tbuckley/cabot-search huggingface dataset:
Final analysis of the NEOMET trial of neoadjuvant metformin: Examining effects on Ki67, gene expression, and pathway analysis in primary operable breast cancer.
Authors: A. M. Thompson, T. Iwamoto, L. Jordan, C. Purdie, S. E. Bray, L. Baker, G. Hardie, L. Pusztai, S. L. Moulder, J. A. Dewar, S. M. Hadad
Journal: Journal of Clinical Oncology (2011)

534 Background: Metformin is associated with a reduced incidence of breast cancer and enhanced response to neoadjuvant chemotherapy in epidemiological studies of diabetic women. Cell line and xenograft studies suggest metformin, widely used in the treatment of diabetes, may be a candidate anti-cancer agent. This randomized phase II neoadjuvant trial examined the effects of metformin on Ki67 and gene expression in primary breast cancer, testing the hypothesis that metformin has anti-cancer effects in women with breast cancer. Methods: Non-diabetic women with operable, primary invasive breast cancer received pre-operative metformin. The trial had two components: a pilot cohort of 8 luminal A patients had core biopsy at three time points: at presentation; a week later without treatment (internal control); then following metformin 500mg o.d. for one week increased to 1g b.d. for a further week up to definitive surgery. A further 47 Luminal A and Luminal B patients had core biopsy measurement at diagnosis, were randomized to metformin or no metformin, and 2 weeks later had core biopsy prior to resection. Ki67 measurements and transcriptome analyses were performed on formalin fixed paraffin embedded tissues. Results: The mean percentage of cells staining for Ki67 fell significantly in both the pilot cohort (p=0.041, paired t-test) and patients randomized to metformin (p=0.027, Wilcoxon rank test) following metformin treatment, but was unchanged in the control arm. By Ingenuity Pathway Analysis, the TNFR1 signaling pathway was most significantly affected by metformin: TGFB, MEKK were commonly up regulated and cdc42 down regulated. The mTOR and AMPK pathways were also significantly affected. By Gene Set Analysis the p53, BRCA1 and cell cycle pathways had reduced expressed following metformin. Conclusions: This window of opportunity trial presents evidence of antiproliferative and anti-cancer effects via specific biomarker pathways for metformin action in primary breast cancer and provides support for further trials testing the use of metformin in the treatment of breast cancer.
Impact of cytogenetics on clinical outcome in multiple myeloma: A risk stratification model.
Authors: R. Verma, L. Kumar, R. Gupta, A. Halder, A. Sharma, R. Saxena
Journal: Journal of Clinical Oncology (2011)

e18576 Background: We prospectively studied 90 patients of multiple myeloma for the presence of translocations involving IgH (14q32) locus, del 13q14 and presence of numerical chromosomal abnormalities. An attempt was made to correlate their effect on outcome and to formulate a risk scoring system. Methods: Purified bone marrow plasma cells, using magnetic activated cell sorter (MACS) with CD 138 micro beads were used. Fluorescent in situ Hybridization was used to detect IgH (14q32) translocations and del 13q14, while numerical chromosomal abnormalities were detected by conventional cytogenetics. Results: Patients' median age was 55 years (range, 34 to 75 years) and 67 were males (M: F: 2.9: 1). 24 patients had International staging system (ISS) stage I, stage II- 46 and 20 patients had stage III. On conventional cytogenetics metaphases were obtained in 53 (58%) patients; with numerical chromosomal abnormalities in 21 of 53 (40%), these included- hyperdiploid in 16 and hypodiploid-5. Remaining patients had normal metaphases. del 13q14 and t(14q32) were present in 51 (56%) and 75 (83%) patients, respectively. 65/90 (72%) patients received therapy with novel molecules and were evaluated using EBMT response criteria. Absence of del 13q14 was associated with higher response rate (23/26 vs 26/39, P <0.04) and better overall survival (79% vs 67%, p =0.07) and event free survival (70% vs 37%, p <0.03) at two years. Based on presence (1) or absence (0) of del 13q14 and ISS (I=0 vs II=0.5 vs III=1), a risk scoring model was obtained. 69% of the patients belonged to low risk category (risk score ≤1) and 31% were in high risk (risk score >1). Patients belonging to low risk had a higher response (91% vs 40%, p<.0001), better overall (77% vs 61%, p<.01) and event free (58% vs 32%, p<.01) survival at two years compared to patients with high risk. Conclusions: del 13q14 and International staging system (ISS) are two important parameters and could be used to prognosticate patients at diagnosis.
Multidisciplinary risk assessment to reveal cancer treatments in complex cancer patients.
Authors: Olivier Huillard, Pascaline Boudou-Rouquette, Anne Chahwakilian, Vincent Montheil, Audrey Thomas-Schoemann, Galdric Orvoen, Laure Cabanes, Jean-Philippe Durand, Anatole Cessot, Julie Giroux, Antoine Tesniere, Jean Stephanazzi, Helen Mosnier-Pudar, Jerome Alexandre, Francois Goldwasser
Journal: Journal of Clinical Oncology (2014)

