tbuckley/cabot-search huggingface dataset:
Central pathology review of early-stage ovarian carcinoma: Description and correlation with follow-up—A study by the Spanish Group for Ovarian Cancer Research (GEICO).
Authors: Jose Antonio Lopez-Guerrero, Ana Gutierrez Pecharroman, José Palacios, Ignacio Romero, Eva Maria Cristobal Lana, David Hardisson, Francisco Vera-Sempere, Carmen Illueca, BegoÃƒÂ±a Vieites, Angel Garcia, Javier Ibarra de la Rosa, Sofia Hakin Alonso, Rosa Guarch Troyas, Encarna Andrada, Santiago Montes, Francisco Pastor, Maria Carmen Gomez, Maria Amparo Torroba, Emanuela D'Angelo, Andres Poveda
Journal: Journal of Clinical Oncology (2014)

5583 Background: The reported experience with early-stage (FIGO stage I/IIB) ovarian carcinoma (ESOC) is limited. It represents 15% of all diagnosed cases and the impact on prognosis of their different histological subtypes has not been clearly defined. The aim of this study is to analyze the frequency of ESOC histologies and their correlation with follow-up. Methods: A centralized pathological review of ESOC was performed from samples belonging to the GEICO ESOC Registry, which includes 1179 patients. A total of 573 samples from 24 Spanish Hospitals were collected, stained with H&E and reviewed by two pathologists. Final diagnosis was achieved by consensus and compared with diagnosis of origin (DO). Histological classification was performed according to WHO criteria, except for serous subtype classified with 2-tier grading system (Malpica et al. Am J Surg Pathol 2004; 28:496-594). Results: Thirty-four cases (6%) were excluded after revision. The remaining 539 were classified as following: 130 (24%) high-grade serous (HGS), 24 (4%) low-grade serous (LGS), 45 (8%) high-grade endometrioid (HGE), 96 (18%) low-grade endometrioid (LGE), 75 (14%) mucinous (MUC), 134 (25%) clear cell carcinoma (CCC), 35 (6.6%) mixed (Mix) and 2 (0.4%) undifferentiated (U). Concordance with DO was of 76% (Kappa=0.495; p<0.0001), discrepancies being more frequent for Mix and U histologies. Median follow-up was 74 months (range: 0-250) and 105 (18%) recurrences were reported. The univariate analysis showed a 5-years recurrence free survival (RFS) of 70% for HGS vs 83% of other histologies (p=0.008); a 74% for CCC vs. 82% (p=0.06); and a 89% for LGE vs. 78% (p=0.021). The multivariate analysis showed that higher stage [HR= 3 (1.6-5.7); p=0.001], HGS [HR= 2 (1.2-3.3); p=0.005] and CCC [HR= 2.1 (1.3-3.4); p=0.003] constituted independent factors of poor prognosis. Conclusions: Frequency of histological subtypes in ESOC differs from advanced stages. HGS and CCC histological subtypes constitute independent poor prognostic factors in ESOC. The series herein reported could provide the basis for exploring molecular profiles in order to design specific clinical trials in ESOC.
Randomized phase II trial of carboplatin combined with weekly paclitaxel (CP) and docetaxel alone (D) in elderly patients (pts) with advanced non-small cell lung cancer (NSCLC): NJLCG 0801.
