tbuckley/cabot-search huggingface dataset:
Prospective comparison of different methods of identifying Lynch Syndrome (LS) associated endometrial cancer (EC) and prognostic factor (PF) impact.
Authors: Ignacio Romero, Zaida Garcia-Casado, Pedro Martinez, Carmen Illueca, Cristina Zorrero, Jose Manuel Bosch, Lucas Minig, Jose Antonio Lopez-Guerrero, Andres Poveda
Journal: Journal of Clinical Oncology (2016)

e17102 Background: Different criteria have been used to identify LS in EC but not prospectively compared. Methods: We prospectively registered EC cases. We performed a three-generation pedigree, Microsatellite Instability (MSI), staining for Mismatch Repair Proteins (MMRPro) and complete sequencing, and large rearrangement screening for MLH1, MSH2 and MSH6, and EPCAMlast exon loss. Results: We included 98EC patients with a median age of 62 years (31-86), type I EC 82.5%, FIGO 2009 stages I-II, III and IV were 78%, 14% and 8% respectively. EC pathologic criteria related to LS such as lower uterine segment, dedifferentiation (D), tumoral lymphocytes infiltration (TIL) and peritumoral lymphocytes were observed in 35.7%. Loss of MMRPro was found in 29%, MSI-high (MSI-H) in 28%, defective MMR (MMRPro loss and/or MSI-H) in 33% that lowered to 21% if MLH1-methylation was excluded (termed “really defective MMR”). Bethesda Criteria (rBC), Amsterdam II (A-II), SGO (5-10%), SGO (20-25%) were fulfilled in 15.6%, 5.2%, 18.9% and 12.5% respectively. Deleterious mutations were detected in 7%; 2 MLH1, 2 MSH2 and 3 MSH6. Sensitivity (S) and specificity (E) analysis (table 1) showed the higher E (97%) for A-II and the higher S (67%) for MMRPro loss. Receiver operating curves (ROC) were calculated (table 1) and for both SGO (20-25%) and “really defective MMR” AUC reached 0.66. For stage I-III, with a median follow-up of 45 months (0-78) and median relapse free survival (RFS) at 5 years of 82% only type II histology remained PF whereas MSI-H did not. D (p=0.169) and lack of TIL (p=0.430) showed a trend towards worse prognosis. Conclusions: Compared to mutational analysis MMRPro loss has the highest S for identifying LS-EC and SGO (20-25%) and “Really Defective MMR” the highest ROC-AUC. S and E analysis and ROC for identifying LS-EC. Criteria S (%) E (%) AUC CI 95% rBC 43 20 0.65 0.41-0.88 AII 29 97 0.62 0.38-0.87 SGO>20-25% 43 90 0.66 0.42-0.90 SGO>5-10% 43 83 0.63 0.39-0.86 EC-LS histology 43 65 0.54 0.31-0.76 MMRPro Loss 67 29 0.48 0.23-0.72 MSI-H 43 74 0.58 0.35-0.81 Defective MMR 50 68 0.59 0.35-0.83 Really Defective MMR 50 81 0.66 0.41-0.91
Stage-specific roles for Zmiz1 in Notch-dependent steps of early T-cell development
Authors: Qing Wang, Ran Yan, Nancy Pinnell, Anna C. McCarter, Yeonjoo Oh, Yiran Liu, Cher Sha, Noah F. Garber, Yitong Chen, Qingqing Wu, Chia-Jui Ku, Ivy Tran, Amparo Serna Alarcon, Rork Kuick, James Douglas Engel, Ivan Maillard, Tomasz Cierpicki, Mark Y. Chiang
Journal: Blood (2018)
Increase in time to initiating cancer therapy and association with worsened survival in curative settings: A U.S. analysis of common solid tumors.
