tbuckley/cabot-search huggingface dataset:
Post-marketing surveillance of erlotinib for NSCLC in Japan: Interim analyses of 3,488 patients (Pts).
Authors: Y. Ohe, M. Fukuoka, S. Kudoh, K. Nakagawa, T. Johkoh, M. Ando, N. Yamazaki, S. Takemoto, A. Seki
Journal: Journal of Clinical Oncology (2011)

e18007 Background: Erlotinib was approved in Japan in 2007 for recurrent/advanced NSCLC after failure of at least one prior chemotherapy regimen. Previous Phase I/II studies highlighted interstitial lung disease (ILD) as an adverse drug reaction (ADR) of particular concern in Japanese pts. To investigate the safety and efficacy of erlotinib, including ILD incidence and risk factors in Japanese pts, large scale surveillance has been implemented. Methods: From Dec 2007 to Oct 2009, all pts with recurrent/advanced NSCLC treated with erlotinib, were enrolled into the study. The observation period was 12 months, all adverse events (AEs) were collected and ADRs were defined as AEs where causality to erlotinib could not be ruled out. All ILD-like events were assessed by an independent ILD review committee. Overall survival (OS) and progression-free survival (PFS) were also assessed. Interim data were analyzed for pts registered prior to 30 Jun 2008. Results: By Oct 2009, a total of 10,708 pts were enrolled. We analyzed 3,743 pts enrolled by 30 Jun 2008, and data were available for 3,488, excluding 255 pts who were not treated with erlotinib, not available for CRF, or registered more than once. The overall incidence of ADRs was 81.8% (mostly grade 1/2), the most common were skin disorders (68.5%), including rash (63.0%), and gastrointestinal disorders (32%), including diarrhea (23.5%). Physician-assessed ‘ILD-like’ events were reported in 189 pts. Of these, the independent ILD review committee confirmed ILD (all grades) in 158 pts (4.5% of population) with a mortality rate of 1.6%. As risk factors for ILD, multivariate analysis identified smoking status (hazard ratio [HR]: 3.0), history of ILD (HR: 4.1), history of lung infection (HR: 2.0) and ECOG PS 2–4 (HR: 1.6). Median OS and PFS were 260 days and 64 days, respectively. Further data collection and analyses are ongoing and will be reported. Conclusions: Results of this primary analysis from a large surveillance study in unselected pts support the clinical benefits of erlotinib and provide evidence about ILD risk with erlotinib in Japan. No new safety signals were identified. The risk/benefit balance for use of erlotinib in pts with recurrent/advanced NSCLC remains favorable.
In vitro activity of ABT-888 (A), 5-FU (F), and dacarbazine (D) in neuroendocrine tumors (NET).
Authors: Sam Joseph Lubner, Yash Somnay, Dustin A. Deming, Kyle D. Holen, Herbert Chen
Journal: Journal of Clinical Oncology (2014)

236 Background: Low-grade neuroendocrine tumors (NET) have few cytotoxic chemotherapy options. Data suggests that a combination of temozolomide and a fluoropyrimidine has clinical efficacy. ABT-888 is a novel poly-ADP ribose polymerase (PARP) inhibitor that has been tested in a phase 1 setting with temozolomide, with synergy demonstrated in preclinical models of other tumors. We proposed an in-vitro study of ABT-888 with varying concentrations of dacarbazine (D), and 5-FU (F) on human neuroendocrine cells (BON). Methods: BON cells were incubated with varying concentrations and combinations of ABT-888 (2.5, 5 and 10uM), F (25-100uM), and D (25-100uM) for 96 hours. After incubation, cell growth was measured by MTT rapid colorimetric assay with absorbance reported as mean % control. Western blot analysis was performed for chromogranin A, PARP, γH2AXand XIAP to assess for cell death and on-target effects for the population treated with 5-FU. Combination indices (CI) were calculated using the Chou-Talalay method using CompuSyn. CI’s below 1 signified synergy. Results: ABT-888 alone did not demonstrate any antitumor effect (103%). D alone had antitumor effect (74% at 50uM, 67% at 100uM) which was improved by adding ABT-888 (70% at 50uM D; CI 0.73; p=0.06, 60% at 100 uM D; CI 0.88; p=0.0003). F alone had antitumor effect (82% at 50uM and 71% at 100uM) which was improved by adding 2.5uM ABT-888 (71% at 50uM of F; CI=0.59, and 58% at 100uM of F; CI=0.74), and further enhanced with 5uM of concomitant ABT-888 (56% at 50uM of F; CI=0.68, and 49% at 100uM of F; CI=0.76). Western analysis of lysates showed markers of increased apoptosis, decreased PARP, and decreased expression of CgA. The combination of F+D did not demonstrate increased cytotoxicity with the addition of ABT-888 (58% with/without ABT-888 p=0.61). Conclusions: ABT-888 demonstrated in vitro synergy against BON cells with F or D. The combination of all three compounds (A+F+D) did not demonstrate synergy above F+D. Synergy was statistically significant with increasing doses of cytotoxic compounds which are achievable in vivo with current doses of A, F, and D. The combination of ABT-888 with temozolomide or a fluoropyrimidine merits further study in human clinical trials.
Prospective observational study on chemotherapy-induced nausea and vomiting (CINV) for hepatobiliary and pancreatic cancer patients who were to receive chemotherapy including cisplatin by the CINV study group of Japan.
Authors: Junji Furuse, Hideo Baba, Shinichi Ohkawa, Kazuya Sugimori, Kazuhide Yamamoto, Hironobu Minami, Yuko Kitagawa, Hidekazu Kuramochi, A-Hon Kwon, Michiaki Unno, Go Wakabayashi, Keisuke Aiba, Kazuo Tamura
Journal: Journal of Clinical Oncology (2014)

