tbuckley/cabot-search huggingface dataset:
Boosting long-term immune responses to sipuleucel-T (sip-T) by retreatment of patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Tomasz M. Beer, John Corman, Raymond S. Lance, Dwayne Campogan, Tuyen Vu, Heather Haynes, Nancy N. Chang, Nadeem Anwar Sheikh, Brendan D. Curti
Journal: Journal of Clinical Oncology (2017)

196 Background: Sip-T, an autologous cellular immunotherapy for asymptomatic/minimally symptomatic mCRPC, induces immune responses to target antigens prostatic acid phosphatase (PAP) and PA2024, a recombinant protein of PAP and granulocyte macrophage colony-stimulating factor. Immune responses with sip-T correlate with overall survival. PROTECT (phase 3 NCT00779402) assessed sip-T in biochemically recurrent androgen-dependent PC. PROTECT pts developing mCRPC were eligible for P10-1 (phase 2 NCT01338012). Methods: PROTECT pts (sip-T arm) were retreated with sip-T in mCRPC. Antigen presenting cell (APC) activation (CD54 molecule ratio after and before culture with PA2024), cellular (PA2024/PAP ELISPOT; T cell proliferation) and humoral responses were assessed and compared with treatment-naïve mCRPC pts (IMPACT NCT00065442; STAMP NCT01487863; STRIDE NCT01981122). Results: Caucasian men (n=8), median follow-up 9.2 y and age 74 y, had an ECOG PS of 0 (75%) or 1. Median APC activation with sip-T infusion 1 was ~3-fold higher in P10-1 (20; n=7) vs treatment-naïve mCRPC pts (7; n=447). In P10-1, high magnitude cellular and humoral responses were seen at baseline (BL) (Table). Immune memory was heterogeneous, strong BL humoral and/or robust cellular memory was observed. Sip-T boosted PA2024/PAP cellular and humoral responses (Table). Immune responses were maintained up to wk 52, and were higher over time vs 1 st time treated mCRPC pts. Conclusions: Sip-T in an earlier disease setting generated sustained antigen-specific immune memory lasting up to 10 y. Consistent with vaccine-induced immune responses, sip-T retreatment rapidly boosted both cellular and humoral antigen-specific responses in mCRPC pts. Clinical trial information: NCT01338012. [Table: see text]
Comprehensive genomic profiling (CGP) of cervical squamous cell carcinoma (cSCC) to identifiy targeted therapy options.
Authors: Julia Andrea Elvin, Mark Bailey, Benedito A. Carneiro, Siraj Mahamed Ali, Jo-Anne Vergilio, Norma Alonzo Palma, Juliann Chmielecki, Garrett Michael Frampton, Doron Lipson, Phil Stephens, Vincent A. Miller, Melissa Lynne Johnson, Francis J. Giles, Jeffrey S. Ross, Oliver Dorigo
Journal: Journal of Clinical Oncology (2015)

5602 Background: High risk HPV initiates neoplasia in cSCC and progression requires additional genomic alterations (GA). Treatment of localized cSCC is effective but the response to systemic therapy for metastatic disease is inadequate. CGP of 99 advanced stage cSCC was undertaken to identify GA associated with targeted therapeutic options relevant to the systemic treatment of cSCC. Methods: DNA was extracted from 99 FFPE cSCC clinical specimens. Hybridization captured libraries of 236 (FoundationOne, n = 66) or 305 (FoundationOne, n = 33) genes, plus select introns frequently rearranged in cancer were sequenced to high ( > 450x), uniform coverage. HPV16 and HPV 18 viral sequences were detected, but other hrHPVs were not assayed. All classes of genomic alterations (base subs, small in/dels, rearrangements, and copy number alterations) were evaluated and reported. CRGA were defined as GA associated with on-label targeted therapies and targeted therapies in mechanism-driven clinical trials. Results: 99 samples (54% primary,45% metastasis) from women (avg 47.7y) with predominantly advanced stage cSCC were profiled. 368 total GA were identified (3.7 GA per tumor) involving 80 different genes, of which 257 were CRGA (2.57 per tumor). 91% of cSCC cases featured > 1 CRGA, including 67 (67%) cases with CRGA in the PI3K/Akt/mTOR pathway. The most common CRGAs observed were: PIK3CA (41%), MLL2 (18%), PTEN (16%), STK11 (14%), FBXW7 (11%), FGFR3 (4.6%), ERBB2 (4.6%), KRAS (4.6%). To date, we are aware of one patient with abdominal and thoracic nodal metastases and a CGP-identified inactivating mutation in FBXW7 who showed a 6-months partial response to everolimus treatment. FGFR3-TACC3 gene fusions were rarely identified (3%); one late lung recurrence case showed stable disease on a multikinase inhibitor targeting FGFR. Conclusions: Most advanced stage cSCC demonstrate CRGAs, most commonly in the PI3K/Akt/mTOR pathway, and clinical response to mTOR inhibition can be achieved. Other driver events, including FGFR3 fusions, present alternatives for targeted therapy. Patients who have exhausted other SOC for metastatic cSCC have achieved clinical benefit from CGP-directed therapeutic decision-making.
