tbuckley/cabot-search huggingface dataset:
Defining the genetic basis of everolimus sensitivity in metastatic bladder cancer (MBC) by whole-genome sequencing (WGS).
Authors: Gopa Iyer, Matthew I. Milowsky, Hikmat Al-Ahmadie, Aphrothiti Hanrahan, Manickam Janakiraman, Adriana Heguy, Agnes Viale, Nicholas D Socci, Chris Sander, Bernard Bochner, Dean F. Bajorin, Michael F Berger, Barry S. Taylor, David B. Solit
Journal: Journal of Clinical Oncology (2012)

4527 Background: MBC is rarely cured with standard chemotherapy and novel agents are clearly needed. A phase II trial of everolimus in MBC resulted in 1 near-complete response (CR), 1 partial response, and 3 minor responses. We used WGS and a Next Generation exon capture assay to identify the genetic aberrations underlying treatment response. Methods: In the near-CR case, tumor and peripheral blood DNA was subjected to WGS (Illumina) using 2x100 bp paired-end libraries for 40X haploid coverage. Raw sequence data was aligned to hg19 and somatic point mutation detection was performed. Tumor DNA from 13 additional patients on the trial was analyzed using an exon capture sequencing assay. Results: 184 exonic somatic mutations were identified in the everolimus complete responder by WGS, including a 2 bp frameshift truncation in TSC1 and a nonsense mutation in NF2. Sanger sequencing of an additional 96 high-grade bladder tumors found 5 (6.2%) tumors containing TSC1 alterations and no NF2 mutations. Of the 13 patients on the trial who underwent targeted exon sequencing, 3 (23%) possessed nonsense TSC1 mutations and 2 had minor treatment responses (17% and 24% tumor regression). 1 patient with a 7% tumor regression had a somatic missense TSC1 variant. 8 (89%) of 9 patients with tumor progression as best response were TSC1 wild-type. Patients with TSC1-mutant tumors remained on drug for longer duration (7.7 vs. 2 months, p=0.004, Wilcoxon rank sum test). Conclusions: Everolimus is an active agent in MBC in patients with TSC1 mutant tumors. The pattern of co-mutation in patients with TSC1 mutant tumors is complex and combination therapies will likely be required to achieve durable responses in most patients. Our results also highlight the potential utility of WGS in identifying novel predictors of response to targeted inhibitors.
A PHASE I STUDY OF CONVECTION-ENHANCED DELIVERY OF LIPOSOMAL-IRINOTECAN USING REAL-TIME IMAGING WITH GADOLINIUM IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMA
Authors: N. Butowski, K. Bankiewicz, A. Kells, A. Martin, M. Berger, M. Aghi, M. Prados, S. Chang, J. Clarke
Journal: Neuro-Oncology (2014)

BACKGROUND: Chemotherapy for high grade glioma (HGG) is limited by poor activity of available agents and compromised delivery across the blood brain barrier (BBB). Convection enhanced delivery (CED) improves chemotherapy delivery by utilizing fluid convection established as a result of a pressure gradient, obviating the challenges of crossing the BBB while minimizing systemic toxicity. CED of nanoliposomal irinotecan (MM-398) has been optimized in rat, dog, and primate models. A recent study in mice with intracranial glioblastoma xenografts compared routes of delivery for liposomal irinotecan by CED or IV and showed superior anti-tumor activity of CED. A major clinical advance in the use of CED over recent trials is the development of real time CED (RCD), which utilizes MRI to visualize the CED process with the aid of co-convected contrast agents and thus monitor delivery into the brain and to take corrective action for technical complexities. METHODS: With support from an R21 we will conduct the first in human phase I study of CED of liposomal-irinotecan using real-time imaging with gadolinium in patients with recurrent HGG. This is a single center, prospective, 3 + 3 dose escalating, single-arm, phase I trial with a four-level dose escalation, expecting to enroll at least 3 patients in each level and expanding the highest level to 12 patients total. Dose levels are 20 mg, 40 mg, 60 mg, and 80 mg liposomal-irinotecan, given via up to 3 catheters surgically placed in an intra-tumoral (IT) location. Concentration of gadoteridol will be 2 mM for all dose groups; both agents will be combined and co-infused via the same catheters. Subjects in the two lowest dose groups will have tumor volumes of 1-4 cm3, the third dose group will be 2-5 cm3 and the highest dose group will have tumor volume 2-6 cm3. Maximum total volume infused will be 1.0 ml for two lowest dose groups, 1.5 ml for the third dose group, and 2.0 ml for the highest dose group. RESULTS: Interim safety, efficacy, and imaging response results will be presented. Utilizing imaging software, we'll present the correlation of pre-infusion modeling of the drug distribution with post-infusion imaging and determination of the total volume of distribution (Vd) and the Vd to volume infused (Vi) ratio for each infusion. CONCLUSIONS: Image-guided distribution allows for real-time placement and adjustment of cannula for real time CED of MM-398 into the brains of patients with recurrent HGG. SECONDARY CATEGORY: Imaging.
