tbuckley/cabot-search huggingface dataset:
Genetic determinants of long-term response to rapalog therapy in advanced renal cell carcinoma (RCC).
Authors: Martin Henner Voss, Abraham A. Hakimi, Sasinya N. Scott, Shugaku Takeda, Han Liu, Yingbei Chen, Robert John Motzer, Michael F. Berger, James Hsieh
Journal: Journal of Clinical Oncology (2012)

4604 Background: Temsirolimus (T) and everolimus (E) are rapalog inhibitors of the mammalian target of rapamycin (mTOR) with efficacy in advanced RCC [NEJM;356(22):227-81; Lancet;372(9637):449-56]. With reported median progression-free survival (PFS) of 5.5 and 4.9 months (mo), respectively, benefit is typically modest, yet a subset of patients (pts) achieves long-term disease control evident by extended PFS. The oncogenomic background for this is unclear. Methods: We analyzed frozen specimens of tumor and adjacent normal kidney from pts with advanced RCC and documented long-term response to T or E, defined as PFS of ≥ 20mo. Samples from pts with PFS ≤ 2mo served as comparators. Specimens were subjected to whole exome sequencing; a targeted next-generation sequencing platform was used for deep sequencing and investigation of copy number variations (CNV) in 230 genes of interest. Results: In 5 pts with long-term response to T [n=3] or E [n=2], histologic subtypes were clear cell [n=3] and unclassified [n=2] RCC. Median number of prior treatments was 2 (1-3). Two pts remain on therapy, 3 have stopped drug for disease progression; treatment duration was 20, 25+, 27, 28, and 28+ mo. Three control pts progressed after 1, 2, and 2 mo on therapy. Mean target coverage was 86x for whole exome and 443x for targeted sequencing. Three of 5 long-term responders harbored acquired somatic mutations and/or CNV in genes encoding for members of the Phosphoinositide 3-Kinase (PI3K) / mTOR pathway. Effects on amino acid sequence and gene function suggest a hyperactive pathway in all 3. For the other 2 long-term responders genomic changes with possible indirect link to the pathway, but no apparent determinants of treatment response were seen. In 3 control patients with rapid disease progression no genomic alterations suggesting hyperactivation of the pathway were seen. Conclusions: In this retrospective discovery set of RCC pts with unusually long response to rapalog therapy, next generation sequencing using pre-treatment tissue specimens revealed plausible oncogenomic determinants of treatment benefit in 3 of 5 cases. These findings provide basis for further biomarker development and studies in a larger sample set are ongoing.
Safety and immunogenicity of tyrosinase DNA vaccines in patients with melanoma
Authors: J. D. Wolchok, H. Gallardo, M. Perales, T. Rasalan, J. Wang, P. B. Chapman, S. E. Krown, P. O. Livingston, M. Heywood, J. Yuan
Journal: Journal of Clinical Oncology (2007)

3005 Background: T-cell and antibody responses to self antigens on cancer are usually constrained by immunologic tolerance and ignorance. We found that DNA vaccines encoding xenogeneic differentiation antigens, such as tyrosinase (TYR), can mediate tumor protection and regression in implantable mouse models and dogs with spontaneously arising melanoma. Based on this, we conducted a trial of DNA vaccines encoding mouse and human TYR in patients with AJCC stage III/IV melanoma. Methods: HLA-A*0201+ melanoma patients were randomized to 2 different schedules: one group received 3 injections of mouse TYR DNA followed by 3 injections of human TYR DNA while the other group received 3 injections of human TYR DNA followed by 3 injections with the mouse gene. The study was conducted a three different dose levels: 100, 500 and 1,500 mcg DNA/injection, administered IM every 3 weeks. A total of 18 patients were treated, 6 at each dose level being randomized to one of the two schedules. Anti-TYR antibodies and CD8+ T cells recognizing the native human tyrosinase 369-377 (YMDGTMSQV) peptide were measured at fixed time points. T-cell responses were monitored with MHC tetramer and intracytoplasmic IFN-γ staining assays using 10-day in vitro stimulation. Multiparametric flow cytometry was performed to further define the phenotype of responding cells. Results: Most toxicities were transient grade I injection site reactions. Seven patients had CD8+ T cell responses, defined as a &gt;3 standard deviation increase in baseline reactivity to the TYR peptide in either the tetramer or intracellular IFN-γ assay. There was no relationship between dose level or assigned schedule and occurrence of T-cell response. Phenotypic characterization of responding T cells showed that most were consistent with an effector memory phenotype including the expression of granzyme B and surface expression of CD107a. No antibody responses were observed. At a median of 42 months of follow-up, median survival has not been reached and 6/18 patients have died from melanoma (1 in the group of patients who had a T cell response and 5 in the non-responders). Conclusions: Mouse and human TYR DNA vaccines were safe and induced CD8+ T cell responses in 7/18 patients. T cells recognizing a native TYR peptide had a phenotype consistent with that of effector memory cells. No significant financial relationships to disclose.
