tbuckley/cabot-search huggingface dataset:
Oral vorinostat (suberoylanilide hydroxamic acid, SAHA) in relapsed diffuse large B-cell lymphoma (DLBCL): Final results of a phase II trial
Authors: M. Crump, B. Coiffier, E. D. Jacobsen, L. Sun, J. L. Ricker, H. Xie, S. R. Frankel, S. S. Randolph, B. D. Cheson
Journal: Journal of Clinical Oncology (2007)

18511 Background: Vorinostat (Zolinza™) is a histone deacetylase inhibitor (HDACI) approved in the US for the treatment of cutaneous manifestations in patients (pts) with cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following 2 systemic therapies. Clinical responses with vorinostat have been reported in other lymphoma subtypes. Methods: Open-label, single-arm, nonrandomized Phase II trial of oral vorinostat 300 mg bid (initially 14 d/3 wks; amended to 3 d/wk) until disease progression or intolerable toxicity. Eligibility: measurable, relapsed/refractory DLBCL; = 2 prior systemic therapies; adequate hematologic, hepatic and renal function. Pts who had prior HDACI treatment, allogeneic transplant, or had failed &gt; 3 prior therapies were excluded. Primary endpoint: objective response rate (ORR) measured by CT/PET. Secondary endpoints: assessment of response duration (DOR), time to progression (TTP), time to response (TTR) and safety. Results: Eighteen pts (median age, 66 y [range, 59–86 y]; median 2 prior systemic therapies) were enrolled from 5/05 - 3/06 at 8 centers. Seven pts were initially treated with 300 mg bid 14 d/3 wks, but 4 had DLT (Gr 3 muscle spasms; Gr 4 thrombocytopenia, n = 3). The schedule was amended to 300 mg bid 3 d/wk and no other pt had DLT. One pt on the 3d/wk schedule achieved a CR (TTR = 85 d; DOR = 225+ d) and the ORR was 5.6%. One pt had SD for 301 d. Sixteen pts discontinued (DC) due to PD; median TTP for all pts was 44 d. Median number of treatment cycles was 2 (range, 1–14+). Two pts received &gt; 6 cycles (126 d). Common drug-related adverse experiences (AE; mostly = Gr 2) were diarrhea (61%), fatigue (50%), nausea (39%), anemia (33%) and vomiting (33%). Three pts had dose reduction (300 -&gt; 200 mg bid 14 d/3 wks) and none DC due to a drug-related AE. Drug-related AE = Gr 3 included thrombocytopenia (n = 3; 300 mg bid 14 d/3 wk) and asthenia (n = 2; 300 mg bid 3 d/wk). Two pts died on study of causes unrelated to drug: PD + GI hemorrhage (d 40) and acute myocardial infarction (d 95). Conclusion: Vorinostat has modest activity in pts with relapsed DLBCL and is well tolerated at 300 mg bid 3 d/wk or 200 mg bid 14 d/3 wks. The optimal dose/schedule and predictive response biomarkers require further study. No significant financial relationships to disclose.
Electrical and structural adaptations of the paediatric athlete’s heart: a systematic review with meta-analysis
Authors: Gavin McClean, Nathan R Riding, Clare L Ardern, Abdulaziz Farooq, Guido E Pieles, Victoria Watt, Carmen Adamuz, Keith P George, David Oxborough, Mathew G Wilson
Journal: British Journal of Sports Medicine (2017)

