tbuckley/cabot-search huggingface dataset:
Front line therapy with gemcitabine(G) administered immediately prior to pemetrexed (P) for patients (pts) with advanced or metastatic non-small cell lung cancer (NSCLC): Final report of a phase II clinical trial
Authors: H. J. West, R. J. Belt, H. A. Wakelee, M. J. Monberg, L. A. Frye, Z. Ye, C. K. Obasaju
Journal: Journal of Clinical Oncology (2006)

7116 Background: P and G have well demonstrated, single-agent activity in pts with locally advanced or metastatic NSCLC. This phase II study was designed to determine the activity of the combination of PG when G was administered immediately prior to P on day 8 of a 21-day cycle. Methods: Pts with Stage IIIB/IV NSCLC were enrolled. Treatment was G 1250 mg/m 2 on D 1 and 8, with P 500 mg/m 2 on D 8, immediately following G. Treatment was repeated every 21 days for 6 cycles. Pts received folic acid, vitamin B12 and steroid prophylaxis. Results: 54 pts (32 M/22 F) were enrolled in the study. Median age was 65.0 (range = 43 - 87) years, ECOG PS 0: 1 = 35.2%: 57.4%; Stage IIIB (9.3%), Stage IV (90.7%); Histology: adeno (61.1%) squamous (18.5%), and large cell (5.6%). Median dose intensity was 83.2% for P and 82.2% for G. Grade 3 toxicities were neutropenia (12.0%), thrombocytopenia (8.0%), dyspnea (16.0%), febrile neutropenia (10.0%), anemia (4.0%), fatigue (18.0%), nausea (10.0%), vomiting (8.0%), and rash (2.0%). Grade 4 toxicities were neutropenia (28%), thrombocytopenia (4%), dyspnea (6%), anemia (0%), fatigue (4%), nausea (0%), vomiting (0%), rash (0%). Five patients (10%) experienced Grade 1 alopecia. Median TTPD was 4.4 months and survival was 10.6 months. There were 0 CR, 16 PR (35.6%), 16 SD (35.6%), and 12 PD (26.7%), for an overall best response rate of 35.6%. Conclusions: In this study, PG had a disease control rate (ORR + SD) of 71.1% in the front-line treatment of NSCLC, suggesting that this is an active doublet. Administering P on D 8 rather than D 1 did not seem to negatively impact the therapeutic index. [Table: see text]
Abstract 18457: Acetylation of Asymmetric Dimethylarginine - a Novel Pathway of Clearance of Endogenous Methylarginines
Authors: Roman N Rodionov, Jens Martens-Lobenhoffer, Silke Brilloff, Natalia Jarzebska, Norbert Weiss, Stefanie M Bode-Böger
Journal: Circulation (2014)

Background: Epidemiological studies have shown that elevated levels of an endogenous inhibitor of nitric oxide synthases: asymmetric dimethylarginine (ADMA) are associated with cardiovascular diseases. ADMA can be hydrolysed by dimethylarginine dimethylaminohydrolase (DDAH) and metabolized through an alternative pathway by alanine:glyoxylate aminotransferase 2 (AGXT2). We and other have shown that ADMA can also be N-acetylated to form asymmetrical Nα-acetyldimethylarginine (Ac-ADMA) and excreted by the kidneys. The goal of the study was to characterize this novel pathway in physiological settings and in acute overload of ADMA in mice.

Results: We infused ADMA (250 μmol х kg-1 х d-1) in mice for three days using osmotic minipumps implanted intraperitoneally. Mice with saline infusion served as controls. Half of the mice underwent bilateral nephrectomy 24 hours before completion of the infusion, while the other half had a sham surgery. Infusion of ADMA led to increase in plasma ADMA levels both in the sham and nephrectomy groups (0.53 ± 0.07 μmol/l vs. 5.21 ± 3.25 μmol/l, and 0.63 ± 0.09 μmol/l vs. 5.32 ± 3.39 μmol/l). ADMA infusion resulted in significant increase in plasma levels of Ac-ADMA (1.35 ± 0.45 nmol/L vs. 4.77 ± 0.88 nmol/L) in the sham operated mice. Plasma Ac-ADMA levels were dramatically increased by nephrectomy (45.08 ± 9.25 nmol/L vs. 229.65 ± 91.30 nmol/L). Next we assayed tissue levels of Ac-ADMA in the unstressed healthy C57BL6 mice. The highest levels of Ac-ADMA were observed in the pancreas and in the small intestine as compared to the other organs (255.70 ±.63.34 pmol/g and 102.59 ± 9.22 pmol/g, respectively).

