Revised International Prognostic Scoring System (IPSS) Predicts Survival and Leukemic Evolution of Myelodysplastic Syndromes Significantly Better Than IPSS and WHO Prognostic Scoring System: Validation by the Gruppo Romano Mielodisplasie Italian Regional Database

2013 ◽  
Vol 31 (21) ◽  
pp. 2671-2677 ◽  
Author(s):  
Maria Teresa Voso ◽  
Susanna Fenu ◽  
Roberto Latagliata ◽  
Francesco Buccisano ◽  
Alfonso Piciocchi ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Scoring System ◽  
Prognostic Value ◽  
Cox Regression ◽  
Group Performance ◽  
Eastern Cooperative Oncology Group ◽  
Prognostic Scores ◽  
International Prognostic Scoring System ◽  
Ratio Test ◽  
Ferritin Concentration

Purpose The definition of disease-specific prognostic scores plays a fundamental role in the treatment decision-making process in myelodysplastic syndrome (MDS), a group of myeloid disorders characterized by a heterogeneous clinical behavior. Patients and Methods We applied the recently published Revised International Prognostic Scoring System (IPSS-R) to 380 patients with MDS, registered in an Italian regional database, recruiting patients from the city of Rome (Gruppo Romano Mielodisplasie). Patients were selected based on the availability of IPSS-R prognostic factors, including complete peripheral-blood and bone marrow counts, informative cytogenetics, and follow-up data. Results We validated the IPSS-R score as a significant predictor of overall survival (OS) and leukemia-free survival (LFS) in MDS (P < .001 for both). When comparing the prognostic value of the International Prognostic Scoring System (IPSS), WHO Prognostic Scoring System (WPSS), and IPSS-R, using the Cox regression model and the likelihood ratio test, a significantly higher predictive power for LFS and OS became evident for the IPSS-R, compared with the IPSS and WPSS (P < .001 for both). The multivariate analysis, including IPSS, WPSS, age, lactate dehydrogenase, ferritin concentration, Eastern Cooperative Oncology Group performance status, transfusion dependency, and type of therapy, confirmed the significant prognostic value of IPSS-R subgroups for LFS and OS. Treatment with lenalidomide and erythropoiesis-stimulating agents was shown to be an independent predictor of survival in the multivariate analysis. Conclusion Our data confirm that the IPSS-R is an excellent prognostic tool in MDS in the era of disease-modifying treatments. The early recognition of patients at high risk of progression to aggressive disease may optimize treatment timing in MDS.

scholarly journals The Prognostic Value of the De Ritis Ratio for Progression-Free Survival in Patients with NET Undergoing [177Lu]Lu-DOTATOC-PRRT: A Retrospective Analysis

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 635
Author(s):  
Tristan Ruhwedel ◽  
Julian M. M. Rogasch ◽  
Kai Huang ◽  
Henning Jann ◽  
Imke Schatka ◽  
...  
Keyword(s):  
Retrospective Analysis ◽  
Prognostic Value ◽  
Cox Regression ◽  
Cox Model ◽  
Performance Status ◽  
Eastern Cooperative Oncology Group ◽  
Progression Free Survival ◽  
Ratio Test ◽  
Free Survival ◽  
Prognostic Accuracy

Background: The De Ritis ratio (aspartate aminotransferase [AST]/alanine aminotransferase [ALT]) has demonstrated prognostic value in various cancer entities. We evaluated the prognostic capability of the De Ritis ratio in patients with metastatic neuroendocrine tumors (NET) undergoing peptide receptor radionuclide therapy (PRRT). Methods: Unicentric, retrospective analysis of 125 patients with NET undergoing PRRT with [177Lu]Lu-DOTATOC (female: 37%; median age: 66 years; G1+G2 NET: 95%). The prognostic value regarding progression-free survival (PFS) was analyzed with univariable and multivariable Cox regression. Prognostic accuracy was determined with Harrell’s C index and a likelihood ratio test. Results: Progression, relapse, or death after PRRT was observed in 102/125 patients. Median progression-free survival (PFS) was 15.8 months. Pancreatic or pulmonary origin, high De Ritis ratio, and high Chromogranin A (CgA) significantly predicted shorter PFS in univariable Cox. In multivariable Cox regression, only high De Ritis ratio >0.927 (HR: 1.7; p = 0.047) and high CgA >twice the upper normal limit (HR: 2.1; p = 0.005) remained independent predictors of shorter PFS. Adding the De Ritis ratio to the multivariable Cox model (age, Eastern Cooperative Oncology Group (ECOG) performance status, primary origin, CgA) significantly improved prognostic accuracy (p < 0.001). Conclusions: The De Ritis ratio is simple to obtain in clinical routine and can provide independent prognostic value for PFS in patients with NET undergoing PRRT.

