tbuckley/cabot-search huggingface dataset:
Weekly low dose irinotecan and daily oral anticancer drug chemotherapy for metastatic colorectal cancer (MCRC) patients more than 75 years old
Authors: K. Sasaki, H. Takasaka, T. Sawada, E. Ezoe, J. Araya, Y. Takada, T. Furuhata, K. Hirata
Journal: Journal of Clinical Oncology (2007)

14594 Background: The percentage of CRC patients more than 75 years old is expected to rise in Japan, too. However we have little data on the efficacy and toxicity of chemotherapy in elderly MCRC patients. The aim of this study was to evaluate the objective tumor response rates and toxicities in elderly MCRC patients treated weekly low dose irinotecan and daily oral anticancer drug (UFT or S-1) chemotherapy. Methods: Patients with MCRC were treated on an out-patient treatment basis with irinotecan 60mg/m(2) as an intravenous 90 minutes infusion on weekly plus UFT 300 mg/m(2) or S-1 60 mg/m(2) in 2 divided doses given orally on day 1 to 5 in every week. All the lesions were evaluated with CT and/or MRI scan. Results: From 2001 to 2005, we treated 20 elderly MCRC patients. There were 13 men and 7 women. Fourteen patients were 75∼79 years old and 6 patients were 80 years or more. Chemotherapy was given more than 3 months (3∼30M). To date, 495 cycles (median 24, range 7–98) have been administered. There were 8 PR, 10 SD and 2 PD. The overall response rate was 40% and disease control rate (PR + SD) was seen 90% of pts. Progression free survival time of this regimen is 9.3 months. Median survival time was 16.0 months. One and 2 years survival rates were 72% and 13%. No toxic death was reported. There was no grade III/IV toxicity and all adverse events were manageable. All patients were treated on an out-patient clinic. Conclusions: These results confirmed that this chemotherapy combination is active with acceptable tolerability and QOL maintenance in elderly patients with MCRC. Chemotherapy in elderly patients with MCRC should not be influenced by the chronologic age of the patient. No significant financial relationships to disclose.
Intratumoral epidermal growth factor receptor (EGFR) antisense (AS) DNA in recurrent squamous cell carcinoma of the head and neck (SCCHN): A phase I trial
Authors: S. Y. Lai, V. W. Lui, P. J. Koppikar, S. M. Thomas, W. E. Gooding, R. R. Seethala, B. F. Branstetter, A. Argiris, J. R. Grandis
Journal: Journal of Clinical Oncology (2007)

6009 Background: SCCHN is characterized by upregulation of the EGFR where EGFR expression levels in the tumor correlate with decreased survival. We developed a novel anti-EGFR therapy with a therapeutic gene consisting of an EGFR AS sequence under the control of the U6 promoter in a pNGVL backbone. We conducted a phase I clinical trial to evaluate the safety and biological effects of EGFR AS in patients with advanced SCCHN. Methods: Patients (pts) with recurrent SCCHN refractory to standard therapies with at least one evaluable and accessible lesion were enrolled in a phase I trial. EGFR AS dose was escalated in successive cohorts of pts (classic “3+3” design) in 6 dose levels: 60 μg, 120 μg, 240 μg, 480 μg, 960 μg and 1920 μg at a concentration of 1 μg/μL. Pts received weekly intratumoral injections of EGFR AS × 4 weeks. Tumors were biopsied before and after the completion of therapy. In addition to treatment response as assessed by tumor volume measurements (PET/CT), levels of target proteins and phosphoproteins were assessed in the tumors. Results: 17 pts were enrolled (median age: 57 years; 15 M / 2 F). No grade 3/4 or dose-limiting toxicities were noted. 4 grade 1 toxicities were reported: injection site pain/swelling (2), localized edema (1) and lethargy (1). EGFR AS was present in the tumor after injection as demonstrated by PCR. 5 pts (29%; 95% CI 10–56%) achieved an objective response (RECIST), including 2 CRs (pCRs confirmed by biopsy) and 3 PRs; 2 pts had stable disease as best response. Median duration of response was 4.5 months (3.0–23.1). Median survival for the entire cohort was 5.4 months with a median survival in responders of 7.9 months. 1 pt who achieved CR is alive without progression at 23.1+ months. Immunohistochemical studies demonstrated decreased EGFR in 2 pts with CR. Assessment of downstream signaling molecules is in progress. Conclusions: Intratumoral EGFR AS was safe and resulted in impressive antitumor activity in pts with recurrent, incurable SCCHN. We plan to study further the use of EGFR AS as an integral component in the curative therapy of SCCHN. No significant financial relationships to disclose.
