Probing versus primary nasal endoscopy for the treatment of congenital dacryocystoceles.

PURPOSE: To compare outcomes and complications of three surgical techniques for the treatment of congenital dacryocystoceles: nasolacrimal probing and irrigation (P+I), P+I plus nasal endoscopy (NE) with intranasal cyst marsupialization, and primary NE with intranasal cyst marsupialization. METHODS: The medical records of children ≤2 years of age at a single academic center with a diagnosis of dacryocystocele from 2012 to 2022 were retrospectively identified and reviewed. The primary outcome was resolution of the dacryocystocele (ie, elimination of the medial canthal mass and resolution of tearing or discharge) after a single procedure ("primary success"). Surgical techniques were compared using exact logistic regression. RESULTS: Of 54 patients, 21 (39%) underwent P+I, 23 (43%) underwent P+I plus nasal endoscopy, and 10 (18%) underwent primary NE. Primary success was 76% for P+I and 100% for the other two cohorts. Most patients (89%) who underwent P+I received general anesthesia compared with none who underwent primary nasal endoscopy. Most complications were related to the use of general anesthesia, with a complication rate of 10% for P+I, 48% for P+I plus NE, and 0% for primary NE. Most P+I procedures required hospital admission compared to half of primary NE procedures. CONCLUSIONS: In our study cohort, primary NE provided good outcomes and was associated with a lower complication rate than P+I with or without NE.

In Utero Exposure to Maternal COVID-19 Vaccination and Offspring Neurodevelopment at 12 and 18 Months.

Importance: Uptake of COVID-19 vaccines among pregnant individuals was hampered by safety concerns around potential risks to unborn children. Data clarifying early neurodevelopmental outcomes of offspring exposed to COVID-19 vaccination in utero are lacking. Objective: To determine whether in utero exposure to maternal COVID-19 vaccination was associated with differences in scores on the Ages and Stages Questionnaire, third edition (ASQ-3), at 12 and 18 months of age. Design, Setting, and Participants: This prospective cohort study, Assessing the Safety of Pregnancy During the Coronavirus Pandemic (ASPIRE), enrolled pregnant participants from May 2020 to August 2021; follow-up of children from these pregnancies is ongoing. Participants, which included pregnant individuals and their offspring from all 50 states, self-enrolled online. Study activities were performed remotely. Exposure: In utero exposure of the fetus to maternal COVID-19 vaccination during pregnancy was compared with those unexposed. Main Outcomes and Measures: Neurodevelopmental scores on validated ASQ-3, completed by birth mothers at 12 and 18 months. A score below the established cutoff in any of 5 subdomains (communication, gross motor, fine motor, problem solving, social skills) constituted an abnormal screen for developmental delay. Results: A total of 2487 pregnant individuals (mean [SD] age, 33.3 [4.2] years) enrolled at less than 10 weeks' gestation and completed research activities, yielding a total of 2261 and 1940 infants aged 12 and 18 months, respectively, with neurodevelopmental assessments. In crude analyses, 471 of 1541 exposed infants (30.6%) screened abnormally for developmental delay at 12 months vs 203 of 720 unexposed infants (28.2%; χ2 = 1.32; P = .25); the corresponding prevalences at 18 months were 262 of 1301 (20.1%) vs 148 of 639 (23.2%), respectively (χ2 = 2.35; P = .13). In multivariable mixed-effects logistic regression models adjusting for maternal age, race, ethnicity, education, income, maternal depression, and anxiety, no difference in risk for abnormal ASQ-3 screens was observed at either time point (12 months: adjusted risk ratio [aRR], 1.14; 95% CI, 0.97-1.33; 18 months: aRR, 0.88; 95% CI, 0.72-1.07). Further adjustment for preterm birth and infant sex did not affect results (12 months: aRR, 1.16; 95% CI, 0.98-1.36; 18 months: aRR, 0.87; 95% CI, 0.71-1.07). Conclusions and Relevance: Results of this cohort study suggest that COVID-19 vaccination was safe during pregnancy from the perspective of infant neurodevelopment to 18 months of age. Additional longer-term research should be conducted to corroborate these findings and buttress clinical guidance with a strong evidence base.

