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Item Alternative lengthening of telomeres (ALT) influences survival in soft tissue sarcomas: a systematic review with meta-analysis(BMC, 2019-03-14) Lawlor, Rita T.; Veronese, Nicola; Pea, Antonio; Nottegar, Alessia; Smith, Lee; Pilati, Camilla; Demurtas, Jacopo; Fassan, Matteo; Cheng, Liang; Luchini, Claudio; Pathology and Laboratory Medicine, School of MedicineAlternative lengthening of telomeres (ALT) is a telomerase-independent mechanism used by a broad range of neoplasms to maintain telomere length, permitting uncontrolled replication during their progression. ALT has been described in different types of sarcoma, but a comprehensive analysis of its clinical significance is still lacking. Therefore, we provide here the first meta-analysis on this topic. METHODS: We searched SCOPUS and PubMed through July 2018 to identify all studies that investigated the prognostic role of ALT in sarcomas. We considered the risk of death (risk ratio, RR) calculated as the number of death vs. total participants during follow-up in ALT+ versus ALT- patients as the primary outcome. The secondary outcome was the hazard ratio (HR), adjusted for the maximum number of covariates available, using ALT- patients as reference. RESULTS: Eight articles comprising a total of 551 patients with sarcomas (226 ALT+ and 325 ALT-) were selected. The ALT+ group showed a higher mitotic count and a higher tumor grade compared with the ALT- group (p < 0.01). Furthermore, we demonstrate a strong impact of ALT on survival. In fact, ALT+ patients showed a statistically significant higher risk of death than ALT- patients, when also considering data from multivariate analyses (RR = 1.50; 95% CI: 1.15-1.96; p = 0.003; HR = 2.02; 95% CI: 1.22-3.38; p = 0.007). CONCLUSIONS: Our results indicate that ALT is associated with an increased risk of death in patients with sarcoma. In these neoplasms, ALT should be taken into account for a precise prognostic stratification and design of potential therapeutic strategies.Item Arsenal(2018) Carroll, Brenna; Jefferson, Corey; Baker, Lesley; Robertson, JeanTraumatic experience inspires the human drive for expression. Survivors carry the memory of trauma with them throughout their lives while they struggle to comprehend its impact. They maintain a fragile stability as their capacity to more forward is challenged and their perception of the world around them is altered. The force of memory compels those who have survived a traumatic event to build a defensive arsenal and to search for and to convey an understanding of their experience. My minimalist abstract ceramic sculpture examines the incidence of trauma and explores the transference of concepts and emotions associated with its effects.Item Association Between Tobacco Related Diagnoses and Alzheimer Disease: A population Study(2022-05) Almalki, Amwaj Ghazi; Zhang, Pengyue; Johnson, Travis; Fadel, WilliamBackground: Tobacco use is associated with an increased risk of developing Alzheimer's disease (AD). 14% of the incidence of AD is associated with various types of tobacco exposure. Additional real-world evidence is warranted to reveal the association between tobacco use and AD in age/gender-specific subpopulations. Method: In this thesis, the relationships between diagnoses related to tobacco use and diagnoses of AD in gender- and age-specific subgroups were investigated, using health information exchange data. The non-parametric Kaplan-Meier method was used to estimate the incidence of AD. Furthermore, the log-rank test was used to compare incidence between individuals with and without tobacco related diagnoses. In addition, we used semi-parametric Cox models to examine the association between tobacco related diagnoses and diagnoses of AD, while adjusting covariates. Results: Tobacco related diagnosis was associated with increased risk of developing AD comparing to no tobacco related diagnosis among