tbuckley/cabot-search huggingface dataset:
Pembrolizumab as first-line therapy in cisplatin-ineligible advanced urothelial cancer: Results from the total KEYNOTE-052 study population.
Authors: Arjun Vasant Balar, Daniel E. Castellano, Peter H. O'Donnell, Petros Grivas, Jacqueline Vuky, Thomas Powles, Elizabeth R. Plimack, Noah M. Hahn, Ronald De Wit, Lei Pang, Mary Savage, Rodolfo F. Perini, Stephen Michael Keefe, Dean F. Bajorin, Joaquim Bellmunt
Journal: Journal of Clinical Oncology (2017)

284 Background: Treatment options are limited for patients (pts) with advanced urothelial cancer (UC) ineligible to receive cisplatin-based chemotherapy. Interim results from the first 100 pts enrolled in the phase 2, open-label KEYNOTE-052 (ClinicalTrials.gov, NCT02335424) study suggested first-line pembrolizumab (pembro) had antitumor activity and acceptable safety in this pt population. Results from the fully enrolled study are presented. Methods: Key eligibility criteria included age ≥ 18 y, advanced UC of the renal pelvis, ureter, bladder, or urethra, cisplatin ineligibility (ECOG PS 2, creatinine clearance ≥ 30 to &lt; 60 mL/min, grade ≥ 2 neuropathy or hearing loss, NYHA Class 3 heart failure), no prior systemic chemotherapy for advanced UC, measurable disease per RECIST v1.1, ECOG PS 0-2, and provision of a tumor sample for biomarker analyses. Pembro 200 mg was administered every 3 wk. Imaging was performed at wk 9, then every 6 wk for the first year, and every 12 wk thereafter. The primary end point was confirmed overall response rate (ORR; RECIST v1.1, independent review). Efficacy data are presented for pts with ≥ 4 mo follow-up, and safety data are presented for all pts. Results: In total, 370 pts were enrolled; median age was 74 y (range, 34-94 y); 42% had an ECOG PS 2. Reasons for cisplatin ineligibility included ECOG PS 2 (32%), renal dysfunction (49%), and both ECOG PS 2 and renal dysfunction (10%). ORR (95% CI) was 27% (22%-32%) among pts with ≥ 4 mo follow-up (n = 307); 6% of pts achieved a complete response. Among the ≥ 4 mo follow-up group, median (range) time to response was 2.0 (1.6-4.8) mo; median (range) duration of response was not reached (1+ to 14+ mo). 78% of responders had a response for ≥ 6 mo (KM estimate). PFS and OS rates at 6 mo were 31% and 67%, respectively (KM estimate). Any grade and grade ≥ 3 drug-related AEs occurred in 229 (62%) and 58 (16%) pts. 19 (5%) pts discontinued treatment because of a drug-related AE. Conclusions: Results from the fully enrolled KEYNOTE-052 study confirm that pembro elicits clinically meaningful and durable responses in cisplatin-ineligible pts with UC, including elderly pts and those with poor performance status. Clinical trial information: NCT02335424.
Peripheral primitive neuroectodermal tumor of the mandible with cytogenetic &amp; molecular biology aberrations
Authors: S. J. Alrawi, D. Tan, M. Sullivan, J. Winston, W. Hicks, T. Loree, N. Rigual
Journal: Journal of Clinical Oncology (2004)

