tbuckley/cabot-search huggingface dataset:
A phase I open-label study to evaluate safety, tolerability and pharmacokinetic (PK) profile of VB4–845, an anti-EpCAM immunotoxin, in subjects with SCCHN
Authors: J. Quenneville, D. Fitsialos, M. Rasamoelisolo, M. Cross, N. Glover, G. MacDonald
Journal: Journal of Clinical Oncology (2005)

5539 Background: Head and neck cancer is the sixth most common cancer accounting for ∼5% of newly diagnosed malignancies in North America. VB4–845 is a fusion protein engineered from the fusion of a truncated form of Pseudomonas Exotoxin A to a humanized scFv specific for the epithelial cell adhesion molecule, Ep-CAM. Ep-CAM is highly expressed on carcinoma cells of epithelial origin, with limited normal cell expression. VB4–845 targets and kills Ep-CAM-positive tumors. A phase I trial was completed to determine the the maximum tolerated dose (MTD) and the pk profile of intratumoural injected drug in patients with advanced SCCHN. Methods: Dose escalation was completed using modified Fibonacci increments with a minimum 3 subjects per dose level. VB4–845 was administered over 5 consecutive days by intratumoral injection at escalating dose levels of 20, 40, 80, 130, 200, and 280 μg. After a 23 day rest, a 2nd cycle of drug was given at each dose level. In subjects with more than one lesion, the most accessible lesion ≤ 5 cm in any greatest dimension was injected (indicator/target lesion). All toxicities were assessed according to the NCI CTC v3. Blood samples were collected at different times in the study to determine pk and to assess immunogenicity of VB4–845. Results: VB4–845 safety profile was positive as no DLTs were observed. Only mild treatment-related side-effects, such as injection site pain were noted. Pk analysis of VB4–845 injected intratumoral showed the drug to have a clearance rate of 3–4hrs. Most patients developed an anti-VB4–845 with most of the response being directed against the toxin. Independently-verified clinical responses were observed in 43% of the patients with Ep-CAM-positive tumors; 2 significant regressions and 4 minor regressions. Four other patients with Ep-CAM-potive tumors had stable disease for an overall tumour growth control rate (objective responses plus stable disease) of 71%. Conclusions: VB4–845 was safe at all dose levels tested suggesting that higher dose levels can be explored. Moreover, clinical endpoints indicate that even under phase I testing conditions, VB4–845 treatment is efficacious against Ep-CAM-positive SCCHN tumors. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Viventia Biotech Viventia Biotech
A phase I/II study of cetuximab (cet) in combination with S-1 and oxaliplatin (SOX) in first-line treatment for metastatic colorectal cancer (mCRC) (JACCRO CC-06).
Authors: Akihito Tsuji, Yu Sunakawa, Tadamichi Denda, Yasutaka Takinishi, Masahito Kotaka, Hiroaki Tanioka, Ken Shimada, Mitsugu Kochi, Takanori Watanabe, Masato Nakamura, Hiroto Ueda, Michio Inukai, Toshiki Masuishi, Satoshi Tani, Yuji Negoro, Tatsuya Okuno, Masahiro Takeuchi, Wataru Ichikawa, Masashi Fujii, Toshifusa Nakajima
Journal: Journal of Clinical Oncology (2014)