341 Background: There has been no nationwide survey on CINV or validation of the guideline in Japan. The aim of the study is to investigate occurrence of CINV in hepatobiliary and pancreatic (HBP) cancer patients who are to receive chemotherapy including high and moderate emetic risk for the first time. In addition, primary care medical staffs' perception on CINV for their patients is also studied. Methods: A nationwide survey on CINV was conducted by the CINV study group of Japan. 21 institutions participated in the study. A 7-day diary for CINV was provided to the patient prior to chemotherapy to record daily occurrence and severity of CINV and an amount of food intake. Acute and delayed CINV was defined as nausea and vomiting which developed within or after 24 hours after the start of chemotherapy, respectively. The medical staffs also filled out questionnaires about their patient’s CINV. Results: A total 103 HBP cancer patients of 1,952 patients registered in this study during the period from April 2011 to December 2012 were analyzed. These patients’ diary and their medical staffs' report were sent to the central office. Underlying diseases were biliary tract cancer (70 patients), hepatocellular carcinoma (23) and pancreatic cancer (10). There were 62 males with a median age of 69 (range: 37-83) and 41 females with a median age of 63 (range: 41-80). MEC was given to 4 as was HEC to 99 patients. Acute nausea was experienced in 6 (5.8%), while was noted delayed nausea in 25 (24.3%). Acute vomiting was noted in 2 (1.9%) patients, while delayed vomiting was experienced in 6 (5.8%). The predictive factors for delayed nausea were female and motion sickness. The predictive factor for delayed vomiting was morning sickness. Medical staffs overestimated the incidence of acute and delayed nausea/vomiting. Conclusions: CINV seems to be under control with management by the guideline, but delayed nausea remained to be high and needs further investigation.
Chemotherapy safe handling and safe labeling guideline concordance evaluation: A Canadian experience.
Authors: Kathy Vu, Sherrie Hertz, Esther Green, Leonard Kaizer, Maureen E. Trudeau, Vicky Simanovski, Andrea Lischka
Journal: Journal of Clinical Oncology (2012)

179 Background: The safe delivery of chemotherapy is of utmost importance to patients, health care providers and systems administrators. Cancer Care Ontario and the Program for Evidence-Based Care published two guidelines addressing issues of chemotherapy safety: Safe Handling of Parenteral Cytotoxics (Safe Handling) in 2007 and Key Components of Chemotherapy Labeling (Safe Labeling) in 2009. Concordance with the two documents was evaluated across systemic treatment hospitals in Ontario in order to direct quality improvement initiatives. Methods: Since 2009, concordance with Safe Handling has been assessed annually by self-reported questionnaire as part of the regular provincial performance review process. In 2011, concordance with Safe Labeling was assessed by submission and scoring of five standardized chemotherapy labels demonstrating core and additional criteria. Core criteria included patient and drug information, administration information, as well as adherence to other guidelines related to abbreviations and units of measurement. Individualized regional scorecards were compiled highlighting areas of discordance and then used to develop improvement plans. Results: As of October 2011, 98% of Ontario hospitals providing chemotherapy had updated policies and procedures in place for the safe handling of cytotoxics, significantly improved compared to a baseline of 77% in 2009. Baseline evaluation of Safe Labeling performed in 2011 showed a provincial average of 64% concordance for core criteria and 63% for additional criteria. Regionally, concordance scores ranged from 55% to 80% for core criteria and 38% to 75% for additional criteria. Conclusions: Concordance with safety practice guidelines has the potential to improve significantly with continued measurement and performance management. A baseline assessment serves to identify areas for quality and process improvements. Continued evaluation of guideline concordance is necessary in order to achieve the desired target rate for the province.
Retrospective evaluation of Middle Eastern patients (pts) with type II diabetes mellitus (DM) and colorectal cancer (CRC): Validation of metformin effect on overall survival (OS).
Authors: Amal Al Omari, Hadeel Abdelkaleq, Maysa Al-Hussaini, Rim Turfa, Nour Awad, Salwan S. Al Mutar, Hesham M. Hassabo, Ibrahim Halil Sahin, Manal Hassan, Chris R. Garrett
Journal: Journal of Clinical Oncology (2014)