Abstract 16869: Clinical Relevance of Troponin I in Advanced Chronic Kidney Disease for Suspected Coronary Artery Disease
Authors: Balaram Krishna J Hanumanthu, Bhavin Chokshi, Lilian Bizzocchi, Muhammad Pervez, Poonam Mahato, Sachin Batra, Belinda Jim
Journal: Circulation (2018)

Background: Troponin elevations are common in advanced chronic kidney disease (CKD) but its association with angiographically significant coronary artery disease (CAD) remains unclear. We wish to elucidate the test characteristics of troponin in chronic kidney disease population. Methods: We retrospectively reviewed the charts of all patients who underwent coronary angiograms performed at Jacobi Medical Center between April 2007 to May 2017. Significant CAD was defined as ≥70% on angiography. We divided patients into subgroups of mild CKD (I,II,III) and advanced CKD (IV,V) based on MDRD staging for CKD classification. Results: Baseline characteristics of cardiovascular risk factors were similar among patients with mild and advanced CKD except hypertension (81 vs 96, p &lt; 0.001), diabetes (52 vs 66, p = 0.015), LDL (93 vs 78, p=0.004) and lower HDL (79 vs 91, p = 0.01), respectively. Of 795 patients, 371 had angiographically significant CAD. Accuracy of troponins in predicting significant CAD was greater in advanced CKD (AUC 0.76) as compared to mild CKD (AUC 0.62), p = 0.016). Troponin I &gt; 0.254 was 62% sensitive and 60% specific in mild CKD and Troponin I &gt; 0.47 was 73% sensitive and 73% specific in advanced CKD. Conclusions: We conclude that troponin retains its diagnostic value and infact has a higher accuracy in advanced CKD patients with angiographically significant CAD.