Molecular Follow-Up of Disease Progression and Interferon Therapy in Chronic Myelocytic Leukemia
Authors: Dina Ben-Yehuda, Svetlana Krichevsky, Eliezer A. Rachmilewitz, Ayelet Avraham, Giuseppe A. Palumbo, Francesco Frassoni, Dvora Sahar, Hanna Rosenbaum, Ora Paltiel, Michal Zion, Yinon Ben-Neriah
Journal: Blood (1997)
Long-term outcome from RTOG 9517: A phase I/II study of accelerated partial breast irradiation (APBI) with mulitcatheter brachytherapy (MCT) following lumpectomy for early-stage breast cancer.
Authors: Julia R. White, Kathryn A. Winter, Robert R. Kuske, John S. Bolton, Douglas W. Arthur, Troy Scroggins, Rachel Rabinovitch, Tracy R. Kelly, Leonard M. Toonkel, Frank A. Vicini, Beryl McCormick
Journal: Journal of Clinical Oncology (2012)

147 Background: Comparison of APBI to whole breast irradiation post lumpectomy for breast conservation is ongoing in phase III trials. However, APBI has gained acceptance in clinical practice despite relatively limited long-term data. RTOG 9517 studied MCT, one of the earliest methods of APBI, and can uniquely provide long-term cancer outcomes. Methods: Eligibility was stage I/II unifocal breast cancer &lt;3cm, invasive non-lobular histology without EIC, negative surgical margins, and 0-3 positive axillary nodes; no extracapsular extension. The target volume was the lumpectomy cavity plus a 2 cm radial and 1 cm ant/post margin. Low Dose Rate (LDR), 45 Gy in 3.5-5 day, or High Dose Rate (HDR) 34 Gy in 10 BID fractions over 5 days was delivered. A rapid dosimetry review was done to assure dose delivery per protocol. Systemic therapy was per physician’s discretion. The primary endpoint was HDR and LDR MCT reproducibility. This analysis focuses on ipsilateral breast failure (IBF), contralateral breast cancer events (CBE), regional (RF) and distant failure (DF) (cumulative incidence) disease-free (DFS), relapse-free (RFS), and overall survival (OS), (Kaplan-Meier). Results: The median follow up is 12.1 years (yr). 100 patients were accrued from 1997-2000; 98 were evaluable; 65 HDR and 33 LDR MCT. Median age was 62; 88% had T1 tumors; 12% T2; 81% p N0, 19% pN1; 77% ER and/or PR +; 19% ER - and PR -; 33 % received adjuvant chemotherapy and 64% antiendocrine therapy. There have been 6 IBF for a 10 yr rate of 6.2%; 2 IBF were outside the APBI field. There were 5 total RF for a 10 yr rate of 5.2%, respectively. There have been 5 CBE for a 10 yr rate of 4.2%. Failure patterns were: 4 isolated IBF, 1 isolated RF, 8 DF only, 1 IBF+RF, 1 IBF+RF+DF, 1 RF+CBE, 1 RF+DF, 3 CBE, and 1 CBE+DF (21 total failures). Eleven patients have developed DF; 8 have died of breast cancer, 22 have died from other causes. The 10 yr DFS, RFS and OS are 69.8%, 71.9%, and 78.0%, respectively. Conclusions: This multi-institutional phase II trial studying MCT-APBI continues to report durable local regional cancer control rates with long term follow-up. Supported by NCI U10 grants CA21661 and CA37422.
