tbuckley/cabot-search huggingface dataset:
Ipilimumab retreatment following induction therapy: The expanded access program (EAP) experience.
Authors: Kim Allyson Margolin, Omid Hamid, Jeffrey S. Weber, Anna C. Pavlick, F. Stephen Hodi, Asim Amin, Kelly Bennett, Tracy Michener, David R. Minor
Journal: Journal of Clinical Oncology (2013)

9041 Background: Phase III study MDX010-020 for patients (pts) with advanced melanoma showed that retreatment (ReRx) with ipilimumab (Ipi) upon disease progression could result in further clinical benefit (Hodi et al. NJEM 2010). The Ipi EAP (CA184-045), conducted from 3/2010 to 3/2011, allowed ReRx with Ipi for a subset of pts with progression after benefit from their initial Ipi (SD for ≥3 months or objective response). Methods: Pts with unresectable stage III/IV melanoma who progressed on ≥1 systemic therapies or had no alternative treatment options were eligible for the EAP. Pts who received 3 mg/kg Ipi i.v. q 3 wks up to 4 doses on the EAP were eligible for ReRx using the same regimen if they had not experienced unacceptable toxicity requiring Ipi discontinuation (e.g., grade 4 any severe adverse events (AEs), grade 3/4 immune-related AEs (excluding endocrinopathies)), and had disease progression after clinical benefit defined as ≥3 months SD or objective response, or delayed response following progressive disease not requiring a different interval therapy. Endpoints of this retrospective analysis were clinical benefit defined by objective response or SD ≥3 months and toxicities measured by occurrence of serious adverse events (SAEs), irAEs, or death on study. Results: 108/2155 pts (5%) met the eligibility criteria for ReRx. Among these 108 pts, grade 3 drug-related SAEs during initial therapy were endocrinopathies only (4%). During ReRx, grade 3 drug-related SAEs, all &lt;2%, were colitis, diarrhea, GI hemorrhage, fatigue and dehydration, similar to the toxicities of Ipi in the full EAP cohort of 2155 pts. Three pts (3%) of the 108 in this ReRx cohort had drug-related GI SAEs leading to discontinuation of Ipi. Among these pts who underwent ReRx, the median OS from the 1st initial therapy dose was 21.1 months. Conclusions: In this analysis of EAP pts who experienced benefit from initial Ipi therapy (including those with durable SD who subsequently progressed) and received ReRx with Ipi, no new safety signals were identified. The potential benefit of Ipi ReRx on OS will be prospectively evaluated in an ongoing phase II study in which pts who qualify are randomized to Ipi ReRx or physician’s choice alternative therapy. Clinical trial information: NCT00495066.
Effectiveness of platinum-based adjuvant chemotherapy for muscle-invasive bladder cancer: A weighted propensity score analysis.
Authors: Fumitaka Shimizu, Satoru Muto, Masataka Taguri, Takeshi Ieda, Takatsugu Okegawa, Raizo Yamaguchi, Shigeo Horie
Journal: Journal of Clinical Oncology (2017)

