tbuckley/cabot-search huggingface dataset:
Phase I/II study of docetaxel (DOC) and S-1 for patients (pts) with advanced gastric cancer (AGC)
Authors: I. Hyodo, K. Yamaguchi, W. Koizumi, H. Narahara, T. Kato, T. Akiya, Y. Sakata
Journal: Journal of Clinical Oncology (2005)

4064 Background: New combination chemotherapy with DOC and oral DPD-inhibitory fluoropyrimidine, S-1 for pts with AGC was investigated in the multicenter phase I/II study as; 1) agents are active for AGC, 2) different modes of action, and 3) down-regulation of thymidylate synthase by DOC. Methods: Eligibility criteria included; pathologically confirmed AGC, measurable lesions, PS 0–1, ≤1 prior chemotherapy, ≥20 years old, adequate organ functions and written IC. DOC was administered (60–120 min., i.v.) on day 1 and the dose was escalated by 10 mg/m2 from the starting dose of 50mg/m2 in phase I part. S-1 was fixed at the conventional daily dose of 80 mg/m2 on days 1–14. The treatment was repeated every 4 weeks. The recommended dose (RD) of combined DOC+S-1 was studied in every 3–6 pts cohort and determined according to the pre-defined DLTs. 45 pts were planned to enroll at the RD level in phase II part. Results: 50 eligible pts were enrolled in this study from 9/02 to 6/04. In phase I part, all 3 pts enrolled in the starting dose level showed intolerable toxicities (grade 3 neutropenia with infection in one pt and grade 4 neutropenia on day 8 during S-1 administration in 2 pts). Then the dose of DOC was de-escalated to 40 mg/m2 and this dose level was determined as RD for phase II part. 46 out of 47 pts enrolled were evaluable for safety and 44 pts for efficacy, respectively. Pt characteristics were as follows; median age 65 (range 42–79), M/F 31/15, PS0/1 26/20, histological type differentiated/undifferentiated 29/17 and chemonaïve/pre-treated 25/21 pts. 9 pre-treated pts (45%) and 12 chemonaïve pts (50%) showed response (RECIST). Overall response rate was 48% (95%CI: 33–63%). Pts received a median of 3 courses (range 1–6). Common grade 3+ toxicities were neutropenia (70%), leucopenia (39%), anemia (22%), and anorexia (20%). These toxicities were tolerable and manageable. No treatment-related death was observed. Preliminary survival analyses showed an estimated median survival of 377 days (95%CI: 266–488 days). Matured survival data will be presented at the meeting. Conclusions: This new regimen with DOC and S-1 showed promising activity and manageable toxicity, thereby leading to a further phase III study with this regimen in pts with AGC. No significant financial relationships to disclose.
Phase I/II study of gemcitabine plus S-1 with concurrent radiotherapy in patients of unresectable locally advanced pancreatic cancer.
Authors: Tatsuya Ioka, Kazuhiro Katayama, Nobuko Ishida, Hironari Sueyoshi, Ryoji Takada, Takuo Yamai, Nobuyasu Fukutake, Reiko Ashida, Hirofumi Akita, Hidenori Takahashi, Yoshifumi Kawaguchi, Koji Konishi, Teruki Teshima
Journal: Journal of Clinical Oncology (2014)

261 Background: We conducted chemoradiotherapy of gemcitabine plus S-1, key drugs for pancreatic cancer. Methods: Patients were eligible for the study if they had received a histopathological diagnosis of locally advanced pancreatic cancer and were diagnosed as unresectable by multiple clinicians including surgeons due to main arterial invasions and more. Radiation (RT) was perfomed for twenty-eight days continuously except Saturday, Sunday and National holiday in 1.8Gy once daily (total 50.4Gy). PTV was defined as GTV plus 10-15mm. Prophylactic irradiation to regional lymph nodes was not performed. Administration level of the anti-cancer drugs was referred to the following table. Results: A total of fifteen cases were enrolled to the phase I study from February, 2006 through May, 2007. RT was achieved in 13 of 15 cases (87%). Two cases of DLT occurred in level 2 (two cases of emesis) while three did in level 3 (one case of emesis and two of neutropenia of grade 4). We decided level 3 as MTD and level 2 as recommended dose. The overall response rate (more than PR) was 33.3% (5 in 15 cases) and tumor-control (more than SD) was achieved in 13 of 15 cases (87%). The one-year and two-year survival rate was 86.7% and 44.4%, respectively. Conclusions: We conducted the phase 1 study of chemoradiotherapy with two key drugs of pancreatic cancer and achieved the recommended dose in this phase I study. Ongoing study We have already finished the enrollment of 110 cases for a phase II randomized allocated study, comparing the chemoradiotherapy of administration dose decided in this phase 1 study with the combination therapy of gemcitabine plus S-1. Now we are carefully following the patients to compare two-year survival rate as a primary endpoint in phase II study. Clinical trial information: NCT01430052.
Exploratory analysis to investigate clinical factors that may influence trastsuzumab efficacy in patients with HER2-positive gastric cancer.
Authors: Takeru Wakatsuki, Keisho Chin, Satoshi Matsusaka, Mariko Ogura, Masato Ozaka, Mitsukuni Suenaga, Eiji Shinozaki, Izuma Nakayama, Nobuyuki Mizunuma
Journal: Journal of Clinical Oncology (2014)

