tbuckley/cabot-search huggingface dataset:
Abstract A036: Blocking DNA and RNA synthesis by targeting glutamine metabolism in prostate cancer
Authors: Qian (Kevin) Wang, Michelle van Geldermalsen, Angel Pang, Blake Zhang, Jeff Holst
Journal: Cancer Research (2018)

Abstract Cancer cells greatly increase their uptake of nutrients (glucose, amino acids, and lipids), and metabolize them to provide the necessary building blocks for new cancer cells. It was recently shown that extracellular amino acids make up by far the majority of the carbon sources used by cancer cells for cell division, highlighting amino acid uptake as a viable therapeutic target. In addition, amino acids such as glutamine are critical in providing nitrogen for purine and pyrimidine metabolism. We have previously shown that glutamine uptake is mediated predominantly by ASCT2 in prostate cancer, with ASCT2 knockdown blocking cell growth in vitro and in vivo. Using the TCGA dataset, we have discovered increased expression of downstream glutamine metabolism enzymes in approximately 25% of prostate cancer patients. One of these enzymes, guanine monophosphate synthase (GMPS), is a glutamine amidotransferase involved in de novo purine biosynthesis and is responsible for the last step in the synthesis of the guanine nucleotide. Expression of GMPS correlates with increasing Gleason score in prostate cancer patient samples. Furthermore, patients with high GMPS expression had significantly reduced disease-free survival in the TCGA dataset. Immunofluorescent staining shows that GMPS is localized in both the cytoplasm and nucleus of LNCaP and PC-3 cells—consistent with a secondary role for GMPS in p53 stabilization. Inhibition of GMPS using decoyinine significantly decreased cell growth of both LNCaP and PC-3 cells. Knockdown of GMPS by shRNA significantly decreased cell growth, which could be rescued by addition of extracellular guanosine to the media, suggesting a direct effect on nucleotide synthesis. These results show the importance of downstream glutamine metabolism in prostate cancer, and suggest that GMPS is a potential therapeutic target in “glutamine-addicted” prostate cancers. Citation Format: Qian (Kevin) Wang, Michelle van Geldermalsen, Angel Pang, Blake Zhang, Jeff Holst. Blocking DNA and RNA synthesis by targeting glutamine metabolism in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A036.
Correlation of fatty acid receptor (CD36) positive circulating epithelial tumor cells (CETCs) with aggressiveness of breast cancer disease.
Authors: Dorothea Schott, Monika Pizon, Ulrich Pachamnn, Katharina Pachmann
Journal: Journal of Clinical Oncology (2018)

e24032 Background: Breast cancer is one of the leading causes of cancer death for women worldwide. Major hurdles for a successful treatment are cancer metastases, resistance to therapy and disease recurrence. The presence of CETCs is closely related to metastasis formation, but the mechanisms through which CETCs promote recurrence of disease are still unclear. CD36 is found in the cell membrane of tumor cells and responsible for taking up fatty acid. It is known that CD36 is a general marker of metastatic cells and its amplification is specifically correlated with metastasis in a large number of human tumors. Therefore, the aim of this study was to determine the metastatic marker CD36 on CETCs and on tumorspheres and to correlate their frequency with clinicopathological features in breast cancer patients. Methods: CETCs were determined from blood of 42 patients suffering from breast cancer. The number of vital CETCs and their expression of CD 36 was investigated using the maintrac method. Tumorsphere assay was used for determination of circulating cancer stem cells (cCSCs) from the peripheral blood. Results: CD36 expressing CETCs were detected in 95 % of breast cancer patients. Breast cancer patients with metastatic disease had a significantly higher fraction of CD36 positive CETCs as compared to patients without metastases. The fraction of CD36 positive CETCs was significantly higher in patients with HER2 positive primary tumor. Furthermore, triple negative breast cancer patients had significantly more CD36 positive CETCs as compared to hormone receptor positive tumors. Interestingly, the frequency of CD36 positive CETCs correlated significantly with a blinded determination of Ki-67 proliferation index in tumor tissue. Tumorspheres cultured from the peripheral blood were highly positive for CD36 staining and positively correlated with stage of disease. Conclusions: We, here, show for the first time that breast cancer patients have detectable CETCs with a high frequency of CD36 positivity which highly correlated with progression of cancer disease. Our findings suggest that using a CD36 antibody treatment may be an effective strategy to fight cancer.
Real world experience with nivolumab in Indian patients with metastatic renal cell carcinoma: A single centre experience.
Authors: Amit Rauthan, Poonam Patil, S.P. Somashekhar, Shabber Zaveri
Journal: Journal of Clinical Oncology (2018)

