tbuckley/cabot-search huggingface dataset:
Concomitant chemoradiotherapy using docetaxel, cisplatin, and 5-FU for patients with advanced hypopharyngeal cancer.
Authors: K. Shiga, T. Ogawa, K. Kato, Y. Asada, T. Kobayashi
Journal: Journal of Clinical Oncology (2011)

e16029 Background: Chemotherapy using TPF protocol has shown efficacy in the neo-adjuvant setting for head and neck squamous cell carcinoma (SCC) so far. However, effectiveness of concomitant chemoradiotherapy (CCRT) using TPF protocol has not yet been clearly distinguished. On the other hand, prognoses of the patients with SCC of the hypopharynx, especially those of advanced stage patients, were poor. The aim of this study was to determine the safety and efficacy of newly developed CCRT using TPF protocol in patients with SCC of the hypopharynx. Methods: Patients with previously untreated, histologically proven stage IVA disease were eligible for the study. Sixteen patients were enrolled between January 2002 and September 2008. Treatment consisted of radiotherapy administered once daily to a total dose of 70 Gy, concomitant with 120 hour infusions of 5-FU (600 mg/m2/day), docetaxel (50 mg/m2, day 2) and cisplatin (60 mg/m2, day 2) given during first and fifth weeks of radiotherapy. These drug doses were determined from the results of our former phase I study to assess the dose limiting toxicity of this protocol. Median follow-up period was 34 months. Results: Fifteen patients completed this protocol. Bone marrow suppression was the most common adverse event observed through this study. Grade 4 leukopenia, neutropenia and hemoglobin were observed in 4 (25%), 8 (50%) and 2 (12.5%) of the patients and also those grade 3 events were observed in 5 (31.3%), 4 (25%) and 2 (12.5%) of the patients. Grade 3 lymphopenia were observed in all patients. Grade 3 hyponatremia were observed in 6 (37.5%) of the patients. As all patients showed mucositis at any grade, feeding tube dependence and dietary limitation were observed in two patients at the time of discharge. Complete remission of primary tumor was obtained in all patients. However, planned neck dissection was performed in 3 patients whose neck metastases were remnant after initial treatment. The disease-specific and over-all survival rates at 60 months of the patients were 100% and 68.8%, respectively. Conclusions: Our data suggested that CCRT using TPF protocol was feasible and very effective in patients with advanced stage SCC of the hypopharynx.
Lifelong running reduces oxidative stress and degenerative changes in the testes of mice
Authors: S. Chigurupati, T. G. Son, D. H. Hyun, J. D. Lathia, T. V. Arumugam, M. P. Mattson
Journal: Journal of Clinical Oncology (2008)

14693 Background: One plausible effective link between lifestyle (diet and exercise) and cancer risk is oxidative stress. Regular exercise can counteract the adverse effects of aging on the musculoskeletal, cardiovascular systems and cancer risk. In males the normal aging process is associated with reductions in testosterone production and impaired spermatogenesis, but the underlying mechanisms and their potential epigenetic modification by exercise are unknown. Methods: Here we report that lifelong regular exercise (running) in mice protects the testes against age-related cellular alterations, and that this effect of running is associated with decreased amounts of oxidative damage to proteins, lipids and DNA in spermatogenic and Leydig cells. Results: Six month-old male mice were divided into a sedentary group and a group which ran an average of 1.75 km/day, until the mice reached the age of 20 months. Seminiferous tubules of runners exhibited a full complement of cells at different stages of the spermatogenic process and a clear central lumen with large numbers of spermatozoa, in contrast to sedentary mice which exhibited disorganized spermatogenic cells and lacked spermatocytes in a central lumen. Levels of protein carbonyls, nitrotyrosine, lipid peroxidation products and oxidatively modified DNA were significantly greater in spermatogenic and Leydig cells of sedentary mice compared to runners. Serum testosterone levels are significantly lower in sedentary aged mice compared to runners. These findings suggest that lifelong regular exercise suppresses aging of the testes by a mechanism that involves reduced oxidative damage to spermatogenic and Leydig cells. Conclusions: These findings suggest that lifelong regular exercise suppresses aging of the testes by a mechanism that involves reduced oxidative damage to spermatogenic and Leydig cells and plausible cancer risk. No significant financial relationships to disclose.
Baseline proliferation markers and cytopathologic findings in breast epithelium of women at increased risk for breast cancer
Authors: N. Sneige, Y. Gong, J. Lammey, V. Valero, G. Babiera, H. Kuerer, G. Hortobagyi, B. Arun
Journal: Journal of Clinical Oncology (2005)

