tbuckley/cabot-search huggingface dataset:
The scandal of generic drug pricing: drug regulation policies need review
Authors: Karim Meeran, Sirazum M Choudhury, John Wass
Journal: BMJ (2017)

We welcome the news that the Competitions and Market Authority is now taking drug companies such as GlaxoSmithKline, Pfizer, and Flynn Pharma to task for overcharging the NHS for generic drugs.1 In December, the authority announced that it was investigating Actavis for inflating the price of hydrocortisone, a WHO essential medicine used to treat adrenal insufficiency.2

The price of hydrocortisone has risen by …
Phase II trial of paclitaxel poliglumex (CT-2103) in pre- and post-menopausal women on hormonal replacement therapy (HRT) with non-small cell lung cancer (NSCLC).
Authors: M. Batus, R. Mohajer, D. Pach, S. Basu, M. J. Fidler, P. D. Bonomi
Journal: Journal of Clinical Oncology (2011)

e18047 Background: Relationship of estrogen use, smoking, and NSCLC has been reported in several studies. Capthesin B is expressed on most NSCLC and is the major metabolizing enzyme for CT-2103. It is under control of estrogen and in phase III front line studies, women with estradiol levels >30 had the largest survival benefit. The objective of this study was to evaluate CT-2103 as single agent therapy for women with baseline estradiol levels >30 or in combination with EstroGel in post-menopausal women with heavily pretreated advanced NSCLC. The primary endpoint was progression free survival with safety, response, and overall survival as secondary endpoints. Methods: 29 stage IV NSCLC patients with PS 0, 1 or 2 who had previous treatment with at least one cytotoxic chemotherapy and an EGFR inhibitor, participated. CT-2103 was given as IV infusion once every 21 days (1 cycle). Tumor response (using RECIST criteria) was assessed after even numbered cycle. Toxicities assessed at each patient visits. Study discontinued at the time of progression or unacceptable toxicity. Results: 29 patients with 3.4 average lines (ranging 2-7) of previous treatment, received CT-2103 treatment plus estradiol patches for serum levels <30. Average number of CT-2103 cycles was 2.8 (1-6 cycles). Median time to progression was 44 days (36.5-51.5) with median overall survival 223 days (153-282). 11 (37.9%) of 29 patients had stable disease and 1 (3.4%) partial response. No major toxicity reported except grade 1 and 2 peripheral neuropathy in 6 (20.6%), no hair loss or allergic reaction reported. Conclusions: Paclitaxel poliglumex was relatively well tolerated. Despite encouraging preliminary clinical results in women with high estradiol levels and intriguing preclinical observations, the PFS and overall survival results suggest that further testing of this treatment strategy is not warranted.
Molecular and genetic alterations associated with therapy resistance and relapse of acute myeloid leukemia
Authors: Hubert Hackl, Ksenia Astanina, Rotraud Wieser
Journal: Journal of Hematology & Oncology (2017)

The majority of individuals with acute myeloid leukemia (AML) respond to initial chemotherapy and achieve a complete remission, yet only a minority experience long-term survival because a large proportion of patients eventually relapse with therapy-resistant disease. Relapse therefore represents a central problem in the treatment of AML. Despite this, and in contrast to the extensive knowledge about the molecular events underlying the process of leukemogenesis, information about the mechanisms leading to therapy resistance and relapse is still limited. Recently, a number of studies have aimed to fill this gap and provided valuable information about the clonal composition and evolution of leukemic cell populations during the course of disease, and about genetic, epigenetic, and gene expression changes associated with relapse. In this review, these studies are summarized and discussed, and the data reported in them are compiled in order to provide a resource for the identification of molecular aberrations recurrently acquired at, and thus potentially contributing to, disease recurrence and the associated therapy resistance. This survey indeed uncovered genetic aberrations with known associations with therapy resistance that were newly gained at relapse in a subset of patients. Furthermore, the expression of a number of protein coding and microRNA genes was reported to change between diagnosis and relapse in a statistically significant manner. Together, these findings foster the expectation that future studies on larger and more homogeneous patient cohorts will uncover pathways that are robustly associated with relapse, thus representing potential targets for rationally designed therapies that may improve the treatment of patients with relapsed AML, or even facilitate the prevention of relapse in the first place.
Effect of neoadjuvant chemoradiotherapy (nCRT) on survival in patients with borderline resectable (BR) pancreatic adenocarcinoma (PDA) with acceptable peri-operative morbidity.
Authors: Rebecca Manget Minter, Mary Uan-Sian Feng, Mahmoud Al-Hawary, Jincheng Shen, Matthew J Schipper, Filip Bednar, Erica Proctor, Susanne Gray Warner, Mark M. Zalupski, Diane M. Simeone
Journal: Journal of Clinical Oncology (2014)