Authors: Alok A. Khorana, Katherine Tullio, Paul Elson, Nathan A. Pennell, Matthew F. Kalady, Daniel Raymond, Eric A. Klein, Jame Abraham, Stephen R. Grobmyer, Emily Elizabeth Monteleone, Brian James Bolwell
Journal: Journal of Clinical Oncology (2017)

6557 Background: Increase in time to treatment initiation (TTI) for new cancer diagnoses causes patient distress and may adversely affect outcomes. We investigated trends in TTI for common solid tumors treated with curative intent, determinants of delayed TTI and impact on overall survival. Methods: We utilized population-based, prospective data from the National Cancer Database for newly diagnosed US patients with early-stage breast, prostate, lung, colorectal, renal and pancreas cancers from 2004-13. TTI was defined as days between diagnosis of cancer and first treatment (surgery, systemic or radiation therapy). Negative binomial regression and Cox proportional hazard models were used for analysis. Results: The study population of 3,672,561 patients included breast (N = 1,368,024), prostate (N = 944,246), colorectal (N = 662,094), non-small cell lung (NSCLC)(N = 363,863), renal(N = 262,915) and pancreas (N = 71,419) cancers. Median TTI increased from 21 days in 2004 to 29 days in 2013 (P &lt; 0.0001). Aside from year, determinants of delays included care at academic centers and change in treating facility. Increased TTI was associated with worsened overall survival (OS) for stages I and II breast, lung, renal, and pancreas cancers, and stage II colorectal cancers, with hazard ratios per week of delay ranging from1.005 (1.002-1.008) to 1.030 (1.025-1.035), adjusting for comorbidities and other variables. Prolonged TTI ( &gt; 6 wks) was associated with substantially worsened OS e.g., 5-yr OS for stage I NSCLC was 56% (±0.2) for TTI ≤ 6wks v 43% (±0.2) for TTI &gt; 6 wks and for stage I pancreas was 38% (±0.6) v 29% (±1) respectively (P &lt; 0.0001 for both). Conclusions: TTI has lengthened significantly over recent years, associated with multiple factors. Increase in TTI is associated with substantial increase in mortality ranging from 0.5-3.2% per week of delay in curative settings such as early-stage breast, lung and pancreas cancers. Simplifying access and navigation of complex health systems is essential to diminish this apparently iatrogenic impact on outcomes.
Clinical activity of the selective DRD2 antagonist ONC201, an imipridone, in metastatic endometrial cancer (mEC).
Authors: Lorna Rodriguez-Rodriguez, Janice M. Mehnert, Ann W. Silk, Nancy Chan, Jyoti Malhotra, Joseph Aisner, Tracie Saunders, Bangning Yu, Siobhan Dickerson, Rohinton Tarapore, Joshua E. Allen, Martin Stogniew, Wolfgang Oster, Howard Kaufman, Bruce George Haffty, Joseph R. Bertino, Mark N. Stein
Journal: Journal of Clinical Oncology (2017)

5592 Background: mEC is a generally incurable, with limited therapeutic options. ONC201 is the founding member of the new class of compounds called imipridones that are orally active small molecules. ONC201 a specific antagonist of the G protein-coupled receptor DRD2 exerts antitumor activity via a series of established signaling pathways (dual inhibition ERK/AKT, integrated stress response). DRD2 expression is elevated in malignant versus normal endometrial tissue. Furthermore ONC201 has shown anti-cancer activity in preclinical models of EC. Methods: In a Phase I trial that included an expansion cohort, a total of 28 evaluable patients (pts) were treated with ONC201 at doses from 125mg every 3 weeks to 625 weekly. Five of these patients had advanced mEC. Results: The median age for the mEC patients was 60 years (56-72), the median number of prior treatments was 5 (3-6), 3 patients had prior radiation and all patients had prior surgery. One patient received 375mg ONC201 while the other 4 patients received 625mg ONC201, orally every 3 weeks. The median number of doses was 3 (2-14). Two of 5 patients exhibited regressions in individual metastatic lesions, however they did not qualify as overall objective responses by RECIST criteria. One of these two patients experienced stable disease for 42 weeks. There were no reported SAEs and no Grade &gt; 1 AEs attributed to study drug. Conclusions: ONC201 is clinically active and well tolerated with oral administration in refractory mEC patients. Clinical trial information: NCT02250781. [Table: see text]
Indirect treatment comparison of nivolumab versus placebo as an adjuvant therapy for resected melanoma.
