tbuckley/cabot-search huggingface dataset:
Syncope and Motor Vehicle Crash Risk
Authors: Anna-Karin Numé, Gunnar Gislason, Christine B. Christiansen, Deewa Zahir, Mark A. Hlatky, Christian Torp-Pedersen, Martin H. Ruwald
Journal: JAMA Internal Medicine (2016)

<h3>Importance</h3> Syncope may have serious consequences for traffic safety. Current clinical guideline recommendations on driving following syncope are primarily based on expert consensus. <h3>Objective</h3> To identify whether there is excess risk of motor vehicle crashes among patients with syncope compared with the general population. <h3>Design, Setting, and Participants</h3> Danish nationwide cohort study from January 1, 2008, to December 31, 2012. Through individual-level linkage of nationwide administrative registers, all Danish residents 18 years or older were identified. Of 4 265 301 eligible Danish residents, we identified 41 039 individuals with a first-time diagnosis of syncope from emergency department or hospital. <h3>Main Outcomes and Measures</h3> Rate of motor vehicle crashes (including nonfatal and fatal crashes), based on multivariate Poisson regression models, using the total Danish population as reference. <h3>Results</h3> The 41 039 patients with syncope had a median age of 66 years (interquartile range [IQR], 47-78 years); 51.0% were women; and 34.8% had cardiovascular disease. Through a median follow-up of 2.0 years (IQR, 0.8-3.3 years), 1791 patients with syncope (4.4%) had a motor vehicle crash, 78.1% of which led to injury (n = 1398) and 0.3% to death (n = 6). The crude incidence rate of motor vehicle crashes was almost doubled among patients with syncope (20.6 per 1000 person-years; 95% CI, 19.7-21.6) compared with the general population (12.1; 95% CI, 12.0-12.1), with a rate ratio (RR) of 1.83 (95% CI, 1.74-1.91) after adjustment for age, sex, socioeconomic position, and relevant comorbidities and pharmacotherapy. Men had a relatively higher rate of motor vehicle crashes (RR, 1.91; 95% CI, 1.79-2.03) than women (RR, 1.74; 95% CI, 1.63-1.87). The excess risk of motor vehicle crashes persisted throughout the follow-up period. The 5-year crash risk following syncope was 8.2% (95% CI, 7.5%-8.8%) among the population aged 18 to 69 years compared with 5.1% (95% CI, 4.7%-5.4%) in the general population. <h3>Conclusions and Relevance</h3> Prior hospitalization for syncope was associated with increased risk of motor vehicle crashes throughout the follow-up period. This study suggests that syncope should be considered as one of several factors in a broad assessment of fitness to drive.
The role of metastatectomy in metastatic renal cell cancer following the treatment with a molecular targeted agent.
Authors: R. Levey, A. Flaherty, R. J. Amato
Journal: Journal of Clinical Oncology (2010)

e15053 Background: The recent treatment shift for metastatic clear cell renal cell cancer is the use of molecular targeted agents. A complete response is rare, more common is prolonged stability or partial response. For those patients with metastatic sites that are surgically accessible who have demonstrated stability or regression, are evaluated for the role of surgery. The purpose is to define the role of metastatectomy following the treatment with a molecular targeted agent. We will report on the safety, whether it improves the progression-free survival and overall survival, in patients who have undergone a metastatectomy following a molecular targeted agent. Methods: Nineteen patients with metastatic clear cell renal cell cancer were treated with a molecular targeted agent [RAD001 mammalian target of rapamycin (mTOR) inhibitor) or sorafenib (tyrosine kinase inhibitor)] and were evaluated following prolonged stability or a sustained partial response for surgical resection. Evaluation consisted of the following; whether surgical complete resection was achieved, progression free survival post surgery, and overall survival. Those patients with viable tumor were offered 6 months of adjuvant therapy using the same molecular targeted agent prior to metastatectomy. Results: Fourteen of nineteen patients (74%) achieved surgical complete resection. All patients achieved negative surgical margins. Three of nineteen patients (16%) had post operative complications associated with bleeding. There was no associated post operative mortality. 37% of the patients have not had recurrent disease ranging from 6 to 19 months. Those that recurred, the majority were within 6 months. Seventeen of the nineteen (89%) remain alive to date. Conclusions: Following the use of molecular targeted agents, complete surgical resection can be achieved and is safe. Patients have demonstrated a delay in the onset of development of new metastatic disease. This data provides the foundation for a prospective study to evaluate the role of metastatectomy in metastatic renal cell cancer patients treated with a molecular targeted agent in order to establish criteria for surgical resection. No significant financial relationships to disclose.
