tbuckley/cabot-search huggingface dataset:
Multicenter phase II study of neoadjuvant chemotherapy consisted with S-1 and oxaliplatin followed by gastrectomy for locally advanced gastric cancer.
Authors: Yoshihiro Okita, Hironaga Satake, Hiroyuki Okuyama, Masato Kondo, Akira Miki, Takanori Watanabe, Yukimasa Hatachi, Masahito Kotaka, Shigeyoshi Iwamoto, Takeshi Kato, Akihito Tsuji
Journal: Journal of Clinical Oncology (2016)

TPS180 Background: Prognosis for locally advanced gastric cancer, such as clinical T4 disease, bulky nodal involvement, type 4 and large type 3 gastric cancer, was not satisfactory even by D2 gastrectomy followed by adjuvant chemotherapy. Neoadjuvant chemotherapy is another promising approach. In our phase I study, neoadjuvant chemotherapy of S-1 and oxaliplatin (SOX) had manageable toxicities and good pathological complete response rate (33%) in patients with locally advanced gastric cancer. Based on the results of this phase I study, we initiate a multi-institutional, single-arm, open label, phase II study (Neo G-SOX PII study). The aim of this study is to evaluate the efﬁcacy and safety of the neoadjuvant chemotherapy of S-1 and oxaliplatin (SOX) followed by gastrectomy with D2/3 lymph node dissection; clinical T4; clinically resectable gastric cancer of type 4 or large type 3 (over 8 cm); bulky nodal involvement around major branched arteries to the stomach Methods: Eligibility criteria include histologically proven adenocarcinoma of the stomach; clinical T4; clinically resectable gastric cancer of type 4 or large type 3 (over 8 cm); bulky nodal involvement around major branched arteries to the stomach; resectable peritoneal dissemination (pathological CY1 or P1, except for clinical CY1 or P1). Patients receive two cycles of neoadjuvant chemotherapy with S-1 (80 mg/m2, p.o., days 1-14 followed by 1 week rest) and oxaliplatin (130 mg/m2 at day 1), followed by D2 or higher surgery with no residual disease. Patients with pathological R0/1 resection received S-1 (80 mg/m2, p.o., days 1-28 followed by 2 week rest) for 1 year as adjuvant chemotherapy. Primary endpoint is curative resection rate. Key secondary endpoints include pathological response, R0/1 resection rate, dose-intensity, overall survival, relapse free survival and safety. We set the threshold curative resection rate at 65% and the expected curative resection rate at 80%. Given a one-sided α of 0.1 and statistical power of 80%, 40 patients was required. Clinical trial information: UMIN000018661 Clinical trial information: UMIN000018661.
The impact of dose reduction and time delay in irinotecan- and oxaliplatin-based chemotherapies on outcomes in metastatic colorectal cancer.
Authors: Naoki Mashita, Goro Nakayama, Naomi Hayashi, Chie Tanaka, Daisuke Kobayashi, Mitsuro Kanda, Suguru Yamada, Tsutomu Fujii, Hiroyuki Sugimoto, Masahiko Koike, Shuji Nomoto, Michitaka Fujiwara, Yuichi Ando, Yasuhiro Kodera
Journal: Journal of Clinical Oncology (2014)

631 Background: This study was designed to evaluate the influence of dose reduction and schedule modification on outcomes in patients with metastatic colorectal cancer (mCRC). Methods: Pooled datasets from two previous phase II trials of FOLFIRI (CCOG-0502; n = 36) and mFOLFOX6 (CCOG-0704; n = 30) in patients with mCRC were analyzed retrospectively. The RDIs of irinotecan and oxaliplatin were compared to response rate (RR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). To assess the effects of dose reduction and time delay, we defined ‘dose index (DI)’ as the ratio of the actual delivered total dose to the planned total dose and ‘time index (TI)’ as the ratio of the planned duration to the actual duration of therapy. Relative dose intensity (RDI) was computed by multiplying DI by TI. DI and TI of irinotecan and oxaliplatin were compared to response rate (RR), disease control rate (DCR) and progression-free survival (PFS). Results: In patients receiving FOLFIRI therapy, the median DI and TI of irinotecan were 0.92 and 0.90, respectively. RRs were 59% vs. 12% in the higher vs. lower DI groups (p &lt; 0.01), and 35% vs. 35% in the higher vs. lower TI groups (p = 1.00), respectively. Median PFS was 10.2 vs. 5.0 months in the higher vs. lower DI groups (p &lt; 0.01), and 6.1 vs. 6.7 months in the higher vs. lower TI groups (p = 0.48), respectively. In mFOLFOX6 therapy, the median DI and TI of oxaliplatin were 0.97 and 0.82, respectively. RRs were 44% vs. 36% in the higher vs. lower DI groups (p = 0.65), and 44% vs. 36% in the higher vs. lower TI groups (p = 0.65), respectively. Median PFS was 7.7 vs. 6.7 months in the higher vs. lower DI groups (p = 0.13), and 8.5 vs. 5.9 months in the higher vs. lower TI groups (p = 0.02), respectively. Multivariate analyses showed that DI of irinotecan (HR 8.48; 95% CI, 2.94-24.51, p &lt; 0.01) and TI of oxaliplatin (HR 2.74; 95% CI, 1.02-7.33, p = 0.04) were the independent prognostic factors for PFS. Conclusions: Dose reductions in irinotecan and time delays in oxaliplatin could have significant impact on PFS in patients receiving FOLFIRI and FOLFOX6, respectively.
Model of quality care indicators for patients with colorectal, lung, and breast cancer.
Authors: Eduardo Diaz-Rubio
Journal: Journal of Clinical Oncology (2014)

