tbuckley/cabot-search huggingface dataset:
Exposure-response relationship for ramucirumab (RAM) from the randomized, double-blind, phase III REVEL trial (docetaxel [DOC] vs DOC plus RAM) in second-line treatment of metastatic non-small cell lung cancer (NSCLC).
Authors: Egbert F. Smit, Maurice Perol, Martin Reck, Federico Cappuzzo, Paolo Bidoli, Roger B. Cohen, Ling Gao, C. Steven Ernest, Pablo Lee, Annamaria Zimmermann, David Ferry, Joseph Treat, Allen S. Melemed, Edward B. Garon
Journal: Journal of Clinical Oncology (2015)

8053 Background: An exploratory exposure-response analysis for RAM was performed using data from the REVEL trial (NCT01168973). Methods: Patients received RAM (10 mg/kg) or placebo (PL) + DOC (75 mg/m2) every 3 weeks (q3w). Sparse pharmacokinetic (PK) samples were collected; a population PK (PopPK) analysis was conducted. PopPK model-predicted RAM exposure parameters (Cmin,1, Cmin,ss, Cmax,ss, and Cave,ss) were used to evaluate the relationship between RAM exposure and measures of efficacy and safety. Cmin,1 and Cave,ss are presented. Kaplan-Meier, Cox regression, and ordered categorical analyses evaluated these relationships. Results: Analyses included 376 RAM+DOC pts and 366 PL+DOC pts. Similar trends were seen for all four exposure parameters. As RAM exposure increased, greater improvements (smaller HRs) were seen in OS and PFS (table below). A statistically significant correlation was also seen for RAM exposure and grade ≥ 3 febrile neutropenia and hypertension. Conclusions: Results from exposure-response analyses suggest improvements in efficacy and increased toxicity may occur with increasing RAM exposure. RAM at a dose of 10 mg/kg q3w in combination with DOC is appropriate for the NSCLC indication. Clinical trial information: NCT01168973. Median (months) Hazard ratio (95% CI)a OSb PL+DOC 13.3 RAM+DOC Cmin,1 Q1 11.1 1.19 (0.89, 1.59) Q2 14.6 0.80 (0.58, 1.08) Q3 12.6 0.85 (0.63, 1.14) Q4 17.1 0.67 (0.48, 0.93) PFSb PL+DOC 5.5 RAM+DOC Cmin,1 Q1 5.6 0.92 (0.72, 1.18) Q2 7.0 0.71 (0.55, 0.90) Q3 5.7 0.84 (0.67, 1.07) Q4 7.0 0.71 (0.55, 0.90) Grade ≥3 AEc Hypertension (%) Febrile Neutropenia (%) PL+DOC 2.8 11.8 RAM+DOC Cave,ss Q1 4.3 7.5 Q2 5.3 19.1 Q3 13.8 22.3 Q4 6.4 21.3 aAdjusted for significant prognostic factors. bRAM+DOC pts stratified by Cmin,1 quartile (µg/mL) (n = 94 for each): Q1 ≤ 15.7; Q2 > 15.7 ≤ 20.7; Q3 > 20.7 ≤ 27.9; Q4 > 27.9; compared to PL+DOC pts. cRAM+DOC pts stratified by Cave,ss quartile (µg/mL) (n = 94 for each): Q1 ≤ 79.3; Q2 > 79.3 ≤ 97.4; Q3 > 97.4 ≤ 118; Q4 > 118; compared to PL+DOC pts.
Phase II trial of carboplatin (C) and bevacizumab (BEV) in patients (pts) with breast cancer brain metastases (BCBM).
