tbuckley/cabot-search huggingface dataset:
Long-term quality of life in high-risk prostate cancer: Results of a phase III randomized trial.
Authors: Abdenour Nabid, Nathalie Carrier, André-Guy Martin, Jean-Paul Bahary, Luis Souhami, Marie Duclos, François Vincent, Sylvie Vass, Boris Bahoric, Robert Archambault, Céline Lemaire
Journal: Journal of Clinical Oncology (2014)

5 Background: To evaluate long-term quality of life (QOL) in 630 patients with high-risk prostate cancer (HRPC) treated in a prospective randomized phase III trial (PCS IV clinical trials, Gov. # NCT 00223171). Methods: Patients were randomized to radiotherapy (RT) plus 36 or 18 months of androgen deprivation therapy (ADT). QOL was assessed by two validated tools: EORTC30 (30 items) and PR25 (25 items). The 55 items were regrouped into 21 scales: 15 for EORTC30 and six for PR25. All items and scales scores were linearly transformed to a 0 to 100 points scale. A p value less than 0.01 was considered statistically significant and a difference between groups in mean scores of greater than or equal to 10 points as clinically relevant. Patient-reported outcomes were filled out before treatments, every six months during ADT, four months after and then once a year for five years. All items and scales scores were analysed with general linear model with repeated measures to evaluate changes between groups and over time periods. Results: Three hundred ten patients were randomized to 36 months and 320 to 18 months of ADT, with a median follow-up of 79 months, there was no difference in survival outcomes. The global adherence to QOL questionnaires was 72.4% (10,052 out of 13,880). When comparing the two groups, 6 out of 21 scales (physical, emotional, and social functioning, fatigue, hormonal treatment-related symptoms, and sexual active) and 14 out of 55 items (trouble with long walks, stay in bed during the day, weakness, tenseness, worry, irritable, depressed, close to a toilet, blood in stools, hot flushes, enlarged breasts, interested in sex, sexually active, enjoyable sex) were statistically significant (p&lt; 0.01) in favor of the 18 months ADT group. None of the 21 scales reached clinical relevance (mean scores greater than or equal to 10 points) sexual active being the highest score with 9.0 points of difference. For the 14 statistically significant items, interest in sex with 9.9 points and sexually active with 8.1 points were close to clinical relevance and hot flushes with 24 points and enjoyable sex with 18 points had important clinical relevance at 42 months. Conclusions: In HRPC treated with RT and ADT, reducing the duration of ADT from 36 to 18 months improves QOL, without a negative impact on survival. Source of Funding: AstraZeneca Pharmaceuticals grant. Clinical trial information: PCS IV clinical trials, Gov. # NCT 00223171.
Patient-reported outcomes (PROs) from TH3RESA, a phase 3 study of trastuzumab emtansine (T-DM1) versus treatment of physician’s choice (TPC) in patients with pretreated HER2-positive advanced breast cancer.
Authors: Karen Bartley, Hans Wildiers, Sung-Bae Kim, Ian E. Krop, Jennifer Kang, Ron Yu, Abraham C. F. Leung, Caroline Trudeau, Antonio Gonzalez-Martin
Journal: Journal of Clinical Oncology (2014)