9694 Background: The aim of phase II chemoprevention (CP) trials is to screen potential chemopreventive agents and to identify surrogate endpoint biomarkers that can be used in large prevention studies. Tamoxifen is approved for the risk reduction of breast cancer and was shown to reduce proliferation in breast epithelium. Therefore, proliferation markers are one of the potential markers, which can be used in phase II CP studies. We are currently conducting 2 prospective clinical prevention studies evaluating changes in proliferation and apoptosis induced by celecoxib (C) or anastrazole (A) in breast tissue of high risk women. Here, we report baseline cytopathologic findings, expression of ER and Ki-67. Methods: High risk women were enrolled and underwent baseline fine needle aspiration (FNA) and started C (400 mg BID) or A (1 mg QD). ER and Ki-67 in FNA was assessed using immunohostochemistry. Immunoreactivity was scored as the percentage of positive nuclei; ≥ 10% was considered positive for ER. Ki-67% was measured as a continues variable. Cytologic specimens were classified as proliferative or non-proliferative. We compared Ki-67 levels and ER with each other and with presence of proliferation using Fisher’s test. Results: 68 women have been enrolled and data is available for 29. Median age: 56 years (range: 42–71). Risk factors include: Gail risk > 1.67% (n=9), LCIS (n=5), or AH (n=4), or contralateral breast cancer (n=11). 72% (21/29) of the samples were ER positive. The average ER expression was 42.2% (range: 0–100%), and % Ki-67: 2.31 (range: 0–10%). Proliferative changes were seen in 27.5% (8/29) of the samples. There was no significant correlation between with ER expression and Ki-67. ER and Ki-67 did not correlate with cytopathologic findings. Conclusions: We have previously shown that ER expression is downregulated with celecoxib. Although no significant correlation between ER and Ki-67 and proliferation was apparent in this current study, these markers are independent markers significant in predicting response to a chemopreventive intervention. Further analysis with other proliferation (COX-2, EGFR, Her-2/neu) and apoptosis markers (Bcl-2, TUNEL apoptosis) are currently going on. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration NCI
Recurrence-free survival results from a pilot study of adjuvant gefitinib in resected hepatocellular carcinoma (HCC).
Authors: Akhil Chopra, Gilberto Lopes, Lavina D. Bharwani, Chung Yip Chan, Alexander Chung, Peng Chung Cheow, Choon Kiat Ho, Kui Hin Liau, Winston Woon, Jee Keem Low, Alex Yuang-Chi Chang
Journal: Journal of Clinical Oncology (2015)

