tbuckley/cabot-search huggingface dataset:
A phase II trial of modified gemcitabine plus S-1 combination as the first-line treatment in patients with advanced biliary tract cancer.
Authors: Nai-Jung Chiang, Jen-Shi Chen, Ming-Huang Chen, Shih-Hung Yang, Chiun Hsu, Chia-Jui Yen, Hsiao-Hui Tsou, Shan Yanshen, Li-Tzong Chen
Journal: Journal of Clinical Oncology (2017)

417 Background: Gemcitabine plus platinum, notably cisplatin, is conceived as the standard regimen for advanced biliary tract cancer (ABTC) nowadays. Recent randomized phase II study (JCOG0805) showed that gemcitabine plus S-1 was more promising than S-1 alone in ABTC, and a randomized phase III, UMIN 000001685, is currently ongoing to compare the efficacy of gemcitabine plus either S-1 (GS) or cisplatin (GC) in ABTC. Herein, we report the results of a single arm phase II of modified GS in Taiwanese ABTC patients, NCT02425137. Methods: Patients with chemonaïve ABTC were eligible to receive 800mg/m 2 gemcitabine with 10 mg/m 2 /min infusion, on day 1 plus daily 80/100/120 mg of S-1 (based on BSA) days 1-10, in a 2-week cycle. With Optimal Simon’s two-stage design and (p 0 = 0.4, p 1 = 0.6) for 12-week disease control rate (proportion of patients with complete or partial response [CR/PR] or stable disease ≥ 12 weeks [SD ≥ 12weeks ]) and given error probabilities (alpha = 0.05, beta = 0.2), the null hypothesis (p 0 ) would be rejected if 24 or more patients with CR/PR/SD ≥ 12weeks were observed among 46 accruals. Tumor response was assessed by CT/MRI every 6 weeks according to RECIST v1.1. Results: Between May 2015 and April 2016, totally 46 evaluable patients were enrolled to receive a median of 9.5 cycles (range: 3-31) of modified GS. After a median of 8.7 months (95% CI, 6.7-9.1) follow-up, 10 (21.7%) patients achieved PR and additional 23 (50%) had SD &gt; 12weeks . The median progression-free survival and overall survival was 5.6 (95% CI, 4.4-7.2) and 10.8 (95% CI, 7.6-not reached) months, respectively. All grade 3 treatment-related AEs were &lt; 5%. The dose intensity of S-1 and gemcitabine were both more than 95%. Conclusions: By the observation of 33 patients with PR/SD ≥ 12weeks , the null hypothesis was rejected. Modified GS is an active regimen with excellent safety profiles and deserves further investigation for the management of Asian ABTC patients. Clinical trial information: NCT 02425137.
RETRACTED: Exosome-Mediated miR-155 Transfer from Smooth Muscle Cells to Endothelial Cells Induces Endothelial Injury and Promotes Atherosclerosis
Authors: Bin Zheng, Wei-na Yin, Toru Suzuki, Xin-hua Zhang, Yu Zhang, Li-li Song, Li-shuang Jin, Hong Zhan, Hong Zhang, Jin-shui Li, Jin-kun Wen
Journal: Molecular Therapy (2017)

The vascular response to pro-atherosclerotic factors is a multifactorial process involving endothelial cells (ECs), macrophages (MACs), and smooth muscle cells (SMCs), although the mechanism by which these cell types communicate with each other in response to environmental cues is yet to be understood. Here, we show that miR-155, which is significantly expressed and secreted in Krüppel-like factor 5 (KLF5)-overexpressing vascular smooth muscle cells (VSMCs), is a potent regulator of endothelium barrier function through regulating endothelial targeting tight junction protein expression. VSMCs-derived exosomes mediate the transfer of KLF5-induced miR-155 from SMCs to ECs, which, in turn, destroys tight junctions and the integrity of endothelial barriers, leading to an increased endothelial permeability and enhanced atherosclerotic progression. Moreover, overexpression of miR-155 in ECs inhibits endothelial cell proliferation/migration and re-endothelialization in vitro and in vivo and thus increases vascular endothelial permeability. Blockage of the exosome-mediated transfer of miR-155 between these two cells may serve as a therapeutic target for atherosclerosis. The vascular response to pro-atherosclerotic factors is a multifactorial process involving endothelial cells (ECs), macrophages (MACs), and smooth muscle cells (SMCs), although the mechanism by which these cell types communicate with each other in response to environmental cues is yet to be understood. Here, we show that miR-155, which is significantly expressed and secreted in Krüppel-like factor 5 (KLF5)-overexpressing vascular smooth muscle cells (VSMCs), is a potent regulator of endothelium barrier function through regulating endothelial targeting tight junction protein expression. VSMCs-derived exosomes mediate the transfer of KLF5-induced miR-155 from SMCs to ECs, which, in turn, destroys tight junctions and the integrity of endothelial barriers, leading to an increased endothelial permeability and enhanced atherosclerotic progression. Moreover, overexpression of miR-155 in ECs inhibits endothelial cell proliferation/migration and re-endothelialization in vitro and in vivo and thus increases vascular endothelial permeability. Blockage of the exosome-mediated transfer of miR-155 between these two cells may serve as a therapeutic target for atherosclerosis.