153 Background: Progression-free survival and objective response rate were significantly improved with T-DM1 vs TPC in TH3RESA. The impact of treatment on quality of life is a key aspect in determining treatment value. Here we present the PRO results from the TH3RESA study. Methods: Patients were randomized 2:1 to T-DM1 (3.6 mg/kg every 21 days) or TPC. Patients were asked to complete the EORTC QLQ-C30 (a 30-item questionnaire assessing symptom bother, functioning and health status) and the EORTC QLQ-BM22 (a 22-item survey evaluating pain from bone metastases) at the start of each cycle. Data from patients with a baseline and ≥1 post-baseline assessment were included; a clinically meaningful difference was defined as ≥10 points. Time to pain progression (TPP) was assessed using the Kaplan-Meier method and Cox proportional-hazards models. Results: A greater proportion of patients in the T-DM1 arm (n=297) vs. the TPC arm (n=117) experienced a clinically meaningful improvement in global health status (57.8% [95% CI; 52.0–63.3] vs. 47.1% [95% CI; 38.4–56.4]). The most bothersome symptoms in the T-DM1 arm as measured by the EORTC QLQ-C30 were fatigue and pain. Over the first 10 T-DM1 treatment cycles, 19–30% of patients reported being impacted “quite a bit” or “very much” by fatigue, and 16–25% by pain. Nausea/vomiting and diarrhea were perceived as more tolerable, with 1–5% and 1–4% of patients reporting “quite a bit” or “very much” impact, respectively. TTP was 2.9 months in the T-DM1 arm vs 3.6 months in the TPC arm, but was not significantly different (HR 1.12 [95% CI; 0.82–1.52], p = 0.495). Mean baseline EORTC QLQ-BM22 pain scores were similar in the T-DM1 (n = 306) and TPC arms (n = 130); (25.4 ± 23.8 [SD]) and (27.3 ± 24.4), respectively. There were no clinically meaningful changes in pain levels from baseline over time in either arm. Conclusions: For patients on T-DM1, the most impactful symptoms were fatigue and pain, while the least bothersome were diarrhea and nausea/vomiting; distribution of severity of impact was relatively stable over the first 10 cycles of treatment. TPP was similar between the T-DM1 and TPC arms. Clinical trial information: NCT01419197.
Possibile role of vascular endothelial growth factor (VEGF) levels in immunodepleted plasma of metastatic colorectal cancer (mCRC) patients (pts) treated with a biweekly administration of capecitabine plus oxaliplatin (XELOX-2) plus bevacizumab: Preliminary results.
Authors: N. Silvestris, A. Azzariti, L. Porcelli, A. E. Quatrale, A. Paradiso, G. Colucci
Journal: Journal of Clinical Oncology (2011)

e14155 Background: Serum VEGF has been proposed as a surrogate biomarker for bevacizumab activity even if literature data are conflicting. Our study deepened the hypothesis that VEGF levels in immunodepleted plasma of mCRC pts could be a possible pharmacodynamic marker for this drug. Methods: We evaluated previously untreated mCRC pts receiving 4 cycles of XELOX-2 regimen (Fedele et al., ASCO 2009) in combination with bevacizumab (5 mg/kg on day 1 q2w). The determination of VEGF levels, total and free (meaning after immunodepletion of plasma samples) were measured at baseline and the days before the 2nd and the 5th cycle. Results: Four pts treated as above described and 3 pts treated with adjuvant FOLFOX-4 regimen (control arm) were considered. We observed that free VEGF levels significantly decreased from baseline to day 14 and 74 of bevacizumab treatment of about 40% and more than 50% in all patients with partial response. In Pts 3 with stable disease, the baseline level of VEGF free was lower with a decrease of 51% at 14 and 74 days. Conversely, the determination of total VEGF showed a slight reduction of its level (max 20%) after 14 and 74 days and an increase of about 30% in two samples (after 74 days) (Table 1). Analysis in pts receiving FOLFOX-4 regimen showed no significant variation among samples. Conclusions: These preliminary results can suggest that the measure of baseline circulating free VEGF levels may be useful as a predictive biomarker for bevacizumab-based treatment, with more efficacy when it is higher. The evaluations of other 3 pts will be ready within one month. VEGF levels (pg/mL) Baseline VEGF levels (pg/mL) Before the 2nd cycle VEGF levels (pg/mL) Before the 5th cycle Response to treatment free total free total free total Pts 1 188,5 230 117,5 171,25 92,5 207,5 PR Pts 2 128,75 152,5 77,5 150 77,5 206,25 SD Pts 3 182,5 255 98,75 223,75 58,75 197,5 PR Pts 4 185,5 240 101,5 212,75 83,5 213,5 PR Control 1 140 200 126,25 205 Control 2 226,25 227,5 212,5 206,25 Control 3 230,75 235 225,5 228,5 Abbreviations: PR, partial response; SD, stable disease.
Sunitinib (SU) plus extended courses of irradiated allogeneic lymphocytes (IAL) for patients with metastatic renal cell carcinoma (RCC).
Authors: Mark N. Stein, Lien Huzzy, Monica Anand, Chandrika Jeyamohan, Tina M. Mayer, Robert S. DiPaola, Mecide Meric Gharibo, Roger Strair
Journal: Journal of Clinical Oncology (2013)