scholarly journals Myosteatosis as a novel prognostic biomarker after radical cystectomy for bladder cancer

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Shimpei Yamashita ◽  
Yuya Iwahashi ◽  
Haruka Miyai ◽  
Takashi Iguchi ◽  
Hiroyuki Koike ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Radical Cystectomy ◽  
Cox Regression ◽  
Group Performance ◽  
Performance Status ◽  
Eastern Cooperative Oncology Group ◽  
Psoas Muscle ◽  
Hounsfield Units ◽  
Computed Tomography Images ◽  
Psoas Muscles

AbstractThis study aims to evaluate the influence of myosteatosis on survival of patients after radical cystectomy (RC) for bladder cancer. We retrospectively identified 230 patients who underwent RC for bladder cancer at our three institutions between 2009 and 2018. Digitized free-hand outlines of the left and right psoas muscles were made on axial non-contrast computed tomography images at level L3. To assess myosteatosis, average total psoas density (ATPD) in Hounsfield Units (HU) was also calculated as an average of bilateral psoas muscle density. We compared cancer-specific survival (CSS) between high ATPD and low ATPD groups and performed cox regression hazard analyses to identify the predictors of CSS. Median ATPD was 44 HU (quartile: 39–47 Hounsfield Units). Two-year CSS rate in overall patients was 76.6%. Patients with low ATPD (< 44 HU) had significantly lower CSS rate (P = 0.01) than patients with high ATPD (≥ 44 HU). According to multivariate analysis, significant independent predictors of poor CSS were: Eastern Cooperative Oncology Group performance status ≥ 1 (P = 0.03), decreasing ATPD (P = 0.03), non-urothelial carcinoma (P = 0.01), pT ≥ 3 (P < 0.01), and pN positive (P < 0.01). In conclusion, myosteatosis (low ATPD) could be a novel predictor of prognosis after RC for bladder cancer.

Pancreatic cancer outcomes in Nova Scotia: Searching for small windows of opportunity.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16219-e16219
Author(s):  
Peiran Sun ◽  
Ravi Ramjeesingh
Keyword(s):  
Older Adults ◽  
Pancreatic Cancer ◽  
Multivariate Analysis ◽  
Nova Scotia ◽  
Group Performance ◽  
Performance Status ◽  
Eastern Cooperative Oncology Group ◽  
Healthcare Delivery ◽  
Wait Times ◽  
Significant Difference

