tbuckley/cabot-search huggingface dataset:
Response by Resor and Mauri to Letter Regarding Article, “Impact of Optimal Medical Therapy in the Dual Antiplatelet Therapy Study”
Authors: Charles D. Resor, Laura Mauri
Journal: Circulation (2017)

In Response:We thank Drs Taqueti and Bhatt for their interest in our article 1 and their question regarding proton pump inhibitor (PPI) use in the study.In our subgroup analysis on the impact of optimal medical therapy (OMT) on the treatment effect of continued dual antiplatelet therapy, we observed an unexpected association between use of OMT and lower rates of GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries) moderate or severe bleeding.Dr Taqueti rightly notes that differential rates of PPI use in the on and off OMT groups could potentially mediate this association.Although not included in our original publication, we have now assessed the rates of PPI use in each subgroup and noted no significant differences (on OMT: 21.4% versus off OMT: 21.2%; P=0.981).In addition, PPI use was evenly balanced across OMT subgroups within each randomization arm.After including PPI use in multivariable adjustment, OMT use remained associated with lower rates of bleeding (hazard ratio, 0.70; confidence interval, 0.52-0.93;P=0.013), consistent with the prior impression of unmeasured confounding as the primary driver of this association.We
Palliative care services help caregivers move on with their lives
Authors: A. P. Abernethy, D. C. Currow
Journal: Journal of Clinical Oncology (2004)

8029 Background: Palliative care practitioners consider loved ones close to the patient as part of the “unit of care”. The objective of this study is to use a population-based strategy to evaluate the impact of palliative care services (PCS) on the loved ones of deceased individuals. Methods: Questions on the need for, uptake rate of, and impact of PCS were included in an annual health survey of South Australian residents. The survey used trained interviewers for previously piloted, face-to-face questions. The survey was of 8800 households in late 2001 and 2002, standardized for age and gender; 6052 completed the survey. This population-based method for the evaluation of PCS has previously been described. Results: Thirty eight percent (2321) indicated that someone close to them had died of a terminal illness in the preceding 5 years; 74% had cancer. Overall, 45% (1050) reported use of PCS. Twenty-seven percent (633) of respondents provided some level of care for the deceased person and 10% (232) provided day-to-day hands-on care. When the deceased individual accessed PCS, respondents were more likely to be able to move on with their life (92% vs. 89%, p=0.008). The benefit of PCS was more significant for caregivers (86% vs. 78%, p=0.03) than non-caregivers (96% vs. 93%, p=0.06). This influence of PCS is predominantly in the first two years, such that at 6 months 81% of caregivers with PCS had been able to move on while 63% without PCS had moved on; the lines intersected at 2 years at 90% (p=0.03). Conclusions: Access to palliative care services benefits bereaved loved ones by helping them move on with their lives; caregivers derive the greatest benefit. These represent some of the first robust population-based data on the durable impact of PCS. No significant financial relationships to disclose.
Pharmacokinetic characterization of the novel oral prenyl transferase inhibitor AZD3409: The first analysis in healthy male volunteers
Authors: P. McCormack, M. Macpherson, D. Wilson, A. Lindsay, T. Parry, A. Holt, A. Hughes
Journal: Journal of Clinical Oncology (2004)

3172 Background: AZD3409 is a novel, oral, antitumor agent that acts as a prenyl transferase inhibitor. It has potentially broad antitumor activity both as monotherapy and in combination with other anticancer treatments. AZD3409 is a double pro-drug; its metabolism involves conversion to a thiol-ester intermediate, then, intracellularly, to a thiol-acid active species. In preclinical studies, AZD3409 achieves up to 90% inhibition of FTase in tumors at well tolerated doses. In enzyme studies AZD3409 is also known to inhibit GGTase-1. Here we report preliminary results of a pharmacokinetic assessment of AZD3409 conducted during a single ascending dose study in healthy human volunteers. Methods: Cohorts of a maximum of 8 healthy male volunteers were dosed at each dose level (6 active, 2 placebo) in a randomized, double-blind, alternating panel design. Three cohorts were initially recruited (aged 20 to 58 years), with replacements allowed, up to a dose level of 1000 mg. Single oral doses of 20 to 2500 mg were then administered through 9 dose modifications over three months. Samples for pharmacokinetic assessment of ester and acid were taken for up to 72 hours following dosing. Results: Exposure (both Cmax and AUC) to both thiol-ester and thiol-acid increased with increasing dose. Maximum plasma concentrations were achieved between 1 and 4 hours after dosing for the thiol-ester (median value = 1.5 hours) and between 1 and 5 hours after dosing for the thiol-acid (median value = 2 hours) with a tendency for tmax to occur later at the higher doses. Plasma concentrations declined with half-lives of 15–20 hours for the thiol-ester and 15–30 hours for the thiol-acid. The coefficient of variation for the parameters of exposure was approximately 50% for both moieties. Conclusions: Preliminary single dose data on AZD3409 suggests linear pharmacokinetics over the dose range. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca
Final results of the multicenter randomized phase II PAZOGIST trial evaluating the efficacy of pazopanib (P) plus best supportive care (BSC) <i>vs</i> BSC alone in resistant unresectable metastatic and/or locally advanced gastrointestinal stromal tumors (GIST).
Authors: Jean-Yves Blay, Mathieu Molimard, Claire Cropet, Julien Domont, Maud Toulmonde, Emmanuelle Bompas, Philippe Alexandre Cassier, Isabelle Laure Ray-Coquard, Maria Rios, Antoine Adenis, Antoine Italiano, Axel Le Cesne, Olivier Bouche, Olivier Mir, Florence Duffaud, Francois Bertucci, Nicolas Isambert, Aurelie Belleville, Julien Gautier, David Pérol
Journal: Journal of Clinical Oncology (2015)