individuals aged 60-74 years (female hazard ratio [HR] =1.26, 95% confidence interval [CI]: 1.07 – 1.48, p-value = 0.005; and male HR =1.33, 95% CI: 1.10 - 1.62, p-value =0.004). Tobacco related diagnosis was associated with decreased risk of developing AD comparing to no tobacco related diagnosis among individuals aged 75-100 years (female HR =0.79, 95% CI: 0.70 - 0.89, p-value =0.001; and male HR =0.90, 95% CI: 0.82 - 0.99, p-value =0.023). Conclusion: Individuals with tobacco related diagnoses were associated with an increased risk of developing AD in older adults aged 60-75 years. Among older adults aged 75-100 years, individuals with tobacco related diagnoses were associated with a decreased risk of developing AD.Item Characteristics of children ≤36 months of age with DIPG: A report from the international DIPG registry(Oxford University Press, 2022) Bartlett, Allison L.; Lane, Adam; Chaney, Brooklyn; Yanez Escorza, Nancy; Black, Katie; Cochrane, Anne; Minturn, Jane; Bartels, Ute; Warren, Kathy; Hansford, Jordan; Ziegler, David; Diez, Blanca; Goldman, Stewart; Packer, Roger; Kieran, Mark; DeWire-Schottmiller, Mariko; Erker, Craig; Monje-Deisseroth, Michelle; Wagner, Lars; Koschmann, Carl; Dorris, Kathleen; Shih, Chie-Schin; Hassall, Tim; Fisher, Paul; Wang, Stacie S.; Tsui, Karen; Sevlever, Gustavo; Zhu, Xiaoting; Dexheimer, Phillip; Asher, Anthony; Fuller, Christine; Drissi, Rachid; Jones, Blaise; Leach, James; Fouladi, Maryam; Pediatrics, School of MedicineBackground: Children ≤36 months with diffuse intrinsic pontine glioma (DIPG) have increased long-term survival (LTS, overall survival (OS) ≥24 months). Understanding distinguishing characteristics in this population is critical to improving outcomes. Methods: Patients ≤36 months at diagnosis enrolled on the International DIPG Registry (IDIPGR) with central imaging confirmation were included. Presentation, clinical course, imaging, pathology and molecular findings were analyzed. Results: Among 1183 patients in IDIPGR, 40 were eligible (median age: 29 months). Median OS was 15 months. Twelve patients (30%) were LTS, 3 (7.5%) very long-term survivors ≥5 years. Among 8 untreated patients, median OS was 2 months. Patients enrolled in the registry but excluded from our study by central radiology review or tissue diagnosis had median OS of 7 months. All but 1 LTS received radiation. Among 32 treated patients, 1-, 2-, 3-, and 5-year OS rates were 68.8%, 31.2%, 15.6% and 12.5%, respectively. LTS had longer duration of presenting symptoms (P = .018). No imaging features were predictive of outcome. Tissue and genomic data were available in 18 (45%) and 10 patients, respectively. Among 9 with known H3K27M status, 6 had a mutation. Conclusions: Children ≤36 months demonstrated significantly more LTS, with an improved median OS of 15 months; 92% of LTS received radiation. Median OS in untreated children was 2 months, compared to 17 months for treated children. LTS had longer duration of symptoms. Excluded patients demonstrated a lower OS, contradicting the hypothesis that children ≤36 months with DIPG show improved outcomes due to misdiagnosis.Item Choosing profile double-sampling designs for survival estimation with application to PEPFAR evaluation(Wiley, 2014-05) An, Ming-Wen; Frangakis, Constantine E.; Yiannoutsos, Constantin T.; Biostatistics, School of MedicineMost studies that follow subjects over time are challenged by having some subjects who dropout. Double sampling is a design that selects and devotes resources to intensively pursue and find a subset of these dropouts, then uses data obtained from these to adjust naïve estimates, which are potentially biased by the dropout. Existing methods to estimate survival from double sampling assume a random sample. In limited-resource settings, however, generating accurate estimates using a minimum of resources is important. We propose using double-sampling designs that oversample certain profiles of