tbuckley/cabot-search huggingface dataset:
Levels of circulating endothelial cells (CECs) and monocytes as pharmacodynamic markers of SU11248 activity in patients (pts) with metastatic imatinib-resistant GIST
Authors: A. Norden-Zfoni, J. Manola, J. Desai, J. Morgan, C. L. Bello, S. E. Deprimo, D. R. Shalinsky, C. Baum, G. D. Demetri, J. Heymach
Journal: Journal of Clinical Oncology (2005)

9036 Background: Clinical testing of targeted agents can be accelerated by non-invasive biomarkers to assess relevant drug actions. SU11248 is an oral multitargeted tyrosine kinase inhibitor of VEGFR-1, 2, and 3, PDGFR, KIT, and FLT-3 with antiangiogenic and antitumor activities. To identify potential pharmacodynamic markers of its activity, we investigated changes in monocytes, which express VEGFR1, and CECs, which express VEGFR2. By targeting tumor vasculature, VEGFR-2 inhibition may increase the release of mature CECs (CD45- CD31+ CD146+ CD133-). Methods: Pts enrolled in a phase 1/2 trial of SU11248 for metastatic imatinib-resistant GIST received SU11248 orally once daily for 14 or 28 days (d) followed by 14d without treatment per cycle. CBC and differential were assessed pre- and post-treatment in 73 pts; CECs were assessed serially by 4-color flow cytometry in 16 pts. Clinical benefit (CB) was defined as PR or SD >6 months. Results: Monocyte levels decreased by 54% from 770 cells/μl at baseline to 350 cells/μl on day 14 (p<0.001, Mann-Whitney, n=73), but lymphocytes did not change (1410 to 1380 cells/μl, p=0.90). Monocytes then increased during the 14d without treatment (320 vs. 540 cells/μl, p<0.001, n=64). The decrease in monocytes was greater in pts with PD then in pts with CB (58% vs. 48%, Wilcoxon Rank Sum, p=0.03). At baseline, mature CECs did not differ significantly between the CB and PD groups (mean 1.6 ± 1.3 [SD] vs. 3.9 ± 4.6 CECs/μl). All 7 pts with CB had a rise in mature CECs after 6–20d of therapy with SU11248 to a mean value of 24.4 ± 35.4 CEC/μl. Only 4 of 9 patients with PD had a rise in CECs to a mean of 6.8 ± 11.6 CEC/μl. There was a statistically significant difference in the rate of change per day in CECs between the two groups (3.8 ± 5.9 CEC/μl vs. -0.01 ± 0.1 CEC/μl, Wilcoxon, p=0.03). Conclusions: In pts with GIST, monocytes decreased during treatment with SU11248, with a greater decrease in pts with PD. In a subset of pts, increases in mature CECs were greater in pts with CB than PD. Monocyte and CEC levels may be pharmacodynamic markers for SU11248 activity, with CECs correlating more closely than monocytes with CB in GIST pts treated with SU11248. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer Pfizer Pfizer
Prognostic impact of perioperative CA-125 levels in patients with endometrial cancer.
Authors: S. Y. Tong, J. Lee, J. Lee, J. W. Kim, C. Cho, S. Kim, S. Park, C. Park, K. Kim
Journal: Journal of Clinical Oncology (2011)

e15573 Background: Endometrial cancer is one of the most common gynecologic cancers in the western world, and serum CA-125 levels have been widely used clinically for preoperative diagnosis and prediction of disease recurrence. The purpose of this study was to determine whether preoperative CA-125 levels could be prognostic factor and whether a change in preoperative to postoperative CA-125 or the postoperative CA-125 could predict overall survival. Methods: We included 495 patients with paired pre-and postoperative CA-125 measurements who underwent surgical treatment for endometrial cancer from 8 tertiary medical centers between 1996 and 2008, and their relationships to clinicopathological factors and overall survival were analyzed with univariate and multivariate methods. Results: In univariate analysis, preoperative and postoperative CA-125, stage, grade, deep myometrial invasion, cervical stromal invasion, pelvic lymph node metastasis, and histologic subtype were significantly associated with overall survival. Differences in overall survival were significant between groups divided on the basis of four preoperative CA-125 cutoff values (35, 70, 100, and 200) and postoperative CA-125 cutoff values (25, 35, 70, and 100). In multivariate analysis, postoperative CA-125 cutoff value of 35 U/ml (HR 1.98, p=0.04), stage (HR 3.42, p=0.002), deep myometrial invasion (HR 2.93, p=0.002), and histologic subtype (HR 2.44, p=0.01) remained independent predictors of prognosis. Conclusions: Both preoperative and postoperative CA-125 correlated with pathological prognostic factor of endometrial cancer. Postoperative CA-125 level could be a better predictor for overall survival than preoperative CA-125 levels.
Trastuzumab in combination with bevacizumab in advanced breast cancer patient resistant to chemotherapy
Authors: J. Ordonez, C. Gomez Martin, H. Cortes-Funes
Journal: Journal of Clinical Oncology (2006)