Long-term survival in unfavorable-risk mRCC patients treated with a combination of autologous immunotherapy (AGS-003) plus sunitinib.
Authors: Asim Amin, Arkadiusz Z. Dudek, Theodore F. Logan, Raymond S. Lance, Jeffrey M. Holzbeierlein, Viraj A. Master, Sumanta Kumar Pal, Jennifer J. Knox, Lawrence Ivan Karsh, Doug Plessinger, Charles A. Nicolette, Robert A. Figlin
Journal: Journal of Clinical Oncology (2014)

4524^ Background: Treatment for metastatic renal cell carcinoma (mRCC) has evolved significantly over the last decade due to enhanced understanding of the biology of RCC resulting in availability of number of agents targeting the VEGF axis and mTOR pathway. These treatments however, usually do not elicit durable responses and may have significant toxicities. AGS-003 is an autologous immunotherapy designed to induce an immune response to patient’s own tumor. In a phase 2 trial, AGS-003 in combination with sunitinib was studied for safety and efficacy. Updated survival data is presented. Methods: In this open label, phase 2 study, subjects with newly diagnosed metastatic clear cell RCC were enrolled. Subjects received sunitinib (4wks on, 2wks off) combined with AGS-003 (every 3wks X 5 doses, then every 12wks) until progression. Subjects were followed for PFS and OS throughout the trial and during a rollover protocol. Results: For the twenty-one subjects (11 intermediate risk, 10 poor risk) treated, the median PFS was 11.2 months and the median OS was 30.2 months. The recently achieved median OS for the intermediate risk population (1 to 2 risk factors) was 57.1 months. Accordingly, 52% of all subjects achieved OS ≥ 30 months and 33.3% of subjects were still alive at 48 months after registration. Five of the original 21 (23% of the study population) have exceeded, or are currently nearing the five-year plus survival mark. The absolute change in CD8+CD28+ memory T cells (the proposed MOA for AGS-003) directly and significantly correlated to prolonged OS, PFS, and best tumor response. Conclusions: When compared to historical estimates of PFS and OS for unfavorable risk patients (time from diagnosis to treatment of less than one year), the addition of AGS-003 to sunitinib resulted in a 50% increase in median PFS, doubling of expected median OS, more than 50% of patients surviving long-term (OS ≥ 30 months) and 33% of patients surviving for at least 54 months. Updated survival and corresponding CD8+CD28+ memory T cell expansion in long-term survivors will be presented. Currently the combination of AGS-003 plus sunitinib is being compared to sunitinib alone in a large phase III study (ADAPT). Clinical trial information: NCT00678119.
Decanucleotide Insertion Polymorphism of F7 Influences Significantly the Risk of Thrombosis in Patients with Essential Thrombocythemia
Authors: Veronika Buxhofer-Ausch, Damla Olcaydu, Bettina Gisslinger, Martin Schalling, Sophie Frantal, Juergen Thiele, Leonhard Müllauer, Hans-Michael Kvasnicka, Robert Kralovics, Heinz Gisslinger
Journal: Blood (2012)
Activation of Nucleic Acid-Sensing Toll-Like Receptors Induces Proliferation, Cytokine Production, Immunogenic Phenotype, and Plasma Cell Differentiation of CLL Cells and Immunoglobulin Production.
Authors: Santanu Paul, Charles C. Chu, Brian A. McCarthy, Erin Boyle, Bettie M. Steinberg, Matthew Kaufman, Jonathan Kolitz, Steven L. Allen, Kanti R. Rai, Nicholas Chiorazzi
Journal: Blood (2007)
Sentinel lymph node evaluation among elderly melanoma patients: Missed opportunities?