Aim To describe the electrocardiographic (ECG) and echocardiographic manifestations of the paediatric athlete’s heart, and examine the impact of age, race and sex on cardiac remodelling responses to competitive sport. Design Systematic review with meta-analysis. Data sources Six electronic databases were searched to May 2016: MEDLINE, PubMed, EMBASE, Web of Science, CINAHL and SPORTDiscus. Inclusion criteria (1) Male and/or female competitive athletes, (2) participants aged 6–18 years, (3) original research article published in English language. Results Data from 14 278 athletes and 1668 non-athletes were included for qualitative (43 articles) and quantitative synthesis (40 articles). Paediatric athletes demonstrated a greater prevalence of training-related and training-unrelated ECG changes than non-athletes. Athletes ≥14 years were 15.8 times more likely to have inferolateral T-wave inversion than athletes &lt;14 years. Paediatric black athletes had significantly more training-related and training-unrelated ECG changes than Caucasian athletes. Age was a positive predictor of left ventricular (LV) internal diameter during diastole, interventricular septum thickness during diastole, relative wall thickness and LV mass. When age was accounted for, these parameters remained significantly larger in athletes than non-athletes. Paediatric black athletes presented larger posterior wall thickness during diastole (PWTd) than Caucasian athletes. Paediatric male athletes also presented larger PWTd than females. Conclusions The paediatric athlete’s heart undergoes significant remodelling both before and during ‘maturational years’. Paediatric athletes have a greater prevalence of training related and training-unrelated ECG changes than non-athletes, with age, race and sex mediating factors on cardiac electrical and LV structural remodelling.
A phase I study of selumetinib (AZD6244/ARRY-142866) in combination with cetuximab (cet) in refractory solid tumors and KRAS mutant colorectal cancer (CRC).
Authors: Dustin A. Deming, William R. Schelman, Sam Joseph Lubner, Daniel Mulkerin, Noelle K. LoConte, Suzanne Fioravanti, Tim Greten, Jens C. Eickhoff, Jill Kolesar, Kathryn Compton, Laurence A Doyle, George Wilding, Austin G. Duffy, Glenn Liu
Journal: Journal of Clinical Oncology (2012)

3103 Background: KRAS mutations have been recognized as clinically important predictors of resistance to EGFR-directed therapies in CRC. Oncogenic activation of the RAS/RAF/MEK/ERK signaling cascade mediates proliferation independent of growth factor receptor signaling. We hypothesized that targeting MEK with selumetinib could overcome resistance to cet in KRAS mutant CRC. A phase I study (NCT01287130) was undertaken to determine the tolerability, and pharmacokinetic profiles of the combination of selumetinib and cet, with an expanded cohort in KRAS mutant CRC at the MTD dose to evaluate preliminary anti-tumor activity. Methods: In the dose escalation portion, patients (pts) with advanced solid tumors received fixed dose cet with escalating doses of selumetinib in cohorts of 3-6 pts. In the expansion cohort, 14 pts with KRAS mutant CRC were enrolled at the MTD level. Results: 15 pts (9 M, 6 F), average age of 60 (41-73) years were treated at 3 dose levels in the dose escalation cohort and 14 pts were treated in the expansion cohort. Pts had the following tumor types: CRC 73%, NSCLC 13%, and H&amp;N 13%, and had received a median of 4 (1-8) prior lines of therapy. 33% (only CRC) had prior EGFR-directed therapies. ECOG PS 0 (40%), 1 (53%), 2 (7%). 13 of 15 pts were evaluable for tolerability and response. One DLT for grade 4 hypomagnesemia occurred, and no other grade 4 toxicities were seen. Grade 3 (20%) toxicities included; rash, hyponatremia, and headache. The most common cycle 1 grade 1 and 2 adverse events included acneiform rash (100%), fatigue (54%), nausea/vomiting, (54%), diarrhea (54%), dry skin (46%), fever (23%), and hypomagnesemia (15%). Most pts (60%) required no dose modifications. The MTD was established at selumetinib 75 mg PO BID and cet 250 mg/m 2 weekly following a 400 mg/m 2 load. Best response included 2 PR in pts with CRC and SD in 4 pts (1 SCC of the tonsil, 1 NSCLC, and 2 CRC). Conclusions: The combination of selumetinib and cet is well tolerated, and preliminary anti-tumor activity was observed in multiple pts. Results of the KRAS mutant CRC expansion cohort will be presented.
Phase II study of first-line radioembolization with yttrium-90 glass microspheres for intrahepatic cholangiocarcinoma.
Authors: Ravi Shridhar, Jessica M. Frakes, Binglin Yue, Richard D. Kim, Gregory M. Springett, Bulent Arslan, Junsung Choi, Bela Kis, Timothy Joseph Yeatman, Kenneth L Meredith, Sarah E. Hoffe
Journal: Journal of Clinical Oncology (2017)

