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Purpose To evaluate the long-term effect of subthreshold nanosecond laser (SNL) treatment on progression to late age-related macular degeneration (AMD). Design Observational extension study of a randomized, sham-controlled trial. Participants Two hundred twelve participants with bilateral large drusen. Methods The Laser Intervention in the Early Stages of AMD (LEAD) study was a 36-month trial where participants were randomized to receive SNL or sham treatment in 1 eye at 6-monthly intervals up to 30 months. After the completion of the LEAD study, the 2 largest recruiting sites offered remaining participants an opportunity to enroll in a 24-month observational extension study. This study thus examined all participants from these 2 sites who were enrolled in the LEAD study at baseline, including the additional observational data. Main Outcome Measures Time to develop late AMD, defined on multimodal imaging, between those randomized the SNL or sham treatment. Results Overall, no significant difference was found in the rate of progression over a 60-month period in those randomized to the SNL compared with the sham group (adjusted hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.36–1.09; P = 0.098), similar to the findings at 36 months in the LEAD Study. However, evidence of treatment effect modification continued to emerge based on the coexistence of reticular pseudodrusen (RPD; P = 0.007, adjusted interaction). Namely, progression was slowed significantly with SNL treatment for those without coexistent RPD (adjusted HR, 0.34; 95% CI, 0.16–0.71; P = 0.004), but it was not significantly different for those with RPD (adjusted HR, 1.81; 95% CI, 0.67–4.88; P = 0.239). Conclusions A 24-month observational extension study to the LEAD Study confirmed that SNL treatment did not significantly reduce the overall rate of progression to late AMD in a cohort with intermediate AMD. However, the persistence of a potential beneficial treatment effect in those without coexistent RPD over a longer follow-up duration of an additional 24 months without additional treatment is encouraging. These findings provide further justification for future trials to examine the potential value of SNL treatment for slowing progression in intermediate AMD.

Background Outcomes are thought to be worse in head and neck (H&N) melanoma patients. However, definitive evidence of inferior outcomes in H&N melanoma in the modern era is lacking. We sought to ascertain whether H&N melanomas carry a worse prognosis than melanomas of other sites. Methods All patients who underwent excision for primary melanoma by fellowship-trained surgical oncologists at a single institution from 2014 to 2020 were queried from the electronic medical record. Patients who had AJCC eighth edition stage I-III disease were included. Results Of 1127 patients, 28.7% had primary H&N melanoma. H&N patients were more likely to be male, older, and present with more advanced AJCC stage. Median follow-up was 20.0 months (IQR 26.4). On multivariable analyses controlling for other variables, H&N melanoma was associated with worse RFS. Notably, H&N melanoma was not associated with worse MSS, DMFS, or OS on univariate or multivariable analyses. Among patients who recurred, H&N patients were significantly more likely to recur locally compared to non-H&N patients. On subgroup analysis, scalp melanoma was also associated with worse RFS compared to patients with melanoma in locations other than the scalp. When patients with scalp melanoma were excluded from analysis, non-scalp H&N RFS was not significantly different from the non-H&N group on univariate or multivariable analyses. Discussion In this series from a high-volume tertiary referral center, the differences in rates and sites of recurrence between H&N and non-H&N melanoma do not impact melanoma-specific or overall survival, suggesting that H&N melanoma patients should be treated similarly with respect to regional and systemic therapies.

Plastic bronchitis, more appropriately termed chyloptysis, is a rare and potentially fatal condition caused by chylous coating of the airways. These cast coating can dislodge and become an obstructive mass in the patient's airway, necessitating rapid intervention. PB is well described to occur following single ventricle physiology heart disease corrective procedures, particularly following Fontan procedures. It is less commonly seen in traumatic settings. We present the youngest known case of a traumatic injury induced plastic bronchitis. A 19-year-old man was involved in a motor vehicle accident with airbag deployment. The airbags struck him in the chest; however, the patient felt well at the time and did not seek medical attention. Several months later the patient began coughing up milky white masses identified as casts. He was initially diagnosed with asthma but did not respond to therapy. He ultimately was found to have evidence of thoracic duct injury. Options for therapy were discussed, including possible thoracic duct ligation. The patient opted to continue a lowfat diet and has remained cast free. This case highlights the importance of considering plastic bronchitis in patients with cast production and a history of trauma to the chest.

Purpose\ud \ud To report surgical and corneal clarity scores (CCSs) of corneo‐limbo‐conjunctival transpositions (CLCTs) in a large number of canine cases.\ud \ud Methods\ud \ud Retrospective review of records that underwent CLCT to repair deep ulcers or perforations between 2002 and 2018. Signalment, concurrent eye disease, additional procedures, pathogenesis, medication, graft orientation, follow‐up, and CCSs were recorded.\ud \ud Results\ud \ud 418 eyes of 399 dogs were included. Brachycephalics were most commonly affected, comprising 325/418 (77.75%) of the eyes. The most commonly affected breeds were Pugs, Shih Tzus, Cavalier King Charles Spaniels, and French Bulldogs, with 116/418 (27.75%), 64/418 (15.31%), 34/418 (8.13%), and 34/418 (8.13%) ulcerated eyes, respectively. Mean age at surgery was 5.5 years (range 59 days‐17.7 years), and median follow‐up time was 100 days (range 3 days‐7.64 years). The most common etiopathogenesis was spontaneous ulceration in 205/418 eyes (49.04%) of which 191 (93.17%) occurred in brachycephalics. Primary keratoconjunctivitis sicca affected 122/418 eyes (29.19%) and injury 39/418 eyes (9.33%). Mean ulcer width was 3.5 mm (0.5‐10 mm). Success rate was 97.13% (406/418 eyes). Failure end points recorded included no menace response, secondary glaucoma, and endophthalmitis. Pre‐existing perforation was found in 101/418 (24.16%) of the eyes and significantly increased failure rate (P < .001). The median CCS was G3 (G0‐G4), which was lower for Pugs (G2). Graft orientation affected CCS, but did not reach statistical significance.\ud \ud Conclusion\ud \ud The high success rate and CCS for CLCT in dogs make it a good technique to treat deep ulcers but a less desirable outcome is anticipated when treating perforations and Pugs.

Purpose To describe a modified keratoleptynsis procedure, as a method of preserving central corneal function, and evaluate the outcome in vision, reduction of corneal thickness and treatment of epithelial corneal ulcers in cases with endothelial cell dysfunction. Methods Forty-four dogs (72 eyes) were affected by progressive corneal edema, with or without ulcerative keratitis. All patients were treated with a dorsal and ventral superficial keratectomy followed by conjunctival flaps, maintaining a clear central cornea. Corneal thickness measurements were obtained via ultrasound biomicroscopy. Results All eyes showed resolution of ocular discomfort postoperatively, with a median time to resolution of 35 days. Two years post-surgery, vision had been lost in 2 of 29 eyes (7%). From the initial population, 23 dogs (39 eyes) had follow-up evaluations of corneal thickness. The mean central corneal thickness was 1359 ± 251 μm prior to surgery. Thickening of the central cornea was observed one week after surgery to 1559 ± 263 μm. Decreased corneal thickness was reported, at 1 month, 4 months, 10 months and 2 years postoperatively (1285 ± 267 μm, 1102 ± 150 μm, 1121 ± 288 μm, 1193 ± 283 μm, respectively). All eyes showed a similar trend of increasing and then decreasing corneal thickness. Conclusions This surgical technique provided statistically significant reduction in central corneal thickness and sustained relief of ocular pain. Reduction in corneal thickness appeared to be maintained 2 years post-surgery, and all patients remained comfortable. Superficial corneal pigmentation and fibrosis resulted in vision loss in two eyes.

Summary This document aims to provide practical guidance for the assessment and management of patients with thrombocytopenia, with a particular focus on immune thrombocytopenia (ITP), during the COVID‐19 pandemic. The intention is to support clinicians and, although recommendations have been provided, it is not a formal guideline. Nor is there sufficient evidence base to conclude that alternative approaches to treatment are incorrect. Instead, it is a consensus written by clinicians with an interest in ITP or coagulation disorders and reviewed by members of the UK ITP forum.