392 Background: The clinical evidence of adjuvant chemotherapy (AC ) is less robust than neoadjuvant chemotherapy (NAC). However, several surveys suggest that urologists prefer to use AC more frequently than NAC. We evaluate the clinical benefit of adjuvant platinum based chemotherapy following radical cystectomy (RC) for muscle-invasive bladder cancer (BCa) in routine clinical practice. Methods: This observational study was conducted to compare the effectiveness of AC versus observation postcystectomy in patients with clinicallymuscle-invasive BCa. Cancer-specific survival (CSS) and overall survival (OS) between the AC group and RC alone group were compared using Kaplan-Meiyer method and log-rank test. After adjusting for background factors using propensity score weighting, differences in CSS and OS between these two groups were compared. Subgroup analyses by the pathological characteristics were performed. Results: In total, 322 patients were included in this study. Of these, 23% received AC postcystectomy. Clinicopathological characteristics showed that patients in the AC group were pathologically more advanced and were at higher risk than the RC alone group. In the unadjusted population, although it is not significantly, the AC group had lower overall survival (3-years OS; 61.5% vs 73.6%, HR 1.44, p = 0.243, log-rank test, AC vs RC alone). In the weighted propensity score analysis, although it is not significantly, AC group were superior than RC alone groups (OS: HR 0.65, 95%CI 0.39-1.09, p = 0.099, log-rank test, AC vs RC alone). Subgroup analyses showed that AC significantly reduced the hazard ratio of OS and CSS in ≥ pT3, pN+, ly+, and v+ subgroups. Conclusions: The weighted propensity score analyses showed that platinum-based AC might be associated with increased CSS and OS in patients with high-risk invasive BCa.
Successful treatment of multiple intracranial meningiomas with mifepristone (RU486).
Authors: Patrizia Farina, Giuseppe Lombardi, Mehdi Touat, Marc Sanson
Journal: Journal of Clinical Oncology (2014)

TPS2108 Background: Meningiomas, the most frequent primary brain tumors in adults, are twice more frequent in females compared to males. Several evidence suggest a role for female sex hormones, and particularly progesterone, whose receptor (PR) is highly expressed in the majority of grade I meningiomas. Mifepristone (RU 486) is a synthetic steroid with high affinity for both the progesterone and glucocorticoid receptors. In vitro and in vivo studies suggest an antitumor effects of mifepristone on meningiomas. A phase III randomized trial failed to demonstrated its efficacy in meningioma patients. However a subgroup of patients may still benefit from RU486, particularly multiple meningiomas (diffuse meningiomatosis) which are less frequent, but have a higher female predominance and a higher PR expression. Methods: Three female patients with multiple meningiomas inaccessible to either surgical or radiosurgical treatment were treated with mifepristone at 200 mg per day. Results. The treatment was well tolerated (one patient reported hypothyroidism, one patient reported benign ovarian cystadenoma). MRI brain follow-up revealed a partial response (>50% reduction) in two patients and a complete stabilization in the other. All the three patients are now stable after 5 to 9 years of treatment. Conclusion. These encouraging results strongly support a prospective clinical trial in this pre-selected population of multiple meningioma female patients.
Assessment of peripheral blood T regulatory cells (Tregs) in PNET/Ewing sarcoma: A prospective study.
Authors: Tilak Tvsvgk, Surender Kumar Sharawat, Ritu Gupta, Sandeep Agarwala, Shah Alam Khan, Shishir Rastogi, Sreenivas Vishnubhatla, Sameer Bakhshi
Journal: Journal of Clinical Oncology (2012)

9580 Background: Tregs in bone marrow have been previously evaluated in PNET patients; however, data on peripheral blood ccirculating Tregs is lacking. The objective of our study was to determine baseline Treg frequency in PNET patients and correlate the same with patient characteristics and outcome. Methods: Samples of 5ml venous blood were obtained from 38 newly diagnosed PNET patients at diagnosis along with six healthy controls. Flow cytometric analysis was done for detecting Treg cells [CD4+CD25+FoxP3+]. Results: Thirty-eight patients with median age 17 years; male/female ratio of 5.5:1 had significantly higher baseline Tregs than healthy controls [9.17%±.3.08 vs 3.16±1.49%; p=&lt;0.0001]. Eight patients (21.1%) had fever at baseline presentation. The disease was extra-skeletal in one and metastatic at baseline in 11 (28.9%) patients. Ten patients relapsed on standard protocol of therapy and seven died. The median Treg frequency was 8.84% (Range: 2.49-16.31). When the Tregs were categorized as high and low based on the median value, patients with fever had a significantly higher Tregs than those without fever [11.3%±.3.5% vs 8.6% ±. 2.7%; p=0.02]. No significant association of peripheral blood Treg cells frequency was noted with other factors like age, sex, metastatic disease, relapse or death. The EFS was 55% and OS 70% of the entire cohort at a median follow up of 14 months. There was no significant difference in the EFS or OS between the high and low Treg cell groups [EFS- 52% vs 64%; p=0.99 and OS-75% vs 70%; p=0.26]. Conclusions: This is the first study on circulating Tregs in PNET, and it shows that the peripheral blood Treg frequencies are higher in these patients as compared to healthy controls. Further, PNET patients with fever had significantly higher Treg frequency. However, Tregs did not differ with respect to metastatic disease at presentation, EFS or OS.
TROG 03.06 and VCOG PR 01-03: The "timing of androgen deprivation therapy in prostate cancer patients with a rising PSA (TOAD)" collaborative randomised phase III trial.
Authors: Gillian M. Duchesne, Julie Bassett, Catherine D'Este, Mark Frydenberg, Leo Ledwich, Jeremy Laurence Millar, Roger L Milne, Rosemary Smith, Nigel Spry, Martin R. Stockler, Rodney Syme, Sandra Turner, Keen Hun Tai, Henry Woo
Journal: Journal of Clinical Oncology (2015)