Dose adjustment of axitinib based on AUC in sunitinib-pretreated metastatic renal cell carcinoma.
Authors: Yuji Miura, Chiyo K. Imamura, Keita Uchino, Takeshi Kishida, Nobuaki Matsubara, Toshiaki Shinojima, Keiichi Kondo, Fumiya Hongo, Kenichi Yoshimura, Yusuke Tanigawara, Toshimi Takano
Journal: Journal of Clinical Oncology (2017)

457 Background: Axitinib is one of the standard second-line therapies after sunitinib in patients (pts) with metastatic renal cell carcinoma (mRCC). The previous study showed that higher exposure and diastolic blood pressure (dBP) were independently associated with better clinical outcomes. However, many factors, such as antihypertensive agents use, usually affect dBP. Therefore, axitinib dose adjustment based on its exposure could be more adequate than that based on dBP. Methods: We conducted a prospective phase II trial of axitinib dose adjustment for Japanese pts with mRCC previously treated with sunitinib. Starting dose of axitinib was 5 mg BID. We assayed blood axitinib levels on day 1 and calculated the area under concentration-time curve from 0 to 12 hours (AUC 0-12 ). We determined the individual sufficient dose (SD) to reach AUC 0-12 value at the steady state of 150 ng*hr/mL. After day 15, axitinib dose was adjusted to keep over SD according to adverse drug reaction for each patient. The primary endpoint is 6-month progression-free survival (6m-PFS) rate. Secondary endpoints include toxicity and objective response rate. With power of 80% and one-sided alpha of 10%, thirty-two pts were required to reject 48% of 6m-PFS rate under expected 69% 6m-PFS rate. Results: Between May 2013 to March 2015, 26 pts were enrolled when the trial closed for poor accrual. Pts’ characteristics were: median age 71 years, male 20 (77%), PS 0 19 (73%), and International Metastatic RCC Database Consortium intermediate risk 24 (92%). Median SD of axitinib was 3 mg BID (range 1-16). SD was given at a median of 78% (range 0-100) of total administration day until 6 months. Two pts did not receive the planned SD because their SD was over 10 mg BID. Therefore, the two pts were excluded from safety analysis; meanwhile all pts were included in efficacy analysis. The 6m-PFS rate was 85% (95% CI 66-94, p &lt; 0.01). The median PFS was 10.6 months (95% CI 7.2-16.7). The most common grade 3 to 4 adverse events during the first 6 months were hypertension (79%), decrease appetite (29%), fatigue (13%), and hand-foot syndrome (13%). Conclusions: The individual dose adjustment of axitinib to keep over 150 ng*hr/mL of AUC 0-12 on day 1 for sunitinib-pretreated mRCC is feasible. Clinical trial information: UMIN000009579.
