tbuckley/cabot-search huggingface dataset:
Initial safety results of an open-label phase II trial of erlotinib in non-small cell lung carcinoma (NSCLC)
Authors: A. García-Velasco, R. Pérez-Carrión, J. de Castro, P. Garrido, R. García, J. L. González-Larriba, G. Martín, M. Provencio, M. L. Amador, L. Paz-Ares
Journal: Journal of Clinical Oncology (2007)

18038 Background: Erlotinib is an orally selective and reversible inhibitor of HER1/EGFR tyrosine kinase. Erlotinib has demonstrated to be effective in the treatment of advanced non-small-cell lung cancer, in terms of longer survival, better quality of life and delayed symptom progression. The TargeT trial is a large open-label, non-randomized, phase II study carried out in 101 Spanish institutions. Methods: Eligibility criteria included stage IIIB-IV previously treated patients (p) with confirmed NSCLC. Patients harboring mutations in EGFR gene or p unsuitable for chemotherapy were also allowed to enter the study and received erlotinib as first line treatment. Subjects were treated with 150 mg/day po until disease progression or unacceptable toxicity. Dose reductions were allowed. Primary end-point was time to progression. Results: By the time of this analysis, data from 1,522 p were available. Median age: 65 y (range 26–95); most p were male (71.9%); active/former a smoker (78.3%). Around half of the p had adenocarcinoma histology, including bronchioloalveolar carcinoma (53%) and 81.8% exhibited stage IV. ECOG PS 0/1/2 were (%) 21/54/25. The % p receiving erlotinib as 1 st /2 nd /3 rd -line treatment were 29/38/33. Safety data were available for 1,255 p. 6.9% p did not experience any adverse event. As expected most common adverse events were rash (any grade: 61%; gr. 3/4: 11%), and diarrhea (any gr.: 31%; gr. 3/4: 4%) 5.6% p withdrew prematurely the trial due to AE. Erlotinib-related AEs leading to treatment discontinuation were cutaneous toxicity in 21 p (17 gr. 3/4), diarrhea in 6 p (4 gr. 3/4), hepatic toxicity in 1 p, cholestasis in 1 p, and interstitial pneumonitis in 1 p. No unexpected toxicities were reported. 10% of p had dose reductions mainly due to rash and diarrhea. Response rate in these p was 18.7%; time to progression 3.8 months (95% CI: 3.5–4.2); and overall survival 6.0 months (95% CI: 5.5–6.4). Conclusions: These initial interim safety results of erlotinib in real-life clinical setting in a large number of unselected patients with advanced non-small-cell lung cancer confirm the favorable toxicity profile and good tolerability of erlotinib. No significant financial relationships to disclose.
A randomized, placebo-controlled trial of celecoxib in men prior to receiving prostatectomy for clinically localized adenocarcinoma of the prostate: Evaluation of drug-specific biomarker modulation
Authors: M. A. Carducci, J. R. Walczak, E. Heath, W. G. Nelson, A. M. DeMarzo, M. Zahurak, A. J. Dannenberg, H. Parnes, T. L. DeWeese, A. W. Partin
Journal: Journal of Clinical Oncology (2007)