Presurgical bevacizumab and sunitinib induced changes in primary clear cell renal tumor tissue.
Authors: A. Bex, E. Jonasch, F. Vyth-Dreese, C. de Hoog, T. Dellemijn, A. W. Griffioen
Journal: Journal of Clinical Oncology (2010)

4607 Background: Intratumoral angiogenesis may form a barrier to protect the tumor against the immune system. Angiogenic factors suppress endothelial cell (EC) adhesion molecule expression, preventing an effective leukocyte infiltrate in the tumor. We demonstrated previously that angiogenesis inhibitors may counteract these effects both in vitro and in preclinical in vivo models. These observations have not been investigated in primary tumour tissue of metastatic renal cancer (mRCC) patients exposed to targeted agents. Methods: Primary tumor tissue from two institutional review board approved prospective single arm trials of presurgical sunitinib (n=15) and bevacizumab (n=18) were analysed and compared to untreated tumor tissue (n=15). After written informed consent patients received 4 cycles of bevacizumab and 2 cycles of sunitinib. Sunitinib was withheld 1-14 days and bevacizumab 4 weeks before CN. Immunohistochemistry by light or confocal laser scanning microscopy (CLSM) was used to analyse microvessel density (MVD)(CD31+34), endothelial proliferation (Ki67), leukocyte subsets (CD8+, Foxp3+ and CD8+/Foxp3+ ratio) and tumor- and vascular apoptosis (parp p85+). Parameters were counted in 10 high power fields (HP), numbers are mean per field ± standard deviation (SD) including p-values. Results: Decreased MVD and increased tumor and vascular apoptosis was observed after antiangiogenic therapy, particularly after bevacizumab (p<0.05). Numbers of CD4+ CD25+ Foxp3+ cells/HP (mean(SD)) in tumor tissue were 1.3 (2.6) for controls versus 1.5 (1.3) for sunitinib and 5.8 (7.8) (p<0.05) for bevacizumab. CD8+/Foxp3+ ratio was 43.0 (70.8) for controls versus 101.6 (162.1) (p 0.3196) for sunitinib and 10.3 (17.9) (p 0.07) for bevacizumab. Pericyte coverage was significantly increased in treated tumors. EC proliferation was low in bevacizumab treated tumors (p <0.05) but varied with the time of sunitinib withdrawal. Conclusions: Inhibition of angiogenesis alters immune and immunoregulatory cells in primary mRCC tissue. Ongoing analyses will determine the prognostic implications of these findings. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer Pfizer
Phase I/II study of capecitabine and PHY906 in hepatocellular carcinoma
Authors: Y. Yen, S. So, M. Rose, M. W. Saif, E. Chu, L. Chen, S. Liu, A. Foo, R. Tilton, Y. Cheng
Journal: Journal of Clinical Oncology (2008)

4610 PHY906, a Chinese medicine formula, has been used for 1,700 years for the treatment of diarrhea, vomiting, nausea, stomach cramps, and fever. PHY906 was found to potentiate the antitumor efficacy of capecitabine in hepatocellular carcinoma (HCC) xenografts. A Phase I/II, multicenter, open-label, dose-escalation, safety and efficacy study of capecitabine / PHY906 was initiated in patients with advanced HCC. Patients were required to have measurable, recurrent, metastatic, or unresectable HCC, Karnofsky status of 70% or above, and adequate organ and hematologic parameters. Study objectives were: Phase I - to determine the safety and tolerability of the two-drug combination; Phase II - to measure antitumor response and to assess patients’ quality of life (QoL). Patients were considered evaluable after two cycles of treatment. The initial dose regimen (capecitabine 1,000 mg/m2 BID; PHY906 1,000 mg BID) was found to have unfavorable toxicities. Thus, capecitabine was reduced to 750 mg/m2 BID and PHY906 to 600 mg BID. Subsequently, a new cohort of 750 mg/m2 BID capecitabine plus 800 mg BID