High Cumulative Illness Rating Scale (CIRS) Score in CLL Correlates with Short CLL Telomere Length and Decreased Survival
Authors: Lin Yang, Sara Beiggi, Yunli Zhang, Sara Kost, Robert Schmidt, Gangimeg Ishdorj, Dhali H.S. Dhaliwal, Versha Banerji, Sabine Mai, Spencer B. Gibson, James B. Johnston
Journal: Blood (2016)
Ten-year results of a German Hodgkin Study Group randomized trial of standard and increased dose BEACOPP chemotherapy for advanced Hodgkin lymphoma (HD9)
Authors: V. Diehl, J. Franklin, B. Pfistner, A. Engert
Journal: Journal of Clinical Oncology (2007)

LBA8015 Background: The HD9 trial was designed to compare standard and dose escalated versions of a novel chemotherapy BEACOPP in advanced Hodgkin lymphoma. The previous analysis in 2004 showed improved tumor control and overall survival due to dose escalation. The present 10 year analysis in March 2007 aimed to update and confirm these results and to monitor late effects. Methods: Patients aged 16–65 years with untreated Hodgkin lymphoma stage IIB/IIIA and risk factors or stage IIIB/IV were randomized to (A) 4 double cycles COPP/ABVD, (B) 8 cycles standard-dose BEACOPP or (C) 8 cycles increased-dose BEACOPP (doxorubicin, cyclophosphamide and etoposide at 140%, 192% and 200% of standard doses, respectively), each followed by irradiation of initial bulky and residual disease. Accrual of at least 900 patients was planned so as to detect a 9–10% improvement in the primary endpoint, freedom from treatment failure (FFTF), with a power of 80% (alpha=5%). Results: 1196 of 1201 eligible, randomized patients were evaluable (261, 469 and 466 in arms A, B and C, respectively). Median follow-up times were 122, 111 and 107 months in arms A, B and C respectively (29–32 months longer than in 2004). Corresponding 10-year FFTF rates were 64%, 70% and 82% respectively (p&lt;0.0001). FFTF was significantly better in the increased-dose arm than in the standard-dose arm (p&lt;0.0001). 10-year overall survival rates were 75%, 80% and 86% respectively (p=0.0005). Overall survival was also significantly better in the increased-dose arm than in the standard-dose arm (p=0.0053). Death due to HL was 11.5%, 8.1% and 2.8% in arms A, B and C respectively. 74 second malignancies were documented: 1, 7 and 14 acute myeloid leukemias (AML); 7, 8 and 5 non-Hodgkin lymphomas; 7, 16 and 9 solid tumors/others in arms A, B and C respectively. The corresponding overall secondary malignancy rates were 6.7% , 8.9% and 6.8%. Conclusions: Even after 10 years, dose escalation of BEACOPP chemotherapy results in a stabilized significant improvement in long-term FFTF and OS rates. The risk of secondary AML, although increased in this study after increased-dose BEACOPP, amounts to 0.9% in the succeeding study with increased BEACOPP with 1502 patients and 4 years median follow-up. No significant financial relationships to disclose.