5001 Background: Cyclooxygenase-2 (COX-2) has been postulated as a pharmacological target for preventing a variety of epithelial malignancies including prostate cancer (PCa). We conducted a randomized, double-blind study evaluating celecoxib (C) on biomarkers in normal and PCa tissue at prostatectomy (RRP). Methods: Patients with Gleason sum ≥ 7, pre-study PSA ≥ 15 ng/ml, clinical stage T2b, T2c, or any combination of PSA, Stage, or two or more cores positive for PCa received either C at 400 mg po bid or placebo for 4–6 wks pre-RRP. The primary endpoint was to compare and correlate tissue PG levels with histologic and secondary endpoints performed on prostate tissue and serum from the two comparable groups. Outcomes included PG levels, quantitative RT-PCR for mRNA levels of COX-1 and COX-2, oxidized DNA bases; measurement of apoptosis, proliferation, angiogenic-potential assays and histologic comparison of treated/untreated tissue specimens; PSA levels; and tissue levels of C. Estimates of change in endpoints required 30 patients per arm. Results: Seventy three subjects consented with 64 randomized and included in the intent to treat analysis; 2 had missing data for primary endpoints. Age, baseline PSA, race and Gleason score were comparable across treatment groups. The regimen was well tolerated with no serious adverse events. There was no treatment effect observed in the PG, COX mRNA levels or oxidized DNA base levels in the RRP specimens. Tumor tissue contained significantly less COX-2 mRNA levels than benign tissue (p=&lt;0.0001). Of the markers of apoptosis and proliferation assessed, Ki-67 was higher in tumor samples, and p21 was less in C treated samples. Celecoxib was present in tumor tissue demonstrating that it reached the target, but there were no observed effects in the study endpoints. There was no toxicity greater grade 1 except hepatic toxicity in a placebo group subject. Conclusions: Our results show a lack of effect of C on PCa despite demonstrating that C was present in tissue samples. At this time, we cannot recommend further studies of C as a PCa preventative agent when dosed at 400 mg PO BID. The study was supported by a grant from the NCI, DCP (#NO1-CN-95000–46) and Pfizer, Inc. No significant financial relationships to disclose.
Temsirolimus (TEM) maintenance therapy after response of castration-resistant prostate cancer (CRPC) to docetaxel (TAX).
Authors: Urban Emmenegger, Christopher M. Booth, Scott R. Berry, Srikala S. Sridhar, Eric Winquist, Nesan Bandali, Annabelle Chow, Christina R. Lee, Ping Xu, Shan Man, Robert S. Kerbel, Yoo-Joung Ko
Journal: Journal of Clinical Oncology (2012)

e15177^ Background: There are no standard treatments for men who have demonstrated a good response to TAX without signs of progression. The mTOR pathway is involved in many aspects of CRPC, and mTOR inhibitors have shown significant anti-CRPC activity in preclinical testing. Therefore, we designed a phase II trial to explore whether maintenance therapy with TEM has the potential to prolong response to TAX without compromising quality of life. Methods: For this single-arm, multicenter phase II trial we recruited CRPC pts with documented treatment response by PSA (&gt; 50% decline from baseline) or RECIST (1.0) criteria following ≥ 6 to 10 cycles of TAX (75 mg/m 2 q3wks). Subjects received weekly TEM (25 mg iv x 4/cycle). The primary endpoint was time to treatment failure (TTF; RECIST or symptomatic progression). Secondary endpoints included safety (NCI-CTCAE v3.0), quality of life (FACT-P, PPI), changes in PSA, objective tumor response rate, and overall survival. We were also studying surrogate markers of TEM activity, including the enumeration of circulating endothelial cells (CEC) as a potential indicator of the antiangiogenic effects of TEM. Results: 19 pts have been enrolled to data after a median of 7 cycles of TAX. The mean age was 68 years (range 51-82), and the median baseline PSA 17.3 (0.02-380.7). 15 pts had received prior local radiation therapy, 6 surgery. 17 pts had bone metastases, 9 visceral and 8 nodal disease. Pts received a median of 4 cycles of TEM (maximum 23 and continuing), resulting in a median TTF of 5.8 (95%CI 3.8-9.2) months. No PSA responses were seen (time to PSA progression 1.8 months), but 1 PR. 8 pts achieved SD. 12 pts have been discontinued due to treatment failure (RECIST [4], symptomatic [7], combined [1]), and 3 for other reasons, including TEM-associated toxicity (lymphedema [1]). TEM has been generally well tolerated without unexpected adverse events or negative impact on quality of life. The median overall survival has not yet been reached. There is a trend for TEM to reduce viable CEC amid large inter/intrapatient CEC variability. Conclusions: TEM maintenance therapy in CRPC pts that have responded to TAX appears to be well tolerated and results in meaningful prolonged TTF.
Join the Swiss Sports Physiotherapy Association in celebrating 15 years of quality education: Bern, November 24<sup>th</sup>, 2017
Authors: Mario Bizzini
Journal: British Journal of Sports Medicine (2017)

The Swiss Sports Physiotherapy Association (SSPA) will hold its 15th annual conference on 24 November, 2017 in Bern, capital of Switzerland and home of this event since 2005 (figure 1). The goal of SSPA has been to organise a high-quality scientific congress featuring international speakers. The content has been dictated by the conditions that are prevalent in our major sports, and the issues that are relevant to sports physiotherapy. Thus themes have included prevention and rehabilitation of ACL injuries, diagnosis and management of shoulder problems, management of acute hamstring strain and return to sport. In 2017, we focus on tendons. (But that’s not all!)



Figure 1 
2003–2017 SSPA conference poster for Bern,24 November, 2017.