PHY906 was added. Both latter regimens were well tolerated (N=4 for PHY906 600 mg BID, N=26 for PHY906 800 mg BID). The capecitabine 750 mg/m2 BID and PHY906 800 mg BID regimen was used for the Phase II study. Thirty-four patients participated in the Phase II study; 31 at US sites and 3 at Taiwan sites. Among the 27 evaluable patients at US sites, four (14.8%) achieved minor response (MR), 14(51.9%) had stable disease (SD), and 9(33.3%) exhibited progressive disease after two cycles of treatment. Median survival time was higher for the 20 Child-Pugh A patients (10.9 months vs. 9.2 months overall). Asian patients (N=12) had a higher overall 12-month survival rate (68%) than non-Asians (26%, N=15)[p=0.02]. Patients’ QoL did not appear to deteriorate significantly during treatment. Based on the results obtained with Child-Pugh A patients, additional Phase II studies in such patients in which the effectiveness of the capecitabine / PHY906 combination is compared to that of sorefinib (recently approved for the treatment of HCC) appear warranted. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration PhytoCeutica Inc. PhytoCeutica Inc. PhytoCeutica Inc.
Oncogenotoxicology: A new approach to individual therapy and to the follow-up of patients
Authors: M. Gamulin, M. Grgic, S. Bonassi, J. N. Lucas, A. Fucic
Journal: Journal of Clinical Oncology (2007)

21131 Background: The growing awareness of differences in inter-individual response to radiochemical exposure calls for a new approach in the therapy and follow-up of cancer patients. Results obtained by genotoxicological methods (Bonassi, 2006) showed that surrogate tissue could be used to predict cancer risk. Chromosome aberration (CA) and micronucleus (MN) assay enables:determination of radio- and chemosensitivity level in a patient, adjustment of therapy and detection of chromosomal rearrangements possibly related to the development of secondary cancer using fluorescent in situ hybridization (FISH) Methods: Ten women with breast cancer (BP) and 10 men with oropharinx cancer (OP) were analyzed before, during and after radiotherapy by CA and MN assay. Confounding parameters (age, diagnostics, smoking, drinking) were monitored and matched. Results were compared with 20 matched control subjects. The BP group received an irradiation dose of 60 Gy and the OP group of 62 Gy Results: Before therapy, the OP patients had a significantly higher MN frequency than BP and controls (23.2±4.9‰ versus 6.3±1.6 ‰ and 6.7±3.7‰). On measurements taken 6 and 12 months after the therapy, OP patients continued to have a significantly higher MN frequency than BP patients (60.2±11.4‰ vs. 8.4±2.4‰ and 30.7±4.7‰ vs.5.11±2.5‰, respectively). CA frequency was similar in both groups before therapy (2.5±1.1% in BC and 3.4±1.3% in OP; controls 1.2%). Twelve months after the therapy, the elimination of CA in OP patients was significantly slower than in BC patients (17.7±10.9% vs. 8±5.4%, respectively). As OP patients consumed more than 120 g/day of pure alcohol, it is possible that alcohol could have caused additional genome damage (Maffei, 2002). The highest inter-individual difference in genome damage was observed in BP patients Conclusions: The results show that the CA and MN assay are sensitive methods which can be used to introduce a new concept, oncogenotoxicology, whose goal is to improve the therapy results by evaluating inter-individual differences in response to radiochemical treatment and to improve the evaluation of risk of secondary cancer development. FISH in suspension (Wu, 2005) will allow automation of CA detection, and facilitate a more accurate prospective study of the same population. No significant financial relationships to disclose.