dropouts as more efficient alternatives to random designs. First, we develop a framework to estimate the survival function under these profile double-sampling designs. We then derive the precision of these designs as a function of the rule for selecting different profiles, in order to identify more efficient designs. We illustrate using data from the United States President's Emergency Plan for AIDS Relief-funded HIV care and treatment program in western Kenya. Our results show why and how more efficient designs should oversample patients with shorter dropout times. Further, our work suggests generalizable practice for more efficient double-sampling designs, which can help maximize efficiency in resource-limited settings.Item The Clinical Impact of Combining Neutrophil-to-Lymphocyte Ratio with Sarcopenia for Improved Discrimination of Progression-Free Survival in Patients with Colorectal Cancer(MDPI, 2022-01-15) Lee, Su Young; Chung, Eric; Cho, Eun-Suk; Lee, Jae-Hoon; Park, Eun Jung; Shin, Su-Jin; Baik, Seung Hyuk; Lee, Kang Young; Kang, Jeonghyun; Anesthesia, School of MedicineThis study aimed to evaluate the clinical impact of combined sarcopenia and inflammation classification (CSIC) in patients with colorectal cancer (CRC). The skeletal muscle index (SMI) and neutrophil-to-lymphocyte ratio (NLR) were measured in 1270 patients who underwent surgery between January 2005 and April 2014. A Cox proportional hazards model was used to evaluate the correlation of sarcopenia, NLR, and CSIC, with progression-free survival (PFS). The integrated area under the curve (iAUC) was used to compare the discriminatory performance of each model. Using the cut-off values for SMI suggested by Martin et al. and for an NLR of 2.26, the CSIC was defined as follows: nonsarcopenia with low NLR (group 1), nonsarcopenia with high NLR (group 2), sarcopenia with low NLR (group 3), and sarcopenia with high NLR (group 4). Sarcopenia alone was not statistically significant. Multivariate analysis identified that CSIC (group 4 vs. group 1; hazard ratio (HR), 1.726; 95% CI, 1.130–2.634; p = 0.011) and NLR (HR, 1.600; 95% CI, 1.203–2.128; p = 0.001) were independently associated with PFS. The CSIC improved the prediction accuracy of PFS compared with NLR (iAUC mean difference = 0.011; 95% CI, 0.0018–0.028). In conclusion, the combination of sarcopenia and NLR could improve prognostic accuracy, and thus compensate for the limitation of sarcopenia.Item COVID-19 Diagnosis and Risk of Death Among Adults With Cancer in Indiana: Retrospective Cohort Study(JMIR Publications, 2022-10-06) Valvi, Nimish; Patel, Hetvee; Bakoyannis, Giorgos; Haggstrom, David A.; Mohanty, Sanjay; Dixon, Brian E.; Surgery, School of MedicineBackground: Prior studies, generally conducted at single centers with small sample sizes, found that individuals with cancer experience more severe outcomes due to COVID-19, caused by SARS-CoV-2 infection. Although early examinations revealed greater risk of severe outcomes for patients with cancer, the magnitude of the increased risk remains unclear. Furthermore, prior studies were not typically performed using population-level data, especially those in the United States. Given robust prevention measures (eg, vaccines) are available for populations, examining the increased risk of patients with cancer due to SARS-CoV-2 infection using robust population-level analyses of electronic medical records is warranted. Objective: The aim of this paper is to evaluate the association between SARS-CoV-2 infection and all-cause mortality among recently diagnosed adults with cancer. Methods: We conducted a retrospective cohort study of newly diagnosed adults with cancer between January 1, 2019, and December 31, 2020, using electronic health records linked to a statewide SARS-CoV-2 testing database. The primary outcome was all-cause mortality. We used the Kaplan-Meier estimator to estimate survival during the COVID-19 period (January 