Authors: Alexander Noor Shoushtari, Morganna Louise Freeman, Keith A. Betts, Komal Gupte-Singh, Ella X. Du, Corey Ritchings, Sumati Rao
Journal: Journal of Clinical Oncology (2018)

9593 Background: There are no randomized trials of nivolumab and placebo as adjuvant therapy in patients with resected melanoma. This study uses pooled data from CheckMate 238 and EORTC 18071 to evaluate the number of patients needed to treat (NNT) based on recurrence-free survival (RFS) for nivolumab vs. placebo and nivolumab vs. ipilimumab over 12 and 18 months. Methods: Patients with stage IIIB or IIIC cutaneous melanoma from the two trials were pooled using propensity score weighting. The following characteristics were adjusted for: age, gender, race, ECOG, time from resection, disease stage, presence of tumor ulceration, lymph node involvement (microscopic vs. macroscopic), baseline LDH, and pretreatment events. The NNTs to achieve one additional recurrence-free survivor for nivolumab compared to placebo and ipilimumab were calculated as the reciprocal of the difference of the weighted RFS rates between treatments at month 12 and month 18. Results: After adjustment, baseline characteristics were balanced between the two trials. 1,286 patients with stage IIIB and IIIC cutaneous melanoma treated with nivolumab (N = 277), ipilimumab (N = 644), and placebo (N = 365) were included in the study. After weighting, the RFS rates of nivolumab, ipilimumab, and placebo were 74.2%, 61.9%, and 48.7% at 12 months and 70.7%, 54.1%, and 41.8% at 18 months, respectively. At month 12, NNT to achieve one additional recurrence-free survivor of nivolumab vs. placebo was 3.9 (95% CI: 3.0, 5.6) and nivolumab vs. ipilimumab was 8.1 (95% CI: 5.2, 18.7). At month 18, NNT to achieve one additional recurrence-free survivor decreased for both nivolumab vs. placebo (3.5; 2.7, 4.7) and nivolumab vs. ipilimumab (6.0; 4.2, 10.8). Conclusions: In patients with resected stage IIIB and IIIC cutaneous melanoma, adjuvant nivolumab was associated with the highest RFS rates compared to placebo and ipilimumab. To prevent one recurrence/death at 12 months, 4 patients would need to be treated with nivolumab instead of observation. With longer follow-up, the number needed to be treated to prevent one recurrence/death decreased, suggesting the magnitude of the clinical benefit may become more prominent over time. Clinical trial information: NCT02388906 and NCT00636168.
Chimeric antigen receptor engineered allogeneic CD27-negative T cells for the treatment of CD19+ leukemia.