Authors: Nancy U. Lin, Rebecca Sue Gelman, W. Jerry Younger, Jessica Sohl, Rachel A. Freedman, A. Gregory Sorensen, Elizabeth Bullitt, Gordon J Harris, Daniel Morganstern, Bryan P. Schneider, Ian E. Krop, Eric P. Winer
Journal: Journal of Clinical Oncology (2013)

513 Background: The anti-tumor and anti-edema effects of BEV provide a rationale for testing in BCBM. Carboplatin (C) is associated with CNS responses across multiple tumor types. We evaluated BEV + C in pts with BCBM. Methods: Pts with progressive, measurable BCBM (&gt;/= 1 cm in longest dimension) were eligible. Cycle 1: BEV 15 mg/kg on Day 1, followed on Day 8 by carboplatin AUC=5 (plus trastuzumab if HER2+). In subsequent cycles, pts received BEV + C on Day 1 (plus trastuzumab if HER2+) of a 3 week (wk) cycle. Standard brain MRI was obtained at baseline (BL) and every 2 cycles. Non-CNS scans (CT or MRI) were performed after 2 cycles, 4 cycles, then every 4 cycles. Correlative brain imaging was obtained at BL, 12-96 hours after the first dose of BEV, and after 2 cycles. Circulating tumor cells and blood for VEGF polymorphisms were also collected. The primary endpoint was composite CNS objective response rate (CNS ORR). CNS partial response required all of the following: &gt;/= 50% reduction in volumetric sum of target CNS lesions compared to BL, no progression of non-target lesions, no new lesions, stable/decreasing steroid dose, no progressive neurologic signs or symptoms, and no progression of non-CNS disease by RECIST 1.0. The study used a 2-stage design to distinguish between ORR 5% vs 20% (responses in &gt;/= 1/12 pts to enter 2 nd stage; responses in &gt;/= 4/37 pts needed to be promising). Results: 38 pts were enrolled between 11/3/09-8/24/12 (30 HER2+; 8 HER2-negative). Most (76%) pts had received &gt;/=2 lines of metastatic chemotherapy. 97% of pts with HER2+ disease received prior trastuzumab; 73% had prior lapatinib. All but 5 pts progressed after WBRT and/or SRS. As of 1/15/13, 3 pts remain on protocol therapy; 22 patients have died. The composite CNS ORR was 63% (95% CI 46%-78%). CNS ORR by RECIST was 45%. CNS responses were observed in both HER2+ and HER2-negative pts. Of 34 pts with &gt;/= 24 wks potential follow-up time, median number of cycles was 8 (range 1-19). One grade 2 CNS hemorrhage event was reported; there were no cases of grade 3/4 CNS hemorrhage. Conclusions: BEV + carboplatin is associated with a high rate of durable CNS response in pts with BCBM. Updated results, including progression-free and overall survival will be presented. Clinical trial information: NCT01004172.
Protein profiling utilizing SELDI technology may detect ductal carcinoma in situ (DCIS) with high reliability in patient's serum
Authors: I. Meinhold-Heerlein, C. Mundhenke, F. Rösel, W. Jonat, K. Nagasaki, M. Von Bergen, N. Maass
Journal: Journal of Clinical Oncology (2004)

9654 Background: Several methods are suited to classify different cancer types by testing RNA or protein expression. There is no method available to screen for DCIS. This study was performed to differentiate normal, premalignant, and malignant cases by protein profiling of human serum samples. In addition, the diagnostic value of SELDI-MS (surface-enhanced laser desorption ionisation -mass spectroscopy) for early diagnosis of DCIS was investigated. Methods: SELDI-MS potentiates quantitative measurement of complex protein mixtures such as blood serum. According to their isoelectric point, proteins of 5 to 200 kDa were separated on a mass spectroscopy sample carrier, and then analysed. Based on the obtained protein profiles, algorithms to predict the sample type were developed. Blood samples from about thirty women were analysed including cases without any breast-related lesion, with lesions of premalignant, and malignant phenotype, respectively. Results: SELDI analysis revealed a good differentiation between premalignant lesions and normal controls. For DCIS, the prediction strength was more than 80%; 12 different proteins were differentially expressed, four of them were used for the set-up of a decision tree. In contrast, due to their heterogeneity the protein expression spectra of patients with invasive breast cancer did not reach a significant prediction strength. Conclusion: Utilizing SELDI technique, the identification of differentially expressed proteins in serum samples -related to women with tumors of different malignant progression -turned out to be possible. In addition, the method may become available to predict the existence of DCIS, or to detect other pre-invasive lesions. No significant financial relationships to disclose.
Falls, physical performance deficits, and functional losses in cancer survivors with chemotherapy-induced neuropathy (CIPN): A University of Rochester CCOP study.