PIK3CA gene alterations in bladder cancer: Analysis of correlative series of transurethral resection (TUR)—Correlation with grade histology and tumor size.
Authors: Daniel E. Castellano, Juan Sepulveda, Monica Martinez-Fernandez, Marta Dueñas Porto, Ramon Garcia Escudero, Felipe Villacampa, Federico de la Rosa, Jose Duarte, Victor Martinez, Jesus Paramio
Journal: Journal of Clinical Oncology (2012)

4584 Background: PI3K pathway involvement in bladder cancer is well documented and activating mutations of the gene have been identified, particularly in tumors of low grade and stage. We have analyzed hot spot mutations and copy number in PIK3CA gene as well as mRNA expression levels in tumor tissue of pts with urothelial cell carcinoma (UCC). Methods: 90 pts were analyzed. In 85 pts, fresh tissue from tumor and adjacent normal tissue was collected. All pts signed an informed consent and basic demoghrapics data were collected. Histology confirmation of UCC was required. PIK3CA alterations were analyzed by quantative-PCR. Results: Patient«s characteristics were: median age 73 years, Ta 45.5%, T1 41.1%, T2 12.2%; high-grade histology 43.4%, low-grade 51,1%, PULMP 4,4%. With a median follow-up of 10.0 months, 21% tumor recurrences were observed. 13% normal tissue and 51,8% tumor samples harbored alterations in PIK3CA gene, including alterations affecting the helical domain (mutations 65%, amplifications 60%, both 21%). According to T stage the distribution was: 10/36 Ta, 26/35 T1 y 6/10 T2. (p&lt;0.05). When analyzing factors related to tumor recurrence, it was found that PIK3CA gene mutations in E542 or E545 had a lower recurrence risk (p-value ²0.045). Differential expression analysis (genome-wide transcriptome analysis/microarray) showed that tumors bearing altered PIK3CA gene are more similar to non-tumoral samples comparing with tumors bearing wtPIK3CA gene. Moreover, overexpressed genes in mutant samples are mainly involved in G-protein and Wnt signaling, whereas underexpressed genes are involved in cell morphogenesis and cell polarity. Conclusions: We observed that PIK3CA gene alterations is an early carcinogenesis event in UCC pts, and more frequently found in larger tumor stages. These data support that PIK3CA status may constitute a good prognostic tool, as well as a therapeutic target in stratified groups for bladder cancer.
Inflammatory marker levels and prediction of patient-reported symptoms in patients with advanced pancreatic cancer receiving gemcitabine-based chemotherapy.
Authors: Xin Shelley Wang, Qiuling Shi, Donghui Li, Cathy Eng, Raza H Bokhari, David R. Fogelman
Journal: Journal of Clinical Oncology (2014)

e20699 Background: The high symptom burden reported by patients being treated for advanced pancreatic cancer could be driven by both disease and treatment. Few clinical studies have addressed the association between inflammation and symptom outcomes, focusing solely on clinical outcomes. Here, we present our longitudinal study of identifying critical circulating cytokines predictive of higher symptom burden in patients with advanced pancreatic cancer receiving gemcitabine-based chemotherapy. Methods: Patients rated symptoms at baseline and weekly for 16 weeks of chemotherapy via the M. D. Anderson Symptom Inventory (MDASI). Blood samples were collected prior to chemotherapy for cytokine assay. Longitudinal symptom responses and predictive baseline inflammatory markers were analyzed by mixed-effect modeling. All models were adjusted for age, sex, comorbidities, minority status, and body mass index. Results: Of the 45 enrolled patients, the most severe MDASI symptom was fatigue, followed by lack of appetite, drowsiness, disturbed sleep, and pain. Poor appetite, disturbed sleep, and pain improved significantly during the 16-week study (all P<.05). Among 10 cytokine markers assayed and after adjusting for covariates, baseline interleukin (IL)-6 (est=.66, P=.002), insulin-like growth factor (IGF)-1 (est=–1.24, P=.001), and midkine (est=.72, P=.002) were significantly related to the severity of the 5 most severe symptoms. In additional, baseline tumor necrosis factor-α (est=1.44, P=.028), chemokine (C-X-C motif) ligand 16 (est=1.39, P=.043) were significantly related to fatigue development. Conclusions: Our results suggest that elevated IL-6, midkine, and lower IGF1 levels at baseline predicted severity of symptom outcomes during gemcitabine-based chemotherapy in patients with advanced pancreatic cancer. In very limited survival period in these highly symptomatic patients, systemic symptoms, especially cachexia-related symptoms, present a serious challenge for patient care. This study provides evidence of the role of peripheral inflammation underlying the development of multiple symptoms. Clinical trial information: NCT00805688.