464 Background: Treatment of patients with RCC using IAL from a haploidentical donor (sibling/parent), without prior conditioning of the recipient, induced tumor regressions in 3/13 patients with minimal toxicity (Strair J Clin Onc 2003:3785). Responses were not detected until after 2-3 courses, consistent with an immunologic mechanism. We hypothesize that combining the angiogenesis inhibitor SU with IAL will improve outcomes given the potential immune stimulatory benefit of VEGF inhibition and the benefit from preventing clinical progression prior to the development of an immune response in patients with rapid disease progression. Single agent SU has a median PFS of 11mos and response rate of 31%. Methods: Eligible pts with measurable metastatic clear cell RCC, no prior systemic therapy, adequate organ function, no CNS met, and a suitable donor (≥2/6 HLA A, B, DR match, CMV-, HIV-, HepB/C-) received SU 50mg/day in a 4 wk on/2wk off schedule with IAL administration commencing at the start of cycle number 2 of SU. IAL was given once every 8-16 weeks. The primary objective of the study is to determine the PFS of the combination of SU and IAL in 35 patients for 80% power to detect an increase in median PFS from 11 to 18 months. Results: A pre-planned futility analysis was performed. To date 9 pts (7M/2F), median age 63 (range 49-74) have been treated with 29 cycles of DLI. Median number of DLI/pt 2(1-7). 5 pts discontinued DLI due to disease progression, 4 due to loss of donor availability. Median time to disease progression was 41 weeks (range 12-180 weeks), with 4 pts on study for &gt;80 weeks. Response rate (CR+PR): 44% (1/9 CR, 3/9 PR, 2/9 SD, 3/9 PD). DLI was well tolerated with G2 fever in 1pt and G1 fever in 5 pts as the only DLI related AEs. SU related AE lead to SU dose reduction in 8/9 pts. Conclusions: Co-administration of SU and IAL is feasible and safe with no significant IAL related toxicity. Further study accrual is required to determine if SU plus IAL is superior to single agent SU. Clinical trial information: NCT00853125.
The role of KLHDC8B deficiency in Hodgkin lymphoma pathogenesis.
Authors: M. M. Krem, S. J. Salipante, J. D. Wechsler, M. S. Horwitz
Journal: Journal of Clinical Oncology (2010)

e18528 Background: The malignant cell in Hodgkin lymphoma (HL) is the binucleated, giant Reed-Sternberg (RS) cell. In recent years the RS cell has been determined to be a B cell of germinal center origin. However, the genetic and molecular aberrations underlying the pathogenesis of the RS cell are incompletely understood. Although chromosomal instability is strongly implicated in RS cell formation, the mechanisms behind chromosomal instability in HL and the evolution of the RS cell remain largely unknown. We have recently identified a novel gene, KLHDC8B, which appears responsible for several familial cases of HL. Methods: A tetracycline-inducible vector carrying an shRNA targeting KLHDC8B was transfected into HeLa cells and HMy2.C1R lymphoblasts, resulting in knockdown of KLHDC8B as determined by Western blotting. Cells were assessed microscopically for binucleation. We also expressed a KLHDC8B-GFP fusion protein in HeLa cells, followed by immunohistochemical staining assessed by confocal microscopy. Cells were again assessed microscopically for binucleation. Live cell microscopy was performed to follow mitoses in real time. Results: KLHDC8B encodes a protein predicted to contain seven kelch repeat domains, is expressed during mitosis, and localizes to the midbody. Depletion of KLHDC8B through RNA interference leads to an increase in binucleated cells, implicating its involvement in RS cell formation. We have also expressed a KLHDC8B-GFP fusion protein, which appears to function as a dominant-negative form of KLHDC8B; the fusion protein localizes to the midbody, but results in increased binucleation and failed cytokinesis, as demonstrated by confocal and live cell microscopy. Conclusions: The increase in binucleated cells upon depletion of KLHDC8B implicates its involvement in RS cell formation. Disrupted cytokinesis, rather than cell fusion, appears to be the mechanism of binucleation. Other cancer genes such as BRCA1, BRCA2, and aurora kinases also encode proteins with midbody localization during cytokinesis; altered expression of midbody proteins and spindle checkpoint genes may represent an underexplored pathway in HL pathogenesis and tumorignesis in general. No significant financial relationships to disclose.
Hematopoietic Stem Cell Transplantation As a Successful Salvage Strategy for Relapsed Acute Promyelocytic Leukemia (APL): A Mayo Clinic Series
Authors: Gita Thanarajasingam, James M. Foran, Vivek Roy, Lisa Sproat, William J. Hogan, Mark R. Litzow, Aref Al-Kali, Naseema Gangat, Mrinal M. Patnaik
Journal: Blood (2014)
All-Trance Retinoid Acid (ATRA) Makes Refractory Immune Thrombocytopenia (RITP) Less Refractory: A Retrospective Study of Ritp Patients Treated with Combination Therapies Including ATRA
Authors: Min Wang, Xiao-hui Zhang, Wei Han, Yu Wang, Dai-Hong Liu, Lan-Ping Xu, Kai-Yan Liu, Hai-xia Fu, Meng Lv, Yi Zhou, Xiao-Jun Huang
Journal: Blood (2012)
Multigene predictors developed on breast cancer cell lines to predict patient chemotherapy response: A validation study on the NSABP B-27 trial.
Authors: K. Shen, G. Tang, J. P. Costantino, S. J. Anderson, C. Kim, K. L. Pogue-Geile, N. Song, M. J. Gabrin, C. E. Geyer, N. Wolmark
Journal: Journal of Clinical Oncology (2011)