Conclusions: In this study we demonstrated that acute ADMA loading leads to elevation in Ac-ADMA, which is consistent with the hypothesis that Ac-ADMA is formed directly from ADMA in vivo. Dramatic increase in plasma Ac-ADMA levels after bilateral nephrectomy indicates that Ac-ADMA is predominantly eliminated via the kidneys. Increased Ac-ADMA levels in pancreas and intestine suggest that these organs might be the major sources of this metabolite. In a next step we want to identify the enzyme responsible for acetylation of ADMA and explore the clinical implications of this novel pathway of ADMA metabolism.
Phase II trial of high dose adjuvant chemo-radiotherapy (55 Gy in 5 wks) after resection of pancreatic adenocarcinoma
Authors: J. Balosso, P. Hammel, T. Andre, B. Roullet, C. Louvet, A. Botton, M. Flesch, D. Jaubert, B. Vie
Journal: Journal of Clinical Oncology (2004)

4111 Background: Radiotherapy (Rth) of 45 Gy or equivalent, with 5FU bolus infusion is the usual adjuvant treatment scheme for resected adenocarcinoma of the pancreas. This work intends to demonstrate the feasibility of a higher dose of Rth with continuous 5FU infusion. Methods: Inclusion criteria were any adenocarcinoma of the pancreas or the biliary tract completely resected with negative or positive microscopic margins, age < 75 years. Adjuvant treatment began when possible, without limited delay, at least 4 weeks after surgery. Pts received 55 Gy of chemo-Rth: 45 Gy in 25 fract (median vol. = 2000 ml), 5 d/wk combined with 5FU continuously infused 250 mg/m2/d during the 5 wks; a 10 Gy concomitant boost (median vol. = 1000 ml) was given in celiac axis and tumor bed in 8 fract during wks 4 & 5, six hours apart the large volume irradiation. All pts gave writing consent. Endpoints were tolerance, relapse free survival and overall survival. Results: From Oct 1998 to March 2001, 80 pts have been included, aged 34 to 75 years, sex ratio was balanced, 7 cases were tumors of biliary tract. Most of the tumors were pT2-T3 and pN0-N1, median diameter was 30 mm. All the pts completed the treatment, 72% without any delay in the Rth schedule, 83% without any delay in chemotherapy and with the total planned dose. Only five pts required hospitalization during a mean duration of 3 wks. Maximal toxicities (OMS scale) were grade 2–3 leucopenia in 6 pts, grade 2 anemia in 2 pts, grade 2–3 diarrhea in 12 pts, grade 2–3 nausea-vomiting in 19 pts, grade 2 mucositis in 5 pts, two delayed gastro-intestinal bleeding without any related death. 45% of the pts had stable body weight. Fifty one relapses happened until July 2003, forty one have been at least radiologically documented: 46% were metastatic diseases only, 17% were local relapse only and 37% were local and metastatic relapse. Median relapse free survival is 11 months and median overall survival is 21 months. The 3 ys overall survival is 36 %. Conclusions: This chemo-Rth with 10 Gy above the classical adjuvant scheme of 45 Gy is clearly safe and feasible. The very low toxicity and the persistence of many local relapses urge to study a more effective scheme. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Sanofi-Synthelabo, France Sanofi-Synthelabo, France
Effect of modulation of MET with the small molecule inhibitor PF-04217903 on osteosarcoma metastasis in vivo.
Authors: L. M. Niswander, L. M. Guenther, A. Mendoza, C. Khanna, J. G. Christensen, L. J. Helman, S. Kim
Journal: Journal of Clinical Oncology (2010)