15, 2020, to December 31, 2020). We further modeled SARS-CoV-2 infection as a time-dependent exposure (immortal time bias) in a multivariable Cox proportional hazards model adjusting for clinical and demographic variables to estimate the hazard ratios (HRs) among newly diagnosed adults with cancer. Sensitivity analyses were conducted using the above methods among individuals with cancer-staging information. Results: During the study period, 41,924 adults were identified with newly diagnosed cancer, of which 2894 (6.9%) tested positive for SARS-CoV-2. The population consisted of White (n=32,867, 78.4%), Black (n=2671, 6.4%), Hispanic (n=832, 2.0%), and other (n=5554, 13.2%) racial backgrounds, with both male (n=21,354, 50.9%) and female (n=20,570, 49.1%) individuals. In the COVID-19 period analysis, after adjusting for age, sex, race or ethnicity, comorbidities, cancer type, and region, the risk of death increased by 91% (adjusted HR 1.91; 95% CI 1.76-2.09) compared to the pre-COVID-19 period (January 1, 2019, to January 14, 2020) after adjusting for other covariates. In the adjusted time-dependent analysis, SARS-CoV-2 infection was associated with an increase in all-cause mortality (adjusted HR 6.91; 95% CI 6.06-7.89). Mortality increased 2.5 times among adults aged 65 years and older (adjusted HR 2.74; 95% CI 2.26-3.31) compared to adults 18-44 years old, among male (adjusted HR 1.23; 95% CI 1.14-1.32) compared to female individuals, and those with ≥2 chronic conditions (adjusted HR 2.12; 95% CI 1.94-2.31) compared to those with no comorbidities. Risk of mortality was 9% higher in the rural population (adjusted HR 1.09; 95% CI 1.01-1.18) compared to adult urban residents. Conclusions: The findings highlight increased risk of death is associated with SARS-CoV-2 infection among patients with a recent diagnosis of cancer. Elevated risk underscores the importance of adhering to social distancing, mask adherence, vaccination, and regular testing among the adult cancer population.Item Creatinine to Cystatin-C Ratio in Renal Cell Carcinoma: A Clinically Pragmatic Prognostic Factor and Sarcopenia Biomarker(Oxford University Press, 2023) Schmeusser, Benjamin N.; Biermann, Henry; Nicaise, Edouard H.; Ali, Adil A.; Patil, Dattatraya H.; Midenberg, Eric; Helman, Talia; Armas-Phan, Manuel; Nabavizadeh, Reza; Joshi, Shreyas S.; Narayan, Vikram M.; Bilen, Mehmet A.; Psutka, Sarah P.; Ogan, Kenneth; Master, Viraj A.; Urology, School of MedicineIntroduction: Low creatinine to cystatin-C ratio (Cr/Cys-C) may be a biomarker for low-muscle mass. Furthermore, low Cr/Cys-C is associated with decreased overall survival (OS), but to date, has not been examined in patients with renal cell carcinoma (RCC). Our objective is to evaluate associations between low Cr/Cys-C ratio and OS and recurrence-free survival (RFS) in patients with RCC treated with nephrectomy. Methods: We performed a retrospective review of patients with RCC treated with nephrectomy. Patients with end-stage renal disease and less than 1-year follow up were excluded. Cr/Cys-C was dichotomized at the median for the cohort (low vs. high). OS and RFS for patients with high versus low Cr/Cys-C were estimated with the Kaplan-Meier method, and associations with the outcomes of interest were modeled using Cox proportional Hazards models. Associations between Cr/Cys-C and skeletal muscle mass were assessed with correlations and logistic regression. Results: A total of 255 patients were analyzed, with a median age of 64. Median (IQR) Cr/Cys-C was 1 (0.8-1.2). Low Cr/Cys-C was associated with age, female sex, Eastern Cooperative Oncology Group Performance Status ≥1, TNM stage, and tumor size. Kaplan-Meier and Cox regression analysis demonstrated an association between low Cr/Cys-C and decreased OS (HR = 2.97, 95%CI, 1.12-7.90, P =0.029) and RFS (HR = 3.31, 95%CI, 1.26-8.66, P = .015). Furthermore, a low Cr/Cys-C indicated a 2-3 increase in risk of radiographic