Isolated limb infusion (ILI) is used to treat in-transit melanoma metastases confined to an extremity. However, little is known about its safety and efficacy in octogenarians and nonagenarians (ON). ON patients (≥ 80 years) who underwent a first ILI for American Joint Committee on Cancer seventh edition stage IIIB/IIIC melanoma between 1992 and 2018 at nine international centers were included and compared with younger patients (

Background Acral lentiginous melanoma is associated with worse survival than other subtypes of melanoma. Understanding prognostic factors for survival and recurrence can help better inform follow-up care. Objectives To analyze the clinicopathologic features, melanoma-specific survival, and recurrence-free survival by substage in a large, multi-institutional cohort of primary acral lentiginous melanoma patients. Methods Retrospective review of the United States Melanoma Consortium database, a multi-center prospectively collected database of acral lentiginous melanoma patients treated between January 2000 and December 2017. Results Of the 433 primary acral lentiginous melanoma patients identified (median [range] age: 66 [8–97] years; 53% female, 83% white), 66% presented with stage 0–2 disease and the median time of follow-up for the 392 patients included in the survival analysis was 32.5 months (range: 0–259). The 5-year melanoma-specific survivals by stage were 0 = 100%, I = 93.8%, II = 76.2%, III = 63.4%, IIIA = 80.8%, and IV = 0%. Thicker Breslow depth ((HR) = 1.13; 95% CI = 1.05–1.21; P < .001)) and positive nodal status ((HR) = 1.79; 95% CI = 1.00–3.22; P = .050)) were independent prognostic factors for melanoma-specific survival. Breslow depth ((HR = 1.13; 95% CI = 1.07–1.20; P < .001), and positive nodal status (HR = 2.12; 95% CI = 1.38–3.80; P = .001) were also prognostic factors for recurrence-free survival. Conclusion In this cohort of patients, acral lentiginous melanoma was associated with poor outcomes even in early stage disease, consistent with prior reports. Stage IIB and IIC disease were associated with particularly low melanoma-specific and recurrence-free survival. This suggests that studies investigating adjuvant therapies in stage II patients may be especially valuable in acral lentiginous melanoma patients.

A Man with Weight Loss, Diarrhea, and Abdominal Pain A 44-year-old man from the Caribbean was evaluated at the hospital because of diarrhea, weight loss, and abdominal pain. Fever and headache had ...

Rationale: Unlike traditional biopsy, liquid biopsy, which is a largely non-invasive diagnostic and monitoring tool, can be performed more frequently to better track tumors and mutations over time and to validate the efficiency of a cancer treatment. Circulating tumor cells (CTCs) are considered promising liquid biopsy biomarkers; however, their use in clinical settings is limited by high costs and a low throughput of standard platforms for CTC enumeration and analysis. In this study, we used a label-free, high-throughput method for CTC isolation directly from whole blood of patients using a standalone, clinical setting-friendly platform. Methods: A CTC-based liquid biopsy approach was used to examine the efficacy of therapy and emergent drug resistance via longitudinal monitoring of CTC counts, DNA mutations, and single-cell-level gene expression in a prospective cohort of 40 patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer. Results: The change ratio of the CTC counts was associated with tumor response, detected by CT scan, while the baseline CTC counts did not show association with progression-free survival or overall survival. We achieved a 100% concordance rate for the detection of EGFR mutation, including emergence of T790M, between tumor tissue and CTCs. More importantly, our data revealed the importance of the analysis of the epithelial/mesenchymal signature of individual pretreatment CTCs to predict drug responsiveness in patients. Conclusion: The fluid-assisted separation technology disc platform enables serial monitoring of CTC counts, DNA mutations, as well as unbiased molecular characterization of individual CTCs associated with tumor progression during targeted therapy.

Introduction\ud \ud Patients with cancer who develop small bowel obstruction are at high risk of malnutrition and morbidity following compromise of gastrointestinal tract continuity. This study aimed to characterise current management and outcomes following malignant small bowel obstruction.\ud \ud \ud \ud Methods\ud \ud A prospective, multicentre cohort study of patients with small bowel obstruction who presented to UK hospitals between 16th January and 13th March 2017. Patients who presented with small bowel obstruction due to primary tumours of the intestine (excluding left-sided colonic tumours) or disseminated intra-abdominal malignancy were included. Outcomes included 30-day mortality and in-hospital complications. Cox-proportional hazards models were used to generate adjusted effects estimates, which are presented as hazard ratios (HR) alongside the corresponding 95% confidence interval (95% CI). The threshold for statistical significance was set at the level of P ≤ 0.05 a-priori.\ud \ud \ud \ud Results\ud \ud 205 patients with malignant small bowel obstruction presented to emergency surgery services during the study period. Of these patients, 50 had obstruction due to right sided colon cancer, 143 due to disseminated intraabdominal malignancy, 10 had primary tumours of the small bowel and 2 patients had gastrointestinal stromal tumours. In total 100 out of 205 patients underwent a surgical intervention for obstruction. 30-day in-hospital mortality rate was 11.3% for those with primary tumours and 19.6% for those with disseminated malignancy. Severe risk of malnutrition was an independent predictor for poor mortality in this cohort (adjusted HR 16.18, 95% CI 1.86 to 140.84, p = 0.012). Patients with right-sided colon cancer had high rates of morbidity.\ud \ud \ud \ud Conclusions\ud \ud Mortality rates were high in patients with disseminated malignancy and in those with right sided colon cancer. Further research should identify optimal management strategy to reduce morbidity for these patient groups.

BACKGROUND: Hürthle cell metaplasia is common in hyperplastic nodules, particularly within the setting of lymphocytic thyroiditis (LT). The Bethesda System for Reporting Thyroid Cytopathology indicates that it is acceptable to classify Hürthle cell–predominant fine-needle aspiration (HC FNA) specimens as atypia of undetermined significance (AUS) rather than suspicious for a Hürthle cell neoplasm (HUR) within the setting of multiple nodules or known LT. The goal of the current study was to address whether this approach is justified. METHODS: HC FNA specimens were identified and correlated with ultrasound and surgical pathology reports if available. Multinodularity was determined based on findings on macroscopic examination if imaging results were unavailable. RESULTS: A total of 698 HC FNA specimens were identified, including 576 resected nodules, 455 of which (79%) were benign. The overall risk of malignancy for HUR was 27%, whereas the risk of malignancy for AUS was 10%. The mean size of the benign nodules was 2.1 cm on surgical resection specimens, with multiple nodules noted in 293 cases (64%) and histologic LT noted in 116 cases (25%). The mean size of the malignant nodules was 2.8 cm, with multiple nodules and histologic LT noted in 74 cases (61%) and 22 cases (18%), respectively. The malignancy rate did not differ between solitary or multiple nodules (P = .52) or in the presence or absence of LT (P = .12). However, size did significantly differ between malignant and benign nodules (P < 0.01). CONCLUSIONS: The malignancy rate did not differ significantly in the presence of multiple nodules or LT, although the latter demonstrated a statistical trend. A diagnosis of AUS over HUR based solely on the presence of multinodularity is not warranted.

Introduction Dipstick urinalysis is a widely used screening tool in the evaluation of men with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH). As limited data support the use of dipstick urinalysis, we have used data from three recently published studies to assess clinical outcomes in those who had dipstick urinalysis findings for blood, glucose, and/or leukocytes. Methods We analyzed data from three observational studies involving men interested in using over-the-counter tamsulosin: a self-selection study (SSS) and two actual-use studies of 8-week (AUS8) and 24-week (AUS24) durations. Subgroup analyses focused on pooled data from participants not using α-blockers or other prescription medication for LUTS suggestive of BPH (nonRx users) and who had urine dipstick findings. Data from participants using α-blockers (AUS8) or any prescription BPH medications (SSS and AUS24) are presented as reference. Results Overall, 2488 nonRx users underwent dipstick urinalysis and 680 (27.3%) had positive findings including traces of blood (332; 13.3%), glucose (259; 10.4%), and/or leukocytes (245; 9.8%). Among users of prescription medicines, 21.6% (37/171) in SSS, 27.4% (23/84) in AUS8, and 31.1% (47/151) in AUS24 had urine dipstick findings. The 200 dipstick-positive nonRx users in SSS underwent per protocol urological assessment: 26 (13.0%) had a newly diagnosed condition causing/contributing to urinary symptoms of which 2.9% were identified as medically important conditions. Among nonRx users with or without a dipstick finding, medically important conditions reported included prostate cancer (1.0% vs. 1.0%, respectively) and urolithiasis (1.0% vs. 0.3%, respectively). The proportion of men with dipstick urinalysis findings was similar between men who regularly visited their physician and those who did not. Conclusion Dipstick urinalysis did not markedly increase the detection of undiagnosed medically important conditions that cause/contribute to urinary symptoms, suggesting that this test may not be a very effective screening tool for men with LUTS. Funding Boehringer Ingelheim Pharmaceuticals, Inc. Electronic Supplementary Material The online version of this article (10.1007/s12325-019-01042-0) contains supplementary material, which is available to authorized users.

