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.     

Clinical utility of the AJCC 8th edition pT1 subclassification and impact on practice patterns in stage I seminoma

BackgroundThe American Joint Committee on Cancer 8^th edition staging guidelines for testicular cancer established a 3 cm cutoff to subclassify stage T1 seminomas (<3 cm = pT1a and ≥3 cm = pT1b). The efficacy of this cutoff in predicting metastatic disease and impact on treatment patterns have not been studied.MethodsWe retrospectively reviewed patients with pT1 testicular seminoma in the National Cancer Database from 2004 to 2016. Receiver operating curves were used to determine the efficacy of the 3 cm tumor cutoff in identifying metastatic disease, and multivariable regression was used to compute the effect of tumor size on the rate of adjuvant therapy among Stage I patients.ResultsA total of 10,134 patients with pT1 seminoma were evaluated. The current size cutoff of 3 cm for subclassification did not exhibit high discrimination in identifying metastatic disease (area under receiver operating curve: 0.546). Surveillance has grown as the preferred treatment after orchiectomy ?32.1% in 2004 to 81.2% in 2015. However, the rate of adjuvant therapy for pT1, Stage I seminomas associated positively with tumor size even with adjustment for year of diagnosis. For tumors above 3 cm, the odds ratio stabilized around 1.9. By using the 3 cm cutoff to guide adjuvant therapy, up to 85% of T1b patients may be overtreated.ConclusionThe 3 cm cutoff for subclassification of Stage I seminoma does not predict metastatic recurrence but is associated with increased receipt of adjuvant therapy. A 3 cm cutoff and the pT1a/b classification may therefore contribute to overtreatment in many young patients with a long life expectancy for whom minimizing adverse effects should be prioritized.     

Neurogenic Obesity-Induced Insulin Resistance and Type 2 Diabetes Mellitus in Chronic Spinal Cord Injury

The population with SCI is at a significant risk for both insulin resistance and type 2 diabetes mellitus (T2DM) secondary to neurogenic obesity. The prevalence of insulin resistance and T2DM in persons with SCI suggests that disorders of carbohydrate metabolism are at epidemic proportions within the population. However, the true frequency of such disorders may be underestimated because biomarkers of insulin resistance and T2DM used from the population without SCI remain nonspecific and may in fact fail to identify true cases that would benefit from intervention. Furthermore, diet and exercise have been used to help mitigate neurogenic obesity, but results on disorders of carbohydrate metabolism remain inconsistent, likely because of the various ways carbohydrate metabolism is assessed. The objective of this article is to review current literature on the prevalence and likely mechanisms driving insulin resistance and T2DM in persons with SCI. This article also explores the various assessments and diagnostic criteria used for insulin resistance and T2DM and briefly discusses the effects of exercise and/or diet to mitigate disorders of carbohydrate metabolism brought on by neurogenic obesity.     

Subtype‐specific differences in transmission cluster dynamics of HIV‐1 B and CRF01_AE in New South Wales,Australia

IntroductionThe human immunodeficiency virus 1 (HIV‐1) pandemic is characterized by numerous distinct sub‐epidemics (clusters) that continually fuel local transmission. The aims of this study were to identify active growing clusters, to understand which factors most influence the transmission dynamics, how these vary between different subtypes and how this information might contribute to effective public health responses.MethodsWe used HIV‐1 genomic sequence data linked to demographic factors that accounted for approximately 70% of all new HIV‐1 notifications in New South Wales (NSW). We assessed differences in transmission cluster dynamics between subtype B and circulating recombinant form 01_AE (CRF01_AE). Separate phylogenetic trees were estimated using 2919 subtype B and 473 CRF01_AE sequences sampled between 2004 and 2018 in combination with global sequence data and NSW‐specific clades were classified as clusters, pairs or singletons. Significant differences in demographics between subtypes were assessed with Chi‐Square statistics.ResultsWe identified 104 subtype B and 11 CRF01_AE growing clusters containing a maximum of 29 and 11 sequences for subtype B and CRF01_AE respectively. We observed a > 2‐fold increase in the number of NSW‐specific CRF01_AE clades over time. Subtype B clusters were associated with individuals reporting men who have sex with men (MSM) as their transmission risk factor, being born in Australia, and being diagnosed during the early stage of infection (p < 0.01). CRF01_AE infections clusters were associated with infections among individuals diagnosed during the early stage of infection (p < 0.05) and CRF01_AE singletons were more likely to be from infections among individuals reporting heterosexual transmission (p < 0.05). We found six subtype B clusters with an above‐average growth rate (>1.5 sequences / 6‐months) and which consisted of a majority of infections among MSM. We also found four active growing CRF01_AE clusters containing only infections among MSM. Finally, we found 47 subtype B and seven CRF01_AE clusters that contained a large gap in time (>1 year) between infections and may be indicative of intermediate transmissions via undiagnosed individuals.ConclusionsThe large number of active and growing clusters among MSM are the driving force of the ongoing epidemic in NSW for subtype B and CRF01_AE.     

Effects of Electroconvulsive Therapy on the Electrocardiogram in Geriatric Patients with Stable Cardiovascular Diseases

Eight elderly patients (mean age +/- SD, 73.2 +/- 9.5 years) were studied with Holter electrocardiographic monitoring for 24 h before and 24 h after an electroconvulsive therapy (ECT) treatment. Patients with a history of cardiac disease but who were not experiencing any active cardiac symptoms were chosen for study. They were not receiving either cardioactive medications or psychotropic agents that can effect cardiac rhythm or conduction. Each patient served as his own control, with direct comparison of the periods before and after the treatment. There were no differences before and after ECT in the electrocardiogram. One minute after the seizure, patients were hypertensive and tachycardic. ECT does not appear to pose additional risk in stable, elderly patients with a history of cardiac disease.     

