tbuckley/cabot-search huggingface dataset:
Retrospective study comparing tolerability of weekly paclitaxel in two group of metastatic breast cancer patients: Age 65 and older compared with younger than age 65.
Authors: Agnieszka I. Jagiello Gruszfeld, Zbigniew Nowecki, Izabela Lemanska, Renata Irena Sienkiewicz, Halina Rudnicka, Jerzy Giermek, Tadeusz Pienkowski
Journal: Journal of Clinical Oncology (2014)

e20528 Background: Weekly paclitaxel (PCL) is the active agents for the treatment of advanced breast cancer (ABC), and the safety and efficacy of this program has been carefully explored. The tolerability of a lot of cytotoxic combinations usually used in ABC treatment, is unsatisfactory in elderly patients. We therefore performed a retrospective study to compare the toxicity profiles of weekly PCL (80mg/m2) in two group patients: aged 65 years and older vs younger than 65 years. Methods: We evaluated 139 metastatic breast cancer patients who are treated at our Center from Jun. 2012 to Sep. 2013: 71 pts in the group 1 ( ≥65 ) and 68 pts in the group 2 (< 65). The mean of age was 73.5 (range: 65 – 88) in the group nr 1 and 61 (range: 38 – 64) in the group nr 2. The majority of pts (89%) were treated in 2nd or 3rd line of chemotherapy. Localizations of metastatic lesions, HR and HER2 – receptors status , Karnofsky Performance Status were similarly in each group. Treatment was continued to progression or unaccepted toxicity. Results: All pts were evaluated for toxicity. Grade 3 or 4 neutropenia was significantly more common in the older pts (14 vs 6%). FN was not observed. Fatigue, anemia and thrombocytopenia (grade 1-3) were more common in the older group. Peripheral sensory neuropathy (grade 1-2) increased with every cycle of treatment, but in a similar manner in the two groups. Grade 3-4 neuropathy was not recorded. Nausea and vomiting were a limited problem in both groups with prophylactic antiemetic treatment (ondasetron 8 mg iv and dexaven 10 mg iv ). Only in 2 pts in group 1 and 1 pts in group 2 treatment was interrupted due to toxicity (1 allergic reaction, 1 neutropenia and 1 thrombocytopenia). In 56% of pts in older group the dose of PCL was reduced to 60 or 65 mg/m2 during the time of treatment (in majority due to fatigue). In the group 2 only in 12% of pts dose of PCL was reduced. The overall response rate was similarly in the both group (28%). The clinical benefit was 58% vs 51% respectively. The median overall survival rate was yet not reached. Conclusions: These results suggest that the dose of weekly paclitaxel in elderly metastatic breast cancer pts (≥ 65) should be reduced to 60 or 65 mg/m2.
Rechallenge with trabectedin in patients with locally advanced or metastatic soft tissue sarcoma following drug holiday: The experience of the French Sarcoma Group (FSG).
Authors: Esma Saada, Chahineze Rahal, Isabelle Ray Coquard, Antoine Italiano, Christine Chevreau, Nicolas Isambert, Binh Bui, Alexia Cassar, Isabelle Desmoulins, Axel Le Cesne, Jean-Yves Blay, Antoine Thyss
Journal: Journal of Clinical Oncology (2012)

10062 Background: Trabectedin (T) is a marine-derived alkaloid used to treat advanced soft tissue sarcomas (STS) after ifosfamide and/or anthracyclins failure. Since then, the FSG evaluated the clinical benefit in re-administrating T after an initial hold, either medically indicated or upon patient’s request. Methods: Following an online request, clinical and histopathological data were collected from six centers of the FSG who declared to have rechallenged patients. Baseline data were collected and analyze will be used. Results: From 1999 to 2011, 49 pts with T drug holiday have been identified (26 male/ 23 female), with a median age of 50 y [23-75]. Most frequent histotypes were: myxoid liposarcoma (18, 36.7%), leiomyosarcomas (13, 26.5 %) and well-differentiated/dedifferentiated liposarcoma (9, 18%). WHO grade were 1 in 14 (29%), 2 in 19 (39%) and 3 in 5 (10%) pts respectively. Patients who had a maximum of 2, 3 or 4 therapeutic sequences (TS) with T (drug-holiday and rechallenge) were 41/49 ,7/49 and 1/49 respectively. Median number of cycles for 