Clinical outcomes are inferior for individuals with HIV having suboptimal CD4 T-cell recovery during antiretroviral therapy (ART). We investigated if the levels of infection and the response to homeostatic cytokines of CD4 T-cell subsets contributed to divergent CD4 T-cell recovery and HIV reservoir during ART by studying virologically-suppressed immunologic responders (IR, achieving a CD4 cell count >500 cells/μL on or before two years after ART initiation), and virologically-suppressed suboptimal responders (ISR, did not achieve a CD4 cell count >500 cells/μL in the first two years after ART initiation). Compared to IR, ISR demonstrated higher levels of HIV-DNA in naïve, central (CM), transitional (TM), and effector (EM) memory CD4 T-cells in blood, both pre- and on-ART, and specifically in CM CD4 T-cells in LN on-ART. Furthermore, ISR had higher pre-ART plasma levels of IL-7 and IL-15, cytokines regulating T-cell homeostasis. Notably, pre-ART PD-1 and TIGIT expression levels were higher in blood CM and TM CD4 T-cells for ISR; this was associated with a significantly lower fold-changes in HIV-DNA levels between pre- and on-ART time points exclusively on CM and TM T-cell subsets, but not naïve or EM T-cells. Finally, the frequency of CM CD4 T-cells expressing PD-1 or TIGIT pre-ART as well as plasma levels of IL-7 and IL-15 predicted HIV-DNA content on-ART. Our results establish the association between infection, T-cell homeostasis, and expression of PD-1 and TIGIT in long-lived CD4 T-cell subsets prior to ART with CD4 T-cell recovery and HIV persistence on-ART., Author summary A major obstacle to curing HIV infection is our incomplete understanding of the mechanisms regulating the immunologic reconstitution of CD4 T-cells and the establishment and persistence of the latent HIV reservoir. In particular, we still do not know whether and to what extent the relative distribution of HIV infection within the various CD4 T-cell subsets influences: (i) the magnitude of the CD4 T-cell reconstitution, and (ii) the size of the persistent HIV reservoir after ART. In this study, we found that immunological suboptimal responders (ISR), people with HIV having a suboptimal CD4 T-cell recovery during ART, compared with immunological responders (IR) presented: i) higher levels of HIV-DNA in multiple CD4 T-cell subsets, and ii) higher expression of PD-1 and TIGIT exclusively on CM and TM CD4 T-cells pre-ART, indicating higher HIV reservoir maintenance. Paradoxically, we found increased plasma levels of IL-7 and IL-15 (T-cell homeostatic cytokines) be associated with suboptimal CD4 T-cell recovery during ART, which could be explained by the lack of response to these cytokines in CD4 T-cells from ISR. Altogether, these data identify a greater abundance of immune checkpoint molecules, an increased maintenance of HIV infection in long-lived CD4 T-cell subsets, and a different responsiveness to IL-7 and IL-15 as key features of and a mechanism for suboptimal CD4 T-cell recovery in ART-treated, people with HIV.

Coagulation dysfunction and thrombosis are major complications in patients with coronavirus disease 2019 (COVID-19). Patients on oral anticoagulants (OAC) prior to diagnosis of COVID-19 may therefore have better outcomes. In this multicentre observational study of 5 883 patients (≥18 years) admitted to 26 UK hospitals between 1 April 2020 and 31 July 2020, overall mortality was 29·2%. Incidences of thrombosis, major bleeding (MB) and multiorgan failure (MOF) were 5·4%, 1·7% and 3·3% respectively. The presence of thrombosis, MB, or MOF was associated with a 1·8, 4·5 or 5·9-fold increased risk of dying, respectively. Of the 5 883 patients studied, 83·6% (n = 4 920) were not on OAC and 16·4% (n = 963) were taking OAC at the time of admission. There was no difference in mortality between patients on OAC vs no OAC prior to admission when compared in an adjusted multivariate analysis [hazard ratio (HR) 1·05, 95% confidence interval (CI) 0·93–1·19; P = 0·15] or in an adjusted propensity score analysis (HR 0·92 95% CI 0·58–1·450; P = 0·18). In multivariate and adjusted propensity score analyses, the only significant association of no anticoagulation prior to diagnosis of COVID-19 was admission to the Intensive-Care Unit (ICU) (HR 1·98, 95% CI 1·37–2·85). Thrombosis, MB, and MOF were associated with higher mortality. Our results indicate that patients may have benefit from prior OAC use, especially reduced admission to ICU, without any increase in bleeding.

BackgroundPerforming Response Evaluation Criteria in Solid Tumor (RECISTS) measurement is a non-trivial task requiring much expertise and time. A deep learning-based algorithm has the potential to assist with rapid and consistent lesion measurement.PurposeThe aim of this study is to develop and evaluate deep learning (DL) algorithm for semi-automated unidirectional CT measurement of lung lesions.MethodsThis retrospective study included 1617 lung CT images from 8 publicly open datasets. A convolutional neural network was trained using 1373 training and validation images annotated by two radiologists. Performance of the DL algorithm was evaluated 244 test images annotated by one radiologist. DL algorithm’s measurement consistency with human radiologist was evaluated using Intraclass Correlation Coefficient (ICC) and Bland-Altman plotting. Bonferroni’s method was used to analyze difference in their diagnostic behavior, attributed by tumor characteristics. Statistical significance was set atp ResultsThe DL algorithm yielded ICC score of 0.959 with human radiologist. Bland-Altman plotting suggested 240 (98.4 %) measurements realized within the upper and lower limits of agreement (LOA). Some measurements outside the LOA revealed difference in clinical reasoning between DL algorithm and human radiologist. Overall, the algorithm marginally overestimated the size of lesion by 2.97 % compared to human radiologists. Further investigation indicated tumor characteristics may be associated with the DL algorithm’s diagnostic behavior of over or underestimating the lesion size compared to human radiologist.ConclusionsThe DL algorithm for unidirectional measurement of lung tumor size demonstrated excellent agreement with human radiologist.

Merkel cell carcinoma (MCC) is a rare cutaneous malignancy for which factors predictive of disease-specific survival (DSS) are poorly defined.Patients from six centers (2005-2020) with clinical stage I-II MCC who underwent sentinel lymph node (SLN) biopsy were included. Factors associated with DSS were identified using competing-risks regression analysis. Risk-score modeling was established using competing-risks regression on a training dataset and internally validated by point assignment to variables.Of 604 patients, 474 (78.5%) and 128 (21.2%) patients had clinical stage I and II disease, respectively, and 189 (31.3%) had SLN metastases. The 5-year DSS rate was 81.8% with a median follow-up of 31 months. Prognostic factors associated with worse DSS included increasing age (hazard ratio [HR] 1.03, p = 0.046), male sex (HR 3.21, p = 0.021), immune compromise (HR 2.46, p = 0.013), presence of microsatellites (HR 2.65, p = 0.041), and regional nodal involvement (1 node: HR 2.48, p = 0.039; ≥2 nodes: HR 2.95, p = 0.026). An internally validated, risk-score model incorporating all of these factors was developed with good performance (AUC 0.738). Patients with ≤ 4.00 and 4.00 points had 5-year DSS rates of 89.4% and 67.2%, respectively. Five-year DSS for pathologic stage I/II patients with 4.00 points (n = 49) was 79.8% and for pathologic stage III patients with ≤ 4.00 points (n = 62) was 90.3%.A risk-score model, including patient and tumor factors, based on DSS improves prognostic assessment of patients with clinically localized MCC. This may inform surveillance strategies and patient selection for adjuvant therapy trials.

OBJECTIVES: The coronavirus disease 2019 pandemic has overwhelmed healthcare resources even in wealthy nations, necessitating rationing of limited resources without previously established crisis standards of care protocols. In Massachusetts, triage guidelines were designed based on acute illness and chronic life-limiting conditions. In this study, we sought to retrospectively validate this protocol to cohorts of critically ill patients from our hospital. DESIGN: We applied our hospital-adopted guidelines, which defined severe and major chronic conditions as those associated with a greater than 50% likelihood of 1- and 5-year mortality, respectively, to a critically ill patient population. We investigated mortality for the same intervals. SETTING: An urban safety-net hospital ICU. PATIENTS: All adults hospitalized during April of 2015 and April 2019 identified through a clinical database search. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 365 admitted patients, 15.89% had one or more defined chronic life-limiting conditions. These patients had higher 1-year (46.55% vs 13.68%; p < 0.01) and 5-year (50.00% vs 17.22%; p < 0.01) mortality rates than those without underlying conditions. Irrespective of classification of disease severity, patients with metastatic cancer, congestive heart failure, end-stage renal disease, and neurodegenerative disease had greater than 50% 1-year mortality, whereas patients with chronic lung disease and cirrhosis had less than 50% 1-year mortality. Observed 1- and 5-year mortality for cirrhosis, heart failure, and metastatic cancer were more variable when subdivided into severe and major categories. CONCLUSIONS: Patients with major and severe chronic medical conditions overall had 46.55% and 50.00% mortality at 1 and 5 years, respectively. However, mortality varied between conditions. Our findings appear to support a crisis standards protocol which focuses on acute illness severity and only considers underlying conditions carrying a greater than 50% predicted likelihood of 1-year mortality. Modifications to the chronic lung disease, congestive heart failure, and cirrhosis criteria should be refined if they are to be included in future models.

