tbuckley/cabot-search huggingface dataset:
Phase I Chemotherapy Study of Biochemical Modulation of Folinic Acid and Fluorouracil by Gemcitabine in Patients With Solid Tumor Malignancies
Authors: S. Madajewicz, P. Hentschel, P. Burns, R. Caruso, J. Fiore, M. Fried, H. Malhotra, S. Ostrow, S. Sugarman, M. Viola
Journal: Journal of Clinical Oncology (2000)

This phase I biochemical modulation study evaluated the maximum-tolerated dose (MTD), toxicity, and effectiveness of the combination of folinic acid (FA)/fluorouracil (5-FU) followed by escalated dose levels of gemcitabine (FFG) in patients with advanced solid tumors.Patients were refractory to primary treatment and/or without effective treatment options. Twenty-eight patients received an intravenous (IV) infusion of FA 100 mg/m(2) over 1 hour and a 5-FU 450 mg/m(2) IV bolus in the middle of the FA infusion. After the FA infusion, gemcitabine was administered at a steady rate of infusion of 10 mg/m(2)/min over initially 30 minutes and with increases of an additional 15 minutes at each given level. One cycle consisted of six weekly treatments followed by a 2-week rest.The MTD of gemcitabine was established at 900 mg/m(2) given over 90 minutes. Eight patients of 21 with metastatic colorectal cancer achieved responses (one complete response; seven partial responses), for a response rate of 38%. Responses were seen across the gemcitabine doses of 300 to 900 mg/m(2). One patient had prior treatment with FA/5-FU for advanced disease. Patients with colorectal carcinoma had a median survival of 18 months, and the patient with lung carcinoma has been alive for 24+ months.The combination chemotherapy of FFG was well tolerated and may benefit patients with advanced colorectal carcinoma. A phase II evaluation in this patient population is in progress.
Antitumor Activity of BRAF Inhibitor and IFNα Combination in BRAF-Mutant Melanoma
Authors: Francesco Sabbatino, Yangyang Wang, Giosuè Scognamiglio, Elvira Favoino, Steven A. Feldman, Vincenzo Villani, Keith T. Flaherty, Sjoerd Nota, Diana Giannarelli, Ester Simeone, Anna M. Anniciello, Giuseppe Palmieri, Stefano Pepe, Gerardo Botti, Paolo A. Ascierto, Cristina R. Ferrone, Soldano Ferrone
Journal: JNCI Journal of the National Cancer Institute (2016)

BRAF V600E -mediated MAPK pathway activation is associated in melanoma cells with IFNAR1 downregulation. IFNAR1 regulates melanoma cell sensitivity to IFNα, a cytokine used for the adjuvant treatment of melanoma. These findings and the limited therapeutic efficacy of BRAF-I prompted us to examine whether the efficacy of IFNα therapy of BRAF V600E melanoma can be increased by its combination with BRAF-I. BRAF/NRAS genotype, ERK activation, IFNAR1, and HLA class I expression were tested in 60 primary melanoma tumors from treatment-naive patients. The effect of BRAF-I on IFNAR1 expression was assessed in three melanoma cell lines and in four biopsies of BRAF V600E metastases. The antiproliferative, pro-apoptotic and immunomodulatory activity of BRAF-I and IFNα combination was tested in vitro and in vivo utilizing three melanoma cell lines, HLA class I-MA peptide complex-specific T-cells and immunodeficient mice (5 per group for survival and 10 per group for tumor growth inhibition). All statistical tests were two-sided. Differences were considered statistically significant when the P value was less than .05. The IFNAR1 level was statistically significantly ( P < .001) lower in BRAF V600E primary melanoma tumors than in BRAF wild-type tumors. IFNAR1 downregulation was reversed by BRAF-I treatment in the three melanoma cell lines ( P ≤ .02) and in three out of four metastases. The IFNAR1 level in the melanoma tumors analyzed was increased as early as 10 to 14 days following the beginning of the treatment. These changes were associated with: 1) an increased susceptibility in vitro of melanoma cells to the antiproliferative ( P ≤ .04), pro-apoptotic ( P ≤ .009) and immunomodulatory activity, including upregulation of HLA class I antigen APM component ( P ≤ .04) and MA expression as well as recognition by cognate T-cells ( P < .001), of BRAF-I and IFNα combination and 2) an increased survival ( P < .001) and inhibition of tumor growth of melanoma cells ( P < .001) in vivo by BRAF-I and IFNα combination. The described results provide a strong rationale for the clinical trials implemented in BRAF V600E melanoma patients with BRAF-I and IFNα combination.
Renal nerves do not mediate vasoconstrictor responses to acute nitric oxide synthesis inhibition in conscious rats.
Authors: C Baylis, R Braith, B R Santmyire, K Engels
Journal: Journal of the American Society of Nephrology (1997)