170 Background: Older age is a cause of disparity in cancer treatment decision and treatment guidelines for patients with comorbidities, polypharmacy, denutrition or psycho-social frailty are needed. A pre-therapeutic multidimensional assessment might improve the complex patient management. We developed an experimental program of integrated medicine called ARIANE. We report 18 months activity of this outpatient setting evaluation, its feasibility and impact on treatment decision-making. Methods: Complex patients with predefined cancer treatment strategy entered into the program. A one-day evaluation combined consultations of cardiologist, geriatrician, diabetologist, anesthetist, pharmacist, pain specialist, dietician, psychologist and social worker. Evaluation of performance status, EKG, ejection fraction, ASA score, diabetes, social vulnerability and malnutrition was performed including a geriatric assessment, which focused on items like comorbidity (CIRS-G), dependance (ADL, IADL), fails (Up and Go Test), cognitive impairment (MMSE, Clock Drawing Test) and depression (GDS scale). A pharmacist assessed the risk of drug-drug interactions. Results: Eighty-seven pts, median age 81 years (range 25-94), 76% male, 51% PS 0-1, 77% grade 3 or 4 comorbidity were included. Genito-urinary, lung cancers and sarcoma represented 77% of pts. Eighty-two percent of pts were assessed by at least ≥ 7 participants. Identified factors of vulnerability were polypharmacy (n=65; 75%; &gt;3 drugs), social distress or severe malnutrition (both n=21; 24%), depression (n=17; 19.5%) and cognitive impairment (n=13; 15%). We identified drug interaction in 18 pts (27%). The risk assessment resulted in anticancer treatment changes in 47/87 patients (54%): protocol adaptation (n=19/87; 22%), less aggressive treatment (n=15/87; 17.2%), or more intensive therapy (n=13/87; 15%). Conclusions: A one-day multidisciplinary risk assessment is an answer to the complexity of unfit cancer patients and improves the safety of anticancer treatments.
The prognostic role of the host immune response in rectal cancer patients treated with neoadjuvant chemoradiation.
Authors: Thilo Sprenger, Ralph M Wirtz, Selcan Pektas, Hanibal Bohnenberger, Anne Kauffels, Lena-Christin Conradi, Kia Homayounfar, Torsten Liersch, Michael Ghadimi
Journal: Journal of Clinical Oncology (2016)

575 Background: The development of metachronous distant metastasis is – despite remarkable progress - still a challenging problem after multimodality treatment of rectal cancer. The host immune response has been identified as a valid prognostic marker in primary colon cancer but not in rectal cancer after neoadjuvant chemoradiotherpy so far. Methods: We analysed the mRNA and protein expression of the B- and T-cell chemokines CXCL13 and CXCL9 as well as the B-cell marker IGHM in 77 rectal cancer specimens undergoing preoperative chemoradiotherapy and investigated the role of the host immune response on the occurrence of distant metastasis and survival. Results: The intratumoral mRNA expression levels of the T-cell activator CXCL9 (p &lt; 0.001) as well as the B-cell chemokine CXCL13 (p &lt; 0.01) were inversely correlated with the development of distant metastasis. Patients with high CXCL9 (p &lt; 0.0001) or CXCL13 expression (p &lt; 0.01) had a significantly prolonged DFS. Moreover, patients with high mRNA levels of both CXCL9 and CXCL13 had an excellent DFS compared to patients without expression of any of the chemokines (p &lt; 0.0001). Additionally, CXCL9 expression was correlated with an improved CSS (p &lt; 0.05). There was no significant correlation between the B-cell marker IGHM and metastasis or survival. Conclusions: The host immune response represented by intratumoral expression levels of the lymphocyte-activating chemokines CXCL9 and 13 is associated with reduced rates of distant metastases and improved survival in rectal cancers after multimodality treatment. Further investigations are needed to prospectively validate these results and characterize the underlying cellular and molecular mechanisms.
Moving to secondary use of IT solutions: A provincial “near miss indicator” for chemotherapy.
Authors: Vishal Kukreti, Megan Teimoortagh, Annie Cheung, Sharon Gradin, John Gilks, Erin Rae, Leonard Kaizer
Journal: Journal of Clinical Oncology (2014)