478 Background: Epidemiologic data suggest that anti-DM medications may impact OS in CRC pts who have type 2 DM. Although type 2 DM and CRC are major health problems in the Middle East, little data exists on pts with both conditions from this region. Methods: Medical records from 1,835 CRC pts seen at King Hussein Cancer Center between 1/1/2004 and 12/31/2012 were evaluated for prevalence of type 2 DM; those with both conditions were evaluated for anti-diabetic therapy and treatment outcomes (OS and progression-free survival [PFS]). Results: 285 type 2 DM CRC patients were identified (prevalence 15.5%); 19 pts were censored as their anti-DM medications were not known. Median age of 266 pts analyzed was 62.1 years (± 8.9), M: F ratio 1.6:1, non-metformin (n = 109, 41%), metformin only (n = 43, 16%), metformin + insulin (n = 11, 4%), metformin + another oral agent (n = 104, 39%). Metformin use increased over time (19% in 2004 to 71% in 2012). Adjusting for age, gender, body mass index, and stage, type 2 DM pts treated with metformin had a 40% improvement in OS (hazard ratio 0.624, 95% confidence interval 0.44-0.97). Conclusions: These data support previous findings that metformin use in CRC pts with type 2 DM is associated with a superior PFS and OS. Contrary to previously published data there was a statistically significant OS benefit in stage IV pts, while the trend toward OS benefit in stage I-III pts was not statistically significant (see Table). This study was supported by the King Hussein Cancer Center/MD Anderson Sister Institution Network Fund. [Table: see text]
Association between contralateral prophylactic mastectomy and breast cancer outcomes.
Authors: A. M. Brewster, P. A. Parker, I. Bedrosian, W. Dong, S. K. Peterson, S. B. Cantor, M. Crosby, Y. Shen
Journal: Journal of Clinical Oncology (2011)

1578 Background: Contralateral prophylactic mastectomy (CPM) has been shown to reduce the risk of contralateral breast cancer but there is conflicting evidence whether it improves disease-free or overall survival. The objective of the study was to evaluate the clinical benefits of CPM utilizing a large cohort of patients with detailed information available on tumor characteristics, and surgical and systemic treatments. Methods: We included 3,889 female patients with stages I-III breast cancer who were treated at The University of Texas MD Anderson Cancer Center from 1997 to 2009. Cox proportional hazard models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for the associations between CPM and disease-free and overall survival. Results: With a median follow-up time of 4.5 years, CPM was associated with improved disease-free survival (HR 0.75, 95% CI 0.59-0.97) adjusted for stage, nuclear grade, hormone receptor status and chemotherapy. The benefit was seen predominately among the hormone receptor-negative (HR 0.60, 95% CI 0.38-0.95) compared to the hormone receptor-positive patients (HR 0.80, 95% CI 0.58-1.10) but the interaction term was not statistically significant. CPM was also associated with improved overall survival (HR 0.74, 95% CI 0.55-0.99) adjusted for age, race, stage, comorbidities, nuclear grade, hormone receptor status and chemotherapy. Conclusions: CPM was associated with an improvement in breast cancer disease-free and overall survival after controlling for known prognostic factors. The improvement in disease-free survival among the CPM group was largely driven by lower breast cancer deaths and contralateral breast cancers. Further identification of subgroups of patients most likely to benefit from CPM could impact the decision making process for patients and their providers.
Low pegfilgrastim serum concentration at 11<sup>th</sup> day allows chemotherapy intensification in advanced Hodgkin’s disease patients
Authors: E. Cocorocchio, P. Antoniotti, L. Calabrese, R. Balzano, A. Vanazzi, P. F. Ferrucci, V. Raia, F. Peccatori, G. Martinelli
Journal: Journal of Clinical Oncology (2005)