482 Background: The standard of care for unresectable intrahepatic cholangiocarcinoma (ICC) is systemic chemotherapy. The role of liver directed therapy for ICC is controversial given the lack of level I data. We conducted a phase II study to determine the safety and effectiveness of first-line liver directed therapy with radioembolization with yttrium-90 (Y90) glass microspheres for ICC. Methods: Eligible patients were enrolled on an IRB-approved phase II study (NCT01253148). Patients were included if they had no evidence of extrahepatic metastases, Childs-Pugh A, without main portal vein thrombus, bilirubin &lt; 2 mg/dL, ECOG performance status of 0-2, and no prior chemotherapy, liver embolization, or radiation therapy for ICC. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS) and toxicity. Results: Twenty-five patients were enrolled between 2010 and 2013 with a median followup of 13 months (9-20 months). The median age was 76 years. Twenty patients came off study due to progression or death. The overall response rate was 56%. Median PFS was 6 months (95% CI: 4-12 months). This was likely due to tumors appearing larger after treatment due to tumor inflammation despite a decrease in CA19-9 levels. Univariate (UVA) and multivariate analysis (MVA) failed to identify any prognostic factors associated with PFS. Despite the low median PFS, median OS was 22 months (95% CI: 10 months to upper limit not reached). However, UVA and MVA failed to identify and prognostic factors for OS. Treatment was well tolerated with no reported grade 3 gastrointestinal or general disorder toxicities. Grade 3 ALT, AST, and alkaline phosphatase increase were reported in 4%, 4%, and 8%, respectively. Grade 4 hyperbilirubinemia and thrombocytopenia were reported in 4% and 4%, respectively. There were 2 patient who developed sepsis one patient who died within 30 days of treatment. Conclusions: First-line liver directed therapy with radioembolization with Y90 glass microspheres is a safe and effective treatment for ICC. Further prospective clinical trials are needed to identify the proper sequencing of liver directed therapy and systemic chemotherapy. Clinical trial information: NCT01253148.
Utilization and predictors of neoadjuvant chemotherapy for muscle-invasive bladder cancer in the Veterans Health Administration.
Authors: Gurdarshan Singh Sandhu, Suhong Luo, Angelique Zeringue, Kenneth Robert Carson, Kenneth Gerard Nepple, Seth A. Strope, M'Liss A. Hudson, Robert L. Grubb
Journal: Journal of Clinical Oncology (2012)

4594 Background: The survival benefit with neoadjuvant chemotherapy for bladder cancer was established in 2003. However, adoption of this paradigm in clinical practice has been slow. We explored the use of neoadjuvant chemotherapy and identified predictors of its use in a contemporary cohort in the Veterans Health Administration (VA). Methods: Using the national VA Clinical Cancer Registry, all patients diagnosed with clinical stage T2-4, N0 or Nx, M0 bladder cancer from 1997 to 2007 were stratified into surgically (radical cystectomy [RC], n=1,211) and nonsurgically managed groups (n=2,125). Receipt of neoadjuvant chemotherapy was defined as chemotherapy treatment up to 6 months before RC as well as initial treatment only with chemotherapy (without subsequent surgery or radiation) in the nonsurgical group. Temporal trends in neoadjuvant chemotherapy use were evaluated with a chi square test. Predictors of neoadjuvant chemotherapy were examined using a multivariable logistic regression model incorporating demographic, socioeconomic, comorbid, pathologic and hospital factors. Results: 6.3% and 8.3% of patients received neoadjuvant chemotherapy in the surgical and non-surgical group, respectively. Analysis of temporal trends in chemotherapy use demonstrated an increase in neoadjuvant chemotherapy use over time (p&lt;0.0001); from 3% (2003 and before) to 14% annually (2007). On multivariable analysis of both groups, older age and more recent diagnosis were predictive of neoadjuvant chemotherapy use (Table). Other covariates did not predict receipt of neoadjuvant chemotherapy. Conclusions: While overall use of neoadjuvant chemotherapy in the VA population with bladder cancer remains low, use thereof is slowly increasing, with a more recent diagnosis most strongly predicting its use. [Table: see text]
Critical Role for DOCK2 in CD8+/TCR− Graft Facilitating Cells Enhancing Engraftment of Hematopoietic Stem Cells
Authors: Yujie Wen, Mary J Elliott, Yiming Huang, Deborah R Corbin, Yoshinori Fukui, Mariusz Z Ratajczak, Suzanne T Ildstad
Journal: Blood (2011)
Correlation of stable disease (SD) as best response with survival outcomes in patients (pts) with clear cell (cc) metastatic renal cell carcinoma (mRCC) treated with high-dose interleukin-2 (HD IL-2).
Authors: Joseph Merriman, Kinjal Parikh, Srinivas Kiran Tantravahi, Alli M. Straubhar, Archana M. Agarwal, Arun Sendilnathan, Joan Van Atta, Julia A. Batten, Kenneth F. Grossmann, Wolfram E. Samlowski, David D. Stenehjem, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2014)