Background: In sentinel lymph node (SLN)-positive melanoma, two randomized trials demonstrated equivalent melanoma-specific survival with nodal surveillance vs completion lymph node dissection (CLND). Patients with microsatellites, extranodal extension (ENE) in the SLN, or >3 positive SLNs constitute a high-risk group largely excluded from the randomized trials, for whom appropriate management remains unknown.Study design: SLN-positive patients with any of the three high-risk features were identified from an international cohort. CLND patients were matched 1:1 with surveillance patients using propensity scores. Risk of any-site recurrence, SLN-basin–only recurrence, and melanoma-specific mortality were compared.Results: Among 1,154 SLN-positive patients, 166 had ENE, microsatellites, and/or >3 positive SLN. At 18.5 months median follow-up, 49% had recurrence (vs 26% in patients without high-risk features, p < 0.01). Among high-risk patients, 52 (31%) underwent CLND and 114 (69%) received surveillance. Fifty-one CLND patients were matched to 51 surveillance patients. The matched cohort was balanced on tumor, nodal, and adjuvant treatment factors. There were no significant differences in any-site recurrence (CLND 49%, surveillance 45%, p = 0.99), SLN-basin–only recurrence (CLND 6%, surveillance 14%, p = 0.20), or melanoma-specific mortality (CLND 14%, surveillance 12%, p = 0.86).Conclusions: SLN-positive patients with microsatellites, ENE, or >3 positive SLN constitute a high-risk group with a 2-fold greater recurrence risk. For those managed with nodal surveillance, SLN-basin recurrences were more frequent, but all-site recurrence and melanoma-specific mortality were comparable to patients treated with CLND. Most recurrences were outside the SLN-basin, supporting use of nodal surveillance for SLN-positive patients with microsatellites, ENE, and/or >3 positive SLN.

Sentinel lymph node biopsy (SLNB) is routinely recommended for clinically localized Merkel cell carcinoma (MCC); however, predictors of false negative (FN) SLNB are undefined.Patients from six centers undergoing wide excision and SLNB for stage I/II MCC (2005-2020) were identified and were classified as having either a true positive (TP), true negative (TN) or FN SLNB. Predictors of FN SLNB were identified and survival outcomes were estimated.Of 525 patients, 28 (5.4%), 329 (62.7%), and 168 (32%) were classified as FN, TN, and TP, respectively, giving an FN rate of 14.3% and negative predictive value of 92.2% for SLNB. Median follow-up for SLNB-negative patients was 27 months, and median time to nodal recurrence for FN patients was 7 months. Male sex (hazard ratio [HR] 3.15, p = 0.034) and lymphovascular invasion (LVI) (HR 2.22, p = 0.048) significantly correlated with FN, and increasing age trended toward significance (HR 1.04, p = 0.067). The 3-year regional nodal recurrence-free survival for males75 years with LVI was 78.5% versus 97.4% for females ≤75 years without LVI (p = 0.009). Five-year disease-specific survival (90.9% TN vs. 51.3% FN, p 0.001) and overall survival (69.9% TN vs. 48.1% FN, p = 0.035) were significantly worse for FN patients.Failure to detect regional nodal microscopic disease by SLNB is associated with worse survival in clinically localized MCC. Males, patients75 years, and those with LVI may be at increased risk for FN SLNB. Consideration of increased nodal surveillance following negative SLNB in these high-risk patients may aid in early identification of regional nodal recurrences.

The impact of obesity on early-stage melanoma is poorly understood. We examined the impact of overweight and obesity on clinical outcomes in locoregional melanoma.Adults who underwent surgery at Emory University Healthcare between 2010 and 2017 for clinically stage I-II cutaneous melanoma, with known stage, height, and weight at the time of presentation, were identified. The relationship between body mass index (BMI) and clinicopathologic characteristics was assessed.Of 1756 patients, 584 were obese (33.2%; BMI ≥ 30), 658 were overweight (37.5%; BMI ≥ 25 and 30), and 514 were normal weight (29.3%; BMI 25). Demographics associated with obesity included male sex (odds ratio [OR] 2.6, 95% confidence interval [CI] 2.1-3.3; p 0.001) and lower income (OR 1.5, 95% CI 1.2-1.9; p = 0.003). Melanomas in obese patients were thicker (2.0 ± 0.2 mm) than in overweight (1.7 ± 0.1 mm) or normal-weight patients (1.4 ± 0.1 mm; p = 0.002). Ulceration, mitoses, BRAF status, and sentinel lymph node (SLN) status were not affected by obesity. In multivariable analysis, obesity independently predicted increased odds of pathologic stage II melanoma (vs. stage 0 or I; OR 1.9, 95% CI 1.4-2.7, p = 0.001), but not pathologic stage III melanoma (p 0.05). At 33 months' median follow-up, obesity was not an independent predictor of stage-specific overall survival (p 0.05).Obese patients are nearly twice as likely as their normal-weight peers to present with thicker melanomas, but they have similar stage-specific overall survival and SLN positivity. Obesity may promote more aggressive growth of the primary tumor, and barriers to preventive care in obese patients may exacerbate later-stage presentation.

Talimogene laherparepvec (T-VEC) is an oncolytic virus approved for the treatment of unresectable, recurrent melanoma. The role of T-VEC after progression on systemic immunotherapy (IO) remains undefined. The goal of this study was to characterize the efficacy of T-VEC after failure of IO in patients with unresectable metastatic melanoma.An international, multi-institutional review of AJCC version 8 stage IIIB-IV melanoma patients treated with T-VEC after failure of IO was performed at six centers from October 2015-December 2020. Primary outcome was in-field response; secondary outcomes included analyses of in-field and overall progression-free survival (PFS) and in-field and overall disease-free survival (DFS) after a complete response. Subset analysis of T-VEC initiation sequentially after or concurrently with IO was performed.Of 112 patients, median age at T-VEC initiation was 69 years (range 21-93); 65 (58%) were male. Before T-VEC, 57% patients received one IO regimen, 42% received two or more, with most patients (n = 74, 66%) receiving T-VEC sequential to IO. Most were stage 3C (n = 51, 46%) at T-VEC initiation, 29 (26%) received injections to nodal disease. Over median follow-up of 14 months, in-field response at final T-VEC injection was 37% complete (CR), 14% partial (PR). T-VEC initiation sequentially or concurrently did not significantly affect in-field response (p = 0.26). Median in-field PFS was 15 months (95% confidence interval 4.6-NE). Median overall DFS after CR was 32 months (95% confidence interval 17-NE).T-VEC after failure of IO is effective in unresectable, metastatic stage IIIB-IV melanoma. T-VEC initiation sequentially or concurrently did not significantly affect in-field response.

Background Cardiac Society of Australia and New Zealand (CSANZ) guidelines recommend elective high-risk percutaneous coronary intervention (PCI) is not performed in sites greater than 1 hour from cardiac surgery. Methods In hospital outcomes for all patients from Orange Health Service (OHS) from January 2017 to January 2020 who were transferred electively to tertiary centres in Sydney for high risk PCI were examined. Results One hundred and fourteen (114) patients were identified, with 1,259 PCIs performed at OHS over the same period without transfer. The mean age of these 114 patients was 71 years, with 74.6% male. Receiving hospitals were Royal Prince Alfred Hospital, Sydney, NSW (66.7%), Concord Repatriation General Hospital, Concord, NSW (19.3%) and Strathfield Private Hospital, Strathfield, NSW (14%). The definition of high risk and indication for transfer included at least one of: moderate or greater calcification of the target lesion or proximal segment (34%), single or multiple target lesions that in aggregate jeopardised over 50% of remaining viable myocardium (27%), degenerated saphenous vein grafts (14.8%), chronic total occlusions (7.0%) and severe left ventricular (LV) impairment (3.9%). American Heart Society/American College of Cardiology (AHA/ACC) lesion types were A (1%), B1 (4.2%), B2 (40.2%), and C (54.6%). PCI was performed via the femoral route in 96.2%. The mean procedure duration was 72 minutes, mean combined fluoroscopy time was 19 minutes and mean radiation dose as defined by Reference Air Kerma was 1,630 mGy. Complications occurred in 13 patients and were: acute vessel dissection requiring stenting (4), perforation (2), acute vessel closure (4), puncture site related (1), and life-threatening arrhythmia (2). There were no cases of emergent coronary artery bypass graft (CABG) or death. Conclusion This contemporary cohort of high-risk patients transferred electively from a regional PCI centre to a tertiary cardiac unit underwent lengthy PCI procedures, with high radiation doses, and a modest rate of peri-procedural complications, but had otherwise excellent procedural and clinical outcomes.