10762 Background: HER2 positive is associated with up-regulation of VEGF in human breast cancer cells. Superior efficacy was observed if anti-HER2 antibody (trastuzumab) (TZB) is given with anti-VEGF antibody (bevacizumab) (BVB) in xenografs models (Konecny G., 2004). In one phase I study with 9 patients (pt), the combination TZB+BVB was well tolerated without important toxicity, achieving 1 complete response and 4 partial responses (Pegram M, 2005). Methods and Result: We report a clinical case of a 48 years old woman with an advanced resistant breast cancer diagnosed in 1995 and treated with radical surgery for a invasive ductal carcinoma pT2N1M0 HHRR - and c-erbB2 positive (+++). She received adjuvant CMF for 6 cycles and local radiotherapy (XRT). In 2000, lung and liver metastases (mts) with increased CA 15.3 serum levels and was treated with paclitaxel + TZB achieving complete response. Maintenance with TZB was given for one additional year. In 2002, bone and brain mts with increase of CA 15.3 and was treated with vinorelbine + TZB with whole brain irradiation. On March 2005, bone and liver progression was treated with capecitabine + TZB and pelvic XRT with control of the mts. On August, pt developed rapid progression of liver mts with intensive abdominal pain requiring high doses of morphine; progressive jaundice (total bilirubin: 24.4 mg/dl) and low performance status. The level of CA 15.3 was 626 U/ml. We decide treatment with TZB + BVB in a biweekly schedule for 6 consecutive weeks. Whole liver XRT was given in two weeks (15.5Gy). The treatment was well tolerated and the pt improves immediately her clinical situation. Levels of CA 15.3 dropped to 161 U/ml and bilirubin to 4.87 mg/dl. The pt continues the treatment in ambulatory regiment for 7 additional weeks. She had a pathological hip fracture at home and was admitted to the Hospital developing an acute lung tromboembolism dying suddenly. Liver metastases still in clinical and biochemical response. Conclusions: The combination of TZB with BVB could be an effective alternative treatment for pt with advanced and resistant breast cancer, erbB2 positive, and need to be explored in clinical trials. No significant financial relationships to disclose.
Nevus Comedonicus
Authors: Anisha Bhullar, Norashikin Shamsudin
Journal: New England Journal of Medicine (2015)

A 19-year-old man presented with a congenital skin lesion on the left clavicular region. Closely arranged, dilated follicular openings with keratinous plugs resembling classic comedones were distributed linearly along the left clavicle and extending to the upper back.
Phase II trial using combination of oxaliplatin, capecitabine, and celecoxib with concurrent radiation in patients with operable rectal cancer.
Authors: W. S. Ho, F. Lee, M. Roach, A. Small, B. J. Liem, G. Wong, G. Heywood, M. H. Fekrazad, Y. Z. Patt
Journal: Journal of Clinical Oncology (2010)

e14117 Background: Achieving complete pathological response (CPR) with neoadjuvant chemoradiation may predict a higher likelihood of long-term survival in patients with operable rectal cancer. However, studies done with single agent 5-FU based regimen have yielded conflicting data. This may be due to the inherent low activity of 5-FU in treating micrometastatic diseases. In animal models, celecoxib has been shown to increase cytotoxic effects of radiation while exerts protective effects to normal skin. We therefore conducted a phase II trial using combination of oxaliplatin, capecitabine and celecoxib concurrent with radiation in patients with operable rectal cancer. Methods: Twenty-one patients are enrolled in this single-arm phase II trial of neoadjuvant chemoradiation for patients with T3-4N0-2M0 rectal cancer from March 2006 to July 2009. Age range is 30-71 and eight are female. Pretreatment staging are assessed by colonoscopy, endoscopic ultrasound, and CT or PET/CT. Chemoradiation regimen consists of a total dose of 45 Gy radiation therapy in 25 fractions from Monday to Friday over 5 weeks. Oxaliplatin 50 mg/m2/weekly and capecitabine 850 mg/m2/bid are given five days a week with radiation therapy. Celebrex 200 mg bid are given throughout the duration of radiation without a break. Results: Seventeen out of twenty-one patients completed the treatment. Six patients (35.3%) had CPR, four (25.3%) had near complete pathological response (NCPR) and seven (41.1%) had residual disease (RD). The median survival has not been reached for the whole treatment group with a median follow-up of 24 (range 6-42) months. None of the patients with CPR had disease progression with follow-up range from 6-42 months. Grade 2-3 nausea, vomiting and diarrhea were the most common side effects. However, two patients had grade 4 symptoms that required hospitalization and subsequently developed fatal arrhythmia and sepsis. Conclusions: This regimen is effective in inducing a very high rate of CPR in patients with locally advanced resectable colon cancer. This phase II trial is ongoing and anticipate completion in 2010. No significant financial relationships to disclose.
Dectin-1 Deficiency and Mucocutaneous Fungal Infections
Authors: László Maródi, Melinda Erdös
Journal: New England Journal of Medicine (2010)