Authors: Aimee C. Talleur, Jean-Yves Metais, Ying Li, Barbara Rooney, Ardiana Moustaki, Wing H. Leung
Journal: Journal of Clinical Oncology (2016)

3046 Background: Relapsed/refractory pediatric acute lymphoblastic leukemia (ALL) has a poor prognosis. Adoptive immunotherapy with chimeric antigen receptor (CAR) engineered T cells targeted against a tumor associated antigen, such as CD19 on B-lineage leukemia, has shown immense promise in this patient population. An important aspect of CAR therapy is the source of effector cells, autologous or allogeneic. A barrier to using allogeneic T cells is that the naïve subset may lead to graft-versus-host disease (GVHD). A potential strategy to circumvent this would be to use surface markers such as CD27 to distinguish between naïve and memory T cells. CD27 is present on naïve and central memory T cells, but not on effector memory and terminal effector memory T cells. Our objectives were to determine if allogeneic CD27- cells provide superior immunologic memory against pathogens commonly encountered in patients with refractory ALL and have decreased alloreactivity potential compared to CD27+ cells. We also sought to assess the cytotoxic potential of CD27- cells transduced with an anti-CD19 CAR vector against CD19+ leukemia cells. Methods: CD27- and CD27+ cell fractions were isolated from donor PBMC using magnetic microbead separation. Lymphocyte proliferation assays were performed to determine immunologic memory to antigen and mitogen stimuli. Alloreactivity potential was tested using one-way mixed lymphocyte reactions. CD27- cells were transduced with an anti-CD19 CAR and their cytotoxicity against a CD19+ leukemia cell line was determined in vitro via BATDA assay and in vivo in NSG mice. Results: CD27- cells had stronger immunologic memory against pathogens and were less alloreactive than CD27+ cells. CD27- cells expressing an anti-CD19 CAR demonstrated potent killing of a CD19+ leukemia cell line compared to untransduced CD27- cells, both in vitro and in vivo. Conclusions: CD27- allogeneic cells provide pathogen protection, have low GVHD potential and, when transduced with an anti-CD19 CAR, have cytotoxic capability against CD19+ leukemia cells. These findings make CD27- T cells a promising population to be used as effector T cells in CAR therapy, providing dual infection and leukemia control.
Community-based palliative care utilization in elderly pancreatic cancer patients.
Authors: Zhanni Lu, Cecilia M Ganduglia Cazaban, Luis G LeonNovelo, Sriram Yennu, Sadie H Conway, Linda D Highfield, Sharon Hermes Giordano, Hui Zhao
Journal: Journal of Clinical Oncology (2018)

10108 Background: Community-based Palliative Care (CBPC) has shown to stabilize symptoms, alleviate psychological and spiritual burdens, satisfy care preferences, and improve quality of life among care recipients. We evaluated CBPC utilization and predictors in pancreatic cancer patients ≥66 years. Methods: Palliative Care (PC) encounters among pancreatic cancer patients were identified by ICD-9-CM codes using SEER-Medicare data from 2007 to 2013, and patients were followed until 2014. PC encounters outside hospital settings were classified as CBPC. We tested time trends of CBPC utilization and time to PC referral after cancer diagnosis. Multivariable random intercept logistic models were used to determine the predictors of CBPC utilization at the patient and Health Service Area (HSA) levels. Results: 16,106 patients were included, of whom 27.8% used palliative care; of those, 1,530 (9.5%) used CBPC, and 2,956 (18.3%) used Hospital-based Palliative Care (HBPC). CBPC utilization increased from 8.2% in 2007 to 9.4% in 2013 (p = .014). Median (IQR) PC referral time after cancer diagnosis decreased from 5 (2, 11) mo. in 2007 to 2 (1, 5) mo. in 2013 (p = .001). Being female (OR 1.27 [1.12, 1.45]; p < .001), a diagnosis of advanced cancer stage (III/IV: OR 1.29 [1.002, 1.67]; p = .049), cancer treatment participation (OR 2.24 [1.92, 2.60]; p < .001), or residing in an urban area (OR 1.57 [1.03, 2.39]; p = .035) were positively associated with CBPC utilization. Those living in the poorest communities (OR 0.62[0.47, 0.81]; p = .001) and southern SEER Registries (Georgia, Kentucky and Louisiana) (OR 0.15 [0.09, 0.24]; p < .001) were less likely to use CBPC. HSAs with high density of HBPC programs (an indicator of regional health care resources) were positively associated with CBPC usage (OR 1.50 [1.03, 2.20]; p = .035). Conclusions: CBPC usage increased and referral time decreased over 6 years. Patient-level factors, geographic area characteristics, and regional health care resources were associated with likelihood of receiving CBPC.
PS4 Clinical Outcomes in Hispanic Patients Treated with Checkpoint Inhibitors
Authors: D. Saravia, L. Raez, R. Ruiz, T. Munoz-Antonia, D. Sumarriva, D. Cress, B. Hunis, A. Chiappori, H. Powery, P. Izquierdo, L. Mas, G. Lopes, S. Antonia
Journal: Journal of Thoracic Oncology (2018)
Assessing the value of nivolumab (NIVO) versus placebo (PBO) and ipilimumab (IPI) as adjuvant therapy for resected melanoma.