Clinical Prediction Model and Tool for Assessing Risk of Persistent Pain After Breast Cancer Surgery
Authors: Tuomo J. Meretoja, Kenneth Geving Andersen, Julie Bruce, Lassi Haasio, Reetta Sipilä, Neil W. Scott, Samuli Ripatti, Henrik Kehlet, Eija Kalso
Journal: Journal of Clinical Oncology (2017)

Purpose Persistent pain after breast cancer surgery is a well-recognized problem, with moderate to severe pain affecting 15% to 20% of women at 1 year from surgery. Several risk factors for persistent pain have been recognized, but tools to identify high-risk patients and preventive interventions are missing. The aim was to develop a clinically applicable risk prediction tool. Methods The prediction models were developed and tested using three prospective data sets from Finland (n = 860), Denmark (n = 453), and Scotland (n = 231). Prediction models for persistent pain of moderate to severe intensity at 1 year postoperatively were developed by logistic regression analyses in the Finnish patient cohort. The models were tested in two independent cohorts from Denmark and Scotland by assessing the areas under the receiver operating characteristics curves (ROC-AUCs). The outcome variable was moderate to severe persistent pain at 1 year from surgery in the Finnish and Danish cohorts and at 9 months in the Scottish cohort. Results Moderate to severe persistent pain occurred in 13.5%, 13.9%, and 20.3% of the patients in the three studies, respectively. Preoperative pain in the operative area ( P &lt; .001), high body mass index ( P = .039), axillary lymph node dissection ( P = .008), and more severe acute postoperative pain intensity at the seventh postoperative day ( P = .003) predicted persistent pain in the final prediction model, which performed well in the Danish (ROC-AUC, 0.739) and Scottish (ROC-AUC, 0.740) cohorts. At the 20% risk level, the model had 32.8% and 47.4% sensitivity and 94.4% and 82.4% specificity in the Danish and Scottish cohorts, respectively. Conclusion Our validated prediction models and an online risk calculator provide clinicians and researchers with a simple tool to screen for patients at high risk of developing persistent pain after breast cancer surgery.
Evidence for selective benefit of sequential treatment with azanucleosides in patients with myelodysplastic syndromes (MDS).
Authors: Rami S. Komrokji, Susmitha Apuri, Najla Al Ali, Eric Padron, Javier Pinilla-Ibarz, Viet Ho, Alan F. List, Jeffrey E. Lancet
Journal: Journal of Clinical Oncology (2013)

7113 Background: Azanucleosides (AZN) remain the mainstay of therapy in myelodysplastic syndrome (MDS). Sequential use of AZNs is common practice given the limited alternatives. The only published experience described 14 patients showing a 28% response with decitabine (DAC) after failure or lack of response to azacitidine (AZA). To investigate the potential benefit of this approach,we reviewed cases of sequential AZN treatment. Methods: Patients who received treatment with both AZNs were identified through the Moffitt Cancer Center MDS database. Two groups were identified; group one who received DAC after AZA failure and group 2, who received AZA after DAC failure. The primary objective was to estimate overall response rates according to the International Working Group (IWG) 2006 criteria. The Kaplan–Meier method was used to estimate median OS. Results: A total of 39 MDS patients were identified who received treatment with both AZNs. Complete records were available in 31 patients, including 21 patients in group 1 (DAC after AZA) and 10 patients in group 2 (AZA after DAC). The Table summarizes baseline characteristics and response rates. The median OS for Group 1 from diagnosis was 48 months and for group 2 was 100 months (p=0.7). Conclusions: Sequential use of AZNs after failure of first line may be an effective alternative outside the context of clinical trials. Response rate is higher in patients who receive AZA after DAC. Sequential use of HMA should be considered in context of randomized clinical trial of novel agent as the control arm. [Table: see text]
Associations between allergies and risk of hematologic malignancies: Results from the Vitamins and Lifestyle (VITAL) cohort study.