The cornerstone of life-saving therapy in immune-mediated thrombotic thrombocytopenic purpura (iTTP) has been plasma exchange (PEX) combined with immunomodulatory strategies. Caplacizumab, a novel anti–von Willebrand factor nanobody trialed in 2 multicenter randomized controlled trials (RCTs) leading to European Union and US Food and Drug Administration approval, has been available in the United Kingdom (UK) through a patient access scheme. Data were collected retrospectively from 2018 to 2020 for 85 patients (4 children) receiving caplacizumab from 22 UK hospitals. Patient characteristics and outcomes in the real-world clinical setting were compared with caplacizumab trial end points and historical outcomes in the precaplacizumab era. Eighty-four of 85 patients received steroid and rituximab alongside PEX; 26% required intubation. Median time to platelet count normalization (3 days), duration of PEX (7 days), and hospital stay (12 days) were comparable with RCT data. Median duration of PEX and time from PEX initiation to platelet count normalization were favorable compared with historical outcomes (P < .05). Thrombotic thrombocytopenic purpura (TTP) recurred in 5 of 85 patients; all had persistent ADAMTS13 activity < 5 IU/dL. Of 31 adverse events in 26 patients, 17 of 31 (55%) were bleeding episodes, and 5 of 31 (16%) were thrombotic events (2 unrelated to caplacizumab); mortality was 6% (5/85), with no deaths attributed to caplacizumab. In 4 of 5 deaths, caplacizumab was introduced >48 hours after PEX initiation (3-21 days). This real-world evidence represents the first and largest series of TTP patients, including pediatric patients, receiving caplacizumab outside of clinical trials. Representative of true clinical practice, the findings provide valuable information for clinicians treating TTP globally.

Key Points Question Can deep learning systems perform hematoxylin and eosin (H&E) staining and destaining and are the virtual core biopsy samples generated by them as valid and interpretable as their real-life unstained and H&E dye–stained counterparts? Findings In this cross-sectional study, deep learning models were trained using nonstained prostate core biopsy images to generate computationally H&E stained images, and core biopsy images were extracted from each whole slide, consisting of approximately 87 000 registered patch pairs of 1024 × 1024 × 3 pixels each. Comprehensive analyses of virtually stained images vs H&E dye–stained images confirmed successful computational staining. Meaning The findings of this study suggest that whole slide nonstained microscopic images of prostate core biopsy, instead of tissue samples, could be integrated with deep learning algorithms to perform computational H&E staining and destaining for rapid and accurate tumor diagnosis., This cross-sectional study describes the development of deep learning algorithms to virtually dye prostate tissue samples and evaluates the effectiveness of images generated using this method vs hematoxylin and eosin–stained images for histopathological diagnosis of tumors., Importance Histopathological diagnoses of tumors from tissue biopsy after hematoxylin and eosin (H&E) dye staining is the criterion standard for oncological care, but H&E staining requires trained operators, dyes and reagents, and precious tissue samples that cannot be reused. Objectives To use deep learning algorithms to develop models that perform accurate computational H&E staining of native nonstained prostate core biopsy images and to develop methods for interpretation of H&E staining deep learning models and analysis of computationally stained images by computer vision and clinical approaches. Design, Setting, and Participants This cross-sectional study used hundreds of thousands of native nonstained RGB (red, green, and blue channel) whole slide image (WSI) patches of prostate core tissue biopsies obtained from excess tissue material from prostate core biopsies performed in the course of routine clinical care between January 7, 2014, and January 7, 2017, at Brigham and Women’s Hospital, Boston, Massachusetts. Biopsies were registered with their H&E-stained versions. Conditional generative adversarial neural networks (cGANs) that automate conversion of native nonstained RGB WSI to computational H&E-stained images were then trained. Deidentified whole slide images of prostate core biopsy and medical record data were transferred to Massachusetts Institute of Technology, Cambridge, for computational research. Results were shared with physicians for clinical evaluations. Data were analyzed from July 2018 to February 2019. Main Outcomes and Measures Methods for detailed computer vision image analytics, visualization of trained cGAN model outputs, and clinical evaluation of virtually stained images were developed. The main outcome was interpretable deep learning models and computational H&E-stained images that achieved high performance in these metrics. Results Among 38 patients who provided samples, single core biopsy images were extracted from each whole slide, resulting in 102 individual nonstained and H&E dye–stained image pairs that were compared with matched computationally stained and unstained images. Calculations showed high similarities between computationally and H&E dye–stained images, with a mean (SD) structural similarity index (SSIM) of 0.902 (0.026), Pearson correlation coefficient (PCC) of 0.962 (0.096), and peak signal to noise ratio (PSNR) of 22.821 (1.232) dB. A second cGAN performed accurate computational destaining of H&E-stained images back to their native nonstained form, with a mean (SD) SSIM of 0.900 (0.030), PCC of 0.963 (0.011), and PSNR of 25.646 (1.943) dB compared with native nonstained images. A single blind prospective study computed approximately 95% pixel-by-pixel overlap among prostate tumor annotations provided by 5 board certified pathologists on computationally stained images, compared with those on H&E dye–stained images. This study also used the first visualization and explanation of neural network kernel activation maps during H&E staining and destaining of RGB images by cGANs. High similarities between kernel activation maps of computationally and H&E-stained images (mean-squared errors

This report describes the clinical presentation, diagnosis, and histopathologic features of oculodermal melanocytosis in a young dog. A 3-year-old male neutered Labrador Retriever presented with conjunctival and scleral hyperpigmentation of the right eye, with concurrent ipsilateral cutaneous hyperpigmentation involving the right side of the face. Initial skin and conjunctival biopsies revealed an accumulation of histologically benign melanocytes within the dermis and conjunctival stroma, respectively. Enucleation was elected 19 months later by the referring veterinarian due to the progression of ocular pigmentation with concurrent marked corneal lipidosis and the suspicion of a scleral mass. On gross and histopathologic examination of the globe, there was marked panuveal melanocytosis with extension into the sclera, bulbar conjunctiva, and connective tissue surrounding the optic nerve, as well as sharply demarcated ipsilateral hyperpigmentation of the facial skin. The findings are characteristic of oculodermal melanocytosis (nevus of Ota), a dermal melanocytic hamartoma presenting as cutaneous facial hyperpigmentation that corresponds to the distribution of the ophthalmic and maxillary branches of the trigeminal nerve, often with ipsilateral ocular involvement.

Introduction Isolated limb infusion (ILI) is a minimally-invasive procedure for delivering high-dose regional chemotherapy to treat melanoma in-transit metastases confined to a limb. The aim of this international multi-centre study was to identify predictive factors for toxicity and response. Methods Data of 687 patients who underwent a first ILI for melanoma in-transit metastases confined to the limb between 1992 and 2018 were collected at five Australian and four US tertiary referral centres. Results After ILI, predictive factors for increased limb toxicity (Wieberdink grade III/IV limb toxicity, n = 192, 27.9%) were: female gender, younger age, procedures performed before 2005, lower limb procedures, higher melphalan dose, longer drug circulation and ischemia times, and increased tissue hypoxia. No patient experienced grade V toxicity (necessitating amputation). A complete response (n = 199, 28.9%) was associated with a lower stage of disease, lower burden of disease (BOD) and thinner Breslow thickness of the primary melanoma. Additionally, an overall response (combined complete and partial response, n = 441, 64.1%) was associated with female gender, Australian centres, procedures performed before 2005, lower limb procedures and lower actinomycin-D doses. On multivariate analysis, higher melphalan dose remained a predictive factor for toxicity, while lower stage of disease and lower BOD remained predictive factors for overall response. Conclusion ILI is safe and effective to treat melanoma in-transit metastases. Predictive factors for toxicity and response identified in this study will allow improved patient selection and optimization of intra-operative parameters to increase response rates, while keeping toxicity low.