5007 Background: This randomized, prospective phase III trial investigated if immediate intervention with androgen deprivation therapy (ADT) (Arm B) improved overall survival compared to delayed ADT introduction (Arm A) in prostate cancer patients with PSA relapse after definitive therapy, or in asymptomatic men not suitable for curative therapy at diagnosis. Methods: Eligible patients were randomised 1:1, and stratified by planned intermittent or continuous (I or C) ADT; treatment centre; prior therapy (prostatectomy or radiation therapy); relapse-free interval < or ≥ 2 years; and PSA doubling time of < or ≥ 10 months. The primary endpoint was unadjusted overall survival by intention-to-treat. Secondary endpoints were cancer specific survival, time-to-clinical progression, time-to-castration resistance, cancer- and treatment-related complications, and quality of life. Sample size calculations for 80% power, α level of 5%, and a 2-sided statistical test required 750 patients to show a 10% improvement in survival. Results: From September 2004 to July 2012, 293 patients were randomised (A: 151, B:142) with a median follow-up of 5.0 years. There were 46 deaths, 30 for Arm A (delayed) and 16 for Arm B (immediate). Overall survival (OS) (log rank unadjusted) was significantly higher in Arm B than Arm A (p = 0.047), with 6-year survival rates of 86% and 79% respectively. The hazard ratio (HR) for death from all causes for Arm B relative to Arm A (Cox adjusted regression analysis) was 0.54, 95% confidence interval (CI) 0.27,1.06, p = 0.07. Death from prostate cancer was reduced in Arm B (HR 0.50 CI 0.17,1.51, p = 0.22), as was death from other causes (HR 0.57 CI 0.31,1.05, p = 0.07), both non-significantly. Overt local and distant disease progression were significantly reduced in Arm B (HR 0.51 CI 0.34,0.76, p = 0.001; HR 0.54 CI 0.32,0.90, p = 0.018). There was no difference in the time to castrate resistance. In Arm A 34% of patients started ADT within 2 years, while 49% started later than 4 years on trial or had not yet commenced therapy. Conclusions: Overall survival and time to clinical progression were significantly improved for immediate versus delayed ADT. Clinical trial information: 12606000301561.
Phase I trial of novel kinesin spindle protein (KSP) inhibitor SB-715992 IV days 1, 8, 15 q 28 days
Authors: H. A. Burris, P. Lorusso, S. Jones, T. M. Guthrie, J. B. Orr, D. D. Williams, J. P. Hodge, M. Bush, J. Sabry
Journal: Journal of Clinical Oncology (2004)

