tbuckley/cabot-search huggingface dataset:
Comparative benchmarking of regulatory drug approvals by Food &amp; Drug Administration (FDA): A cross disease comparison with gynecologic malignancies.
Authors: Victor Rodriguez-Freixinos, Michelle K. Wilson, Stephanie Lheureux, Cristina Martin-Lorente, Katherine Karakasis, Lisa Wang, Tony Panzarella, Amit M. Oza
Journal: Journal of Clinical Oncology (2015)

e16584 Background: Gynecologic malignancies (GM) represent a major cause of cancer deaths. Improving outcomes of systemic therapy in GM requires development of new active anticancer drugs (AD), their regulatory approval and clinical adoption. Understanding regulatory approvals by the FDA may allow assessment of development in GM, cross disease comparisons and benchmarking. Methods: Using the FDA public website and drug labels we performed a cross sectional analysis of approved AD, indications for ST and GM (new molecular entity [NME], supplemental indications and orphan drugs designations [ODD]) and their supportive trials. Reformulations of previously approved AD, generics, adjunctive, preventive, local therapy, symptom management and noncancerous indications were excluded. Results: From 1990 to 2014, FDA approved 63 NMEs for 135 indications and 9 indications based on previously approved AD. ODD accounted for 28% of indications. GM approvals included 4 NMEs (Olaparib, Topotecan, Paclitaxel and Altretamine) and 11 indications (4 ODD). There were no approvals for endometrial and vulvo-vaginal cancers. No difference was found in NME approvals trend comparing ST to GM (p = 0.14); however, differences in the trial accrual process were detected (Table 1). Unique pivotal, randomized, phase 3 trials supported 61% vs 45% of indications for ST vs GM (p = 0.36), while non-randomized trials supported 10% vs 27% (p = 0.11). Overall survival led to approval of 40% and 36% indications in ST and GM. FDA granted 4 priority reviews and 2 accelerated approvals in GM compared to 66 and 29 in ST. Olaparib is the only biomarker guided approved AD for GM. Conclusions: Comparative benchmarking of pivotal trials and associated drug approval by FDA provide an evidence informed assessment of consistency and equity in regulatory approvals. GM make up 12% of all cancers in US, however GM indications represent 8 % of all ST approvals over the last 25 years. ST GM P value Size: randomized patients, median 577 358 0.011 Sites, median 98 43 0.016 Countries, median 16 7 0.004 Accrual time, days 734 943 0.76 Time to approval, days 183 181 0.98
Sustaining quality cancer care in the NCI Community Cancer Centers Program (NCCCP).
Authors: Kathleen M. Castro, Pamela Spain, Stephanie Teixeira-Poit, Irene Prabhu Das, Brenda A. Adjei, Robert D. Siegel, Steven Clauser, Michael T. Halpern
Journal: Journal of Clinical Oncology (2014)

6536 Background: In 2007, the NCCCP pilot program launched with 16 sites and a goal to improve quality of care, reduce cancer disparities and increase participation in clinical trials. In 2008, NCCCP began to participate in the Commission on Cancer Rapid Quality Reporting System (RQRS). An evaluation of NCCCP in 2010 assessed changes in cancer care quality among the sites before vs. after program implementation compared to non-NCCCP hospitals during the same time period (Halpern et al. 2013). Our current analysis examines if improvements in quality were sustained. Methods: Conducted a retrospective analysis of patients diagnosed and receiving all or part of their initial cancer treatment at an NCCCP facility. Compared concordance rates for 6 NQF- approved quality of care measures (3 breast, 2 colon and 1 rectal) for patients diagnosed between 2006-2007 (pre-NCCCP), 2008-2010 (early NCCCP) and 2011-2013 (later NCCCP). Results: The sample included 17,288 breast, 6,655 colon and 569 rectal cancer patients. Patient-level concordance rates improved significantly for all 6 measures and were sustained for 5. Breast cancer measures showed the greatest improvement from pre-NCCCP and were subsequently sustained. Hormone therapy for hormone receptor positive breast cancer increased from 51% (pre) to 90% (early) to 92% (later). Radiation therapy for breast conserving surgery increased from 72% to 93% to 92%. Colon cancer measures also showed sustained improvements with adjuvant chemotherapy for stage III cancer increasing from 72% to 90% to 89%. However, adjuvant chemotherapy for stage III rectal cancer improved from baseline (83%) to early NCCCP (90%) but then returned to pre-NCCCP rates (83%) later in the program. Significant changes were also seen in disparate populations. Conclusions: Quality of care measures at NCCCP sites increased after program initiation, and this increase was largely sustained over time. Improvement in recording of treatment administration due to the RQRS was a factor in increasing concordance. Concurrent NCCCP activities, including a working group to improve RQRS reporting and presentations of NCCCP results to the participants, may have helped sites significantly improve and sustain quality cancer care.