1029 Background: We developed multigene predictors (MGPs) of chemotherapy sensitivity based on breast cancer cell lines exposed to combination chemotherapy regimens. Performance was assessed by the prediction of pathological complete response (pCR) in National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-27 clinical trial breast cancer patients. Methods: B-27 was a phase III trial of women with operable primary breast cancer assigned to receive 4 cycles of preoperative doxorubicin and cyclophosphamide (AC) (Grp 1) or 4 cycles of AC followed by 4 cycles of docetaxel (either preop [Grp 2] or post-op [Grp 3]). MGPs associated with AC and ACT sensitivity were separately developed based on the in vitro drug response and publicly available microarray genomic profiles of 40 breast cancer cell lines. Validations of the two genomic predictors were conducted blindly by NSABP statisticians to assess accuracy in predicting breast cancer patient pCR to preoperative therapy. Results: 219 patients treated with AC and 102 with ACT were included in this study. For the AC therapy, the MGP score was significantly associated with pCR from univariate analysis (p=0.0002) and multivariate analysis adjusted (p=0.015), and MGP remained the most important factor in predicting chemotherapy response compared to other clinical and biologic variables; prediction accuracy was 79%, sensitivity was 72%, and specificity was 80%; the area under the ROC curve was 0.75 [95% confidence interval: 0.64, 0.86]. For ACT therapy, the prediction accuracy, sensitivity, and specificity were 69.6%, 60%, and 73%, respectively; the area under the ROC curve was 0.64 [0.51, 0.77]. The association between MGP and pCR was statistically significant from univariate analysis, but less significant from multivariate analysis adjusted for covariates. Conclusions: Cell line-derived multigene predictors show promise in the prediction of chemotherapy response in breast cancer patients treated with neoadjuvant chemotherapy.The B-27 study was funded by NCI PHS grants U10-CA−37377, U10-CA−69974, U10-CA−12027, U10-CA−69651, and U24-CA−114732, and with additional support from sanofi-aventis.
Molecular pathways associated with micro-vascular invasion HCC.
Authors: Caroline Yun Ling Chia, Wilson Lek Wen Tan, Nicholas Brian Shannon, Roger Sik Yin Foo, Pierce Kah Hoe Chow
Journal: Journal of Clinical Oncology (2016)

249 Background: Microvascular invasion (MVI) in hepatocellular carcinoma (HCC) has a reported incidence of 15-57%. It is associated with decreased overall and recurrence free survival in post-surgical resection and transplant patients. Currently, the biology of MVI+ HCC remains unknown and the absence of effective adjuvant therapy limits management options to prevent recurrence. Aim: To correlate gene signatures observed at the transcriptomic level with the presence of MVI in HCC, analyze molecular pathways with gene expression tools and validate with TCGA database. Methods: Whole genome expression was studied in two groups of Asian resected HCC tumour specimens: (i) MVI present (MVI+) (n = 14) and (ii) MVI absent (MVI-) (n = 33) both without macrovascular invasion on radiological imaging. 2 distinct pathway analysis tools – gene set enrichment analysis (GSEA) and ingenuity pathway analysis (IPA) were performed to identify significantly enriched pathways potentially explaining the observed MVI+ HCC phenotype. Selected gene sets from the identified pathways were subjected to in-silico validation with TCGA data to confirm their enrichment within MVI+ HCC. Results: Within 14 MVI+ and 33 MVI- HCC studied, we have found a total of 1401 significantly differentially expressed genes between them; 766 genes were up-regulated and 635 genes were down-regulated in MVI+ HCC. At p &lt; 0.05 and FDR &lt; 0.25, GSEA and IPA analyses identified enrichment of PI3K/AKT/mTOR, HIF1α, AMPK signaling and actin-mediated cell kinetics pathways: actiny, Cdc42 signaling and actin pathways regulated by Rho. A 90 gene signature derived from these enriched pathways, created on the basis of biological function was used to compare between average expression within the MVI+ vs MVI- HCCs in the TCGA Asian cohort. Genes found differentially expressed at p &lt; 0.05 corresponded with the enriched pathways: actiny, AMPK signaling and PI3K/AKT/mTOR. Conclusions: These pathways underscore functions in regulation of cell metabolism, growth, proliferation, survival, protein synthesis and cytoskeleton organization in MVI+ HCC. Further studies in these pathways may assist in development of molecular targeted therapies for MVI+ HCC. We propose to carry out a prospective study to validate this.
Adjuvant GM-CSF therapy for patients with resected stage III/IV melanoma: A retrospective review of a single-center experience.
Authors: S. Markovic, P. A. Burch, B. LaPlant, J. M. Heun, R. Bradshaw
Journal: Journal of Clinical Oncology (2011)