10506 Background: GIST is the most common mesenchymal neoplasm of the gastrointestinal tract. Imatinib followed by sunitinib then regorafenib is the usual sequence in advanced setting. P is effective in soft tissue sarcomas; it has never been evaluated in a randomized setting in GIST. Methods: Eligible patients (pts) were randomized (1:1; stratification on number of prior drugs (2 vs ≥3)) to receive P+BSC or BSC. Primary endpoint was Progression-Free Survival (PFS). 80 pts were planned to detect an improvement in the 4-month PFS rate (PFS-4m) from 15% (BSC) to 45% (P+BSC) with 5% two-sided α and 80% power. Secondary objectives included Best Overall Response (BOR), Overall Survival (OS), safety and trough plasma P concentrations (Ct). Results: From Apr 11 to Dec 13, 81 pts (P+BSC: 40, BSC: 41) were randomized. Arms were well balanced; median age: 63y (27-85), 70% males and 54% with ≥ 3 prior drugs. The intent-to-treat analysis based on investigator-assessed progressive disease (PD) showed an improved PFS with PFS-4m of 45.2% (95% CI 29.1-60.0) for P+BSC vs 17.6% (95% CI 7.8-30.8) for BSC (HR: 0.59, 95% CI 0.37-0.96; p = 0.03). 36 pts out of 41 switched to P following investigator-assessed PD (median P duration: 3.5 months (0.1-19), main reasons for discontinuation: PD (52.8%) and toxicity (22.3%)). Centrally-assessed BOR showed stable disease in 84.2% vs 70.7% and PD in 15.8% vs 26.8% of pts in P+BSC and BSC arms. Among all pts treated with P (n = 76), 72.4% experienced grade ≥ 3 related adverse events (AE) (hypertension: 36.8%), including 25% of related serious AE (pulmonary embolism, 9.2%). At the time of analysis, 29 vs 31 pts had died in the P+BSC and BSC arms (OS HR: 0.94, 0.56-1.56). 1 toxic death occurred (hepatic cytolysis). Preliminary results showed a higher median Ct at steady state in pts progression-free at 4 months vs progressive: 25 (2-63) vs 17 (8-35) µg/ml (n = 43; p = 0.08). Conclusions: P combined to BSC improves PFS in advanced GIST resistant to imatinib and sunitinib. In the context of a high switch rate, no difference in OS was found. Further PK analyses are ongoing. Clinical trial information: NCT01323400.
Japanese multicenter phase II study of CHOP followed by radiotherapy (RT) in stage I-II<sub>1</sub> diffuse large B-cell lymphoma (DLBCL) of the stomach
Authors: S. Ishikura, K. Tobinai, A. Ohtsu, S. Nakamura, T. Yoshino, T. Takagi, Y. Tamaki, T. Kinoshita, K. Mera, S. Yamamoto
Journal: Journal of Clinical Oncology (2004)