1, 2, 3 and 4 TS were 7 [3-21], 6 [2-30], 6 [2-9] and 6. Median total number of cycles was 15 [6-43]. Median duration of drug-holiday for 1, 2 and 3 TS were 11 [3-91], 7 [2-29] and 4 months [1-5]. Grade 3-4 toxicities incidence decreased with the number of TS (occurred in 36%, 29%, 14% and 0% of pts with 1, 2, 3 and 4 TS) as well as mean T dose per cycle (1.3 mg/m², 1.2 mg/m², 1.1 mg/m² and 1.1 mg/m² for TS 1, 2, 3, 4). Efficacy decreased with number of TS (Number of CR/PR/SD/PD were 1 (2%)/15 (31%)/33 (67%)/0 for TS1; 0/4 (8%)/29 (59%)/16 (3%) for TS2; 0/1 (14%)/2 (29%)/4 (57%) for TS3 and 0/0/0/1(100%) for TS4). Median overall survival was 5.0 y [2.7-7.3] since T introduction, and 1.5 y [0.1-4.8], 0.8 y [0.5-1.3] and 0.6 y following 2 nd , 3 rd and 4 th T reintroduction respectively. Objective response after TS2 were seen in 4 cases of grade 1 sarcomas. Conclusions: Due to the lack of cumulative toxicities over time with T, its rechallenging in responding patients to T (no progression under T) have to be considered in advanced STS.
NKTR-102 in patients with platinum-resistant ovarian cancer (PROC): Modeling CA125 response and its correlation with tumor response.
Authors: Yen Lin Chia, Ute Hoch, Abraham C. F. Leung, Michael A. Eldon
Journal: Journal of Clinical Oncology (2012)

5048 Background: NKTR-102 is a unique topoisomerase 1 inhibitor that provides continuous exposure to SN38. In heavily pretreated pts with PROC (median of 3 prior therapies; 27 pts were platinum refractory), 145 mg/m 2 NKTR-102 given q14d or q21d demonstrated significant anti-tumor activity (JCO 28:7s, 5013). We present a PK/PD model for CA125 kinetics that can be used to project GCIG response as an aide to selecting dose and schedule. Methods: Data from 55 pts with PROC and elevated CA125 (median baseline = 515 U/mL) were fit with a PK/PD model developed to correlate CA125 dynamics with SN38 conc-time profiles predicted from individual pt dosing history: d[CA125]/dt = Kin*exp(beta*t)*(1-[SN38]/(IC50+[SN38]))-Kout*[CA125]. Results: CA125 profiles were well described by the model, with a population mean SN38 IC50 of 1.1 ng/mL. Typical min and max SN38 conc during treatment were 1.5 and 3 ng/mL for q14d and 0.9 and 2.4 ng/mL for q21d, indicating that both schedules resulted in SN38 exposure near the IC50. The half-life of CA125 decline was 6.4 days, similar to literature values. 46 of 55 pts had pre- and post-treatment tumor measurements for correlation of CA125 response and tumor size. Overall best response by GCIG and RECIST correlated in 57% of pts. 33% of pts with GCIG response showed declines in tumor size, albeit insufficient to classify as RECIST response. 72% of pts with GCIG SD showed at least SD by RECIST. CA125 vs time was simulated for 1000 pts receiving 145 mg/m 2 NKTR-102 q14d or q21d, to allow comparison of CA125 and GCIG response between schedules (see table). The % pts per GCIG response was comparable between schedules, supporting use of the better-tolerated q21d regimen. Conclusions: The PK/PD model described CA125 profiles well, providing a tool to predict drug response from SN38 PK data. Close correlation of CA125 with tumor size is consistent with historical use of CA125 as a surrogate marker. Predicted CA125 profiles for NKTR-102 q14d or q21d were similar, suggesting that the better-tolerated q21d schedule will produce results consistent with those from Ph 2. [Table: see text]
Frontline Ofatumumab in Combination with Hyper-CVAD for Adult Patients with CD-20 Positive Acute Lymphoblastic Leukemia (ALL): Interim Result of a Phase II Clinical Trial
Authors: Koji Sasaki, Hagop M. Kantarjian, Farhad Ravandi, Naval Daver, Tapan M. Kadia, Rita B. Khouri, Yesid Alvarado, Jan A. Burger, Deborah A Thomas, Guillermo Garcia-Manero, Courtney D DiNardo, Naveen Pemmaraju, Nicholas J. Short, Heather Schroeder, Rebecca Garris, Prithviraj Bose, Nitin Jain, Kiran Naqvi, William G. Wierda, Srdan Verstovsek, Jorge E. Cortes, Marina Konopleva, Susan M. O'Brien, Elias J. Jabbour
Journal: Blood (2016)
The evolution of breast cancer screening in the Medicare population: Clinical and economic implications.