571 Background: Both SOX and cet are effective treatments each other in patients (pts) with mCRC. COIN trial indicated that the use of cet in combination with capacitabine and oxaliplatin should not be recommended. However, the safety and efficacy of cet plus SOX are not clear. To evaluate the safety and clinical efficacy of the combination, we conducted a multi-center phase I/II study. Methods: In this trial, we assigned pts with KRAS wild type (wt), EGFR-expressing tumor and no prior chemotherapy to receive cet (initial dose 400, and 250 mg/m 2 weekly) followed by SOX (oxaliplatin on day 1 and S-1 40 mg/m 2 twice daily on days 1-14). The treatment was repeated every 3 weeks. The phase I part was designed to determine the maximum tolerated dose (MTD) and recommended dose (RD) according to the dose adaptation schedule of oxaliplatin (100 mg/m 2 for level 1 and 130 mg/m 2 for level 2). In the following phase II part, the enrolled pts were treated with the RD. The primary endpoint was response rate (RR) evaluated by the external review board according to RECIST criteria v1.1. Secondary endpoints included PFS, OS, and safety. In addition, we prospectively evaluated early tumor shrinkage (ETS). Results: A total of 67 pts were enrolled from January 2012 to February 2013. In the phase I part, level 2 was determined to be the RD. The MTD was not determined because dose limiting toxicity was not confirmed in level 2. In the phase II part, 59 pts including 6 pts of phase I cohort were assessable for the efficacy. The median age was 64 years, 51% of pts were male, and ECOG PS 0 was observed in 85% of pts. The median course of treatment was 5 (range 1-14). The RR was 62.7% (95%CI, 50.4 to 75.1) and ETS was observed in 72% of pts. In safety analysis, grade 3 or worse adverse events were platelet count decreased (13.1%), neutropenia (8.2%), anorexia (11.7%), rash acneform (6.7%) and peripheral neuropathy (3.3%). Conclusions: We determined the RD of cet plus SOX treatment in pts with mCRC. This combination is tolerable at full doses of cet and SOX, with manageable toxicities, and demonstrates advantages in RR for pts with KRAS wt tumor. Updated safety and efficacy data will be presented. Clinical trial information: UMIN000007022.
Impact of Serum Ferritin Levels on the Incidence of Chronic Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Soichiro Sakamoto, Hiroshi Kawabata, Junya Kanda, Tatsuki Uchiyama, Chisaki Mizumoto, Tadakazu Kondo, Tatsuo Ichinohe, Takayuki Ishikawa, Akifumi Takaori-Kondo
Journal: Blood (2010)
Prognostic analysis of esophageal squamous cell cancer patients who received neoadjuvant chemoradiotherapy combined with surgery.
Authors: Xue Li, Daxuan Hao, Yuanyuan Yang, Yougai Zhang, Xiaoyuan Wu, Yongshun Chen, Chunyu He, Wen Wang, Jinsong Liu, Jianhua Wang
Journal: Journal of Clinical Oncology (2016)

97 Background: The neoadjuvant chemoradiotherapy (nCRT) combined with surgery is hopeful to improve the prognosis of locally advanced esophageal cancer but it remains contentious. Several studies showed that nCRT could significantly improve 5-year OS rate of locally advanced esophageal cancer. However, other clinical trials did not come to the same conclusion. This study retrospectively analyzed the esophageal squamous cell cancer (ESCC) patients who received nCRT combined with surgery in our hospital to investigate the prognostic factors for the patients’ survival. Methods: 96 patients with ESCC who received nCRT combined with surgery in our hospital from January 2007 to December 2014 were retrospectively analyzed. They were diagnosed with preoperation stage T3-4N0-1M0. Among them, 34 cases were in stage IIc and 62 cases were in stage IIIc. Prognostic factors for these patients were analyzed. Results: 26 (27.1%) patients received pathologic complete response (pCR) and 80 (83.3%) patients had downstage. The 1-, 3-, 5-year OS rates of all patients were 91.5%, 63.5%, 55.1%. The 1-, 3-, 5-year OS rates of tumor regression grading(TRG) 1, 2, 3 were 88.9%, 54.1%, 36.5% vs 88.4%, 56.4%, 48.6% vs 95.5%, 90.4%, 90.4%(Р = 0.014). The 1-, 3-, 5-year OS rates of pCR and non-pCR were 95.5%, 90.4%, 90.4% vs 88.6%, 55.6%, 45.4%(Р = 0.004). The 1-, 3-, 5-year OS rates of pathological lymph node negative(ypN-) and positive(ypN+) were 97.3%, 71.1%, 59.8% vs 66.7%, 33.3%, 33.3%(Р = 0.002). The 1-, 3-, 5-year OS rates of downstage and no-downstage were 94.9%, 73.9%, 65.6% vs 75.0%, 18.8%, 12.5% (Р = 0.000). Multivariate analyses identified pathologic lymph nodal status (RR = 2.193, 95%CI:1.018-4.726, Р = 0.045) and downstage category (RR = 3.520, 95%CI:1.638-7.568, Р = 0.001) were significant independent prognostic parameters. Conclusions: The nCRT combined with surgery achieved a high rate of long-term survival without increasing postoperative complications in patients with locally advanced ESCC. TRG was closely associated with patient’s prognosis, especially for patients with pCR. Pathologic lymph nodal status and downstage category were independent influencing factors for long-term survival.
Use of oncology drugs in Japan compared to France, Germany, Italy, Spain, Sweden, the United Kingdom, and the United States: A comparison based on data from 1999 to 2009.
Authors: N. E. Wilking, D. Högberg, B. Jönsson, N. Koinuma
Journal: Journal of Clinical Oncology (2011)