2004 Background: The mitotic kinesin KSP plays an exclusive and essential role in assembly and function of the mitotic spindle. KSP represents a novel target for development of therapeutics against cancer. SB-715992 is a unique and selective inhibitor of KSP, that is preferentially overexpressed in malignant cells, functions exclusively in mitosis, and is not expressed in terminally differentiated neurons. In pre-clinical studies in a broad range of human tumor xenografts, doses of SB-715992 below the MTD produced tumor regression and cures. Methods: The current study determines the safety, MTD, and PK profile of SB-715992 administered over 1-hour on days 1, 8, 15 q 28 days. Results: 27 patients (pts) (M/F 15/12) with solid tumors were treated at doses of 1 to 8 mg/m2. Median age was 53 years (range 29–78). Common tumor types included CRC (5), RCC (4), breast (4), and lung (3). 2 pts developed DLT at 8 mg/m2 consisting of Grade (Gr) 3 neutropenia, resulting in the inability to administer the d 15 dose. The 7 mg/m2 dose level was expanded as a potential recommended phase II dose. No Gr 3 or 4 toxicities have been observed at this dose level. At dose levels < 4 mg/m2 drug-related Gr 2 constipation (n=1) and Gr 2 anemia (n=1) were observed. At dose levels ≥ 4 mg/m2, Gr 2 neutropenia (n=2), Gr 3 neutropenia (n=1), Gr 2 anemia (n=1), Gr 3 anemia (n=1), and Gr 3 transaminitis (n=1) have been noted. Increases in AUC0-∞ and Cmax are dose-related without accumulation following multiple doses. SD was observed for 3–4 cycles in 3 pts with RCC, SCCHN, and CRC. For the 7 mg/m2 dose level in Cycle 1, Day 1and 15 median PK values (n=6) were Cmax = 349 and 218 ng/mL; AUC0-∞ = 2965 and 1994 ng.h/mL; t1/2 = 37 and 22 hrs; CL = 5196 and 7546 mL/hr; and Vss = 235 and 240 L. Conclusion: SB-715992 administered on days 1, 8, 15 q 28 days at 7 mg/m2 is the MTD and is recommended for phase II investigations. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline
First-in-human Phase 1 safety, PK, and PD study of the CDK4/6 inhibitor G1T28.
Authors: Renger G. Tiessen, Patrick J. Roberts, Jessica A. Sorrentino, Hannah S. White, Karenann M. Makhuli, John E. Bisi, Jay C. Strum, Ewoud-Jan van Hoogdalem, Rajesh K. Malik
Journal: Journal of Clinical Oncology (2015)

2527 Background: G1T28 is a highly potent and selective CDK4/6 inhibitor being developed as an IV agent for targeted bone marrow chemoprotection and as an oral antineoplastic agent. The CDK4/6 pathway is critical in regulating cell proliferation of certain tumors. In addition, hematopoietic stem and progenitor cells (HSPCs) are dependent upon CDK4/6 for proliferation. Transient G1T28-induced G1 cell cycle arrest of HSPCs renders them resistant to the cytotoxic effects of chemotherapy. Thus, G1T28 could be used for chemoprotection (reduction of chemotherapy-induced myelosuppression) in patients with CDK4/6-independent tumors, or as an antineoplastic agent in patients with CDK4/6-dependent tumors. Methods: The objective of this study was to assess the safety and tolerability of G1T28, as well as to characterize PK and PD (NCT02243150). Part 1 was a double blind, placebo-controlled, single escalating dose study in healthy volunteers of both sexes, where subjects were randomized (3:1) to receive G1T28 or placebo as a single 30-minute IV infusion. In Part 2, 8 subjects will receive single escalating oral doses of G1T28 in three dosing periods. PD assessments included evaluation of ex vivo stimulation of lymphocytes and bone marrow cell cycle analysis. Results: 45 subjects have enrolled in the study to date. In Part 1, G1T28 was administered at doses of 6, 12, 24, 48, 96 and 192 mg/m2. G1T28 was well tolerated, with no dose limiting toxicities or serious adverse events reported. In Part 1, G1T28 exposure (Cmax and AUC) increased proportionally with dose, while clearance was relatively constant. G1T28 at 96 and 192 mg/m2 demonstrated a robust pharmacodynamic effect with a dose-dependent decrease in phytohemagglutinin (PHA)-stimulated lymphocyte proliferation ex vivo. Conclusions: G1T28, a novel CDK4/6 inhibitor, is well tolerated and demonstrates predictable PK and robust PD activity. Based on these results, IV G1T28 will be investigated in Phase 1b/2a studies in patients with CDK4/6-independent tumors to evaluate its potential as a targeted bone marrow chemoprotectant. In addition, the oral formulation will be assessed as an antineoplastic agent in patients with CDK4/6-dependent tumors. Clinical trial information: NCT02243150.
Video-observed treatment for tuberculosis patients in Belarus: findings from the first programmatic experience
Authors: Heorhi Sinkou, Henadz Hurevich, Valiantsin Rusovich, Liudmila Zhylevich, Dennis Falzon, Pierpaolo de Colombani, Andrei Dadu, Masoud Dara, Alistair Story, Alena Skrahina
Journal: European Respiratory Journal (2017)