9567 Background: MET is a tyrosine kinase receptor that is important for normal cell growth and migration. Activating alterations have also been found in several carcinomas. Previous studies in our laboratory have found high levels of MET in 85% of osteosarcoma samples. Both pharmacologic and genetic modulation of MET resulted in a decrease in multiple in vitro parameters of the metastatic phenotype in some osteosarcoma cell lines. PF-04217903 is a novel small molecule tyrosine kinase inhibitor that targets MET and is currently in clinical trials. The results of in vitro testing led us to test the effectiveness of PF-04217903 as an anti-metastatic agent in vivo. Methods: Two highly metastatic osteosarcoma cell lines were injected by tail vein into immunodeficient mice (MNNG-HOS which has constitutively activated MET and MG63.2 which has high levels of total and phospho-MET). Mice were treated with PF-04217903 (30 mg/kg) or vehicle control by gavage 5 days on and 2 days off and euthanized on day 30. Results: For MNNG-HOS, the average number of visible surface nodules in control mice was 4.8 (SD 2.3). Mice treated with PF- 04217903 had a ten-fold reduction in the number of metastatic nodules (average 0.4, SD 0.7, p=0.0001). This treated cohort included 6 out of 9 mice with no visible nodules. Mice injected with MG63.2 cells and treated with PF-04217903 had a 37% reduction in nodules (p=0.016) compared to control mice. Conclusions: Mice treated with the small molecule MET inhibitor PF-04217903 showed a decreased number of metastatic lung nodules in two osteosarcoma cell lines, one with MET activation and one with high-level MET expression. We are currently studying the mechanism by which MG63.2 cells have high levels of MET. These data suggest a potential role for MET inhibition in the treatment of patients with metastatic osteosarcoma. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer
Feasibility of prophylactic haloperidol to prevent delirium in cancer patients.
Authors: Michelle Weckmann, Christopher Nguyen
Journal: Journal of Clinical Oncology (2014)

232 Background: Approximately 2.5 million cancer patients are hospitalized annually and 25-40% of them will suffer from delirium; yet the majority of delirium is not diagnosed or treated. Delirium rates vary by age and reason for hospitalization and can be as high as 70% in hematopoietic stem cell transplant (HSCT) patients post-transplantation. Delirium can have devastating short and long-term complications and research is ongoing to see if it can be prevented. This study aims to: 1) demonstrate the feasibility of using prophylactic haloperidol in HSCT patients; 2) determine the side effects of oral haloperidol in HSCT patients; and 3) explore the hypothesis that prophylactic haloperidol will reduce the rate of delirium following HCST. Methods: All cognitively intact HSCT patients at a large academic institution were approached for study inclusion. Patients with delirium at time of screening or antipsychotic use in the previous 30 days were excluded. All participants received 5 mg oral haloperidol the night prior to transplant and nightly for 2 weeks post-transplant. Participants were seen daily to evaluate for side effects and every other day to evaluate for delirium using the Delirium Rating Scale (DRS-98). Results: Of the 19 patients who enrolled: 5 withdrew; 9 completed the full (2 week) study; and 5 completed a portion of the study. 22% (2 of 9) patients developed delirium (compared to a historical rate of 43% on our unit). Haloperidol was well tolerated with no evidence of major side effects (1 report of mild restlessness and 1 patient had transient evidence of sedation). Conclusions: Oral haloperidol was well tolerated in HSCT patients. While this study was not designed to detect differences in delirium incidence it provides promising evidence that prophylactic haloperidol may decrease delirium post-HSCT.
Endogenous DNA Damage and Repair Enzymes
Authors: Arne Klungland, Yun-Gui Yang
Journal: Genomics Proteomics & Bioinformatics (2015)

Tomas Lindahl completed his medical studies at Karolinska Institute in 1970. Yet, his work has always been dedicated to unraveling fundamental mechanisms of DNA decay and DNA repair. His research is characterized with groundbreaking discoveries on the instability of our genome, the identification of novel DNA repair activities, the characterization of DNA repair pathways, and the association to diseases, throughout his 40 years of scientific career.
Progressive loss of Rap1GAP in benign and invasive thyroid cancer
Authors: A. Nellore, K. Paziana, O. M. Tsgankova, Y. Wang, Y. Lv, K. Puttaswamy, A. B. Troxel, M. D. Feldman, J. L. Meinkoth, M. S. Brose
Journal: Journal of Clinical Oncology (2008)