Authors: Dhruvil R Shah, Anthony D Yang, Emanual Maverakis, Steve R. Martinez
Journal: Journal of Clinical Oncology (2012)

e19001 Background: Elderly patients may not receive indicated therapies offered to younger patients. We hypothesized that elderly patients with intermediate thickness cutaneous melanoma would be less likely to receive a sentinel lymph node biopsy than their younger counterparts. Methods: The Surveillance, Epidemiology, and End Results database was queried for patients who underwent surgery for intermediate thickness cutaneous melanoma (Breslow thickness 0.75 to 4.00 mm) from 2004 to 2008. We excluded patients with mucosal melanoma, those without a biopsy-proven diagnosis, and those diagnosed at autopsy. Patients were categorized according to age by decade. We used multivariate logistic regression models to predict use of sentinel lymph node biopsy. Additional covariates other than age included sex, race/ethnicity, T stage, tumor histology, tumor location, ulceration, and LDH status. Likelihood of undergoing sentinel lymph node biopsy was reported as odds ratios (OR) with 95% confidence intervals (CI); significance was set at p ≤ 0.05. Results: Among 12,283 patients with intermediate thickness cutaneous melanoma, 12,206 had complete information regarding the use of sentinel lymph node biopsy. Of these, 6,642 (54.4%) underwent sentinel node biopsy. On multivariate analysis, patients in the two oldest age categories were less likely to receive sentinel node biopsies (age 70 to 79 years OR 0.65, CI 0.55-0.76 and age 80 years or more OR 0.29, CI 0.24-0.35). Additional factors associated with a decreased likelihood of receiving a sentinel node biopsy included head and neck primary tumor site (OR 0.57, CI 0.51-0.64), high (OR 0.45, CI 0.31-0.65) or unknown (OR 0.32, CI 0.28-0.36) serum LDH, Asian (OR 0.58, CI 0.36-0.94) or unknown (OR 0.51, CI 0.36-0.72) race, and lentigo histology (OR 0.79, CI 0.66-0.95). Conclusions: Elderly patients with intermediate thickness melanoma are less likely to receive sentinel node biopsy than their younger counterparts. The elderly may benefit from sentinel node biopsy, and efforts should be made to increase performance of this procedure in this population. Further research to assess reasons why the elderly are less likely to receive sentinel node biopsy are needed.
Phase I study of the PI3K/mTOR inhibitor PF-05212384 in combination with other antitumor agents.
Authors: Zev A. Wainberg, Geoffrey Shapiro, Giuseppe Curigliano, Stephen Leong, Rebecca Sophie Kristeleit, Maria Alsina Maqueda, Carolyn D. Britten, Michele Milella, Mark R. Middleton, Anthony J. Olszanski, Ulka N. Vaishampayan, Jose A. Lopez-Martin, Karen A. Gelmon, Nicoletta Brega, Kristen J. Pierce, Rachelle Perea, Brett Edward Houk, Nuzhat Pathan, Ashwin Gollerkeri, Albiruni R. A. Razak
Journal: Journal of Clinical Oncology (2015)

2590 Background: Inhibition of phosphatidylinositol-3-kinase (PI3K)-mediated signaling may overcome resistance to different classes of chemotherapies as well as epidermal growth factor receptor (EGFR) inhibitors. PF-05212384 (PF384) is an intravenous (IV) inhibitor of PI3K/mammalian target of rapamycin (mTOR) in development for metastatic colorectal cancer and other solid tumors in combination with other agents. Methods: An ongoing phase I dose escalation study is enrolling cohorts of 3–6 patients (pts) to determine maximum tolerated dose (MTD) and safety of PF384 plus docetaxel (arm A), cisplatin (arm B), or the EGFR tyrosine kinase inhibitor dacomitinib (arm C). Eligible pts have castrate resistant prostate cancer, advanced breast cancer, or non-small cell lung cancer (NSCLC; arm A); urothelial transitional cell cancer, triple negative breast cancer, or NSCLC (arm B); or refractory Her2+ breast cancer, Her2+ esophagogastric cancer, head and neck squamous cell cancer, or EGFR-mutated NSCLC (arm C). Dose assignment is guided by a modified toxicity probability interval method (arms A,B) or zone-based design (arm C). Pts receive a lead-in PF384dose 7 (arms A,B) or 14 days (arm C) prior to cycle 1 day 1. Then, pts receive weekly PF384plus standard chemotherapy (docetaxel or cisplatin 75 mg IV every 3 wk) or dacomitinib (30–45 mg/d orally; started 7 days prior to cycle 1 day 1). Primary endpoint is cycle 1 dose-limiting toxicities (DLTs), including lead-in dose. Secondary endpoints include pharmacokinetics, tumor response, and PI3K pathway protein biomarkers. Results: 52 pts received escalating doses (90–150 mg) of PF384: 14, 12, and 26 pts in arms A, B, and C. Drug-related adverse events in > 30% pts were neutropenia, mucositis, and nausea in arm A; nausea, decreased appetite, fatigue, vomiting, anemia, and hypomagnesaemia in arm B; and mucositis, diarrhea, nausea, dermatitis acneiform, and decreased appetite in arm C. There were no DLTs in arms A or B; in arm C, DLTs were grade 3 mucositis, pneumonitis, and rash, and grade 2 fatigue ( < 75% of planned dose received). Conclusions: PF384can be combined with docetaxel, cisplatin, or dacomitinib with a manageable toxicity profile. Dose escalation to determine MTD is ongoing. Clinical trial information: NCT01920061.
Genetic variant in the microRNA binding site of <i>DOK3</i> (rs2279398G&gt;A) and susceptibility to colorectal cancer.
Authors: Jong Gwang Kim, Hyo-Sung Jeon, Byung Woog Kang, Yee Soo Chae, Soo Jung Lee, Gyu Seog Choi
Journal: Journal of Clinical Oncology (2014)

1537 Background: Single nucleotide polymorphisms (SNPs) located in the 3’-UTR of miRNA target genes could affect miRNA-mediated gene regulation, thereby contributing to the susceptibility or prognosis of colorectal cancer. Docking protein 3 (DOK3) is adapter protein that acts as tumor suppressor through modulating RAS signaling pathway. The present study analyzed SNPs located at putative miRNA-binding sites of the 3’-UTR of various genes and investigated their impact on the susceptibility of colorectal cancer. Methods: One hundred thirty five SNPs were selected in Silicoanalysis for the current study from 3’UTR SNPs of SNP database, which was based on several miRNA database, calculating miRNA bind efficiency on polymorphism, and HapMap database. Here independent two set of study was designed, 380 healthy controls and 371 colorectal adenocarcinoma patients were enrolled in discovery set, and 524 healthy controls and 521 colorectal adenocarcinoma patients were enrolled in replication set. The SNP genotyping was performed using the Sequenom MassARRAY. Results: In discovery set, 16 SNPs were significantly associated with the risk of colorectal cancer in any genetic model from 135 SNP genotyping. Among 16 SNPs, DOK3 rs2279398G>A was significantly associated in replication set as recessive model (adjusted odds ratio (OR) = 0.65, 95% confidence interval (CI) = 0.44-0.97, P = 0.03). In combined analysis, DOK3 rs2279398G>A was associated with significantly decreased risk of colorectal cancer in codominant and recessive model (adjusted OR = 0.84, 95% CI = 0.73-0.96, P = 0.012, adjusted OR = 0.65, CI = 0.49-0.88, P= 0.004, respectively). Conclusions: DOK3 rs2279398G>A may affect the expression of DOK3 by altering miRNA binding efficiency on miRNA-binding sites of the 3’-UTR of DOK3 and impact on colorectal cancer tumorigenesis. This finding suggests that DOK3 rs2279398G>A may be a useful biomarker for determining the susceptibility to colorectal cancer.
Effect of renal function (RF) on outcomes in the adjuvant treatment of older women with breast cancer (&gt;65 years): CALGB/CTSU 49907 (CC) ancillary data study.