e16219 Background: While pancreatic cancer (PC) globally has poor outcomes, there are still regional variation in PC outcomes in Canada. Nova Scotia (NS) has been documented to have some of the worst outcomes in PC but the details and barriers to the care of PC in NS have never been analyzed. Methods: A retrospective chart review was performed on PC patients (pts) diagnosed in NS from 2013 to 2017 for patient characteristics, referral pattern, treatments and wait times. Cox proportional hazards methods were used to analyze overall survival (OS) with Age, Stage, Eastern Cooperative Oncology Group Performance Status (PS), Charleston Comorbidity Index (CCI), receiving ERCP and receiving chemotherapy as covariates in the multivariate analysis. Results: 667 consecutive pts were identified, which included 357 males and 310 females with a median age of 71 at diagnosis. 42 (6.25%) lived beyond 2 years, while 163 (24.4%) survived for under 30 days and 260 (39%) survived for under 60 days. Patients with a limited survival (under 30 days) when compared to pts who survived > 60 days are older (mean 75 vs 71, P < 0.05), had a higher proportion of ECOG > 2 (81.6% vs 20.3%, P < 0.01), and a higher proportion of stage 4 disease (73.9% vs 41.2%, P < 0.01). There was no significant difference in any measure of wait times. Pts with limited survival were less likely to be seen by Medical Oncology (MO) (20.9% vs 70.9%, P < 0.001), and less likely to receive chemotherapy (1.2% vs 45%, P < 0.001) or ERCP (27% vs 53.8%, P < 0.01). Multivariate analysis showed that receiving ERCP (P = 0.027) and chemotherapy(P < 0.001) are independent predictors of survival, even when accounting for PS, CCI, stage, and age. Conclusions: Analysis of PC outcomes in NS demonstrates a large proportion of pts dying within 30 days of diagnosis. Those pts are older and present with higher stage and worse PS but did not have any significant difference in diagnostic and referral wait times. Those pts receive fewer referrals to Oncology services, fewer potentially life prolonging treatments and we uniquely discovered ERCP as an independent predictor of survival in our population. While further work is needed, this study characterized some of the unique challenges of PC care in NS as a province with a higher proportional of older adults and highlights potential opportunities to improve early healthcare delivery in older adults with limited windows for care.

Analysis of Prognostic Factors of Comprehensive Geriatric Assessment and Development of a Clinical Scoring System in Elderly Asian Patients With Cancer

2011 ◽  
Vol 29 (27) ◽  
pp. 3620-3627 ◽  
Author(s):  
Ravindran Kanesvaran ◽  
Huihua Li ◽  
Khai-Nee Koo ◽  
Donald Poon
Keyword(s):  
Prognostic Factors ◽  
Elderly Patients ◽  
Geriatric Assessment ◽  
Comprehensive Geriatric Assessment ◽  
Scoring System ◽  
Group Performance ◽  
Eastern Cooperative Oncology Group ◽  
Disease Stage ◽  
Patients With Cancer ◽  
The Impact

Purpose To determine the impact of each comprehensive geriatric assessment (CGA) domain on overall survival (OS) and develop a prognostic scoring system for elderly patients with cancer. Patients and Methods A retrospective analysis of CGA data collected from 249 consecutive patients with cancer who attended the outpatient geriatric oncology clinic at the National Cancer Center Singapore age 70 years or older was performed. Univariate and multivariate analyses were performed using Cox proportional hazards method to identify significant prognostic factors within the CGA. A simple nomogram to predict OS was developed using regression coefficients from the multivariate model. Concordance between predicted and observed response of the individual patient score was evaluated by means of Harrell's c-index. Calibration was performed using simulated data via bootstrap. Results Median age of the patients was 77 years (range, 70 to 94 years). In our model, age (hazard ratio [HR], 1.04; 95% CI, 1.01 to 1.07), abnormal albumin level (HR, 1.97; 95% CI, 1.23 to 3.15), poor Eastern Cooperative Oncology Group performance status (≥ 2 v < 2: HR, 1.77; 95% CI, 1.15 to 2.72), abnormal geriatric depression scale status (HR, 1.81; 95% CI, 1.29 to 2.56), high malnutrition risk (high v low risk: HR, 1.84; 95% CI, 1.17 to 2.87), and advanced disease stage (late v early: HR, 1.71; 95% CI, 0.98 to 2.95) were independent predictors of survival. Conclusion Results confirm the importance of the CGA in assessment of elderly patients with cancer. The development of this nomogram incorporating these prognostic factors helps predict OS of patients, for further intervention.