Docetaxel versus docetaxel plus irinotecan as second line chemotherapy in advanced non-small cell lung cancer (NSCLC): A randomized phase II trial
Authors: D. Pectasides, D. Farmakis, M. Pectasides, V. Kostopoulou, M. Nikolaou, M. Koumpou, A. Gaglia, P. Kountourakis, N. Mylonakis, T. Economopoulos
Journal: Journal of Clinical Oncology (2004)

7033 Background: Single-agent docetaxel represents the standard treatment in NSCLC patients recurring after platinum-based chemotherapy. Our aim was to evaluate whether its combination with irinotecan would lead to a better outcome with similar toxicity compared to docetaxel monotherapy as second-line chemotherapy in NSCLC. Methods: A total of 130 patients with performance status of 0–2 and recurrent NSCLC previously treated with platinum-based chemotherapy were randomized to either docetaxel 75mg/m2 every 3 weeks or docetaxel 30mg/m2 plus irinotecan 60mg/m2 on days 1 and 8 every 3 weeks. Patients were assessed for toxicity in every cycle and for response every 2 cycles. Results: Treatment arms were well-balanced for patient characteristics. The overall response rate was higher in the combination arm (20% versus 14%), but this difference was not significant (p=0.36). Time to tumor progression showed a trend for being significantly longer in the combination arm (5.6 versus 4.8 months, p=0.065), while overall survival (6.5 versus 6.4 months, p=0.49) and 1-year survival (37% versus 34%, p=0.72) were not significantly different. None of the patients with performance status >1 responded to chemotherapy. Prior exposure to paclitaxel did not affect the possibility for response to docetaxel in either arms. Toxicity was moderate and rather well-tolerated. Grade 3/4 neutropenia and G-CSF administration frequency were similar in both arms. Grade 3/4 thrombocytopenia rate was significantly higher in the combination arm (17% versus 6%, p=0.04), while grade 3/4 anemia rate also showed a trend for being significantly higher in the combination arm (23% versus 12%, p=0.09). Grade 3/4 non-hematologic toxicity occurrence was similar, except for diarrhea (12% for the combination versus 3% for monotherapy, p=0.05). Conclusions: The combination of docetaxel with irinotecan was not superior to docetaxel monotherapy in terms of response rate, median and 1-year survival. Single-agent docetaxel remains the standard second-line regimen in NSCLC. No significant financial relationships to disclose.
The transcription factor Foxo1 controls germinal center B cell proliferation in response to T cell help
Authors: Takeshi Inoue, Ryo Shinnakasu, Wataru Ise, Chie Kawai, Takeshi Egawa, Tomohiro Kurosaki
Journal: The Journal of Experimental Medicine (2017)

Germinal center (GC) B cells cycle between two states, the light zone (LZ) and the dark zone (DZ), and in the latter they proliferate and hypermutate their immunoglobulin genes. How this functional transition takes place is still controversial. In this study, we demonstrate that ablation of Foxo1 after GC development led to the loss of the DZ GC B cells and disruption of the GC architecture, which is consistent with recent studies. Mechanistically, even upon provision of adequate T cell help, Foxo1-deficient GC B cells showed less proliferative expansion than controls. Moreover, we found that the transcription factor BATF was transiently induced in LZ GC B cells in a Foxo1-dependent manner and that deletion of BATF similarly led to GC disruption. Thus, our results are consistent with a model where the switch from the LZ to the DZ is triggered after receipt of T cell help, and suggest that Foxo1-mediated BATF up-regulation is at least partly involved in this switch.