Authors: Brigid K. Killelea, Jessica B. Long, Xiaomei Ma, Rong Wang, Anees B. Chagpar, Joseph Ross, Cary P. Gross
Journal: Journal of Clinical Oncology (2012)

1595 Background: Breast screening has evolved as newer approaches to mammography, ultrasound, and MRI have diffused into clinical practice. The use of these technologies and their impact on screening-related costs and outcomes remain undefined, particularly among older women. Methods: Using the Surveillance Epidemiology and End Results – Medicare linked database, we identified women aged 66 and older without a diagnosis of breast cancer. We constructed two cohorts (2001 vs. 2006) and followed each for two years. We assessed changes in imaging technology, screening-related costs (defined as costs for screening and subsequent imaging and testing, adjusted to 2009 USD), and stage at diagnosis between the two cohorts. Results: There were 136,845 women in the 2001-2002 (earlier) cohort and 137,733 in the 2006-2007 (later) cohort. The mean age was 76.9 and 77.2 respectively, (p&lt;.001). The proportion of women receiving any screening mammogram was 42.5% in the earlier cohort and 43.4% in the later cohort, (p&lt;.001). The use of digital mammography for screening increased from 2.2% to 15.0%, (p&lt;.001). The use of any computer aided detection (CAD) increased from 3.2% to 29.3% (p&lt;.001). MRI use increased from 0.03% to 0.2%, and ultrasound use from 4.0% to 4.5% (p &lt;.001 for both). Average screening-related cost increased 31%, from $101 to $132 (p&lt;.001). There was no significant difference in early stage at diagnosis over time (58.1% of women were in situ/stage I in early period vs. 57.2% in later period, p=.65). Conclusions: The use of digital mammography and CAD increased substantially between 2001 and 2007, contributing to a 31% increase in screening-related costs for women in the Medicare program. The increased cost of screening and downstream testing must be evaluated in context of an absence of benefit in terms of stage at diagnosis.
Efficacy of the Children's Oncology Group (COG) long-term follow-up (LTFU) guidelines in reducing risk of congestive heart failure (CHF) in childhood cancer survivors (CCS).