Abstract 208: Mitochondrial-targeted Grk2 Increases Superoxide Formation And Impairs Cardiomyocyte Respiratory Reserve Capacity
Authors: Priscila Y Sato, J K Chuprun, Jessica Ibetti, John W Elrod, Walter J Koch
Journal: Circulation Research (2014)

β-adrenergic receptors (βARs) are powerful regulators of cardiovascular function and are impaired in heart failure (HF). Signal transduction of βARs is canonically shut down by phosphorylation via G protein-coupled receptor kinase 2 (GRK2) and the subsequent binding of β-arrestins. This process of receptor desensitization is enhanced in HF via the up-regulation of GRK2 and contributes to disease progression. We have recently reported non-canonical actions of GRK2, which contribute to the development of HF independent of βAR desensitization. We have previously shown that GRK2 can act as a pro-death kinase in cardiomyocytes bytranslocating to mitochondria and activating mitochondria permeability transition. This study was designed to gain more understanding of the mitochondrial function of GRK2. We isolated adult cardiomyocytes from cardiac-specific transgenic mice overexpressing GRK2 at levels found in human HF (TgGRK2), and examined superoxide production using the redox sensitive reporter MitoSox Red. Confocal imaging revealed a 4.6 fold increase in superoxide levels in cardiomyocytes overexpressing Grk2 as compared to non-transgenic (NLC) cardiomyocytes (corrected total cell fluorescence 11.59±1.06, TgGRK2 (n= 3 hearts, 88 cells) vs 2.54±0.02 NLC (n=3 hearts, 52 cells), (p&lt;0.001). This indicates that the chronic elevation of GRK2 induces mitochondrial oxidative stress priming the myocyte for enhanced injury. To further explore the mitochondrial actions of GRK2 and consequences of redox stress we examined oxidative phosphorylation by performing oxygen consumption measurements in neonatal rat ventricular myocytes overexpressing GRK2 or GFP-expressing control myocytes. Seahorse analysis showed that cells overexpressing GRK2 have a significant decrease in spare respiratory capacity indicating that cells with elevated GRK2 levels have an impaired capacity to generated ATP during times of stress. Further studies with mutants that limit GRK2 kinase activity or mitochondrial localization demonstrate that mitochondrial GRK2 may be a significant contributor to cellular dysfunction as seen in heart failure.
EGFR genomic gain in Japanese non-small cell lung cancer patients treated with gefitinib
Authors: M. Varella-Garcia, T. Mitsudomi, Y. Yatabe, T. Kosaka, E. Nakajima, W. Franklin, P. A. Bunn, F. R. Hirsch
Journal: Journal of Clinical Oncology (2006)

7164 Background: Increased EGFR gene copy numbers evaluated by fluorescence in situ hybridization (FISH) is excellent predictor of clinical benefit from EGFR tyrosine kinase inhibitors (TKIs) in Caucasian non small-cell lung cancer (NSCLC) patients. This study was performed to verify how this marker performs in Oriental patients. Methods: A cohort of 59 Japanese patients with recurrent NSCLC after surgery was treated with gefitinib 250 mg daily. The cohort included 46% of females, 47% of never-smokers, 68% of patients had prior chemotherapy and 59% had stage III-IV at the time of surgery. Adenocarcinoma was the most common histology (85%). FISH was performed using EGFR /CEP 7 and PathVysion probes (Vysis/Abbott). Specimens were classified as FISH+ when showing gene amplification or high polysomy (≥4 copies of the gene in ≥40% of tumor cells). Effectiveness of gefitinib was concluded when there was 30% tumor shrinkage in imaging studies and/or elevated CEA level decreased