6059 Background: With the early success of kinase inhibitors in the treatment of differentiated thyroid cancer, we seek to better characterize the status of key cell signaling pathways. RAP1 GTPase activating protein (RAP1GAP) regulates the oncogene RAP1, which, in turn, activates the oncogene BRAF. Previously, we identified decreased expression of RAP1GAP in human thyroid cancer cell lines, and a cessation of invasion and anchorage independent proliferation upon rescue of the RAP1GAP phenotype. This study extends these in vitro findings by examining RAP1GAP expression in primary thyroid tumors. Methods: Tissue blocks from patients with papillary thyroid cancer (PTC) were obtained. Immunohistochemistry was performed using a polyclonal RAP1GAP antibody (Santa Cruz) and staining intensity was scored by two independent pathologists on a 0–3 scale. The Wilcoxon signed-rank test was used to measure differences in staining between tumor and adjacent normal tissue on the same slide. The Wilcoxon rank sum test was used to evaluate variation in staining intensity between tissue groups. Tumor genomic DNA was analyzed for the BRAFV600E mutation. Results: 55 tissue blocks were examined (36 PTC, 16 adenomas, 3 hyperplastic nodules). Mean RAP1GAP staining of adjacent normal tissue, benign nodules, and invasive cancer were 2.4 ± 0.50, 2.18 ± 0.65, 1.15 ± 0.52, respectively. Decreases in RAP1GAP staining between benign and invasive nodules and adjacent normal tissue were statistically significant (p<0.001 and p<0.002). Decreases in RAP1GAP staining were more pronounced in invasive tumors than benign lesions (p < 0.0001). BRAFV600E mutation was found in 11 of 34 sequenced PTCs. No difference in RAP1GAP staining was found between PTC tissue with and without BRAFV600E. Conclusions: Our study shows a progressive decline in RAP1GAP levels from normal tissue to benign and then to invasive thyroid lesions, implicating loss of RAP1GAP in the evolution of thyroid carcinoma. Increased activity of RAP1 due to loss of RAP1GAP may lead to tumor invasion by disruption of cell-cell or cell-basement-membrane adhesion. Our study also suggests that loss of RAP1GAP is independent from the BRAFV600E mutation. Further investigation of the control of signaling through RAP1 may lead to new therapeutic targets for thyroid cancer. No significant financial relationships to disclose.
Effect of arterial hypertension, obesity and overnight desaturation on plasma uric acid concentration in obstructive sleep apnoea (OSA) patients
Authors: Robert Plywaczewski, Przemyslaw Bielen, Luiza Jonczak, Monika Targowska, Anna Czyzak-Gradkowska, Dorota Gorecka, Pawel Sliwinski
Journal: European Respiratory Journal (2012)

OSA is often associated with obesity and metabolic syndrome. The aim of this study was to assess prevalence of hyperuricaemia in OSA patients and relations between elevated plasma uric acid (UA) and OSA severity, obesity and cardiovascular diseases. We studied 1144 OSA pts: AHI – 39.7±21.7, BMI – 34.2±6.4 kg/m 2 , mean SaO 2  – 90.8±5.7%, T90 - 26.6±28.9%, Epworth score - 11.3±5.8 points. Hyperuricaemia [males: UA > 7 mg/dl (2005-2007) and > 8.5 mg/dl (since 2008), females: UA > 5.7 mg/dl (2005-2007) and > 6.2 mg/dl (since 2008) was found in 354 pts (30.9%) (different laboratory methods)]. Comparison of subjects with hyperuricaemia and normouricaemia is shown in table.  Logistic regression analysis revealed that arterial hypertension, obesity (BMI > 30 vs ≤ 30 kg/m 2 ) and T90 > 30% were independent predictors of hyperuricaemia (OR-1.76; 95%CI – 1.23-2.51; p=0.002, OR-2.47; 95%CI – 1.67-3.65; p  30% and arterial hypertension.
Alliance A091102: Phase II study of MLN8237 (alisertib) in advanced/metastatic sarcoma.
Authors: Mark Andrew Dickson, Michelle R. Mahoney, Benjamin T. Marchello, Mercedes M. Condy, William D. Tap, Gary K. Schwartz
Journal: Journal of Clinical Oncology (2013)

