tbuckley/cabot-search huggingface dataset:
Phase I trial of huA33 antibody plus 5-fluorouracil (5FU), leucovorin, and oxaliplatin in patients with metastatic colorectal cancer [LUD2003–005]
Authors: C. Renner, G. Ritter, L. Pan, E. Venkatramin, E. W. Hoffman, R. Venhaus, L. Old, A. Knuth, E. Jäger, M. Pfreundschuh
Journal: Journal of Clinical Oncology (2007)

3022 Background: The selective targeting of tumors with monoclonal antibodies (mAb) has emerged as a new therapeutic approach in cancer therapy with the A33 glycoprotein being a promising target in colorectal cancer. Specific tumor localization and low toxicity of a humanised A33 specific mAb (huA33) has previously been demonstrated in patients with colorectal carcinoma. In the present study, we determined the safety and efficacy of the combination of huA33 and 5FU plus leucovorin and oxaliplatin (FOLFOX-4) in patients with metastatic colorectal cancer. Methods: Patients had to present with metastatic colorectal cancer with an expected survival of at least 4 months and no more than 2 different pre-treatment regimens. Patients were excluded if they had previously received oxaliplatin or huA33 mAb. Eligible patients received huA33 (10 mg/m 2 ) by iv infusion weekly for 12 weeks (cycle 1). On study day 15, standard FOLFOX-4 chemotherapy was administered every 2 weeks for 10 weeks. Responding patients received a second cycle of weekly huA33 (10 mg/m 2 ) and biweekly FOLFOX-4 chemotherapy. Results: A total of 19 patients (11 female, 8 male) with a median age of 60 years entered the study. 5 patients had received prior chemotherapy, 2 radiation therapy and 18 surgery. Toxicities observed were as expected for FOLFOX-4 treatment alone with hematological side effects to be most prominent and included (only G3 and G4) 1 anemia and 10 neutropenias. The addition of huA33 to FOLFOX-4 did not change the pattern of known non-hematological toxicities with a low rate (14%) of huA33 mAb associated allergic reactions. One sudden death occurred at cycle five that was neither therapy nor disease related. Within the 16 patients currently available for response assessment, the overall response rate was 38% with 1 CR, 5 PR and 5 disease stabilizations. Conclusion: The combination of FOLFOX-4 as standard chemotherapy for this cohort of patients in combination with the humanized A33 antibody did not increase toxicities and was well tolerated. The overall response rate of 38% is in the response range published so far for the FOLFOX-4 regimen in this setting and warrants further analysis in a larger cohort of patients. [Table: see text]
Differential thymidylate synthase expression in lung cancer adenocarcinoma subtypes.
Authors: Luisella Righi, Valentina Monica, Silvia Novello, Antonia Arru, Federica Massa, Enrica Capelletto, Tiziana Vavalá, Simona Vatrano, Giorgio Vittorio Scagliotti, Mauro Papotti
Journal: Journal of Clinical Oncology (2014)

e18539 Background: Lung adenocarcinoma (ADC) is characterized by lower Thymidylate Synthase (TS) levels compared to squamous carcinoma and high sensitivity to Pemetrexed, an antifolate targeting TS. Lung ADC includes various histological patterns (lepidic, acinar, solid, papillary and micropapillary), often combined together. A comprehensive estimation of the various component percentages is recommended in pathological reports. This single centre observational study aimed to retrospectively assess TS expression, at both mRNA and protein levels, according to the different morphological ADC subtypes. Methods: Formalin-fixed paraffin embedded specimens of 84 consecutive resected lung ADCs (52.4% stage I, 23.8% stage II, 23.8% stage III) diagnosed at San Luigi Hospital between January 2011 and December 2012 were retrospectively collected and the ADC histological subtypes re-assessed. Immunohistochemical expression of TS and Ki67 index were evaluated by semiquantitative H-Score method and percentage of positive nuclei, respectively. TS mRNA expression was assessed by RT-PCR. Results: Among 84 ADCs, 33 (39%) cases had pure histology, including 27/33 (82%) acinar, 4/33 (12%) solid, 2/33 (6%) papillary; the remaining 51 (61%) had more than one growth pattern. A significant differential distribution of TS protein levels was found among different ADC variants (irrespective of being pure or combined tumors) being higher in acinar and solid and lower in lepidic, papillary and micropapillary subtypes (p=0.0005). TS mRNA levels were assessed in 72 cases, including 30/72 (42%) pure (80% acinar, 13% solid, 7% papillary) and 42 combined ADC. A significant overall linear correlation among TS protein and the corresponding gene expression levels was found (p=0.03). TS gene expression levels were significantly higher in solid compared to acinar or papillary variants (p=0.03). Further results for other variants will be available soon. Conclusions: This retrospective study demonstrates a differential expression of TS among different lung ADC subtypes. Prospective evaluation, also in advanced disease, will explore the possible correlation of different TS expression levels in ADC subtypes with the efficacy of pemetrexed.
Association between immune-checkpoint inhibitor induced tumor shrinkage and overall survival in advanced melanoma and NSCLC.
Authors: Yan Feng, Shruti Agrawal, Manish Gupta, Ashok Kumar Gupta, Eric Masson, Amit Roy
Journal: Journal of Clinical Oncology (2014)