4577 Background: HD IL-2 is a standard of care for selected pts with mRCC. Generally objective responses (OR), i.e. complete response (CR) + partial response (PR), of 16-20% are discussed with pts, and not SD. Recent data suggest that cancer immunotherapy may improve survival without inducing OR. Thus, HD IL-2 may provide survival benefit to an additional group of pts not experiencing OR, but only SD as the best response. Methods: All sequential cc mRCC pts treated with HD IL-2 at the University of Utah (1988-2012) were included. Two practitioners independently assessed responses. Best responses were correlated with survival outcomes using Kaplan-Meier analysis. Results: A total of 176 pts (79% male; median age 55 yrs, range 13-76) were included and belonged to the following MSKCC risk categories: 51 (29%) good, 115 (65%) intermediate, and 10 (6%) poor. A CR was identified in 16 (9%), PR in 11 (6%), SD in 52 (30%), progressive disease (PD) in 68 (39%), and not evaluable for response (NE) in 29 (16%) pts. Median overall survival (OS) by risk category for the favorable, intermediate and poor groups was 47.6 (p=0.0005 vs intermediate), 18.0 (p<0.0001 vs poor), and 5.4 (p<0.0001 vs favorable) months (mo), respectively. Table shows correlation of best response with survival outcomes. Conclusions: A clinical benefit of HD IL-2 wasachieved in nearly half of all cc mRCC pts. SD was associated with clinically relevant survival outcomes. There was no statistical difference in outcomes between pts achieving a PR or SD. SD is an important response criterion for treatment with HD IL-2, and may be discussed with pts. Correlation of best responses with survival outcomes in mRCC pts treated with HD IL-2 . PFS, mos OS, mos Overall 5.6 19.9 CR vs PR 113.8 vs 14.8 (HR 0.34, CI 0.12-0.95) 182.0 vs 37.8 (HR 0.23, CI 0.06-0.74) CR vs SD 113.8 vs 11.0 (HR 0.22, CI 0.09-0.47) 182.0 vs 29.2 (HR 0.16, CI 0.04-0.41) SD vs (PD and NE) 11.0 vs 2.6 (HR 0.40, CI 0.28-0.58) 29.2 vs 9.7 (HR 0.42, CI 0.28-0.61) OR vs (SD, PD and NE) 40.3 vs 4.3 (HR 0.27, CI 0.15-0.44) 83.5 vs 16.3 (HR 0.24, CI 0.13-0.42) PR vs SD 14.8 vs 11.0 (HR 0.64, CI 0.28-1.31) 37.8 vs 29.2 (HR 0.68, CI 0.29-1.41)
Protective effect of ursodeoxycholic acid against chemotherapy-induced mucositis.
Authors: Seung Han Kim, Hoon Jai Chun, Jung Min Lee, Sang Yup Lee, Byeong Kwang Choi, In Kyung Yoo, Jae Min Lee, Hyuk Soon Choi, Eun Sun Kim, Bora Keum, Yoon Tae Jeen, Hong Sik Lee, Chang Duck Kim
Journal: Journal of Clinical Oncology (2017)