Authors: Supriya Gupta Mohile, Lin Fan, Jennifer S. Gewandter, Karen Michelle Mustian, Luke Joseph Peppone, Charles E Heckler, Judith O. Hopkins, Shaker R. Dakhil, Jessica Miller, Gary R. Morrow
Journal: Journal of Clinical Oncology (2012)

9014 Background: CIPN impairs quality of life in cancer survivors. Little is known about the prevalence of falls, physical performance (PP) deficits, and functional losses or their association with CIPN toxicities in cancer survivors. Methods: We conducted an analysis of baseline assessments from a phase III randomized clinical trial in cancer survivors with CIPN self reported pain scores of &gt; 4 reflecting leg and foot pain from neuropathy over the past 24 hours on a scale from 0 (“no pain”) to 10 (“pain as bad as you can imagine”). Patients also completed EORTC QLQ-CIPN-20 sensory and motor scales for neuropathy toxicities and self reported falls in the previous 3 months. A PP deficit was defined as “a lot of difficulty” or “unable to do” any of 6 physical tasks (e.g., lifting objects, walking a quarter of a mile). Functional losses were defined as “a lot of difficulty” or “unable to do” any of 5 functional tasks (e.g., managing money, bathing). We examined the association of baseline characteristics and CIPN toxicities with falls, PP deficits and functional losses using logistic regression. Results: Of 421 patients, 11.9% experienced recent falls, 58.6% reported a PP deficit, and 26.6% reported a functional loss. Patients with falls and/or PP deficits were more likely to be older (mean age 60.9 vs 58.9, p=0.02), female (75.3% vs 65.2%, p=0.03) and have less education (&lt;high school: 7.1% vs 0.6%, p&lt;.01). Cancer and chemotherapy history were not different between groups. Patients with falls and/or PP deficits reported higher severity of CIPN toxicities: pain (6.82 vs 6.05, p&lt;0.01), sensory (23.3 vs 19.6, p&lt;0.01), and motor (17.4 vs 12.7, p&lt;0.01). In multivariable analysis, factors associated with having a fall and/or PP deficit included: older age (OR 1.03, p=0.04), low education (OR 9.34, p=0.04), and motor toxicity (OR 1.21, p&lt;0.01). Factors associated with functional losses included: non-white race (OR 3.16, p=0.01), Hispanic ethnicity (OR 5.32, p=0.05), motor toxicity (OR 1.19, p&lt;0.01), and PP deficit (OR 4.94, p&lt;.01). Conclusions: CIPN toxicities, primarily motor, are significantly associated with falls, physical performance deficits, and functional losses.
Reduction of ovarian reserve in young early breast cancer patients: First data of a prospective cohort trial.
Authors: Lea Sanders, Antonia Sophie Wenners, Juliane Koss, Christian Schem, Maret Bauer, Jana Grambach, Fritz Werner Schaefer, Ulrike Schulz, Walter Jonat, Andreas Gerd Schmutzler, Christoph Mundhenke
Journal: Journal of Clinical Oncology (2012)

1084 Background: Breast cancer is the most common malignancy in premenopausal women. Sideeffects of chemotherapy are well known nevertheless the precise effects on ovarian function are inadequately studied by now. Premenopausal women undergoing chemotherapy are at risk for symptoms of sexual hormone deficiency and impaired fertility. Searching for predictive parameters of ovarian reserve after chemotherapy this prospective cohort study has been set up. Methods: 36 young patients with primary breast cancer have been included in this trial after written consent (April 2010 to November 2011) and after the study was approved by the local review board. All women were premenopausal (&lt; 46 years). They all received anthracycline based “A” neo- or adjuvant chemotherapy (as FEC) or combinations with taxanes “T” ( as TAC or FEC/Doc). Before and 6 and 12 months after initiation of chemotherapy age and chemotherapy related changes in hormone (LH, FSH, E2 and Anti-Müllerian hormone) levels, antral follicel count and amenorrhea as parameters of endocrine function and fertility were assessed.The additional impact of parity, BMI and nicotine use on ovarian reserve was also evaluated. Results: There is a correlation of antral follicle count before and 1 year after chemotherapy and a negative correlation of age and follicle count before and after chemotherapy (n.s.). This analysis shows that patients receiving “T” compared to those with “A” have a significant increase of LH (p=0.025) and FSH (mean:24 vs.59 IU/l, p=0.021) between visit 1 and 3. The type of chemotherapy has no influence on antral follicle count and AMH levels within the first 3 visits. BMI is negatively correlated with AMH at all time points (n.s.). BMI, nicotine abuse and age have no influence on the duration of amenorrhea, whereas patients with "T" showed 12 months of amenorrhea instead of 9 months in patients with "A" (n.s.). Conclusions: Our study will contribute to a better understanding and prediction of ovarian reserve of young early breast cancer patients undergoing chemotherapy. The 12 months follow up data suggest to offer fertility preserving measures before chemotherapy especially to patients planned for taxane containing chemotherapy.