Authors: Shunichi Sugawara, Makoto Maemondo, Toshiyuki Harada, Akira Inoue, Nobumichi Matsubara, Kana Watanabe, Osamu Ishimoto, Tomohiro Sakakibara, Yuji Minegishi, Kazuhiro Usui, Masahiro Ando, Naoto Morikawa, Yoshiaki Mori, Akihiko Gemma, Toshihiro Nukiwa
Journal: Journal of Clinical Oncology (2012)

7565 Background: Standard first-line chemotherapy for elderly NSCLC pts has been considered as a monotherapy with vinorelbine or gemcitabine globally. However, we have demonstrated the high efficacy of CP for elderly pts in our previous trial (Ann Oncol 2010). Meanwhile, D has been considered as an alternative option for this population in Japan according to the result of WJTOG9904 (JCO 2006). Thus we compared the two regimens to select the proper candidate for future phase III trial. Methods: Eligible pts were aged 70 years or older with newly diagnosed stage IIIB/IV NSCLC; ECOG performance status 0-1; adequate organ function; written informed consent. Pts were randomized to receive carboplatin (AUC 6) on day 1 and paclitaxel (70mg/m 2 on day 1, 8, and 15) every 4 weeks or D (60mg/m 2 on day 1) every 3 weeks. The primary endpoint was overall response rate (ORR), and secondary endpoints were progression-free survival (PFS), overall survival, and toxicity profile. Assuming that ORR of 40% would be potential usefulness while ORR of 20% would be the lower limit of interest, 40 pts in each arm were required if expect 10% loss to follow up. Results: Between July 2006 and September 2010, 84 pts were enrolled and 41 pts in CP arm and 42 pts in D arm were eligible (median age, 76 years; 75% male; 72% stage IV). Median treatment cycle was 4 in each arm (CP, range 1-6; D, range 1-8). ORRs were 51% (95%CI: 36-66%) and 26% (95%CI: 12-39%) in the CP and D arm, respectively. With a median follow-up of 18.4 months, median PFS were 6.5 and 3.9 months in the CP and D arm, respectively (Logrank, P=0.0027). Grade 3 or severer toxicities were as follows: neutropenia (CP, 56% and D, 79%), anemia (CP, 15% and D, 7%), thrombocytopenia (CP, 10% and D, 0%), infection (CP, 20% and D, 25%). One treatment-related death due to neutropenia, pneumonia, and lethal arrhythmia occurred in D arm but none in CP arm. Conclusions: The platinum doublet CP achieved higher activity with an acceptable toxicity profile for elderly pts with advanced NSCLC compared to monotherapy with D. The superiority of CP to the monotherapy in this trial is consistent with results of recent IFCT-0501 trial (Lancet 2011).
Association of cytokine levels and reductions in spleen size in COMFORT-II, a phase III study comparing ruxolitinib to best available therapy (BAT).
Authors: Claire N Harrison, Jean-Jacques Kiladjian, Heinz Gisslinger, Francesco Passamonti, L. Andres Sirulnik, Ling Wang, Matthew Squires, Laurent Knoops, Giovanni Barosi, Tiziano Barbui, Francisco Cervantes
Journal: Journal of Clinical Oncology (2012)

6625^ Background: Ruxolitinib is a potent and selective oral JAK1/2 inhibitor that has been approved for the treatment of myelofibrosis (MF). Ruxolitinib has demonstrated rapid and durable reductions in splenomegaly and improved disease-related symptoms and quality of life (QoL) in 2 phase 3 studies (COMFORT-I and –II) in patients (pts) with primary MF (PMF), post-polycythemia vera-MF (PPV-MF), or post-essential thrombocythemia-MF (PET-MF). This analysis evaluated associations between cytokine levels and spleen size reductions in the COMFORT-II study. Methods: COMFORT-II is a randomized (2:1), open-label, phase 3 study comparing the safety and efficacy of ruxolitinib with BAT. Spleen volume was measured by MRI every 12 weeks and spleen length by palpation at each study visit. Plasma samples were analyzed using Rules Based Medicines Human MAP v1.6; 89 cytokines were measured at BL and wks 4, 24, and 48. Simple linear regression was used to evaluate the correlation between BL or change from BL in cytokine levels with % change of spleen size. Results: In the ruxolitinib arm, association was found between changes in TNF-α and leptin levels and % spleen volume reduction at wk 24 (TNF-α: N = 93; correlation coefficient [R] = 0.43; false discovery rate adjusted P value [P] &lt; .01; leptin: N = 96; R = -0.28; P = .09) and wk 48 (TNF-α: N = 86; R = 0.43; P &lt; .01; leptin: N = 87; R = -0.34; P = .02) that was not observed with BAT and was independent of JAK2V617F status. For ruxolitinib-treated JAK2V617F+ pts, higher leptin levels at BL were associated with greater % spleen length reductions at wk 48 (N = 45; R = -0.44; P = .11). A clear trend was observed for increased leptin levels that preceded weight gain on ruxolitinib treatment. For ruxolitinib-treated JAK2V617F+ pts, decreased IL-8 at wk 4 was associated with % spleen volume reductions at wk 24 (N = 68; R = 0.28; P = .24) and wk 48 (N = 60; R = 0.38; P = .15). Conclusions: This analysis has shown statistically significant associations between changes in cytokine levels and spleen size reductions. Further analysis is in progress to determine associations between cytokine levels and QoL or symptoms and to confirm these observations in an independent data set.