5594 Objective and Importance: Peripheral primitive neuroectodermal tumors (pPNET) are rare types of malignant neoplasms, most commonly found in the limbs of children and young adults. The authors report an extremely rare case of pPNET of the mandible with rapid progression, with both cytogenic and chromosomal studies representing the first case in the literature sharing clincopathological, molecular biology aberration and surgical reconstruction findings. Clinical Presentation: An 18-year old African American girl presented with rapidly growing painless mass and induration at the chin area of the mandible at the end of her first pregnancy, without any associated symptoms. Intervention: The patient was treated with 2 cycles of outpatient (Adriamycin, Vincristine and Cytoxan) and inpatient treatment (Ifosffamide, Mesna, and VP-16), subsequently patient had partial mandibulectomy, resection floor of the mouth, bilateral selective neck dissection, free fibula flap and osteointegrated implant for reconstruction. Conclusion: The pathological finding of the surgical specimen was pPNET. Fluorescence in situ hybridization (FISH) did not show deletion (5)(p11), or translocation (11; 22)(q24; q12) in the analyzed cells. The detected t (11; 22) is diagnostically important cytogenetic rearrangement typical of ES/pPNET in 90% of tumors. This case represents a rare variant of pPNET. To the best of our knowledge, this is the third reported case of pPNET of the mandible and the first one with cytogenetic and molecular biology study in the literature. Pathological features, chromosomal analysis, cytogenetic and molecular aberrations are crucial for accurate diagnosis. Multidisplinary approach is necessary in the management of this rare tumor. No significant financial relationships to disclose.
Detection of <i>KIT</i> mutants in circulating tumor DNA (ctDNA) and their association with ponatinib anti-tumor activity in patients (pts) with advanced gastrointestinal stromal tumors (GIST).
Authors: Michael C. Heinrich, J. Graeme Hodgson, Margaret von Mehren, George D. Demetri, Jonathan A. Fletcher, Jichao G Sun, Justin R Pritchard, Sen Zhang, Victor M. Rivera, Suzanne George
Journal: Journal of Clinical Oncology (2015)

10517 Background: Ponatinib is a multi-targeted tyrosine kinase inhibitor with potent preclinical activity against a broad range of clinically relevant KIT mutants, including primary-activating (especially exon 11) and secondary-resistance (including exons 17/18) mutants. Ponatinib is being evaluated in a phase 2 trial (NCT01874665), in which TKI-resistant metastatic GIST pts are enrolled in 2 cohorts based on the presence (A) or absence (B) of KIT exon 11 mutations in tumor specimens. We used ctDNA to explore the association between KIT mutation status and anti-tumor activity of ponatinib. Methods: Plasma samples were collected at baseline (BL) and every 8 wks, and a subset analyzed for 7 primary (exons 9, 11, 13) and 20 secondary (exons 13, 14, 17, 18) mutations using BEAMing. The primary trial endpoint was clinical benefit rate (CBR = CR+PR+SD at 16 wks) using modified RECIST 1.1 in cohort A. Associations between changes in ctDNA levels and tumor burden (RECIST lesions) were assessed by calculating an odds ratio (OR) and p-value. Data as of Dec 1, 2014, based on 32 evaluable pts of 45 enrolled pts. Results: 21 pts in cohort A had a BL sample, with secondary mutations detected in 11. All 11 pts had 1 (n = 6) or multiple (n = 5) detectable mutations in exon 17/18, commonly involving residues D820, N822, or Y823 – 1 pt also had a gatekeeper mutation in exon 14 (T670I); the CBR in these pts was 55% (6/11). 11 pts in cohort B had a BL sample, with a secondary mutation (A829P) only detected in 1.Overall (A+B), 15/23 pts (65%) with BL and post BL samples had at least 1 primary or secondary mutation detected. In these pts, a post BL decrease in mutant KIT ctDNA was associated with a reduction in tumor burden at that time point (OR = 13.6; p= 0.035). Additional analyses are ongoing. Conclusions: Primary and/or secondary KIT mutations were detected in ctDNA from a majority of TKI-resistant GIST pts and their levels were associated with tumor burden over time. Importantly, antitumor activity of ponatinib was observed in pts with exon 17/18 mutants detectable by ctDNA. Further exploration of the utility of ctDNA KIT mutation analysis for monitoring responses in GIST is warranted. Clinical trial information: NCT01874665.
Second primary tumors in cancer patients: A retrospective analysis based on institutional tumor registry.
Authors: Luca Fumagalli, Edoardo Botteri, Marzia Adelia Locatelli, Lucia Gelao, Carmen Criscitiello, Silvia Manunta, Nicole Rotmensz, Aron Goldhirsch, Giuseppe Curigliano
Journal: Journal of Clinical Oncology (2013)

