Distinct genomic and immunologic tumor evolution in germline TP53-driven breast cancers.

Pathogenic germline TP53 alterations cause Li-Fraumeni Syndrome (LFS), and breast cancer is the most common cancer in LFS females. We performed first of its kind multimodal analysis of LFS breast cancer (LFS-BC) compared to sporadic premenopausal BC. Nearly all LFS-BC underwent biallelic loss of TP53 with no recurrent oncogenic variants except ERBB2 (HER2) amplification. Compared to sporadic BC, in situ and invasive LFS-BC exhibited a high burden of short amplified aneuploid segments (SAAS). Pro-apoptotic p53 target genes BAX and TP53I3 failed to be up-regulated in LFS-BC as was seen in sporadic BC compared to normal breast tissue. LFS-BC had lower CD8+ T-cell infiltration compared to sporadic BC yet higher levels of proliferating cytotoxic T-cells. Within LFS-BC, progression from in situ to invasive BC was marked by an increase in chromosomal instability with a decrease in proliferating cytotoxic T-cells. Our study uncovers critical events in mutant p53-driven tumorigenesis in breast tissue.

Germline pathogenic variants in neuroblastoma patients are enriched in BARD1 and predict worse survival.

BACKGROUND: Neuroblastoma is an embryonal cancer of the developing sympathetic nervous system. The genetic contribution of rare pathogenic or likely pathogenic germline variants in patients without a family history remains unclear. METHODS: Germline DNA sequencing was performed on 786 neuroblastoma patients. The frequency of rare cancer predisposition gene pathogenic or likely pathogenic variants in patients was compared with 2 cancer-free control cohorts. Matched tumor DNA sequencing was evaluated for second hits, and germline DNA array data from 5585 neuroblastoma patients and 23 505 cancer-free control children were analyzed to identify rare germline copy number variants. Patients with germline pathogenic or likely pathogenic variants were compared with those without to test for association with clinical characteristics, tumor features, and survival. RESULTS: We observed 116 pathogenic or likely pathogenic variants involving 13.9% (109 of 786) of neuroblastoma patients, representing a statistically significant excess burden compared with cancer-free participants (odds ratio [OR] = 1.60, 95% confidence interval [CI] = 1.27 to 2.00). BARD1 harbored the most statistically significant enrichment of pathogenic or likely pathogenic variants (OR = 32.30, 95% CI = 6.44 to 310.35). Rare germline copy number variants disrupting BARD1 were identified in patients but absent in cancer-free participants (OR = 29.47, 95% CI = 1.52 to 570.70). Patients harboring a germline pathogenic or likely pathogenic variant had a worse overall survival compared with those without (P = 8.6 x 10-3). CONCLUSIONS: BARD1 is an important neuroblastoma predisposition gene harboring both common and rare germline pathogenic or likely pathogenic variations. The presence of any germline pathogenic or likely pathogenic variant in a cancer predisposition gene was independently predictive of worse overall survival. As centers move toward paired tumor-normal sequencing at diagnosis, efforts should be made to centralize data and provide an infrastructure to support cooperative longitudinal prospective studies of germline pathogenic variation.

Genome-first approach of the prevalence and cancer phenotypes of pathogenic or likely pathogenic germline TP53 variants.