6527 Background: CHOP followed by RT is regarded as the standard care for localized aggressive lymphoma; however, a prospective confirmation of its applicability to localized gastric lymphoma (GL) is inadequate, and most patients (pts) in Japan have been initially treated with gastrectomy. We conducted a multicenter phase II study to evaluate the feasibility and efficacy of the non-surgical treatment. Methods: Eligibility criteria required intermediate- to high-grade GL, excluding T-cell lymphoma; stage I-II1 (modified Ann-Arbor classification); age 20–75; ECOG performance status 0–1; no prior therapy; adequate organ function; written informed consent. Treatment consisted of 3 cycles of CHOP followed by RT of 40.5 Gy in 27 fractions. Histologic diagnosis was confirmed by central pathology review. The primary endpoint was tolerability of the treatment based on the incidence of serious adverse events (AEs). Results: Fifty-five pts were enrolled during Dec. 1999 and Feb. 2003. Three pts were judged ineligible by the central review and 52 pts were included in this analysis. Patient characteristics were: male/female, 28/24; median age, 61 (range 20–73); stage I/II1, 36/16; DLBCL/others, 52/0; International Prognostic Index low/low-intermediate, 47/5. All pts completed 3 cycles of CHOP and all but one patient, who suffered disease progression, completed planned RT. No serious AEs including massive hemorrhage and perforation of the stomach were observed. Complete response was achieved in 48 of 52 pts (92%, 95% confidence interval: 82–98%), partial response in 1, and progressive disease in 3. Two pts underwent salvage gastrectomy due to disease persistence or recurrence. With a median follow-up period of 25 months, 2-year progression-free and overall survivals were 88% and 94%, respectively. Conclusions: CHOP followed by RT is safe and highly effective in localized gastric DLBCL. This organ-preserving treatment should be considered a reasonable therapeutic option. This study was supported by the Grant-in-Aid for Cancer Research (14–9) from the Ministry of Health, Labour and Welfare, Japan. No significant financial relationships to disclose.
Therapeutic p53 gene agent in the treatment of refractory cancer cases: A phase I study.
Authors: Xia He, Jianhua Xu, Jie Wen
Journal: Journal of Clinical Oncology (2013)

2543 Background: To evaluate the benefit of adding therapeutic p53 gene agent into the standard treatment regimens for refractory cancer cases. Methods: Recombinant adenoviral human p53 gene (rAd-p53), was given intravenously at a dose of 2×10 12 viral particles /day on 5 consecutive days one week before routine anti-cancer treatment start, and was repeated after an interval of 16 days. The inclusion criteria include: 1.Pathologically confirmed recurrent cancers; 2. Disseminated cases; 3. Patients with key organ metastasis; 4.Unresectable lesions; 5.Chemo- or radio-therapy resistant cases. The exclusion criteria include: 1.With severe liver, kidney, heart or hemotologic disorders; 2.Pregnancy; 3.Without informed consent. Efficacy was evaluated according to the results of contrasted MRI or CT. Results: A total of 16 patients entered the study with a median age of 59 years old (range 30-76 years), 13 were male and 3 were female. 5 were recurrent cases(4 HNSCC and 1 esophageal cancer), 5 were widely infiltrated unresectable HNSCC, esophageal carcinoma(2 cases) and undifferentiated thyroid carcinoma(1 case). 3 were disseminated cases(2 NPC and 1 Lung cancer). Two cases were breast cancer with multiple brain metastasis. One was refractory central nervous lymphoma. One patient did not finish the planned chemoradiation due to radiation-induced pneumotitis. Another one patient experienced chemotherapy delay due to A grade 4 hemotologic toxicity. 93.8% patients had shivering and fever after injection of rAd-p53. Other acute toxicities during the treatment included: leukopenia(Grade 3/4) 43.8%, thrombocytopenia (Grade 3/4) 25.0%, oral mucositis(Grade 3/4) 18.8%, vomiting(Grade 2 and above) 31.3%, ALT elevation (Grade 2 and above) 6.3%. No Cr elevation was observed. The acute toxicities were controllable and reversible. At the 3 months after treatment, PR, SD and PD rate were 56.3%, 25.0% and 18.7%, respectively. Conclusions: The therapeutic p53 gene agent can be intravenously safely added to routine anti-cancer regimens with controllable and reversible acute toxicities. A randomized controlled phase II is needed to make clear the role of the therapeutic p53 gene agent.
Phase 1–2a study of TLK286 (a novel glutathione analog) in combination with carboplatin in platinum refractory or resistant (≥ 3<sup>rd</sup> line) ovarian cancer
Authors: J. Kavanagh, L. Lewis, H. Choi, R. Iyer, C. Moore, A. Jameson, J. Keck, R. Parra, K. Patel, G. L. Brown
Journal: Journal of Clinical Oncology (2004)