6699 Background: Pegfilgrastim (PEG) is a new growth factor able to stimulate granulocyte production with a single injection. Basing on a biomathematical model showing a relationship between PEG serum concentration and ANC, subsequent chemotherapy cycles could be safely repeated after 14 days. Thus, PEG could not be associated with all dose intense chemotherapies. Here we report the final results of PEG serum concentration evaluated at 11th day after its injection on 35 blood samples obtained from 11 patients treated for Hodgkin’s disease with “hybrid” chemotherapy regimen. Methods: A single injection of PEG (6 mg) is delivered at 11th day after ChlVPP/ABVVP cycle delivered with a week a part schedule (see British Journal of Haematology, 125, 584–589). Chemotherapy treatment is repeated at day 21 if ANC are above 1x109/L for a maximum of six cycles. Patients considered for this study are evaluated for Peg serum concentration two or more times. An enzyme linked immunosorbent assay test is used for the determination of Peg concentration. A standard curve is performed using a known concentration of PEG (top 4 ng/ml, bottom 0.062 ng/ml). Log Peg concentration is reported on x-axis and the O.D. (450 nanometers) on y-axis. Data are calculated using computer software method. Results: All patients have received chemotherapy regimen as planned on day 21 showing ANC above 1x109/L. The median value of ANC is 6.7 x 109/L (range 3.2–15.2 x 109/L). The median value of PEG serum concentration is 0.215 ng/ml (range 0.081 - 0.592). No differences on PEG serum concentration are detected in those patients with three or more determinations. No patient experiences severe non-hematological toxicity. Conclusions: Our results confirm the predictive value of ANC on PEG serum concentration, that, on 11Th day after Peg dose is ten times lower than EC20. The low value of serum concentration of PEG at that time allows the use of such growth factor in dose intensity chemotherapy programs. No significant financial relationships to disclose.
Exploratory randomized trial to evaluate the effect of indisetron tablets for preventing chemotherapy-induced nausea and vomiting (CINV)/acute-onset diarrhea induced by IRIS/FOLFIRI: HGCSG0704.
Authors: Sosuke Kato, Hiraku Fukushima, Kanji Kato, Satoshi Yuki, Kazuaki Harada, Yoshimitsu Kobayashi, Takahide Sasaki, Nobuyuki Ehira, Ichiro Iwanaga, Minoru Uebayashi, Masayoshi Dazai, Susumu Sogabe, Takuto Miyagishima, Mineo Kudo, Kazuteru Hatanaka, Hirohito Naruse, Miki Tateyama, Yuh Sakata, Yoshito Komatsu
Journal: Journal of Clinical Oncology (2014)

624 Background: Indisetron is a 5-HT 3 receptor antagonist that also antagonizes 5-HT 4 receptors. Indisetron tablets showed the non-inferiority to ondansetron tablets in terms of efficacy for preventing CINV. Moreover, preclinical data administered with irinotecan showed indisetron significantly reduced stool frequency in mice and inhibited the colonic peristalsis in dogs. We designed a pilot study compared with granisetron in the efficacy and tolerability of indisetron for irinotecan-induced nausea, vomiting and especially in diarrhea. Methods: Advanced colorectal cancer patients treated with FOLFIRI or IRIS (Irinotecan + S-1) with or without bevacizumab were enrolled in this study. Treatment: Arm A: indisetron tablets 8mg po day1. Arm B: granisetron 3mg iv day 1. The primary endpoints were the incidence of acute-onset diarrhea and complete protection from vomiting. Secondary endpoints were tolerability, complete protection from nausea and rate of no rescue medication. Results: Between May 2008 and July 2012, 33 patients (pts) were randomized. The study was closed prematurely due to poor accrual. Arm A: 16 pts, arm B 17 pts. Median age A: 68 y.o., B: 66 y.o.: ECOG PS 0/1: A: 12/4, B: 14/3pts. There was no significant difference of the incidence of acute-onset diarrhea between both groups (18.8% in A vs. 35.3% in B, p = 0.438). The proportion of complete protection from vomiting was 87.5% in A and 88.2% in B (p = 1.000). Similarly, complete protection from nausea, rate of no rescue medication, proportion of patients with a complete response (defined as no emetic episodes and no rescue medication) did not have a significant difference. Severity of nausea/vomiting and AE induced by 5-HT 3 receptor antagonist were also similar between two groups. Conclusions: Compared with granisetron, indisetron showed effective and feasible results for preventing CINV induced by FOLFIRI or IRIS. Indisetron had also not improved the incidence of acute-onset diarrhea induced by irinotecan. Clinical trial information: UMIN000010162.
Microvesicle-mediated transfer of genetic phenotype from lung to marrow cells.
Authors: J. M. Aliotta, M. Pereira, A. Amaral, M. Dooner, L. Goldberg, P. J. Quesenberry
Journal: Journal of Clinical Oncology (2011)