Characterization of an anti-Trop-2-SN-38 antibody-drug conjugate (IMMU-132) with potent activity against solid cancers.
Authors: David M. Goldenberg, Edmund A Rossi, Serengulam V. Govindan, Thomas M. Cardillo, William J. McBride, Maria Zalath, Gaby Terracina, Preeti Trisal, Robert M. Sharkey
Journal: Journal of Clinical Oncology (2014)

3107 Background: IMMU-132 is an antibody-drug conjugate (ADC) made from a humanized anti-Trop-2 mAb (hRS7) coupled through a linker to SN-38, the active metabolite of CPT-11. Trop-2 is found in a wide range of tumor, including gastric, pancreatic, triple-negative breast (TNBC), colonic, prostate, and lung. Current Phase I/II clinical trials confirm the anticancer activity of IMMU-132 in cancers expressing Trop-2. The current studies further characterize IMMU-132 in terms of conjugation, mechanism of action (MoA), and efficacy. Methods: SN-38 conjugation to hRS7 was analyzed by HIC, LC-MS, and HPLC. MoA was assessed by comparisons in binding, ADCC, and pro-apoptotic signaling pathways. Efficacy studies were performed in mice bearing human tumor xenografts. Results: IMMU-132 has a drug to antibody ratio of 7.6, <1% aggregation, and no loss in binding to cells or to a Trop-2 chip (cells: KD = 0.63 ± 0.26 nM v 0.54 ± 0.17 nM; BIACore: 0.26 ± 0.14 v 0.51 ± 0.04 nM, IMMU-132 and hRS7, respectively). Linkage chemistry should preserve the active lactone ring form; initial in vivo data suggest that conjugated SN-38 may not be glucuronidated until released. IMMU-132 retains binding to the neonatal receptor, but lost 65% of ADCC activity. Free SN-38 and IMMU-132 mediated the same signaling pathways in cells, with p21WAF1/Cip1 up-regulation, cleavage of caspase 3 and 9, and poly-ADP-ribose polymerase cleavage. IMMU-132 treatment of gastric cancer xenografts (17.5 mg/kg; 2xwk x 4wks) result in significant anti-tumor effects compared to non-specific control ADC (P<0.0001). In tumors not typically treated with irinotecan as a single agent (pancreatic and TNBC), IMMU-132 provided significant tumor growth inhibition. Mice with a TNBC xenograft treated with 12.5 mg/kg IMMU-132 (q4dx4) resulted in 7/8 mice alive at study conclusion (day 105) v only 1/9 in saline-control group (P=0.001). Tumor regressions occur in mice bearing aggressive pancreatic tumor xenografts (untreated median survival = 11 d) when clinically relevant doses of IMMU-132 is given (HED=8 mg/kg; P=0.0003). Conclusions: Conjugation of SN-38 to hRS7 results in a potent ADC that retains characteristics of both the antibody and the drug.
Comparison of Gleason upgrading rates in transrectal ultrasound systematic random biopsies versus US-MRI fusion biopsies for prostate cancer.