Testicular organoid generation by a novel in vitro three-layer gradient system
Authors: João Pedro Alves-Lopes, Olle Söder, Jan-Bernd Stukenborg
Journal: Biomaterials (2017)

A system that models the testicular microenvironment and spermatogonial stem-cell (SSC) niche in vitro has not been produced yet. Here, we developed and characterized a novel three-dimensional multilayer model, the Three-Layer Gradient System (3-LGS), which permits the generation of rat testicular organoids with a functional blood-testis barrier (BTB) and germ cell establishment and proliferation. The model is unique as regards the formation of cellular organizations that more closely represent the in vivo germ-to-somatic cell associations in vitro. Moreover, we also verified the roles of retinoic acid (RA), IL-1α, TNFα and RA inhibitors in germ cell maintenance and BTB organization in vitro. Treatment with RA was beneficial for germ cell maintenance, while IL-1α and TNFα were observed to impair the formation of testicular organoids and germ cell maintenance. Taking in account our characterization and validation results, we propose the 3-LGS as a new platform to investigate the SSC niche in vitro and to search for novel unknown factors involved in germ cell proliferation and differentiation. Moreover, we suggest that this model can be used in other scientific fields to study organogenesis and development by the generation of organoids.
Targeted therapy approvals: Summary and future directions.
Authors: Julia A. Beaver, Gideon Michael Blumenthal, Nina L. Hunter, Todd Palmby, Amna Ibrahim, Robert L. Justice, Richard Pazdur, Patricia Cortazar
Journal: Journal of Clinical Oncology (2014)

e22181 Background: The development of targeted therapies for cancer has thrived with improved understanding of genetic mechanisms and co-development of companion diagnostics. Methods: Clinical trials leading to new drug and new indication approvals were reviewed. Results: The Table below summarizes the targeted therapies for cancer approved by the FDA. Approvals in the last three years are in marker with an asterisk. Conclusions: Identification of molecular targets early in drug development has enabled the co-development of commercial tests. Despite these recent successes, challenges remain. Future development of targeted therapies will need to explore different trial designs across tumor subtypes, continue co-development of companion diagnostics, and integrate combination therapies to better take into account molecular pathways of disease. FDA perspectives and recent developments will be presented. Primary molecular target Approved therapies Indication FDA-approved diagnostic (+ co-approved with dx) ALK Crizotinib* ALK+ NSCLC Yes+ AR Abiraterone acetate, enzalutamide* Prostate No BCR-ABL Imatinib, dasatinib, nilotinib, bosutinib,* ponatinib* Ph Ch+ CML and ALL No BRAF Vemurafenib,* dabrafenib* BRAF mut melanoma Yes+ BTK Ibrutinib* MCL No CD20 Rituximab, tositumomab +I131, ibritumomab,Y ofatumumab, obinutuzumab* NHL, CLL No CD25 Denileukin diftitox CTCL No CD30 Brentuximab* HL, ALCL No CD52 Alemtuzumab CLL No c-Kit Imatinib c-Kit GIST Yes Sunitinib, regorafenib* GIST No CTLA4 Ipilimumab* Melanoma No EGFR Panitumumab KRAS- colorectal (CR) Yes Cetuximab EGFR+ KRAS- CR, H+N Yes+ Erlotinib NSCLC, pancreatic No Erlotinib* EGFR del/mut NSCLC Yes+ Afatinib* Yes+ ER Tamoxifen, toremifene, fulvestrant HR+ breast No HER2 Trastuzumab HER2+ breast and gastric Yes+ Pertuzumab* HER2+ breast Yes Ado-trastuzumab emtansine* Yes+ Lapatinib No MEK Trametinib* BRAF mut melanoma Yes+ mTOR Everolimus* SEGA, breast, pNET No Everolimus, temsirolimus RCC No PDGFR Imatinib DFSP, MDS, HES No RANKL Denosumab* Giant cell tumor of bone No RET Vandetanib,* cabozantinib,* sorafenib* Thyroid No SMO Vismodegib* Basal cell No VEGF Sunitinib, pazopanib, axitinib,* regorafenib,* sorafenib, ziv-aflibercept,* bevacizumab Various (RCC, STS, CR, HCC, lung, glioblastoma) No
A pooled analysis of 1,546 patients with AIDS-related lymphoma (ARL): An assessment of prognostic factors by treatment era.