Comparison of Survival Between Patients With Single vs Multiple Primary Cutaneous Melanomas
Authors: Mary-Ann El Sharouni, Arjen J. Witkamp, Vigfús Sigurdsson, Paul J. van Diest
Journal: JAMA Dermatology (2019)

Melanoma is one of the most rapidly increasing forms of cancer worldwide. Most studies about survival among patients with melanoma consider only the primary tumor and disregard the potential effect of multiple primary tumors. A better understanding of the prognosis of patients with multiple primary melanoma is important for patient counselling and follow-up strategies.To describe the epidemiologic features of multiple primary melanoma in patients from the Netherlands.This retrospective, population-based cohort study included adults with histologically proven, primary, invasive cutaneous melanoma in the Netherlands between January 1, 2000, and December 31, 2014, with a median follow-up of 75.1 months, using data from PALGA, the Dutch Nationwide Network and Registry of Histopathology and Cytopathology. Follow-up data were retrieved from the Netherlands Cancer Registry. Statistical analysis was performed from August 1, 2018, to September 3, 2018.A multivariable Cox model with a time-varying covariate was performed to assess overall survival between patients with a single primary melanoma vs those with multiple primary melanomas. Secondary outcomes included incidence of multiple primary melanoma, differences in Breslow thickness, and time between first and second multiple primary melanoma.Of the 56 929 study patients, 31 916 (56.1%) were female, with a mean (SD) age of 56.4 (16.2) years. A total of 54 645 single primary melanomas and 4967 multiple primary melanomas in 2284 patients were included. The median Breslow thickness decreased from 0.90 mm (interquartile range, 0.55-1.70 mm) for the first melanoma to 0.65 mm (interquartile range, 0.45-1.10 mm) for the second melanoma (P < .001). For their second melanoma, 370 patients (16.2%) had a higher T stage, 1112 (48.7%) had the same T stage, and 802 (35.1%) had a lower T stage. In addition, 841 of 2284 second melanomas (36.8%) in patients with multiple primary melanomas were found during the first year of follow-up, whereas 624 of 2284 (27.3%) were found after 5 years of follow-up. These proportions did not vary when stratified for melanoma stage. Worse overall survival was seen among patients with multiple primary melanomas compared with patients with a single primary melanoma (hazard ratio, 1.31; 95% CI, 1.20-1.42; P < .001).A significant decrease in Breslow thickness between the first and second multiple primary melanoma was found, and overall survival among patients with multiple primary melanomas was significantly worse than that among patients with a single primary melanoma. These findings suggest that more strict follow-up strategies may be warranted for patients with multiple primary melanomas.
Abstract 1492: Evaluation of combinatorial chemotherapeutics nano-carriers at different dosage regimens in breast cancer model: Tumor immune signaling, inhibit angiogenesis and tumor growth
Authors: Adel Al Fatease, Vidhi Shah, Kalei Lopez, Brianna Cote, Deepa Rao, Adam Alani
Journal: Cancer Research (2019)

Abstract The objective of this work is to evaluate the effect of individual &amp; combinatorial delivery of Docetaxel (DTX) and Everolimus (EVR) in polymeric micelles at frequent dosing regimen below their maximum tolerated dose on angiogenesis, efficacy &amp; immune signaling in breast cancer animal model. Based on previous in-vivowork in our lab, the maximum tolerated dose (MTDs) for EVR, DTX &amp; combinatorial micelles is 50, 25 and 20 mg/kg respectively. To achieve our goal, two studies have been conducted. First, in-vivo assessment of anti-angiogenic effects of individual &amp; dual DTX-EVR micelles in murine model at 10%, 30%, and 50% MTD, &amp; MTD dose. Second, in-vivo efficacy evaluation of individual &amp; dual DTX EVR micelles at 10%, 30%, 50% MTD, and MTD dose in orthotropic breast cancer murine model. Relative blood vessel invasion &amp; increase in tumor growth will be evaluated for each dosing treatment. We observed that dual DTX EVR polymeric micelles showed significant inhibition of angiogenesis &amp; tumor growth compared to individual agent. The effect of frequent lower dosing schedule is also currently being investigated for its effect immune signaling. Citation Format: Adel Al Fatease, Vidhi Shah, Kalei Lopez, Brianna Cote, Deepa Rao, Adam Alani. Evaluation of combinatorial chemotherapeutics nano-carriers at different dosage regimens in breast cancer model: Tumor immune signaling, inhibit angiogenesis and tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1492.