to &lt;50% of baseline. Results: FISH results were available in 51 tumors: 35 (69%) were EGFR+ and 29 (57%) were HER2+. There was a significant association between EGFR+ and HER2+ (p = 0.012) and between EGFR FISH+ and of EGFR mutations (p = 0.003). All 9 tumors exhibiting clustered EGFR gene amplification harbored mutations. Response rate assessed in 43 patients was 59% in EGFR+ and 33% in EGFR- (p = 0.11). Gefitinib treatment produced response in 5 (83%) cases with gene amplification and 12 (52%) cases with high polysomy. Response rate was 77% in 22 cases positive for FISH and mutation and 100% in 5 cases with EGFR mutation/FISH- cases. No responses were observed in EGFR WT patients, neither in 9 FISH+ nor in 10 FISH- cases. Survival was not significantly impacted by EGFR (p = 0.42) or HER2 (p = 0.40) FISH status, while EGFR mutation was significantly associated with longer survival (p = 0.005). Conclusion: Patients in this Japanese cohort had more frequently FISH+ status than in the Caucasian populations, which may contribute to higher sensitivity to EGFR TKIs. However, the predictive power of EGFR FISH status for TKI sensitivity seems to be lower supporting significant differences in the mechanisms of EGFR pathway activation in Oriental and Caucasian populations. [Table: see text]
Anti-tuberculosis drug concentrations and treatment outcomes in patients with both tuberculosis and HIV infection
Authors: Shadi Baniasadi, Payam Tabarsi, Seyed Alireza Nadji, Farzad Kobarfard, Raha Eskandari, Fanak Fahimi
Journal: European Respiratory Journal (2013)

Introduction: A poor treatment response in persons with tuberculosis (TB) and HIV infection can be related to low anti-TB drug concentrations, particularly if diarrhea and malabsorption are present. Although therapeutic drug monitoring (TDM) is not routinely recommended, growing bodies of literature suggest that TDM may be a useful tool to optimize therapy.  Aims: We objected in this study to determine serum concentrations of anti-TB drugs and treatment outcomes in HIV/TB patients.  Methods: Using HPLC method, serum concentrations of izoniazid (INH), rifampin (RIF), and pyrazinamide (PZA) were determined 3-5 days after receiving medications and treatment outcomes of the patients were evaluated.  Results: Twenty two patients [median age: 35 years (rang 27-57 years), median CD4+ count: 16 cells/mm3 (range 5-444 cells/mm3)] were enrolled in the study. All patients had low or very low serum concentrations of INH and RIF, 2 h after drugs ingestion. Serum concentrations of PZA were in normal and low ranges in 5 (22.73%) and 17 (77.27%) of the patients respectively. Of 22 patients, 9 (41%) were considered cured. Five patients (22.7%) died during treatment (four of them had low or very low serum concentrations of three medications), three were lost to follow-up, three were still receiving therapy, and two had relapsed (one of them was infected with Mycobacterium Kansasii).  Conclusions: Low and very low serum concentrations of INH, RIF, and PZA and poor treatment outcomes are common among our patient. Future study in a wider patient sample over a longer follow-up period are required to explore the association of between anti-TB drug concentrations and treatment outcomes.
Chromosome Aberrations Induced in Rat Bone Marrow Cells by 7,12-Dimethylbenz[&lt;italic&gt;a&lt;/italic&gt;]anthracene&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Y Kuri, T Sugiyama, Y Nishizuka
Journal: JNCI Journal of the National Cancer Institute (1969)
The training—injury prevention paradox: should athletes be training smarter<i>and</i>harder?