1595 Background: The relative risk of developing a second tumor by site of primary tumor or gender is still unclear. Methods: We retrospectively analyzed data of 24,224 consecutive patients admitted to the European Institute of Oncology between 2000 and 2006 for a first primary invasive tumor. All the data were extracted from the institutional Tumor Registry. All tumors were registered and indexed within the same patient’s record. We limited the analysis to the patients who were diagnosed and received at least one treatment in IEO for their first primary tumor. Follow-up was based on the last registered patient’s control visit. Cumulative incidence was compared across different subgroups by means of the Gray test. The observed cases of second metachronous primary tumors was compared with the number of cancers we expected from the general Italian population. We used the standardized incidence ratio (SIR), defined as the ratio of the number of second cancers observed to the number of second cancers expected, to estimate the relative risk of second cancers, and we calculated 95% confidence intervals (95% CIs) by applying the Wilson and Hilferty approximation for chi-square percentiles. Results: In this population the 5-year cumulative incidence of a second tumor on the average population was 5.0%, SIR (CI 95%) was 1.3 (1.2-1.4). The Table reports details on observed versus expected second metachronous primary tumors by first tumor site. Conclusions: Cancer patients have a higher risk of a second primary tumor than general population. [Table: see text]
Overall survival benefit associated with adjuvant radiotherapy in WHO grade II meningioma
Authors: Chenyang Wang, Tania B Kaprealian, John H Suh, Charlotte D Kubicky, Jeremy N Ciporen, Yiyi Chen, Jerry J Jaboin
Journal: Neuro-Oncology (2017)

Adjuvant radiotherapy (RT) after surgical resection of World Health Organization (WHO) grade II meningioma, also known as atypical meningioma (AM), is a topic of controversy. The purpose of this study is to compare overall survival (OS) with or without adjuvant RT after subtotal resection (STR) or gross total resection (GTR) in AM patients diagnosed according to the 2007 WHO classification.The National Cancer Database was used to identify 2515 patients who were diagnosed with AM between 2009 and 2012 and underwent STR or GTR with or without adjuvant RT. Propensity score matching was first applied to balance covariates including age, year of diagnosis, sex, race, histology, and tumor size in STR or GTR cohorts stratified by adjuvant RT status. Multivariate regression according to the Cox proportional hazards model and Kaplan-Meier survival plots with log-rank test were then used to evaluate OS difference associated with adjuvant RT.GTR is associated with improved OS compared with STR. In the subgroup analysis, adjuvant RT in patients who underwent STR demonstrated significant association with improved OS compared with no adjuvant RT (adjusted hazard ratio [AHR] 0.590, P = .045); however, adjuvant RT is not associated with improved OS in patients who underwent GTR (AHR 1.093, P = .737).Despite the lack of consensus on whether adjuvant RT reduces recurrence after surgical resection of AM, our study observed significantly improved OS with adjuvant RT compared with no adjuvant RT after STR.
STING Contributes to Abnormal Bone Formation Induced by Deficiency of DNase II in Mice
Authors: Rebecca Baum, Shruti Sharma, Jason M. Organ, Christopher Jakobs, Veit Hornung, David B. Burr, Ann Marshak‐Rothstein, Katherine A. Fitzgerald, Ellen M. Gravallese
Journal: Arthritis & Rheumatology (2016)

Cytosolic DNA sensors detect microbial DNA and promote type I interferon (IFN) and proinflammatory cytokine production through the adaptor stimulator of IFN genes (STING) to resolve infection. Endogenous DNA also engages the STING pathway, contributing to autoimmune disease. This study sought to identify the role of STING in regulating bone formation and to define the bone phenotype and its pathophysiologic mechanisms in arthritic mice double deficient in DNase II and IFN-α/β/ω receptor (IFNAR) (DNase II-/- /IFNAR-/- double-knockout [DKO] mice) compared with controls.Bone parameters were evaluated by micro-computed tomography and histomorphometry in DKO mice in comparison with mice triple deficient in STING, DNase II, and IFNAR and control mice. Cell culture techniques were employed to determine the parameters of osteoclast and osteoblast differentiation and function. NanoString and Affymetrix array analyses were performed to identify factors promoting ectopic bone formation.Despite the expression of proinflammatory cytokines that would be expected to induce bone loss in the skeleton of DKO mice, the results, paradoxically, demonstrated an accumulation of bone in the long bones and spleens, sites of erythropoiesis and robust DNA accrual. In addition, factors promoting osteoblast recruitment and function were induced. Deficiency of STING significantly inhibited bone accrual.These data reveal a novel role for cytosolic DNA sensor pathways in bone in the setting of autoimmune disease. The results demonstrate the requirement of an intact STING pathway for bone formation in this model, a finding that may have relevance to autoimmune diseases in which DNA plays a pathogenic role. Identification of pathways linking innate immunity and bone could reveal novel targets for the treatment of bone abnormalities in human autoimmune diseases.
Gene expression profiling in bladder cancer to identify potential therapeutic targets.
Authors: Syed A. Hussain, Daniel H. Palmer, Wing Kin Syn, Joseph J Sacco, Bryony Lloyd, Puthen Jithesh, John R. Arrand, Darren Barton, Jawaher Ansari, David R Sibson, Nicholas David James
Journal: Journal of Clinical Oncology (2013)

