 25-min global ischemia followed by 60-min reperfusion, revealed a similar degree of I/R injury among AL-fed 3 strains. However, “2-day-fasting” induced much better LV functional recovery after I/R in Wt but not in CBS -/- and CTH -/- ( Figure ). Fasting failed to reduce total LDH release into the perfusate even in Wt. In Wt, fasting upregulated CBS mRNA expression in the heart. Heart glutathione contents were comparable indistinguishable between Wt and CTH -/- in either AL - fed or fasting condition. &lt;Conclusions&gt;: These results demonstrate that fasting attenuates myocardial stunning (reversible change) but not myocardial infarction (irreversible damage) and strongly suggest the involvement of H 2 S generated by CBS / CTH in fasting-induced cardioprotection. Further investigation is required to assess the role of homocysteinemia on fasting-induced cardioprotection since both CBS -/- and CTH -/- exhibit hyperhomocysteinemia.