Nitric oxide is a physiologically important peripheral and renal vasodilator. The studies presented here were conducted in the conscious, chronically catheterized, unstressed rat to investigate whether NO interacts with renal efferent sympathetic nerve activity in control of blood pressure, renal vascular resistance, and sodium excretion. Renal clearance studies were conducted in normal rats with innervated kidneys and in a separate group of rats with chronic, bilateral renal denervation. Acute systemic inhibition of NO synthesis with n-nitro L-arginine methyl ester (L-NAME) leads to hypertension, renal vasoconstriction, and natriuresis in rats with intact renal nerves. Chronic renal denervation does not diminish the pressor and renal vasoconstrictor response to NO synthesis inhibition, although the natriuretic response is prevented. Stimulation of renal NO synthesis with the substrate L-arginine produces selective renal vasodilation and a marked osmotic diuresis in the innervated kidney. Renal denervation has little impact on the responses to L-arginine. These studies suggest that in the normal, conscious, chronically catheterized rat in which the sympathetic nervous system is operating at basal levels, renal nerve activity does not contribute to the pressor or renal vasoconstrictor response to NO inhibition or the renal vasodilator response to NO stimulation. These observations contrast with earlier observations made under conditions of stress-induced activation of renal nerve activity.
Integrate whole genomic study of KIT/PDGFRA wild-type (WT) GIST.
Authors: Margherita Nannini, Annalisa Astolfi, Milena Urbini, Valentina Indio, Donatella Santini, Michael C. Heinrich, Christopher L. Corless, Maristella Saponara, Anna Mandrioli, Cristian Lolli, Giorgio Ercolani, Guido Biasco, Maria A. Pantaleo
Journal: Journal of Clinical Oncology (2014)

10513 Background: KIT/PDGFRA wild-type (WT) GIST comprise different subgroups with distinct molecular hallmarks, including defects in the succinate dehydrogenase (SDH) complex and mutations of neurofibromatosis type 1 (NF1), BRAF, or KRAS genes. We investigate the genomic profile of WT GIST for each of known mutations, referred as quadruple WT GIST, by using a massively parallel sequencing and microarray approach, and compare it with the genomic profile of other GIST subtypes. Methods: whole-Transcriptome Paired-End RNA Sequencing was performed on 16 GIST, including 2 KIT/PDGFRA WT GIST patients without SDH-inactivating mutations (GIST_133 and GIST_127), 2 KIT/PDGFRA WT GIST patients harbouring SDHA-mutations (GIST_7 and GIST_10), and 12 KIT or PDGFRA mutated GIST patients (7 harboured exon 11 KIT mutations and 5 harboured exon 18 PDGFRA mutations). Whole-genome gene expression analysis was performed on 9 of the above 16 GIST and extended to include an additional 20 GIST: 1 KIT/PDGFRA WT/SDHA-mutated GIST and 19 KIT or PDGFRA mutated GIST, of which 13 harboured KIT mutations (12 in exon 11 and 2 in exon 9), and 5 harboured PDGFRA mutations (2 in exon 12, 1 in exon 14 and 2 in exon 18). Results: the principal component analysis showed that both GIST_133 and GIST_127 are characterized by a gene expression profile profoundly different from both GIST_7 and GIST_10. No private or cryptic mutations of KIT and PDGFRA, as well as no NF-1, BRAF, RAS mutations were found. The supervised gene expression analysis revealed that GIST_133 and GIST_127 were characterized by an overexpression of molecular markers (CALCRL and COL22A1) and of specific oncogenes including tyrosine and cyclin-dependent kinases (NTRK2 and CDK6) and ERG. Overexpression of NTRK2 (TrkB) and of ERG was confirmed also by quantitative PCR. No mutations were identified in NTRK2, and there were no ERG fusions. Conclusions: The integrated genomic picture of WT GIST, using massively parallel sequencing and gene expression analyses, showed that quadruple WT GIST have an expression signature that is distinct from SDH-mutant GIST as well as GIST harbouring mutations in KIT or PDGFRA, suggesting that they represent another unique group within the family of gastrointestintal stromal tumors.
HPV-targeted tumor-infiltrating lymphocytes for cervical cancer.
Authors: Christian S. Hinrichs, Sanja Stevanovic, Lindsey Draper, Robert Somerville, John Wunderlich, Nicholas P. Restifo, Richard Sherry, Phan Q Giao, Udai S. Kammula, James C. Yang, Steven A. Rosenberg
Journal: Journal of Clinical Oncology (2014)