3053 Background: Immune checkpoint inhibitors enhance immunologic antitumor activity and ongoing studies are exploring the potential of such inhibitors to provide long term (OS) benefits across several cancer types. We describe an exploratory analysis of the association between tumor shrinkage (TS) and OS in patients (pts) with melanoma or NSCLC receiving ipilimumab or nivolumab, immune checkpoint inhibitors that augment T-cell activity by blocking CTLA-4 and programmed death-1 receptors, respectively. Methods: TS and OS associations for ipilimumab in pts with advanced melanoma were assessed using data from 4 phase II studies (CA184-004/007/008/022, n=351). TS and OS associations for nivolumab were assessed in pts with advanced melanoma (n=97) or NSCLC (n=112) using data from cohorts of a phase I study (CA209-003). A nonlinear mixed-effects model was used to describe longitudinal tumor burden data; TS was determined from the model as % decrease from baseline. The relationship between TS and OS was determined by a multivariate Cox proportional-hazards model. Results: Across the pt populations tested, the risk of death decreased with increasing % TS (hazard ratio [HR] coefficients in all 3 models and associated 95% confidence intervals [CIs] <1.0). At 30% TS (corresponding to magnitude of RECIST partial response), the association between TS and OS for pts with melanoma was comparable for ipilimumab or nivolumab treatment (HR [95% CI] of 0.602 [0.543–0.668] and 0.502 [0.381–0.662], respectively, relative to no change in % TS). At 30% TS, the association between TS and OS for NSCLC pts treated with nivolumab was comparable with that seen for melanoma pts (HR [95% CI] of 0.361 [0.252–0.517]). Conclusions: An association was found between the extent of TS and OS across melanoma pts receiving ipilimumab or nivolumab and NSCLC pts receiving nivolumab in this exploratory retrospective analysis. Measuring the extent and timing of TS may have use in predicting potential OS benefits of immune checkpoint inhibitors; however, this observation would need to be prospectively evaluated in data from a well-controlled study. Additional exploratory analyses are ongoing to assess correlates to OS benefit.
Prognostic value of baseline inflammatory markers in inoperable non-small cell lung cancer (NSCLC)
Authors: N. MacDonald, G. Kasymjanova, S. Dobson, H. Kreisman, V. Cohen, J. S. Agulnik, D. Small
Journal: Journal of Clinical Oncology (2006)

17035 Background: Markers of chronic inflammation are not commonly included in standard NSCLC staging, which remains anatomically based. Several studies have reported that an increased C-reactive protein (CRP), a marker of chronic inflammation, presages short survival for NSCLC patients (pts). A cohort of 68 pts with advanced NSCLC (stages 3A, 3B and 4) was studied in order to evaluate the prognostic value for survival of various pretreatment inflammatory parameters. Methods: The following factors were collected at the time of diagnosis prior to treatment: sex, age, stage, performance status, CRP, LDH, hemoglobin, platelets, albumin, and white blood cells (WBC). Statistical evaluation employed univariate and multivariate analyses. Survival was calculated using the Kaplan-Meier method and compared using the log-rank test. Results: Median survival for the entire cohort was ten months (mo) (95% CI 7, 15). Those with stages 3A, 3B (18 pts) had a survival of 11 mo (95% CI 6,15), whereas those with 3B (effusion)/4 (50 pts) had a survival of 8 mo (95% CI 3,13). Univariate analysis identified CRP and WBC as the only significant prognostic factors for survival (p &lt; 0.01). Multivariate analysis also demonstrated that CRP (p = 0.005), and WBC (p=0.009) displayed independent correlation with prognosis. CRP and WBC were then combined into a prognostic index (PI) ranging from 0–2. The total score demonstrated a better stratification value for survival. Both parameters were normal [WBC ≤ 11, CRP ≤ 10] (PI 0) in 26 (38%) pts; one parameter was elevated (PI 1) in 27 (40%) pts; and both parameters were elevated (PI 2) in 15 (22%) others. Pts with PI 0 had a median survival of 14 mo (95% CI 12, 21); those with PI 1 had a median survival of 7 mo (95% CI 5, 10); and pts with PI 2 had a median survival of 5 mo (95% CI 3, 7). Conclusions: Systemic inflammatory markers predicted survival in our cohort with NSCLC. These data need to be confirmed in a larger validation study. Studies on staging systems that include inflammatory markers are indicated. Clinical trials linking anti-inflammatory therapies with chemotherapy should be prioritized. No significant financial relationships to disclose.
The Incredible Heart of Mr. B
Authors: Julia Schoen
Journal: Annals of Internal Medicine (2017)