Carcinogenicity of night shift work
Authors: Elizabeth M Ward, Dori Germolec, Manolis Kogevinas, David McCormick, Roel Vermeulen, Vladimir N Anisimov, Kristan J Aronson, Parveen Bhatti, Pierluigi Cocco, Giovanni Costa, David C Dorman, Loning Fu, Anne Helene Garde, Pascal Guénel, Johnni Hansen, Mikko I Härmä, Kazuaki Kawai, Evgenii A Khizkhin, Anders Knutsson, Francis Lévi, Claudia RC Moreno, Eero Pukkala, Eva Schernhammer, Ruth Travis, Martha Waters, Marianna Yakubovskaya, Hajo Zeeb, Yong Zhu, Shanbeh Zienolddiny, Yann Grosse, Amy L Hall, Lamia Benbrahim-Tallaa, Jennifer Girschik, Véronique Bouvard, Fatiha El Ghissassi, Michelle C Turner, W Ryan Diver, Zdenko Herceg, Natalie Olson, Elaine G Rowan, Harriet Rumgay, Kathryn Z Guyton, Mary K Schubauer-Berigan
Journal: The Lancet Oncology (2019)
Abstract P016: Left Ventricular Hypertrophy is Associated With Incident Dementia: The Atherosclerosis Risk in Communities - Neurocognitive Study
Authors: Faye L Norby, Lin Y Chen, Elsayed Z Soliman, Rebecca F Gottesman, Thomas H Mosley, Alvaro Alonso
Journal: Circulation (2017)

Background: Left ventricular hypertrophy (LVH) is most commonly an indicator of target organ damage due to hypertension and may serve as a marker for chronicity of blood pressure elevation and as an indicator of the long-term burden of vascular risk factors. We assessed whether LVH measured by 12-lead ECG was associated with incident dementia in the Atherosclerosis Risk in Communities – Neurocognitive Study (ARIC-NCS). Methods: Our analysis included 12,665 individuals (23% black race, 56% female, mean age 57) who attended visit 2 in 1990-92. Cornell voltage (SV3 + RaVL) was derived from 12-lead ECG at visit 2 (1990-92), visit 3 (1993-95) and visit 4 (1996-98) as a continuous variable, and the gender-specific Cornell voltage criteria (SV3 + RaVL &gt; 28mm for men, and &gt;22mm for women) was used to define LVH as a dichotomous variable. Incident dementia was defined using a validated algorithm consisting of a full neuropsychological assessment, interviews, informant interviews, hospital discharge codes, or diagnostic codes from death certificates. A cox proportional hazards model was used to evaluate the association between LVH and incident dementia. LVH and Cornell voltage were modeled as time-dependent variables and covariates were updated at each visit. Follow-up time was from baseline until date of dementia, end of follow-up, or the end of 2013, whichever came first. Results: During a mean follow-up of 18 years, we identified 544 participants with LVH and 1195 incident dementia cases. LVH was associated with a higher risk of dementia: multivariable hazard ratio (HR) 1.91, 95% confidence interval (CI) 1.48-2.46 (Table). A 1-standard deviation increase in Cornell voltage (5 mm) was associated with a higher risk of dementia, HR (95% CI) = 1.10 (1.04-1.17). Conclusion: In this large population-based study, LVH measured in mid-life was associated with an increased risk of dementia. Additional research should confirm this association, and these results underscore the need for hypertension control to prevent subclinical brain injury.