Randomized phase II-III study of bevacizumab in combination with chemotherapy in previously untreated extensive small-cell lung cancer: Results from the IFCT-0802 trial.
Authors: Jean-Louis Pujol, Armelle Lavole, Bertrand Mennecier, Oliver Molinier, Pierre Jean Souquet, Fabrice Barlesi, Herve Le Caer, Denis Moro-Sibilot, Pierre Fournel, Jean-Philippe Oster, Patrick Chatellain, Patricia Barre, Gaelle Jeannin, Pierre Mourlanette, Marc Derollez, Dominique Herman, Patrick Renault, Charles Dayen, Franck Morin, Gerard Zalcman
Journal: Journal of Clinical Oncology (2014)

7505 Background: A randomized phase II-III trial was designed to assess efficacy and safety of adding bevacizumab (Bev) to first-line standard chemotherapy (CT) in extensive small-cell lung cancer (SCLC). Methods: Patients with SCLC were enrolled and then received two induction cycles of CT, three weeks apart (cisplatin - etoposide, or cisplatin - cyclophosphamide - epidoxorubicin - etoposide [PCDE]). Responders were randomly assigned 1:1 to receive 4 additional cycles of CT alone or CT plus Bev (7.5 mg/kg) followed by single-agent Bev until progression or unacceptable toxicity. The primary endpoint was response rate (RR) after 4 cycles (i.e. two cycles after randomization). Results: 147 patients were enrolled. After the 2 first CT cycles, RR was observed in 99 patients (67.3%) and among them, 74 patients were eligible for Bev and randomly assigned to CT only (n = 37) or CT plus Bev (n = 37). Median number of CT was 6 in CT alone group and 6 in CT plus Bev group. The median number of additional Bev administrations in the latter group was 4. The percentage of still-responder patients after 4 cycles, including 2 with bevacizumab in the experimental arm, did not differ between the CT arm (89.2%) and the CT+bevacizumab arm (91.9%). Neither progression-free survival (PFS) nor overall survival (OS) significantly differed (median PFS : 5.5 and 5.3 months; median OS: 13.0 and 11.1 months, in CT alone and CT plus Bev groups respectively). In the CT alone group and the CT plus Bev group, 22 (59.5%) versus 23 (62.2%) of patients respectively, experienced one or more grade 3-4 adverse events. Specific Bev-induced toxicity was observed in 15 (40.5%) patients; one unexpected toxicity (fatal subdural hematoma) was reported in the combination group. Evaluation of serum biomarkers will be presented. Conclusions: Bev did not increase the proportion of responder patients at cycle 4. This phase II study failed to demonstrate any signal suggesting an outcome improvement in extensive-SCLC. Consequently this trial will not go further the phase 3 part of the program. Clinical trial information: NCT00930891.
Elevated levels of soluble humanleukocyte antigen-G in the airways are a marker for a low-inflammatory endotype of asthma
Authors: Steven R. White, Jessie Nicodemus-Johnson, Bharathi Laxman, Darcy R. Denner, Edward T. Naureckas, D. Kyle Hogarth, Randi Stern, Alexa Minc, Julian Solway, Anne Sperling, Carole Ober
Journal: Journal of Allergy and Clinical Immunology (2017)
Progression-free survival (PFS) as surrogate endpoint for overall survival (OS) in clinical trials of HER2-targeted agents in HER2-positive metastatic breast cancer (MBC): An individual patient data (IPD) analysis.