S100P tumor-marker response to chemotherapy in patients with advanced pancreatic cancer.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 265-265
Author(s):  
Shuichi Mitsunaga ◽  
Kumiko Umemoto ◽  
Kazuo Watanabe ◽  
Hiroyuki Okuyama ◽  
Yusuke Hashimoto ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Multivariate Analysis ◽  
Tumor Marker ◽  
Tumor Markers ◽  
Group Performance ◽  
Univariate Analysis ◽  
Eastern Cooperative Oncology Group ◽  
Advanced Pancreatic Cancer ◽  
Response To Chemotherapy ◽  
Monitoring Response

265 Background: The serum tumor-marker in monitoring response to chemotherapy is not valid in advanced pancreatic cancer (PC). S100 calcium-binding protein P (S100P) has been reported as a predictive diagnostic index for PC and may serve as an early marker to activity of chemotherapy. The aim of this study was to analyze the correlation between the efficacies of chemotherapy and the kinetics of tumor-markers including serum S100P, carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) in prospective cohort of advanced PC. Methods: Patients who were treatment naïve for advanced PC with liver mets were eligible. Serum levels of S100P, CEA, and CA19-9 were measured at baseline and at one month later. The patients without monitoring of tumor-markers were excluded. A response of tumor-marker was defined as a decrease of at least 25%. Clinical data including radiological response according to the Response Evaluation Criteria In Solid Tumors ver. 1.1 were prospectively collected. S100P, CEA, and CA19-9 responses were tested in association with progression free survival (PFS) and overall survival (OS). Results: Fifty patients were analyzed in this study (male: 64%, median age: 67 years, Eastern Cooperative Oncology Group performance status [PS] 0: 60%). All of 50 patients received chemotherapy (gemcitabine [GEM]: 13 pts, GEM doublets: 34 pts, 5FU-based regimen: 3 pts). PFS and OS were 2.8 and 6.1 months. Responses of S100P, CEA, and CA19-9 were founded in 50%, 16%, and 32% of all, respectively. Multivariate analysis for PFS in Cox regression hazard model was performed using age, gender, PS, CEA, CA19-9, and S100P, and revealed that the independent predictors to longer PFS were responses of S100P (HR to progression: 0.47, P=0.02) and CEA (HR: 0.29, P=0.01). S100P or CEA responders showed better OS in univariate analysis using log-rank test, compared to non-responders of S100P (responder vs. non-responder: 8.4 vs. 3.7 months, P=0.04) or CEA (12.0 vs. 5.9 months, P=0.02), but not in multivariate analysis. Conclusions: Biochemical response of S100P might be useful for monitoring response to chemotherapy in advanced PC, which warranted further study in relationship between serum S100P response and treatment efficacies.

scholarly journals Non-hematologic predictors of mortality improve the prognostic value of the international prognostic scoring system for MDS in older adults

2015 ◽  
Vol 6 (4) ◽  
pp. 288-298 ◽  
Author(s):  
K. Rebecca Fega ◽  
Gregory A. Abel ◽  
Gabriela Motyckova ◽  
Alexander E. Sherman ◽  
Daniel J. DeAngelo ◽  
...  
Keyword(s):  
Older Adults ◽  
Scoring System ◽  
Prognostic Value ◽  
International Prognostic Scoring System ◽  
Predictors Of Mortality

scholarly journals A genomic-clinical nomogram predicting recurrence-free survival for patients diagnosed with hepatocellular carcinoma

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e7942
Author(s):  
Junjie Kong ◽  
Tao Wang ◽  
Shu Shen ◽  
Zifei Zhang ◽  
Xianwei Yang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Risk Model ◽  
Cox Regression ◽  
Group Performance ◽  
Performance Status ◽  
Survival Rates ◽  
Eastern Cooperative Oncology Group ◽  
Staging System ◽  
Recurrence Free Survival ◽  
Free Survival

Liver resection surgery is the most commonly used treatment strategy for patients diagnosed with hepatocellular carcinoma (HCC). However, there is still a chance for recurrence in these patients despite the survival benefits of this procedure. This study aimed to explore recurrence-related genes (RRGs) and establish a genomic-clinical nomogram for predicting postoperative recurrence in HCC patients. A total of 123 differently expressed genes and three RRGs (PZP, SPP2, and PRC1) were identified from online databases via Cox regression and LASSO logistic regression analyses and a gene-based risk model containing RRGs was then established. The Harrell’s concordance index (C-index), receiver operating characteristic (ROC) curves and calibration curves showed that the model performed well. Finally, a genomic-clinical nomogram incorporating the gene-based risk model, AJCC staging system, and Eastern Cooperative Oncology Group performance status was constructed to predict the 1-, 2-, and 3-year recurrence-free survival rates (RFS) for HCC patients. The C-index, ROC analysis, and decision curve analysis were good indicators of the nomogram’s performance. In conclusion, we identified three reliable RRGs associated with the recurrence of cancer and constructed a nomogram that performed well in predicting RFS for HCC patients. These findings could enrich our understanding of the mechanisms for HCC recurrence, help surgeons predict patients’ prognosis, and promote HCC treatment.