Authors: Morganna Louise Freeman, Alexander Noor Shoushtari, Keith A. Betts, Komal Gupte-Singh, Ella X. Du, Corey Ritchings, Sumati Rao
Journal: Journal of Clinical Oncology (2018)

9594 Background: Healthcare value frameworks consider the clinical benefits in the context of cost when assessing the value of cancer therapies. Here, we assess the cost per recurrence-free life month (RFLM) and associated drug and medical services costs using pooled data from CheckMate 238 and EORTC 18071 for NIVO compared to PBO and IPI as adjuvant therapies in patients with resected melanoma. Methods: Patients with stage IIIB or IIIC cutaneous melanoma were pooled using propensity score weighting, adjusting for baseline characteristics. For each treatment, RFLMs within 12 and 18 months were calculated as the area under the weighted Kaplan-Meier curve of RFS. Drug acquisition costs and medical service costs were calculated. No drug costs were considered for PBO. Cost per RFLM was calculated by dividing costs per patient by mean duration of RFLMs. Results: 1,286 patients were included in the analysis. After adjustment, baseline characteristics were balanced between the two trials. Overall, the mean duration of RFLM was highest for NIVO vs. both IPI and PBO. NIVO had lower mean drug cost vs. IPI, and lower mean medical cost vs. both PBO and IPI, attributed to lower hospitalizations. Conclusions: In patients with resected stage IIIB and IIIC cutaneous melanoma, adjuvant NIVO provides lower medical cost per RFLM due to longer recurrence-free periods and savings in medical costs compared to PBO and IPI over 1 year. The value of RFLM with NIVO continues to evolve over time compared to IPI and PBO, with improvement in drug costs per RFLM over 18 months compared to IPI. Longer term follow-up and consideration of subsequent therapies will further characterize the cost-effectiveness of adjuvant NIVO. Outcome measures NIVO 3 mg/kg n = 277 IPI 10 mg/kg n = 644 PBO n = 365 Mean duration of RFLMs Within 12 mo 10.2 9.3 8.1 Within 18 mo 14.5 12.8 10.8 Mean drug cost Within 12 mo $133,213 $488,048 $0 Within 18 mo $133,229 $538,193 $0 Mean medical costs (within 12 mo) $4,494 $12,585 $5,411 Hospitalization $3,960 $11,738 $4,986 Emergency room $14 $25 $3 Outpatient $514 $813 $420 Home health care $6 $9 $2 Mean drug cost per RFLM Within 12 mo $13,091 $52,577 $0 Within 18 mo $9,192 $40,371 $0 Mean medical cost RFLM (within 12 mo) $442 $1,356 $664
TCT-307 Mechanism Triggering Acute Coronary Syndrome by Rupturing Plaque Based on the Cavitation Phenomenon (Bubble Formation and Explosion) at the Distal Left Main Bifurcation by Computational Fluid Dynamic Study
Authors: Marco Zuin, Thach Nguyen, Thao Dang, Ai Vu, Phuoc Luong, Tarneem Darwish, Tu Nguyen, Tuan Nguyen, QUoc Bui, Khoi Che, Thy Dang, Gianluca Rigatelli, Ernest Talarico
Journal: Journal of the American College of Cardiology (2018)
A phase I study of concomitant galinpepimut-s (GPS) in combination with nivolumab (nivo) in patients (pts) with WT1+ ovarian cancer (OC) in second or third remission.