LBA3008 Background: Adoptive T-cell therapy (ACT) is a promising cancer treatment modality with potentially broad application. It is not known if ACT can mediate regression of carcinomas, the most common solid tumors in humans. We studied carcinoma of the uterine cervix, a virally induced malignancy that constitutively expresses the HPV E6 and E7 oncoproteins, as a model cancer to test if ACT can mediate regression of an epithelial malignancy. Methods: We initiated a clinical trial to treat metastatic HPV+ cancers with tumor-infiltrating lymphocytes (TIL) selected for HPV E6- and E7-reactivity (HPV-TIL). Patients from the cervical cancer cohort are reported here. HPV-TIL infusion was preceded b y non-myeloablative conditioning and followed by high-dose bolus aldesleukin. HPV-reactivity was assessed by ELISPOT, IFN-gamma production, and CD137 expression assays. Results: Nine patients were treated on the study. They received a median of 81 x 10 9 T cells (range 33 to 159 x 10 9 ) as a single infusion. The infused cells possessed reactivity against high-risk HPV E6 and/or E7 in 6/8 patients. The two patients with no HPV reactivity did not respond to treatment. 3/6 patients with HPV reactivity demonstrated objective tumor responses by RECIST (1 PR and 2 CR). One patient had a 39% best response. Two patients with widespread metastases had complete tumor responses that are ongoing 18 and 11 months after treatment. One patient with a complete response had a chemotherapy-refractory HPV-16+ squamous cell carcinoma and the other a chemoradiation-refractory HPV-18+ adenocarcinoma. Both patients demonstrated prolonged repopulation with HPV-reactive T cells following treatment. Increased frequencies of HPV-specific T cells were detectable after 13 months in one patient and 6 months in the other. Two patients with HPV-reactive TIL that did not respond to treatment did not display repopulation with HPV-reactive T cells. Conclusions: HPV-TIL can mediate durable, complete regression of metastatic cervical cancer. Continued investigation of HPV-TIL for cervical cancer, and possibly other HPV+ malignancies, is warranted. Cellular therapy can mediate complete regression of an epithelial malignancy. Clinical trial information: NCT01585428.
Effect of vitamin E in nonalcoholic fatty liver disease with metabolic syndrome: A propensity score-matched cohort study
Authors: Gi Hyun Kim, Jung Wha Chung, Jong Ho Lee, Kyeong Sam Ok, Eun Sun Jang, Jaihwan Kim, Cheol Min Shin, Young Soo Park, Jin-Hyeok Hwang, Sook-Hyang Jeong, Nayoung Kim, Dong Ho Lee, Jin-Wook Kim
Journal: Clinical and Molecular Hepatology (2015)