e16585 Background: Drugs constitute a key element in the treatment of solid tumors and in haematology. We have analysed the access and uptake of oncology drugs in 8 countries over a 10 year period (1999-2009) based on sales data provided by IMS Health. Methods: In this analysis we study cancer drugs (ATC code L1+ L2A+B+ L4X) sub divided into a “mature” set of cancer drugs available in 1999 or before (approved for use in any of the study countries) and a set of “new” cancer drugs available in 2000 or later. We have also analysed their use in relation to burden of disease (mg use/ mortality case). Detailed data will be presented. Results: We see very different patterns of spending in countries studied. The table below illustrates the situation in 2009, but the pattern of spending is similar during the whole study period. The highest spending per capita is found in France. In Japan the spending on especially “mature” drugs is high. Spending on “new” cancer drug is strikingly low in the UK. These differences in spending may also be related to differences in cancer burden (cancer incidence here given as age standardized incidence; ASR), as well the cancer panorama (differences in case load of lung cancer, gastric cancer etc.). Conclusions: There are major variations in the spending on cancer drugs between countries in the study. Japan has a high spending on cancer drugs in relation to burden of disease, and this spending is especially high on “mature” drugs. The differences seen may reflect several factors, such as differences in approval times, reimbursement decisions, use of generic drugs, budget allocation, exchange rate fluctuations and differences in interpretations of scientific data. Country Per capita spending (USD) “mature drugs” (% of total) Per capita spending (USD) “new drugs” (% of total) Cancer incidence ASR France 41 (59) 29 (41) 430 Germany 28 (61) 18 (39) 377 Italy 26 (63) 15 (37) 427 Japan 45 (78) 13 (22) 287 Spain 32 (58) 23 (42) 321 Sweden 25 (68) 12 (32) 357 United Kingdom 20 (77) 6 (23) 382 United States 39 (61) 25 (39) 447
Alternating lanreotide and octreotide in the treatment of metastatic neuroendocrine tumors (NETs)
Authors: H. Koussis, A. Scola, F. Cirillo, U. Basso, S. Ziampiri, D. Casara, M. R. Pelizzo, F. Rebustello, R. Behboo, A. Jirillo
Journal: Journal of Clinical Oncology (2008)

17013 Background: Octreotide and Lanreotide are two somatostatin analogues frequently employed in the treatment of well differentiated Neuroendocrine Tumors (NETs). These two agents differ in terms of potency and selectivity for Somatostatin Receptors subtypes (SSTR 1, 2, 3, 4, 5) which are not expressed uniformly on NETs, and therefore may be expected to be partially non cross-resistant. Methods: To evaluate activity and tolerability of an alternating regimen of lanreotide (120 mg day 1) and octreotide (30 mg on day 60), every 90 days, in patients with well differentiated, metastatic NETs. All patients had a positive Indium-Labeled Pentetreotide Scintigraphy (OctreoScan) at baseline and underwent every six months clinical and radiological assessments plus dosage of plasmatic CEA, calcitonin, Cromogranine A, gastrine and urinary 5-OH-indolacetic acid. Results: From 2005 to 2007, 12 pts (7 males, median age 69 years, range 49–80 years) were treated: 7 had recurrent Medullary Thyroid carcinoma (1 MEN 2A syndrome), 4 neuroendocrine gastrointestinal tumor, 1 pheocromocytoma. A total of 76 cycles were administered (range, 4 - 21). Nine patients are evaluable so far: 5 had radiological stabilization of disease (55.6%) and 4 progression. Three patients experienced >50% reduction of tumor markers, 2 patients had stable levels while 3 patients had >50% increase and one did not produce markers, for an overall biochemical response rate of 37.5%. Side effects were mild and consisted in nausea (33% of patients), abdominal discomfort (33% of patients), diarrhoea (66% of patients), and hyper-glicemia in one patient. Toxicity of the two agents appeared to be comparable, with the only exception of Grade 1 diarrhoea which was more frequent after Lanreotide injection. Conclusions: At present time this is the first experience of this association on this type of tumors. Tolerability of combination regimen was acceptable. This study is on ongoing. No significant financial relationships to disclose.
Observation of CNS events in real-world use of enzalutamide (ENZ) and bicalutamide (BIC).
Authors: Ajay Behl, Lorie Ellis, Dominic Pilon, Patrick Lefebvre, Nancy Ann Dawson
Journal: Journal of Clinical Oncology (2016)