Authors: F. Lennie Wong, Smita Bhatia, Seira Kurian, Wendy Landier, Liton Francisco, Wendy M. Leisenring, Melissa M. Hudson, Gregory T. Armstrong, Ann Mertens, Marilyn Stovall, Leslie L. Robison, Steven E. Lipshultz, Saro Armenian
Journal: Journal of Clinical Oncology (2012)

9505 Background: CCS are at risk for left ventricular dysfunction (LVD) and subsequent CHF due to exposure to anthracyclines and chest radiation (RT). COG LTFU guidelines recommend screening for LVD using echocardiograms (ECHOs) every 1-5y depending on anthracycline dose, RT, and age at cancer diagnosis. The relevance and cost-effectiveness of these consensus-based guidelines are unknown. Methods: Life expectancy and age at onset of CHF were projected in a simulated cohort (&gt;1 million) of CCS undergoing screening ECHO per COG guidelines. Intervention for LVD was modeled to reduce annual CHF risk by 30%. Quality-adjusted life-years (QALYs) and lifetime costs with and without ECHO screening were calculated. Non-CHF mortality was estimated from the Childhood Cancer Survivor Study and US population rates. Costs and QOL adjustments were obtained from the Healthcare Cost and Utilization Project and medical literature. Screening was considered cost-effective if it resulted in a &gt;6 month delay in onset of CHF and &lt;$50,000/QALY gained. Results: Recommended screening strategies (Table) were cost-effective in: i) CCS exposed to ≥300mg/m² of anthracycline regardless of RT or age; and ii) CCS diagnosed at age 1-4y, exposed to RT and &lt;300mg/m² of anthracycline. Screening was most cost-effective for CCS diagnosed at age 1-4y exposed to RT + ≥300 mg/m² of anthracycline (1.4y delay in CHF onset; $15,821/QALY gained). Screening as currently proposed was not cost-effective for other age/anthracycline/RT combinations. Conclusions: Recommended ECHO screening strategies are cost-effective for all CCS exposed to ≥300 mg/m² of anthracycline; screening was also cost-effective for those 1-4y at diagnosis, exposed to anthracycline &lt;300 mg/m² + RT. Alternate screening strategies are needed for CCS with other exposure conditions. [Table: see text]
Effective treatment of aggressive B-cell lymphomas by downregulated NIK-induced noncanonical NF-κB pathway activation through inhibition of BAFF.
Authors: Sung Hsin Kuo, Li-Tzong Chen, Kun-Huei Yeh, Hui-Jen Tsai, Hsiao-Wei Lee, Ann-Lii Cheng
Journal: Journal of Clinical Oncology (2013)

e13554 Background: We recently reported that autocrine BAFF (B cell–activating factor belonging to the TNF family) signal transduction pathway contributes to H. pylori-independent growth of gastric diffuse large B-cell lymphoma (DLBCL) (Blood 2008;112:2927-34; Ann Hematol 2010;89:431-6). In this study, we sought to investigate whether activation of BAFF signaling pathway can promote the survival and proliferation of aggressive B-cell lymphoma. Methods: Seven aggressive NHL cell lines (EBV-negative Burkitt’s lymphoma (Ramos), EBV-positive Burkitt’s lymphoma (Raji), EBV-negative undifferentiated lymphoma (MC116), activated B cell (ABC)-like DLBCL (OCI-Ly3, OCI-Ly10), and germinal center B cell (GCB)-like DLBCL (OCI-Ly7, and Pfeiffer) were used in this study. Cell cycle was analyzed by flow cytometry. The DNA-binding activity of NF-kB was determined by the luciferase assay. Expression of non-canonical NF-κB signatures-related proteins (BAFF, BAFF-R, NIK, cIAP1, TRAF2, cIAP1/2, TRAF3, IKKa, p100, p52 and RelB, BCL10, BCL3, and STAT3) was assessed by immunoblotting. Results: Our results showed that in GCB-DLBCL cell lines, activation of BAFF induced recruitment and degradation of TRAF3, which resulted in NIK kinase accumulation, BCL10 Ser 138 phosphorylation, IKKa phosphorylation, and NF-kB p100 processing, thereby resulting in continuous activation of non-canonical NF-kB pathway. This phenomenon also resulted in BCL3 nuclear translocation and STAT3 activation, and subsequently activated STAT3 downstream-regulated genes (BCL2, survivin, and cyclin D1). Furthermore, we found that inhibition of BAFF by short hairpin RNA (shRNA) suppressed the growth of ABC-DLBCL cells and Burkitt lymphoma cells through the down-regulation of BAFF/BAFF-R/TRAF3/NIK/BCL3/NF-kB signaling pathway. Conclusions: Our results indicate that constitutive BAFF signaling activates NIK-induced non-canonical NF-kB signaling pathway in aggressive B-cell lymphoma, and inhibition of BAFF is particularly effective in the treatment of this subgroup of tumors.
Ublituximab plus TGR-1202 activity and safety profile in relapsed/refractory B-cell NHL and high-risk CLL.