5060 Background: TLK286 (Telcyta) is a novel glutathione analog prodrug activated by GST P1–1, which is overexpressed in ovarian cancer, releasing two electrophilic fragments that induce apoptosis. In vitro, TLK286 is not cross resistant to carboplatin and has shown synergistic inhibition in OVCAR3 cells. TLK286 has demonstrated significant single agent activity in two Phase 2 trials in ovarian cancer. Methods: Platinum refractory or resistant ovarian cancer patients (pts) were treated at doses of 500, 750 or 960 mg/m2 of TLK286 in combination with carboplatin (AUC 5) every 4 weeks until tumor progression or unacceptable toxicity. The objectives were to determine the MTD of the combination, and objective response rate (ORR) by RECIST. Results: At interim analysis, 8 pts median age 56 (range 49–68), prior chemotherapy regimens median 3.5 (range 2–5) have received 44+ cycles (median 4 cycles, range 3–11+). All pts have failed paclitaxel and platinum (platinum resistant 63%, refractory 25%) and additional therapies: Doxil (63%), gemcitabine (25%), topotecan (38%) and others (75%). Most common adverse events (AEs) related to TLK286/carboplatin are Grade 1–2 fatigue (5 pts), nausea (8), vomiting (3), neutropenia (3), leukopenia (7). Grade 3 fatigue, vomiting and leukopenia were reported in 1 pt, thrombocytopenia in 3 pts and neutropenia in 5 pts. No Grade 4 AEs or dose limiting toxicities were observed. One CR (13%), 4 PRs (50%) and 3 SDs (38%) are shown (ORR=63% and DSR=100%). Conclusions: TLK286 at 50% of the single agent dose (500 mg/m2) in combination with carboplatin (AUC 5) shows enhanced efficacy with ORR of 63% and DSR of 100% in platinum refractory or resistant (≥ 3rd line) ovarian cancer pts. Further pt follow-up and dose escalation continues. The TLK286/carboplatin combination is an active regimen for future studies in ovarian, NSCLC and breast cancer. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Telik, Inc. Telik, Inc. Telik, Inc. Telik, Inc. Telik, Inc.
Chemotherapy for metastatic colorectal cancer: Why not take a break when it works?
Authors: J.-L. Raoul, F. Trivin, J. Egreteau, E. Boucher
Journal: Journal of Clinical Oncology (2004)

3641 Background: Once objective tumor response (OR) or stable disease (SD) has been achieved in patients (Pts) undergoing palliative chemotherapy (CT) for metastatic colorectal cancer (MCRC), we propose a break, allowing the Pts a CT -free period with visit at 6 weeks then a CT every 3 months; in case of PD, CT is given. Patients and methods: This retrospective series included a random selection of our Pts with MCRC who had had at least 1 break in their CT. Results: 62 Pts, age 60.9 +/- 10.8 yrs, received palliative CT for MCRC and had had at least 1 break in their CT. A break was defined as a period when CT could have been but was not given. Periods of palliative care and interruptions due to side effects were not considered breaks. The 1st break took place in a 1st-line (n=61) or 2-line (n=1) protocol in patients who had OR (n=41) or SD (n=20) after a median 4.5 mo (no difference between OR and SD). Median duration of these 1st break was 6 mo. Kaplan-Meier plots showed that 52.5 +/- 6.4%, 30.7 +/- 6% and 20.5 +/- 5.2% of the Pts were still CT -free at 6, 9, and 12 mo. The CT -free period was longer after OR (median > 6 mo) than after SD (4 mo) (p<0.02). After their first break, 57 Pts received a 2nd CT, 35 with the same CT (10 OR, all after initial OR, 14 SD and 8 PD) and 22 with another CT. After this 2nd cycle, 40 Pts took another break (median 5 mo) and 29.5 +/- 7.4% remained CT -free at 6 mo, 13 % at 1 yr. A 3rd cycle was delivered for 32 Pts (median 3 mo) and 13 of them then had another break (median 4 mo); 9 resumed CT (6 mo) and 5 had another break (4 mo). Globally, Pts had CT for a median 8.5 mo (range 3–30) and was CT -free for a median 11 mo (1–75). Median time without CT was 1.3 times median time with CT. On October 10, 2003, 29 Pts had died, 4 were receiving best supportive cares, 14 were CT -free, and 15 were receiving CT. The 1-, 2- and 3-yr survival rates were 95.2 +/- 2.7%, 70.8 +/- 6.5%, and 48 +/- 8% (11 exposed patients). Conclusions: From this retrospective analysis, we conclude that 1) responders can take a break in CT for MCRC, and 2) breaks can be repeated, 3) without compromising survival. The impact of this approach on quality-of-life, healthcare expenditures, and even overall survival is certainly worth evaluation in a large-scale prospective study. No significant financial relationships to disclose.
A proprietary multi-analyte test to predict neoadjuvant treatment response for esophageal and rectal adenocarcinoma patients.
Authors: Sunil S. Badve, Weiwei Shan, Clare Johnson, Yaeli Biermann-Harrar, Kristen M. Oelschlager, Derek Maetzold, Kenneth Kessler, Romil Saxena, Daniel Rosen, Robert W. Cook
Journal: Journal of Clinical Oncology (2014)