Authors: Stuart M. Lichtman, Constance Cirrincione, Arti Hurria, Aminah Jatoi, Maria Theodoulou, Antonio C. Wolff, Julie Gralow, Daniel Morganstern, Gustav Magrinat, Harvey Jay Cohen, Hyman Muss
Journal: Journal of Clinical Oncology (2013)

9515 Background: CC 49907 showed superiority of standard therapy (cyclophosphamide/doxorubicin [AC] or cyclophosphamide/methotrexate/5-fluorouracil [CMF]) over capecitabine[C]. Dose adjustments made for renal insufficiency (RI) for methotrexate and C; ideal body weight used. Purpose was to analyze the relationship between RF at baseline and 5 endpoints: toxicity, dose modification, therapy completion, relapse-free survival [RFS] and overall survival [OS]. Methods: Pre-treatment RF was calculated (Cockcroft-Gault). Endpoints assessed by regimen. RF was tested as a dichotomous and continuous variable of stages 1,2 vs. 3,4 kidney disease (National Kidney Foundation). Logistic regression modeled the relationship between renal stage and the first three endpoints of toxicity, dose modification and therapy completion. Toxicity divided by hematologic or not. The relationship of RFS and OS with RF was assessed with the logrank test and as a continuous variable with Wald chi square. Results: 619 patients; incidence of stage 3/4 RI(&lt;60 ml/min) was: CMF=72%; AC=64%; C=75%. With AC the incidence of toxicity differed by renal function. 31% of patients with poorer function &gt;grade 3 non-hematologic toxicity vs. 14% with better function(p=0.011). There was a suggestion of effect of RF on OS and RFS for C-treated patients. RF was not associated with dose modification, premature therapy termination, RFS or OS for the CMF-treated patients. Conclusions: 1) AC: declining RF was associated with increased non-hematologic toxicity. 2)Patients with RI who received dose modifications were not at increased risk for complications in comparison to those who did not have renal insufficiency and received full dose. 3)Declining RF did not affect therapy completion. 4)C: suggestion that worse RF was related to poorer RFS or OS. 5)Exclusion of patients from clinical trials with RI based on concern of excessive hematologic toxicity may not be justified with appropriate modification. 6)Results should be considered in the design of clinical trials for older patients.
Location, extent and persistence of hyperdense arteries affects outcome in acute ischemic stroke
Authors: Grant Mair, Ruediger von Kummer, Zoe Morris, Anders von Heijne, Nick Bradey, Lesley Cala, Andre Peeters, Andrew Farrall, Alessandro Adami, Gillian Potter, Geoff Cohen, Peter Sandercock, R. Lindley, Joanna Wardlaw
Journal: Circulation (2014)
Distinct ON/OFF fluorescence signals from dual-responsive activatable nanoprobes allows detection of inflammation with improved contrast
Authors: Mathieu L. Viger, Guillaume Collet, Jacques Lux, Viet Anh Nguyen Huu, Monica Guma, Alexandra Foucault-Collet, Jason Olejniczak, Shivanjali Joshi-Barr, Gary S. Firestein, Adah Almutairi
Journal: Biomaterials (2017)
Persistent oxaliplatin (OX) induced peripheral neuropathy in patients (pts) with colorectal cancer: A descriptive study.
Authors: Sina Vatandoust, Rohit Joshi, Vy Broadbridge, Kenneth B. Pittman, Jacqueline Adams, Nimit Singhal, Margaret Colbeck, Susan Yeend, Timothy Jay Price
Journal: Journal of Clinical Oncology (2012)

e19513 Background: Available data suggest that the OX-induced neuropathy is usually reversible and a minority of pts will have persistent severe (grade 3) side effects (24.1% any grade and 0.7% grade 3 at 18 months follow up from MOSAIC trial). We have explored the frequency of persistent peripheral neuropathy in pts who received OX for colorectal cancer at 2 local centres in South Australia. Methods: Pts who completed treatment with OX for colorectal cancer at least 20 months prior to entering the study were eligible and were sent consent and questionnaire. Neuropathy questions were adapted from the FACT/GOG-Ntx (V.4) questionnaire. No pts received Calcium and Magnesium with OX. Statistical tests used to analyze the data were t-test and chi- square. Results: Of the 56 eligible pts, 27 consented to enrol in the study. Median age was 66 yrs. 19 were stage 3, 8 stage 4. Mean total OX dose was 712.1 mg/m2 (range: 170 - 1200 mg/m2); mean number of OX cycles was 8.2 (range 2 - 13), median time between last dose of OX and completing the questionnaire was 37 months (range 20 - 93). 7 pts (25.9%) had a history of diabetes mellitus and 7 had significant alcohol intake. No pts had neuropathic symptoms prior to treatment with OX. 25 pts (92.7%) experienced neuropathic symptoms during their treatment, 11 had grade 2, and 2 had grade 3 symptoms (limiting self care activities of daily living). At the time of completing the questionnaire, 17 pts (63%) were still symptomatic with 9 pts (33.3%) having grade 2 and 3 pts (11.1%) having grade 3 neuropathic symptoms. In the cohort of pts with persistent grade 2 symptoms, 3 pts had walking difficulty and 2 pts could not drive safely due to side effects. Persistent grade 2/3 symptoms were more common in pts who received total OX doses of 722 mg/m2 or more (p &lt; 0.05). Conclusions: Our observation indicates that a majority of pts will have persistent neuropathy more than 20 months after completing treatment with OX and a significant proportion will still have grade 2/3 symptoms. Higher total OX dose might be one of the risk factors in this group. These results should be further prospectively evaluated in a larger population as these long term side effects may affect pts’ daily activities and safety.