Authors: Stefan Michiels, Lina Pugliano, Delphine Grun, Jana Barinoff, David A. Cameron, Melody A. Cobleigh, Angelo Di Leo, Stephen R. D. Johnston, Giampietro Gasparini, Bella Kaufman, Michel E. Marty, Valentina Nekljudova, Shani Paluch-Shimon, Frederique Penault-Llorca, Dennis J. Slamon, Charles L. Vogel, Gunter Von Minckwitz, Marc E. Buyse, Martine J. Piccart-Gebhart
Journal: Journal of Clinical Oncology (2013)

610 Background: The gold standard endpoint in randomized clinical trials (RCTs) in MBC is OS, which has the disadvantage of requiring extended follow-up and being confounded by subsequent anti-cancer therapies. Although therapeutics have been approved based on PFS, its use as a primary endpoint is controversial. This study, the first IPD meta-analysis of targeted agents in MBC, aimed to collect data from RCTs of HER2-targeted agents in HER2+ MBC, assessing to what extent PFS correlates with, and may be used as, a surrogate for OS. Methods: A search was conducted in April 2011. Eligible RCTs accrued HER2+ MBC patients (pts) in 1992-2008. Collaboration was obtained from industrial partners (Roche, GSK) for industry-led studies. Investigator-assessed PFS was defined as the time from randomization to clinical or radiological progression, or death. A correlation approach was used: at the individual level, to estimate the association between PFS and OS using a bivariate survival model and at the trial level, to estimate the association between treatment effects on PFS and OS. Squared correlation values close to 1.0 would indicate strong surrogacy. Results: The search strategy resulted in 2137 eligible pts in 13 RCTs testing trastuzumab or lapatinib. We collected IPD data from 1963 pts in 9 RCTs. One phase II RCT did not have sufficient follow-up data so that 1839 pts in 8 RCTs were retained (5 evaluating trastuzumab, 3 lapatinib); 6 out of 8 RCTs were first-line. At the individual level, the Spearman rank correlation using Hougaard copula was equal to r=0.66 (95% CI 0.65 to 0.66) corresponding to an r 2 of 0.42. At the trial level, the squared correlation between treatment effects on PFS and OS was provided by R 2 =0.33 (95% CI -0.22 to 0.86) using Hougaard copula and R 2 =0.53 (95% CI 0.22 to 0.83) using log hazard ratios from Cox models. Conclusions: In RCTs of HER2-targeted agents in HER2+ MBC, PFS is moderately correlated with OS and treatment effects on PFS are modestly correlated with treatment effects on OS, similarly to first-line chemotherapy in MBC (Burzykowski et al JCO 2008). PFS does not completely substitute for OS.
Long-term side effects of high-risk neuroblastoma survivors in a referral center in central Illinois.
Authors: Beth Speckhart, Reuben Antony, Karen S. Fernandez
Journal: Journal of Clinical Oncology (2017)

129 Background: Neuroblastoma (NBL) is the most common extra-cranial solid organ malignancy in children. Although low and intermediate-risk patients have a survival of close to 90%, the same cannot be said for patients with high risk (HR) disease. In the last decade multi-modality treatment of HR NBL patients has been intensified to include chemotherapy, surgery, radiation, bone marrow transplantation and immunotherapy and has resulted in improved survival (Yu, 2009). Data regarding the medium to long-term side effects of this intensive multi-modality therapy is now being collected as the population of HR neuroblastoma survivors continues to grow. Methods: We retrospectively reviewed the clinical data of survivors of HR NBL treated at the Children’s Hospital of Illinois diagnosed since 2009 and evaluated the long-term side effects of survivors through 2015. Results: We found 14 NBL patients of whom 10 had HR disease. Four patients died of progressive disease. Therapy-related, long-term side effects occurred in 6 patients: hearing loss (n = 6), adrenal insufficiency (n = 2), focal nodular hyperplasia of the liver (n = 2), linear growth retardation (n = 1). No patient in our cohort developed thyroid or cardiac problems and no patient was diagnosed with a second malignancy in the 5 years of observation. Conclusions: While the improved outcomes seen in HR NBL patients is encouraging, we found in our small cohort hat survivors of multimodality therapy for high-risk neuroblastoma experience significant long-term effects of treatment which impact their quality of life as well as growth and development. As the number of NBL survivors increases our understanding of the long-term therapy related side effects will continue to improve. Larger longitudinal studies are needed to monitor for other possible side effects that may manifest overtime such as cardiomyopathy, disturbances in sexual development, fertility, intellectual function, learning problems and therapy related second malignancies later in life.