Pathogenic or likely pathogenic (P/LP) germline TP53 variants are the primary cause of Li-Fraumeni syndrome (LFS), a hereditary cancer predisposition disorder characterized by early-onset cancers. The population prevalence of P/LP germline TP53 variants is estimated to be approximately one in every 3,500 to 20,000 individuals. However, these estimates are likely impacted by ascertainment biases and lack of clinical and genetic data to account for potential confounding factors, such as clonal hematopoiesis. Genome-first approaches of cohorts linked to phenotype data can further refine these estimates by identifying individuals with variants of interest and then assessing their phenotypes. This study evaluated P/LP germline (variant allele fraction ≥30%) TP53 variants in three cohorts: UK Biobank (UKB, n = 200,590), Geisinger (n = 170,503), and Penn Medicine Biobank (PMBB, n = 43,731). A total of 109 individuals were identified with P/LP germline TP53 variants across the three databases. The TP53 p.R181H variant was the most frequently identified (9 of 109 individuals, 8%). A total of 110 cancers, including 47 hematologic cancers (47 of 110, 43%), were reported in 71 individuals. The prevalence of P/LP germline TP53 variants was conservatively estimated as 1:10,439 in UKB, 1:3,790 in Geisinger, and 1:2,983 in PMBB. These estimates were calculated after excluding related individuals and accounting for the potential impact of clonal hematopoiesis by excluding heterozygotes who ever developed a hematologic cancer. These varying estimates likely reflect intrinsic selection biases of each database, such as healthcare or population-based contexts. Prospective studies of diverse, young cohorts are required to better understand the population prevalence of germline TP53 variants and their associated cancer penetrance.

Biallelic BRCA Loss and Homologous Recombination Deficiency in Nonbreast/Ovarian Tumors in Germline BRCA1/2 Carriers.

PURPOSE: Breast and ovarian tumors in germline BRCA1/2 carriers undergo allele-specific loss of heterozygosity, resulting in homologous recombination deficiency (HRD) and sensitivity to poly-ADP-ribose polymerase (PARP) inhibitors. This study investigated whether biallelic loss and HRD also occur in primary nonbreast/ovarian tumors that arise in germline BRCA1/2 carriers. METHODS: A clinically ascertained cohort of BRCA1/2 carriers with a primary nonbreast/ovarian cancer was identified, including canonical (prostate and pancreatic cancers) and noncanonical (all other) tumor types. Whole-exome sequencing or clinical sequencing results (n = 45) were analyzed. A pan-cancer analysis of nonbreast/ovarian primary tumors from germline BRCA1/2 carriers from The Cancer Genome Atlas (TCGA, n = 73) was used as a validation cohort. RESULTS: Ages of nonbreast/ovarian cancer diagnosis in germline BRCA1/2 carriers were similar to controls for the majority of cancer types. Nine of 45 (20%) primary nonbreast/ovarian tumors from germline BRCA1/2 carriers had biallelic loss of BRCA1/2 in the clinical cohort, and 23 of 73 (32%) in the TCGA cohort. In the combined cohort, 35% and 27% of primary canonical and noncanonical BRCA tumor types, respectively, had biallelic loss. High HRD scores (HRDex > 42) were detected in 81% of tumors with biallelic BRCA loss compared with 22% (P < .001) of tumors without biallelic BRCA loss. No differences in genomic profile, including mutational signatures, mutation spectrum, tumor mutational burden, or microsatellite instability, were found in primary nonbreast/ovarian tumors with or without biallelic BRCA1/2 loss. CONCLUSION: A proportion of noncanonical primary tumors have biallelic loss and evidence of HRD. Our data suggest that assessment of biallelic loss and HRD could supplement identification of germline BRCA1/2 mutations in selection of patients for platinum or PARP inhibitor therapy.

Germline pathogenic variants in 786 neuroblastoma patients.