161 Background: In Ontario, 93% of outpatient IV chemotherapy is prescribed through Systemic Treatment Computerized Order Entry Systems (ST CPOE). To support this, Cancer Care Ontario (CCO) has developed guidelines, evaluation tools, a Community of Practice (COP) and quality indicators. Using data collected in ST CPOE systems a “Near Miss Indicator” is being developed. Methods: Clinical consensus indicated that intercepted order rate, a proxy for a near miss indicator, would further the provincial safety agenda. This is defined as the percent of course 1, day 1 intravenous (IV) chemotherapy drug orders that were changed post-first time prescribing a new regimen (excludes clinical trials). An extraction standard for dose adjustments was developed encompassing clinical and laboratory values and body surface area (BSA). Three months of data was collected from 3 centres using the same ST CPOE system. Results: A total of 6822 orders were reviewed for possible near misses; 1,446 (21.2%) were course 1 orders. For course 1, day 1 IV chemotherapy drug orders, 209 (3.2%) were changed. Most orders were changed several hours to days post prescribing and hence were not felt to represent normal clinical workflows. Physicians modified 65 and pharmacy modified 169 orders. “Other” was chosen as the reason for change in 95 (45.5%) of orders and despite multidisciplinary team review, these records were not interpretable. A near miss rate of 2.2% resulted (32/1,446). Clinical and laboratory values and BSA were equally responsible. A fourth category of “dose rounding for ease” by pharmacy was identified and felt to possibly represent poor regimen builds and pharmacy workload. Conclusions: A near miss indicator is under development via a process of identifying a need, exploration of data and socialization of the results through a COP. Initial results show a low near miss indicator rate of 2.2% which is felt to be clinically actionable. Future system modifications may facilitate capture of this indicator. The feasibility of extending the indicator to multiple vendor ST CPOEs is under study.
A phase II trial of the effect of chemotherapy in the management of intraocular retinoblastoma: A 7 years follow up report
Authors: S. Shehata, A. N. A. Mohammed, H. A. Mohammad
Journal: Journal of Clinical Oncology (2005)

8556 Background: Is to evaluate the efficacy of systemic chemotherapy in the treatment of intraocular retinoblastoma of different sizes. Methods: 39 eyes of 29 retinoblastoma patients were included. They were grouped according to tumor size and the presence or absence of vitreous seeds. A 6-cycle regimen consisting of etoposide and carboplatin was used in all cases. Ocular ultrasonography and occasionally CT were used to evaluate the mass size pre-and post chemotherapy treatment. Results: With a median follow up to 39 months, complete resolution of the mass (all of Reese-Elisworth eye groups 2 & 3) was observed in 13 eyes with chemotherapy treatment alone and in 10 eyes with the addition of small-dose radiotherapy. Initial good response, followed by tumor progression after cessation of chemotherapy was reported in 8 eyes (Reese-Elisworth eye group 4 & 4). All were treated by external beam radiotherapy with good response in 6 eyes, while enucleation was required in 2 eyes. In 2 eyes, the entire vitreous cavity was involved by the tumor and both chemotherapy and external beam radiotherapy (EBRT) showed no response and required enucleation. Conclusions: For small sized intraocular retinoblastoma, the combination of Etoposide plus Carboplatin chemotherapy is an effective modality of treatment and can eliminate the need for EBRT or enucleation. For large sized tumors, additional external beam radiotherapy and/or enucleation is required. No significant financial relationships to disclose.
Safety and efficacy of 2-weekly cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Alice Clement-Zhao, Marie Auvray, Benjamin Verret, Yann Alexandre Vano, Antoine Angelergues, Stephane Oudard
Journal: Journal of Clinical Oncology (2015)