4085 Background: Standard of care for locoregional esophageal (EC) and rectal (RC) adenocarcinoma is chemotherapy/radiotherapy (CTRT) followed by surgery. 25-30% of EC and RC patients exhibit extreme resistance to pre-operative CTRT (exCTRT) and receive no therapeutic benefit. A similar number have a pathologic complete response (pathCR) and may benefit from avoiding surgery. We previously reported an IHC-based multi-center study that accurately identified EC patients as exCTRT or non-exCTRT (CTRT responders). The present multi-center study applies the assay for prediction of EC patient pathCR, and extends the test to predict RC patient exCTRT and pathCR. Methods: Formalin-fixed, paraffin-embedded (FFPE) tissue sections from diagnostic biopsies were processed by IHC to detect three predictive biomarkers: NF-kB, SHh, and Gli1. Sections were reviewed by a pathologist to determine a labeling index (LI) score for each biomarker correlating with the number of positively stained EC or RC cells within a tissue section. LI scores from each case were compared to a training set of 167 adenocarcinoma tumor samples using logistic regression analysis to predict pathCR in a cohort of 65 EC cases, or pathCR and exCTRT in a cohort of 10 RC cases (5 pathCR and 5 exCTRT). Predicted outcomes were compared to Tumor Regression Grade (TRG), determined by blinded, independent pathology. Results: Prediction of EC pathCR achieved an uncorrected area under the curve (AUC) of 0.83 with a specificity of 87%. Initial application of the pathCR assay to RC cases resulted in 100% specificity (5/5 non-pathCR cases called non-pathCR) and 60% sensitivity (3/5 pathCR cases called pathCR). Conversely, application of the exCTRT assay to RC cases resulted in 100% specificity (5/5 non-exCTRT cases called non-exCTRT) and 60% sensitivity (3/5 exCTRT cases called exCTRT). Conclusions: The current study demonstrates the potential of this assay to predict pathCR in EC and pathCR and exCTRT in RC. Predicting response to CTRT in both EC and RC will enable design of treatment regimens specific to a patient’s response, thereby improving the risk to benefit ratio for both CTRT and surgery.
Early intraperitoneal chemotherapy following cytoreductive surgery in the patients with far advanced gastric cancer
Authors: J. H. Cheong, W. J. Hyung, J. Kim, J. Chen, S. H. Choi, S. H. Noh
Journal: Journal of Clinical Oncology (2004)

4265 Background: The survival of patients with stage IV gastric cancer even without distant metastasis is poor due to frequent peritoneal failure. The aim of this study was to investigate the impact of early postoperative intraperitoneal chemotherapy (IPT) after cytoreductive surgery on the survival of patients with far advanced gastric cancer. Methods: Between 1993 and 2000, a total of 154 patients with stage IV gastric cancer were enrolled to the study. All patients underwent potentially curative or palliative resection. At the end of operation the residual disease states were recorded according to AJCC/TNM system; R0 indicates curative resection, R1 indicates microscopic residual tumor at resection margin or diameter of each residual tumor less than 3mm, and R2 represents macroscopic residual tumor larger than 3 mm. All patients received 15mg of intraperitoneal mitomycin C before closure of the abdominal wound. 500mg/m2 of 5-Fluorouracil and 40 mg/m2 of cisplatin were administered intraperitoneally on postoperative days 1–4, and this was repeated at 4-week intervals. A total of 12 cycles were scheduled for all patients. Results: Of 154 patients, R0 resection was achieved in 37, R1 in 56, and R2 in 61. All patients received a mean of 4.3 IPT perfusions (range 1–12). There were 35 (22.7%) postoperative complications and 4 (2.6%) mortality. The most frequent hematologic toxicity (grade 3–4) was leukopenia. The major nonhematologic toxicities (grade 3–4) were emesis and nephrotoxicity. After a mean follow-up period of 18.4 months, 23 patients remain alive without evidence of recurrence, whereas 131 patients died due to recurrence or progression of disease. The median survival period for all 154 patients was 12.2 months. When survival according to the residual tumor was analyzed, median survival was 25.6 months in the R0 group, 16.6 months in the R1 group and 7.2 months in the R2 group (p < 0.0001). Conclusions: IPT after cytoreductive surgery was found to be effective method to improve the prognosis of far advanced gastric cancer. The results also suggest that complete cytoreductive surgery is mandatory for achieving the beneficial effect of IPT. No significant financial relationships to disclose.