Authors: Arie Carneiro, Paulo Priante Kayano, Tiago MendonÃÂ§a Lopez Castilho, Arjun Sivaraman, Oliver Rojas Claros, Ary Serpa Neto, Renee Zon Filippi, Ronaldo Hueb Baroni, Gustavo Caserta Lemos
Journal: Journal of Clinical Oncology (2017)

57 Background: US-MRI fusion biopsy (FB) showed that it improves the detection of clinically significant prostate cancer (PCa). A more accurate diagnostic method is desirable to avoid misclassification, which in turn is particularly important in appropriate decision making on treatment for PCa (active surveillance or focal therapy or radical treatment). We aimed to compare the Gleason upgrading (GU) rates and the concordance of the Gleason scores in the biopsy versus final pathology after the surgery in patients who underwent only TRUS systematic random biopsies versus US-MRI FB for PCa. Methods: A retrospective analysis of patients’ prospective collected data that underwent prostate biopsy and subsequent radical prostatectomy were included from January 2011 to June 2016 at our institution. The study cohort was divided into: US-MRI FB (Group A) and only TRUS systematic random biopsy (Group B). US-MRI FB was performed in patients who had a previous MRI with a focal lesion classified by Likert score ≥ 3, otherwise a TRUS systematic random biopsy was performed. All biopsies and surgical specimens were analyzed by the same uropathologist and MRIs were analyzed by two expert urological radiologists. Results: 73 men underwent US-MRI FB and 89 TRUS systematic random biopsy. The GU rate was higher in group B (31.5% vs 16.4%; p = 0.027). GU according to Gleason grade pattern was higher in Group B against Group A (40.4% vs 23.3%; p = 0.02). Analyses from separate Gleason grade pattern showed that Gleason score 3+4 presented less GU in group A (24.1% vs 52.6%; p = 0.043). The Bland-Altman plot analysis showed a higher bias in Group B compared to group A (-0.27 [-1.40 to 0.86] vs -0.01 [-1.42 to 1.39]). In the multivariable logistic regression the only independent predictor of GU was the use of TRUS systematic random biopsy (2.64 [1.11 – 6.28]; p = 0.024). Conclusions: The US-MRI FB appears to be related to a decrease in GU rate and an increase in the concordance between biopsy and final pathology in comparison to TRUS random biopsy, that leads to greater accuracy on diagnosis and better treatment decision.
EGFR-Dependent Regulated Intramembrane Proteolysis of EpCAM—Response
Authors: Ya-Ting Hsu, Pawel Osmulski, Yao Wang, Yi-Wen Huang, Lu Liu, Jianhua Ruan, Victor X. Jin, Nameer B. Kirma, Maria E. Gaczynska, Tim Hui-Ming Huang
Journal: Cancer Research (2017)

We would like to thank Dr. Gires for the letter concerning our article (1). We are very glad that Dr. Gires considers our data on how EGFR activation affects endometrial cancer cell invasiveness via EpCAM activity novel and interesting. The study highlights not only the function of EpCAM as a cell adhesion molecule but also its transcriptional activity and the interplay of both functions on the invasiveness of endometrial cancer cells. Regarding the mechanism of EpCAM cleavage, we agree with Dr. Gires that using inhibitor of ADAM17 with and without EGFR inhibition would have provided additional detail on EpEX release. We understand the ectodomain shedding by α- and/or β-proteases is a prerequisite for the regulated intramembrane proteolysis of EpCAM (2, 3). As our studies have mainly focused on the transcriptional activity of EpICD, we have not pursued experiments to inhibit ADAMs and TACE. Future studies using these inhibitors will shed light on the mechanisms underlying the shedding of EpEX.In conclusion, we would like to clarify here, based on our data, that EpICD release mediated by EGFR activation may depend on γ-secretase activity; however, additional studies beyond the scope of this article are needed to dissect the mechanisms underlying the release of EpEX by EGFR.See the original Letter to the Editor, p. 1775No potential conflicts of interest were disclosed.
Phase 1 study of JNJ-42756493, a pan-fibroblast growth factor receptor (FGFR) inhibitor, in patients with advanced solid tumors.