We …
Bevacizumab in addition to chemotherapy first-line for right-side metastatic colorectal cancer: A cost-effectiveness analysis.
Authors: Gong Chen, Maobai Liu, Te Li, Bin Wu
Journal: Journal of Clinical Oncology (2017)

777 Background: To test the cost-effectiveness of bevacizumab treatment compared with cetuximab plus irinotecan, fluorouracil, and leucovorin (FOLFIRI) as first-line treatment for patients with right-side metastatic colorectal cancer (mCRC). Methods: A Markov model was developed to Chinese clinical practice. The model incorporated clinical and utility data from published literatures, resource utilization and unit prices based on local charge. The lifetime horizontal was used and sensitivity analyses were carried out to test the robustness of the model results. The impact of patient assistance program (PAP) was also evaluated in scenario analyses. Results: Baseline analysis showed that the addition of cetuximab gained additional 0.232 QALYs with more $60,371 relative to bevacizumab therapy, resulting in an ICER of $259,775 /QALY. When PAP was available, the incremental cost decreased to $24,161, which yielded an ICER of $60,371 /QALY, which indicated that the strategy was not cost-effective at a willingness-to-pay (WTP) threshold of 3 times the per capita GDP of China ($22,200/QALY). Sensitivity analyses found that the costs of bevacizumab was the most influential parameter. Conclusions: Bevacizumab treatment for right-side mCRC is not a cost-effective option in comparison with standard chemotherapy in Chinese context.
Long-term responders and survivors on pazopanib for soft tissue sarcomas (STS): Subanalysis of two European Organisation for Research and Treatment of Cancer (EORTC) clinical trials 62043 and 62072.
Authors: Bernd Kasper, Saskia Litière, Sandrine Marreaud, Stefan Sleijfer, Jaap Verweij, Sebastian Bauer, Jan M. Kerst, Winette T.A. Van Der Graaf
Journal: Journal of Clinical Oncology (2013)

10553 Background: Pazopanib has recently received approval in US, EU &amp; Japan for use in certain STS subtypes. We conducted a retrospective analysis on pooled data from two EORTC clinical trials on pazopanib in STS in order to characterize long term responders and survivors. Methods: Patients selected for analysis were treated with pazopanib in phase II study 62043 (n = 142) and phase III study 62072 (PALETTE) (n = 246). Combined median progression-free survival (PFS) was 4.0 months; median overall survival (OS) was 11.3 months. 34 % of patients had a PFS ≥ 6 months (n = 133) and were defined as long term responders; 33 % of patients survived ≥ 18 months (n = 128), defined as long term survivors. Following patient characteristics were studied: gender, age, performance status, tumor localization, histology, grading, treatment exposure and dose modifications, severity of adverse events and post protocol therapy. Results: Clinical cut-off dates for this analysis resulted in a pooled database with a median follow-up of 2.3 years. Patient characteristics were compared between four subgroups based on short / long term PFS and OS, respectively. 79 patients were both long term responders and long term survivors. The descriptive analysis confirmed the importance of known prognostic factors such as age, performance status and grading, but did not add additional characteristics translating into long term response or survival. We identified 12 patients remaining on pazopanib for more than two years: 9 aged younger than 55 years, 9 females, four with smooth muscle tumors and nine with low or intermediate grade tumors at initial diagnosis. Only two of those patients achieved a partial response; the remaining 10 experienced stable disease as best overall response. Median time on pazopanib in these patients was 2.4 years with the longest duration of 3.7 years. Four patients were still on pazopanib at the end of the studies with a median PFS of 2.3 years and a median OS of 2.8 years. Conclusions: 34 % and 33 % of STS patients given pazopanib in these studies have a long PFS and / or OS respectively. 3.1 % of patients demonstrate a clinical benefit even beyond 2 years.
Ginsenoside Rg3 restores hepatitis C virus–induced aberrant mitochondrial dynamics and inhibits virus propagation
Authors: Seong‐Jun Kim, Jae Young Jang, Eun‐Jung Kim, Eun Kyung Cho, Dae‐Gyun Ahn, Chonsaeng Kim, Han Seul Park, Soung Won Jeong, Sae Hwan Lee, Sang Gyune Kim, Young Seok Kim, Hong Soo Kim, Boo Sung Kim, Jihyung Lee, Aleem Siddiqui
Journal: Hepatology (2017)