Interplay of demographics, geography and COVID-19 pandemic responses in the Puget Sound region: The Vashon, Washington Medical Reserve Corps experience.

BACKGROUND: Rural U.S. communities are at risk from COVID-19 due to advanced age and limited access to acute care. Recognizing this, the Vashon Medical Reserve Corps (VMRC) in King County, Washington, implemented an all-volunteer, community-based COVID-19 response program. This program integrated public engagement, SARS-CoV-2 testing, contact tracing, vaccination, and material community support, and was associated with the lowest cumulative COVID-19 case rate in King County. This study aimed to investigate the contributions of demographics, geography and public health interventions to Vashon's low COVID-19 rates. METHODS: This observational cross-sectional study compares cumulative COVID-19 rates and success of public health interventions from February 2020 through November 2021 for Vashon Island with King County (including metropolitan Seattle) and Whidbey Island, located ~50 km north of Vashon. To evaluate the role of demography, we developed multiple linear regression models of COVID-19 rates using metrics of age, race/ethnicity, wealth and educational attainment across 77 King County zip codes. To investigate the role of remote geography we expanded the regression models to include North, Central and South Whidbey, similarly remote island communities with varying demographic features. To evaluate the effectiveness of VMRC's community-based public health measures, we directly compared Vashon's success of vaccination and contact tracing with that of King County and South Whidbey, the Whidbey community most similar to Vashon. RESULTS: Vashon's cumulative COVID-19 case rate was 29% that of King County overall (22.2 vs 76.8 cases/K). A multiple linear regression model based on King County demographics found educational attainment to be a major correlate of COVID-19 rates, and Vashon's cumulative case rate was just 38% of predicted (p < .05), so demographics alone do not explain Vashon's low COVID-19 case rate. Inclusion of Whidbey communities in the model identified a major effect of remote geography (-49 cases/K, p < .001), such that observed COVID-19 rates for all remote communities fell within the model's 95% prediction interval. VMRC's vaccination effort was highly effective, reaching a vaccination rate of 1500 doses/K four months before South Whidbey and King County and maintaining a cumulative vaccination rate 200 doses/K higher throughout the latter half of 2021 (p < .001). Including vaccination rates in the model reduced the effect of remote geography to -41 cases/K (p < .001). VMRC case investigation was also highly effective, interviewing 96% of referred cases in an average of 1.7 days compared with 69% in 3.7 days for Washington Department of Health investigating South Whidbey cases and 80% in 3.4 days for Public Health-Seattle & King County (both p<0.001). VMRC's public health interventions were associated with a 30% lower case rate (p<0.001) and 55% lower hospitalization rate (p = 0.056) than South Whidbey. CONCLUSIONS: While the overall magnitude of the pre-Omicron COVID-19 pandemic in rural and urban U.S. communities was similar, we show that island communities in the Puget Sound region were substantially protected from COVID-19 by their geography. We further show that a volunteer community-based COVID-19 response program was highly effective in the Vashon community, augmenting the protective effect of geography. We suggest that Medical Reserve Corps should be an important element of future pandemic planning.

Multiple Tissue Biomarkers Independently and Additively Predict Prostate Cancer Pathology Outcomes.