e16546 Background: Nivolumab is a human IgG4 programmed death-1 immune checkpoint inhibitor antibody approved for use in multiple cancers. Nivolumab is approved for use as second line therapy in Renal cell cancers(RCC), and has become available for use in India since Oct 2016. There is no long term data about use of Nivolumab in Indian patients. Methods: This is a single centre, retrospective Indian study, which included metastatic RCC patients who received Nivolumab. The endpoints were objective response rate and adverse events (AE). Results: 15 patients received Nivolumab at 3mg/kg dose, every 2 weekly, between May 2016 and Jan 2018. Median age of patients was 66 years (range 44-82 years). ECOG status at presentation ranged between 1-3. All patients had received oral TKIs as first line therapy- 8 patients received Sunitinib, 7 patients received Pazopanib. 3 patients also received Everoliums as 2nd line therapy. Response was assessed by RECIST criteria at 2 months. 3 patients(20%) achieved complete response (CR), 2 patients(13%) achieved partial response, 3 had stable disease(20%) and 7 patients(46.6%)had progressive disease. 2 patients who had CR, completed treatment for 13 months and have stopped treatment, without any evidence of progression. The median progression free survival (PFS) is 5 months. Adverse events occurred in 6 patients (40%). The common adverse events were fatigue in 33.3% (grade 1), colitis in 6.6%(grade 1) and skin rash in 20%(grade 1). There were no grade 3,4 adverse events and no treatment related discontinuation. Conclusions: Nivolumab is a very effective second line regimen in selected patients with metastatic RCC. Seeing CR in this group of progressive patients has been very encouraging. Long-term responses even after discontinuing therapy have been seen in responding patients. It is well tolerated, though immune related AEs are known. Continued use of Nivolumab will help in better assessment of the safety and efficacy in Indian patients.
Abstract 15071: Sensitivity to Significance Threshold in ’Real World’ Application of a Polygenic Risk Score for Resting QT Interval
Authors: Michael A Rosenberg, Steven A Lubitz, HongHuang Lin, Gulum Kosova, Paul Huang, Roy Perlis, Christopher Newton-Cheh
Journal: Circulation (2016)

Intro: Polygenic risk scores (PGS) provide the opportunity for direct application of genome wide association studies (GWAS) to clinical populations. While conventionally, genome-wide significance (...
P05.59 Epidemiology and etiology of meningiomas: a population based study from Germany
Authors: Dr B Holleczek, D Zampella, Prof Dr S Urbschat, PD Dr F Sahm, Prof Dr J Oertel, R Ketter
Journal: Neuro-Oncology (2018)

Meningiomas are mostly benign tumours that originate from the coverings of brain and spinal cord. They reveal a normal karyotype or, typically, a monosomy for chromosome 22. They are the most frequently diagnosed primary brain tumour accounting for 33.8% of all primary brain tumours. Compared to the malignant glial tumours, meningiomas are relatively understudied with regards to etiologic risk factors and their epidemiology. In particular, population. Population-based data from Saarland, a federal state in South-Western Germany, were used and included 917 patients diagnosed between 2000 and 2014 with a first meningioma (ICD 10: D32). Vital-status follow-up of the patients was available until 2018. Incidence and mortality rates per 100,000 person years were derived based on the European standard population. Period estimates of 5-year relative survival (RS) as up-to-date estimates of disease-specific survival were derived by sex, age and WHO grade. This population-based study not only included patients treated in the regional university hospital but also those treated elsewhere or those without any surgery. Mean age of the patients at diagnosis was 63 years and of those with available information, 69%, 28% and 3% had grade I, II and III meningiomas. In the study period, the incidence and mortality rates were 2.3 and 0.3 among men and 5.6 and 0.3 among women, respectively. The incidence of females was almost 2.5-fold compared to that of men. Overall 5-year RS was 95%. It decreased from 99% of patients <=54 years to 92% of patients >=70 years. It was 98%, 93% and 71% among patients with grade I, II and III meningiomas, respectively. Even though the disease-specific mortality of meningiomas is small, it substantially increased both by age and grade. In this abstract, we highlight current knowledge about meningioma epidemiology and etiology and suggest future research directions.
Genomic profiling of high-intermediate risk endometrial cancer to differentiate recurrence risk.
Authors: Zachary Christopher Dobbin, Emily E. Landers, Angelina I Londono, Ashwini A. Katre, Eddy Shih-Hsin Yang, Jonathan David Boone, Kerri S. Bevis, John Michael Straughn, Warner King Huh, Charles A. Leath, David Crossman, Ronald David Alvarez, Rebecca Christian Arend
Journal: Journal of Clinical Oncology (2016)