796 Background: Gastrointestinal mucositis is a serious side effect of chemotherapy. It increases the frequency of infection, risk of bleeding, and duration of hospitalization, consequently reducing subsequent chemotherapy doses. Ursodeoxycholic acid (UDCA), which is currently used in various liver diseases, exerts direct cytoprotective effects by stabilizing membranes, inhibiting apoptosis, and acting as an antioxidant. The protective effect of UDCA against chemotherapy-induced mucositis was assessed using an in vivo animal model. Methods: Sprague-Dawley rats were randomly assigned to the following 5 groups: non-chemotherapy and vehicle; 5-fluorouracil (5-FU) and vehicle; 5-FU and 10 mg/kg/day UDCA; 5-FU and 100 mg/kg/day UDCA; and 5-FU and 500 mg/kg/day UDCA. 5-FU (400 mg/kg) or physiological saline (control) was administered by intraperitoneal injection. UDCA was orally administered 1 day before 5-FU injection for 6 days. One day after the final UDCA dose, rats were sacrificed, and the intestines were dissected for tissue sampling and laboratory analysis. Results: UDCA promoted a higher body weight recovery, decreased villus destruction, and reduced inflammatory cytokines levels, at doses of 10 and 100 mg/kg/day. Villous fusion and destruction were pronounced in the 5-FU group compared with those observed in the UDCA-treated group or controls. The jejunal villous lengths were as follows: 212.8±58.0 µm, 331.3±18.0 µm, and 310.0±112.6 µm, in the 5-FU and vehicle, 5-FU and 10 mg/kg UDCA (p = 0.006), and 5-FU and 100 mg/kg UDCA groups (p = 0.046), respectively. Real-time polymerase chain reaction (RT-PCR) showed that IL-6 and TNF-α levels decreased in the 10 mg/kg and 100 mg/kg UDCA co-administration groups. Further, myeloperoxidase activity decreased in the UDCA co-administration group. Conclusions: UDCA significantly attenuated the reduction of the height of small intestinal villi and reduced inflammatory cytokine levels, thus highlighting the potential of UDCA as a preventive agent against chemotherapy-induced gastrointestinal mucositis. The specific protective mechanisms of UDCA on the gastrointestinal tract should be determined.
Longitudinal study of lung function in very prematurely born infants
Authors: Sanja Zivanovic, Jessica Lo, Mireia Alcazar Paris, Alan Lunt, Mark Thomas, Rupa Odedra, Tom De'ath, Sandy Calvert, Neil Marlow, Janet Peacock, Anne Greenough
Journal: European Respiratory Journal (2013)

Introduction : Small airway function of prematurely born infants may deteriorate over the first year after birth.

Aims and objectives : To determine whether small airway function, assessed by measuring the degree of gas trapping, changed between one and 12 years in children born extremely prematurely and whether any changes were affected by neonatal factors.

Methods : A subset of 42 children from the United Kingdom Oscillation Study (UKOS) who had detailed pulmonary function measurements at one and 12 years at a single centre were studied. Lung volumes were assessed by plethysmography (FRCpleth) and helium gas dilution (FRChe); the degree of gas trapping was calculated as the FRCHe: FRCpleth ratio. Changes in FRCHe: FRCpleth and the effects of gestation, sex, and oxygen dependency at 36 weeks PMA (BPD36) were analysed using mixed models.

Results : Nineteen of the infants were born between 23-25 weeks gestation and 23 between 26 and 28 weeks; 24 (57%) had BPD36. The mean (SD) for FRCHe: FRCpleth at one and 12 years were 0.90 (0.12) and 0.84 (0.12) respectively. For those with BPD36, the mean ratios were 0.87 (0.13) at age one year and 0.81 (0.13) at age 12 years; for those without BPD36, they were 0.94 (0.11) and 0.87 (0.10) respectively. Overall, there was a reduction in FRCHe: FRCpleth of 5.9% (95% CI: 0.70%, 11%; p=0.026) between ages one and 12 years after adjusting for birth weight, gestational age, sex and BPD36. There was no significant difference in the degree of deterioration between the children who had and not had BPD36.