The treatment of tuberculosis requires daily intake of multiple medications for between 6 months and 2 years, or more [1, 2]. This long duration predisposes to the interruption of medications with the risk of the emergence of drug resistance, death, disease persistence and continued transmission of tuberculosis in the community. Directly observed treatment, together with patient support, has been recommended to improve adherence [3]. However, daily treatment observation presents challenges for both patients and observers, which have limited its implementation [4]. Digital technologies, like video (or virtually)-observed treatment (VOT) can help bridge the gap between patients and health services and promote adherence [5]. VOT usually requires patients to film themselves taking medications on a computer or mobile device and then transmit these images to a remote observer via the internet [6–9]. Video technology has been available for more than a decade, but the increasing availability of smartphones and broadband internet is making VOT practical to implement even in resource-constrained settings. Belarus has started implementing video-observed treatment for patients with tuberculosis using smartphones <http://ow.ly/q1dM307W7hC>
Weight loss in solid tumors: Clinical features and prognostic importance.
Authors: Shiva Shrotriya, Aynur Aktas, Bassam N. Estfan, Lisa A. Rybicki, Declan Walsh
Journal: Journal of Clinical Oncology (2013)

e20572 Background: Large cancer databases provide valuable information on weight change and its impact on different clinical parameters. Body weight change in adults with solid tumors was examined in outpatients. The objective was to determine if demographics, clinical and biochemical indices are predictive of weight loss (WL). The effect of WL and other parameters on survival were also assessed. Methods: Electronic medical records (EMR) for outpatient visits from a tertiary cancer center were retrospectively reviewed. Body weight and other clinical parameters on first visit (V1) - within a year post diagnosis - last visit (V2) ≥3 weeks after V1. WL at V2 from V1 categorized as: ≤5%, 5.01-10%, &gt;10%. Results summarized by descriptive statistics, level of association and survival analysis. Results: N = 5901; Mean age (±SD): 61 ± 12 years; 82% were Caucasians; 16% African Americans. Common cancers were genitourinary (GU) 31%; gastrointestinal (GI) 16%; breast 15%; lung 15%; head and neck 6%; brain 5% and others 12%. Metastatic disease in 18%. Bone, brain, lymph nodes – common. 45% had radiotherapy and 41% chemotherapy. Median (min, max) weight, kgs: V1=81(32.0, 223), V2=79.4(34, 221). Median duration (min, max), days V1→V2: 195 (22, 1080). Weight loss V1→V2: ≤5% (73%), 5.01-10% (13%) and &gt;10% (14%). Median change in BMI V1→V2: -0.2 (-19, 13). Median change systolic/diastolic blood pressure (BP) V1→V2: -3(-99, 80)/-1(-57, 47). Change in REE V1→V2: -13(-890, 365). Median survival for 5.01-10.0% WL= 9.4 months, &gt;10.0% = 5.3 months and not observed for ≤ 5%. Conclusions: Majority lost ≤ 5% of body weight by V2. WL maximum for head and neck cancer and GI. High BMI predicted greater WL compared to normal or underweight. ≤5% WL had a survival advantage 5.01-10% and &gt;10%. WL remained prognostic for survival even after adjusting for other prognostic factors.
Liver carcinogenesis by FOS-dependent inflammation and cholesterol dysregulation
Authors: Latifa Bakiri, Rainer Hamacher, Osvaldo Graña, Ana Guío-Carrión, Ramón Campos-Olivas, Lola Martinez, Hans P. Dienes, Martin K. Thomsen, Sebastian C. Hasenfuss, Erwin F. Wagner
Journal: The Journal of Experimental Medicine (2017)