e17103 Background: While the majority of patients diagnosed with endometrial cancer (EMCA) have low-risk disease at the time of diagnosis, a subset of patients with Stage I disease are classified as high-intermediate risk (H-IR) based on pathologic risk factors. H-IR EMCA patients have a 30% risk of recurrence. While adjuvant therapy may improve progression free survival, there is limited data to suggest an improvement in overall survival. Methods: Under IRB approval we performed a pilot study isolating the RNA from paraffin embedded tissue from 16 patients who underwent surgery at UAB between July 2000 and November 2010. All patients met criteria for H-IR EMCA which included presence of 1-3 pathologic risk factors: a) outer 1/2 or 1/3 myometrial invasion; b) presence of LVSI; c) grade 2 or 3 tumor. No patient received adjuvant therapy after surgery. We selected 8 patients who recurred within 3 years and 8 controls who did not have a recurrence. Patients were matched for stage, grade, race, age, presence or absence of LVSI, depth of invasion, and size of tumor. RNA expression of the two groups were compared using the NanoString platform utilizing the nCounter PanCancer Pathways Panel (770 genes). Data was analyzed using the nSolver Software and Ingenuity Pathway Analysis (IPA). Results: Using a fold change of greater than or equal to ± 1.5 and a p-value of < 0.05, 10 genes were significantly up-regulated (2 to 6 fold) in H-IR EMCA patients that recurred: MMP3, INHBB, TNF, NR4A, PLA2G3, CLCF1, LAMB3, RAD51, FOS, LEFTY2. Two genes were significantly down-regulated (1.5 fold): COL27A1 and BAIAP3. Five pathways were statistically different between the two groups using IPA: Aryl hydrocarbon receptor signaling, cyclins and cell cycle regulation pathway, bladder cancer signaling pathway, colorectal cancer metastasis pathway, and rheumatoid arthritis pathway. Conclusions: This pilot study identified significantly differentially expressed genes in patients with H-IR EMCA who experience a recurrence compared to those patients that do not recur. Based on these findings, it may be possible to develop a genetic signature to identify patients that may benefit from adjuvant therapy rather than using pathologic criteria alone.
Comprehensive molecular profiling of advanced gynecologic malignancies.
Authors: Luis Rojas, Casey B. Williams, David Starks, Kirstin Anne Williams, Brian Leyland-Jones
Journal: Journal of Clinical Oncology (2017)