Authors: Roisin Eilish O'Cearbhaill, Sacha Gnjatic, Carol Aghajanian, Alexia Iasonos, Jason A. Konner, Nicolle Losada, Debra Sarasohn, Teresa Rasalan, William P. Tew, Dmitriy Zamarin, Phillip Wong, Paul Sabbatini
Journal: Journal of Clinical Oncology (2018)

5553 Background: WT1 is highly expressed in serous ovarian cancer. GPS is WT1-targeting heteroclitic peptide tetravalent non-HLA-restricted vaccine, and has shown promising phase 2 activity in AML, mesothelioma and myeloma. Efficacy of GPS may be enhanced through checkpoint blockade, providing a rationale for combining it with anti-PD1 antibody, nivo. We conducted a phase I study to evaluate the safety and immunogenicity of the combination in WT1+ OC in remission. Methods: Pts with WT1+ OC in ≥2nd remission were enrolled from 06/16-07/2017, and received GPS (800 mcg) x 6 total doses mixed with adjuvant (0.5 ml) and 70 mcg GM-CSF (all s.c. in extremities) and nivo 3 mg/kg IV q2wks over 12 weeks. DLTs were assessed using CTCAE criteria, with detection of > 2/10 DLTs deeming the combination unsafe. Treatment was continued until disease progression or toxicity. Immune responses (IgG & IgM WT1 antibody, T cell assays) induced by the combination were evaluated. The 1-year progression-free survival (PFS) rate, defined as the interval from start of preceding chemo to date of progression or death, is an exploratory objective. Results: n=11; Median age 61 yrs (41-76). 7 pts in 2nd and 4 pts in 3rd remission. 1 DLT (gr 3 myositis with myocarditis post GPS and nivo #2). Most common AEs were Gr ≤2 fatigue and injection site reactions. Immune Response Results: n=9; Serum levels of antigen-specific IgG (against both individual WT1 peptides in GPS and the full-length WT1) significantly increased in 86% of evaluable pts between study wks 6-27. Antigen-specific T cell responses to individual WT1 peptides were observed between 6-15 wks, primarily CD4 and to a smaller extent, CD8 T cells. 1yr PFS rate was 64% in the ITT analysis (7/11) and 70% (7/10) in pts who had > 2 GPS/nivo doses. Conclusions: Administration of GPS in combination with nivo was safe, well tolerated and induced high frequency of T- and B-cell immune responses, warranting further evaluation. The 1yr PFS rate compares favorably to historic rates of approximately 50% in comparable populations. Additional cohorts are planned to receive the current combination along with vaccination against additional tumor-associated antigens. Clinical trial information: NCT02737787.
Prevalence of proteinuria in urologic patients.
Authors: Adam Bezinque, Sabrina L Noyes, Samer Kirmiz, Sumi Dey, Brian R. Lane
Journal: Journal of Clinical Oncology (2016)

e16075 Background: Chronic kidney disease (CKD) is classified according to cause, glomerular filtratrion rate (GFR), and proteinuria. In the urology clinic, patients might be expected to more commonly present with proteinuria, particularly if they have known CKD, have kidney disease (cancer or benign), and/or after surgery. We compared the prevalence of proteinuria in the general urology clinic, in kidney cancer patients, and in patients suspected of having CKD. Methods: Cross-sectional study of three populations including the general population, urology patients, kidney cancer patients, and patients that had both a urinalysis and albumin-to-creatinine ratio (ACR). Proteinuria was classified under KDIGO guidelines. Results: In 5,027 urologic patients, 81.5% were A1, 16% were A2, and 2.5% were A3. Of 1,015 kidney cancer patients, 78% were A1, 18% were A2, and 3.9% were A3. For 893 urology patients that had both a urinalysis and ACR, 77% were A1-urinalysis, 17% were A2-urinalysis, 5.6% were A3-urinalysis, 67% were A1-ACR, 26% were A2-ACR, and 7.2% were A3-ACR. Conclusions: The population risk of proteinuria in the urology clinic is 18.5%, which is similar to reported rates in the general population (~20%). Although the average urology patient does not appear to be at an increased risk for proteinuria, patients with kidney cancer (21.9%) and/or suspicion of CKD may be at increased risk for macroalbuminuria (3.9-7.2% vs. 2.5%). We recommend further evaluation of patients with proteinuria detected by urinalysis to have either repeat urinalysis or ACR to quantify their individual risk.