Human hepatocellular carcinomas (HCCs), which arise on a background of chronic liver damage and inflammation, express c-Fos, a component of the AP-1 transcription factor. Using mouse models, we show that hepatocyte-specific deletion of c-Fos protects against diethylnitrosamine (DEN)-induced HCCs, whereas liver-specific c-Fos expression leads to reversible premalignant hepatocyte transformation and enhanced DEN-carcinogenesis. c-Fos–expressing livers display necrotic foci, immune cell infiltration, and altered hepatocyte morphology. Furthermore, increased proliferation, dedifferentiation, activation of the DNA damage response, and gene signatures of aggressive HCCs are observed. Mechanistically, c-Fos decreases expression and activity of the nuclear receptor LXRα, leading to increased hepatic cholesterol and accumulation of toxic oxysterols and bile acids. The phenotypic consequences of c-Fos expression are partially ameliorated by the anti-inflammatory drug sulindac and largely prevented by statin treatment. An inverse correlation between c-FOS and the LXRα pathway was also observed in human HCC cell lines and datasets. These findings provide a novel link between chronic inflammation and metabolic pathways important in liver cancer.
First-line cisplatin plus pemetrexed therapy for selected patients with advanced nonsquamous non-small cell lung cancer.
Authors: Kazuhisa Nakashima, Haruyasu Murakami, Hisao Imai, Akira Ono, Tetsuhiko Taira, Hirotsugu Kenmotsu, Tateaki Naito, Masahiro Endo, Toshiaki Takahashi
Journal: Journal of Clinical Oncology (2014)

e19142 Background: The AVAPERL (MO22089) trial demonstrated that induction therapy with first-line cisplatin, pemetrexed (Pem) and bevacizumab (Bev) followed by continuation maintenance therapy with Pem plus Bev improved progression-free survival (PFS) compared with Bev alone (median, 10.2 v 6.6 months) in patients with advanced nonsquamous non-small cell lung cancer (nsNSCLC). However, this survival data was based on selected patients who were eligible for Bev therapy and maintenance therapy. Methods: To assess the efficacy of cisplatin plus Pem therapy in selected patients with advanced nsNSCLC, we retrospectively reviewed consecutive patients who received first-line chemotherapy with cisplatin and Pem at Shizuoka Cancer Center between July 2009 and January 2013. Results: A total of 102 patients were included in this study (Group A), of whom 65 (64%) were eligible for Bev therapy (Group B). 37 patients were ineligible for Bev therapy because of major blood vessel invasion (n = 16), hemoptysis (n = 15), or use of anticoagulant or thrombolytic agents (n = 13). Of 65 patients who were eligible for Bev therapy, 41 (63%) were suitable for maintenance therapy (Group C), and 12 received continuation maintenance therapy with Pem (Group D). Median PFS was 5.5 months in Group A, 5.8 months in Group B, 8.1 months in Group C, and 16.6 months in Group D. Conclusions: PFS for selected patients with advanced nsNSCLC was also favorable in this study. First-line induction therapy with cisplatin and Pem followed by continuation maintenance therapy with Pem is a reasonable treatment option for patients with advanced nsNSCLC who are eligible for Bev therapy.