e17082 Background: Precision medicine has been studied in patients with advanced, heavily-treated cancers by administering molecularly targeted monotherapies. Rational combination approaches that are selected based upon molecular analysis, tailored for each patient based upon their past medical history, performance status and unique molecular profile, and curated to prevent the development of resistance represent a possible solution that warrants further exploration. Methods: The primary aim of this proposal, Identifying Molecular Drivers of Cancer (NCT02470715), is to recognize genetic drivers of cancer by performing comprehensive genomic profiling (CGP) and/or proteomic characterization, and further translational research of patient samples. A molecular tumor board discussed results upon receipt and recommended customized combinations. Final decisions of implementation were the choice of the treating physician. Results: CGP was evaluable in 46/64 (72%) advanced gynecologic malignancies (GYN). The remaining 18 are either awaiting therapy or too early for evaluation. Thirty three/45 (73%) patients received combination therapy matched to the CGP. Fourteen/34 (41%) matched patients achieved CR, 12/34 (35%) achieved a PR, 6/34 (18%) achieved SD, and 2/34 (6%) had progression after 3 cycles. Clinical benefit rate was 94%. For ovarian cancer (25 pts), the response rate was 75% and the median progression-free survival (PFS) is 8.5 months and ongoing in 4 patients. Twelve/46 (26%) patients received CGP, but were treated with standard treatments because of insurance denial or inability to get drugs. Two/12 (17%) achieved a CR, 3/12 (25%) achieved SD, and 7/12 (58%) had progression. The PFS for patients that received standard therapies was 1 month. Median number of prior therapies in all patients was 4. Conclusions: Management of advanced gynecologic malignancies with customized combinations of approved agents based on the patient’s tumor CGP was feasible, resulted in superior therapeutic outcomes and improved PFS compared to standard therapies in heavily pretreated controls within this cohort. This precision oncology therapeutic model for gynecologic malignancies deserves prospective large scale evaluation. Clinical trial information: NCT02470715.
Optimal timing of lobectomy for clinical stage IA non-small cell lung cancer.
Authors: Chi-Fu Jeffrey Yang, Hanghang Wang, Arvind Kumar, Matthew G. Hartwig, Thomas A. D'Amico, David Harpole, Mark F. Berry
Journal: Journal of Clinical Oncology (2016)

8549 Background: The precise relationship between timing of lobectomy following diagnosis of non-small cell lung cancer (NSCLC) and survival has not been studied previously. This study sought to determine the association between the timing of lobectomy and survival in patients with clinical stage IA NSCLC. Methods: The association between timing of lobectomy and survival for patients with clinical stage IA NSCLC in the National Cancer Data Base (2003-2011) was assessed using Multivariable Cox proportional hazards analysis. Restricted cubic spline functions were used to model the relationship between timing of surgery and mortality. Results: The median time to surgery was 37 days (25th/75th: 23/58) and 10,305 (61%) patients underwent surgery more than 30 days after diagnosis. RCS analysis demonstrated the hazard ratio (HR) associated with time between diagnosis and surgery increased steadily the longer resection was delayed, indicating that increased waiting for surgery led to worse long-term survival. Delaying surgery beyond 37 days was associated with an increased risk of death in both univariable and multivariable analysis (HR 1.11; 95% CI: 1.04-1.17; p < 0.001). For patients older than 75 years (n = 3974), the median time to surgery was 40 days (25th/75th: 25/61) and 2,574 (65%) patients underwent surgery more than 30 days after diagnosis. Delaying surgery beyond 40 days was associated with an increased risk of death in both univariable and multivariable analysis (HR 1.16; 95% CI: 1.04-1.29; p < 0.01). Conclusions: Delaying surgical resection of early stage NSCLC is associated with worsening of long-term survival. Efforts to reduce delays are needed as the majority of patients in the National Cancer Data Base waited longer than a month for surgery after diagnosis.
Multivariate analysis of prognostic factors among 706 mucosal melanoma patients.
Authors: Bin Lian, Chuanliang Cui, Li Zhou, Xin Song, Xiaoshi Zhang, Di Wu, Zhihong Chi, Lu Si, Xinan Sheng, Yan Kong, Bixia Tang, Li Li Mao, Xuan Wang, Si Ming Li, Jie Dai, Xieqiao Yan, Xue Bai, Nan Zheng, Charles M. Balch, Jun Guo
Journal: Journal of Clinical Oncology (2017)