404 Background: Epidermal growth factor receptor (EGFR) pathway activation or over-expression plays an important role both in cirrhosis and hepatocellular carcinogenesis. We hypothesized that gefitinib (G), an oral tyrosine kinase inhibitor of EGFR, should reduce recurrence rate and/or prolong recurrence free survival when given in adjuvant setting. Methods: We designed a multicenter pilot study with a plan to enroll 40 HCC patients with complete resection and or with positive resection margin or residual disease &lt; 0.5 cm (microscopic disease). Treatment consisted of G 250 mg orally daily for 6 months starting within 6 weeks of surgery. Follow-up included serum alpha-fetoprotein levels and imaging studies every 3 months for the first 2 years, every 6 months for years 3-5 and yearly thereafter. Main endpoints were recurrence-free survival, toxicity and correlative genetic studies. All statistical analyses were carried out on an intention-to-treat basis. The end point of recurrence free survival will be presented here. Results: 65 patients consented to the study, 40 were eligible and 25 were screen failures due to: diagnosis other than HCC (6 patients); poor post-operative recovery (9 patients); unresectable disease (3 patients); withdrawal of consent (2 patients); 1 patient had 2 cancers, and 4 developed metastatic disease.39 patients had R0 resection, whereas 1 patient had R1 resection. 4 female, 36 male. All patients completed 6 months of adjuvant G. Toxicities were mild; mainly grade 1 and 2 skin toxicity, diarrhea and pruritis. Median age - 63 years, median Child score-6, median TNM stage - II, median size - 4.9cm. 20 patients had liver cirrhosis. With a median duration of follow up of 4.1 years, the median recurrence free survival was 24 months. (95% CI 20-48). Conclusions: A median recurrence free survival of 24 months in patients with resected hepatocellular carcinoma treated with 6 months of adjuvant gefitinib compares favorably to historical data. Toxicity of gefitinib was mild and easily manageable. We await results of correlative genetic studies to identify potential prognostic and predictive biomarkers before considering embarking on a larger study. Clinical trial information: NCT00282100.
Phase I trial of elotuzumab, lenalidomide, and low-dose dexamethasone in patients with relapsed or refractory multiple myeloma.
Authors: S. Lonial, R. Vij, T. Facon, P. Moreau, X. Leleu, A. Mazumder, J. L. Kaufman, C. Westland, C. Tsao, A. K. Singhal, S. Jagannath
Journal: Journal of Clinical Oncology (2011)

8076 Background: Elotuzumab is a humanized monoclonal IgG1 antibody targeting human CS1, a cell surface glycoprotein that is highly and uniformly expressed on multiple myeloma (MM) cells with limited expression in normal tissues. In preclinical studies lenalidomide enhanced the antitumor activity of elotuzumab. Methods: This phase I study assessed the maximum tolerated dose (MTD), safety, and efficacy of elotuzumab with lenalidomide plus low-dose dexamethasone in patients with relapsed/refractory MM. Three patient cohorts were treated with escalating doses of elotuzumab (5, 10, and 20 mg/kg IV on days 1, 8, 15, and 22 every 28 days in the first 2 cycles, and days 1 and 15 of subsequent cycles), lenalidomide (25 mg PO days 1–21), and dexamethasone (40 mg PO weekly). After the first 5 patients received up to 6 cycles of therapy, the protocol was amended to permit treatment until disease progression. Results: Twenty-nine patients were enrolled with a median age of 60 years (range, 41–83) and a median of 3 prior therapies (range, 1–10). At the time of analysis patients had received a median of 10.5 treatment cycles and 25 doses of elotuzumab, and 11 patients continued to receive treatment. During the dose escalation phase, there were no DLTs and the MTD was not reached. Among 28 treated patients, the most frequent grade 3/4 treatment emergent toxicities were neutropenia (36%) and thrombocytopenia (21%); 2 patients experienced 3 serious infusion-related reactions (1 patient with a grade 4 hypersensitivity reaction and 1 with two grade 3 stridor events) during the first treatment cycle. A partial response or better was achieved by 82% of all patients, 95% of lenalidomide-naïve patients (n=22), 94% of those with prior thalidomide (n=16), and 83% of those refractory to the most recent MM therapy (n=12). The median time to response was 7 weeks. For the 20 mg/kg cohort, the median time to progression has not been reached at a median 12.7 months follow-up. Updated results will be presented at the meeting. Conclusions: A phase II trial of elotuzumab (10 vs 20 mg/kg) with lenalidomide/dexamethasone is ongoing.
Multicenter phase II study of cetuximab (C) with concomitant radiotherapy (RT) followed by consolidation chemotherapy (CT) in locally advanced non-small cell lung cancer (NSCLC).
Authors: A. P. Kotsakis, S. S. Ramalingam, A. A. Tarhini, D. E. Heron, R. Smith, D. Friedland, D. P. Petro, L. E. Raez, J. R. Brahmer, J. S. Greenberger, S. Dacic, P. Hershberger, R. J. Landreneau, C. P. Belani, J. D. Luketich, A. Argiris
Journal: Journal of Clinical Oncology (2011)