241 Background: The care of an oncology patient is a complex process with important clinical, social and financial repercussions. The purpose of this work is to develop quality care indicators for the medical care of patients with cancer. It is fundamental that health organisations adopt such models based on quality standards with the intention to promote excellence in the care of cancer patients. Methods: Research for scientific evidence, revision and selection of standards using the Delphi method was employed and definition of indicators was established. Results: 50 quality indicators were created directed to: Organisation: Multidisciplinary committees; informed consent; patient security; elapsed time between diagnosis and treatment; tumour registry; treatment protocols. Colorectal cancer: Histopathology report and markers; chemotherapy for advanced/metastatic cancer; evaluation of staging of colorectal cancer; liver metastases; adjuvant chemotherapy; evaluation of history family; biological therapy and RAS gene mutation; radiotherapy; quality of surgical notes. Breast cancer: Histopathology report and markers; initial staging; hormonotherapy; other treatments; elapsed time between histological diagnosis and treatment and between surgery and adjuvant treatment; pre-operative assessment and conservative surgery focused on the armpit; access availability to initial radiological studies.Lung cancer: Histopathology report and markers; initial staging; elapsed time between histological diagnosis and treatment; concomitant chemoradiotherapy; evaluation of chemotherapy response; adjuvant chemotherapy; elapsed time till the completion of staging; surgery; chemotherapy with good functional status; adjuvant radiotherapy; concomitant chemoradiotherapy for small cell lung cancer. End of life: Organisation of palliative care; outpatient attention; identify patients; access to care; pain management; information availability; psycosociological support; constipation management; counselling of family after death. Conclusions: The indicators constitute a reference model based on standards in order to measure care quality and to compare achieved results among health institutions.
Biological indicators of response and resistance to PARP inhibition in BRCA wild-type breast cancer.
Authors: Saima Noor Hassan, Amanda Esch, Laura Heiser, Joe W. Gray
Journal: Journal of Clinical Oncology (2015)

125 Background: Although PARP inhibitors are currently being tested in clinical trials in breast cancer patients, it is not well understood which subgroup of patients will best respond to such therapy or how to combine anti-PARP therapy to improve therapeutic response. Methods: We assessed the response of a panel of 8 HER2-negative breast cancer cell lines against three PARP inhibitors: veliparib, olaparib, and BMN 673. Efficacy of carboplatin as a single agent and in combination with PARP inhibitors was determined. Therapeutic response and cellular phenotype were elucidated using live-cell imaging, high-content imaging and immunofluorescence. We computed IC50 as the measure of sensitivity to each PARP inhibitor across the panel of cell lines. Cellular phenotype was ascertained by quantifying endpoints for apoptosis and DNA damage. Results: BMN 673 demonstrated the highest potency, with IC50 values in the nanomolar range, while the IC50 values of olaparib and veliparib were in the micromolar range. Drug sensitivity was independent of BRCA mutational status. Biomarkers of apoptosis and DNA damage varied with the PARP inhibitor and across different cell lines. The resistant cell lines could be classified into two groups that varied in DNA damage response and cell death due to DNA damage. A combined DNA damage – cell death (DDD) Response Score was developed and correlated strongly with IC50 values in BRCA wild-type breast cancer cell lines. The DDD Response Score identified cell lines that were highly sensitive to single-agent PARP inhibitors or carboplatin. A Response Score that identified intermediate sensitivity may predict which cell lines may benefit from the combination of anti-PARP therapy and carboplatin. Conclusions: Overall, a spectrum of response to three different PARP inhibitors was identified in a panel of eight breast cancer lines. Cellular phenotype can help classify resistant cancer cell lines. We have developed an experimental approach that may help to inform which breast cancer subtypes may benefit from PARP inhibitors and carboplatin, both as single agents, and in combination.
Volumetric Aerobiological Survey of Conidial Fungi in the North‐East Netherlands
Authors: F. Beaumont, H. F. Kauffman, T. H. van der Mark, H. J. Sluiter, K. de Vries
Journal: Allergy (1985)