284 Background: Cabazitaxel (C) administered on a 3-weekly dose schedule has shown a survival benefit in mCRPC patients (pts) pre-treated with docetaxel (D) with concerns about toxicity. We sought to evaluate safety and efficacy of a 2-weekly C schedule. Methods: At the EGP hospital from November 2013 to September 2014, 26 mCRPC pts for whom C was indicated (previously treated with D) received C 16 mg/m² on days 1 and 15 of a 4 weeks-cycle plus daily 10 mg prednisone, until completion of 6 cycles, disease progression, unacceptable toxicity or death. We analyzed safety with toxicity grade ≥ 3 and efficacy, including PSA response, time to biochemical progression (TTBP), radiological progression-free survival (rPFS) and overall survival (OS). Results: 26 pts received C in a 2-weekly schedule; full data are available for 20 pts. Median age was 66.5 years, 34.6% of pts were &gt;70 years; 30.8% had ECOG PS 2; 47.8% had Gleason ≥ 8; 53.8% had lymph node metastases; 96.2% had bone metastases; none had lung or liver metastases. Median D cycles previously received were 6; respectively 80% and 88.4% of pts had received ≥ 2 hormonal manipulations and abiraterone acetate (AA). Median baseline hemoglobin was 12.2 g/dL, median PSA 104.6 ng/mL; 42.9% of pts had ALP ≥ 1.5N, 33.3% had LDH ≥ 1.5N. 4 pts (15%) had grade 1 thrombocytopenia at baseline, 1 (3.8%) had grade 4, reflecting diffuse bone marrow involvement. All pts received G-CSF in primary prophylaxis. Median number of C administration was 7, only 4 pts stopped C because of toxicity (2 for asthenia, 1 for febrile neutroepnia, 1 for thrombocytopenia). Toxicities grade ≥3 were: anemia 33.3%; thrombocytopenia 30%; neutropenia 23.8%; febrile neutropenia 5% (1 pt); no grade ≥3 diarrhea was observed. 45% (9 pts) achieved ≥30% PSA response and 30% (6 pts) ≥50% PSA response. Clinical, biological or radiological response occurred in 50% (10 pts). Median TTBP and rPFS were 3.0 months (2.2-3.6) and 4.2 months (2.8-7.4) respectively. Median OS was not reached at the time of data collection. Conclusions: 2-weekly 16 mg/m² C schedule has a manageable toxicity profile in heavily D and AA pretreated mCRPC pts, and warrants controlled prospective evaluation compared to the standard 3-weekly C schedule.
Analysis of second primary cancers in gastroinstestinal stromal tumor patients using SEER database.
Authors: Krishna Bilas Ghimire, Barsha Nepal, Binay Kumar Shah
Journal: Journal of Clinical Oncology (2013)

327 Background: Development of second primary cancers among gastrointestinal stromal tumor (GIST) patients is not very well studied. This study was conducted to evaluate second primary malignancies in GIST patients using U.S. Surveillance, Epidemiology, and End Results (SEER) cancer registry database. Methods: We analyzed the Surveillance, Epidemiology, and End Results (SEER Stat) database: Incidence - SEER 13 Regs Research Data, Nov 2011 Sub, Vintage 2009 Pops (1992-2009) using MP-SIR session. We analysed secondary cancer rate among adult GIST patients during the period 1992-2009. We also compared the risk of secondary malignancies in pre- (1992-2001) to post-imatinib (2002-2009) eras. We used SEER MP-SIR session and Graph pad scientific software to calculate p value. Results: There were 2,436 (693 in pre-imatinib era and 1,743 in post-imatinib era) GIST patients reported during 1992-2009 period in SEER database. Among them, 163 GIST patients developed second primary malignancy, which is significantly higher than expected in general population, with observed/expected (O/E) ratio: 1.31, p value = &lt;0.05, (95% CI: 1.11-1.52) and excess risk of 39.76 per 10,000 population. The total number of second primary cancers in GIST in pre- and post-imatinib eras were 69 and 94, p value = &lt;0.0001 with observed/expected (O/E) ratio of 29.18 and 48.22 respectively. The total number of second primary solid tumors in pre- and post-imatinib era was: 59 and 84, p value=0.0008 and O/E ratio: 20.18 vs 43.32 respectively. Conclusions: This study showed overall increased risk of second primary malignancies among GIST patients as compared to general population. There was significantly increased risk of second primary malignancies, especially solid tumors in post-imatinib era. [Table: see text]
A phase I study of CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3‐kinase P110δ, in combination with anti-CD20 monoclonal antibody therapy and/or bendamustine in patients with previously treated B-cell malignancies.
Authors: I. W. Flinn, M. T. Schreeder, S. E. Coutre, J. Leonard, N. D. Wagner-Johnston, S. De Vos, R. V. Boccia, L. Holes, S. Peterman, L. L. Miller, A. S. Yu
Journal: Journal of Clinical Oncology (2011)