169 Background: ToGA study showed significant survival benefit of trastuzumab in patients with HER2 positive gastric cancer (GC); however, clinical factors which can impact its efficacy prior to treatment are still unknown. Hence, we conducted this exploratory analysis whether clinical factors could influence trastuzumab efficacy in patients with HER2 positive GC. Methods: Thirty-three HER2 positive GC patients, who were treated by trastuzumab with chemotherapy in our institute from 2011 March to 2012 December, were enrolled. Clinical factors according to ToGA study and tumor markers were examined. We retrospectively analyzed whether these clinical factors were associated with progression-free survival (PFS) and overall survival (OS). These endpoints were estimated using by Kaplan-Meier methods and compared by the log-rank test. The Cox regression analysis including only clinical factors of which p-value was less than 0.02 was done. Results: Median follow-up period was 10.8 months. Median age was 63 y.o. and 64% of the patients were male. PS 0-1, GEJ cancer, visceral metastasis (lung or liver), previous gastorectomy, previous chemotherapy, number of metastatic site (1-2), and number of metastatic lesion (1-4) were found in 97%, 27%, 58%, 36%, 21%, 76%, and 27% of the patients, respectively. Sixty-seven% and 94% of the patients were differentiated type and HER2 3+ by IHC, respectively. Baseline median CEA and CA19-9 levels were 5.2 ng/ml and 109.4 U/ml, respectively. Median PFS was 9.5 months (95% CI: 5.5-13.5) and median OS was not reached. Overall response rate by RECIST was 71.4%. Lower CA19-9 levels were associated with longer PFS in univariate analysis. Patients who had lower CA 19-9 levels showed a median PFS of 12.2 months vs. 6.9 months for patients who had higher CA19-9 levels (HR: 0.41 [95%CI: 0.17-1.00], p=0.042), however this result was not conserved in multivariate analysis. No clinical factors were associated with OS. Conclusions: Lower CA19-9 levels were associated with favorable PFS in the patients with HER2 positive GC upon when treated by trastuzunab. External clinical validations and further molecular analyses are needed to validate this result.
Comprehensive geriatric assessment (CGA) in men age 70 or over with localized prostate cancer.
Authors: Georgina E.C. Osborne, Duncan Charles Gilbert, Angus Robinson, Ashok Nikapota, Fiona McKinna, Michelle Villanueva, Alistair E. Ring
Journal: Journal of Clinical Oncology (2014)