Background Chest pain is the second most common presenting symptom to emergency departments (ED) in Australia, although up to 85% of these patients do not have an acute coronary syndrome (ACS). Cardiologist-led rapid access chest pain clinics (RACPC) have been proposed overseas to assist in the management of such patients, with prompt outpatient assessment if patients are deemed low risk and discharged from the ED. The use of RACPCs in Australia has been only recently proposed; we therefore sought to examine one such RACPC in an Australian context. Methods and Results 1133 consecutive patients were seen at a metropolitan RACPC, between August 2008 and February 2017. There was a high preponderance of cardiovascular risk factors. Exercise stress testing (EST) was the default investigation upon discharge from ED, with a total of 1038 ESTs performed in 1113 patients (93%), with low numbers of other functional tests, and a small, but increasing number of coronary computed tomography (CT) scans performed over this period. Eighteen patients subsequently underwent revascularisation (1.6% of the total cohort), and none of these patients were readmitted at any time with an ACS between the interval of their index ED presentation to these investigations or treatments. Five (0.4%) patients represented to ED within 48 hours, none due to a cardiovascular cause. A total of 24 (2.1%) patients represented between 2 and 28 days, with none of these due to an ACS. Conclusions Following ED assessment of acute chest pain as low risk—with direct ED referral for exercising testing followed by RACPC review—results in very low readmission rates at 48 hours and at 28 days. Moreover, these readmissions were almost always not of cardiovascular aetiology, and occurred despite relatively longer waiting periods for both EST (8 days) and between EST and RACPC review (11 days), than the prespecified 72 to 96 hours as defined by the clinic protocol. Further investigation into this model of care in Australia is suggested.

In the setting of cancer, T cells upregulate coinhibitory molecules that attenuate TCR signaling and lead to the loss of proliferative capacity and effector function. Checkpoint inhibitors currently in clinical use have dramatically improved mortality from melanoma yet are not effective in all patients, suggesting that additional pathways may contribute to suppression of tumor-specific CD8+ T cell responses in melanoma. Here, we show that FcγRIIB, an inhibitory Fc receptor previously thought to be exclusively expressed on B cells and innate immune cells, is upregulated on tumor-infiltrating effector CD8+ T cells in an experimental melanoma model and expressed on CD8+ T cells in patients with melanoma. Genetic deficiency of Fcgr2b resulted in enhanced tumor-infiltrating CD8+ T cell responses and significantly reduced tumor burden. Adoptive transfer experiments of Fcgr2b-/- tumor antigen-specific T cells into FcγRIIB-sufficient hosts resulted in an increased frequency of tumor-infiltrating CD8+ T cells with greater effector function. Finally, FcγRIIB was expressed on CD8+ memory T cells isolated from patients with melanoma. These data illuminate a cell-intrinsic role for the FcγRIIB checkpoint in suppressing tumor-infiltrating CD8+ T cells.

Treatment for lower urinary tract symptoms (LUTS) is often delayed, as it is considered a natural progression of aging. We described baseline demographic and clinical characteristics of men currently not using prescription medications for benign prostatic hyperplasia (BPH) but interested in self-directed use of over-the-counter (OTC) tamsulosin and who had participated in OTC tamsulosin-simulated studies.Pooled baseline data from four OTC tamsulosin-simulated studies were analyzed for men who were currently not using BPH prescription medication and who believed that OTC tamsulosin was appropriate for use or were interested in purchasing it. Data from the OTC-simulated studies for men using BPH prescription medication and from the BPH registry, which included men diagnosed with BPH, were used for comparison.Overall, 3285 non-prescription-using men (mean age +/- standard deviation [SD], 60.6 +/- 11.6 years) were included. Average American Urological Association Symptom Index (AUA-SI) total score was 17.6; 25.5% reported urinary symptoms for5 years. Overall, 46.7% of these men had1 visit/year with their physicians. Baseline characteristics of prescription users from the OTC-simulated studies (n = 364; mean age ± SD, 68.3 +/- 9.1 years; mean AUA-SI score, 18.5) and of men from the BPH registry (n = 5042; 64.8 +/- 10 years; 11.6) were similar to those of non-prescription users.Non-prescription users had long term moderate-to-severe male LUTS, yet remained untreated; self-management may be a viable alternative strategy for this population. Disease characteristics of men not using BPH prescription medication and interested in using OTC tamsulosin were similar to those using BPH medication or diagnosed with BPH.

Introduction Dissemination of tumor to the leptomeninges, subarachnoid space, and cerebrospinal fluid (CSF) is termed leptomeningeal metastasis (LM) and occurs in approximately 5% of patients with solid tumors. LM is associated with dismal clinical prognosis, and routine cytologic and radiologic methods for diagnosing LM have limited sensitivity. The CellSearch immunomagnetic rare cell capture assay is FDA-approved to detect circulating tumor cells (CTCs) in peripheral blood, but whether it may have a role in identifying CSF CTCs is still unclear. Material and methods CSF specimens from 20 patients with clinically suspected solid tumor LM collected from 2 institutions between October 2016 and January 2019 were evaluated with routine CSF cytology and underwent concurrent CTC testing with the CellSearch assay (Menarini-Silicon Biosystems, Huntingdon Valley, PA). The results of CTC testing were compared to routine CSF cytology and radiologic studies for detecting LM. Results The CellSearch assay achieved a sensitivity of 88.9% and specificity of 100% for detecting LM (using a threshold of 1 CTC/mL of CSF as the definition of a positive CTC result). One patient with negative CSF cytology but positive CTCs developed positive cytology 37 days later. Conclusions In this proof-of-principle pilot study, we demonstrate that the CellSearch assay can be successfully integrated with the routine CSF cytologic workflow to aid in the diagnosis of solid tumor LM. Importantly, CTCs detected by this rare cell capture assay are found in a subset of patients with non-positive routine CSF cytology, which may have significant implications for patient management.

The eighth edition of the American Joint Committee on Cancer (AJCC8) Staging Manual provides important information for staging and prognostication; however, survival estimates for patients with Stage I-III Merkel cell carcinoma (MCC), a rare disease, may be as practical using data from large-volume centers as that collated for the AJCC analysis. As such, we compared our institutional outcomes to AJCC8.Patients who presented from 2005 to 2017 with MCC to two high-volume centers were included. Demographics, clinicopathologic characteristics, survival and recurrence data were compiled, and outcomes compared to AJCC8.A total of 409 patients were included. Median age was 75 (range 29-98) years, and 68% were male. Median follow-up was 16 months (0-157). Five-year overall survival (OS) was 70%; 5-year disease-specific survival (DSS) was 84%. When stratified by extent of disease, 5-year OS was higher for patients with local disease compared to those with nodal disease (72.6% vs 62.7%, p=0.005). Similarly, patients with local disease had higher 5-year DSS than those with nodal disease (90.1% vs 76.8%, p=0.002). Five-year recurrence-free survival was 59.2% for all patients, 65.0% for local disease and 48.3% for nodal disease (p=0.033).Here, MCC patients with local or nodal disease have substantially higher OS rates than predicted in AJCC8 (5-year: 72.6% vs 50.6%; 62.7% vs 35.4%, respectively). Importantly, 5-year DSS was significantly better than the OS rates reported presently and in AJCC8. As clinicians and patients rely on AJCC to accurately prognosticate and guide treatment decisions, these estimates should be reassessed and updated to more accurately predict survival outcomes.

BACKGROUND. Isolated limb infusion (ILI) is a minimally invasive procedure for delivering high-dose regional chemotherapy to patients with locally advanced or in-transit melanoma located on a limb. The current international multicenter study evaluated the perioperative and long-term oncologic outcomes for patients who underwent ILI for stage 3B or 3C melanoma. METHODS. Patients undergoing a first-time ILI for stage 3B or 3C melanoma (American Joint Committee on Cancer [AJCC] 7th ed) between 1992 and 2018 at five Australian and four United States of America (USA) tertiary referral centers were identified. The primary outcome measures included treatment response, in-field (IPFS) and distant progression-free survival (DPFS), and overall survival (OS). RESULTS. A total of 687 first-time ILIs were performed (stage 3B: n = 383, 56%; stage 3C; n = 304, 44%). Significant limb toxicity (Wieberdink grade 4) developed in 27 patients (3.9%). No amputations (grade 5) were performed. The overall response rate was 64.1% (complete response [CR], 28.9%; partial response [PR], 35.2%). Stable disease (SD) occurred in 14.5% and progressive disease (PD) in 19.8% of the patients. The median follow-up period was 47 months, with a median OS of 38.2 months. When stratified by response, the patients with a CR or PR had a significantly longer median IPFS (21.9 vs 3.0 months; p < 0.0001), DPFS (53.6 vs 12.7 months; p < 0.0001), and OS (46.5 vs 24.4 months; p < 0.0001) than the nonresponders (SD + PD). CONCLUSION. This study is the largest to date reporting long-term outcomes of ILI for locoregionally metastatic melanoma. The findings demonstrate that ILI is effective and safe for patients with stage 3B or 3C melanoma confined to a limb. A favorable response to ILI is associated with significantly longer IFPS, DPFS, and OS.