In order to obtain actual data about the qualitative and quantitative occurrence of airborne fungi in The Netherlands, a viable‐volumetric sample survey with the Andersen sampler was undertaken. From April 1981 to the end of June 1983, one day a week samples were taken on the unobstructed rooftop of a hospital in the N‐E Netherlands. An average of 268 Colony Forming Units (CFU), per sample, per cubic metre of air were found. Almost three‐quarters of the total catch consisted of seven genera, Cladosporium predominating. Botrytis showed in surprisingly high numbers when compared with other surveys, while Alternaria occurred in very low concentrations. Most atmospheric airborne spora were found between May and September. Aspergillus and Penicillium prevailed in the autumn and winter months, although were present the year‐round. Momentary weather conditions seemed less important for the overall spore picture than the average meteorological characteristics for a whole season. The obtained aero‐mycological information may be useful in determining clinical strategies for skin testing and serological investigations in patients with suspected mould allergies.
Clinical outcome of patients with metastatic renal cell carcinoma who interrupted VEGFR-TKI after achieving stable disease or better response.
Authors: Dong Hoe Koo, Inkeun Park, Jae-Lyun Lee, Jin-Hee Ahn, Dae Ho Lee, Dalsan You, In Gab Jeong, Cheryn Song, Bum-Sik Hong, Jun Hyuck Hong, Hanjong Ahn
Journal: Journal of Clinical Oncology (2015)

459 Background: The purpose of the this study is to evaluate the clinical outcome of VEGFR-TKIs interruption in patients with metastatic renal cell carcinoma (mRCC) after achieving stable disease (SD) or better response. Methods: A retrospective analysis of medical records and imaging studies was performed on all patients with mRCC treated with VEGFR-TKIs between January 2008 and July 2014 (n=505). Patients who achieved SD or better response under VEGFR-TKI and later discontinued VEGFR-TKIs for any reason with the exception of disease progression were included in the analysis. Outcomes analyzed were progression free survival (PFS) after VEGFR-TKIs discontinuation, patterns of disease progression, time to subsequent therapy (TST), response to VEGFR-TKI resumption, and time to treatment failure (TTF) after TKI resumption. Results: We identified 32 patients (sunitinib=20, sorafenib=7, and pazopanib=5). The responses to VEGFR-TKIs were CR (n=4), PR (n=11), SD (n=15), and controlled but non-measurable (n=2). Median time to interruption from the initiation of VEGFR-TKI therapy was 16.6 months (95% CI, 12.8-20.3). The main causes of VEGFR-TKI interruption was toxicity (n=19, 59.4%), will to have treatment holiday (n=7, 21.8%), patient’s refusal (n=3, 9.4%), and others (n=3, 9.4%). At the time of analysis, 16 patients had disease progression and 1 patient was dead. With a median follow-up duration of 56.6 months (range, 12.6-167.4), median PFS from VEGFR-TKI interruption was 23.8 months (95% CI, 12.5-35.0), and the median TST was 26.2 months (95% CI, 15.9-36.6). The progression was observed in pre-existing lesions in 7 patients (43.7%) or new lesions developed in 9 (56.3%). Among 11 patients who received VEGFR-TKI resumption, 2 patients (18.2%) achieved a PR and the stable disease was observed in 9 (81.8%) with a median TTF of VEGFR-TKI resumption of 6.2 months (95% CI, 4.0-8.4). Conclusions: In patients with mRCC controlled with VEGFR-TKIs, VEGFR-TKI could be interrupted at least temporarily when clinically warranted.
Clinical and preclinical evaluation of taxane sensitivity in gastric cancer (GC): Relevance of GC histology.
Authors: Giuseppe Galletti, Kyle Cleveland, Alex Matov, James E. Hayes, Robert J. Klein, Duane C. Hassane, Leonardo V. Nicacio, Paraskevi Giannakakou, Manish A. Shah
Journal: Journal of Clinical Oncology (2013)