Phase I trial of the oral histone deacetylase inhibitor MS-275 administered with food
Authors: E. A. Donovan, A. Sparreboom, W. Figg, J. Trepel, K. Maynard, J. Zwiebel, G. Melillo, M. Gutierrez, J. Doroshow, S. Kummar
Journal: Journal of Clinical Oncology (2006)

13036 Background: The histone deacetylase (HDAC) inhibitor MS-275, a synthetic benzamide derivative, has demonstrated antitumor activity in vitro &amp; in vivo. After determining maximum tolerable dose (MTD = 2 mg/m 2 ) &amp; dose limiting toxicity (DLT) for MS-275 given to fasting patients (pts) weekly ×4 q6 weeks, we explored toxicity profile, MTD, &amp; pharmacokinetics (PK) of MS-275 when given po on the same schedule with food. Methods: MS-275 at 2, 4, or 6 mg/m 2 was administered to pts with advanced malignancy &amp; PS ≤2, LFTs ≤2.5 × normal, adequate hematopoietic &amp; renal function, &amp; normal resting MUGA. PK samples were analyzed by LC-MS. Data for pts in the fed state were compared to data obtained in previous cohorts of pts treated in the fasting state. Protein acetylation assessed by a novel flow cytometric assay &amp; HDAC enzymatic activity were measured in peripheral blood mononuclear cells (PBMC). Results: 16 pts received a median of 2 cycles (1–5) of MS-275 2–6 mg/m 2 with food. No DLT occurred on 2 or 6 mg/m 2 (n = 3 each), while 1 pt on 4 mg/m 2 (n = 10) had a DLT: grade 3 hypophosphatemia. For 2–6 mg/m 2 other grade 3 toxicities were neutropenia &amp; lymphopenia. Grade 1–2 toxicities in &gt;1 pt were leucopenia, anemia, thrombocytopenia, fatigue, nausea, vomiting, headache, hypoalbuminemia, hypophosphatemia, hyponatremia, &amp; hypocalcemia. MTD has not been reached; current dose level is 8 mg/m 2 . Comparing PK for fasting &amp; fed pts on 2–4 mg/m 2 , there was no difference in T max (0.5h); average C max &amp; AUC were 35% &amp; 25% lower, respectively, in fed pts; this difference is not statistically significant. Interindividual variability in exposure to MS-275 increased from 52% in fasting pts to 100% in fed pts. PBMC protein acetylation &amp; HDAC inhibition were seen at all dose levels (2–6 mg/m 2 ) in fed pts. Of 9 pts evaluable for response (2–4 mg/m 2 ), 2 of 6 pts on 4 mg/m 2 had stable disease. Conclusions: MTD has not yet been established for MS-275 given with food on this schedule but is ≥4 mg/m 2 weekly x4 q6 weeks. Interindividual variability in exposure increases with food. Whether intestinal absorption is decreased when MS-275 is given with food requires further evaluation with additional patients. Drug-related protein hyperacetylation &amp; HDAC inhibition were observed. [Table: see text]
The influence of partial hepatectomy (PH) on pharmacokinetics of docetaxel (D) in sprague-dawley rats (SDR) with experimental mammary neoplasm models (EMNM)
Authors: H. B. Demirkan, O. Yilmaz, C. Çoker, M. Gümüstekin, J. Batu, M. Bülbül, T. Canda, M. Alakavuklar
Journal: Journal of Clinical Oncology (2006)