288 Background: The impact of nCRT for patients (pts) with BR PDA has been debated, with wide variation in practice. Most studies in pts undergoing nCRT have no or historic controls, rather than a direct comparison of BR pts treated in the same era. We aimed to assess the effect of nCRT on operative, pathologic, and survival endpoints in pts with BR PDA. Methods: 241 pts underwent pancreatectomy (177 without and 64 with nCRT) for PDA (2001-2011). CT scans at dx were re-reviewed by a pancreatic radiologist using a standardized template. Pts were categorized as resectable, BR, or unresectable according to 2012 NCCN criteria. BR pts (n=74) were extracted for analysis. Survival was compared using log-rank tests; pathologic features and peri-op factors were compared using Wilcoxon rank sum tests (continuous variables) or Fisher's exact test (binary variables). Results: Median follow up was 26 ±21 months. nCRT was associated with higher 1 and 3 yr OS, lower margin and node positivity, decreased pre-op CA19-9, and lower post-op pancreatic fistula (POPF), with higher operative time, vascular reconstructions, and transfusion (PRBCs). On univariate analysis, POPF negatively impacted survival (HR 2.34, 1.16-4.75, p=0.02) as did pre-op CA19-9&gt;150 U/mL (HR 2.11, 1.16-3.87, p=0.015). Conclusions: Pts receiving nCRT for BR PDA had higher 1 and 3 yr OS, more negative margins, and fewer positive nodes, with minimal additional peri-op co-morbidity, compared with pts going directly to surgery. These data support consideration of enrolling all pts with BR PDA into a neoadjuvant program prior to resection. [Table: see text]
Surgery with curative intent in patients (pts) treated with first-line chemotherapy (CT) + bevacizumab (BEV) for metastatic colorectal cancer (mCRC): First BEAT and NO16966
Authors: J. Cassidy, D. Cunningham, S. R. Berry, F. Rivera, S. J. Clarke, A. Kretzschmar, E. Díaz-Rubio, E. Van Cutsem, L. B. Saltz
Journal: Journal of Clinical Oncology (2008)

4022 Background: Resection of initially unresectable metastatic lesions in pts with mCRC who have responded to systemic therapy offers a potential for cure in selected pts. Here we describe the frequency, outcome and safety of pts undergoing resection of metastatic lesions with curative intent in two large clinical trials (First BEAT: phase IV uncontrolled; NO16966: phase III, placebo [P] controlled) using standard CT plus BEV as first-line treatment for pts with initially unresectable mCRC. Methods: BEAT enrolled 1,965 pts and 1,400 pts were enrolled in the P controlled part of NO16966. In both trials pts received first-line CT plus BEV 5mg/kg q2w (5-FU-based CT) or 7.5mg/kg q3w (capecitabine-based CT). CT was physician’s choice in BEAT. Pts were randomised 1:1 between XELOX or FOLFOX and then BEV or P in NO16966. Data were collected prospectively. Surgery was recommended 6 to 8 weeks after BEV discontinuation. Surgery with curative intent was a predefined secondary endpoint in BEAT. Criteria for initial unresectability of metastatic lesions was not defined in either trial and was based on investigators’ evaluations. Results: 215/1,914 (11.2%) eligible pts underwent surgery with curative intent in BEAT; 170 pts (8.8%) had no residual disease following surgery (79% R0 resection). Overall survival (OS) is not mature, but preliminary 2-year OS is 44% for the overall ITT population and 82% for R0 resected pts (p<0.0001). In NO16966, 44/699 (6.3%) pts receiving BEV underwent R0 resection compared with 34/701 (4.9%) pts receiving P (p=NS). R0 resection rates in pts with no extrahepatic metastatic disease were 11.5% in BEAT and 12.3% vs 11.5% (p=NS) in NO16966. No clinically meaningful increase in wound-healing complications or bleeding events was observed compared with either historical data or control. Conclusions: Safety and feasibility of secondary resection of metastatic lesions with curative intent does not appear to be compromised in pts receiving BEV plus CT. Updated efficacy data, including relapse-free survival, will be presented at the meeting. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen, Roche, sanofi-aventis Roche, sanofi-aventis Amgen, Bayer, Bristol-Myers Squibb, Genentech, ImClone, Merck, Pfizer Oncology, Roche, sanofi-aventis, Taiho Roche Roche
Morbidity and mortality results from a prospective randomized trial comparing mesorectal excision with or without lateral lymph node dissection for clinical stage II and III lower rectal cancer: Japan Clinical Oncology Group study JCOG0212.
Authors: S. Fujita, S. Saito, Y. Moriya, J. Mizusawa, K. Nakamura, N. Saito, Y. Kinugasa, Y. Kanemitsu, M. Ohue, S. Fujii, Y. Akazai, M. Shiozawa, T. Yamaguchi, H. Bandou, T. Aoki, K. Murata, K. Shirouzu, N. Takiguchi, Y. Saida
Journal: Journal of Clinical Oncology (2011)