Background/Aims Vitamin E improves the biochemical profiles and liver histology in nonalcoholic steatohepatitis, but the role of vitamin E is not clearly defined in the management of nonalcoholic fatty liver disease (NAFLD) which includes both simple steatosis and steatohepatitis. Co-morbid metabolic syndrome increases the probability of steatohepatitis in NAFLD. In this study, we aimed to determine the short-term effects of vitamin E and off-treatment durability of response in a propensity-score matched cohort of NAFLD patients with metabolic syndrome. Methods A retrospective cohort was constructed by retrieving 526 consecutive NAFLD patients from the electronic medical record data warehouse of a tertiary referral hospital in South Korea. Among them, 335 patients (63.7%) had metabolic syndrome and were eligible for vitamin E therapy. In order to assess the effect of vitamin E, propensity score matching was used by matching covariates between control patients (n=250) and patients who received vitamin E (n=85). Results The PS-matched vitamin E group (n=58) and control group (n=58) exhibited similar baseline metabolic profiles. After 6 months of vitamin E therapy, the mean ALT levels decreased significantly compared to PS-matched control (P<0.01). The changes in metabolic profiles (body weight, lipid and glucose levels) did not differ between control and vitamin E groups during the study period. Conclusions Short-term vitamin E treatment significantly reduces ALT levels in NAFLD patients with metabolic syndrome, but metabolic profiles are not affected by vitamin E. Keywords: Nonalcoholic fatty liver disease; Vitamin E; Metabolic syndrome; Propensity score
Phase I evaluation of AZD2171, a highly potent and selective inhibitor of VEGFR signaling, in combination with selected chemotherapy regimens in patients with advanced solid tumors
Authors: P. M. Lorusso, E. Heath, M. Valdivieso, M. Pilat, A. Wozniak, S. Gadgeel, A. Shields, T. Puchalski, R. Ewesuedo
Journal: Journal of Clinical Oncology (2006)

3034 Background: AZD2171 is an oral, potent, selective inhibitor of vascular endothelial growth factor receptor (VEGFR). Trials have demonstrated that inhibition of the VEGF pathway, in combination with certain chemotherapy, provides benefit to patients with a broad range of solid tumors. Methods: This Phase I trial was conducted in heavily pretreated solid tumor patients. In a single protocol, escalating doses of AZD2171 were evaluated (20, 30 and 45 mg) in combination with four separate chemotherapy regimens: mFOLFOX6 (oxaliplatin 85 mg/m 2 ; 5-FU 400 mg/m 2 ; leucovorin 400 mg/m 2 q2 weeks; Arm 1); irinotecan 300 mg/m 2 q3 week (Arm 2); docetaxel 75 mg/m 2 (Arm 3) and pemetrexed 500 mg/m 2 (Arm 4). The primary objective was to evaluate safety and tolerability of the combinations and secondary objective to evaluate pharmacokinetic (PK) interaction and clinical efficacy. Maximum tolerated dose (MTD) toxicity was defined through two cycles. Results: 46 patients have been enrolled: 28/35 evaluable for efficacy/toxicity. The MTD has been reached in two arms: Arm 2 - 20 mg AZD2171 and Arm 4 - 30 mg AZD2171. Arm 3 enrollment continues at 45 mg AZD2171. Two dose-limiting toxicities (DLTs) were observed in eight patients at 30 mg AZD2171 in Arm 1. Enrollment of an additional cohort of less heavily pre-treated patients is ongoing to determine the tolerability of 30 mg AZD2171 with FOLFOX. DLTs have included grade 3 fatigue in Arms 1, 2 &amp; 4; grade 3 diarrhea in Arm 1; grade 3 hand-foot syndrome &amp; grade 4 neutropenic fever in Arm 2; and grade 3 hypertension in Arm 4. AZD2171 did not appear to have a major effect on the PK profile of any chemotherapy regimen tested. Steady-state values are comparable with AZD2171 monotherapy. There have been 13 responses (minor response, n=5; partial response, n=6; complete response, n=2; stable disease ≥ 4 cycles, n=6) in heavily pretreated patients, some having demonstrated resistance to identical chemotherapies. Duration of response has been impressive (4-22+ cycles). Conclusions: AZD2171 combinations have been well tolerated with expected toxicities and encouraging responses. [Table: see text]
Subsequent Cancer in Patients With Chronic Lymphocytic Leukemia—A Possible Immunologic Mechanism
Authors: Mark H. Greene, M.D., Robert N. Hoover, M.D., Joseph F. Fraumeni, Jr., M.D., F.A.C.P.
Journal: JNCI Journal of the National Cancer Institute (1978)