12021 Background: Docetaxel (Taxotere-Aventis) is used in the treatment of breast, lung, head and neck, prostate and ovarian cancers. Recently, PH for isolated hepatic metastases of breast cancer has been reported in Japan and France. PH is an experimental model of hepatic insufficiency. Therefore we aimed to study the influence of PH on pharmacokinetics of D in SDR with EMNM. Methods: After the approval of Local Ethical Commitee on Laboratory Animal Researches, 40 female 50-day-old SDR were injected with 50 mg/kg body weight N-nitroso-N-methylurea (NMU) in 09% NaCL solution intraperitoneally. 5 female 50-day-old SDR were only injected with 09% NaCL solution intraperitoneally. After 6-months follow-up period for the formation of EMNM, 8 rats in the Group D+H were hepatectomized partially. Baseline venous blood samples were taken. 24 hours after PH, 6 rats were alive. There were 8 rats in the Group D (without hepatectomy). Before chemotherapy and 1 hour after intravenous infusion of 5 mg/kg body weight D, blood samples were taken for biochemical analyses from both groups. 5., 15., 30. minutes and 1., 2., 4., 5. hours after D infusion, arterial blood samples were taken for pharmacokinetic analyses. Biochemical and Pharmacokinetic tests (BPT) were done by auto-analyzer Hitachi Modular Analytic and HPLC (High Performance Liquid Chromatography) respectively. Area under the concentration-time curve [AUC (0–60)] was determined for each group. Statistical analyses were done by SPSS 11.0 for Windows at the 5% significance level. Results: PH affected liver functions and serum albumin levels negatively (p = 0.028). Although D infusion didn’t affect serum ALT and bilirubine levels, low serum albumin was detected 1 hour after chemotherapy in both groups (p= 0.028 and p= 0.030). AUC( 0–60 ) of plasma D in hepatectomized rats were greater than the other group (p = 0.015). Conclusion: During the treatment of cancer patients in posthepatectomy period with taxanes (D), dose adjustment must be done. In both groups, statistically significant low serum albumin after D infusion may be as a result of decreased intertitial fluid pressure, albumin extravasation and edema formation caused by taxanes. Physiological and preventive studies are needed. No significant financial relationships to disclose.
Setting Priorities for Occupational Cancer Research and Control: Synthesis of the Results of Occupational Disease Surveillance Studies&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Robert Dubrow, M.D., Ph.D., David H. Wegman, M.D.
 5
Journal: JNCI Journal of the National Cancer Institute (1983)

The objectives of this paper were 1) to identify occupations with potentially high cancer risk by combining the results of 12 major occupational disease surveillance studies, 2) to develop a quantitative methodology for accomplishing the first objective, and 3) to make recommendations concerning priorities for occupational cancer research and control on the basis of the results of this analysis in conjunction with other available epidemiologic, industrial hygiene, toxicologic, and employment data. It was suggested that the first priority be the investigation and control of occupational exposure to asbestos, particularly in the automobile repair and construction industries. Of the 34 occupational groups found to be at high risk for lung cancer in this analysis, 18 have potential asbestos exposure. The second priority was suggested to be research into the consistent lung-cancer excess found among motor vehicle drivers. This excess may be due to occupational exposure to diesel and gasoline engine exhaust, to cigarette smoking, or to both of these factors.