3548 Background: Mesorectal excision (ME) is the international standard surgical procedure for lower rectal cancer. However, lateral pelvic lymph node metastasis is occasionally found in patients with clinical stage II, III rectal cancer, and therefore lateral lymph node dissection (LLND) is the standard procedure in Japan. We conducted a randomized controlled trial to confirm the non-inferiority of ME to ME with LLND in terms of efficacy. The primary analysis is planned for 2015, and this study is now in the follow-up stage. Morbidity and mortality were examined in this study. Methods: Only surgeons specialized in both procedures from 33 Japanese institutions participated in the study. Eligibility criteria included histologically proven rectal cancer; clinical stage II/III; main lesion located in the rectum and the lower margin below the peritoneal reflection; no lateral pelvic lymph node swelling; PS of 0 or 1; patient age 20-75 years. After surgeons had confirmed R0 resection by the ME procedure, patients were randomized intraoperatively to ME only or ME with LLND by phone call to the Data Center. The primary endpoint was relapse-free survival, and the planned sample size was 700. Postoperative morbidity and hospital mortality were compared between the two groups. Results: A total 701 patients were randomized to ME (n = 350) or ME+LLND (n = 351) between June 2003 and August 2010. The incidence of lateral pelvic lymph node metastasis was 7.4% in the ME+LLND group. The incidences of postoperative grade 3 or 4 complications in the ME group and the ME+LLND group were 16.1% and 21.7%, respectively (p = 0.07), and the corresponding incidences of anastomotic leakage, including all grades, were 10.6% and 8.9%, respectively (p = 0.45). The reported hospital mortality rate was 0.14%: one patient in the ME+LLND group died of anastomotic leakage followed by sepsis. Conclusions: The ME group tended to show lower postoperative morbidity than the ME+LLND group. The primary analysis planed for 2015 is pivotal to prove non-inferiority of ME to ME+LLND in terms of relapse-free survival.
Brain metastases (BM) as the primary site of relapse in two randomized phase III pemetrexed (P) trials in advanced non-small cell lung cancer (NSCLC).
Authors: W. F. Ortuzar, E. J. Pennella, W. J. John, L. Simms, G. Peng, J. Treat, C. K. Obasaju
Journal: Journal of Clinical Oncology (2010)