sarcopenia. Conclusions: Lower Cr/Cys-C is associated with inferior oncologic outcomes in RCC and, pending validation, may have utility as a serum biomarker for the presence of sarcopenia in patients with RCC treated with nephrectomy.Item Demographics and Clinicopathologic Profile of Pulmonary Sarcomatoid Carcinoma with Survival Analysis and Genomic Landscape(MDPI, 2023-04-26) Ullah, Asad; Ahmed, Asim; Yasinzai, Abdul Qahar Khan; Lee, Kue Tylor; Khan, Israr; Asif, Bina; Khan, Imran; Tareen, Bisma; Kakar, Kaleemullah; Andam, Gul; Heneidi, Saleh; Khan, Jaffar; Khan, Hina; Karki, Nabin R.; Del Rivero, Jaydira; Karim, Nagla Abdel; Pathology and Laboratory Medicine, School of MedicineBackground: Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of non-small cell lung cancer (NSCLC) with an aggressive clinical nature and poor prognosis. With novel targeted therapeutics being developed, new ways to effectively treat PSC are emerging. In this study, we analyze demographics, tumor characteristics, treatment modalities, and outcomes of PSC and genetic mutations in PSC. Methods: Data from the Surveillance, Epidemiology, and End Results (SEER) database were reviewed to analyze cases of pulmonary sarcomatoid carcinoma from 2000 to 2018. The molecular data with the most common mutations in PSC were extracted from the Catalogue Of Somatic Mutations in Cancer (COSMIC) database. Results: A total of 5259 patients with PSC were identified. Most patients were between 70 and 79 years of age (32.2%), male (59.1%), and Caucasian (83.7%). The male-to-female ratio was 1.45:1. Most tumors were between 1 and 7 cm in size (69.4%) and poorly differentiated (grade III) (72.9%). The overall 5-year survival was 15.6% (95% confidence interval (95% CI) = 14.4-16.9)), and the cause-specific 5-year survival was 19.7% (95% CI = 18.3-21.1). The five-year survival for those treated with each modality were as follows: chemotherapy, 19.9% (95% CI = 17.7-22.2); surgery, 41.7% (95% CI = 38.9-44.6); radiation, 19.1% (95% CI = 15.1-23.5); and multimodality therapy (surgery and chemoradiation), 24.8% (95% CI = 17.6-32.7). On multivariable analysis, age, male gender, distant stage, tumor size, bone metastasis, brain metastasis, and liver metastasis were associated with increased mortality, and chemotherapy and surgery were associated with reduced mortality (p < 0.001). The best survival outcomes were achieved with surgery. The most common mutations identified in COSMIC data were TP53 31%, ARID1A 23%, NF1 17%, SMARCA4 16%, and KMT2D 9%. Conclusions: PSC is a rare and aggressive subtype of NSCLC, usually affecting Caucasian males between 70 and 79. Male gender, older age, and distant spread were associated with poor clinical outcomes. Treatment with surgery was associated with better survival outcomes.Item Diagnostic Evidence GAuge of Single cells (DEGAS): a flexible deep transfer learning framework for prioritizing cells in relation to disease(BMC, 2022-02-01) Johnson, Travis S.; Yu, Christina Y.; Huang, Zhi; Xu, Siwen; Wang, Tongxin; Dong, Chuanpeng; Shao, Wei; Zaid, Mohammad Abu; Huang, Xiaoqing; Wang, Yijie; Bartlett, Christopher; Zhang, Yan; Walker, Brian A.; Liu, Yunlong; Huang, Kun; Zhang, Jie; Medicine, School of MedicineWe propose DEGAS (Diagnostic Evidence GAuge of Single cells), a novel deep transfer learning framework, to transfer disease information from patients to cells. We call such transferrable information "impressions," which allow individual cells to be associated with disease attributes like diagnosis, prognosis, and response to therapy. Using simulated data and ten diverse single-cell and patient bulk tissue transcriptomic datasets from glioblastoma multiforme (GBM), Alzheimer's disease (AD), and multiple myeloma (MM), we demonstrate the feasibility, flexibility, and broad applications of the DEGAS framework. DEGAS analysis on myeloma single-cell transcriptomics identified PHF19high myeloma cells associated with progression.