A single-arm, open-label, multicenter phase I/II study of the combination of panobinostat (pan) and carfilzomib (cfz) in patients (pts) with relapsed/refractory multiple myeloma (RR MM).
Authors: Jesus G. Berdeja, Joseph Mace, Ruth E. Lamar, Victor Gian, Patrick Brian Murphy, Manish R. Patel, Lowell L. Hart
Journal: Journal of Clinical Oncology (2012)

TPS8115 Background: Despite novel therapies, MM remains an incurable disease. Changes in histone modification are commonly found in human cancers including MM. Preclinical studies demonstrate synergistic anti-MM activity with histone deacetylase inhibitors (HDACi) and proteasome inhibitors (PI) through the dual inhibition of the proteasome and aggresome pathways. Pan is an oral pan-HDACi which has shown synergy with bortezomib in clinical studies. Cfz is a 2nd generation PI which has shown marked anti-MM activity with an improved safety profile. In this trial we evaluate the safety and efficacy of the combination of pan and cfz in pts with RR MM. Methods: This multi-center US study plans to enroll up to 52 adults with RR MM. The phase I study will determine the MTD of the combination of cfz and pan and follow a standard dose escalation design. Pan will be administered orally three times weekly during weeks 1 and 3 of each 28-day cycle (Days 1, 3, 5, 15, 17, 19) at a starting dose of 20 mg. Cfz will be administered intravenously on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Cfz starting dose will be 20mg on days 1,2 of cycle 1 with escalation to the corresponding dose level beginning at 27 mg , if well tolerated. Dose modifications will not be permitted during cycle 1 unless a pt experiences a DLT. A maximum of four dose levels will be evaluated. Approximately 24 pts will be enrolled during the phase I portion to establish the MTD. In the phase II portion of this study, pts with RR MM will receive treatment with the optimal dose of pan and cfz established during phase I. Pts will be assessed for response to treatment after each cycle (4 weeks). Pts with objective response or stable disease will continue treatment until disease progression or unacceptable toxicity occurs. The primary endpoint is to establish the optimal doses of cfz and pan that can be administered to pts with RR MM (phase I) and to evaluate the overall response rate (phase II). Secondary endpoints include time-to-progression, progression-free survival, overall survival and safety. Approximately 25 pts are planned for the phase II portion. Current status: As of 1/27/12 3 patients have been enrolled.
Identification of patients with post-induction CNS 2 status and outcomes in acute lymphoblastic leukemia.