Authors: Rastislav Bahleda, Rodrigo Dienstmann, Barbara Adamo, Anas Gazzah, Jeffrey R. Infante, Bob Zhong, Suso J. Platero, Hans Smit, Timothy Perera, Kim Stuyckens, Jacqueline Bussolari, Vijay Peddareddigari, Jean-Charles Soria, Feng Roger Luo, Josep Tabernero
Journal: Journal of Clinical Oncology (2014)

2501 Background: JNJ-42756493 is an orally bioavailable FGFR 1, 2, 3 and 4 inhibitor with nanomolar antitumor activity in cell lines and in vivo models with FGFR pathway aberration. Methods: This first in human study consists of 3 parts: dose escalation part 1to determine the recommended phase 2 dose (RP2D), dose confirmation part 2 with focus on pharmacodynamic effects, and dose expansion part 3 to evaluate the antitumor activity in selected solid tumors with FGFR gene amplification, mutation or translocation at the RP2D. Biomarkers include tumor tissue genomic profiling, skin/tumor biopsies and soluble serum markers. Toxicity is graded with CTCAE-4 and antitumor activity is assessed using RECIST 1.1. Results: As of 27 January 2014, 37 patients have been treated at 6 dose levels (0.5, 2, 4, 6, 9 and 12 mg daily continuously) in part 1. Most common (≥ 20% of patients) adverse events (AEs) were hyperphosphatemia (60%), asthenia (46%), dry mouth (30%), constipation (27%), abdominal pain (22%), stomatitis (22%), and vomiting (22%); all were ≤ Grade 2 in toxicity. Ten (27%) patients had ≥ Grade 3 AEs, and one dose limiting toxicity of Grade 3 AST/ALT elevation was noted at 12 mg dose. Daily 9 mg continuous dosing was declared the RP2D. Seven (19%) patients had serious AEs, including 1 death, but none were drug-related. Six (16%) patients had dose reductions due to drug-related hyperphosphatemia at 9 and 12 mg. Pharmacokinetics were linear, dose proportional and predictable with a half-life of 50 to 60 hours. Exposure dependent increases in phosphate blood levels were observed at doses up to 9 mg, thereafter reaching a plateau. Also a trend was seen for increase in FGF23 and decrease in PTH. Out of 8 patients enrolled to date with FGFR pathway aberration, we observed 1 partial response in a bladder cancer patient with FGFR3-TACC3 translocation and 1 near complete response in an urothelial cancer of renal pelvis harboring FGFR2 truncation at the RP2D. Four patients (2 lung cancer, 1 chondrosarcoma and 1 breast cancer patients with FGFR1 amplification) had stable disease. Conclusions: JNJ-42756493 has favorable pharmaceutical properties, with manageable side effects at the RP2D and evidence of antitumor activity. Clinical trial information: NCT01703481.
구연 : 만성 B형간염 환자에서 분리된 클레부딘 내성 B형간염바이러스의 클로닝과 약제감수성연구
Authors: Kyun Hwan Kim, Yong Kwang Park, Won Hyeok Choe, Chang Hong Lee, Byung Kook Kim, Soon Young Ko, Eun Sook Cho, Hyo Sun Choi, Sung Hyun Ahn, So Young Kwon
Journal: Clinical and Molecular Hepatology (2009)
10-year update of E2197: Phase III doxorubicin/docetaxel (AT) versus doxorubicin/cyclophosphamide (AC) adjuvant treatment of LN+ and high-risk LN- breast cancer and the comparison of the prognostic utility of the 21-gene recurrence score (RS) with clinicopathologic features.