367(HAPO) study. 3,4Fifteen institutional review boards approved our protocol, and none rejected the trial on ethical grounds.In addition, an independent data and safety monitoring committee regularly reviewed the trial.Some participants would not even have met the criteria for gestational diabetes (more evidence of clinical equipoise).We strongly disagree with an assertion that we unnecessarily exposed participants to harm.Randomized trials are necessary provided that there is sufficient uncertainty and that the results will resolve the dispute among physicians, which was the case for the treatment of mild gestational diabetes. 5We agree that our results may encourage previously reluctant physicians to treat gestational diabetes, but such treatment is now supported by evidence from a clinical trial rather than by expert opinion alone.
Outcome of localized and advanced diffuse large B-cell non-Hodgkin bone lymphoma (DBL)
Authors: F. Aubin, M. Isler, R. Turcotte, T. Ducruet, J. Beaudet
Journal: Journal of Clinical Oncology (2007)

18527 Background: DBL represents less than 2% of all lymphomas in adults. Over the years, combined-modality treatment (CMT) using an anthracycline-based chemotherapy regimen (ChT) and radiotherapy (RT) has emerged for the treatment of localized DBL (LDBL). Methods: Data were collected from the HMR oncology orthopaedic data bank. Thirty patients with localized and advanced DBL at diagnosis treated at HMR between December 1993 and August 2004 were included. Primary end-points were event-free survival (EFS) and overall survival (OS). Statistical analyses were performed using Kaplan-Meier and Cox proportional hazard models. Results: The median follow-up was 38.6 months. Fourteen patients had limited stage I-II disease while 16 patients had stage IV disease. Femur (33%) and spine (33%) were the most frequently involved bone sites. Ten patients had bulky disease (&gt;10cm). Patients were treated as followed: 50% with CMT, 33% ChT alone and 17% only RT. CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) was the only chemotherapy regimen used. Four patients received rituximab (R-) combined with CHOP. Patients received an average of 5 cycles of ChT (range 1–8). RT dose was between 30 and 40 Gy for 70% of patients. Doses of 30 Gy and higher show a tendency to offer an OS advantage (hazard ratio (HR) =0.2, 95%CI 0.03- 1.35). The 5-year estimates EFS and OS were respectively 48% (95%CI 27%-71%) and 60% (95%CI 38%-82%) for the whole group and 70% (95%CI 50%-99%) and 81% (95%CI 57%-99%) for patients with LDBL. All four patients treated with R-CHOP have a sustained complete remission (CR). Patients receiving CMT have significantly improved EFS (p=0.02, HR=0.25, 95%CI0.08–0.83) but not OS. Patients with advanced disease may benefit from CMT for EFS (HR=0.23, 95%CI 0.05–1.12). Factors which adversely affect EFS and/or OS (univariate analyses) are: stage IV disease (p&lt;0.05 EFS/OS), axial localisation (p&lt;0.05 EFS) and IPI 4 (p=0.072 EFS, p&lt;0.05 OS). Conclusion: This study supports CMT as an efficient treatment for DBL. Patients treated with R-CHOP have a favourable outcome. RT dose of 30–40 Gy appears sufficient to obtain a prolonged CR. No significant financial relationships to disclose.
A phase II study of weekly irinotecan and carboplatin for previously untreated extensive disease small cell lung cancer
Authors: T. Mio, M. Kawahara, H. Yoshioka, K. Yanagihara, T. Daimon, K. Furuse
Journal: Journal of Clinical Oncology (2008)