37 Background: Docetaxel (D) is a standard treatment for advanced gastric cancer based on the TAX-325 study (van Cutsem, JCO 2006). We asked the question, do all subtypes of GC benefit equally from D therapy? Methods: We performed a post-hoc analysis of the TAX-325 study. We classified randomized patients as diffuse or non-diffuse histology and correlated histology with clinical outcomes using a Cox proportional hazards model. Preclinical studies involved 13 GC cell lines (4 intestinal subtype, 7 diffuse subtype, 2 unknown), assessed for D sensitivity using the Sulforhodamine B (SRB) cytotoxicity assay, microtubule bundling, mitotic arrest by immunofluorescence as evidence of drug-target engagement, and apoptosis assessment by Caspase 8, Caspase 3, and PARP cleavage by Western Blot. Results: In post hoc analysis of TAX-325, patients were classified as diffuse (n=206) or non-diffuse (n=239). Non-diffuse GC showed a significant improvement in overall survival with the addition of D (12.1 v 8.8 mo, p=0.002), whereas diffuse histology was not associated with an improvement in survival (8.3 v 8.5 mo, p=0.66). Preclinical studies similarly reveal that 5/7 diffuse GC cell lines were resistant to D by SRB assay compared with 1/4 intestinal GC cell lines (IC50 &gt; 600 nM). To examine drug target engagement, a dynamic measure of D activity, 4/6 diffuse GC cell lines showed lack of D engagement on the microtubule network at physiologic D concentrations (0-100 nM). 5/6 diffuse cell lines demonstrated no apoptosis. Additionally, we found that 0/9 GC cell lines expressed P-glycoprotein, ruling out multidrug resistance as an etiology for diffuse GC resistance to D. Conclusions: In exploratory analysis, we observed diffuse GC to be resistant to the addition of D to standard chemotherapy in a random assignment phase III clinical trial. In vitro analyses support these clinical findings and demonstrate intrinsic D resistance in diffuse GC, unrelated to multidrug resistance. Ongoing mechanistic studies focus on the molecular basis of taxane sensitivity in GC to predict treatment efficacy. These findings will inform future clinical studies aimed at individualized therapy.
Renal function in bladder cancer patients after trimodality therapy: Long-term results of a large institutional experience.
Authors: Hannah J. Roberts, Michael Drumm, Andrzej Niemierko, Saveli Goldberg, Rebecca Helen Clayman, Niall M. Heney, Adam S. Feldman, Matthew F Wszolek, M Dror Michaelson, Richard J. Lee, Philip James Saylor, Anthony L. Zietman, William U. Shipley, Jason A. Efstathiou
Journal: Journal of Clinical Oncology (2016)

453 Background: Maintenance of renal function following treatment of bladder cancer presents an ongoing challenge. The decline following radical cystectomy is well documented. However, in patients undergoing trimodality bladder-sparing therapy consisting of transurethral resection (TURBT) and concurrent chemoradiation followed by adjuvant chemotherapy, renal function is poorly understood. Methods: We performed a retrospective review of 178 patients with muscle-invasive bladder cancer who underwent bladder-sparing therapy between 2001 and 2013 and collected nadir creatinine values in the month preceding TURBT and at 1, 3, 5, 7, and 9 years post treatment initiation. Wilcoxon signed-rank test and mixed effects analysis were performed to compare the pre-treatment and post-treatment levels of creatinine and EGFR and to analyze their temporal change. Results: Median follow-up was 48 months (range: 1 to 162 months). The mean pre-treatment creatinine and EGFR were 1.12 mg/dl and 71 mg/dl, respectively. Cr increased to 1.21 mg/dl and EGFR decreased to 65 mg/dl at 1 year following treatment initiation (p = 0.001, p = 0.002). All post-treatment values were also significantly different from pre-treatment values (all p values &lt; 0.002), but there was no significant difference between the post-treatment values over time. Conclusions: Following bladder-sparing therapy for muscle invasive bladder cancer, renal function was generally well preserved in the long term. Although there was a modest yet statistically significant decrease in renal function that occurred during the first year, there was no further decline up to 9 years. While this initial decrease in function is of unknown clinical significance, the lack of further decline after 1 year is different from similar studies following cystectomy.
Docetaxel (D) followed by castration (C) improves anti-tumor effects in human prostate cancer cell-bearing SCID mice
Authors: A. Hussain, Y. Tang, M. A. Khan, O. Goloubeva
Journal: Journal of Clinical Oncology (2005)