Importance: Neuroblastoma accounts for 12% of childhood cancer deaths. The genetic contribution of rare pathogenic germline variation in patients without a family history remains unclear. Objective: To define the prevalence, spectrum, and clinical significance of pathogenic germline variation in cancer predisposition genes (CPGs) in neuroblastoma patients. Design Setting and Participants: Germline DNA sequencing was performed on the peripheral blood from 786 neuroblastoma patients unselected for family history. Rare variants mapping to CPGs were evaluated for pathogenicity and the percentage of cases harboring pathogenic (P) or likely pathogenic (LP) variants was quantified. The frequency of CPG P-LP variants in neuroblastoma cases was compared to two distinct cancer-free control cohorts to assess enrichment. Matched tumor DNA sequencing was evaluated for "second hits" at CPGs and germline DNA array data from 5,585 neuroblastoma cases and 23,505 cancer-free control children was analyzed to identify rare germline copy number variants (CNVs) affecting genes with an excess burden of P-LP variants in neuroblastoma. Neuroblastoma patients with germline P-LP variants were compared to those without P-LP variants to test for association with clinical characteristics, tumor features, and patient survival. Main Outcomes and Measures: Rare variant prevalence, pathogenicity, enrichment, and association with clinical characteristics, tumor features, and patient survival. Results: We observed 116 P-LP variants in CPGs involving 13.9% (109/786) of patients, representing a significant excess burden of P-LP variants compared to controls (9.1%; P = 5.14 × 10-5, Odds Ratio: 1.60, 95% confidence interval: 1.27-2.00). BARD1 harbored the most significant burden of P-LP variants compared to controls (1.0% vs. 0.03%; P = 8.18 × 10-7; Odds Ratio: 32.30, 95% confidence interval: 6.44-310.35). Rare germline CNVs disrupting BARD1 were also identified in neuroblastoma patients (0.05%) but absent in controls (P = 7.08 × 10-3; Odds Ratio: 29.47, 95% confidence interval: 1.52 - 570.70). Overall, P-LP variants in DNA repair genes in this study were enriched in cases compared to controls (8.1% vs. 5.7%; P = 0.01; Odds Ratio: 1.45, 95% confidence interval: 1.08-1.92). Neuroblastoma patients harboring a germline P-LP variant had a worse overall survival when compared to patients without P-LP variants (P = 8.6 × 10-3), and this remained significant in a multivariate Cox proportional-hazards model (P = 0.01). Conclusions and Relevance: Neuroblastoma patients harboring germline P-LP variants in CPGs have worse overall survival and BARD1 is an important predisposition gene affected by both common and rare pathogenic variation. Germline sequencing should be performed for all neuroblastoma patients at diagnosis to inform genetic counseling and support future longitudinal and mechanistic studies. Patients with a germline P-LP variant should be closely monitored, regardless of risk group assignment.

Dysplastic Pulmonary Valve Infective Endocarditis With an Atrial Septal Defect-A Black Swan Event: When Rarity Brings Clarity.

ABSTRACT: A case of infective endocarditis of a dysplastic pulmonic valve along with atrial septal defect has been described. Right-sided endocarditis has now increased in frequency because of cardiac invasive procedures and intravenous drug abuse. Although the tricuspid valve usually bears the brunt of right-sided endocarditis, there have now been increasing reports of pulmonary valve infective endocarditis.

Pathology of pulmonary tuberculosis: has the tiger changed it's stripes?