Conclusion : These results suggest that small airway function deteriorates between one and 12 years in children born very prematurely.
Institutional variation in the thoroughness of pathologic assessment and pathologic complete response rates for locally advanced rectal cancers treated with neoadjuvant chemoradiation.
Authors: Oliver S Chow, Sujata Patil, Metin Keskin, Jesse Joshua Smith, Maria Widmar, David D. Smith, Karin Avila, Jinru Shia, Peiguo Chu, Julio Garcia-Aguilar
Journal: Journal of Clinical Oncology (2017)

696 Background: A pathologic complete response (pCR) after neoadjuvant therapy and surgical excision is associated with a better prognosis and guides the management of patients with locally advanced rectal cancer. It is not known whether the thoroughness of pathologic assessment correlates with the finding of pCR. Methods: We introduce a surrogate measure for the thoroughness of pathologic assessment by taking the ratio of maximum residual tumor size and the number of cassettes prepared from the tumor: the Tumor Size to Cassette Ratio (TSCR). We retrospectively reviewed pathology reports from 259 patients with Stage II/III rectal cancer enrolled in a multicenter prospective clinical trial to determine whether TSCR is associated with pCR. Results: Of 247 included patients, 71 (29%) had a pCR. The pCR rate ranged from 0-45% and TSCR ranged from 0.0004 to 1.67 across the twelve trial sites. TSCR was significantly associated with pCR on univariable analysis. On multivariable analysis, TSCR remained significantly associated with pCR (odds ratio of 0.05; 95% CI 0.008-0.302) after adjusting for clinical stage, tumor size, distance from anal verge, radiation dose, and the number of neoadjuvant cycles of FOLFOX received. Conclusions: Pathologists tend to assess rectal cancer specimens with a pCR more thoroughly, but the thoroughness of pathologic assessment of residual tumor specimens varies between institutions. The thoroughness of pathologic assessment is associated with pCR. This raises the need for further standardization in the assessment of rectal cancer specimens after neoadjuvant chemoradiation.
Results of a phase II study of pralatrexate in patients with advanced/metastatic relapsed transitional cell carcinoma of the urinary bladder.
Authors: Yohann Loriot, Karim Fizazi, Joan Carles, Garry Alan Weems, Lacey Chance, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2012)

4574 Background: Antifolate agents have demonstrated activity in transitional cell carcinoma (TCC), a disease with very poor outcomes in advanced stages. Pralatrexate (FOLOTYN, Allos Therapeutics, Inc., Westminster, CO), a folate analogue targeting dihydrofolate reductase, is designed for enhanced uptake and accumulation in tumor cells. The objective of this study was to examine the activity and safety of pralatrexate in patients (pts) with advanced/metastatic TCC of the urinary bladder after failure of prior chemotherapy. Methods: Pts with histologically confirmed TCC (&gt;50% TCC in tumor) received pralatrexate 190 mg/m² intravenously on days 1 and 15 of a 28‑day cycle supplemented with vitamin B 12 and folic acid. Included pts had Eastern Cooperative Oncology Group performance status of 0–1, measurable disease, and prior treatment with ≤1 platinum- and/or methotrexate-based regimen in the recurrent/metastatic setting. Results: Thirty pts were enrolled and treated. All pts received prior platinum-based therapy, and 7 pts (23%) received methotrexate in a multidrug regimen. One pt had a confirmed partial response (PR); 4 additional pts had unconfirmed PRs. Twelve pts had stable disease. The median number of cycles received was 2 (range, 1–24), and median time on treatment was 56 days (range, 1–714). The median progression-free survival (PFS) and overall survival for all pts was 4.0 months (95% confidence interval [CI], 2.1–4.5) and 9.3 months (95% CI, 5.6–13.2), respectively. Eight pts (27%) had PFS &gt;6 months and 3 pts (10%) had PFS &gt;12 months. Eight pts (27%) underwent dose reductions, all due to mucositis. Six pts (20%) discontinued the study due to treatment-related adverse events (AEs)—mainly mucositis. The most frequent treatment-related AEs were stomatitis (77%), asthenia (30%), vomiting (27%), and anemia, nausea, and neutropenia (23% each). Conclusions: Pralatrexate showed evidence of activity and durable disease control when used as a single agent in pts with advanced bladder cancer, although the overall response rate was modest. Further study of pralatrexate in this setting should focus on improving drug delivery and evaluation of novel combination approaches.