Learning through simulation: the next dimension in quality improvement

Simulation modeling offers several distinct gains in learning opportunities beyond traditional quality improvement tools. A simulation model captures complex, multivariate system components and replicates system operation in compressed time. The visual aspect enables workers to "see" the effect of proposed changes and thus eliminates much of the fear of failure typically associated with change. Most important, simulation permits design of a total solution, addressing interactions of all system components.     

Industrial progress concerning latex allergy in surgery

Latex allergy has been well described in the literature, but it remains a constant worry for high-risk groups. We wish to show that the manufacturing industry has made real progress in response to this iatrogenic pathology. The high-risk groups are defined, in addition to the allergies with which they are associated: foodstuffs, ethylene oxide, airborneallergens. The criteria necessary to have available high-quality sterile surgical gloves are stated: they must be either hypo-allergenic or non-allergenic dependent upon the circumstances of use, they must guarantee protection against the transmission of infection and allow the medical practitioner complete freedom of movement. In the same way urinary catheters for intermittent probing, penile sheaths and condoms are mentioned. Powder must definitely be eliminated from any medical glove, because it can both be a vector for latex particles and can be the cause of granulomas in the abdominal cavity. The European Community standards (CE) and the recommendations of the American Associations of Allergology are explained. Sterilization by gamma irradiation is one sign of real progress, outperforming ethylene oxide which is too allergenic. The composition of the gloves must ensure an effective barrier against both allergens and infections. Pre-lubricated latex-free urinary catheters, penile sheaths and latex-free condoms represent substantial improvements for the population at risk. Since 1995 considerable progress has been made by the manufacturing industry in response to the needs of both allergologists and surgeons.     

Forebrain connections of the hamster intergeniculate leaflet: comparison with those of ventral lateral geniculate nucleus and retina

The hamster intergeniculate leaflet (IGL), part of the circadian rhythm regulatory system, has very extensive interconnections with subcortical visual nuclei. The present investigation describes IGL connections with the hamster diencephalon and telencephalon and compares them with ventral lateral geniculate nucleus (VLG) connections and retinal projections. Connections of the geniculate nuclei were evaluated using anterograde transport of iontophoretically injected Phaseolus vulgaris leucoagglutinin and by retrograde transport of cholera toxin beta fragment. The cholera fragment was also injected intraocularly to trace retinal efferents. The IGL has ipsilateral and contralateral projections to the anterior and posterior hypothalamic nuclei, the ventral preoptic, lateral and dorsal hypothalamic areas, but not to the core ventromedial nucleus and very sparsely to the paraventricular nucleus. There are also IGL projections to the medial and lateral zona incerta, anteroventral, anterodorsal, reuniens, parataenial, paraventricular, centrolateral, central medial, and laterodorsal thalamic nuclei. IGL projections to the telencephalon are found in the horizontal limb of the diagonal band, olfactory tubercle, nucleus of the lateral olfactory tract, posterior bed nucleus of the stria terminalis, ventral pallidum, and in nuclei of the medial amygdala. The only substantial VLG projections are to bed nucleus of the stria terminalis, IGL, medial zona incerta, central medial and laterodorsal thalamic nuclei. Several of the IGL targets, the bed nucleus of the stria terminalis and zona incerta in particular, send projections back to the IGL and VLG. In addition, cells are present in the caudal cingulate cortex that project to both nuclei. Retinal projections are found in many of the regions receiving IGL innervation, including nuclei of the medial basal telencephalon, the posteromedial bed nucleus of the stria terminalis, and nuclei of the hypothalamus. A retinal projection is also visible in the lateral olfactory tract from which it extends rostrally, then medially along the base of the rhinal fissure. Fibers also extend caudally, in a superficial location, to perirhinal cortex. The results further demonstrate the widespread connections of the IGL and support the idea that the IGL modulates olfactory, photic, and circadian rhythm regulation of regulatory physiology and behavior.     

Oxidative bioactivation of the lactol prodrug of a lactone cyclooxygenase-2 inhibitor.

The lactol derivative of a lactone cyclooxygenase-2 inhibitor (DFU) was evaluated in vivo and in vitro for its potential suitability as a prodrug. DFU-lactol was found to be 10 to 20 times more soluble than DFU in a variety of aqueous vehicles. After administration of DFU-lactol at 20 mg kg-1 p.o. in rats, a Cmax of 7.5 microM DFU was reached in the plasma. After oral administration, the ED50s of DFU-lactol in the carrageenan-induced paw edema and lipopolysaccharide-induced pyresis assays in rats are comparable with the ED50s observed when dosing with DFU. Incubations of DFU-lactol with rat and human hepatocytes demonstrated that the oxidation of DFU-lactol can be mediated by liver enzymes and that a competing pathway is direct glucuronidation of the DFU-lactol hydroxyl group. Assays with subcellular fractions from rat liver indicated that most of the oxidation of DFU-lactol occurs in the cytosolic fraction and requires NAD(P)+. Human liver cytosol can also support the oxidation of DFU-lactol to DFU when NAD(P)+ is added to the incubations. Fractionation of human liver cytosolic proteins showed that at least three enzymes are capable of efficiently effecting the oxidation of DFU-lactol to DFU. Incubations with commercially available dehydrogenases suggest that alcohol and hydroxysteroid dehydrogenases are involved in this oxidative process. These data together suggest that lactols may represent useful prodrugs for lactone-containing drugs.