7019 Background: C, an anti-EGFR monoclonal antibody, enhances the efficacy of both RT and CT. We evaluated a novel strategy of RT plus C followed by consolidation CT plus C for the treatment of stage III NSCLC. Methods: Eligible were pts with unresectable stage IIIA or IIIB NSCLC, ECOG performance status (PS) 0-1, no history of pulmonary fibrosis and adequate end organ function. Pts were treated with chest RT (73.5 Gy in 35 fractions/7 weeks, once daily, with lung and tissue heterogeneity corrections (63 Gy without corrections) and C 250 mg/m2 weekly during RT (after a loading dose of 400 mg/m2 the week prior to starting RT). C was continued after RT completion and during consolidation therapy for 26 weeks. Paclitaxel 200 mg/m2 and carboplatin AUC of 6 were given for 3 cycles (every 3 weeks) after 4-6 weeks from RT. Primary endpoint was the overall survival. Results: Thirty-eight eligible pts were analyzed (2 ineligible pts were excluded from analysis). 25 males; median age 67 yrs; PS 0: 19, PS 1: 19; 14 adenocarcinomas, 10 squamous, 14 non-otherwise specified; Stage: 13 IIIA, 25 IIIB. Median corrected RT dose: 73.5 Gy (56-73.5); median C doses: 18. 33 pts received at least 1 cycle of consolidation. Grade 3/4 toxicities during RT/C were (in > 1 pt): pulmonary embolism (2/2), infection (2/1), fatigue (2/0) and rash (3/0). Grade 3/4 toxicities during consolidation: neutropenia (7/9), neutropenic fever (0/2), lymphopenia (4/0), infection (0/1), rash (2/0). One pt died of pneumonitis, possibly related to C. Best response using RECIST in 31 evaluable pts: 4 CR, 17 PR, 4 SD, 6 PD. With a median follow up of 17.75 months, the median OS and PFS were 17.1 and 9.3 months, respectively. Pts with EGFR positive tumors by FISH (17 of 28 tested) had a trend towards better PFS (p=0.07). Conclusions: C with RT followed by consolidation therapy was associated with acceptable toxicities and efficacy comparable to RT/CT. There was no associated grade 3-4 esophagitis. Supported in part by P50 CA090440.
MicroRNAs related to intrinsic resistance to oxaliplatin and the irinotecan metabolite SN-38 in 10 colorectal cancer cell lines.
Authors: Niels Frank Jensen, Rolf Soekilde, Jan Stenvang, Birgitte Sander Nielsen, Thomas Litman, Nils Brünner, Maria Unni Rømer
Journal: Journal of Clinical Oncology (2012)