On Being a Doctor21 March 2017The Incredible Heart of Mr. BJulia Schoen, MSJulia Schoen, MSFrom University of Michigan Medical School, Ann Arbor, Michigan.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M16-1514 Audio Reading - “The Incredible Heart of Mr. B” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "The Incredible Heart of Mr. B," by J. Schoen. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail It was my first day of clinical rotations as a medical student. To say I was anxious would be the understatement of the year. And then I met my first patient: Mr. B. I was scared to even touch him. I had never taken care of a patient before. He was unshaven, and his wiry, gray hair stuck out in all the wrong directions. His belly was bulging with fluid. His feet were mottled and scabbed. He told me that he had come to the hospital for worsening heart failure. Despite his size, Mr. B's hospital gown made him look ... Author, Article, and Disclosure InformationAffiliations: From University of Michigan Medical School, Ann Arbor, Michigan.Corresponding Author: Ms. Schoen; e-mail, [email protected]umich.edu. PreviousarticleNextarticle Advertisement Audio Reading - “The Incredible Heart of Mr. B” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "The Incredible Heart of Mr. B," by J. Schoen. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics 21 March 2017Volume 166, Issue 6Page: 447-448KeywordsBloodDyspneaHeartHeart murmursLungsSweatThoraxTouchVeinsWheelchairs ePublished: 21 March 2017 Issue Published: 21 March 2017 Copyright & PermissionsCopyright © 2017 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Global and MYC-Specific Translation Is Enhanced in Activated Chronic Lymphocytic Leukemia Cells Carrying NOTCH1 C.7541_7542delct Mutations
Authors: Annalisa D'Avola, Alison Yeomans, Samantha Drennan, Matthew Rose-Zerilli, Jonathan C. Strefford, Freda K Stevenson, Andrew J Steele, Graham Packham, Francesco Forconi
Journal: Blood (2016)
E2208: Randomized phase II study of paclitaxel with or without the anti-IGF-IR antibody cixutumumab (IMC-A12) as second-line treatment for patients with metastatic esophageal or GE junction cancer.
Authors: Steven J. Cohen, Yang Feng, Paul J. Catalano, Edith P. Mitchell, Peter J. O'Dwyer, Sam Joseph Lubner, George A. Fisher, Mary Frances Mulcahy, Barbara Burtness, Al Bowen Benson
Journal: Journal of Clinical Oncology (2014)