Authors: Arun Gurunathan, Ami Vijay Desai, L. Charles Bailey, Yimei Li, John Choi, Susan R. Rheingold
Journal: Journal of Clinical Oncology (2015)

10033 Background: In the past decade there has been increased scrutiny of the prognostic implications of low level blasts (CNS 2) in the cerebrospinal fluid (CSF) of pediatric patients with acute lymphoblastic leukemia (ALL). The significance of CSF blasts is complicated by the increased cell recovery by newer cytocentrifuge machines (Huppman, et al. Am J Clin Pathol. 2012). Methods: A retrospective cohort study was conducted at the Children’s Hospital of Philadelphia (CHOP) to compare the proportion of CNS 2 CSF results using Shandon (2005–2008) and Wescor (2010-2014) cytocentrifuge machines. Logistic regression was used to compare CNS 2 results from the two time periods. Outcomes of patients with at least one post-Induction CNS 2 CSF result were tracked, focusing on proportion of patients who ultimately relapsed using Fisher’s exact test. Infant ALL was analyzed separately. Results: Of the 306 de novo ALL patients (excluding 10 infants) identified, 273 had pre-B ALL and 33 had T-ALL. Of the 4477 lumbar punctures analyzed in this cohort, there was a 6.7-fold increase in proportion of CNS 2 results on the new (Wescor) machine (2% vs. 0.3%, p < 0.0001). This remained significant after adjusting for gender, immunophenotype, and end of induction risk stratification. In both time periods, the majority of CNS 2 results were CNS 2a. Of the 42 patients who were CNS 2 at least once post-Induction in either period, 9 relapsed (8 pre-B ALL; 1 T-ALL). Having a post-Induction CNS 2 CSF did confer an increased risk of relapse (21.4% vs. 8.8%, p = 0.025), primarily due to increased non-CNS relapse. Two of 3 patients with CNS 2 CSF on the Shandon relapsed; 7 of 39 patients who had a CNS 2 CSF on the Wescor relapsed. Despite the small sample size in Infant ALL, there was also an increase in CNS 2 results on the Wescor (4.5-fold increase, p = 0.042). Conclusions: The enhanced efficiency of cell recovery afforded by the Wescor cytocentrifuge machine resulted in increased proportion of CNS 2 results. Having a CNS 2 CSF on the Shandon was more predictive of relapse than on the Wescor. The finding that post-induction CNS 2 status is associated with an increased risk of relapse (non-CNS > CNS) warrants further investigation and may influence management decisions.
Higher incidence of EGFR exon 19 deletion in younger (age 40 or younger) patients with adenocarcinoma of the lung.
Authors: Eri Sugiyama, Koichi Goto, Genichiro Ishii, Shigeki Umemura, Kiyotaka Yoh, Seiji Niho, Hironobu Ohmatsu, Kanji Nagai, Yuichiro Ohe
Journal: Journal of Clinical Oncology (2012)

7044 Background: The proportion of younger patients (≤ 40 years) with lung cancer is reported to be 2-5%. The most frequent histologic type of them is adenocarcinoma, however little is known about the pathological and molecular characteristics of younger patients with lung adenocarcinoma. Methods: Between July 1992 and April 2011, a total of 7443 patients were diagnosed as lung cancer in National Cancer Center Hospital East and 165 patients of whom (2.2%) who were 40 years or younger were identified. Among them, 44 patients with adenocarcinoma who underwent surgical resection were selected for this study. In addition, 185 elderly patients with &gt; 40 years who underwent surgical resection matching gender and smoking status were selected as a control group. Histological predominant growth pattern and any coexisting variant pattern, the status of EGFR mutations were compared between these two groups. Results: The median age in ≤ 40 years patients was 37 years (range, 21 to 40 years) and that in elderly patients was 68 years (range, 42 to 83 years). Between these two groups, there were no significant differences in the distribution of histological predominant growth patterns (lepidic; 31.8% vs. 26.5%, papillary; 34.1% vs. 37.3%, acinar; 9.1% vs. 16.2%, and solid; 25.0% vs. 20.0%, p=0.78) and the incidence of EGFR mutations (40.9% vs. 45.9%; p=0.55). However, signet-ring cell component were significantly found in the younger patients than elderly (11.4% vs. 0%; p&lt;0.01). The incidence of EGFR exon 19 deletion was significantly higher in younger patients than elderly, in contrast, that of EGFR exon 21 L858R was significantly higher in elderly patients (exon 19 del; 31.7% vs. 18.9%, L858R; 4.6% vs. 25.4%, p=0.0091). Three of 17 adenocarcinomas (17.7%) with EGFR-wild type in younger patients showed positive for ALK translocation. Conclusions: Younger patients with lung adenocarcinoma showed significantly higher proportion of EGFR exon 19 deletion genotype and containing histologically signet-ring cell component comparing with elderly patients. EGFR exon 19 deletion genotype may be related to pathogenesis of lung adenocarcinoma in younger patients.