Among 4,869 patients with chronic lymphocytic leukemia (CLL) from the series of the End Results Program of the National Cancer Institute, Bethesda, Maryland, second primary cancers developed in 234 patients, compared to 204.9 expected. The risk was significantly elevated for malignant melanoma, soft-tissue sarcomas, and lung cancer. The frequency of rectal cancer was also elevated, but not significantly. The excess risk for these specific sites persisted throughout the period of follow-up, suggesting a susceptibility state that complicated the leukemic process rather than suggesting methodologic, diagnostic, or therapeutic effects. Immunologic defects in CLL may be involved in the etiology of excess risk for these sites, because a similar array of nonlymphoid tumors was seen following therapeutic immunosuppression among renal transplant recipients.
The patient reported outcomes measurement information system—Cancer (PROMIS-Ca): Cancer-specific application of a generic fatigue measure
Authors: D. Cella, J. Lai, S. F. Garcia, B. B. Reeve, K. P. Weinfurt, J. George, A. Stone
Journal: Journal of Clinical Oncology (2008)

6537 Background: PROMIS-Ca is a cancer-specific extension of an NIH Roadmap effort to standardize measures of self-reported symptoms (pain; fatigue; anxiety; depression), physical function, and social function (http://www.nihpromis.org). PROMIS provides item banks that support brief-yet-precise computerized adaptive testing and multiple short form options. PROMIS-Ca extends PROMIS to oncology by ensuring the cancer-relevance and performance of its generic item banks. To illustrate, we customized the PROMIS Fatigue item bank to cancer and developed a link ("cross-walk") between the generic PROMIS-Fatigue and the cancer-specific PROMIS-Ca Fatigue banks. Methods: We first calibrated a 95-item PROMIS Fatigue bank on a sample of 803 people representative of the US general population, with norms set on a T distribution (M=50; SD=10). The 72-item PROMIS-Ca Fatigue bank contains 56 calibrated items from the generic PROMIS Fatigue bank. Its psychometric properties were evaluated on a second sample of 513 cancer patients (72% female, 81% White, mean age=56, mean time since diagnosis=4.1 years). Analyses included item scalability, dimensionality, and IRT model fit. Using general population calibration data, we examined differential item functioning (DIF) between PROMIS-Ca Fatigue and PROMIS Fatigue banks. A cross- walk between these banks was established by equating item parameters using non-DIF items via the Stocking-Lord method. Results: All pre-set analysis criteria were met by 54 items; however, 6 showed DIF between PROMIS and PROMIS-Ca. Stocking-Lord results (using 48 non-DIF items) showed that the cancer sample was slightly more homogeneous and reported more severe fatigue (T-score=53.3) compared to norms. Thus, a fatigue continuum was built by equating item parameters from PROMIS and PROMIS-Ca Fatigue banks. Conclusions: Comparable item parameters between PROMIS and PROMIS-Ca Fatigue banks provide cross-walk information that enables one to measure fatigue with questions relevant to oncology, and compare their fatigue results to the general US population. Further research in this area will enable comparisons across multiple diseases. No significant financial relationships to disclose.
A phase II study of neoadjuvant chemotherapy with TAC in LABC in Pakistani patients
Authors: A. G. Alidina, A. M. Lal, I. Vaziri, S. M. Khan, A. T. Valimohd
Journal: Journal of Clinical Oncology (2005)