Systemic immune inflammation index and treatment response in patients with metastatic renal cell cancer.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 591-591 ◽  
Author(s):  
Kadriye Bir Yücel ◽  
Arzu Yasar ◽  
Gokhan Ucar ◽  
Gungor Utkan ◽  
Nuriye Yildirim ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Treatment Response ◽  
Renal Cell ◽  
Prognostic Value ◽  
Cox Regression ◽  
Performance Status ◽  
Univariate Analysis ◽  
Cell Cancer ◽  
Immune Inflammation

591 Background: To investigate the prognostic value of the pretreatment inflammatory characteristics on treatment response and survival. Methods: We included 151 patients with metastatic renal cell carcinoma (mRCC) Patients’ charts were retrospectively analyzed for their clinical, pathological and demographic features. Systemic immune inflammation index (SII) cut off is estimated with median value. Overall survival (OS) was estimated by Kaplan-Meier method for univariate analysis and Cox-regression for multivariate analysis. Results: In high SII group (SII > 844) overall survival is 11 months and in low SII group (SII < 844) overall survival is 22 months (p = 0,008). Median OS is lower in the hypercalcemic group (7 months vs.18 months, P = 0,013). In patients with anemia and thrombocytosis, OS is lower (41 months vs. 13 months p = 0,001 and 6 months vs. 18 months p = 0,01). In multivariate analysis, anemia, SII, and ECOG performance status were able to predict OS (HR = 2,69, HR = 2,04, HR = 2,57) Conclusions: In patients with mRCC, SII may have a prognostic value and higher score may related with decreased overall survival.

Novel risk scoring system for metastatic renal cell carcinoma (mRCC) patients (pts) treated with cabozantinib (C).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 734-734
Author(s):  
Meredith R Kline ◽  
Dylan J. Martini ◽  
Yuan Liu ◽  
Julie M. Shabto ◽  
Bradley Curtis Carthon ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Scoring System ◽  
Group Performance ◽  
Eastern Cooperative Oncology Group ◽  
Risk Scoring ◽  
Ecog Ps ◽  
Risk Scoring System

734 Background: Cabozantinib (C) is an effective treatment for metastatic renal cell carcinoma (mRCC) patients (pts). The international mRCC database consortium (IMDC) criteria is the gold standard for mRCC risk stratification. We created a risk scoring system for mRCC pts treated with C. Methods: We performed a retrospective review of 87 mRCC pts treated with C at Winship Cancer Institute from 2015-19. Overall survival (OS) and progression free survival (PFS) were defined as months from C initiation. The baseline characteristics and inflammation biomarkers included were monocyte, neutrophil, and platelet-to-lymphocyte ratios (MLR, NLR, and PLR respectively), RCC histology, body mass index (BMI), metastatic sites (mets), and Eastern Cooperative Oncology Group performance status (ECOG PS). Upon variable selection in multivariable analysis (MVA), elevated baseline MLR (≥0.71), presence of sarcomatoid histology, ECOG PS > 1, and absence of bone metastases were assigned 1 point. A three-level risk scoring system was created: low (score = 0-1), intermediate (score = 2), and high risk (score = 3-4). The Kaplan-Meier method, Cox proportional hazard model, and Uno’s C-statistics were used to examine performance. Results: The majority of pts were males (71%) with clear-cell RCC (75%). Most pts (67%) received 1+ prior line of therapy. High and intermediate risk pts had significantly shorter OS and PFS compared to low risk pts (Table). The C-statistics for our risk scoring system were higher than IMDC in predicting OS (0.7 vs. 0.62) and PFS (0.65 vs 0.57). Conclusions: Pts treated with C may benefit from risk scoring using RCC histology, ECOG PS, mets, and MLR. These results are hypothesis-generating and should be validated in a larger study.[Table: see text]

HER2-low and gastric cancer: A prognostic biomarker?