4518 Background: Characterization of gene expression patterns in bladder cancer (BC) allows the identification of pathways involved in its pathogenesis, and may stimulate the development of novel therapies targeting these pathways. Methods: Between 2004 and 2005, cystoscopic bladder biopsies were obtained from 19 patients and 11 controls. These were subjected to whole transcript-based microarray analysis. Unsupervised hierarchical clustering was used to identify samples with similar expression profiles. Results: Hierarchical clustering defined signatures, which differentiated between cancer and normal, muscle-invasive or non-muscle invasive cancer and normal, g1 and g3. Pathways associated with cell cycle and proliferations were markedly upregulated in muscle-invasive and grade 3 cancers. Genes associated with the classical complement pathway were downregulated in non-muscle invasive cancer. Osteopontin was markedly overexpressed in invasive cancer as compared to normal tissue. Conclusions: This study contributes to a growing body of work on gene expression signatures in BC. The data support an important role for osteopontin in BC, and identify several pathways worthy of further investigation. [Table: see text]
Mutation-based treatment recommendations from next generation sequencing data: A comparison of web tools.
Authors: Jaymin Patel, Eric Reiner, Veerle Bossuyt, Lianne Epstein, James Platt, Michael DiGiovanna, Gina G. Chung, Andrea Silber, Tara Beth Sanft, Erin Wysong Hofstatter, Sarah Schellhorn Mougalian, Maysa M. Abu-Khalaf, Peter Gershkovich, Christos Hatzis, Lajos Pusztai
Journal: Journal of Clinical Oncology (2015)

e12564 Background: The purpose of this study was to examine if different websites identify similar or different therapeutic options for a given set of genomic anomalies detected during tumor profiling. Methods: Targeted sequencing of 315 genes from 47 metastatic breast cancer biopsies was performed using the FoundationOne assay (Foundation Medicine). All reported genomic anomalies from each case were used to query the Drug Gene Interaction Database (DGIdb), My Cancer Genome, Personalized Cancer Therapy (PCT), and cBioPortal, for drug and clinical trial recommendations. These recommendations along with those provided by FoundationOne were then evaluated for concordance. Results: Eighty four distinct genes had either a mutation or a copy number change in at least one of the 47 cases. The median number of alterations per case was 5 (range 2-18). For 37 genes (44%), there was at least one FDA approved drug recommendation. The recommendation source that identified the most FDA approved drugs was DGIdb (for 32 genes) followed by FoundationOne (for 25 genes), cBioPortal (for 23 genes) and PCT (for 8 genes). The most commonly recommended drugs were everolimus and temsirolimus for 11 genes (PIK3CA, PIK3R1, PTEN, STK11, AKT-1,-2-,3, TSC2, KIT, PDGFRB, KRAS). Overall, 6 cases (13%) had at least 1 gene with the same FDA approved drug recommendation from 4 sources, 30 cases (64%) had an overlapping recommendation from 3 sources, 7 cases (15%) from 2 sources and 4 cases (9%) with no overlapping recommendations at all. Clinical trial recommendations were reported for 44 genes. The source with the most complete clinical trial recommendation was the FoundationOne report (44 genes) followed by the PCT website (8 genes). Overall, 77% of the cases had an FDA approved drug recommendation for at least one mutated gene concordant across > 3 sources, and 74% had a clinical trial recommendation concordant across > 2 sources. Conclusions: We observed substantial but only partial overlap in potential treatment options from different web tools based on the same input data.
Comparison of clinical parameters and survival in Vietnam era (V) versus non-Vietnam era (non-V) veterans with non-Hodgkin lymphoma (NHL).
Authors: Shanthi Srinivas, Victor T Chang, Leroy Cordero Floyd, Basil Kasimis, Melanie L. Gonzalez, Monica McPherson, Janet Cogswell, Barbara Crump, Lourdes Duque, Emma R Paz-Querubin
Journal: Journal of Clinical Oncology (2012)