8596 Background: Published phase II clinical data suggest a survival advantage of adjuvant GM-CSF (250 mcg/day x14 days every 28 days) therapy in patients with resected advanced stage III/IV melanoma (Spitler et al, JCO, 18:1614, 2000). Preliminary reports of a randomized phase III clinical trial (E4697) of adjuvant GM-CSF with/without a peptide vaccine in the same patient population do not suggest a statistically significant survival benefit of GM-CSF over placebo. Thus, we sought to retrospectively review our clinical experience with adjuvant GM-CSF therapy administered on a compassionate use protocol to patients with resected advanced stage III/IV melanoma. Methods: Following IRB approval we abstracted medical records of patients with resected advanced stage III/IV melanoma treated at our institution since 2000. Nearly 1000 patients with resected advanced stage III/IV melanoma were identified, some of whom were treated with adjuvant GM-CSF on a compassionate use protocol following complete surgical resection. Of those, we selected only patients with sufficient follow-up data to identify relapse-free and overall survival (OS). Herein are our preliminary findings; final case-control analysis will be presented at the Annual meeting. Results: Of the first 253 retrospectively reviewed patients, 219 met eligibility criteria. Only 70 patients in this cohort had resected stage IV melanoma and 149 patients had resected stage III disease. Analysis of median OS data by disease stage demonstrated that patients with resected stage III melanoma treated with GM-CSF (n = 56) vs observation (n = 93) exhibited median OS of 8.6 (95% CI = 5.1-NR) and 5.2 (95% CI = 3.7-NR) years respectively. Patients with resected stage IV melanoma treated with GM-CSF (n = 30) vs observation (n = 40) exhibited median OS of 6.6 (95% CI = 3.3-10.0) and 6.8 (95% CI = 2.4-NR) years respectively. Conclusions: Preliminary analysis of our data suggests further research is warranted to understand the impact of adjuvant GM-CSF in patients with resected stage III melanoma. Full case-control analysis of the entire data set will be presented at the Annual Meeting.
Effect of the European Organization for Research and Treatment of Cancer (EORTC) on social life for cancer survivors in Europe.
Authors: Lifang Liu, Lotte Mosser, Jaap C. Reijneveld, Francoise Meunier
Journal: Journal of Clinical Oncology (2016)

218 Background: Cure is not a dream but a reality for a large group of cancer patients nowadays. In Europe around 4 million patients successfully lived beyond the 5th year after cancer diagnosis. With improved survival rate and an ageing population, there will be more survivors in the near future. They wish to enter or maintain in the job market, and to finance desired house and insurance. However, the lack of sufficient data and knowledge on the ability to perform gets in the way on their path to normal social life. Methods: From 2013 the EORTC set the scene addressing societal issues faced by cancer patients involving key stakeholders including cancer patients themselves, care givers, bankers, insurers, employers and policy makers. These efforts have matured into an innovative research infrastructure in Europe integrating existing patients’ cohorts, including data from clinical trials, (population-based) cancer registries, surveys and social media. The research scope covers from quantifying the magnitude of the problem, assessing the economic burden, to formulating evidence-based EU recommendations for rehabilitation of cancer survivors. Particularly, variation and inequality across member states will be extensively investigated. Results: EORTC has a long tradition of collection data and follow-up patients since 50 years. Currently he is forming a consortium with the European Commission Joint Research Center (EC-JRC), European Network of Cancer Registry (ENCR), and other key experts in EU on the project. Several nation-wide research models are being built to address country-specific questions that cancer survivors face. Conclusions: A sustainable research infrastructure with dedicated partners and network address cancer survivorship is being built in Europe. This joint effort saves repetition in collecting data that already exist, synergizes expertise and methodology in addressing cancer survivorship questions.