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16086-e16086
Author(s):  
Bruno Cezar de Mendonça Uchôa ◽  
Rafaela Pirolli ◽  
Luciana Beatriz Mendes Gomes Siqueira ◽  
Francisca Giselle Rocha Moura ◽  
Ana Paula Rondina Correa ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Multivariate Analysis ◽  
Prognostic Value ◽  
Cox Regression ◽  
Prognostic Biomarker ◽  
Statistical Significance ◽  
Gastroesophageal Junction ◽  
Rank Test ◽  
Cancer Center ◽  
First Line

e16086 Background: The role of HER2 positive (HER2+) as a prognostic biomarker for gastric/gastroesophageal junction cancer (G-GEJC) is controversial. Recently, the HER2-low (HER2l) concept has emerged and proved to predict response to trastuzumab deruxtecan in metastatic scenario. Data on HER2l prognostic value are missing. Methods: All consecutive patients with metastatic G-GEJC, tested for HER2 in the primary tumor or in the metastatic tissue before initiating first-line therapy at A.C. Camargo Cancer Center, were retrospectively recruited. The primary objective was to compare the overall survival (OS: from the metastasis diagnosis to death by any cause) between HER2l and HER2 negative (HER2-) populations. Secondarily, we aimed to compare the first-line progression-free survival (PFS) between HER2l and HER2-, to analyze prognostic factors associated with OS and to compare the OS between HER2+ and HER2l/HER2-. The HER2 immunohistochemistry (IHC) tests were performed with the Ventana anti-HER2/neu kit, by specialized gastrointestinal pathologists of the study center, using the AJCC HER2 scoring criteria for gastric cancer. In situ hybridization (ISH) was done when IHC 2+ was detected. HER2+ were IHC 3+ or 2+ amplified by ISH; HER2l, 1+ or 2+ non-amplified; HER-, 0+. Kaplan-Meier curves, Log-Rank test and Cox regression were used for survival analysis. Cox regression was used for uni and multivariate analysis. Results: From June, 2008 to July, 2020, 398 patients were included (48 HER2+; 103 HER2l; 247 HER2-). The median follow-up was 31 months (m). Median age at diagnosis was 58 years; the majority were men (62.8%), caucasian (50.8%), with gastric (81% vs 19% GEJ), diffuse (50.3%), de novo metastatic (57.0%) tumors. In comparison to HER2l/HER2-, HER2+ group had superior rates of men, GEJC, intestinal subtype and non-visceral metastasis. Central nervous system metastases were uncommon, and proportionally higher in HER2+ tumors (HER2+: 6.2%; HER2l: 2.9%; HER2-: 2.0%; p = 0.27). There were no imbalances between HER2l and HER2- groups. The median OS was similar for HER2l and HER2- (13m for both; HR 1.0, 95%CI 0.76-1.31; p = 1.0), as it was the PFS (5m for both; HR 0.84, 95%CI 0.65-1.08; p = 0.18). These results did not vary on dependence of IHC + (0 vs 1 + vs 2+). HER2+ tumors had a superior median OS (17m vs 13m for HER2l/HER2-; HR 0.70, 95%CI 0.49-0.99; p = 0.046). When ungrouping HER2l/HER2-, this numerical difference remains, with a loss of statistical significance (17m vs 13m vs 13m; HR 0.87, 95%CI 0.74-1.02; p = 0.12). HER2+, > 1 line of treatment and metastasectomy were predictive for improved OS in multivariate analysis. HER2l was neither predictive for OS nor PFS. Conclusions: Although HER2-low emerged as a new predictive biomarker in metastatic gastric cancer, its prognostic value could not be proved in this study, with an absence of impact in OS. HER2+, however, was associated with improved survival.

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