Authors: Joseph A. Sparano, Anne O'Neill, Robert James Gray, Edith A. Perez, Lawrence N. Shulman, Silvana Martino, Sunil S. Badve, Frederick L. Baehner, Barrett H Childs, Carl N. Yoshizawa, Steve Rowley, Nancy E. Davidson, Steven Shak, Lori J. Goldstein
Journal: Journal of Clinical Oncology (2012)

1021 Background: At 5 years, AT did not improve disease free survival or overall survival and RS was a more accurate predictor of relapse than standard clinicopathologic characteristics for patients with hormone receptor (HR) positive tumors. Methods: A Phase III Intergroup trial tested adjuvant AT vs. AC. Women with 1-3 N + or N - and T-size &gt; 1cm were randomized to 4 cycles of AT (60 mg/m 2 /60 mg/ m 2 ) or AC (60 mg/m 2 /600 mg/m 2 ) q 3 wk x 4. Patients(pts) with ER + and/ or PR + tumors received tam for 5 yrs. Pts were stratified by nodal, HR (ER+ PR+, ER+PR-, ER-PR+, ER-PR-, ER/PR unk) and menopausal status. The primary endpoint was DFS. A sample of 465 pts with HR + breast cancer with 0 to 3 positive axillary nodes who did (N =116) or did not have a recurrence had tumor tissue evaluated using the 21- gene assay. Grade and HR expression were evaluated locally and centrally. Results: 2952 pts were randomized between 7/30/98 and 1/21/00. 2883 were eligible and analyzable. Arms were balanced for age, HR, menopause, nodes, surgery, grade and T-size: median age 51; 64% ER +; 65% LN-; grade: 10% low, 38% int., 46% high; and median T-size - 2.0 cm. At a median follow-up of 11.5 years the DFS/OS results are shown in the table below. RS was a highly significant predictor of recurrence including node negative and node positive disease (P &lt; .0001) and predicted recurrence more accurately than clinical variables. Conclusions: At 11.5 yrs. median follow-up, there remains no difference in DFS or OS, although there continue to be fewer events in the AT arm in the prespecified ER/PR negative subgroup. At 10 years, the RS continues to be a more accurate predictor of relapse than standard clinical features. [Table: see text]
Cetuximab (C-mab) and chemo-radiation (CT-RT) for loco-regional advanced squamous cell carcinoma of the head and neck (HNC): A phase II study
Authors: M. C. Merlano, G. Numico, E. G. Russi, M. Benasso, I. Colantonio, R. Vigna Taglianti, L. Lanzilotta, V. Vigo, A. Bacigalupo
Journal: Journal of Clinical Oncology (2007)

6043 Background: C-mab is a monoclonal antibody targeting EGFR. C-mab combined with radiotherapy (RT) improved loco- regional control and overall survival over RT alone in HNC pts (Bonner 2006). Prior data of C-mab and CT-RT (Pfister 2006) were encouraging but the trial was stopped due to an excess of severe toxicities, suggesting the need for a less toxic scheduling. For these reasons we evaluate the safety and activity of C-mab combined with alternating CT-RT in HNC pts. Methods: The primary end-point is C.R. rate. The optimal two stage design was used: the calculated sample size is 45 pts. Eligible pts have locally advanced, measurable, untreated, stage III/IV HNC (excluding nasopharynx). Chemotherapy (CT) consists of Cis-PT 20 mg/m 2 /day and bolus 5Fu 200 mg/m 2 /day from day 1 to 5, repeated on days 22 and 43. RT, 2 Gy/day, 5 days a week, is given in the pauses between the chemotherapy courses and after the last CT week, up to a total dose of 70 Gy. Results: From 10/2005 to 12/2006 24 pts were enrolled: median age 59 (49–75); median ECOG P.S. 0 (0–1); Stage IV 73%; N1–3 86%; EGFR &gt;80% cells: 55%; EGFR 3+: 91%; most pts had hypopharynx cancer, only 1 had oral cavity tumor. Toxicity is evaluable on 20 pts (4 ongoing). Grade 3–4 toxicities included febrile neutropenia (20%), diarrhea (20%), hypomagnesaemia (10%), mucositis (60%). Unexpected skin toxicity, starting as desquamating moist dermatitis and confined at the irradiated field, occurred in 18/20 pts, usually during the second part of the treatment. Acute colon diverticulitis with perforation (1 pt), gastric perforation (1 pt), fatal myocardial infarction (1 pt) and arterial thrombosis (1 pt) also occurred. Responses, evaluated 3 months after the treatment, are available for the first 16 pts. Objective responses were observed in all them (11 CR + 5 PR). Two PRs were then rendered disease free with salvage surgery. At a maximum follow-up of 15 months, 16/20 pts are alive and 16/20 progression free. Conclusions: This trial showed a skin toxicity not previously reported in other experiences of C-mab combined with RT or CT-RT. Preliminary activity data seems to confirm the Pfister experience. No significant financial relationships to disclose.