Authors: Stefan K. Barta, Michael Samuel, Xiaonan Xue, Jeanette Y. Lee, Nicolas Mounier, Lawrence D. Kaplan, Josep-Maria Ribera, Michele Spina, Umberto Tirelli, Rudolf Weiss, Lionel Galicier, Francois Boue, Wyndham Hopkins Wilson, Christoph Wyen, Kieron Dunleavy, Richard F. Little, Scot C. Remick, Mendel Goldfinger, Ariela Noy, Joseph A. Sparano
Journal: Journal of Clinical Oncology (2013)

8524 Background: Management of ARL evolved in the last 2 decades. We previously reported prognostic factors in a pooled analysis of 1,546 patients with ARL, and here present analysis of these factors over time to determine if their prognostic significance has changed. Methods: Following a systematic review, we assembled individual patient data from 19 prospective phase 2/3 clinical trials (published 1993-2010) for ARL (n=1,546). Factors analyzed include age, sex, histology, CD4 count, prior history of (h/o) AIDS, &amp; age-adjusted (aa) IPI. The endpoint was overall survival (OS) expressed as the hazard ratio (HR) for death. We used separate Cox proportional hazard models adjusted for the other covariates to determine the significance of each variable in the following time periods: pre-cART [combination antiretroviral therapy] (&lt;1996; n=388), early cART (‘96-‘00; n=694), modern cART (‘01-‘04; n=282) &amp; current era (‘05-‘10; n=182). We also combined all enrollments in one Cox model to test for difference in association with OS over enrollment periods. Results: Rituximab use was limited in the early cART (20%) compared with the modern cART (83%) and current (93%) eras. Histology &amp; sex were not significantly associated with OS in any time period. Increasing age was associated with worse OS in the pre-cART (HR 1.02; p&lt;0.01) and current (HR 1.05, p=0.04) eras. A prior h/o AIDS increased risk of death during early cART (HR 1.31, p=0.047) but was not significant after 2000. Meanwhile, baseline CD4 count &lt;50 was a poor prognostic factor during early (HR 1.78, p&lt;0.01) and modern cART (HR 2.76, p=0.001) eras, but not in the current era. The aaIPI predicted worse OS in each time period (pre-cART: HR 1.54, p&lt;0.0001; early cART: HR 1.49, p&lt;0.0001; modern cART: HR 1.52, p&lt;0.01; current era: HR 2.34, p&lt;0.0001). No significant interaction between each prognostic factor with enrollment was found. Conclusions: In this pooled analysis of 1,546 patients with ARL, aaIPI was the only consistently significant prognostic factor and its effect was magnified in the current era. HIV-related factors gained prognostic relevance in the early and modern cART era but may not be as relevant with current treatment strategies.
BRAF V600E and survival benefit of anti-EGFR monoclonal antibody (mAb) therapy for metastatic colorectal cancer (mCRC): A meta-analysis.