524 Background: Chemotherapy of metastatic colorectal cancer is based on 5-flourouracil combined with either oxaliplatin or irinotecan (active metabolite: SN-38). Identification of predictive biomarkers of drug response is needed to provide a better personalized treatment. In this study we aimed to identify microRNAs related to intrinsic resistance to oxaliplatin or irinotecan in a panel of ten colorectal cancer cell lines. Methods: Drug sensitivity towards oxaliplatin and SN-38 was determined for ten colorectal cancer cell lines (Colo-205, DLD-1, HCC-2998, HCT-15, HCT-116, HT-29, KM12, LoVo, LS-174T, and SW620), using the cell viability MTT assay and the cell death LDH assay. In addition, two cell lines (DLD-1 and LoVo) were exposed to the drugs for 6, 24 or 48 hours. MicroRNA expression profiles were generated using the Exiqon miRCURY LNA microarray platform (including 840 microRNAs), and four differentially expressed microRNAs were validated by independent qRT-PCR measurements. Results: The drug sensitivities of the ten colorectal cancer cell lines varied about 50 times between the least and most sensitive cell lines. Correlation of drug sensitivity data to microRNA expression data across the ten cell lines yielded about 25 microRNA biomarker candidates, for each of the drug/assay combinations. Following short-term drug treatment 10-20 microRNAs were altered for each drug/cell line combination. Validation by qRT-PCR showed a very good correlation to the microarray data. MicroRNAs identified by correlation to drug sensitivity and by short-term treatment were compared, and less than 10% were identified by both approaches, perhaps representing the most promising candidates. These candidates are for SN-38 miR-15a, miR-22, miR-24, miR-98, miR-142-3p, miR-1290, and let-7b, and for oxaliplatin miR-23b, miR-27a, miR-192, miR-200a, miR-222, miR-886-5p, and miR-1308. Conclusions: In the present study we identified a number of microRNAs that are potentially involved in intrinsic resistance and/or could be predictive biomarkers for either irinotecan or oxaliplatin.
Increased Efflux of Oxidized Glutathione (GSSG) Causes Glutathione Depletion in Sickle Erythrocytes.
Authors: Erfan Nur, Rudi de Waart, Mirjam Verwijs, Hans-Martin Otten, Dees P. Brandjes, Ronald P.J. Oude Elferink, Bart J. Biemond
Journal: Blood (2009)
Hypogonadism in male cancer patients treated with the tyrosine kinase inhibitors sunitinib (SUN) or sorafenib (SOR)
Authors: P. Wolter, H. Wildiers, D. Vanderschueren, H. Dumez, P. Clement, P. Schöffski
Journal: Journal of Clinical Oncology (2009)

3565 Background: SUN and SOR are multi-targeted tyrosine kinase inhibitors (TKIs) inhibiting several kinases (VEGFR- 1,2; c-kit; PDGFR-α,β; flt-3; RET). SUN is approved for treatment of imatinib-resistant gastrointestinal stromal tumors (GIST) and metastatic renal cell carcinoma (RCC), SOR is used for RCC and hepatocellular carcinoma. We observed in some pts with fatigue under TKI treatment low testosterone (T) levels and started assessing the incidence and severity of gonadal dysfunction prospectively in male pts receiving these TKIs. Methods: Gonadal status (serum total testosterone (TT), free testosterone (FT), sex-hormone binding globulin (SHBG), luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were evaluated in pts with RCC or GIST under SUN or SOR. SUN was given at a daily dose of 50 mg p.o. 4 weeks on, 2 weeks off, SOR at a daily oral dose of 800 mg. Results: We identified 27 pts (median age 63, range: 27–77), for which data on gonadal function were available, 23 RCC (85 %), 4 GIST (15%), with 22 (85.5%) receiving SUN and 5 (18.5%) SOR. Median treatment duration was 48 (2–202) weeks, 13 (48%) underwent dose reductions, in 4 (15%) pts due to grade 3 fatigue. All pts had at least once during TKI treatment T levels lower than normal (TT &lt; 300 ng/dL and/or FT &lt; 5 ng/dL), 17 (63%) had a low T with normal LH/FSH, 4 (15%) a low T with an elevated LH/FSH and 6 (22%) a low T and elevated FSH, but normal LH. The median TT level in the whole group was 194 ng/dL (21–477, normal range: 300–1,000 ng/dL), the median FT level in the whole group was 4.01 (0.45–9.07, normal range: 5–20 ng/dL). In the SUN cohort the median levels for TT and FT were slightly lower on day 28 in comparison to day 1 (184.5 vs 206 ng/dL for TT and 3.935 vs 4.225 ng/dl for FT). Pts with information available on testosterone at baseline (n = 8) tended to have slightly diminished baseline T levels (median: 222.5 [61–319] ng/dL), but 50% of these pts had been treated with other TKIs before. Two pts with grade 3 fatigue under SUN had very low T levels shortly after starting SUN (21 and 28 ng/dL, respectively). Conclusions: We observed a high incidence of hypogonadism in male RCC and GIST pts under treatment with SUN or SOR. Hypogonadism may likely contribute to the fatigue associated with these agents. [Table: see text]
Meta-analysis of hematologic toxicities in patients with cancer treated with sunitinib.
Authors: Tomohiro Funakoshi, Asma Latif, Kamyar Arasteh, Matt D. Galsky
Journal: Journal of Clinical Oncology (2013)