Authors: Matthew Alexander Lunning, Julie Vose, Nathan Hale Fowler, Loretta J. Nastoupil, Marshall T. Schreeder, Tanya Siddiqi, Christopher Flowers, Jonathon Brett Cohen, Susan Blumel, Myra Miguel, Warner H Tse, Emily K. Pauli, Kathy Cutter, Peter Sportelli, Hari P. Miskin, Michael S. Weiss, Swaroop V.S. Vakkalanka, Srikant Viswanadha, Susan Mary O'Brien
Journal: Journal of Clinical Oncology (2015)

8548 Background: Ublituximab (UTX) is a novel glycoengineered anti-CD20 mAb. TGR-1202 is a novel once daily oral PI3Kδ inhibitor. UTX + TGR-1202 has shown strong synergistic activity in-vitro (Lugano 2013). This phase I trial evaluates the safety and efficacy of the combination of UTX + TGR-1202 in patients (pts) with heavily pre-treated rel/ref NHL and CLL. Methods: A 3 + 3 design is utilized with rel/ref NHL or CLL pts accruing independently. No limits on prior therapies (Tx). Pts refractory to prior PI3K or BTK inhibitors are eligible. UTX administered D 1, 8, 15 of Cyc 1 & 2, followed by D 1 of Cyc 4, 6, 9 & 12. TGR-1202 is daily, with an improved micronized formulation introduced in later cohorts. Primary endpoints: Safety and dose limiting toxicities (DLT). Secondary endpoints: Efficacy (ORR, CR rate). Results: 32 pts enrolled and evaluable for safety: 12 CLL/SLL, 10 FL, 8 DLBCL, 1 MZL and 1 Richter’s. Med age 64 yo (range 35-82); 20 M/12 F; Median prior Tx = 3 (range 1-9). AE's (all causality) include: Day 1 infusion reactions at 44%, neutropenia 41% (31% Gr 3/4), diarrhea 34%, (0% Gr 3/4), and nausea 28% (0% Gr 3/4). To date, TGR-1202 related hepatotoxicity has not been reported. One DLT has occurred: a pt with Gr 3 neutropenia at study entry which worsened (cohort 1). A dose-response relationship has been observed with TGR-1202. 28/32 are evaluable for efficacy with best response in the table below. To date, of all 32 pts, 89% (16/18) in the higher dose cohorts remain progression-free compared to 57% (8/14) in the lower dose cohorts. Of the 10 CLL pts, all remain progression-free at a median of 8 months (range 2 – 12+ months). Conclusions: The combination of UTX + TGR-1202 is well tolerated with activity in rel/ref NHL and CLL with a dose-response relationship observed. Dose escalation continues with enrollment ongoing at the highest dose cohort and in recently opened expansion cohorts. Clinical trial information: NCT02006485. Type TGR-1202 Higher dose TGR-1202 Lower dose Pts (n) CR PR ORR n (%) PD Pts (n) CR PR ORR n (%) PD CLL/SLL 3 - 3 3 (100%) - 7 - 4 4 (57%) - DLBCL 4 2 1 3 (75%) 1 3 - - - 2 FL 6 1 2 3 (50%) - 4 - - - - Richter’s 1 - - - - - - - - - Total 14 3 6 9 (64%) 1 14 - 4 4 (29%) 2 Higher dose, 1200 original and 600/800 micronized; Lower dose, 800 original and 400 micronized.