Hepatitis C virus (HCV) alters mitochondrial dynamics associated with persistent viral infection and suppression of innate immunity. Mitochondrial dysfunction is also a pathologic feature of direct-acting antiviral (DAA) treatment. Despite the high efficacy of DAAs, their use in treating patients with chronic hepatitis C in interferon-sparing regimens occasionally produces undesirable side effects such as fatigue, migraine, and other conditions, which may be linked to mitochondrial dysfunction. Here, we show that clinically prescribed DAAs, including sofosbuvir, affect mitochondrial dynamics. To counter these adverse effects, we examined HCV-induced and DAA-induced aberrant mitochondrial dynamics modulated by ginsenoside, which is known to support healthy mitochondrial physiology and the innate immune system. We screened several ginsenoside compounds showing antiviral activity using a robust HCV cell culture system. We investigated the role of ginsenosides in antiviral efficacy, alteration of mitochondrial transmembrane potential, abnormal mitochondrial fission, its upstream signaling, and mitophagic process caused by HCV infection or DAA treatment. Only one of the compounds, ginsenoside Rg3 (G-Rg3), exhibited notable and promising anti-HCV potential. Treatment of HCV-infected cells with G-Rg3 increased HCV core protein-mediated reduction in the expression level of cytosolic p21, required for increasing cyclin-dependent kinase 1 activity, which catalyzes Ser616 phosphorylation of dynamin-related protein 1. The HCV-induced mitophagy, which follows mitochondrial fission, was also rescued by G-Rg3 treatment.G-Rg3 inhibits HCV propagation. Its antiviral mechanism involves restoring the HCV-induced dynamin-related protein 1-mediated aberrant mitochondrial fission process, thereby resulting in suppression of persistent HCV infection. (Hepatology 2017;66:758-771).
Retrospective review of cytotoxic chemotherapy and anti-angiogenic combinations in renal cell carcinoma: A single institution experience.
Authors: Bradley Curtis Carthon, Manal Tabba, Carla Ellis, Wayne Harris, Mehmet Asim Bilen, Daniel Canter, Viraj A. Master, Omer Kucuk
Journal: Journal of Clinical Oncology (2017)

523 Background: Despite many therapeutic advances, Renal Cell Carcinoma (RCC) still is a leading cause of cancer morbidity and mortality. A recent phase 2 study has examined the combination of Sunitinib and Gemcitabine in a poor risk RCC trial population (Michaelson et al., Cancer 2015). There is limited data on such combinations in a non-clinical trial population. This retrospective study examines our institutional experience in treating predominantly high risk RCC patients with a combination of gemcitabine and an anti-angiogenic agent. Methods: IRB approval was obtained in order to review pathological and clinical data of RCC patients. A retrospective cohort was identified of RCC patients treated with Gemcitabine as well as an anti-angiogenic agent (Sunitinib or Pazopanib) between January 2011 and December 2015 at the Winship Cancer Institute at Emory University. Patient data was reviewed for clinical and pathological characteristics, treatments, prognostic factors, and tolerance. Kaplan Meier analysis was used to assess treatment associated time-to-disease progression (TTP) and overall survival (OS). Results: 12 patients received Gemcitabine and either Sunitinib (n=11) or Pazopanib (n=1). Clear cell (n=5) and non-clear cell varieties including papillary (n=5), chromophobe (n=1), and collecting duct (n=1) RCC were represented. The median line of therapy was 2 (range 0-5 prior therapies). 50% of patients were poor risk, 33% were intermediate risk, and 17% of patients had good risk disease by Heng Criteria. The overall median TTP was 2.9 months (range 0.82-16.5 months) and overall median OS was 8.3 months (range 2.3-16.5 months). This regimen was well tolerated with the most common adverse effects being fatigue in 50% (6/12) of patients, fever in 33% (4/12) of patients, and nausea in 33% (4/12) of patients. Conclusions: Our experience suggests that this combination is effective in advanced and heavily pretreated RCC patients, including poor risk RCC patients outside of a clinical trial format. Additional prospective data using similar combinations, may provide improved outcomes of RCC patients, especially with non-clear cell RCC patients.
Bevacizumab in combination with first-line metastatic chemotherapy in patients with advanced nonsquamous non-small cell lung cancer (NSCLC): Results from the cohort study EOLE.
Authors: Christos Chouaid, Roland Schott, Lionel Falchero, Franck Bonnetain, Julien Neaume, Jaafar Bennouna, Naila Tagieva
Journal: Journal of Clinical Oncology (2012)