e18047 Background: In NSCLC patients with adenocarcinoma or large cell carcinoma, symptomatic BM frequently occur following treatment. Considering the particular activity of P in nonsquamous NSCLC, we retrospectively analyzed two large randomized trials to determine the investigators' reported pattern of symptomatic relapse in the brain. Methods: Two large, phase III studies of P in advanced NSCLC were included in this retrospective analysis. One study (N = 1725) tested cisplatin plus P versus cisplatin plus gemcitabine in chemotherapy-naive patients with advanced NSCLC (Scagliotti JCO 2008) and the other (N = 571) tested P versus docetaxel in previously treated patients (Hanna JCO 2004). Patients (pts) with known BM at study entry were excluded. Each study was analyzed separately to determine the rate of BM reported as the only site of progressive disease (PD) by treatment group and histology. Logistic regression was used to obtain an odds ratio (OR) for the treatment effect on BM while controlling for potential confounding factors. Results: Overall, 71.5% of pts in P-containing arms (819 of 1145) and 68.2% of pts in non-P-containing arms (785 of 1151) experienced PD. BM relapse rates by treatment arm, study, and histologic subgroup are summarized below (Table). Conclusions: Nonsquamous advanced NSCLC pts treated with P either in first-line or second-line in phase III studies may have reduced risk of developing BM as the first site of PD. This retrospective analysis is limited due to the lack of prospectively performed, periodic brain CT scans; therefore this analysis reflects symptomatic BM only. Nonetheless, these findings may imply a possible positive effect on the control of BM with P in the nonsquamous population. BM relapse rates P-containing arms Non-P-containing arms Fisher's exact P value Overall (both studies) 3.2% (26 of 819) 6.6% (52 of 785) 0.002 Scagliotti study only 3.6% (22 of 621) 6.5% (39 of 604) 0.025 Hanna study only 2.0% (4 of 198) 7.2% (13 of 181) 0.023 All nonsquamous pts (both studies) 3.0% (18 of 602) 7.3% (42 of 577) <0.001 All squamous pts (both studies) 3.7% (8 of 217) 4.8% (10 of 208) 0.635 OR for treatment effect of P (95% confidence intervals) 0.494 (0.32, 0.75) Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly Lilly
The Efficacy of Bortezomib-CHOP In Patients with Advanced Stage T or NK/T Cell Lymphomas: The Results of Multicenter Phase II Study.
Authors: Seok Jin Kim, Hyeon-Seok Eom, Jin Seok Kim, Hye Jin Kang, Hyo Jung Kim, Sung-Kyu Park, Jooryung Huh, Young Hyeh Ko, Cheolwon Suh, Won Seog Kim
Journal: Blood (2010)
Impact of single agent daily prednisone on survival and toxicities in post-docetaxel men with metastatic castration-resistant prostate cancer (mCRPC): An analysis of 2 phase III trials.
Authors: Guru Sonpavde, Gregory Russell Pond, Arnoud J. Templeton, Eugene D. Kwon, Johann S. De Bono
Journal: Journal of Clinical Oncology (2016)

213 Background: Daily oral prednisone (P) has been employed for the therapy of mCRPC, alone or in combination regimens. Despite palliative benefits and PSA responses, the overall clinical impact of P is unknown and it may foster resistance mechanisms. We performed a pooled analysis of control arms of randomized trials which either did or did not administer single agent P to evaluate its impact on overall survival (OS) and toxicities. Methods: Individual patient data from control arms ofrandomized trials of post-docetaxel men receiving placebo or P + placebo were eligible for analysis. Patient demographics, survival, and toxicity data were collected. The impact of P on OS and toxicities was investigated in Cox regression models adjusted for known clinical and laboratory prognostic factors. Statistical significance was defined as a p-value &lt; 0.05 and all tests were two-sided. Results: The control arms of 2 randomized phase III trials were available totaling 794 men: the COU-AA-301 trial (n = 394) administered P plus placebo and the CA184-043 trial (n = 400) administered placebo alone. P plus placebo was not significantly associated with OS compared to placebo alone in a multivariable analysis (HR = 0.89 [95% CI 0.72-1.10], p = 0.27). Other factors associated with poor OS were Eastern Cooperative Oncology group (ECOG)-performance status (PS) ≥ 1, Gleason Score ≥ 8, liver metastasis, high PSA, hypoalbuminemia, and elevated LDH.In contrast, CTCAE grade ≥ 3 therapy-related toxicities were significantly increased with P plus placebo compared to placebo alone (HR = 1.48 (1.03-2.13), p = 0.034) in a multivariable analysis. Other baseline factors significantly associated with a higher risk of grade ≥ 3 toxicities were ECOG-PS ≥ 1, hypoalbuminemia and elevated LDH. Conclusions: P plus placebo compared with placebo alone for post-docetaxel men with mCRPC was not associated with extension of OS, but was associated with higher grade ≥ 3 toxicities. With the exception of the use of P in combination with abiraterone, P alone or in combination regimens should be questioned given its unclear palliative benefits and association with increased toxicities.
Exceptional responses in patients with upper gastrointestinal malignancies enrolled in first-in-man studies: 2002-2012.
Authors: Zachary L Reese, Danielle Tometich, Shiven B. Patel, Sunil Sharma, Ignacio Garrido-Laguna
Journal: Journal of Clinical Oncology (2015)