3064 Background: The class I phosphatidylinositol 3-kinases (PI3Ks) regulate cellular functions relevant to oncogenesis. Expression of the PI3K p110δ isoform (PI3Kδ) is restricted to cells of hematopoietic origin. CAL-101 is an isoform-selective inhibitor of PI3Kδ that has demonstrated substantial single-agent clinical activity in patients with indolent B-cell non-Hodgkin lymphoma (iNHL) and chronic lymphocytic leukemia (CLL). Methods: This phase I study has evaluated CAL-101 in combination with anti-CD20 monoclonal antibody therapy and/or bendamustine in patients with previously treated iNHL and CLL. All patients received CAL-101 100 or 150 mg orally twice per day (BID) in 28-day cycles for up to 12 cycles. CAL-101 was administered starting on Day 1 of Cycle 1 with rituximab 375 mg/m2 given weekly for 8 weeks (RC regimen), or bendamustine 90 mg/m2 given on Days 1 and 2 of each cycle for 6 cycles (BC regimen). Tumor response was evaluated according to standard criteria. Results: At data cutoff, patient accrual was 12 for iNHL and 8 for CLL. Patient characteristics included: median age [range] of 64 [51-87] years; 65% males; 40% with refractory disease; and a median [range] of prior therapies of 3 [1-9]. 15 patients received CAL-101 100 mg BID (8 RC/7 BC) and 5 patients received 150 mg BID (3 RC/2 BC). Grade ≥3 adverse event rates have been as expected: including neutropenia and thrombocytopenia each in 2/9 patients receiving BC, and increased ALT/AST in 3/12 patients with iNHL. Among 18 evaluable patients, there were preliminary overall response rates of 10/11 (including 1 complete response) in patients with iNHL, and 5/7 in patients with CLL. Compared to baseline, on-treatment peripheral lymphocyte counts were stable or decreased in 8/8 patients with CLL. Accrual is ongoing and updated data will be presented. Conclusions: Early results from this phase I study of CAL-101, an oral PI3Kδ isoform-selective inhibitor administered in combination with rituximab or bendamustine, show acceptable safety and promising clinical activity in patients with previously treated iNHL and CLL.
Glioma-associated antigens associated with prolonged survival in a phase I study of ICT-107 for patients with newly diagnosed glioblastoma.
Authors: S. Phuphanich, C. J. Wheeler, J. Rudnick, M. Mazer, M. Nuno, X. Fan, J. Bender, E. S. Hawkins, K. L. Black, J. Yu
Journal: Journal of Clinical Oncology (2011)

2042 Background: Active immunotherapy offers the potential for high tumor-specific toxicity and sustained tumoricidal activity. We developed a dendritic cell (DC) immunotherapy to target specific glioma-associated antigens and induce a potent T cell response. Methods: In this study HLA-A2 or A1 positive patients were vaccinated with DC pulsed with MHC class I peptides from tumor associated antigens (TAA) expressed on gliomas. TAA epitopes included HER2, TRP-2, gp100, MAGE-1, IL13Rα2, and AIM-2. TRP-2, HER2 and AIM-2, are also overexpressed on glioblastoma multiforme (GBM) cancer stem cells. In this phase I trial, mononuclear cells isolated by leukapheresis from newly diagnosed GBM patients and differentiated into DC, were pulsed with TAA peptides, and administered intradermally three times at two week intervals. Results: 16 newly diagnosed GBM patients were enrolled since May 2007 with last follow up as of 1/28/2011. Vaccination was followed by adjuvant chemotherapy. TAA expression by qRT-PCR showed all patients expressed at least three TAA with 75% expressing all six, 87% expressing five and 94% expressing four. Correlations of increased PFS and quantitative expression of MAGE1 (p=0.03), AIM2 (p=0.003), gp100 (p=0.05) and HER2 (p=0.04) was observed. Variable changes in antigen expression were observed in the recurrent tumors. 7 of 15 tested (47%) had increased IFN gamma immune responses to a pool of the peptides. Immune responders showed a trend toward better survival. Six patients continue to show no tumor recurrence, three of whom have gone almost four years (43.5-49.8 m) and three more than 2.5 years (31.1-34.2 m). Median progression-free survival time was 16.9 months with median OS survival time not reached. At two years, the PFS rate was 43.75%; the two-year OS rate was 80.2%. Conclusions: Expression of four ICT-107 targeted antigens in the pre-vaccine tumors correlate with prolonged survival as measured by PFS and OS in newly diagnosed GBM patients. A randomized placebo controlled phase II trial is currently underway.