Molecular characterization of squamous cell carcinoma of the anal canal (SCCA).
Authors: Benjamin Adam Weinberg, Heinz-Josef Lenz, David Arguello, Wafik S. El-Deiry, Joanne Xiu, Zoran Gatalica, Zhuqing Liu, Sting Chen, Hesham El Ghazaly, Jimmy J. Hwang, Philip Agop Philip, Anthony Frank Shields, John Marshall, Mohamed E. Salem
Journal: Journal of Clinical Oncology (2017)

538 Background: Nivolumab has shown promising results in SCCA patients. The majority of SCCA cases have been linked to prior human papillomavirus (HPV) infection. However, HPV negative tumors are frequently TP53 mutated and often resistant to therapy. Molecular characteristics of SCCA are largely undefined. Here we explored the underlying biology of SCCA and the differences between TP53-wild type ( TP53-WT) and TP53-mutated ( TP53-MT) tumors. Methods: SCCA specimens underwent multiplatform testing with protein expression (IHC), gene amplification (ISH), and sequencing (NGS). Tumor mutational burden (TMB) was calculated using only somatic nonsynonymous missense mutations. Chi-square tests were used for comparative analyses. Results: In total, 253 tumors were studied. The most frequently mutated genes included PIK3CA (24%), BRCA2 (14%), FBXW7 (12.4%), TP53 (9.7%), and PTEN (8.9%). In a subset of 23 tumors subjected to Illumina NextSeq (592 gene) testing, the most common mutations were NOTCH2 (30%), NOTCH1 (27.3%), POLE (21.7%) , TSC2 (17.4%), PTEN (14.3%), BRAF (13.6%), BRCA2 (13.0%), PIK3CA (13.0%), and FBXW7 (9.5%). Tumors frequently expressed MRP1 (97.6%), EGFR (92.7%), TOP2A (88.5%), TOPO1 (69.5%), MGMT (67.8%), and RRM1 (59.9%). Expression of PD-1 was seen in 55.8% (24/43) of tumors, and PD-L1 in 15.4% (9/34). HER2 was amplified in 2% (3/147) of samples, which has not been previously described in SCCA. When compared with TP53-WT (n = 93) tumors, T P53-MT (n = 10) had higher rates of BRAF (22% vs. 1%, p &lt; 0.001) and RB1 mutations (44% vs. 0%, p &lt; 0.001), whereas TP53-WT had higher expression of TOPO1 (76% vs. 40%, p = 0.01) and TUBB3 (19% vs. 50%, p = 0.02). There were no differences between the two groups in the frequency of PD-1 or PD-L1 expression. Mean TMB was 8.6 mutations/megabase and, using a TMB cut-off &gt; 17 mutations/megabase to define high vs. low TMB, 6.7% of tumors were TMB-High. High TMB did not correlate with PD-1 (p = 0.50) or PD-L1 status (p = 0.52). Conclusions: Molecular profiling differences between TP53-MT and TP53-WT SCCA indicate different carcinogenic pathways and biology, which may influence response to therapy. Low frequency mutations in several druggable genes may provide therapeutic opportunities for patients with SCCA.