Lower urinary tract symptoms (LUTS) attributed to benign prostatic hyperplasia (BPH) are common in men, considerably affecting quality of life. The self-directed use of over-the-counter (OTC) tamsulosin (0.4 mg) and potential safety risks were evaluated in an open-label, uncontrolled, exploratory, 8-week OTC-simulated study. Men (≥ 18 years) were recruited via mass advertising about bothersome LUTS. In a working retail environment, respondents reviewed the product and decided whether it was appropriate for them to use (self-selection phase). After purchasing the product, participants’ ability to use it as directed by the proposed drug facts label (DFL) was assessed (home-use phase). Of 1446 eligible men, 679 completed the self-selection phase, and 73.9% (502/679) self-selected to use tamsulosin correctly according to the DFL. Of 369 participants who purchased tamsulosin and entered the home-use phase, 321 took one or more doses of tamsulosin and participated in at least one telephone interview. In total, 85.4% (274/321) of participants adhered to the ‘Stop Use’ and ‘Directions’ instructions in the DFL. Overall, 139 (39.6%) participants experienced one or more adverse events (AEs); 65 (18.5%) were deemed drug-related, including dizziness (11 [3.1%]), ejaculation disorder (6 [1.7%]), and semen volume decrease (6 [1.7%]). No unexpected AEs were reported. Of the men interested in self-managing their LUTS, a majority had moderate-to-severe LUTS of long duration. Most men were able to appropriately self-select and use tamsulosin in concordance with DFL instructions and directions. No unexpected AEs were reported during self-directed use. With further label refinement, an over-the-counter tamsulosin option might be feasible. ClinicalTrials.gov NCT01726270.

Background Talimogene laherparepvec (TVEC) is an FDA-approved oncolytic herpes virus used to treat unresectable stage IIIB to IV metastatic melanoma via intralesional injection. This study aims to characterize the efficacy TVEC in patients with unresectable stage IIIB to IV melanoma. Methods We performed a multi-institutional, IRB-approved review of all patients who received TVEC at 3 centers from October 2015 to October 2018. Clinicopathologic characteristics, TVEC treatment data, and outcomes were assessed. Results One hundred and twenty-one patients received TVEC, of which 80 patients had available treatment response data with at least 3-month follow-up. Anatomic sites treated were 19 (24%) head and neck, 9 (11%) upper extremity, 12 (15%) torso, and 40 (50%) lower extremity. Thirty-four (42.5%) patients did not receive therapy before TVEC. Side effects were mild and self-limited, most commonly flu-like symptoms seen in 22 (28%) patients. Median follow-up was 9 months (range 3 to 28 months), with complete local response in 31 (39%) and partial response in 14 (18%) patients. Of complete responders, 29 (37%) had no evidence of disease at last follow-up and received a median of 6 (range 2 to 12) cycles of therapy. Conclusions Talimogene laherparepvec is a well-tolerated, durable treatment option for patients with unresectable locoregional melanoma, particularly in stage IIIB/C disease. Additionally, we found that TVEC can be administered safely across anatomic sites that are otherwise not amenable to other local therapies.

BACKGROUND For young people in families with Huntington's disease (HD) the challenge of having an affected family member (AFM) compounds challenges related to being at risk of HD themselves. OBJECTIVE This study aimed to quantitatively examine the experiences of young people in families with HD, adding to existing qualitative studies regarding teenagers and young adults in families with HD. METHODS The experiences of young people with living in a family with HD were captured by an online anonymous questionnaire, available worldwide through the Huntington's Disease Youth Organization. The questionnaire contained mostly forced choice questions. RESULTS Most participants (n = 84/101, 83.2%) provide assistance to an AFM and 46.4% (n = 39/84) wish they didn't have to look after their AFM. Many participants (n = 64/78, 82.1%) reported feeling anxious about being at risk; 64.9% (n = 50/77) agreed it is a barrier in their life. Over one third (n = 29/76, 38.2%) of participants disagreed that they have support in relation to being at risk, despite 85.5% (n = 65/76) agreeing it is important to have support and ongoing follow up. CONCLUSIONS Young people in families with HD endure considerable emotional, social and practical burden secondary to having an AFM and being at risk themselves. Without increased support and services, the effects of being a young caregiver and living at risk are likely to have long term impacts on the well-being of these young people.

Background Remote ischemic preconditioning (RIPC) attenuates myocardial damage during elective and primary percutaneous coronary intervention. Recent studies suggest that coronary microcirculatory function is an important determinant of clinical outcome. The aim of this study was to assess the effect of RIPC on markers of microcirculatory function. Methods and Results Patients referred for cardiac catheterization and fractional flow reserve measurement were randomized to RIPC or sham. Operators and patients were blinded to treatment allocation. Comprehensive physiological assessments were performed before and after RIPC/sham including the index of microcirculatory resistance and coronary flow reserve after intracoronary glyceryl trinitrate and during the infusion of intravenous adenosine. Thirty patients were included (87% male; mean age: 63.1±10.0 years). RIPC and sham groups were similar with respect to baseline characteristics. RIPC decreased the calculated index of microcirculatory resistance (median, before RIPC: 22.6 [interquartile range [IQR]: 17.9–25.6]; after RIPC: 17.5 [IQR: 14.5–21.3]; P =0.007) and increased coronary flow reserve (2.6±0.9 versus 3.8±1.7, P =0.001). These RIPC‐mediated changes were associated with a reduction in hyperemic transit time (median: 0.33 [IQR: 0.26–0.40] versus 0.25 [IQR: 0.20–0.30]; P =0.010). RIPC resulted in a significant decrease in the calculated index of microcirculatory resistance compared with sham (relative change with treatment [mean±SD] was −18.1±24.8% versus +6.1±37.5; P =0.047) and a significant increase in coronary flow reserve (+41.2% [IQR: 20.0–61.7] versus −7.8% [IQR: −19.1 to 10.3]; P Conclusions The index of microcirculatory resistance and coronary flow reserve are acutely improved by remote ischemic preconditioning. This raises the possibility that RIPC confers cardioprotection during percutaneous coronary intervention as a result of an improvement in coronary microcirculatory function. Clinical Trial Registration URL: www.anzctr.org.au/ . Unique identifier: CTRN12616000486426.

The significance and management of melanoma in situ (MIS) at the margin of excision of invasive melanoma is debated. Patients undergoing excision of invasive melanoma from 2000 to 2016 with MIS at the margin were identified. A cohort without MIS was matched for age, gender, location, and Breslow depth. Thirty-two patients with 33 cases of MIS at the margin were identified. Melanoma was located on the head/neck (66.7%), extremities (24.2%), and trunk (9.1%). Median Breslow depth was 1.0 mm (range 0.25-10.80). Margin treatment included re-excision (45.5%), re-excision plus imiquimod (3.0%), imiquimod alone (9.1%), and observation alone (42.4%). At a median follow-up of 91 months (range 28-126), five patients (15.2%) with a median Breslow depth of 4.75 mm (range 1.10-6.70) developed local recurrence (LR). Three underwent re-excision of the positive margin and two were observed. Intervention for positive margins did not decrease LR compared with observation (P = 0.905, OR = 1.125, 95% confidence interval [CI] 0.162-7.824). All five patients with LR were alive at the last follow-up. There were two recurrences in the matched cohort (6.1%); both were alive at the last follow-up. Risk of LR is higher with MIS at the margin, but this does not seem to impact survival. Larger studies may elucidate predictive factors and interventions that decrease risk for LR.