Masitinib plus carboplatin and gemcitabine for treatment of patients with advanced triple negative breast cancer: An open label phase Ib/II trial.
Authors: Mario Campone, Jean-Marc Ferrero, Katharina Gunzer, Frank Priou, Patrice Dubreuil, Colin Mansfield, Alain Moussy, Olivier Hermine
Journal: Journal of Clinical Oncology (2015)

1070 Background: Masitinib (MAS) is a selective inhibitor of c-Kit and mast cell function, both of which have been linked to disease progression and poor prognosis in triple negative breast cancer (TNBC). This trial evaluated MAS in combination with either carboplatin (C) and/or gemcitabine (G) as a treatment of advanced TNBC. We report here findings from the cohort receiving MAS plus CG. Methods: This dose-escalating phase I study assessed the safety and maximum tolerated dose of MAS plus C (AUC5) and G (1000 mg/m2on days 1 and 8) over a 3 week cycle in patients (pts) with metastatic or locally advanced TNBC. Dose Limiting Toxicity (DLT) was defined as grade 3 for non-hematological adverse event (AE) or any grade 4 AE related to MAS. Phase II evaluated efficacy of the combination. Results: Twenty-one pts received MAS combined with CG. Reduction of dose was performed for MAS (from 9 to 6 mg/kg/day) and G (-25%) due to occurrence of DLT. In this cohort (n=13), 10/13 pts (77%) reported grade 3-4 AE (including neutropenia, 38% and thrombocytopenia, 38%); and 5/13 pts (38%) reported serious AE (including neutropenia, 15%). No treatment related deaths were reported. Overall, median OS was 10.2 months (95%CI [9.2;16.4]) and median PFS was 4.7 months (95%CI [2.1;10.8]). Objective response rate was 43%. Conclusions: The safety profile of MAS (6 mg/kg/day) plus C (AUC5) and G (750 mg/m2) was acceptable, thereby defining the combination’s MTD and recommended dose for further study. Efficacy findings seem to compare favorably against historic benchmarks (see table). MAS may therefore potentially offer patients a new active compound for treatment of metastatic or locally advanced TNBC. A confirmatory phase III trial evaluating MAS (6 mg/kg/day) in combination with C (AUC5) and G (750 mg/m2) has been initiated. MAS + CG (n = 21) *Benchmark CG (n = 62) OS (months) 10.2 7.7 PFS (months) 4.7 3.6 Objective Response Rate 43% 32% Complete 0% 2% Partial 43% 31% * O’Shaughnessy J, (2011) N Engl J Med 364:205.
A novel small molecule inhibitor of p300/CBP for the treatment of castration-resistant prostate cancer: Preclinical evaluation.