e18516 Background: The incidence of NHL has been increasing in the US population. Agent Orange exposure has been implicated in the development of B cell lymphoproliferative disorders including NHL. We explored possible differences in the clinical and lab parameters and predictors of survival in V versus Non-V veterans with diagnosis of NHL at the VAHCSNJ. Methods: In an IRB-approved protocol, the records of veterans diagnosed with NHL from January 1997 to December 2011 were reviewed for demographic, clinical, and pathology data, including HIV, Hep B, Hep C titers, Vietnam Veteran status and survival. We tabulated the ECOG Performance Status (PS), International Prognosis Index (IPI)/ Follicular Lymphoma International Prognostic Index (FLIPI), Charlson Comorbidity Index (CMI), the Kaplan-Feinstein Index (KFI), the Cumulative Illness Rating Scale (CIRS) and Vietnam status. Cox regression analyses were performed to determine predictors of survival. Results: There were 152 veterans who met the eligibility criteria; 78 V and 74 non-V; the groups did not differ by PS, stage, beta 2microglobulin (b2m), and HIV status, IPI/FLIPI. Differences in their clinical features are summarized (Table). The proportion of V vets with high grade lymphomas was greater than non V vets (p .036). Survival predictors for both the V and non-V veterans were the age, PS, hemoglobin, LDH, albumin, grade, IPI/FLIPI. However, in V veterans, b2m (p&lt; 0.001) and stage were additional predictors of survival. Median survival for V veterans was 1454 days (95%CI 864-3377) and Non-V was 1824 days (95% CI 560-2075). Conclusions: The V veterans were younger with higher grade disease compared to the Non-V veterans. While their stage and PS were not different, survival was shorter. These should be studied further in a larger sample. [Table: see text]
Accuracy of ultrasound during neoadjuvant therapy for breast cancer to predict pathologic response.
Authors: Michael Luke Marinovich, Nehmat Houssami, Petra Macaskill, Gunter Von Minckwitz, Jens U. Blohmer, Les Irwig
Journal: Journal of Clinical Oncology (2014)

1089 Background: Early assessment of response to neoadjuvant chemotherapy (NAC) for breast cancer may allow therapy to be tailored; however the optimal method for response assessment has not been established. We estimated the accuracy of ultrasound (US) to predict pathologic response (pCR) after NAC using common response criteria and pCR definitions, and estimated incremental accuracy of US over known prognostic variables. Methods: Participants in the GeparTrio trial with US tumor measurements at baseline and after two (of six) NAC cycles, and randomised to no change in NAC, were eligible. US partial response in two dimensions was assessed by World Health Organisation (WHO 2D) criteria; Response Evaluation Criteria In Solid Tumors (RECIST) and WHO criteria were also applied to the longest diameter (1D). Four pCR definitions were applied. Sensitivity (correct prediction of pCR), specificity (correct prediction of no-pCR), and diagnostic odds ratios (DORs) were calculated. Areas under the curve (AUCs) were derived from logistic regression models of the probability of pCR, including patient variables with and without US. Results: In 832 patients, there was a significant trend for decreasing DORs as the pCR definition became less stringent (p=0.01). For WHO 2D, DORs for the pCR definitions were 4.07 (ypT0 ypN0), 3.75 (ypT0/is ypN0), 3.14 (ypT0/is ypN+/-), and 2.65 (ypT0/is/1a ypN+/-). DORs did not differ between US criteria (p=0.60). Comparable high sensitivity and lower specificity within pCR definitions were found for WHO 2D and RECIST; WHO 1D was highly specific with low sensitivity. Sensitivity was highest for prediction of ypT0 ypN0 by WHO 2D (sensitivity=81.7% specificity=47.6% vs. 42.3% and 80.4% for WHO 1D). Adding US to models including patient variables (age, T stage, histology, subtype) improved the AUC for predicting pCR by 2-3%, regardless of US criterion or pCR definition. Conclusions: US accuracy is highest for the prediction of pCR defined as ypT0 ypN0, shown by previous studies to be most predictive of long term survival. WHO 2D and RECIST criteria maximise sensitivity, while specificity is maximised by WHO 1D. Knowledge of the US result modestly improves the prediction of pCR by patient characteristics.