Authors: Mazyar Shadman, Roland B. Walter, Anneclaire DeRoos, Emily White
Journal: Journal of Clinical Oncology (2012)

1527 Background: Several case-control studies have suggested a reduced risk of hematologic malignancies (HMs) for individuals with allergies, but results have been inconsistent, and prospective cohort studies have not confirmed this association. Herein, we used the large prospective VITAL study to examine this association. Methods: 64,847 men and women, aged 50-76, completed a baseline questionnaire in 2000-2002 and reported on their current allergies and history of physician-diagnosed asthma. Individuals with prior cancer other than non-melanoma skin cancer were excluded from this analysis. Incident HMs were identified through December 2009 by linkage to the SEER registry; those with a diagnosis of a non-HM during follow-up were censored at the time of that diagnosis. Multivariable Cox proportional hazards models were built with adjustment for sex, race/ethnicity, education, smoking, self-rated health, physical activity, history of anemia in the year before baseline, vegetable use and family history of leukemia or lymphoma. Results: Our analysis included 64,839 participants, among whom 681 (1.03%) incident HMs were found (MDS [69], AML (41], myeloproliferative disorders [60], mature B-cell neoplasms [262], chronic lymphocytic leukemia [107], plasma cell disorders [83], Hodgkin lymphoma [23], T-cell/NK-cell neoplasms [22], and others [14]). In multivariable analyses, a history of any allergy was associated with increased risk of HM (HR=1.21; 95% CI 1.02-1.43, p=0.02). This association was seen for current allergies to plants/grass/trees (HR 1.27 [1.06-1.52], p&lt;0.001) but not for allergies to mold/dust, animals, insects, food, or medications. We did not find an association between a history of asthma and incident HMs (HR=0.95 [0.72-1.26]). Conclusions: Our study indicates a moderately increased risk of HMs inindividuals with a history of allergy, especially to plant, grass or trees. While no causality can be inferred, this may suggest a possible carcinogenic role for chronic stimulation of the immune system. However, further mechanistic investigations focusing on the biochemical markers of immune system as well as on possible gene effect modifiers are needed.
Allogeneic transplantation for myelofibrosis: Benefit of dose intensity.
Authors: Uday R. Popat, Roland Bassett, Julianne Chen, Amin Majid Alousi, Paolo Anderlini, Stefan O. Ciurea, Chitra Hosing, Roy B. Jones, Partow Kebriaei, Issa F. Khouri, Sergej Konoplev, Marcos De Lima, Yago Nieto, Betul Oran, Muzaffar H. Qazilbash, Gabriela Rondon, Elizabeth J. Shpall, Srdan Verstovsek, Borje Andersson, Richard E. Champlin
Journal: Journal of Clinical Oncology (2013)

7011 Background: We did a prospective study of busulfan (bu) and fludarabine (flu) conditioning in patients with myelofibrosis. After observing a high relapse rate in the initial cohort, we increased the intensity of conditioning regimen for subsequent patients, hypothesizing that increased dose intensity delivered with PK guidance will reduce relapse rate without increasing non relapse mortality (NRM), thereby improving overall outcome. Methods: Patients with intermediate or high risk MF were eligible if they had adequate organ function and at least 9/10 matched related or unrelated donor. Of the 46 consecutive patients, 15 (bu low group) received IV busulfan 130 mg/m 2 x 2 (day -3,-2). Of the remaining 31 (bu high group), 27 received IV busulfan dose to a target daily AUC of 4000 μmol.min x 4 (day -5 to -2) and 4 patients received a fixed dose of 100 mg/m 2 x 4 (days -5 to -2). All patients received fludarabine 40mg/m 2 x 4 (day -5 to -2). Results: 23 males and 23 females with a median age of 58 years (27-74) had intermediate (25) or