184 Background: There has been a four-fold increase in incidence of prostate cancer (PC) in men age 70 or older in England in the last 30 years. Which treatment (surgery, radiotherapy, or surveillance) is right for which patient depends on a number of factors including the risk of death from competing causes and fitness for the proposed treatment. Objective assessments such as those included in a Comprehensive Geriatric Assessment (CGA) might be helpful in this regard. The primary objective of this study is to describe CGA scores of a cohort of older men with PC. The secondary objectives are to examine if a single score (the Vulnerable Elders Survey [VES-13]), is a suitable screening test for a full CGA and to assess whether scores predict radiotherapy toxicity. Methods: Patients age 70 and older with localised PC completed a CGA prior to commencement of radical radiotherapy. The CGA assessed WHO performance status (PS), activities of daily living (ADL), instrumental activities of daily living (IADL), Charlson co-morbidity index, number of medications, mini-nutritional assessment (MNA), social network index (SNI), G8 score, and VES-13. Participants had acute radiotherapy toxicity assessed 12 weeks post-treatment completion. Results: As of September 2013, 100 patients had been recruited. Median age was 74.5 (range 70 to 82). Ninety five percent of patients had a PS less than two. Using the VES-13 tool, 5.2% scored greater than two. 22.6% scored less than 14 on G8 scoring. Additionally, 13.5% were not fully independent on ADLs, 4.2% were not fully independent on IADLs, 32.3% scored greater than one on the Charlson Index, 12.3% had a history of depression or dementia, and 52.9% were on more than three prescription medications. Fourteen percent were at risk of malnutrition and 2.3% were malnourished according to MNA scores, 25.0% had SNI scores less than three and 9.3% of patients had fallen at least once in the preceding three months. Twelve week follow-up data regarding acute radiotherapy toxicity is currently being collected; these will be correlated with the CGA components and presented at the 2014 ASCO Genitourinary Cancers Symposium. Conclusions: These data demonstrate that many older men with localised prostate cancer are vulnerable according to a CGA. Correlations observed between radiotherapy toxicity and CGA scores would have important implications for therapeutic decisions.
Prospective, multicenter, observational analysis of 5-HT<sub>3</sub>-receptor antagonist antiemetic prescribing with different chemotherapy regimens
Authors: V. Scurti, D. Sichetti, M. Romero
Journal: Journal of Clinical Oncology (2005)

8253 Background: The 5-HT3-receptor antagonists (5-HT3-RAs) remain the mainstay of antiemetic treatment during cancer treatments, and are recommended by guidelines as prophylaxis for highly and moderately emetogenic chemotherapy (HEC/MEC) in combination with corticosteroids (Koeller et al Support Care Cancer 2002;10:519–22). This ongoing prospective, multicenter analysis conducted by the Italian Society of Hospital Pharmacy (SIFO) aims to determine the 5-HT3-RA prescribing habits in cancer patients in Italy. Methods: Recruitment includes cancer patients receiving HEC/MEC. It is assumed that at least 500 patients will receive a 5-HT3-RA, 200 of whom will receive cyclophosphamide-, carboplatin- or anthracycline-based chemotherapy. Data are being collected via a physician- and patient-completed clinical report form. At day 3, patients are interviewed by telephone regarding symptoms of emesis and compliance with prescribed antiemetic therapies. Results: To date, 534 patients have been enrolled in 23 centers in Italy; 501 (93.8%) received treatment for acute emesis and 437 (87.2%) received at least one 5-HT3-RA. Of these 437: 167 received a chemotherapy regimen containing cyclophosphamide, carboplatin or anthracyclines; 93% received prophylactic 5-HT3-RA treatment; 54% received 5-HT3-RA polytherapy (94% corticosteroid) and 46% monotherapy, respectively (Table). Ondansetron (O) was the most frequently prescribed 5-HT3-RA (51%), followed by tropisetron (T; 28.1%) and granisetron (G; 21.3%). O was most often prescribed at 8mg (96%), T at 5mg (73.2%) and G at 3mg (68.8%). Conclusions: Not all patients are receiving 5-HT3-RAs in accordance with the guidelines. Efficacy data will be analyzed according to chemotherapy and 5-HT3-RA agent. No significant financial relationships to disclose.
Novel live tumor cell diagnostic test utilizing biophysical and molecular biomarkers to assess local, advanced, and metastatic prostate cancer.
Authors: Kevin B. Knopf, Michael S. Manak, Wendell R. Su, Thiagarajan Meyyappan, Andrew Min, Robert J. Saphirstein, Brad J. Hogan, Matt J. Whitfield, Jonathan S. Varsanik, Mani Foroohar, Naveen Kella, Ray Hernandez, Kimberly M. Rieger-Christ, Travis B. Sullivan, Hani H. Rashid, Vladimir Mouraviev, David Albala, Ashok C. Chander, Grannum R. Sant
Journal: Journal of Clinical Oncology (2015)