TPS10594 Background: Approximately 13,000 cases of soft tissue and bone are diagnosed annually in the US. Despite primary surgery many patients develop recurrent disease. Response rates to chemotherapy are low and new agents are needed. Gene array studies have shown Aurora Kinase A (AURKA) commonly overexpressed. Inhibition of AURKA by shRNA or by a specific AURKA inhibitor blocks in vitro proliferation of multiple sarcoma subtypes. MLN8237 (alisertib) is a novel and oral, ATP-competitive, selective small-molecule inhibitor of AURKA. We hypothesize that alisertib will be an effective treatment for advanced/metastatic sarcoma. Methods: This CTEP-sponsored, investigator-initiated, multi-center phase II study uses alisertib in patients with advanced/metastatic sarcoma and is conducted through the Alliance for Clinical Trials in Oncology (Alliance A091102). Patients must have adequate performance status, organ function, and measurable disease (RECIST v1.1). Patients are enrolled in one of five cohorts, depending on histology: 1) liposarcoma, 2) leiomyosarcoma, 3) undifferentiated sarcoma, 4) malignant peripheral nerve sheath tumor, or 5) other. Patients are treated with alisertib 50mg PO BID d1-d7 every 21 days until either progressive disease or unacceptable toxicity. The primary endpoint is objective overall response rate (ORR). Secondary endpoints include progression-free survival (PFS) and overall survival (OS). Translational objectives include correlation of ORR, PFS and OS with baseline and post-treatment markers of AURKA inhibition in tumor biopsies and baseline and post-treatment [F-18] FLT-PET scans. A Simon two-stage design is used for each of the 5 cohorts and one confirmed response in the first 9 patients expands enrollment in that cohort to 24. Enrollment began in December 2012. As of January 2013, 14 pts have been enrolled. Funded by the Alliance for Clinical Trials in Oncology. Clinical trial information: NCT01653028.
Ultrasound (US)-guided fine-needle aspiration cytology (FNAC) for the prediction of sentinel node (SN) metastases and its effect on the nomogram for melanoma patients.
Authors: C. A. Voit, A. C. J. Van Akkooi, P. Siegel, W. Sterry, A. Schoengen, G. Schaefer-Hesterberg, A. M. Eggermont
Journal: Journal of Clinical Oncology (2011)

8550 Background: Ultrasound (US) guided fine needle aspiration cytology (FNAC) prior to the surgical sentinel node (SN) procedure has recently been proven to have an increased accuracy due to the introduction of new US morphology criteria. This study reports on a larger dataset, increased follow-up and analyzed US-FNAC versus the validated Memorial Sloan Kettering Cancer Center (MSKCC) Nomogram (Wong et al., 2005). Methods: Prior to SN-biopsy patients (pts) underwent lymphoscintigraphy followed by US-exam. US images were prospectively scored for predetermined morphologic criteria. FNAC was performed in all suspicious US. All pts underwent a SN biopsy. Sensitivity (sens), specificity (spec) and negative/positive predictive value (NPV and PPV) and Hazard Ratios (HR) were calculated for prognostic factors and correlated with survival. Multivariate analyses were performed and compared to the nomogram. Results: Since 2001 over 1000 consecutive pts have been included into a prospective database. Median Breslow thickness was 1.6 mm, 56% were male, mean follow-up 33 months for all pts, 56 months for the first 400 pts., ulceration present in 24%. SN positivity rate was 20%(n=202). Sens and spec. of US-FNAC was 106/196(54%) and 768/779(99%). PPV and NPV were 91% and 90%. Peripheral perfusion showed a sens of 69% and PPV of 56%. Balloon shaped lymph nodes had a sens of 25% and PPV of 94%. 5-ys overall survival (OS) was 55% for US-FNAC positive vs. 92% for US-FNAC neg compared to 65% vs. 93% for SN histological pos and neg pts. There was no increase in late relapses for the first 400 pts (194 at risk at 5 yrs). The MSKCC nomogram accurately predicted SN involvement in this external dataset. Multivariate analysis for OS demonstrated that both the MSKCC Nomogram (HR 3.2, (1.5 – 6.8) P=0.002) and US-FNAC (HR 4.6 (2.6 – 8.2) P<0.001) were independent prognostic factors for OS. Conclusions: This large dataset has validated previous results on the accuracy of US-FNAC performed with new morphology criteria and the MSKCC- nomogram. US-FNAC and MSKCC are independent prognostic factors for OS. US-FNAC might be able to improve the accuracy of the nomogram, a follow-up study will address this.
Hepatic metastasectomy following FOLFOX therapy in patients with colorectal metastases
Authors: C. A. Arciero, R. R. Salem, J. Lacy, E. R. Sigurdson, J. P. Hoffman, J. C. Watson, N. Joseph, H. S. Cooper, N. J. Meropol, B. Burtness
Journal: Journal of Clinical Oncology (2006)