4638 Background: Traditionally, chemotherapy is used to treat patients with advanced prostate cancer after they have failed hormone ablation therapy. However, hormone resistance can lead to chemo-resistance. For instance, a significant proportion of patients with hormone refractory prostate cancer (HRPC) over-express bcl-2, which can lead to pleiotropic resistance to a variety of cytotoxic agents. Thus, drugs that show activity in HRPC may also be active (and perhaps more so) in hormone-naïve patients. How best to integrate hormone therapy with chemotherapy for optimal treatment outcome remains an open question. Methods: Approximately 160 SCID mice were inoculated with human LNCaP prostate cancer cells. When tumor volumes reached about 300 mm3, mice were treated with different combinations of docetaxel and surgical castration. Results: Among the ten treatment conditions tested, docetaxel (D) followed by castration (C) provided the most significant anti-tumor effects, as determined by both tumor volumes at 4 weeks post treatment (see Table 1), and by growth-delay analyses (D followed by C versus C followed by D, p=0.0003; D followed by C versus D plus C, p=0.01; D followed by C versus D, p=0.03). Concurrent chemo-hormone therapy had an impact on tumors similar to that of docetaxel treatment alone. Castration followed by docetaxel was less effective than the above treatments, while castration alone was least effective. Conclusions: These prostate cancer xenograft studies suggest that a treatment sequence of docetaxel followed by hormone therapy may have significant anti-tumor activity. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis
Raltitrexed-eloxatin (TOM OX) salvage chemotherapy (CHT) in gemcitabine (GEM) resistant metastatic pancreatic cancer (PC): a phase II trial
Authors: M. Reni, E. Bonetto, L. Pasetto, G. Aprile, S. Cordio, P. Passoni, S. Dell’oro, G. Luppi, C. Milandri, C. Fugazza
Journal: Journal of Clinical Oncology (2005)

4115 Background: Information on the impact on outcome of salvage CHT in PC is limited. Many patients (pts) with progressive disease (PD) requiring further treatment are the target population for prospective trials. TOM and OX have non cross-resistant activity in PC cell lines, diverse toxicity profile and can be used at full doses in combination. Methods: The main endpoint of the study was to assess the response rate of TOMOX in GEM resistant (progression-free survival - PFS < 12 months after GEM containing CHT) metastatic PC. Quality of life (QL) was assessed using the EORTC questionnaires. TOM was given at 3 mg/m2 and OX at 130 mg/m2 every 3 weeks until PD or a maximum of 6 cycles. Tumor was assessed every 2 cycles. The sample size was 40 pts (π0 .10; π1 .25; α .10; β .10). Results: Between Dec 02 and Mar 04, 41 pts (median age 61 yr, 25 with performance status (PS) > 80) were enrolled. Previous PFS was 1–11 months (median 6). Previous therapy included surgery (18) and radiotherapy (14); 26 pts had PD during previous CHT, and 15 had a PFS <5 months since the end of previous therapy. A total of 137 cycles were delivered: 13 (32%) pts received 6 cycles, 28 interrupted CHT due to PD (21), pt or physician’s decision (5), persistent thrombocytopenia (1) and death of heart failure (1). Dose intensity was 92% for both drugs. Grade >2 toxicity consisted of neutropenia in 5 pts (12%), thrombocytopenia in 3 (7%), liver and vomiting in 2 (5%), anemia, diarrhea, and fatigue in 1 (2%). Ten pts (24%) yielded a partial response, 11 a stable disease, 15 PD, 5 discontinued CHT before tumor assessment. Median and 1-yr survival (OS) was 4.8 months and 15%. OS was significantly longer in pts with previous PFS > 6 months (p=0.005; significance level after multiple comparison adjustment 0.01). Previous surgery or CHT regimen, PS, and age did not predict OS. Median and 6-month PFS was 1.8 months and 19%. Clinically significant improvement in QL was observed in 10–50% (median 27%) of pts, depending on domain, and score was stable or increased in 43–95% (median 77%) of pts. Conclusions: TOMOX regimen was feasible, had limited toxicity and relevant activity in GEM resistant metastatic PC and may constitute a treatment opportunity in this setting No significant financial relationships to disclose.