Authors: Tim J Gabbett
Journal: British Journal of Sports Medicine (2016)

Background There is dogma that higher training load causes higher injury rates. However, there is also evidence that training has a protective effect against injury. For example, team sport athletes who performed more than 18 weeks of training before sustaining their initial injuries were at reduced risk of sustaining a subsequent injury, while high chronic workloads have been shown to decrease the risk of injury. Second, across a wide range of sports, well-developed physical qualities are associated with a reduced risk of injury. Clearly, for athletes to develop the physical capacities required to provide a protective effect against injury, they must be prepared to train hard. Finally, there is also evidence that under-training may increase injury risk. Collectively, these results emphasise that reductions in workloads may not always be the best approach to protect against injury. Main thesis This paper describes the ‘Training-Injury Prevention Paradox’ model; a phenomenon whereby athletes accustomed to high training loads have fewer injuries than athletes training at lower workloads. The Model is based on evidence that non-contact injuries are not caused by training per se , but more likely by an inappropriate training programme. Excessive and rapid increases in training loads are likely responsible for a large proportion of non-contact, soft-tissue injuries. If training load is an important determinant of injury, it must be accurately measured up to twice daily and over periods of weeks and months (a season). This paper outlines ways of monitoring training load (‘internal’ and ‘external’ loads) and suggests capturing both recent (‘acute’) training loads and more medium-term (‘chronic’) training loads to best capture the player's training burden. I describe the critical variable—acute:chronic workload ratio—as a best practice predictor of training-related injuries. This provides the foundation for interventions to reduce players risk, and thus, time-loss injuries. Summary The appropriately graded prescription of high training loads should improve players’ fitness, which in turn may protect against injury, ultimately leading to (1) greater physical outputs and resilience in competition, and (2) a greater proportion of the squad available for selection each week.
Abstract 12609: A Novel Cell Ablation Strategy Defines the Regenerative Potential of the Embryonic Mouse Heart
Authors: Anthony C Sturzu, Rajarajan Kuppusamy, Derek Passer, Alyssa K Riley, Timothy C Tan, Marc C Engles, Rebecca Feistritzer, Keston D Robertson, Marielle Scherrer-Crosbie, Ibrahim J Domian, Sean M Wu
Journal: Circulation (2013)
Induction of Fas (Apo-1, CD95)-Mediated Apoptosis of Activated Lymphocytes by Polyclonal Antithymocyte Globulins
Authors: Laurent Genestier, Sylvie Fournel, Monique Flacher, Olga Assossou, Jean-Pierre Revillard, Nathalie Bonnefoy-Berard
Journal: Blood (1998)
A phase I clinical and pharmacokinetic study of flavopiridol administered concurrently with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) for advanced solid tumors
Authors: R. D. Meng, R. D. Carvajal, A. N. Tse, M. A. Shah, H. Dials, D. Brukner, E. M. O’Reilly, D. P. Kelsen, G. K. Schwartz
Journal: Journal of Clinical Oncology (2006)

13515 Background: Flavopiridol, a potent cyclin-dependent kinase inhibitor, enhances oxaliplatin-induced apoptosis in HCT116 colon cancer cells in vitro, especially with concurrent therapy. Significant tumor regressions were also observed in HCT116 xenografts treated with flavopiridol and oxaliplatin therapy versus either therapy alone. Methods: Therefore, an ongoing phase I trial in advanced solid tumors was designed in which flavopiridol at a fixed dose (40 mg/m 2 over 1 hour) was administered concurrently with escalating doses of oxaliplatin (60 mg/m 2 -&gt; 80 mg/m 2 over 2 hours), given as part of a modified FOLFOX6 regimen at standard doses every 14 days. Patients then received escalating doses of infusional 5-fluorouracil over 48 hours (900 mg/m 2 /day -&gt; 1200 mg/m 2 /day). Standard phase I eligibility criteria apply. Prior FOLFOX or oxaliplatin was allowed. Results: Median characteristics of nineteen evaluable patients: age 54 (39–77), KPS 80% (70–90), 9 males/10 females, 3 prior regimens (range 1 to 10). The combination has been well-tolerated, with 1 dose limiting toxicity occurring with oxaliplatin at 85 mg/m 2 and infusional 5-fluorouracil at 1200 mg/m 2 /day (grade 3 hyponatremia and grade 3 syncope). Pharmacokinetic studies for flavopiridol indicate no appreciable difference in Cmax despite escalation of oxaliplatin dose. We have observed 1 partial response to treatment in pancreatic cancer. Stable disease has been seen in 5 patients, including 1 breast cancer (3 months), 1 gastric cancer (2 months), 1 anal cancer (7 months) and 2 colorectal cancers (5+ months), with one patient previously treated with oxaliplatin. Conclusions: The combination of flavopiridol and modified FOLFOX6 can be given safely without a significant increase in toxicity. The pharmacokinetic data for flavopiridol remains unchanged despite escalating doses of oxaliplatin. Activity has been observed in several tumor types, with promising activity noted for colorectal cancers even with prior oxaliplatin chemotherapy. Therefore, further dose escalation of flavopiridol is currently planned. No significant financial relationships to disclose.