211 Background: Over-treatment of prostate cancer affects 144,000 patients annually in the U.S. due to the inaccuracy of current diagnostics for risk stratification. Functional molecular and biophysical biomarkers combined with clinically actionable diagnostic platforms are used for evaluating the local invasiveness and metastatic potential of cells derived from biopsy. Such a diagnostic test may improve patient outcomes in low-to high-risk prostate cancers according to D’Amico’s definition. This study describes the development of a novel phenotypic diagnostic using a set of biomarkers measured with a proprietary live cell assay coupled with innovative machine vision algorithms for patient tumor samples using a unique microfluidic platform. Methods: We assessed 60 prostate cancer samples collected post radical prostatectomy (RP). We report the assay details for culturing live tumor cells ex vivo, enabling automated imaging of phenotypic biomarkers. The test is designed to sustain survival of prostate tumor cells from fresh biopsy/surgical samples for up to three days prior to analysis of phenotypic characteristics. Results: We show that this test distinguishes live normal and tumor cells via molecular and biophysical biomarkers. The primary biomarkers are calculated using objective machine vision algorithms and are used to derive secondary metrics termed “Metastatic Potential (MP) and Oncogenic Potential (OP)”. In comparing clinical measures with results of this test, concordance analysis show that OP and MP are statistically significant in distinguishing between Gleason 6 and Gleason 7 with 85% sensitivity and 80% specificity. Conclusions: This phenotypic diagnostic generates scoring metrics of MP and OP that correlate with 1) aggressive vs. indolent Gleason 6, 2) seminal vesicle invasion, 3) occurrence of margins after RP, 4) lymph node invasion and 5) systemic metastatic process. These results will further help stratify patient tumors to improve clinical decision-making in low to intermediate- and high-risk prostate cancer populations, and potentially avoid unnecessary surgery or radiation, ultimately leading to improved patient quality of life.
Duration of response to androgen-deprivation therapy (ADT) and efficacy of secondary hormone therapy, docetaxel (D), and cabazitaxel (C) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Antoine Angelergues, Denis Maillet, Aude Flechon, Mustafa Ozguroglu, Florence Mercier, Aline Guillot, Sylvestre Le Moulec, Gwenaelle Gravis, Philippe Beuzeboc, Christophe Massard, Thibault De La Motte Rouge, Nicolas Delanoy, Reza-Thierry Elaidi, Stephane Oudard
Journal: Journal of Clinical Oncology (2014)

282 Background: Early CRPC (&lt;12 months, m) with 1st hormonal therapy (HT) was found to predict poor efficacy of 2nd HT, but did not seem to impair the benefit of D-based chemotherapy. We evaluated the impact of this variable in our cohort of patients (pts) treated also with second-line chemotherapy C. Methods: Records of 132 consecutive mCRPC pts were retrospectively collected in 9 centers. PSA response ≥ 30% and time to biochemical progression (TTBP) with 1st- and 2nd-HT, D and C were evaluated according to time to progression to CRPC (&lt;12 m and ≥12 m). PSA-response, TTBP and Overall Survival (OS) were compared using exact, Wilcoxon and log-rank tests, respectively. Results: All patients received first HT, D and C, and 94 of them received second HT. Time to CRPC &lt;12 m was associated with a reduced OS and poor PSA-response and TTBP with second HT. Taxanes showed a similar PSA response whatever the time to CRPC but TTBP was slightly shorter in men with time to CRPC &lt;12m. Conclusions: This retrospective analysis of 132 pts with mCRPC suggests that rapid progression to CRPC (&lt;12 m) is associated with a poor prognosis and a low response to second-HT. PSA response to taxanes does not seem to be affected by time to CRPC, but TTBP is shorter in men with early CRPC. Prospective randomized trials are needed to confirm these results. [Table: see text]
Multiple immunological mechanisms of cancer cachexia in patients with solid tumors.
Authors: Kenji Gonda, Masahiko Shibata, Izumi Nakamura, Shinji Ohki, Koji Kono, Tatsuo Shimura, Seiichi Takenoshita
Journal: Journal of Clinical Oncology (2016)

