Site of metastatic recurrence impacts prognosis in patients with high-grade upper tract urothelial carcinoma

PurposeMetastatic recurrence occurs in over 25% of upper tract urothelial carcinoma patients treated with radical nephroureterectomy. While metastatic recurrence suggests poor prognosis, the impact of the specific site of recurrence on prognosis is not well documented.Materials and methodsWe retrospectively analyzed 188 patients who underwent radical nephroureterectomy for high-grade, node-negative upper tract urothelial carcinoma at our institution from 2003 to 2018 without receiving neoadjuvant or adjuvant chemotherapy. Competing-risks survival analysis was performed to evaluate the cumulative incidence and predictors of metastatic recurrence. The Kaplan-Meier method and log-rank test were used to estimate and compare recurrence site-specific survival probabilities following metastatic recurrence. Cox regression analyses were performed to assess site-specific prognoses.ResultsOf the 188 patients, 47 (25%) developed metastatic recurrence over a median follow-up of 30 months (interquartile range: 10.5–58.5 months). The 1- and 2-year cumulative incidences of metastatic recurrence were 13.6% and 23.6%, respectively. On multivariable analysis, lymphovascular invasion was significantly predictive of metastatic recurrence (subhazard ratio: 2.6, P = 0.01). Of the 47 patients who developed recurrence, 38 (80.9%) died over a median follow-up of 10 months (interquartile range: 5–20 months). Metastatic recurrence was most common in the lungs (n= 13, 28%) and at multiple sites (n= 14, 30%). Median time to recurrence was shorter for recurrences at multiple sites (6.5 months) and those in the liver (13 months) and bone (18 months) compared to other sites. Patients who recurred in the liver (hazard ratio: 6.3, P = 0.007), bone (hazard ratio: 4.9, P = 0.02), and multiple sites (hazard ratio: 4.6, P = 0.01) had significantly worse prognosis compared to those who recurred in lymph nodes. Statistical significance persisted after adjusting for treatment with salvage therapy.ConclusionsA significant proportion of high-grade upper tract urothelial carcinoma patients recur systemically after radical nephroureterectomy. Lymphovascular invasion is a predictor of metastatic recurrence and may inform decisions regarding perioperative chemotherapy. Hepatic and osseous recurrences have relatively quicker onset and less favorable prognosis compared to other sites. These findings may benefit future efforts to develop recurrence site-specific treatment plans and highlight the necessity of subsequent endeavors to explore the genetic associations of recurrence in upper tract urothelial carcinoma.     

Enolase 1 of Candida albicans binds human CD4+ T cells and modulates naïve and memory responses

To obtain a better understanding of the biology behind life-threatening fungal infections caused by Candida albicans, we recently conducted an in silico screening for fungal and host protein interaction partners. We report here that the extracellular domain of human CD4 binds to the moonlighting protein enolase 1 (Eno1) of C. albicans as predicted bioinformatically. By using different anti-CD4 monoclonal antibodies, we determined that C. albicans Eno1 (CaEno1) primarily binds to the extracellular domain 3 of CD4. Functionally, we observed that CaEno1 binding to CD4 activated lymphocyte-specific protein tyrosine kinase (LCK), which was also the case for anti-CD4 monoclonal antibodies tested in parallel. CaEno1 binding to naïve human CD4⁺ T cells skewed cytokine secretion toward a Th2 profile indicative of poor fungal control. Moreover, CaEno1 inhibited human memory CD4⁺ T-cell recall responses. Therapeutically, CD4⁺ T cells transduced with a p41/Crf1-specific T-cell receptor developed for adoptive T-cell therapy were not inhibited by CaEno1 in vitro. Together, the interaction of human CD4⁺ T cells with CaEno1 modulated host CD4⁺ T-cell responses in favor of the fungus. Thus, CaEno1 mediates not only immune evasion through its interference with complement regulators but also through the direct modulation of CD4⁺ T-cell responses.     