4020 Background: Paclitaxel has activity in previously treated metastatic esophagus/GE junction cancer. Given activation of IGFR signaling in these patients (pts), we performed a randomized phase II study of paclitaxel ± cixutumumab (anti-IGF1R). Methods: Pts with metastatic measurable adenocarcinoma or squamous cell carcinoma of esophagus/GE junction who had progressed on one line of systemic therapy (recurrence within 6 months of adjuvant permitted) were randomized 1:1 to receive paclitaxel, 80 mg/m2 IV days 1,8,15 Q28 alone (Arm A) or with cixutumumab, 10 mg/kg days 1,15 Q28 (Arm B). CT imaging Q2 cycles. Key eligibility: ECOG PS 0-2, no prior taxane, fasting glucose ≤ 160 mg/dL, HgbA1C ≤ 7%. Primary endpoint PFS. Secondary endpoints OS, RR, toxicity. 90 pts would provide 90% power to detect a PFS difference of 3.5 m in experimental arm vs. 2m in control. Results: 94 pts were enrolled between 9/2010 and 10/2012 and 87 were evaluable for efficacy (43 Arm A, 44 Arm B). Pt characteristics were balanced between arms: median age 62 (range 40-89), 78% male, 94% Caucasian, 82% adenoca, 16% squamous ca, 54% GE junction, 18% lower esophageal, PS 0/1=39%/56%. Median number of cycles=2 on both arms. Most common grade 3/4 non-heme tox (%) Arm A(fatigue=8, hyperglycemia=5,hypophosphatemia=5), Arm B (hyperglycemia=11, muscle weakness=5, mucositis=5). Grade 3/4 heme tox (%ArmA/B):anemia 10/9, neutropenia 8/18, plts 0/2. 2 deaths in Arm A and 1 in Arm B were judged possibly related to therapy. Median PFS for all patients was 2.6 (90% CL [2.0-3.5]) months. Median PFS for Arms A and B were 2.6 (90% CL [1.8-4.1]) and 2.3 (90% CL [2.0-3.6]) months, respectively (p=0.72). Median OS for all patients was 6.4 (90% CL, 5.0-7.9) months. Median OS for Arms A and B were 6.5 (90% CL, 4.6-9.5) and 6.4 (90% CL, 4.9-8.0) months, respectively (p=0.92). The RR (CR+PR) for Arm A and B were 12% [90% CI: 5%, 23%] and 14% [90% CI: 6%, 25%], respectively. Conclusions: The addition of cixutumumab to paclitaxel in second-line therapy of metastatic esophageal/GE junction cancer was well tolerated but did not improve clinical outcome. Clinical trial information: NCT01142388.
A phase II study of combination epigenetic therapy in metastatic colorectal cancer (mCRC): A phase II consortium (P2C)/Stand Up 2 Cancer (SU2C) study.
Authors: Nilofer Saba Azad, Anthony B. El-Khoueiry, Michelle R. Mahoney, Douglas Adkins, Patrick J. Flynn, Nathan Bahary, George P. Kim, Henry Clement Pitot, Charles Erlichman, Ross C. Donehower, James Gordon Herman, Stephen Baylin, Nita Ahuja
Journal: Journal of Clinical Oncology (2013)

3539 Background: Therapy with decitabine and entinostat (ENT: HDAC inhibitor) shows synergistic effect in re-expression of tumor-suppressor genes and growth inhibition in CRC cell lines and in vivo studies. Methods: We conducted a phase II, multi-institutional study of SQ 5-azacitidine (AZA) and oral ENT in mCRC pts. A 28 day cycle included: AZA at 40 mg/m 2 d1-5 and 8-10 with ENT 7 mg d3 and 10. Initial eligibility criteria included: ECOG PS 0-1, good end organ function, and biopsiable disease for cohort A (CoA). An interim analysis indicated that toxicity which crossed pre-specified safety boundary was secondary to disease. A 2nd cohort B (CoB) with eligibility restrictions: &lt;2 prior regimens in KRAS-mutated CRC pts, &lt;3 prior regimens if KRAS wild-type, and liver disease limited to &lt;30% of volume was accrued. Serial tumor biopsies and research blood were collected to assess for methylation/expression changes in circulating tumor DNA and biopsies, respectively. The primary endpoint was response as measured by RECIST criteria using a 2-stage Simon design. Results: 47 pts were initially enrolled (24 CoA, 23 CoB). Pts received a median of 2 cycles on both cohorts (1-16 CoA, 2-6 CoB). Pts had a median of 4 prior therapies for CoA (range 2-9) and 3 for CoB (range 2-6). Gr 4 AEs attributable to treatment for CoA included hyperglycemia (1) and hypokalemia (1); other common Gr 3 AEs included anemia (3), decreased lymphocytes (7), fatigue (3), and nausea (3). CoB pts experienced grade 3 chest pain (1), neutropenia (2), leucopenia (2), urinary tract obstruction (1), and hypophosphatemia (1). No responses have been observed. Results of translational objectives will be presented at the meeting. Conclusions: SQ AZA and ENT therapy does not have clinical activity as defined by confirmed response in aCRC. Follow-up for survival, response to subsequent therapy, and correlative analysis are ongoing. Supported in part by N01-CM-2011-00099. Clinical trial information: NCT01105377. [Table: see text]
Bevacizumab-based therapy in patients with heavily pretreated ovarian and other Mullerian tract cancers.
Authors: Jutta Anna Kurbacher, Jutta Lepique, Susanne Herz, Gabriele Wessling, Christian M. Kurbacher
Journal: Journal of Clinical Oncology (2013)