311 Background: First-in-man (FIM) studies test the efficacy and safety of novel therapeutic agents with proven in vitro activity when used for the first time in humans. Patients with advanced upper gastrointestinal malignancies (UGIM) have limited systemic treatment options. We established a database of FIM studies published from 2002-2012 to identify exceptional responders in patients with UGIM. Methods: Using a Scopus search, we compiled a database of published FIM studies enrolling patients with UGIM between 2002 and 2012. We identified exceptional responders to therapy among these patients as a complete response or a partial response lasting at least 6 months. Results: We identified 84 FIM studies enrolling at least one patient with UGIM. In total 554 patients with UGIM were enrolled including 290 pancreatic adenocarcinomas (52.3%), 110 gastric adenocarcinomas (19.9%), 83 esophageal carcinomas (15.0%), 41 hepatocellular carcinomas (7.4%), and 30 cholangiocarcinomas/gallbladder carcinomas (5.4%). One patient with pancreatic cancer treated with bosutinib, a src kinase inhibitor, had a complete response with a progression-free survival (PFS) of 42 months. Four partial responses were reported including one pancreatic cancer patient treated with CHR-3996, a histone deacetylase inhibitor (PFS 12 mo); two pancreatic cancer patients treated with trametinib, a MEK inhibitor (10 and 11.75 mo); and one cholangiocarcinoma patient treated with SB-743921, a kinesin inhibitor (11 mo). Two additional partial responses were noted without available PFS data including one pancreatic cancer patient treated with KOS-1584, a second generation epothilone, and one gastric cancer patient treated with apatinib, a VEGFR-2 inhibitor. Conclusions: Exceptional responses are seen in patients with UGIM enrolled in FIM studies. Actionable genetic aberrations may be driving disease in these patients. Further studies are needed to understand these responses at the molecular level. These molecular studies could open new treatment opportunities for patients with advanced UGIM.
Comparing surgical tissue versus biopsy tissue in the development of a clear cell renal cell carcinoma xenograft model.
Authors: Yiyu Dong, Brandon Manley, A. Ari Hakimi, Jonathan A. Coleman, Paul Russo, James Hsieh
Journal: Journal of Clinical Oncology (2016)

519 Background: The use of xenograft tumor models is considered the ideal platform to investigate the effects and toxicities of novel drugs in primary human tumors. The establishment of a personalized xenograft model using preoperative or pretherapy biopsy for patients with metastatic or high risk disease could improve selection of targeted therapy. We report on our xenograft model using various tissue sources including biopsies and correlation with patient’s clinical features. Methods: 56 specimens from primary and metastatic ccRCC from 48 patients were collected. After surgery (n=35) or biopsy (n=21) the specimen was transplanted either subcutaneously or after cell culture to immunodeficient mice. Tumor engraftment was followed for up to 4 months. Successfully engrafted patient-derived tumors were passaged to further mice. Conformation of xenograft tumors with formalin-fixed, paraffin-embedded and Hematoxylin and eosin stained tumor sections was done to assure morphological concordance with the patients tumor. We used a two-tailed two proportion z-test to compare the number of successful xenografts harvested from surgical tissue or biopsy tissue. Results: Overall 25 of the 56 specimens were successful in growing tumor in our immunodeficient mice. The frequency of success based on the type and site of tissue harvest may be seen in Table 1. We found biopsy tissue to be significantly more successful compared to surgical tissue, 61.9% compared to 34.2% (p-value=0.044). Conclusions: We believe our xenograft model, using biopsy tissue, demonstrates the feasibility of a real time personalized in vivo model to aid in the selection of targeted treatments for systemic therapy in ccRCC patients. [Table: see text]