Background: India accounts for the highest number of TB cases globally (almost one-fifth of the global burden and almost two-thirds of the cases in South East Asia. Furthermore, the development of drug resistance of varying levels such as multi-drug resistant TB (MDR-TB), extensively-drug resistance TB (XDR-TB) and total-drug resistant TB (TDR-TB) has been on the increase, and now India also features in the 27 high-MDRTB-burden countries. Almost parallel to these developments, in the last few years, we have been encountering less common morphological forms of pulmonary TB (PTB) at autopsies. With these less common manifestations of the disease, we undertook this study to examine the changing trends in the morphological pattern of pulmonary TB over the recent years. Methods: In this 3-year retrospective study, adult autopsy cases of PTB (that significantly contributed to the final cause of death) were studied in detail. HIV-positive cases were excluded from the study. The clinical details, gross appearances of the pulmonary lesions, microscopic pattern and Ziehl-Neelsen (ZN) staining were studied. Extrapulmonary involvement and causes of death were documented. Results: Pulmonary tuberculosis as a cause of death at autopsy was seen in 130 adult patients over 3 years. The age range was between 12 to 70 years. Anti-tuberculous therapy had been administered in 33 of them, but only one patient had taken complete therapy. Dyspnea was the commonest respiratory symptom seen in 51 cases (39.2%). Tuberculous bronchopneumonia was the commonest lesion (45.3%), miliary lesions (including localized miliary) accounted for 26% while fibrocavitary lesions (including the ones not involving apex) were seen in 13% cases. Other morphologies included nodular forms of TB (13%), localized miliary lesions (11.9%), and fibrocavitary lesions, not necessarily involving the apex (11.7% of all fibrocavitary cases), and predominant pleuritis with underlying lung involvement by TB in 1 case. Many cases of TB bronchopneumonia had a bronchocentric pattern of distribution (14.7%). On microscopy, caseating granulomas were seen in 93% cases, only caseation necrosis was seen in 4.6% cases, and necrotizing granulomas with abscess-like reaction in 11.5% cases. ZN staining was positive in 92 cases (70.7%). All the extrapulmonary lesions showed caseating granulomas histologically. The final cause of death was found to be primarily tuberculous in 106 cases (81.5%), whereas in 24 cases (19.5%) pulmonary TB was attributed to the secondary cause of death. Conclusion: The typical apical involvement of secondary TB was not seen in most of our cases. This could indicate a difference in the morphology and the pattern of lung involvement in recent years. The difference in gross morphology does not affect the pattern of involvement of the lung. In our study, we have observed both; a change in morphology, i.e., more cases of TB bronchopneumonia, and a change in the pattern of involvement like nodular forms, localized miliary forms, and fibrocavitary lesions not necessarily involving the apex. We postulate that this less common manifestation of pulmonary TB is closely related to the development of multi-drug and microbial resistance posing serious medical challenges.

Resurgence of diphtheria in Northern Gujarat: A retrospective study done in Banas Medical College and Research Centre, Palanpur, Gujarat.

Background: A diphtheria outbreak occurred in Banaskantha district in the northern part of Gujarat in 2019-2020. This study was undertaken to study and generate information on the resurgence of the disease in this region and to generate information regarding the status of vaccination in this region and what strategies can be adopted to avoid re-emergence of the disease in the future. Materials and Methods: This is a hospital-based, retrospective, descriptive study done on patients of diphtheria who were admitted in Banas Medical College and Research Institute, Palanpur from September 2019 to January 2020. Throat swab was taken from all the patients and information regarding symptoms, vaccination, and demographic characteristic was collected. Treatment in the form of ADS, injection crystalline penicillin/erythromycin and other supportive treatment was given. Result: Out of 188 patients, 27 patients (14.36%) were less than 5 years of age, 118 patients (62.76%) and 38 patients (20.21%) were of age group 5-10 and 11-18 years, respectively. Total of five patients (2.66%) were of age more than 18 years. Out of 188 patients, 102 (54.25%) were males and 86 patients (45.74%) were females. All the patients (188) were found to be unvaccinated. Among 188 throat swabs that were tested, 21 samples (11.17%) were found to be culture positive for Corynebacterium diphtheriae. Antidiphtheric serum was given in 181 patients (96.27%) according to the requirement. Out of 188 patients, 155 patients (82.44%) improved with treatment and were discharged. Total of 23 patients (12.23%) were referred to higher center for tracheostomy and for management of other complications. Six patients (3.19%) left against medical advice and four patients (2.12%) expired despite all measures taken. Conclusion: Diphtheria is a disease that can easily be prevented by vaccination. Our study highlights need to increase awareness about vaccination among people of Banaskatha district and all measures should be taken to give full vaccination to children less than 5 years of age and booster vaccination should be encouraged in adolescents and adults so that future resurgence of disease can be prevented.

Association of Inherited Mutations in DNA Repair Genes with Localized Prostate Cancer.