A phase 3 study of durvalumab with or without bevacizumab as adjuvant therapy in patients with hepatocellular carcinoma at high risk of recurrence after curative hepatic resection or ablation: EMERALD-2
Authors: J. Knox, A. Cheng, S. Cleary, P. Galle, N. Kokudo, R. Lencioni, J. Park, J. Zhou, H. Mann, S. Morgan, X. Liu, S. Chin, G. Vlahovic, J. Fan
Journal: Annals of Oncology (2019)
Abstract 1091: Comparison of TCR repertoires between cancer tissues and lymph nodes in colorectal cancer patients
Authors: Kazuma Kiyotani, Tatsuo Matsuda, Eisaku Miyauchi, Yu-Wen Hsu, Satoshi Nagayama, Makda Zewde, Jae-Hyun Park, Taigo Kato, Makiko Harada, Nobuaki Suzuki, Hiroaki Nagano, Shoichi Hazama, Yusuke Nakamura
Journal: Cancer Research (2019)

Tumor draining lymph nodes (TDLNs) are located in the routes of lymphatic drainage from a primary tumor and have the highest metastasis in various types of solid tumors. TDLNs are considered as a tissue to activate the antitumor immunity, where antigen-specific effector T cells are generated and released to the blood stream. These effector T cells then infiltrate into the tumor site and attack cancer cells. However, T cell receptor (TCR) repertoire in TDLNs has not been well characterized. We performed TCR sequencing of cancer tissues, corresponding normal mucosa tissues and a total of 203 regional lymph nodes, including 67 metastasis-positive lymph nodes from 23 colorectal cancer patients with lymph node metastasis. Metastasis-positive lymph nodes showed a significantly lower TCR diversity and shared TCR clones more frequently with primary tumor tissues compared to metastasis-negative TDLNs. Hierarchical clustering and principal component analyses also supported that TCR repertoires in metastasis-positive TDLNs were more similar to primary tumor tissues than metastasis-negative TDLNs. These finding suggest that cancer-reactive T cell clones might expand in the metastasis-positive TDLNs, although we have not tested their reactivity against cancer cells. We are now examining whether the T cells in TDLNs can recognized autologous cancer cells.Citation Format: Kazuma Kiyotani, Tatsuo Matsuda, Eisaku Miyauchi, Yu-Wen Hsu, Satoshi Nagayama, Makda Zewde, Jae-Hyun Park, Taigo Kato, Makiko Harada, Nobuaki Suzuki, Hiroaki Nagano, Shoichi Hazama, Yusuke Nakamura. Comparison of TCR repertoires between cancer tissues and lymph nodes in colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1091.
Multicenter analysis of outcomes in blastic plasmacytoid dendritic cell neoplasm offers a pretargeted therapy benchmark
Authors: Justin Taylor, Michael Haddadin, Vivek A. Upadhyay, Erwin Grussie, Neha Mehta-Shah, Andrew M. Brunner, Abner Louissaint, Scott B. Lovitch, Ahmet Dogan, Amir T. Fathi, Richard M. Stone, Martin S. Tallman, Raajit K. Rampal, Donna S. Neuberg, Kristen E. Stevenson, Steven M. Horwitz, Andrew A. Lane
Journal: Blood (2019)
Abstract 4843: TP53-stabilization with APR-246 enhances antitumor effects of immune checkpoint blockade in preclinical models
Authors: Arnab Ghosh, Judith Michel, Lauren Dong, Nathan Suek, Hong Zhong, Sadna Budhu, Olivier de Henau, Jedd Wolchok, Taha Merghoub
Journal: Cancer Research (2019)

Abstract An emerging body of literature suggests a role of TP53 pathway in antitumor immunity including antigen presentation and T cell proliferation. Stabilization of TP53 could therefore alter the immune tumor microenvironment, enabling the immune system to target tumor cells more effectively. APR-246 covalently modifies the core domain of cellular TP53 through the alkylation of thiol groups, leading to reactivation of endogenous TP53 activity. To further study the effect of APR-246 on antitumor immunity we used a B16 pre-clinical melanoma mouse model. In vitro treatment of B16 cells with APR-246 caused intracellular accumulation of TP53, leading to increased apoptosis. However, treatment of B16-melanoma bearing mice with APR-246 monotherapy did not result in a statistically significant change in tumor growth or survival. Analyses of the tumor immune microenvironment showed increased immune potentiating M1 polarized tumor-associated macrophages, and Granzyme B activity in CD8+ T cells, suggesting enhanced anti-tumor immunity. Concomitantly, there was increased PD-L1 expression in the macrophages, PD-1 expression on CD8+ T cells, and Foxp3+ Tregs in tumors from APR-246 treated animals. Therefore, we decided to combine anti-PD-1 antibody (RMP-1) to APR-246 treatment in tumor-bearing mice. The combination led to a significant delay in tumor growth (P &amp;lt; 0.001) and improved survival of B16-bearing mice compared to anti-PD1 or APR-246 monotherapies (P &amp;lt; 0.01). Improved responses were also seen in MC38 colorectal cancer-bearing mice (P &amp;lt; 0.01). The anti-tumor effects of APR-246 and anti-PD1 were T cell dependent and abrogated in hosts lacking T cells. Analyses of the tumor immune microenvironment showed that the combination decreases proliferation but increases cytolytic activity of CD8+ T cells compared to anti-PD1 alone. We next studied the effect of combining APR-246 with anti-PD1+ anti-CTLA-4 (9B9). Combination of APR-246 with dual immune checkpoint blockade using anti-PD1 and anti-CTLA-4 showed further tumor growth inhibition in B16-melanoma compared to monotherapies (P &amp;lt; 0.001). Our studies support a role for restoring TP53 in the tumor microenvironment and provide evidence that reactivation of TP53 by APR-246 can enhance anti-tumor immune responses and inhibit tumor growth in preclinical models. Citation Format: Arnab Ghosh, Judith Michel, Lauren Dong, Nathan Suek, Hong Zhong, Sadna Budhu, Olivier de Henau, Jedd Wolchok, Taha Merghoub. TP53-stabilization with APR-246 enhances antitumor effects of immune checkpoint blockade in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4843.