19078 Background: The prognosis for the patients with extensive disease small cell lung cancer (ED-SCLC) is still poor. We conducted a phase II study to evaluate the efficacy and safety of weekly irinotecan (CPT) and carboplatin (CBDCA) regimen for patients with ED-SCLC. Methods: Patients with previously untreated ED-SCLC, ECOG-PS 0–2, adequate organ function and willingness to provide informed consent were eligible. Patients with massive pleural effusion and symptomatic brain metastasis were excluded. CBDCA (AUC 2) and CPT (50 mg/m2) were administered on days 1 & 8 of every 3-week cycle. Treatment was continued until progression, up to a maximum of 6 cycles or unacceptable toxicity. The primary endpoint was response rate. Toxicity and efficacy analyses were performed on the intent-to-treat (ITT) population. Toxicity was graded by CTC version 2.0. Planned sample size was 55 patients. Results: Between Dec. 2003 and Sep. 2006, 56 patients were enrolled and 55 patients were eligible. Patients baseline characteristics are: 47 men and 7 women; PS0=14, PS1=38, PS2=3; median age 64 years. A total of 215 cycles were administered with an average of 3.9 cycles per patient. Of 55 ITT patients, 5 achieved CR, 36 PR, 4 SD and 4 PD, resulting in an ORR of 74.5%. Six patients could not be evaluated for response due to early withdrawal. Median survival is 14.1 months (CI 95%: 11.5–17.0) and 1 year survival rate is 58.15%. Median time to progression is 5.1 months (CI 95%: 4.6–6.8). The chief grade >2 toxicities included leukocytopenia 2 (0.9%), neutropenia 32(14.7%), appetite loss 10 (4.6%), nausea 7(3.2%), infection 5 (2%), fatigue 5(2%), diarrhea 2 (0.9%), One grade 5 infection was reported. Conclusions: Weekly CBDCA and CPT is well tolerated and has promising anti-cancer activity in ED-SCLC. No significant financial relationships to disclose.
Impact of CYP2C19 Metabolizer Status on Patients With ACS Treated With Prasugrel Versus Clopidogrel
Authors: Jacob A. Doll, Megan L. Neely, Matthew T. Roe, Paul W. Armstrong, Harvey D. White, Dorairaj Prabhakaran, Kenneth J. Winters, Suman Duvvuru, Scott S. Sundseth, Joseph A. Jakubowski, Paul A. Gurbel, Deepak L. Bhatt, E. Magnus Ohman, Keith A.A. Fox
Journal: Journal of the American College of Cardiology (2016)
Small Molecule Activators Of AMPK Block The Glycogen Production Required For Transformation Of Myeloid Leukemia Cells
Authors: Haymanti Bhanot, Mamatha M. Reddy, Atsushi Nonami, Ellen L. Weisberg, Kelly Xing, Sabrina K. Salgia, John M. Asara, Richard M. Stone, James D. Griffin, Martin Sattler
Journal: Blood (2013)
Thousand mile journey (part II): collaborative steps to advance the management of groin pain in athletes
Authors: Adam Weir
Journal: British Journal of Sports Medicine (2015)

Last year I wrote an editorial, “From disruption to consensus: the thousand mile journey”,1 to accompany the British Hernia Society's position statement on the treatment of sportsman's groin.2 This was the first time a consensus approach had been trialled in the field of groin pain in athletes. Since this first step on the long journey to improve outcomes for athletes with groin pain, the field has advanced further. The first World Conference on Groin Pain in Athletes was held in Doha, Qatar, in November 2014. After the conference, the “Doha Agreement Meeting on Terminology and Definitions in Groin Pain in Athletes” was held in Aspetar Hospital.

EB White stated that “there is …
Effect of EGFR and IGF1R on feedback activation of AKT arising from inhibition of mTOR in malignant pleural mesothelioma (MPM).
Authors: M. Brevet, S. Shimizu, Q. Zhou, A. Olshen, M. F. Zakowski, V. W. Rusch, M. Ladanyi
Journal: Journal of Clinical Oncology (2010)