667 Background: Cancer cachexia is a mixed and multiple factorial condition and commonly seen in patients with advanced cancer, and has long been reported that host-immune function is critically participated. Chronic inflammation plays a key role in the progress of malignant diseases and has been reported to relate with immune suppression and nutritional impairment seen in patients with advanced diseases. Methods: Peripheral blood mononuclear cells (PBMC) were collected from 18 normal healthy volunteers and 112 patients with gastrointestinal cancer. These cells were used for the detection of MDSC (myeloid-derived suppressor cells: CD11b + CD14 - CD33 + ) by flow cytometry. PBMC was also used for the PHA-blastogenesis of lymphocytes which is a marker of cell mediated immunity (stimulation indices: SI) and for the production assay of cytokines including IFN-G, IL-6 and IL-10. Serum levels of soluble cytokine receptors including sIL-2R and sTNF-R1, and anti-inflammatory molecules such as IL-10 and IL-1 receptor antagonist (IL-1RA) were also measured. For the evaluation of nutritional status, serum concentrations of rapid turnover protein (RTP) including prealbumin, transferrin and retinol binding protein was measured. NLR (neutrophil/lymphocyte ratio) was calculated and used as a marker of chronic inflammation. Results: The circulating levels of MDSC was significantly increased in esophageal, gastric and colorectal carcinomas than in normal volunteer and significantly inversely correlated with serum concentration of RTP and with SI, and correlated with markers for inflammation. The levels of sIL-2R and sTNF-R1 were increased in patients with gastric and colorectal and inversely correlated with the levels of RTP and SI. In patients with cachexia, serum concentrations of IL-10 were increased and the production of IFN-G was decreased. Conclusions: It is suggested that suppression of cell-mediated immune function exists in patients with cancer cachexia and the immunological mechanisms of nutritional damages in these patients are even partially driven by Th2-dominant condition of CD4(+) cells and MDSC. These complicated mechanisms are also involved in inflammation-related immunological condition such as SIRS and CARS.
Genetically Defined Racial Differences Underlie Risk of Relapse in Childhood Acute Lymphoblastic Leukemia
Authors: Jun J. Yang, Wenjian Yang, Cheng Cheng, Meenakshi Devidas, Xueyuan Cao, Dario Campana, Michael J. Borowitz, Cheryl L. Willman, William Paul Bowman, Gregory Reaman, William L. Carroll, Stephen P. Hunger, William E. Evans, Ching-Hon Pui, Mary V. Relling
Journal: Blood (2008)
Valproate as a novel radiosensitizer in selective internal radiation therapy (SIRT) for unresectable hepatocellular carcinoma.
Authors: Kenneth Chin, Sunil Kumar Udumala, Ravi Kumar Kannadorai, Sidney Wing Kwong Yu, Pierce K. H. Chow
Journal: Journal of Clinical Oncology (2016)

314 Background: A large majority of Hepatocellular Carcinomas (HCC) present in locally advanced or metastatic stages; patients are usually poor candidates for surgical resection. Yttrium-90 Selective Internal Radiation Therapy (SIRT) is employed in both palliative and bridging therapy for unresectable HCCs. Histone Deacetylase Inhibitors (HDACi) are an emerging class of chemotherapeutics which exert their cytotoxicity through epigenetic modification. By maintaining DNA in an open conformation, it increases the surface area exposed for radiation damage- a postulated mechanism of its radiosensitizing effect. It is envisioned that HDACi will greatly augment therapeutic efficacy in brachytherapy. Here, the radiosensitizing effects of valproate, a known HDACi is investigated as potential adjunct with SIRT. Methods: 3 HCC cell lines were studied: HepG2, Hep3B and JNN4. They were first treated at various concentrations of valproate and cell viability was assessed. Next, a Caspase-3/7 assay was carried out to assess cell apoptosis. Westernblot analysis was performed on treated cells to elucidate histone acetylation status with Anti-Acetyl H3/H4 Antibodies. Finally, a clonogenic survival assay compared the effect of Yttrium-90, Lutetium-177, valproate and combination treatment on clonogenic proliferation. Results: Cell viability studies showed that valproate is cytotoxic to all HCC cell lines at concentrations from 10mM. Westernblot analysis demonstrated that valproate treatment maintained histone acetylation across all HCC cell lines validating it’s mechanism of action. Clonogenic Survival demonstrated a significant reduction of cell survival for all HCC cell lines treated with valproate and Isotope as compared to monotherapy. Conclusions: The use of HDACi such as valproate is not only novel in SIRT but showed great promise as an adjunct therapy. Experiments not only demonstrated its cytotoxicity, but also, reduction in clonogenic and proliferative ability of cancer cells. It can be postulated that the co-administration of valproate with SIRT will enhance therapeutic efficacy, allowing more aggressive and efficacious treatment of HCC.