Venetoclax (VEN) and tyrosine kinase inhibitor (TKI) combinations in Philadelphia chromosome-positive (Ph+) acute myeloid leukemia (AML) and chronic myeloid leukemia myeloid blast phase (CML MBP).
Authors: Abhishek Maiti, Farhad Ravandi, Jorge E. Cortes, Elias Jabbour, Kayleigh Marx, Naval Guastad Daver, Guillermo Garcia-Manero, Marina Konopleva, Christopher Brent Benton, Lucia Masarova, Courtney Denton Dinardo, Prithviraj Bose, Kiran Naqvi, Sherry A. Pierce, Hagop M. Kantarjian, Nicholas James Short
Journal: Journal of Clinical Oncology (2019)

e18515 Background: Ph+ AML and CML MBP have poor outcomes. VEN synergizes with BCR-ABL TKIs in vitro and may eradicate Ph+ leukemic stem cells. However, the clinical activity of VEN+TKI regimens is unknown. Methods: We conducted a retrospective study on patients (pts) with Ph+ AML and CML MBP who received regimens with VEN+TKI at our institution. Results: We identified 6 pts with relapsed/refractory (R/R) Ph+ AML and 7 with CML MBP (2 transformed from chronic phase, 5 R/R). 10 pts (77%) were refractory to prior therapy and 3 (23%) had relapsed disease. Pt characteristics are shown in the Table. 5 AML pts (83%) had complex cytogenetics. Pts with CML MBP had received a median of 2 prior TKIs (range 1-3). 7 pts received decitabine-based combinations and 6 pts received intensive chemotherapy in combination with VEN+TKI. TKIs included ponatinib (n=7), dasatinib (n=4), bosutinib (n=1) and nilotinib (n=1). Among 12 evaluable pts, the overall response rate (CR + CRi + MLFS) was 50% (Table). In addition, 1 pt with AML developed aplastic marrow, underwent stem cell transplantation, and is still alive. Pts with CR/CRi vs. those without CR/CRi had higher median number of Ph+ metaphases (100% vs. 32%, p&lt;0.01) and higher baseline BCR-ABL1 PCR (100% vs. 0.5% p=0.01). The only AML pt who achieved CR/CRi had 100% Ph+ metaphases. After a median follow-up of 10.9 months (mo), 5 pts are alive (1 AML, 4 CML MBP). The median overall survival for pts with AML and CML MBP were 2 mo and not reached, respectively. The median relapse-free survival was 8.2 mo. Conclusions: VEN+TKI combinations show encouraging activity in pre-treated, advanced Ph+ leukemias, particularly CML MBP. Clonal burden of Ph+ cells correlated with response. Prospective trials are needed to evaluate VEN+TKI combinations in Ph+ leukemias. Pt characteristics and outcomes (n/N [%] / median [range]). [Table: see text]