Dementia praecox and manic-depressive insanity in 1908: A Grade of Membership analysis of the Kraepelinian dichotomy

Grade of Membership (GoM) analysis, a multivariate classification technique based on fuzzy-set mathematics, was applied to the demographic, history, and mental-state data on 53 dementia praecox cases and 134 manic-depressive insanity cases admitted to Kraepelin's University Psychiatric Clinic in Munich in 1908. The original data recorded by Kraepelin and his collaborators on specialZählkarten (counting cards) were rated and coded in terms of the Present State Examination (PSE) Syndrome Check List. The statistical analysis resulted in a high degree of replication of Kraepelin's clinical entities. However, the dichotomy of dementia praecox and manic-depressive insanity was not fully supported. The catatonic syndrome tended to occupy an intermediate position between the two major psychoses. The possibility is discussed that catatonia in Kraepelin's time shared certain clinical features with the later diagnostic groupings of schizoaffective disorder, cycloid psychoses, and other atypical forms of psychotic illnesses.     

Gender differences in HIV risk behaviors in an adult emergency department in New York City

Background The human immunodeficiency virus (HIV) epidemic in the US increasingly involved urban heterosexual adults, particularly women, belonging to ethnic minority groups. An understanding of gender-based differences in HIV risk behaviors within these groups would be of value in the ongoing struggle to limit HIV transmission in metropolitan centers. Methods This was a prospective study of demographic and historical characteristics and HIV risk behaviors. The study utilized a structured interview format, which was administered to all patients treated by participating emergency department physicians. Results On univariate analysis of data obtained from 1,460 patients who had neither a known HIV infection nor a chief complaint or final emergency department diagnosis associated with HIV risk behaviors, men were more likely to be older, homeless, to have ever injected drugs, used crack, engaged in same-gender sex, paid for sex, been incarcerated, or had syphilis or gonorrhea. Women were more likely to report prior chlamydia infection or to report that their sole sex partners had other partners within the past year. On multivariate analysis, variables independently associated with male gender included homelessness, injection drug use, crack use, any prior sexually transmitted disease (in subjects 35 years of age or older), and sex with prostitutes. In a separate analysis of patients admitting to drug use, the male predominance of other risk behaviors was not observed; the only significant differences between genders were a higher rate of prostitution among women and a higher rate of sexual contact with a prostitute among men. Conclusions In patients visiting an inner-city emergency department in the Bronx, HIV risk behaviors are generally more common in men, but rates of risk behaviors among male and female drug users are comparable. This work was supported in part by a collaborative agreement with the Centers for Disease Control and Prevention (U64/CCU200714). Drs. Shuter, Alpert, and DeShaw were supported in part by a training grant (5-T32-AI070183) from the National Institute of Allergy and Infectious Diseases. This study was presented in part at the 32nd Annual Meeting of the Infectious Diseases Society of America, October 1994, Orlando, Florida.     

Cost of smoking to the Medicare program, 1993

Medicare expenditures attributable to smoking in 1993 were estimated using a multivariate model that related expenditures to smoking history, health status, and the propensity to have had a smoking-related disease, controlling for sociodemographics, economic variables, and other risk factors. Smoking-attributable Medicare expenditures are presented separately for each State and by type of expenditure. Nationally, smoking accounted for 9.4 percent of Medicare expenditures--$14.2 billion, with considerable variation among States. Smoking accounted for 11.4 percent of Medicare expenditures for hospital care, 11.3 percent of nursing home care, 5.9 percent of home health care, and 5.6 percent of ambulatory care.     

Caffeine Pretreatment Enhances Clinical Efficacy and Reduces Cognitive Effects of Electroconvulsive Therapy

In an open clinical trial, depressed patients received age-dosed, brief-pulse electroconvulsive therapy (ECT) either with or without 500 mg i.v. caffeine sodium benzoate before each treatment. Caffeine-pretreated patients required fewer ECT treatments, and after three to four treatments, their Hamilton Depression Scale (HDS) scores were significantly lower. At the end of the ECT course, both groups reached the same reduction in HDS scores. Of five memory tests, one showed better performance at the end of the ECT course for the caffeine-pretreated compared with the non-caffeine-pretreated patients. The results argue that caffeine-modified ECT differs from unmodified ECT in speed of response and the effects on cognitive tests.