9569 Background: Mucosal melanoma is rare and associated with extremely poor prognosis. Little is known about its outcome and prognostic analysis. In this study, we evaluated prognostic factors among mucosal melanomas. Methods: The survival rates, Relapse Free Survival (RFS), Overall Survival (OS) and prognostic factors were compared for 706 mucosal melanomas at different anatomical sites. Results: Mucosal melanoma from nasal pharyngeal and oral (268 pts), upper and lower gastrointestinal (GI) (221 pts), gynecological and urological (196 pts) had a similar survival with a 1-y survival rate (88%, 83%, 86%), 2-y survival rate (66%, 57%, 61%), 5-y survival rate (27%, 16%, 20%), respectively. Multivariate analysis revealed that Depth of Invasion (p &lt; 0.001), Lymph node metastases (p &lt; 0.001), Distant metastases (p &lt; 0.001) were three independent prognostic factors for OS among 706 pts. Anatomical site (p = 0.031), Depth of Invasion (p &lt; 0.001), Lymph node metastases (p &lt; 0.001) were three independent prognostic factors for RFS among 543 pts. KPS status, Depth of Invasion, Lymph node metastases, Distant metastases were independent factors for OS among nasal pharyngeal and oral pts. Depth of Invasion, Lymph node metastases, CKIT Mutation were independent factors for RFS among nasal pharyngeal and oral pts. Gender, Lymph node metastases, Distant metastases were independent factors for OS among GI pts. Gender, Depth of Invasion, Lymph node metastases were independent factors for RFS among GI pts. Lymph node metastases, Distant metastases were independent factors for OS among Gynecological and Urological pts. Depth of Invasion, Lymph node metastases were independent factors for RFS among Gynecological and Urological pts. Conclusions: This is the first prognostic analysis for mucosal melanoma with the largest sample size for the first time. with few exceptions, It revealed that Depth of Invasion, Lymph node metastases, Distant metastases were independent prognostic factors for OS, Depth of Invasion and Lymph node metastases were independent prognostic factors for RFS. These results should be incorporated into the establishment of stage system and design of future clinical trials involving patients with mucosal melanoma.
Lowering the <i>P</i> Value Threshold
Authors: Inmaculada Hernandez, Walid F. Gellad, Chester B. Good
Journal: JAMA (2018)

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Impact of remission and stem cell transplant (SCT) on survival outcomes in elderly relapsed acute myeloid leukemia (rAML) patients: US Cancer Registry experience.
Authors: Abdalla Aly, Saurabh Ray, Jackie Kwong, Anuj Shah, Marc Botteman
Journal: Journal of Clinical Oncology (2018)

e19002 Background: SCT is a potential curative option for rAML. However, many rAML patients (pts) do not receive SCT due to death or failure to achieve remission. This analysis examined the impact of remission and SCT on mortality in elderly rAML pts. Methods: rAML pts aged 66-75 years (y) were identified by medical claims associated with ICD-9 code 205.02 in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database (2009-2014). Pts were categorized depending on whether they had remission post-rAML (ICD-9 code 205.01) and were followed from relapse to the earliest of death, SCT, or end of follow-up. SCT rates by remission status were estimated after adjusting for the competing risk of death. Post-rAML overall survival (OS) was assessed using the Kaplan-Meier method comparing SCT and non-SCT pts by remission status. Results: 474 rAML pts (median age, 70 y, median follow up, 4.4 mo) were included. SCT rates were higher in the remission (14.4%) vs non-remission pts (4.5%; Table). Independent of SCT status, median OS was higher in the remission vs non-remission pts (10.9 vs 2.5 mo, log rank P < .001). Median OS was higher in SCT vs non-SCT pts (16.3 vs 4.2 mo, log rank P < .001) regardless of remission status. Post-rAML OS was highest for pts in remission who also had a SCT. Conclusions: While both remission and SCT independently reduce mortality, SCT is important in reducing mortality among rAML pts regardless of remission status. Therapies that improve both remission and SCT rates may therefore provide greater survival gains in this high unmet need population. No Remission Remission Total N 283 191 474 Median follow up, mo 2.2 5.6 4.4 Died without SCT, n (%) 256 (91) 121 (63) 377 (80) Censored, n (%) 15 (5) 43 (23) 58 (12) SCT Rate, % 4.5 14.4 8.5 Median OS, mo All 2.5 10.9 4.6 SCT 16.3 17.2 16.3 No SCT 2.3 10.0 4.2 6-month OS, % All 24 69 42 SCT 83 85 84 No SCT 22 66 39 12-month OS, % All 12 46 26 SCT 56 60 59 No SCT 10 44 23 24-month OS, % All 4 29 14 SCT 33 47 43 No SCT 3 26 12