BACKGROUND: Distinguishing indolent from aggressive prostate cancer remains a key challenge for decision making regarding prostate cancer management. A growing number of biomarkers are now available to help address this need, but these have rarely been examined together in the same patients to determine their potentially additive value. OBJECTIVE: To determine whether two previously validated plasma markers (transforming growth factor ß1 [TGFß1] and interleukin-6 soluble receptor [IL6-SR]) and two validated tissue scores (the Genomic Evaluators of Metastatic Prostate Cancer [GEMCaP] and cell cycle progression [CCP] scores) can improve on clinical parameters in predicting adverse pathology after prostatectomy, and how much they vary within tumors with heterogeneous Gleason grade. DESIGN, SETTING, AND PARTICIPANTS: A case-control study was conducted among men with low-risk cancers defined by biopsy grade group (GG) 1, prostate-specific antigen (PSA) ≤10 ng/mL, and clinical stage ≤ T2 who underwent immediate prostatectomy. We collected paraffin-fixed prostatectomy tissue and presurgical plasma samples from 381 cases from the University of California, San Francisco, and 260 cases from the University of Washington. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Pathologic outcomes were minor upgrading/upstaging (GG 2 or pT3a) or major upgrading/upstaging (GG ≥ 3 or ≥ pT3b), and multinomial regression was performed to determine putative markers' ability to predict these outcomes, controlling for PSA, percent of positive biopsy cores, age, and clinical site. For upgraded tumors, a secondary analysis of the GEMCaP and CCP scores from the higher-grade tumor was also performed to evaluate for heterogeneity. RESULTS AND LIMITATIONS: Overall, 357 men had no upgrading/upstaging event at prostatectomy, 236 had a minor event, and 67 had a major event. Neither TGFß1 nor IL6-SR was statistically significantly associated with any upgrading/upstaging. On the contrary, both the CCP and the GEMCaP score obtained from Gleason pattern 3 tissue were directly associated with minor and major upgrading/upstaging on univariate analysis. The two scores correlated with each other, but weakly. On multinomial analysis including both scores in the model, the CCP score predicted minor upgrading/upstaging (odds ratio [OR] 1.62, 95% confidence interval [CI] 1.05-2.49) and major upgrading/upstaging (OR 2.26, 95% CI 1.05-4.90), p =  0.04), and the GEMCaP score also predicted minor upgrading/upstaging (OR 1.05, 95% CI 1.03-1.08) and major upgrading/upstaging (OR 1.07, 95% CI 1.04-1.11), p <  0.01). The other clinical parameters were not significant in this model. Among upgraded tumors including both Gleason patterns 3 and 4, both the GEMCaP and the CCP score tended to be higher from the higher-grade tumor. The main limitation was the use of virtual biopsies from prostatectomy tissue as surrogates for prostate biopsies. CONCLUSIONS: Biomarker signatures based on analyses of both DNA and RNA significantly and independently predict adverse pathology among men with clinically low-risk prostate cancer undergoing prostatectomy. PATIENT SUMMARY: Validated biomarker scores derived from both prostate cancer DNA and prostate cancer RNA can add independent information to help predict outcomes after prostatectomy.

Copy number gains at chr3p25 and chr11p11 are associated with lymph node involvement and survival in muscle-invasive bladder tumors.

Patients with muscle-invasive bladder cancer (MIBC) have poorer prognoses if cancer has metastasized to the lymph nodes. Genomic markers of lymph node involvement (LNI) would be useful for treatment planning, especially if measured at the biopsy stage, but large-scale studies of tumor tissue at any stage are needed to discover robust markers of LNI. We performed a genome-wide query of copy number alterations (CNA) in 237 MIBC surgical tumor specimens from patients in The Cancer Genome Atlas who had radical cystectomy and lymphadenectomy without neoadjuvant treatment. Pathology reports were independently reviewed to confirm LNI, and copy number data was analyzed to confirm gene-level gains and losses while adjusting for tumor purity and ploidy. Using logistic regression and elastic net models, we identified the CNA most significantly associated with LNI. Multivariable logistic regression was used to describe these CNA associations while adjusting for clinical variables. Kaplan-Meier and Cox regression were used to describe their association with overall survival. Gains in 26 genes were identified as having strong associations with LNI. After adjusting for age, gender, race, pathological tumor stage, histology, and number of nodes examined, gains in 22 genes on chr3p25 or chr11p11 remained significantly associated with LNI (p<0.01) and improved model discrimination over clinical variables alone (p = 0.04). They were also associated with shorter overall survival (adjusted p = 0.02). These results suggest that a simple genomic test for gains in chr3p25 and chr11p11 could inform adjuvant treatment or clinical trial decisions if validated in external cohorts. Additional studies will also be needed to determine if these CNA are detectible in biopsy tissue and can inform clinical decisions at the preoperative stage.

An improved CTC isolation scheme for pairing with downstream genomics: Demonstrating clinical utility in metastatic prostate, lung and pancreatic cancer.