2119 Background: Neoadjuvant chemotherapy (NC) is the standard treatment for locally advanced breast cancer (LABC). The objective of this study is to determine the response rates and the rates of breast conservation therapy with NC containing taxotere, Adriamycin and cyclophosphamide (TAC) in patients with LABC. Methods: Phase II prospective study to determine the efficacy and tolerability of TAC in NC with LABC admitted at AKUH Pakistan. Study was started in 1/03 and is still ongoing. Women were eligible if they were; histological confirmed invasive infiltrating carcinoma, T3, T4, N2, N3, M0, as per AJCC. PS 0–1, with adequate renal, liver and hematological functions. Patients were treated with regimens containing T (75 mg/m2), A (50 mg/m2) and C (500 mg/m2) 3 to 6 cycles. Followed by surgery and pathological assessment. The post-surgical treatment cycles of TAC regimen and radiotherapy is given on the basis of staging. Tamoxifen was given if they were found hormonal receptor positive. Results: We have thus far accrued 30 patients with mean age 48 years; 53% were premenopausal; all pts were PS 0–1, 67% had T3, 33% had T4, while 20% had inflammatory breast cancer. Forty-seven percent had clinically positive axillary lymphadenopathy; 33% had grade III and 66% had grades I or II. All 30 pts had ductal invasive histology. Hormonal receptors were positive in 67%. The overall response rate in all 30 pts was 94% with complete pathological response (pCR) in 27% and partial response (PR) in 67%. Disease progression was seen in one patient. Grades III-IV toxicities were: alopecia 100%, asthenia 12%; neutropenic fever 20%; mucositis 33%, and nausea & vomiting 6%. Three pts received growth factors. All patients were operated, 60% had a radical mastectomy and 40% had BCT. Data on the DFS and OS will be presented in future. Conclusions: Neoadjuvant chemotherapy containing Taxotere, Adriamycin and Cyclophosphamide achieved significant pathological complete response and breast conservation therapy in patients with locally advanced breast cancer. No significant financial relationships to disclose.
Chloride and membrane potential dependence of sodium ion-proline symport.
Authors: R W Chesney, I Zelikovic, A Budreau, D Randle
Journal: Journal of the American Society of Nephrology (1991)

Proline accumulation by renal proximal tubule brush border membrane vesicles is Na+ dependent, but little is known about the role of anions or membrane potential on proline uptake. Recent studies in a variety of transport systems, including rat renal brush border membrane vesicles, indicate that halide anions chloride (Cl-) and bromide (Br-) are essential for glycine, beta-alanine, gamma-aminobutyric acid, and taurine uptake, so the possibility that Na(+)-proline symport is Cl- dependent was explored. Also, the role of membrane potential on transport was assessed by determining the effect of external anions with different membrane permeabilities. The ratio of initial rate Cl- stimulated to thiocyanate (SCN)(-)-stimulated uptake values serves to measure Cl- dependence. The initial rate of proline uptake to equilibrium value was 3.11 +/- 0.5 (SE) in the presence of Cl- versus SCN-. The ratio for D-glucose, whose uptake is governed only by electrogenic status of the membrane, was 0.61 +/- 0.47 (P less than 0.001 versus proline). In another series of experiments, uptake values for various anions as a percent of equilibrium (I/E x 100) were: SCN-, 84.9 +/- 10.9; NO3, 49.9 +/- 11.0; SO4(2-), 27.3 +/- 4.4; F-, 68.5 +/- 18.3; Cl-, 164.1 +/- 44.6; Br-, 150.6 +/- 30.2; I-, 56.7 +/- 13.5. The stoichiometry of uptake by Hill plot analysis of proline uptake in the presence of varying concentrations of Na+ (0 to 100 mM) and Cl- (0 to 100 mM) was 2Na+:1Cl-:1 proline.(ABSTRACT TRUNCATED AT 250 WORDS)