Authors: Michael Sorich, Andrew Rowland, Mafalda Dias, Ross Allan McKinnon, Ganessan Kichenadasse, Michael Wiese, Christos Stelios Karapetis
Journal: Journal of Clinical Oncology (2015)

e14605 Background: BRAF V600E mutation is a known marker of poor prognosis for individuals with mCRC. However, whether it is also a predictive marker of the efficacy of anti-EGFR mAb therapy is uncertain. Methods: A systematic review and random-effects meta-analysis of RCTs was undertaken to evaluate the effect of BRAF V600E on the progression-free survival (PFS) and overall survival (OS) benefit of anti-EGFR mAb therapy for mCRC. Treatment effect was reported as a hazard ratio (HR) with 95% confidence interval (CI). Results: Six RCTs (n = 4295) met the inclusion criteria for assessment of OS, while 7 RCTs (n = 4609) met the inclusion criteria for assessment of PFS. Of the 2497 participants with RAS WT tumors across the 7 RCT substudies, 261 (10.5%) were BRAF mutant. For both OS and PFS, the HR point estimates for RAS WT / BRAF V600E tumors were situated midway between those of RAS WT / BRAF WT tumors and RAS mutant tumors. However, the reduction in efficacy (RAS WT / BRAF V600E vs RAS WT / BRAF WT) was not statistically significant (P = 0.57 and P = 0.18 for OS and PFS, respectively). For PFS, but not OS, the HR for the RAS WT / BRAF V600E tumors significantly different from RAS mutant tumors (P = 0.02). Conclusions: There is currently insufficient evidence to definitively claim that BRAF V600E is a negative predictive marker of anti-EGFR mAb benefit in RAS WT mCRC. Despite including data from 7 large RCTs comprising > 4000 participants, a larger sample size is required for adequate power to distinguish clinically meaningful differences. OS HR (95% CI), n PFS HR (95% CI), n RAS WT / BRAF WT 0.78 (0.66, 0.91), 2121 0.58 (0.48, 0.71), 2236 RAS WT / BRAF V300E 0.91 (0.56, 1.48), 246 0.76 (0.52, 1.12), 261 RAS MT 1.06 (0.93, 1.19), 1928 1.10 (0.93, 1.30), 2112
Conditional survival estimates for lung cancer histologic subtypes in the U.S. (2004-2008).
Authors: Kailash Mosalpuria, Yan Xing, Chung-Yuan Hu, Vijaya Raj Bhatt, Apar Kishor Ganti
Journal: Journal of Clinical Oncology (2015)

7550 Background: Conditional survival (CS) is a more accurate measure of survival probability among cancers associated with a poor prognosis. We calculated lung cancer-specific CS estimates to help clinicians and patients with informed decision making. Methods: Lung cancer patients with at least 3 years of follow-up were identified from the Surveillance Epidemiology and End Results registry (2004-2008). American Joint Commission on Cancer, sixth edition was used for staging non-small cell lung cancer (NSCLC). Stages 1 to 3 SCLC were classified as limited stage (LS), and stage 4 was classified was extensive stage (ES). Multivariate Cox regression models were built separately by stage to calculate the adjusted 1-6 year cancer-specific survival and overall survival. The multiplicative law of probability was then used to compute the X-year conditional survival where the (x+y) year survival is divided by y years of patients who have survived. The following were adjusted: age, sex, ethnicity, marital status, SEER region, year of diagnosis, radiation, and definitive surgery. Results: A total of 127,992 patients were included in the final cohort. Patients diagnosed with stage IA NSCLC had a 3-year survival probability of 73%. This increased to 76% in patients who were alive at 3 years following diagnosis. The three- year conditional overall survival (COS) estimates from diagnosis (time 0) to 3 years for the other stages were as follows: stage 1B: 54% to 68%, stage 2A: 54% to64%, stage 2B: 37% to 58%, stage 3A: 25% to 51%, stage 3B: 14% to 43%, and stage 4: 6% to 29%. For Stage 1A NSCLC 3-year conditional cancer-specific survival (CCSS) estimates improved from 82% to 87%, stage 1B: 63% to 80%, stage 2A: 62% to74%, stage 2B: 44% to 69%, stage 3A: 30% to 60%, stage 3B: 18% to 53%, and stage 4: 8% to 35%. For LS-SCLC, 3-year COS improved from 16% at diagnosis to 52% at 3 years; for ES-SCLC it increased from 3% to 47%. For LS- SCLC, 3-year CCSS improved from 19% at 0 years to 63% at 3 years whereas for ES-SCLC it improved from 4% to 53%. Conclusions: Three-year COS and CCSS estimates improve dramatically over time for survivors with advanced stages. These prognostic data are critical to patients for both treatment and non-treatment related life decisions.