e21092 Background: We have previously shown that lung-derived microvesicles (MVs) can enter target marrow cells, resulting in increased levels of lung-specific mRNAs. Marrow which has been exposed to MVs also show increased production of pulmonary epithelial cells after transplantation into irradiated mice. The present studies have addressed the universality of the mRNA modulation and the underlying mechanisms. Methods: see results section Results: Co-culture of heart, brain, liver, and lung tissue opposite murine marrow, but separated by a 0.4 micron cell-impermeable membrane, show tissue specific elevations of mRNA. MVs were found to contain lung-specific mRNA and 200 microRNAs. Proteomic studies of MVs showed 75 individual proteins, some of which are known to be associated with MV biogenesis and trafficking. Studies using rat/mouse hybrid cultures demonstrated that the target cell induced lung-specific mRNA elevations were mediated by transcriptional mechanisms. In these experiments, rat lung was co-cultured across from murine marrow cells and RT-PCR was performed using rat or mouse-specific primers for surfactant B. High levels of mouse-specific surfactant B were seen in the co-cultured marrow cells indicating that transcription had been induced in the target cells. These conclusions were supported by additional studies employing the transcription factor inhibitors. RNase treatment of conditioned media prior to marrow cell co-culture suggested that transfer of RNA may be involved in these mRNA elevations. However, our transcriptional studies indicate that we are not observing a simple transfer of MV lung-specific mRNA. One possible mechanism may be transfer of microRNA with epigenetic changes resulting in lung-specific mRNA production. Conclusions: These observations suggest the existence of unique pathways for information transfer and cell phenotype determination. MV transfer may represent an underlying mechanism for much of the reported stem cell plasticity in different tissues.
Molecular pathology from lipid profiles of human transitional cell carcinoma of the urinary bladder and adenocarcinoma of the prostate by desorption electrospray ionization (DESI) imaging mass spectrometry.
Authors: A. L. Dill, L. S. Eberlin, A. B. Costa, D. R. Ifa, L. Cheng, T. A. Masterson, M. O. Koch, T. L. Ratliff, R. G. Cooks
Journal: Journal of Clinical Oncology (2010)

e21043 Background: In this study, desorption electrospray ionization (DESI) mass spectrometry (MS) was used in an imaging mode to interrogate the lipid profiles of thin tissue sections of human transitional cell carcinoma (TCC) of the urinary bladder and adenocarcinoma of the prostate to determine whether DESI-MS could discriminate between cancerous and noncancerous tissues. Methods: DESI-MS images showing the spatial distributions of particular glycerophospholipids (GPs) and free fatty acids in the ion mode were compared to serial tissue sections that were stained with hematoxylin and eosin (H&E) among 19 matched pairs of cancerous and noncancerous bladder tissues and among 34 pairs of tissue from prostate cancer patients. Increased absolute and relative intensities were utilized to assess for particular compounds in the tumor regions of the samples. Principal component analysis (PCA) was used to generate unsupervised statistical images from the negative ion mode data and which were used to assess for agreement between the DESI and H&E stained images. Results: Of the 19 sample pairs of bladder cancer investigated, in 15 cases the DESI-MS and PCA images agree with the pathological diagnosis of cancer and normal from the H&E stained tissue. In 3 pairs of sample tissue a border of normal urothelium appears as “cancerous” in the DESI-MS images. One case is not understood, in which the DESI-MS and PCA images do not match the pathological diagnosis. Among the lipids detected in human prostate tissue, cholesterol sulfate was identified as a differentiating compound. Cholesterol sulfate is found exclusively in cancerous tissues and in high grade prostatic intraepithelial neoplasia as determined by detailed histopathological examination, but is absent from normal tissue. Conclusions: Overall DESI-MS imaging shows promise as a molecular pathology technique for diagnosing cancerous and normal tissue on the basis of GP profiles. This is the first report describing cholesterol sulfate as a potential tumor marker for human prostate cancer. No significant financial relationships to disclose.