e16533 Background: Bevacizumab (Bev) is approved for the therapy (Tx) of primary and platinum-sensitive recurrent Mullerian tract cancers (MTC) such as ovarian (OC), fallopian tube (FTC), type II endometrial (EC-II), and peritoneal papillary-serous carcinomas (PPSC). However, the role of Bev in the ≥ 3rd line Tx of MTCs is still unclear.This retrospective study summarizes our long-term experiences with Bev in patients (pts) with heavily pretreated MTC who did not qualify for recruitment into a controlled clinical trial. Methods: A total of 74 intensively pretreated MTC pts (OC, n = 65; FTC, n = 2; EC-II, n = 4; PPSC, n = 3) were included in this study with 43 (58.1%) being platinum-resistant. Pts had failed a median of 4 (range 1-10) prior chemotherapies (CTx ). Tx included Bev monotherapy (group A, n = 17), Bev + metronomic CTx (group B, n = 37), and Bev + conventionally dosed CTx (Group C, n=20). Bev was administered at either 10 mg/kg BW q2w or 15 mg/kg BW q3w. Adverse effects were classified according to CTCAE Vs 4.03. TTP was calculated from the start of Bev until progression, OS was calculated from the start of Bev until death or loss to follow up. Results: Most common Tx related toxicities were hypertension, proteinuria, headache, inflammation/infection, epistaxis, and subileus. Hypertension which often required adequate treatment was limiting in only one case as also were renal toxicity and infection. Median TTP was 27.8 wks and median OS was 53.6 wks with no significant difference between platinum-resistant and –sensitive pts. In regard to both TTP and OS, there was a non-significant trend favoring groups A (33.4/63.0 wks) and B (29.9/61.6 wks) vs group C (19.2/35.4 wks). Conclusions: Bev based Tx was active and generally well tolerated in this hard-to-treat population of pts with recurrent MTC. Both TTP and OS were equal or even superior to any conventional CTx used in this setting. Moreover, clinical platinum-resistance did not predict a worse clinical outcome. Although this is not a randomized trial, our results argue in favor that Bev should be preferably given either as single agent or combined with metronomic CTx in pts with heavily pretreated MTCs. Further clinical trials of Bev in recurrent MTCs may prove useful.
Ascitic derived primary pancreatic cancer cell cultures from different patients as a platform for personalized medicine.
Authors: Talia Golan, Dikla Atias, Camila Avivi, Iris Barshack, Raanan Berger
Journal: Journal of Clinical Oncology (2012)

e14646 Background: In Pancreatic Cancer (PC) challenges in drug development include: obtaining metastatic cancer tissue for research, developing and validating biomarkers predicative for personalized therapeutic decisions. We have recently developed a novel therapeutic model for PC to address these challenges based on the isolation of viable PC cells derived from ascitic fluid. Methods: Ascitic fluid was obtained from PC patients undergoing palliative paracentesis. In several patients ascites was obtained several times during the course of their disease. Ascitic-derived primary PC cells were isolated, cultured and identified for each patient in vitro. Informed consent was obtained for all patients. Results: We successfully established ascitic-derived primary cell cultures in 87% (53/61) of the ascites obtained. Homogeneous epithelial PC enriched cell cultures were identified; CK 7/8 (epithelial marker) staining by FACS in 90-95% of the cells, IHC strong staining of CK 7 and negative staining for CK 5/6 in the majority of cells in the cultures. We observed a wide range in doubling time and migration properties among the patients' cell cultures. The diverse nature of each individual patient's cell cultures were further demonstrated by varying chemo-sensitivity to gemcitabine and additional therapeutic agents. Morphological changes were observed at different stages of disease, most cells initially displayed a characteristic epithelial morphology. With more advanced disease a mixed morphological appearance "epithelial-mesenchymal" was seen and up regulation of various epithelial-mesenchymal-transition markers were observed by real-time PCR. Conclusions: We have developed a unique primary ascitic-derived PC cell culture model. These cell lines have the potential to serve as a relevant model to study signaling pathways in PC progression, and to assess the sensitivity to therapeutic agents in a short time frame, therefore supporting personalized treatment decisions.