BACKGROUND: Identification of germline mutations in DNA repair genes has significant implications for the personalized treatment of individuals with prostate cancer (PrCa). OBJECTIVE: To determine DNA repair genes associated with localized PrCa in a diverse academic biobank and to determine genetic testing burden. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional study of 2391 localized PrCa patients was carried out. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Genetic ancestry and mutation rates (excluding somatic interference) in 17 DNA repair genes were determined in 1588 localized PrCa patients and 3273 cancer-free males. Burden testing within individuals of genetically determined European (EUR) and African (AFR) ancestry was performed between biobank PrCa cases and cancer-free biobank and gnomAD males. RESULTS AND LIMITATIONS: AFR individuals with localized PrCa had lower DNA repair gene mutation rates than EUR individuals (1.4% vs 4.0%, p = 0.02). Mutation rates in localized PrCa patients were similar to those in biobank and gnomAD controls (EUR: 4.0% vs 2.8%, p = 0.15, vs 3.1%, p = 0.04; AFR: 1.4% vs 1.8%, p = 0.8, vs 2.1%, p = 0.5). Gene-based rare variant association testing revealed that only BRCA2 mutations were significantly enriched compared with gnomAD controls of EUR ancestry (1.0% vs 0.28%, p = 0.03). Of the participants, 21% and 11% met high-risk and very-high-risk criteria; of them, 3.7% and 6.2% had any germline genetic mutation and 1.0% and 2.5% had a BRCA2 mutation, respectively. Limitations of this study include an analysis of a relatively small, single-institution cohort. CONCLUSIONS: DNA repair gene germline mutation rates are low in an academic biobank cohort of localized PrCa patients, particularly among individuals of AFR genetic ancestry. Mutation rates in genes with published evidence of association with PrCa exceed 2.5% only in high-risk, very-high-risk localized, and node-positive PrCa patients. These findings highlight the importance of risk stratification in localized PrCa patients to identify appropriate patients for germline genetic testing. PATIENT SUMMARY: In the majority of patients who develop localized prostate cancer, germline genetic testing is unlikely to reveal an inherited DNA repair mutation, regardless of race. High-risk features increase the possibility of a germline DNA repair mutation.

Performance of polygenic risk scores for cancer prediction in a racially diverse academic biobank.

PURPOSE: Genome-wide association studies have identified hundreds of single nucleotide variations (formerly single nucleotide polymorphisms) associated with several cancers, but the predictive ability of polygenic risk scores (PRSs) is unclear, especially among non-Whites. METHODS: PRSs were derived from genome-wide significant single-nucleotide variations for 15 cancers in 20,079 individuals in an academic biobank. We evaluated the improvement in discriminatory accuracy by including cancer-specific PRS in patients of genetically-determined African and European ancestry. RESULTS: Among the individuals of European genetic ancestry, PRSs for breast, colon, melanoma, and prostate were significantly associated with their respective cancers. Among the individuals of African genetic ancestry, PRSs for breast, colon, prostate, and thyroid were significantly associated with their respective cancers. The area under the curve of the model consisting of age, sex, and principal components was 0.621 to 0.710, and it increased by 1% to 4% with the inclusion of PRS in individuals of European genetic ancestry. In individuals of African genetic ancestry, area under the curve was overall higher in the model without the PRS (0.723-0.810) but increased by <1% with the inclusion of PRS for most cancers. CONCLUSION: PRS moderately increased the ability to discriminate the cancer status in individuals of European but not African ancestry. Further large-scale studies are needed to identify ancestry-specific genetic factors in non-White populations to incorporate PRS into cancer risk assessment.

Acute respiratory distress syndrome: A study of autopsy findings.