high-risk (21) disease. Donors were matched sibs (19), matched unrelated (23), or mismatched unrelated (4). With a median follow-up of 2.1 years (range 0.1-6 years), 3-year overall survival(OS), event-free survival (EFS), cumulative incidence (CI) of non-relapse mortality (NRM), and CI of relapse were 69%, 50% , 13%, and 37%, respectively. Multivariate Cox regression analysis showed that Bu-high dose (HR 0.41; p=0.04) and peripheral blood CD 34 count (HR 1.7; p=0.03) were significantly associated with EFS, and high CD-34 count was significantly associated with OS (HR 1.87; p=0.04). Table shows details of 3-year outcomes of low-dose and high-dose group. All patients engrafted with a median time to neutrophil engraftment of 13 (0-27) days and a median time to platelet engraftment of 24 (0-268) days. Cumulative incidence (CI) of grade II-IV, grade III, IV acute GVHD, and Chronic GVHD were 22%, 5%, and 39%, respectively. Conclusions: Higher dose busulfan, delivered with pharmacokinetic dose adjustment, reduces relapse without increasing non-relapse mortality, resulting in better EFS in patients with MF. Clinical trial information: NCT00475020. [Table: see text]
A phase I study of enzastaurin (Enz) combined with pemetrexed (Pem) in advanced non-small cell lung cancer (NSCLC)
Authors: T. Takahashi, N. Yamamoto, H. Murakami, Y. Ohe, H. Kunitoh, H. Nokihara, M. Koshiji, T. Tamura
Journal: Journal of Clinical Oncology (2009)

2572 Background: Enz is an oral serine-threonine kinase inhibitor that is designed to suppress tumor growth through PKC and PI-3 kinase/AKT. Pre-clinical data shows Enz's synergistic activity with Pem in many cancer cell lines including NSCLC. This phase 1 study is to evaluate the safety, pharmacokinetics (PK), and clinical activity of two schedules of Enz combined with Pem in patients (pts) with previously treated advanced NSCLC. Methods: An oral daily dose of 500 mg Enz was given once daily (QD) in cohort 1 or twice daily (BID) in cohort 2 in combination with 500 mg/m 2 Pem on day 1 in repeated 21-day cycles. Cycle 1 started with a 7-day Enz lead-in treatment that preceded Pem administration: a loading dose of 1125 mg on day 1 followed by 500 mg total daily dose on days 2–7. Blood samples for PK evaluation were collected on day 2 of cycle 1 (following loading dose) and day 1 of cycle 2 (steady- state). Samples were analyzed for Enz, Pem, and its active metabolites. Results: 12 pts (8 males, 4 females; ECOG PS 0–1) with median age of 62 (49 - 74) were enrolled into this study and completed safety evaluation for cycle 1: 8 pts with adenocarcinoma, 3 pts with squamous cell carcinoma, and one with other. All pts had received prior platinum-based chemotherapy. Total analyte concentrations (sum of Enz and its metabolites) reached steady-state by day 8 of dosing. Total analyte mean steady-state average concentrations (%CV) following QD and BID dosing were 2850 nmol/L (53.5%) and 3420 nmol/L (39.5%), respectively. Exposures following loading dose were within the range of concentrations seen at steady-state. Enz dosing regimen (QD or BID) did not alter Pem PK. One dose-limiting toxicity (Grade 3 QTc prolongation) occurred 1 day after the Enz loading dose in cohort 1. Grade 3/4 toxicities occurring in 6 pts included leukocytopenia, neutropenia (3 pts each), increased ALT, and increased AST (2 pts each). To date, 1 pt achieved PR and 6 pts achieved SD. 5 pts received more than 10 cycles of treatment without disease progression; 4 of these pts are still on therapy. Conclusions: Both schedules of Enz in combination with Pem are well tolerated and clinically active in pts with advanced NSCLC. [Table: see text]
Growth modulation index (GMI) as a metric of clinical benefit assessment among advanced soft tissue sarcoma (ASTS) patients receiving trabectedin as salvage therapy.