235 Background: TERRAIN, a randomized, double-blind, multi-center, phase II trial compared efficacy and safety of ENZ to BIC in men with mCRPC. Although ENZ and BIC fall within the same drug classification, rates of seizure and other central nervous system (CNS) events, observed in non-clinical trial populations have not been explored. The objective of this study was to compare rates of real world CNS events in patients treated with ENZ or BIC. Methods: Retrospective claims from Truven Health MarketScan database were used to identify patients with a PC diagnosis; ≥1 claim for ENZ or BIC (index date) after 9/1/2012; &gt; 6 months of continuous eligibility prior to index date (baseline period) and no use of ENZ or BIC prior to index. Patients were followed until 12/2014 or loss to follow-up. Patients were excluded if they had a CNS condition or another cancer diagnosis during the baseline period. CNS conditions were defined as a diagnosis for amnesia or memory impairment, anxiety, ataxia, cognitive disorders, confusion, convulsions, disturbance in attention, dizziness, falls, fatigue/asthenia, hallucinations, headaches, insomnia, pain, paresthesia, seizures, weakness, or other CNS disorders. Kaplan-Meier (KM) survival curves were used to compare the KM rates of developing any CNS conditions between patients who initiated ENZ relative to patients who initiated BIC. A subgroup analysis of patients with metastatic disease was performed. Results: The table below compares the development of CNS conditions between ENZ and BIC patients. Conclusions: This study shows that rates of CNS events are significantly higher in patients initiating ENZ as compared to BIC, even when controlling for metastatic status. [Table: see text]
Evaluation of state comprehensive cancer control plans for content related to stomach cancer.
Authors: James Randolph Hillard
Journal: Journal of Clinical Oncology (2016)

8 Background: Since 1998, each US state, as well as some US territories and tribal groups, has had a written Comprehensive Cancer Control Program (CCCP). These plans are charged by the National CCCP with emphasizing “primary prevention of cancer”, supporting “early detection and treatment activities”, and promoting “health equity as it relates to cancer control.” Since stomach cancer still causes over 10,000 deaths a year in the US, since it is in many cases preventable, since its prognosis is highly related to timeliness of diagnosis, and since minority populations are disproportionately affected, it would appear to be an appropriate target for state CCCPs. In 2014, the World Health Organization recommended increased prevention efforts, in an extensive monograph titled “Helicobacter pylori as a Strategy for Preventing Gastric Cancer.” Methods: We reviewed the cancer control plans available on the CDC website, http://www.cdc.gov/cancer/ncccp/ccc_plans.htm as of July 1, 2015. These included those of all 50 states, the District of Columbia, 7 US territories, and 7 Native American/Alaskan Native Tribes. These plans were searched for the words “stomach,” “gastric,” “helicobacter,” and “pylori.” Results: 38 of 65 (58%) of CCCs mentioned the words “stomach” or “gastric” in their text, but only 5 (0.8%) had goals or strategies related to stomach cancer. Of plans which did mention stomach cancer, 19 (32%) mentioned it in the contest of smoking, 16 (25%) in terms of health disparities, and 15 (23%) in terms of diet. Only 5 states (10%), and 5 (36%) territories or tribes mentioned the terms “helicobacter” or “pylori”. Some of the identified risk factors were idiosyncratic (e.g. relating HPV infection to stomach cancer) or inaccurate (e.g. “there is no evidence that” eradication of H. pylori changes the course of disease after cancer has developed, or “fecal occult blood test should not be used for cancer screening,” since 99% of positives are caused by gastritis due to H. pylori). Conclusions: Stomach cancer currently receives little attention in State CCCPs. H. pylori infection as a target for prevention efforts receives far less attention still. Important opportunities for control of this cancer are being neglected.
Blood cell-derived nanovesicles as biomarkers of homeostasis in gastrointestinal cancer.
Authors: Rado Jansa, Roman Stukelj, Vid Sustar, Apolonija Bedina Zavec, Borut Stabuc, Veronika Kralj Iglic
Journal: Journal of Clinical Oncology (2013)