373 Background: Sunitinib is a small molecule which inhibits receptor tyrosine kinases involved in cell proliferation and angiogenesis. Though the incidence and risk of unique toxicities associated with sunitinib, such as hypertension and thromboembolic events, have been previously reported, the incidence and risk of hematologic toxicities have been less well characterized. Methods: We searched Medline and the American Society of Clinical Oncology online database of meeting abstracts up to July 2012 for relevant clinical trials. Eligible studies included phase II and III trials and expanded access programs with sunitinib that reported adequate safety data profile reporting neutropenia, thrombocytopenia or anemia. The relative risk (RR), summary incidence and 95% confidence intervals (CI) were calculated. Results: A total of 8,526 patients from 60 trials of sunitinib as a single agent revealed that the incidence of sunitinib-associated all-grade and high-grade (grade 3-4) hematologic toxicities were, respectively: neutropenia: 42.1% and 12.8%; thrombocytopenia: 44.7% and 10.7% and anemia: 50.4% and 6.2%. Sunitinib-treated patients (2,667 subjects from 10 randomized trials) had a significantly increased risk of all-grade (RR = 3.58; 95% CI, 1.71–7.49) and high-grade (RR = 3.32; 95% CI, 1.60–6.90) neutropenia, all-grade (RR = 4.59; 95% CI, 2.76–7.63) and high-grade (RR = 5.84; 95% CI, 2.22–15.41) thrombocytopenia and all-grade anemia (RR = 1.15; 95% CI, 1.00–1.31). Subgroup analysis revealed the significantly higher relative risk of high-grade neutropenia in patients receiving sunitinib monotherapy than in patients receiving concomitant therapy (p = 0.026). There was no statistically significant difference in the incidence of hematologic toxicities between subgroups; renal cell cancer (RCC) versus non-RCC or continuous daily sunitinib dosing versus intermittent dosing. Conclusions: Sunitinib is associated with a significant increase in the risk of developing all-grade and high-grade neutropenia and thrombocytopenia and all-grade anemia compared with control.
The ‘weekend warrior’ physical activity pattern: how little is enough?
Authors: Mark Hamer, Gary O’Donovan, I-Min Lee, Emmanuel Stamatakis
Journal: British Journal of Sports Medicine (2017)

The dose–response relationship between physical activity and health is of great interest to policy makers, clinicians and individuals. Several recent analyses of large-scale population data have advanced our understanding, particularly in teasing apart minimal and optimal physical activity dosage. For example, if we focus on ‘minimal’ dose, 15 min a day of moderate-intensity exercise lowered mortality in a sample of more than 400 000 adults from Taiwan.1 A recent meta-analysis of nine cohort studies revealed that undertaking some moderate to vigorous physical activity (MVPA) but less than the guidelines was associated with 22% reduction in mortality risk in older adults.2 For those fortunate to be able to be performing the ‘optimal’ levels of physical activity, an analysis of more than 600 000 adults of all ages from the USA and Europe showed that a nearly optimal threshold for longevity occurred at three to five times the physical activity recommendation (39% reduction in all-cause mortality). Note that the additional benefit over and above doses corresponding to one to two multiples of the physical activity guideline (31% reduction in all-cause mortality) was rather modest in general.3 

In a new study4 using a …