CONTEXT: In this autopsy study, the various morphological patterns of acute respiratory distress syndrome (ARDS) have been analyzed and compared along with their etiopathogenesis. AIMS: We aimed to study the prevalence and clinicopathological correlation of ARDS based on age, gender, hospital stay, symptoms, clinical diagnosis, gross, and microscopy findings. SUBJECTS AND METHODS: Total 130 cases of ARDS were studied over a period of 5 years. Age, gender, hospital stay duration, symptoms, clinical diagnosis, gross and microscopic lung finding, clinicopathological correlation, and cause of death were documented and analyzed. Special stains were done whenever required. STATISTICAL ANALYSIS: This is an observational study, and simple statistics such as mean, median, and standard deviation have been used for continuous variables. RESULTS: The prevalence of ARDS among the adult autopsy was 6.05%. Majority of the cases were in the age group of 18-30 years (36.9%), with a male: female ratio of 1.7:1. Chief complaints were fever (71%), breathlessness (54.6%), and chills (43.8%). The main clinical diagnoses were ARDS (41.6%), sepsis (28.3%), acute febrile illness (17%), and lower respiratory tract infection (12.5%). Most of the patients had a hospital stay of <1 day. Associated conditions mostly included chronic alcoholism (16.1%), pregnancy (16.1%), and chronic smoking (10.7%). Major findings on gross examination were intrapulmonary hemorrhage (38.5%), ARDS (33%), pulmonary edema (13%), and pneumonia (15.3%).On microscopy, major findings were hyaline membrane (84.6%), intrapulmonary hemorrhage (76.1%), pulmonary edema (75.3%), organizing fibrin (55.3%), and bronchopneumonia (36.2%). CONCLUSION: Infections were one of the major predisposing causes of ARDS. Due to the short interval, the underlying cause for ARDS often goes undiagnosed.

SARS-CoV-2 Seropositivity and Seroconversion in Patients Undergoing Active Cancer-Directed Therapy.

PURPOSE: Multiple studies have demonstrated the negative impact of cancer care delays during the COVID-19 pandemic, and transmission mitigation techniques are imperative for continued cancer care delivery. We aimed to gauge the effectiveness of these measures at the University of Pennsylvania. METHODS: We conducted a longitudinal study of SARS-CoV-2 antibody seropositivity and seroconversion in patients presenting to infusion centers for cancer-directed therapy between May 21, 2020, and October 8, 2020. Participants completed questionnaires and had up to five serial blood collections. RESULTS: Of 124 enrolled patients, only two (1.6%) had detectable SARS-CoV-2 antibodies on initial blood draw, and no initially seronegative patients developed newly detectable antibodies on subsequent blood draw(s), corresponding to a seroconversion rate of 0% (95% CI, 0.0 TO 4.1%) over 14.8 person-years of follow up, with a median of 13 health care visits per patient. CONCLUSION: These results suggest that patients with cancer receiving in-person care at a facility with aggressive mitigation efforts have an extremely low likelihood of COVID-19 infection.

Rates of COVID-19-Related Outcomes in Cancer Compared With Noncancer Patients.

Cancer patients are a vulnerable population postulated to be at higher risk for severe coronavirus disease 2019 (COVID-19) infection. Increased COVID-19 morbidity and mortality in cancer patients may be attributable to age, comorbidities, smoking, health care exposure, and cancer treatments, and partially to the cancer itself. Most studies to date have focused on hospitalized patients with severe COVID-19, thereby limiting the generalizability and interpretability of the association between cancer and COVID-19 severity. We compared outcomes of SARS-CoV-2 infection in 323 patients enrolled in a population-based study before the pandemic (n = 67 cancer patients; n = 256 noncancer patients). After adjusting for demographics, smoking status, and comorbidities, a diagnosis of cancer was independently associated with higher odds of hospitalization (odds ratio = 2.16, 95% confidence interval = 1.12 to 4.18) and 30-day mortality (odds ratio = 5.67, 95% confidence interval = 1.49 to 21.59). These associations were primarily driven by patients with active cancer. These results emphasize the critical importance of preventing SARS-CoV-2 exposure and mitigating infection in cancer patients.

SARS-CoV-2 seropositivity and seroconversion in patients undergoing active cancer-directed therapy.