e18005 Background: EOLE, a large cohort of 423 patients included in 1 year (July 2010 – July 2010) with locally advanced, metastatic or recurrent non-squamous NSCLC, aimed to describe the targeted population receiving first-line bevacizumab (Bev) in addition to chemotherapy with regards to progression-free survival, overall survival, safety and quality of life in real clinical practice. Methods: Patients who received physician’s choice of 1st-line Bev-containing treatment were included in this cohort study. Results: This analysis describes the inclusion data of 417 patients consisting of adenocarcinoma (92%), large cell carcinoma (4%), undifferentiated carcinoma in predominantly non-squamous (3%), bronchoalveolar carcinoma (1%). Patient characteristics were as follow: the median age being 60 (years) [32; 84], more males than females (68%), 40% had a baseline ECOG Performance Status (PS) 0, 47% of PS 1 and 12% of PS 2, most patients had Stage IV disease (91%), 13% of patients had never smoked. Tumor location was reported as central for 17% of patents and among them 4% was in contact with the large vessels. For 3% of the lesions a cavitation was notified; and 20% of included patients had brain metastases. The main comorbidities at the inclusion were: cardiovascular (45%), arterial thromboembolic and /or venous (20%) with pulmonary embolism (3%); related to the tumor lesion - bloody sputum (4%) and hemoptysis (1%). 68% of patients have received the dose of Bev 7.5mg/kg q3w; for 49% of patients Bev was combined with cisplatin/pemetrexed, 24% with carboplatin/paclitaxel, 13% with carboplatin/pemetrexed and 7% with cisplatin/gemcitabine. The EGFR mutation analysis was carried out for about 50% of patients. Conclusions: Compared to AVAil and SAil studies, EOLE cohort included more patients classified as having: a baseline PS of 2 (p &lt;0.0001, Fisher test), a never smoked status (p&lt;0.0001, chi2 test) and an adenocarcinoma (92%) (p&lt;0.0001, chi2 test). Around a half of included patients received combination Bev - cisplatin /pemetrexed.
ERCC1 and RRM1 but not EGFR gene expression is predictive of shorter survival in advanced non-small cell lung cancer (NSCLC)
Authors: G. Selvaggi, P. Ceppi, M. Volante, S. Saviozzi, S. Novello, R. Calogero, M. Papotti, G. V. Scagliotti
Journal: Journal of Clinical Oncology (2006)

10030 Background: Pivotal studies indicate a role of excision repair cross-complementation 1 (ERCC1) and ribonucleotide reductase M1 (RRM1) in conferring a differential sensitivity to cytotoxic chemotherapy and epidermal growth factor receptor (EGFR) has been recently deeply investigated in NSCLC. Methods: We retrospectively collected 70 formalin-fixed paraffin-embedded (FFPE) bronchoscopic/fine needle aspiration biopsies of NSCLC to investigate the expression levels of ERCC1, RRM1 and EGFR by Real-Time PCR (Lord R et al. Clin Cancer Research 2002, 8:2286–91). Results were correlated with survival using the Kaplan-Meier method. Results: Sixty-one (87%) specimens were successfully amplified. Median age was 62 years (range 26–75), male/ female ratio 44/17, stage III/IV 20/41; 43 patients received cisplatin-based chemotherapy; overall median survival (MS) was 13.3 months over a median follow-up time of 45 months. ERCC1 expression level ranged from 0.70 to 15.12, RRM1 0.60–17.82. By adopting cut-off values according to median expression levels, we found a strong correlation between ERCC1 and RRM1 mRNA levels (r=0.410; p&lt;0.001). MS in patients with low ERCC1 was significantly longer (16.9 vs 11.3 months, p&lt;0.006) as well as in patients with low RRM1 (13.9 vs 10.9 months, p&lt;0.03). Concomitant high expression levels of ERCC1 and RRM1 (n=26) are predictive of a worse outcome (13.9 vs 10.9 months, p&lt;0.05). Among patients treated with cisplatin-based regimens, low ERCC1 levels were also predictive of a significantly longer MS (23.0 vs 11.6 months, p&lt;0.002). A lower median ERCC1 level (3.2 vs 4.7) and a correlation with a better outcome were also observed in females vs males. No correlation between gene expression levels and histology was reported. No significant correlation between EGFR expression levels (range 0.5–85.8) and survival was found, even when different cut-off values were tested. Conclusions: This retrospective study further validates ERCC1 and RRM1 as good candidates genes to customize chemotherapy. Prospective studies based on the selection of patients according to genes expression levels are a research priority in early and advanced stages of NSCLC. [Table: see text]