Prognostic Significance of Pathologic Features in Localized Prostate Cancer Treated With Radical Prostatectomy: Implications for Staging Systems and Predictive Models
Authors: David I. Quinn, Susan M. Henshall, Anne-Maree Haynes, Phillip C. Brenner, Raji Kooner, David Golovsky, Jayne Mathews, Gordon F. O’Neill, Jennifer J. Turner, Warick Delprado, John F. Finlayson, Robert L. Sutherland, John J. Grygiel, Phillip D. Stricker
Journal: Journal of Clinical Oncology (2001)

Although predicting outcome for men with clinically localized prostate cancer (PC) has improved, the staging system and nomograms used to do this are based on results from the North American health system. To be internationally applicable, these models require testing in cohorts from a variety of different health systems based on the predominant PC case identification methods used.We studied 732 men with localized PC treated with radical prostatectomy and no preoperative therapy between 1986 and 1999 at one Australian institution to determine the effect of clinicopathologic features on disease-free survival.Preoperative serum prostate-specific antigen (PSA) concentration, Gleason score, pathologic stage, and year of surgery were independent predictors of outcome. Although margin status demonstrated only a trend toward significance in multivariate modeling overall, it proved to be independent in subgroups based on later year of surgery (1986 to 1994 v 1995 to 1998), preoperative PSA of less than 10 ng/mL, and Gleason score > or = 7. Adjuvant radiation therapy improved disease-free survival rates in patients with multiple surgical margin involvement.This work confirms the prognostic significance of pathologic stage, Gleason score, and preoperative serum PSA. In the context of a contemporaneous screening effect in Australia, these findings may have implications for methods that predict outcome following surgery as screening becomes more prevalent in a population. The independent prognostic effect of margin status may alter with an increase in the proportion of screening-identified PCs. Staging systems and nomograms that predict outcome following surgery require validation in cohorts with different health practices before being universally applied.
Comparison of multidimensional assessment systems with regard to risk prediction for exacerbations of COPD
Authors: Takashi Motegi, Takeo Ishii, Kumiko Hattori, Koichiro Kamio, Kouichi Yamada, Misuzu Kurahara, Akihiko Gemma, Kozui Kida
Journal: European Respiratory Journal (2011)

Aim:  Acute Exacerbations of COPD (AECOPD) are major concerns with regard to morbidity, mortality and economic burden. In this study, we compared the efficacy of 3 assessment systems for predicting AECOPD: BODE index (Body mass index, airway Obstruction, Dyspnea, Exercise capacity); DOSE index (Dyspnea, airway Obstruction, Smoking status, Exacerbations); and ADO index (Age, Dyspea, airway Obstruction).   Participants and methods:  The frequency of exacerbations (FE) for a 1-year period was retrospectively studied for 183 consecutive patients with COPD. Following parameters were used to compare the results: pulmonary function tests, 6-minute walking test, MMRC dyspnea scale, low-attenuation area (LAA%) on HRCT and FE.   Results:  The study included 183 patients (M/F 170/13). The mean age and FEV 1 %predicted were 71.4 years and 55.7%, respectively. The mean annual exacerbation rate was 0.57 per patient-year. FE was significantly correlated with the following parameters: lower FEV 1 %predicted (p   Conclusions:  The DOSE index appears to be superior to the BODE and ADO indices interms of predicting exacerbations of COPD.