Improvements in technologies to yield purer circulating tumor cells (CTCs) will enable a broader range of clinical applications. We have previously demonstrated the use of a commercially available cell-adhesion matrix (CAM) assay to capture invasive CTCs (iCTCs). To improve the purity of the isolated iCTCs, here we used fluorescence-activated cell sorting (FACS) in combination with the CAM assay (CAM + FACS). Our results showed an increase of median purity from the CAM assay to CAM + FACS for the spiked-in cell lines and patient samples analyzed from three different metastatic cancer types: castration resistant prostate cancer (mCRPC), non-small cell lung cancer (mNSCLC) and pancreatic ductal adenocarcinoma cancer (mPDAC). Copy number profiles for spiked-in mCRPC cell line and mCRPC patient iCTCs were similar to expected mCRPC profiles and a matched biopsy. A somatic epidermal growth factor receptor (EGFR) mutation specific to mNSCLC was observed in the iCTCs recovered from EGFR(+) mNSCLC cell lines and patient samples. Next-generation sequencing (NGS) of spiked-in pancreatic cancer cell line and mPDAC patient iCTCs showed mPDAC common mutations. CAM + FACS iCTC enrichment enables multiple downstream genomic characterizations across different tumor types.

Mutational Landscape of Aggressive Prostate Tumors in African American Men.

Prostate cancer is the most frequently diagnosed and second most fatal nonskin cancer among men in the United States. African American men are two times more likely to develop and die of prostate cancer compared with men of other ancestries. Previous whole genome or exome tumor-sequencing studies of prostate cancer have primarily focused on men of European ancestry. In this study, we sequenced and characterized somatic mutations in aggressive (Gleason ≥7, stage ≥T2b) prostate tumors from 24 African American patients. We describe the locations and prevalence of small somatic mutations (up to 50 bases in length), copy number aberrations, and structural rearrangements in the tumor genomes compared with patient-matched normal genomes. We observed several mutation patterns consistent with previous studies, such as large copy number aberrations in chromosome 8 and complex rearrangement chains. However, TMPRSS2-ERG gene fusions and PTEN losses occurred in only 21% and 8% of the African American patients, respectively, far less common than in patients of European ancestry. We also identified mutations that appeared specific to or more common in African American patients, including a novel CDC27-OAT gene fusion occurring in 17% of patients. The genomic aberrations reported in this study warrant further investigation of their biologic significant role in the incidence and clinical outcomes of prostate cancer in African Americans. Cancer Res; 76(7); 1860-8. ©2016 AACR.

Performance of the Genomic Evaluators of Metastatic Prostate Cancer (GEMCaP) tumor biomarker for identifying recurrent disease in African American patients.

Evaluation of prostate cancer prognosis after surgery is increasingly relying upon genomic analyses of tumor DNA. We assessed the ability of the biomarker panel Genomic Evaluators of Metastatic Prostate Cancer (GEMCaP) to predict biochemical recurrence in 33 European American and 28 African American prostate cancer cases using genome-wide copy number data from a previous study. "Biomarker positive" was defined as ≥20% of the 38 constituent copy number gain/loss GEMCaP loci affected in a given tumor; based on this threshold, the frequency of a positive biomarker was significantly lower in African Americans (n = 2; 7%) than European Americans (n = 11; 33%; P = 0.013). GEMCaP positivity was associated with risk of recurrence [hazard ratio (HR), 5.92; 95% confidence interval (CI), 2.32-15.11; P = 3 × 10(-4)] in the full sample and among European Americans (HR, 3.45; 95% CI, 1.13-10.51; P = 0.032) but was not estimable in African Americans due to the low rate of GEMCaP positivity. Overall, the GEMCaP recurrence positive predictive value (PPV) was 85%; in African Americans, PPV was 100%. When we expanded the definition of loss to include copy-neutral loss of heterozygosity (i.e., loss of one allele with concomitant duplication of the other), recurrence PPV was 83% for European American subjects. Under this definition, 5 African American subjects had a positive GEMCaP test value; 4 went on to develop biochemical recurrence (PPV = 80%). Our results suggest that the GEMCaP biomarker set could be an effective predictor for both European American and African American men diagnosed with localized prostate cancer who may benefit from immediate aggressive therapy after radical prostatectomy.