Effect of chemotherapy on topoisomerase (TOP) expression and activity in colon carcinoma cells
Authors: G. Cartei, G. Palù, M. Palumbo, A. Trestin, S. Richter, L. Barzon, F. Salmaso, M. Mattiazzi, D. Pastorelli
Journal: Journal of Clinical Oncology (2004)

3749 Background: Aim of this study was the evaluation of TOP expression and activity in human cancer cell lines after administration of anti-tumour drugs. Methods: A lymphocytic cell line (Jurkat) and two colon Adenocarcinoma cells lines (LOVO and HT-29) were treated with 1–10 mcM 5-fluorouracile, oxaliplatin, methotrexate and gemcitabine, either as single agents or in combination. Cells were harvested at baseline and at +2h, +3h, +6h and +24h from the beginning of treatment. After RNA extraction, expression of TOP1, TOP2A, TOP 2B was measured by quantitative real-time RT-PCR and correlated with enzymatic activity. Moreover, the cytotoxic effect of the drugs was evaluated on cell lines by MTT assay. Wherever TOP was evaluated by an enzymatic assay. Results: All tested drugs induced TOP1, TOP2A, TOP2B expression at 2–3 h of incubation, with mRNA values ranging from 107% to 910% of baseline levels. TOP expression returned to baseline values at +6h of incubation. Among the different drugs, gemcitabine, oxaliplatin and the combination of 5-fluorouracile + oxaliplatin or methotrexate were the most effective topoisomerase inductors. The increase of mRNA levels corresponded to an increased topoisomerase activity in vitro. Conclusions: Evaluation of cytotoxic activity in vitro showed the schedule including an inductor of TOP (e.g. gemcitabine) followed after +3 h by TOP1 (topotecan) or TOP 2A (etoposide) inhibitors had a synergistic effect, at variance with other sequential administrations of the 2 drugs. In conclusion, anti-tumor drugs acting on DNA replication or cell metabolism induce TOP1, TOP 2A, TOP2B after 2–3 h. Sequential administration of these anticancer drugs with TOP inhibitors show synergistic activity in vitro. No significant financial relationships to disclose.
Postoperative chemoradiotherapy in patients with rectal cancer, prognostic factors for disease control and survival
Authors: M. Hetnal, K. Malecki, S. Korzeniowski, T. Zemelka
Journal: Journal of Clinical Oncology (2006)

13575 Background: The aim of this paper is an assessment of results of adjuvant chemoradiotherapy in patients with rectal cancer with respect to prognostic factors, causes of treatment failures and treatment tolerance. Methods: 178 pts with Dukes’ stage B or C rectal cancer received postoperative chemoradiotherapy between 1993 and 2002. Median age was 62; 110 patients were males, 68 were females. Median follow-up time was 45 months. Main endpoints of the analysis were locoregional recurrence-free survival (LRRFS), distant relapse free survival (DRFS), disease free survival (DFS) and overall survival (OS). Kaplan-Meier method was used to calculate survival rates. Univariate and multivariate analyses of prognostic factors were performed using log rank and Cox’s proportional hazard method. Results: The 5-year LRRFS was 73%, DRFS was 80%, DFS was 61% and OS was 65%. Lymph node involvement and method of resection (AR favoured) were the only independent prognostic factors for LRRFS. Lymph node involvement, in particular when four or more are involved, was independent prognostic factors for DFS. For DRFS are histological grade, lymph node involvement and extracapsular extension of the lymph node metastases. For OS, the independent prognostic factors were infiltration of the pararectal fatty tissue, lymph node involvement in particular when four or more are involved, total number of chemotherapy cycles (at least six favoured). The 5-year LRRFS was 73%, DRFS was 80%, DFS was 61% and OS was 65%. Radiation therapy was well tolerated in 45% of patients. Most common early reactions were diarrhoea, nausea/vomiting and leucopoenia. Conclusions: Involvement of lymph nodes and method of resection were the only independent prognostic factors for LRRFS. Prognostic factors for OS were infiltration of the pararectal fatty tissue, lymph node metastases, four or more involved lymph nodes, total number of chemotherapy cycles. No significant financial relationships to disclose.
Role of Yttrium-90 Ibritumomab Tiuxetan (Zevalin®) in Inducing and Maintaining Complete Molecular Response in B Non Hodgkin’s Lymphoma Patients in Clinical Complete Remission after Chemotherapy Regimen.
Authors: Enrico Orciuolo, Gabriele Buda, Sara Galimberti, Giuseppe Boni, Nadia Cecconi, Mario Petrini
Journal: Blood (2007)