Multiple studies have demonstrated the negative impact of cancer care delays during the COVID-19 pandemic, and transmission mitigation techniques are imperative for continued cancer care delivery. To gauge the effectiveness of these measures at the University of Pennsylvania, we conducted a longitudinal study of SARS-CoV-2 antibody seropositivity and seroconversion in patients presenting to infusion centers for cancer-directed therapy between 5/21/2020 and 10/8/2020. Participants completed questionnaires and had up to five serial blood collections. Of 124 enrolled patients, only two (1.6%) had detectable SARS-CoV-2 antibodies on initial blood draw, and no initially seronegative patients developed newly detectable antibodies on subsequent blood draw(s), corresponding to a seroconversion rate of 0% (95%CI 0.0-4.1%) over 14.8 person-years of follow up, with a median of 13 healthcare visits per patient. These results suggest that cancer patients receiving in-person care at a facility with aggressive mitigation efforts have an extremely low likelihood of COVID-19 infection.

In situ Generated Ru(0)-HRO@Na-ß From Hydrous Ruthenium Oxide (HRO)/Na-ß: An Energy-Efficient Catalyst for Selective Hydrogenation of Sugars.

A green process for the hydrogenation of sugars to sugar alcohols was designed in aqueous medium using hydrous ruthenium oxide (HRO) as a pre-catalyst supported on Na-ß zeolite. Under optimized reaction conditions, sugars such as xylose, glucose, and mannose converted completely to the corresponding sugar alcohols xylitol, sorbitol, and mannitol with 100% selectivity. The pre-catalyst (HRO) is converted in situ to active Ru(0) species during the reaction under H2, which is responsible for the hydrogenation. The catalyst was recyclable up to five cycles with no loss in activity. The reduction of HRO to the active Ru(0) species is dependent on the reaction temperature and H2 pressure. Ru(0) formation increased and consequently an increased hydrogenation of sugars was observed with an increase in reaction temperature and hydrogen pressure. Further, in situ generation of Ru(0) from HRO was assessed in different solvents such as water, methanol, and tetrahydrofuran; aqueous medium was found to be the most efficient in reducing HRO. This work further demonstrates the use of supported HRO as an efficient pre-catalyst for biomass-based hydrogenation reactions.

Rates of COVID-19-related Outcomes in Cancer compared to non-Cancer Patients.

Cancer patients are a vulnerable population postulated to be at higher risk for severe COVID-19 infection. Increased COVID-19 morbidity and mortality in cancer patients may be attributable to age, comorbidities, smoking, healthcare exposure, and cancer treatments, and partially to the cancer itself. Most studies to date have focused on hospitalized patients with severe COVID-19, thereby limiting the generalizability and interpretability of the association between cancer and COVID-19 severity. We compared outcomes of SARS-CoV-2 infection in 323 patients enrolled prior to the pandemic in a large academic biobank (n=67 cancer patients and n=256 non-cancer patients). After adjusting for demographics, smoking status, and comorbidities, a diagnosis of cancer was independently associated with higher odds of hospitalization (OR 2.16, 95% CI 1.12-4.18) and 30-day mortality (OR 5.67, CI 1.49-21.59). These associations were primarily driven by patients with active cancer. These results emphasize the critical importance of preventing SARS-CoV-2 exposure and mitigating infection in cancer patients.

A Rare TP53 Mutation Predominant in Ashkenazi Jews Confers Risk of Multiple Cancers.

Germline mutations in TP53 cause a rare high penetrance cancer syndrome, Li-Fraumeni syndrome (LFS). Here, we identified a rare TP53 tetramerization domain missense mutation, c.1000G>C;p.G334R, in a family with multiple late-onset LFS-spectrum cancers. Twenty additional c.1000G>C probands and one c.1000G>A proband were identified, and available tumors showed biallelic somatic inactivation of TP53. The majority of families were of Ashkenazi Jewish descent, and the TP53 c.1000G>C allele was found on a commonly inherited chromosome 17p13.1 haplotype. Transient transfection of the p.G334R allele conferred a mild defect in colony suppression assays. Lymphoblastoid cell lines from the index family in comparison with TP53 normal lines showed that although classical p53 target gene activation was maintained, a subset of p53 target genes (including PCLO, PLTP, PLXNB3, and LCN15) showed defective transactivation when treated with Nutlin-3a. Structural analysis demonstrated thermal instability of the G334R-mutant tetramer, and the G334R-mutant protein showed increased preponderance of mutant conformation. Clinical case review in comparison with classic LFS cohorts demonstrated similar rates of pediatric adrenocortical tumors and other LFS component cancers, but the latter at significantly later ages of onset. Our data show that TP53 c.1000G>C;p.G334R is found predominantly in Ashkenazi Jewish individuals, causes a mild defect in p53 function, and leads to low penetrance LFS. SIGNIFICANCE: TP53 c.1000C>G;p.G334R is a pathogenic, Ashkenazi Jewish-predominant mutation associated with a familial multiple cancer syndrome in which carriers should undergo screening and preventive measures to reduce cancer risk.