152 Background: Nanovesicles (NVs) are membrane-enclosed fragments of cell interior which are pinched off from membranes of cells of all types (including cancer) in the last stage of the budding process. They are involved in cell-cell communication and can promote tumor growth and invasion. Interactions of tumor-derived NVs with blood cells, especially platelets are hypothetically reflected in vesiculability of platelets by means of concentration of NVs in blood isolates. Also we hypothesized that in patients whose plasma mediates stronger attractive interaction between membranes the concentration of NVs in blood isolates would be lower. Methods: NVs were isolated from 2.7 ml samples of blood of 29 patients with gastrointestinal cancer, 44 patients with other gastrointestinal diseases, additional 13 patients who were treated by imatinib due to gastrointestinal stromal tumor (GIST) and 50 healthy volunteers, by repeated centrifugation and washing, and counted by flow cytometry. We followed patients with GIST for 32 months. Ability of blood plasma to mediate attractive interaction between membranes was assessed by the angle of contact between giant phospholipid vesicles prepared by electroformation, which adhered due to addition of plasma to the suspension of NVs. Results: The concentration of NVs was considerably (44%, p = 0.0005) higher in the blood isolates of patients with gastrointestinal cancer than in the population of healthy volunteers and considerably (34%, p = 0.025) higher in patients with gastrointestinal cancer than in patients with other gastrointestinal diseases. We observed a considerable (average 13 fold peak) but transient (about one month within 32 montth follow up interval) increase of concentration of NVs in blood isolates due to treatment with imatinib.We found a negative correlation between the concentration of NVs and the average contact angle between adhered giant phospholipid vesicles (r = –0.50, p = 0.031). Conclusions: Concentration of NVs is increased while the ability of plasma to mediate attractive interaction between membranes is decreased in patients with gastrointestinal cancer. Treatment with imatinib caused transient increase of concentration of NVs in isolates from blood.
Characterization of a novel regulator of AKT/mTOR signaling in gastric cancer.
Authors: Shikha Satendra Singh
Journal: Journal of Clinical Oncology (2016)

68 Background: Gastric cancer (GC) is a leading cause of cancer-related death with poor prognosis and “one-size fits all approach”. Dysregulation of PI3K/Akt/mTOR pathway is a common event in GC with PIK3CAmutations reported to correlate with poor prognosis. With prognosis far from satisfactory, we aimed to identify novel surrogate biomarkers. We hypothesize the role of DP103, a DEAD-box RNA helicase, as a novel surrogate biomarker for GC by regulating the PI3K/Akt/mTOR pathway. Additionally, we shed light on high DP103 GC cells responding to Akt/mTOR dual inhibitor treatment, indicating its potential role as a surrogate biomarker for GC treatment. Methods: Tissue microarray data from GC cohorts were used in correlation analysis between DP103 and PIK3CA expression. Effect of DP103 knockdown was assessed on functions downstream of PI3K/Akt/mTOR pathway including apoptosis, autophagy and cell invasion. Next, DP103 depletion studies were done and PI3K/Akt/mTOR pathway proteins were assessed. Further, immunoprecipitation studies assessed for DP103 interacting partners from PI3K/Akt/mTOR pathway in GC. Results: Herein, we provide clinical evidence of DP103 upregulation in GC patients’ tissues compared to normal gastric tissues. Additionally, we showed a positive correlation between DP103 and PIK3CA expression in GC patients’. DP103 knockdown resulted in decrease in cell invasion and an increase in apoptosis and autophagy. Further, decrease in phosphorylation of PI3K/Akt/mTOR pathway proteins was observed with DP103 depletion. Mechanistically, we discovered a novel physical interaction between DP103 and PI3K in GC. Conclusions: Here we summarized, current understanding of DP103 regulating PI3K/Akt/mTOR pathway in GC and discuss potential use as a new surrogate biomarker for better clinical application.
Asparaginase-Associated Pancreatitis in Childhood Acute Lymphoblastic Leukemia: A Ponte Di Legno Toxicity Working Group Report on Clinical Presentation and Outcome
Authors: Wolthers Benjamin Ole, Thomas Leth Frandsen, Andre Baruchel, Andishe Attarbaschi, Shlomit Barzilai, Antonella Colombini, Escherich Gabriele, Hiroto Inaba, Gábor Kovács, Der-Cherng Liang, Marion Mateos, Veerle Mondelaers, Anja Moricke, Tomasz Ociepa, Elizabeth Raetz, Sujith Samarasinghe, Lewis B. Silverman, Inge M. van der Sluis, Martin Stanulla, Lynda M. Vrooman, Michihiro Yano, Ester Zapotocka, Kjeld Schmiegelow
Journal: Blood (2016)