Authors: Nigel Brooks, Neil Pegg, Jenny Worthington, Barbara Young, Amy Prosser, Jordan Lane, David Taddei, Matthew Joseph Schiewer, Nicolas Gordon, Karen E. Knudsen
Journal: Journal of Clinical Oncology (2017)

168 Background: Targeted degradation of androgen receptor (AR) and androgen receptor variants (ARV) remains an attractive therapeutic opportunity for patients with castrate resistant prostate cancer (CRPC). E1A binding protein (p300) and CREB binding protein (CBP) are two closely related histone acetyl transferase proteins that act as transcriptional activators of AR. We have developed potent, selective and orally active small molecule inhibitors of the bromodomain of p300/CBP and investigated their role in regulating the expression and function of AR and ARV. Methods: Binding affinity to p300, CBP and BRD4 was measured in a surface plasmon resonance (SPR) assay and potency and functional activity was demonstrated in a panel of prostate cells lines representing hormone responsive (LNCaP), hormone independent (DU145, PC3) and castrate resistant disease (22Rv1, C4-2, VCaP, LNCaP-AR). Effects of p300/CBP inhibitors (and the BET inhibitor, JQ1), on AR, AR-V7 splice variant and c-Myc protein, as well as c-Myc, KLK3 and TMPRSS2 gene expression, were assessed in 22Rv1 cells in vitro. In vivoeffects on biomarkers were measured in a 22Rv1 xenograft model. Results: CCS1357, an in vitro probe compound, binds to p300 and CBP with high affinity (Kd=4nM) and selectivity (Kd=245nM; BRD4) and is a potent inhibitor of cell proliferation in castrate resistant cell lines (IC50=100nM in LnCaP-AR; 350nM in 22Rv1) with minimal effects in hormone independent lines. CCS1357 significantly down-regulated AR-FL, AR-V7 and c-Myc protein by Western, an effect not seen with JQ1 at equivalent proliferation IC50s. CCS1357 effects were reversed by the proteasome inhibitor, MG132. CCS1357 also caused a profound inhibition of c-Myc, KLK3 and TMPRSS2 genes measured by qPCR in 22Rv1 cells in vitro. A preclinical candidate (CCS1477) given as a single oral dose (30mg/kg) inhibited plasma PSA and tumour AR and AR-V7 in a 22Rv1 xenograft model. Conclusions: Small molecule inhibition of the bromodomain of p300/CBP, leads to down-regulation of AR, ARV and c-Myc as well as inhibition of key downstream PD biomarkers including PSA and TMPRSS2 and represents a promising new approach for the treatment of CRPC.
Final results of a phase III trial to evaluate bursectomy for patients with subserosal/serosal gastric cancer (JCOG1001).
Authors: Hitoshi Katai, Yuichiro Doki, Yukinori Kurokawa, Junki Mizusawa, Takaki Yoshikawa, Yutaka Kimura, Shuji Takiguchi, Yasunori Nishida, Takeshi Sano, Kenichi Nakamura, Mitsuru Sasako, Masanori Terashima
Journal: Journal of Clinical Oncology (2021)

206 Background: We previously reported that the superiority of bursectomy was not demonstrated for subserosal(SS)/serosal(SE) gastric cancer by the second interim analysis performed with 54% of the expected events observed. We report the final 5-year follow-up data. Methods: Eligibility criteria included histologically proven adenocarcinoma of the stomach, cT3(SS) or cT4a(SE). Patients were intraoperatively randomized to non-bursectomy arm or bursectomy arm. Primary endpoint was overall survival (OS), and secondary endpoint was relapse-free survival (RFS). A total of 1,200 patients were required to detect a hazard ratio of 0.77 with a one-sided alpha of 5% and 80% power. Results: A total of 1204 eligible patients with cT3 / cT4a gastric cancer were randomized (602 in non-bursectomy arm, 602 in bursectomy arm, respectively). Patients’ background and operative procedures were well balanced between the arms. The 5y-OS were 76.5% (95% CI, 72.8 to 79.7) in non-bursectomy arm and 74.9% (71.2 to 78.2) in bursectomy arm. Hazard ratio (HR) for bursectomy was 1.03 (0.83-1.27, one-sided p = 