13523 Background: Advances in systemic therapy for metastatic colon cancer may render patients (pts) candidates for hepatic metastasectomy (HM) with curative intent. We retrospectively reviewed our experience with HM following oxaliplatin chemotherapy. Methods: Pts were identified from the records of 5 surgeons who performed HM at two institutions. Pts were included if FOLFOX (bolus 5-FU/leucovorin d1 or d 1 + 2, followed by 46 hour 5-FU infusion; oxaliplatin 85–130mg/m2 d 1 q 14 d) chemotherapy had been given for &gt; 1 cycle prior to HM and complete resection of hepatic metastases was achieved. Data on radiographic (RECIST) and pathologic response and outcome were collected. Pathologic complete response (pCR) was defined as no residual cancer. Near pCR was defined as residual mucin in the liver, without residual cancer cells, or necrosis with atypical glands. Results: Thirty-six pts were identified. Males 21/36, median age 55 (range 37–77), rectum/rectosigmoid primary 5 (13.9%), adenocarcinoma 100%, synchronous metastases or metastases within 6 months (m) of primary diagnosis 24/32 (75%), median cycles of FOLFOX = 7 (range 2 to &gt;30), bevacizumab (B) 9 (25%). Mean number of hepatic lesions pre-chemotherapy 1.9 (range 1–7), tumor size 1 to &gt;10cm. Radiographic responses to pre-operative FOLFOX included partial response (PR) 9/30 (30%), CR 2/30 (6.7%), progressive disease 3/30 (10%), stable disease 16/30 (53.5%). Operations included right (R) hepatectomy 12, extended (ext) R hepatectomy 3, partial R hepatectomy 2, left (L) hepatectomy 3, partial L hepatectomy 1, ext L hepatectomy 1, trisegmentectomy 2, caudate lobectomy 1, multiple wedge resections ± radiofrequency ablation 7. pCR 2 (5.6%); near pCR 3 (8.3%). At a median follow up of 12.9 m from HM, 9/36 (25%) recurred; liver only (3), portal lymph nodes (1), other extrahepatic sites (5). One pt died at 18.3 m. Conclusions: HM after FOLFOX chemotherapy, with or without B, results in a high progression-free and overall survival at 12.9 m. This retrospectively identified population included pts with conventionally adverse prognostic features including rectal cancers, synchronous metastases, large lesions and/or high lesion number. Prospective studies of the utility of pre-HM chemotherapy are warranted. [Table: see text]
QRS duration predicts sudden cardiac death in hypertensive patients: The losartan intervention for endpoint reduction in hypertension (LIFE) study
Authors: Daniel P. Morin, Lasse Olkarinen, Matti Viltasalo, Lauh Tolvonen, Markku S. Nieminen, Sverre E. Keldsen, Bjorn Dahloef, Richard B. Devereux
Journal: Journal of the American College of Cardiology (2007)