Authors: Nicolas Penel, George D. Demetri, Jean-Yves Blay, Sophie Cousin, Robert G. Maki, Sant P. Chawla, Ian Robert Judson, Margaret von Mehren, Patrick Schoffski, Jaap Verweij, Paolo Giovanni Casali, Sjoerd Rodenhuis, Javier Gomez, Antonio Nieto, Patrik Zintl, Maria Jose Pontes Valero, Alexia Cassar, Axel Le Cesne
Journal: Journal of Clinical Oncology (2012)

10013 Background: Von Hoff has proposed GMI &gt;1.33 in cancer clinical trials as a sign of drug activity. GMI is the ratio between time to progression (TTP) with the nth line (TTP n ) of therapy divided by the TTP n-1 with the n-1th line of therapy. With this endpoint, each patient is his/her own control. Methods: We have carried out a retrospective analysis of 279 pretreated ASTS patients treated in four consecutive phase II trials with trabectedin 1.5 mg/m², given as a 24-hour infusion every 3 weeks. Results: The study population consisted of 170 women and 109 men with a median age of 52. The two most common histologies were leiomyosarcoma (145 patients, 52%) and liposarcoma (59, 21%). 142 (51%) patients received one prior line and 137 (49%) ≥2 lines. The median TTP n was 2.8 months (range: 0.2-26.8), whereas the median TTP n-1 was 4.0 months (range: 0.3-79.5). The Spearman correlation coefficient between TTP n-1 and TTP n was 0.07 (p=0.23). The median GMI was 0.6 (range: 0.0-14.4). 177 patients (63%) had a GMI &lt;1, 21 (8%) a GMI = 1-1.33 and 81 (29%) a GMI &gt;1.33. The median overall survival (OS) strongly correlated with GMI groups: OS was 9.1, 13.9 and 23.8 months, respectively (p=0.0005, log-rank test). There were also a strong correlations between response rate and GMI (p&lt;0.0001, Fisher exact test), and between GMI and progression-free survival (&lt;0.0001, log-rank test). The logistic regression analysis retained only performance status (PS) [OR=1.76 if PS=0; p&lt;0.04] associated with GMI&gt;1.33. Sarcoma grade (p=0.21), histological subtype (p=0.16), and number of prior chemotherapy lines (p=0.95) were not associated with GMI&gt;1.33. Conclusions: Overall,≈30% of patients experienced GMI&gt;1.33 regardless of histological subtype or grade, and number of prior lines of chemotherapy. Patients with PS=0 benefit more from trabectedin. GMI&gt;1.33 is associated with longer OS (median ≈24 months). GMI is better defined than previously described parameter such as "Tumor Growth Rate" (Lopez-Martin, Abstract 3293, ASCO 2003). GMI as an indicator of drug activity merits further exploration in this setting.
The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: Guidelines for Reporting Observational Studies
Authors: Erik von Elm, Douglas G Altman, Matthias Egger, Stuart J Pocock, Peter C Gøtzsche, Jan P Vandenbroucke
Journal: PLoS Medicine (2007)

Much biomedical research is observational. The reporting of such research is often inadequate, which hampers the assessment of its strengths and weaknesses and of a study's generalisability. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Initiative developed recommendations on what should be included in an accurate and complete report of an observational study. We defined the scope of the recommendations to cover three main study designs: cohort, case-control, and cross-sectional studies. We convened a 2-day workshop in September 2004, with methodologists, researchers, and journal editors to draft a checklist of items. This list was subsequently revised during several meetings of the coordinating group and in e-mail discussions with the larger group of STROBE contributors, taking into account empirical evidence and methodological considerations. The workshop and the subsequent iterative process of consultation and revision resulted in a checklist of 22 items (the STROBE Statement) that relate to the title, abstract, introduction, methods, results, and discussion sections of articles. 18 items are common to all three study designs and four are specific for cohort, case-control, or cross-sectional studies. A detailed Explanation and Elaboration document is published separately and is freely available on the Web sites of PLoS Medicine, Annals of Internal Medicine, and Epidemiology. We hope that the STROBE Statement will contribute to improving the quality of reporting of observational studies.
ABO Identical and Washed Transfusions Are Candidate Strategies to Reduce Early Mortality in Acute Promyelocytic Leukemia (APL)
Authors: Majed A. Refaai, Kelly F Henrichs, Joanna M. Heal, Amy E Schmidt, Jason H. Mendler, Scott A. Kirkley, Christopher Aquina, Debra Masel, Jane Liesveld, Neil Blumberg
Journal: Blood (2016)