e13607 Background: NF2 inactivation is one of the major genetic alterations in MPM and has recently been causally associated with activation of the mTOR pathway. In other cancers, inhibition of the mTOR pathway by rapamycin is associated with AKT feedback activation. This paradoxical AKT activation is mediated by IGF1R in some cancers, but may be mediated by other RTKs in certain settings. EGFR and MET are frequently expressed and activated in MPM. To define the therapeutic potential of mTOR inhibition in MPM, we examined rapamycin with and without EGFR and IGF1R inhibition in 13 MPM cell lines. Methods: The RTK inhibitors (TKI) erlotinib (EGFR inhibitor) and MK-0646 (IGF-1R inhibitor, gift of Merck) were tested in combination with rapamycin, an mTOR inhibitor, on 13 mesothelial cell lines. Results: Rapamycin (0.1nM- 72h) induces AKT feedback activation in 10/13 MPM cell lines when cultured in RPMI+10%FCS. This feedback activation disappears when the cells are cultured in RPMI without FCS. MK-0646 in combination with rapamycin induced a significant decrease of cell proliferation in 6 cell lines (compared to either alone), with decreased phospho- AKT in most lines. Sensitivity to the IGF-1R inhibitor MK-0646 did not correlate with expression of total IGF-1R or phosho- IGF-1R by ELISA. Erlotinib in combination with rapamycin induced a significant decrease of cell proliferation in 7/13 MPM cell lines (compared to either alone). Three cell lines show sensitivity to either TKI in combination with rapamycin. Among the 3 cell lines resistant to the combination of rapamycin + erlotinib/MK-0646, 2 cell lines show no AKT feedback activation when rapamycin was given alone. The third cell line, Meso 9, is highly sensitive to rapamycin despite prominent AKT feedback activation. Conclusions: In MPM as in other cancers, the inhibition of mTOR by rapamycin induces AKT feedback activation which can be blocked by TKIs. Our results identify EGFR and IGF1R as mediators of this effect in MPM. The characterization of the RTKs involved in this feedback activation could permit the development of new therapeutic strategies. No significant financial relationships to disclose.
Efficacy and safety of every-2-weeks cetuximab combined with FOLFOX or FOLFIRI as first-line therapy in patients with <i>KRAS</i> wild-type metastatic colorectal cancer (mCRC): An Asia-Pacific nonrandomized phase II study (APEC).
Authors: Ann-Lii Cheng, Gerardo H. Cornelio, Lin Shen, Timothy Jay Price, Tsai-Shen Yang, Ik-Joo Chung, Guanghai Dai, Jen-Kou Lin, Atul Sharma, Kun-Huei Yeh, Brigette Ma, Adel Zaatar, Zhongzhen Guan, Nehal Masood, Vichien Srimuninnimit, Thomas Cheung Yau, Barbara Sarholz, Robert S.C. Lim
Journal: Journal of Clinical Oncology (2013)

e14501 Background: Randomized studies have shown that weekly cetuximab added to first-line FOLFOX or FOLFIRI improves clinical outcome in patients (pts) with KRAS wild-type (wt) mCRC. This Asia-Pacific multicenter study investigated FOLFOX or FOLFIRI + every 2 weeks cetuximab (C) as first-line therapy in pts with KRAS wt mCRC. Methods: Eligible pts received every 2 weeks cetuximab (d1 500 mg/m 2 q14d) with, based on investigator’s choice, either FOLFOX (oxaliplatin 100 mg/m 2 , folinic acid [FA] 200 mg/m 2 L-form or 400 mg/m 2 racemic, then 5-fluorouracil [5-FU], as a 400 mg/m 2 iv bolus and a 2400 mg/m 2 infusion over 46 h) or FOLFIRI (irinotecan 180 mg/m 2 , FA 200 mg/m 2 L-form, or 400 mg/m 2 racemic, then 5-FU, as a 400 mg/m 2 iv bolus and a 2400 mg/m 2 infusion over 46 h), until disease progression, unacceptable toxicity or consent withdrawal. Primary endpoint was tumor response; assessed radiologically (RECIST 1.0) every 8 weeks. Results: Data cut-off was 86 weeks after the date of last patient included. The ITT/safety population comprised 289 pts; 65.1% received FOLFOX + C and 34.9% FOLFIRI + C. Baseline characteristics were generally well balanced. Leukocyte count &gt;10000/mm 3 was more frequent (16.5% vs 7.9%) and prior adjuvant treatment less frequent (21.3% vs 46.5%) in pts receiving FOLFOX + C. Response (CR or PR) was observed in 170 (58.8%) pts. The overall R0 resection rate was 10.0%. Survival data are not mature. Cetuximab dose intensity was &gt;80% in 77.7% (FOLFOX + C) and 74.3% (FOLFIRI + C) of pts. Most frequent grade 3/4 adverse events (&gt;10% in either arm) were neutropenia, diarrhea, hypokalemia, neuropathy (FOLFOX + C only) and skin reactions. Conclusions: Efficacy and safety profiles of every 2 weeks cetuximab combined with FOLFOX or FOLFIRI were similar to those reported for either chemotherapy plus weekly cetuximab in pivotal studies. Clinical trial information: NCT00778830. [Table: see text]
Precision Therapy for Pediatric Cancers
Authors: Javed Khan, Lee J. Helman
Journal: JAMA Oncology (2016)

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