Undiagnosed diabetes in breast, colorectal, lung, and prostate cancer: incidence and risk factors.

Our study describes the incidence and risk factors for undiagnosed diabetes in elderly cancer patients. Using Surveillance, Epidemiology, and End Results-Medicare data, we followed patients with breast, colorectal, lung, or prostate cancer from 24 months before to 3 months after cancer diagnosis. Medicare claims were used to exclude patients with diabetes 24 to 4 months before cancer (look-back period), identify those with diabetes undiagnosed until cancer, and construct indicators of preventive services, physician contact, and comorbidity during the look-back period. Logistic regression analyses were performed to identify factors associated with undiagnosed diabetes. Overall, 2,678 patients had diabetes undiagnosed until cancer. Rates were the highest in patients with both advanced-stage cancer and low prior primary care/medical specialist contact (breast 8.2%, colorectal 5.9%, lung 4.4%). Nonwhite race/ethnicity, living in a census tract with a higher percent of the population in poverty and a lower percent college educated, lower prior preventive services use, and lack of primary care and/or medical specialist care prior to cancer all were associated with higher (P ≤ 0.05) adjusted odds of undiagnosed diabetes. Undiagnosed diabetes is relatively common in selected subgroups of cancer patients, including those already at high risk of poor outcomes due to advanced cancer stage.

The impact of improved microarray coverage and larger sample sizes on future genome-wide association studies.

Genome-wide association studies (GWAS) have identified many single nucleotide polymorphisms (SNPs) associated with complex traits. However, the genetic heritability of most of these traits remains unexplained. To help guide future studies, we address the crucial question of whether future GWAS can detect new SNP associations and explain additional heritability given the new availability of larger GWAS SNP arrays, imputation, and reduced genotyping costs. We first describe the pairwise and imputation coverage of all SNPs in the human genome by commercially available GWAS SNP arrays, using the 1000 Genomes Project as a reference. Next, we describe the findings from 6 years of GWAS of 172 chronic diseases, calculating the power to detect each of them while taking array coverage and sample size into account. We then calculate the power to detect these SNP associations under different conditions using improved coverage and/or sample sizes. Finally, we estimate the percentages of SNP associations and heritability previously detected and detectable by future GWAS under each condition. Overall, we estimated that previous GWAS have detected less than one-fifth of all GWAS-detectable SNPs underlying chronic disease. Furthermore, increasing sample size has a much larger impact than increasing coverage on the potential of future GWAS to detect additional SNP-disease associations and heritability.

Prevalence and incidence of comorbidities in elderly women with ovarian cancer.

OBJECTIVE: Studies suggest comorbidity plays an important role in ovarian cancer. We characterized the epidemiology of comorbid conditions in elderly U.S. women with ovarian cancer. METHODS: Women with ovarian cancer age ≥66 years, and matched cancer-free women, were identified using the National Cancer Institute's Surveillance, Epidemiology, and End Results registry linked to Medicare claims. Prevalence before diagnosis/index date and 3- and 12-month incidence rates (per 1000 person-years) after diagnosis/index date were estimated for 34 chronic and acute conditions across a broad range of diagnostic categories. RESULTS: There were 5087 each of women with ovarian cancer and cancer-free women. The prevalence of most conditions was similar between cancer and cancer-free patients, but exceptions included hypertension (51.8% and 43.5%, respectively), osteoarthritis (13.4% and 17.3%, respectively), and cerebrovascular disease (8.0% and 9.8%, respectively). In contrast, 3- and 12-month incidence rates (per 1000 person years) of most conditions were significantly higher in cancer than in cancer-free patients: hypertension (177.3 and 47.4, respectively); thromboembolic event (145.3 and 5.5, respectively); congestive heart failure (113.3 and 28.6, respectively); infection (664.4 and 55.2, respectively); and anemia (408.3 and 33.1, respectively) at 12 months. CONCLUSIONS: Comorbidities were common among elderly women. After cancer diagnosis, women with ovarian cancer had a much higher incidence of comorbidities than cancer-free women. The high incidence of some of these comorbidities may be related to the cancer or its treatment, but others may have been prevalent but undiagnosed until the cancer diagnosis. The presence of comorbidities may affect treatment decisions.