PROXIMAL NEUROMUSCULAR CONTROL PROTECTS AGAINST HAMSTRING INJURY IN MALE FOOTBALL PLAYERS: A PROSPECTIVE STUDY WITH EMG TIME-SERIES ANALYSIS DURING MAXIMAL SPRINTING
Authors: Joke Schuermans, Lieven Danneels, Damien Van Tiggelen, Tanneke Palmans, Erik Witvrouw
Journal: British Journal of Sports Medicine (2017)

Background Hamstring injuries remain a substantial problem in male football. Proximal neuromuscular control (‘core stability’) is considered to be of key importance in hamstring injury prevention, although scientific evidence regarding the exact nature of the core-hamstring association is non-existing at present. Objective To investigate whether core muscle activation patterns during sprinting are associated with hamstring injury risk. Design Cohort study. Setting Amateur football division. Participants 60 male football players with no recent history of hamstring injury were recruited for the multi-muscle EMG time series analysis during sprint. Assessment Hamstring-, gluteal and trunk muscle activity time-series during the airborne- and stance phases of over-ground sprint acceleration were collected prior to follow up (1.5 seasons). Main Outcome Measurements EMG signals of the above-mentioned muscles were processed and explored in function of (1) the time within the running cycle and (2) injury occurrence during follow up. Results Players that remained injury free, presented significantly higher amounts of gluteal muscle activity during the front swing phase (p=0.018), and higher amounts of trunk muscle activity during the backswing phase of sprinting (p=0.0011). In particular, the risk of sustaining a hamstring injury during follow up lowered 87% and 46%, with each increment in normalized muscle activity of the Gluteus Maximus during front swing and the trunk muscles during backswing, respectively (p&lt;0.02). Conclusions Muscle activity of the proximal core unit during explosive running presented to be associated with hamstring injury occurrence. Higher amounts of gluteal – and trunk muscle activity during the airborne phases of sprinting were able to protect participants against injury during follow up. Hence, the present results provide a basis for improved, evidence based, rehabilitation and prevention, particularly focusing on increasing neuromuscular control of the gluts and trunk muscle during sport specific activities (eg. sprint drills, agility drills).
Brief Research Report: Novel Compound BCR-ABL Mutations in Late Chronic Phase Imatinib Sensitive CML Patients Are Associated with Progression to Advance Disease Phase
Authors: Zafar Iqbal, Afia Muhammad Akram, Tanveer Akhtar, Aamer Aleem, Muhammad Farooq Sabar, Zeba Aziz, Nadia Sajid, Mahmood Rasool, Muhammad Asif, Mehmood Husssain Qazi, Saleh Oraibi, Ammara T Gill, Khalid Al Jamaan, Mudassar Iqbal, Ahmad Mukhtar Khalid
Journal: Blood (2016)
The heterogeneity and clinical relevance of circulating tumor-initiating cells in hepatocellular carcinoma using an integrated immunomagnetic-microfluidic platform.
Authors: Xin-Rong Yang, Yun-Fan Sun, Yang Xu, Zhou Jian, Jia Fan
Journal: Journal of Clinical Oncology (2014)

e15132 Background: Circulating tumor-initiating cells (CTICs) with stem cell-like properties play important roles in tumor metastasis and recurrence. Little is known about CTICs biology and their clinical relevance. By using a novel integrated immunomagnetic-microfluidic platform, we investigated CTICs heterogeneity, molecular feature and clinical relevance in HCC. Methods: The CTICs detection platform was constructed and cell capture efficiency was evaluated using spiked cell experiments and was further compared with CellSearch system. We applied a four-channel microfluidic chip to investigate the composition of CTICs via simultaneous detection of 4 CTICs subsets (EpCAM+, CD133+, CD90+ and CD24+) in 14 primary HCCs and 13 recurrent HCCs. The dynamic changes of 4 CTICs subsets were serially monitored in 5 HCC patients. The retrieved CTICs were subjected to single-cell RNA profile. Results: A paired comparison in 25 HCC patients indicated that the number of EpCAM+ CTICs detected by microfluidic platform was significantly higher compared with CellSearch system (0.66±0.70 vs. 0.19±0.29, P=0.038). EpCAM+ CTICs ≥0.75/ml detected by the platform was a significant predictor of early recurrence (P<0.001). The median proportion of EpCAM, CD133, CD90 and CD24 subsets was 66.67%, 9.06%, 0%, and 0% in primary HCC and 0%, 0%, 52.27% and 9.09% in recurrent HCC, respectively. Serial CTICs monitoring in 5 patients suggested that the HCC recurrence was associated with an increase in CD90+ CTICs. Remarkably, acquired resistance to transcatheter arterial chemoembolization chemotherapy was accompanies by increasing proportion of CD24+ CTICs (0% to 75%). Single-cell transcriptional profiling showed heterogeneity among individual CTICs, separating 4 CTIC subsets into two distinct populations: EpCAM+ and CD24+ cells with epithelial phenotype, CD133+ cells and CD90+ cells with mesenchymal feature. Conclusions: CTICs heterogeneity was existed during tumor progression. The platform represents a novel and informative tool for accurate CTICs detection and characterization, enabling in-depth cancer biology research and clinical cancer management.