0.598). The 5y-RFS were 70.7% (66.9 to 74.2) in non-bursectomy arm and 66.8% (62.9 to 70.5) in bursectomy arm [HR: 1.131 (0.93-1.38)]. HR for death was almost similar in all sub-categories (0.73-1.29) except cN2 (13th edition of Japanese Classification of Gastric Carcinoma); HR classified by cN was 1.06 (95% CI: 0.75-1.49) for cN0 (n = 521), 1.25 (0.92-1.71) for cN1 (n = 525), and 0.59 (0.32-1.06) for cN2 (n = 158) (p = 0.048 for interaction). The most frequent site of recurrence was the peritoneum [74 (12.3%) in non-bursectomy arm, 73 (12.1%) in bursectomy arm], and bursectomy arm showed a trend of increasing liver metastasis (n = 45, 7.5%) as compared with non-bursectomy arm (n = 33, 5.5%). Six independent poor prognostic factors were identified by multivariable analysis for OS: age ≥ 66 (vs. ≤ 65) (HR, 1.30; 95% CI, 1.04-1.62), macroscopic type 3/5 (vs. type 0/1/2) (1.43; 1.15-1.79), total gastrectomy (vs. distal gastrectomy) (1.44; 1.03-2.02), pT3 (vs. pT1-2) (1.77; 1.17-2.676), pT4 (vs. pT1-2) (3.00; 1.99-4.53), pN1 (vs. pN0) (2.34; 1.52-3.59), pN2-3b (vs. pN0)(4.02; 2.82-5.74) and adjuvant chemotherapy (vs. without chemotherapy) (0.53; 0.42-0.67), but bursectomy was not significant (1.10 0.89-1.36). Conclusions: In the final analysis as well as in the interim analysis, bursectomy was not recommended as a standard treatment for cT3 or cT4 gastric cancer. Clinical trial information: UMIN000003688.
Prospective evaluation of testosterone (T) recovery and PSA relapse following 18 months of androgen deprivation (ADT) after prostatectomy (RP): Results from the TAX-3501 trial.
Authors: Michael Thomas Schweizer, Peng Huang, Cora N. Sternberg, Ronald De Wit, Evelyne Brana Ecstein-Fraisse, Michael W. Kattan, Adam S Kibel, Mario A. Eisenberger
Journal: Journal of Clinical Oncology (2013)

5023 Background: Surgical adjuvant trials in men with prostate cancer (PCa) employing progression free (PFS) and overall survival (OS) endpoints require large sample sizes and long-term follow-up, challenging planned study completion. Recent adjuvant trials are designed to evaluate PSA progression as the primary study endpoint. Since PSA is T-responsive, a thorough understanding of T recovery kinetics after ADT is needed. Methods: TAX-3501 was a randomized phase III adjuvant study post-RP in men with high-risk PCa (n=228) comparing 18 months of hormonal therapy with (CHT) or without (HT) docetaxel either immediately (I) or deferred (D). We analyzed the T recovery data in 108 patients treated with HT who had at least one post-treatment T value. Results: After a median post-treatment follow-up of 676 days (d) (interquartile range 478-847 d) 90 (83%) and 64 (59%) of men had T recovery to &gt;150 ng/dL and to baseline respectively. No significant differences in T recovery between groups were observed (Table). The median time to T recovery from the last day of treatment to &gt;150 ng/dL was 306 d (95% CI, 294-345 d) and to baseline was 487 d (95% CI, 457-546 d). The baseline T recovery in the combined docetaxel [i.e. I(CHT)+D(CHT)] and HT arms [i.e. I(HT)+D(HT)] was not significantly different at 458 d (95% CI, 336-529 d) and 535 d (95% CI, 457-749 d) respectively (HR 1.4, P=0.18). After a median total follow-up of 3.4 years(IQR 2.3–3.8 years) 39/228 (17%) patients had PSA progression, metastatic progression occurred in 1 patient. Conclusions: Prospective analyses of T kinetics in TAX-3501 indicate that recovery is prolonged after 18 months of HT and PSA relapses occur late. Given that PSA is androgen responsive, concomitant post-HT T monitoring is critical for understanding PSA relapse rates after HT. Further, since the correlation of PSA relapse with PFS and OS in the adjuvant setting remains poorly defined, metastasis-free survival may be a more reliable and meaningful clinical endpoint. Clinical trial information: NCT00283062. [Table: see text]