Frequency of radiation-induced malignancies post-adjuvant radiotherapy for breast cancer in patients with Li-Fraumeni syndrome.

PURPOSE: Women with Li-Fraumeni syndrome (LFS), a cancer predisposition syndrome caused by germline mutations in TP53, have an over 50% risk of developing breast cancer by age 70. Patients with LFS are at risk for radiation-induced malignancies; however, only small case series have prior investigated radiation risks in the treatment of breast cancer. We therefore aimed to investigate the risk of malignancy in breast cancer patients with LFS following adjuvant radiotherapy. METHODS: A single-institution retrospective chart review was conducted for female breast cancer patients with confirmed germline TP53 mutation. The frequency of radiation-induced malignancies in LFS patients was compared to non-LFS breast cancer cases reported in the Penn Medicine Cancer Registry via statistical analyses. RESULTS: We identified 51 female LFS breast cancer patients with 74 primary diagnoses. Fifty-seven% had a history of breast cancer only, and 25% had breast cancer as their presenting diagnosis of LFS. LFS-associated breast cancers were predominantly invasive ductal carcinoma (48%) and HER2+ (58%). Twenty patients underwent adjuvant radiotherapy with a median follow-up of 12.5 (2-20) years. Of 18 patients who received radiation in a curative setting, one (6%) patient developed thyroid cancer, and one (6%) patient developed sarcoma in the radiation field. This risk for radiation-induced malignancy associated with LFS was higher for both sarcoma and thyroid cancer in comparison with the control cohort. CONCLUSIONS: We found a lower risk of radiation-induced secondary malignancies in LFS breast cancer patients than previously reported in the literature (33% risk of radiation-induced sarcoma). These findings suggest that LFS may not be an absolute contraindication for radiotherapy in breast cancer. The potential risk for locoregional recurrence without radiotherapy must be weighed against the long-term risk for radiation-induced malignancies in consideration of adjuvant radiotherapy for LFS breast cancer patients.

Seroprevalence of transfusion transmitted infections in healthy blood donors: A 5-year Tertiary Care Hospital experience.

INTRODUCTION: Transfusion transmitted infections (TTIs) can cause threat to bloody safety as blood transfusion is an important mode of transmission of TTI to the recipient, hence, to prevent transmission of these diseases, screening tests on blood bags is an important step for blood safety. AIM: This study was undertaken with the aim of determining the seroprevalence of TTI in healthy blood donors in a tertiary care blood bank. MATERIALS AND METHODS: A retrospective study was carried out over a period of 5 years from January 2007 to December 2011. Serum samples were screened for hepatitis B surface antigen (HBsAg), antibodies to human immunodeficiency virus (HIV) Type 1 and 2, hepatitis c virus (HCV) and syphilis using enzyme-linked immunosorbent assays with the third generation kits and venereal disease research laboratory test, respectively. RESULTS: A total of 76,653 healthy donors were included out of which majority of donors were male (91.79%). The overall seroprevalence of HIV, HBsAg, HCV, and syphilis were 0.26%, 1.30%, 0.25%, and 0.28%, respectively. CONCLUSION: Methods to ensure a safety blood supply should be encouraged. For that, screening with a better selection of donors and use of sensitive screening tests including nucleic acid testing technology should be implemented.