The mechanisms responsible for late and very late stent thrombosis remain incompletely understood. This study aimed to evaluate the incidence and morphologic predictors of intrastent thrombus in patients after drug-eluting stent (DES) implantation using optical coherence tomography (OCT). A total of 208 patients with 262 DES who underwent follow-up OCT examination >6 months after DES implantation were included. The detailed vascular morphology including characteristics of neointima was analyzed. Thrombus was identified in 24 patients (11.5%) 11 months after DES implantation. Minimal lumen cross-sectional area was significantly smaller in the thrombus group than in the nonthrombus group (2.9 ± 1.7 vs 4.6 ± 2.0 mm(2); p

We determine if men with self-reported lower urinary tract symptoms can make a correct decision to use an over-the-counter alpha-1 blocker. Furthermore, we assess the frequency of medically significant conditions presenting with urinary symptoms in these consumers.Subjects reviewed a mock-up of an over-the-counter product for male lower urinary tract symptoms (part 1). Subjects who selected the product underwent urine dipstick testing and male subjects completed the AUA Symptom Index (part 2). Urological assessment was conducted in women; in men younger than 45 years; men 45 years old or older who reported "Do Not Use" symptoms listed on the over-the-counter label; who had glucose, leukocytes and/or blood in their urine; or had an AUA-SI score of 20 or greater.Of the 1,967 subjects enrolled 1,953 completed part 1 (men/women 1,697/256), 1,311 (1,294/17) entered part 2 and 1,289 (1,274/15) were evaluated. Frequently reported baseline medical conditions were hypertension (45.8%/46.7%) and dyslipidemia (36.4%/60.0%). Lower urinary tract symptoms were present for more than 3 years in 47.6% of men and 40% of women. Mean AUA-SI score was 18.9. Urine dipstick results were positive in 20.9% of men. Overall 729 men and 12 women underwent urological assessment, and 517 (70.9%) men had urologist confirmed lower urinary tract symptoms while 200 (27.4%) did not. Newly diagnosed medically significant conditions causing/contributing to lower urinary tract symptoms were identified in 21 (2.9%) men and 2 (16.7%) women.Most men correctly selected the over-the-counter product for the management of lower urinary tract symptoms/benign prostatic hyperplasia, while most women correctly deselected to use the product. Since few men had undiagnosed medically significant conditions causing/contributing to urinary symptoms, the risk of harm due to incorrect selection was low.

A case of left-main stem STEMI presenting "out of hours" is discussed, wherein an excellent result was achieved with acute thrombolysis.

In this case, prompt stenting of the dissection entry flap allowed for stabilization and eventual healing of a severe catheter-induced aortic dissection, without resort to surgical intervention.

Limited data exist characterizing complications after axillary lymphadenectomy for melanoma. With high rates of complications reported after dissection for breast cancer and data suggesting that completion lymphadenectomy may have limited therapeutic benefit, this study characterized morbidity to facilitate clinical decision-making. Using a broad definition for complications, patients who underwent axillary dissection for melanoma at a single center (from 2003 to 2015) were assessed through retrospective chart review. Patients were stratified by potential risk factors for complications; outcomes were compared. Two hundred fifty-four axillary dissections in 239 patients were identified. Assessed risk factors for complications included age > 55 years (n = 133, 52%), body mass index (BMI) ≥ 30 kg/m2 (n = 90, 40%), diabetes (n = 40, 16%), smoking (n = 81, 32%), extremity primary (n = 71, 28%), therapeutic lymphadenectomy (n = 105, 41%), and adjuvant radiation (n = 33, 13%). Wound complications were observed in 51 patients with 38 (15%) seromas, 3 (1%) dehiscences, and 10 (4%) hematomas. There were 5 (2%) reoperations, all for hematoma. Thirty-day readmission rate was 6% (n = 14). Importantly, lymphedema occurred in only 13 (5%) patients. Wound dehiscence occurred only in smokers (p = 0.03) and was associated with adjuvant radiation (p = 0.04). Twenty-eight (11%) patients developed frozen shoulder, which was related to smoking (p = 0.02). Lymphedema was more likely in patients after therapeutic dissection (p = 0.04). All other risk factors were not associated with increased complications. This analysis supports historical data that axillary dissection for melanoma is a low-risk procedure, with smoking, therapeutic lymphadenectomy, and adjuvant radiation associated with increased morbidity. Although morbidity of lymphadenectomy is often cited as a reason to alter surgical approach or even forgo intervention, this may be less of a concern for axillary dissection.

The fastest and most manoeuvrable terrestrial animals are found in savannah habitats, where predators chase and capture running prey. Hunt outcome and success rate are critical to survival, so both predator and prey should evolve to be faster and/or more manoeuvrable. Here we compare locomotor characteristics in two pursuit predator-prey pairs, lion-zebra and cheetah-impala, in their natural savannah habitat in Botswana. We show that although cheetahs and impalas were universally more athletic than lions and zebras in terms of speed, acceleration and turning, within each predator-prey pair, the predators had 20% higher muscle fibre power than prey, 37% greater acceleration and 72% greater deceleration capacity than their prey. We simulated hunt dynamics with these data and showed that hunts at lower speeds enable prey to use their maximum manoeuvring capacity and favour prey survival, and that the predator needs to be more athletic than its prey to sustain a viable success rate.

Summary Background Delusional infestation (DI) is a well-recognized clinical entity but there is a paucity of reliable data concerning its epidemiology. Knowledge of the epidemiology is fundamental to an understanding of any disease and its implications. Epidemiology is most accurately assessed using population-based studies, which are most generalizable to the wider population in the U.S. and worldwide. To our knowledge, no population-based study of the epidemiology (particularly incidence) of DI has been reported to date. Objectives To determine the incidence of delusional infestation (DI) using a population-based study. Methods Medical records of Olmsted County residents were reviewed using the resources of the Rochester Epidemiology Project to confirm the patient's status as a true incident case of DI and to gather demographic information. Patients with a first-time diagnosis of DI or synonymous conditions between 1 January 1976 and 31 December 2010 were considered incident cases. Results Of 470 identified possible diagnoses, 64 were true incident cases of DI in this population-based study. The age- and sex-adjusted incidence was 1·9 [95% confidence interval (CI) 1·5–2·4] per 100 000 person-years. Mean age at diagnosis was 61·4 years (range 9–92 years). The incidence of DI increased over the four decades from 1·6 (95% CI 0·6–2·6) per 100 000 person-years in 1976–1985 to 2·6 (95% CI 1·4–3·8) per 100 000 person-years in 2006–2010. Conclusions Our data indicate that DI is a rare disease, with incidence increasing across the life span, especially after the age of 40 years.

Summary Background The study of patients with bleeding problems is a powerful approach in determining the function and regulation of important proteins in human platelets. We have identified a patient with a chronic bleeding disorder expressing a homozygous P2RY12 mutation, predicting an arginine to cysteine (R122C) substitution in the G-protein-coupled P2Y12 receptor. This mutation is found within the DRY motif, which is a highly conserved region in G-protein-coupled receptors (GPCRs) that is speculated to play a critical role in regulating receptor conformational states. Objectives To determine the functional consequences of the R122C substitution for P2Y12 function. Patient/methods We performed a detailed phenotypic analysis of an index case and affected family members. An analysis of the variant R122C P2Y12 stably expressed in cells was also performed. Results ADP-stimulated platelet aggregation was reduced as a result of a significant impairment of P2Y12 activity in the patient and family members. Cell surface R122C P2Y12 expression was reduced both in cell lines and in platelets; in cell lines, this was as a consequence of agonist-independent internalization followed by subsequent receptor trafficking to lysosomes. Strikingly, members of this family also showed reduced thrombin-induced platelet activation, owing to an intronic polymorphism in the F2R gene, which encodes protease-activated receptor 1 (PAR-1), that has been shown to be associated with reduced PAR-1 receptor activity. Conclusions Our study is the first to demonstrate a patient with deficits in two stimulatory GPCR pathways that regulate platelet activity, further indicating that bleeding disorders constitute a complex trait.

To identify changes in the incidence of cutaneous melanoma over time in the fastest-growing segment of the US population-middle-aged adults.By using the Rochester Epidemiology Project resource, we identified patients aged 40 to 60 years who had a first lifetime diagnosis of melanoma between January 1, 1970, and December 31, 2009, in Olmsted County, Minnesota. The incidence of melanoma and overall and disease-specific survival rates were compared by age, sex, year of diagnosis, and stage of disease.Between 1970 and 2009, age- and sex-adjusted incidence increased significantly over time (P.001) from 7.9 to 60.0 per 100,000 person-years, with a 24-fold increase in women and a 4.5-fold increase in men. Although not significant (P=.06), the incidence of melanoma increased with age. Overall and disease-specific survival improved over time, with hazard ratios of 0.94 (P.001) and 0.93 (P.001) for each 1-year increase in the year of diagnosis, respectively. Each 1-year increase in the age at diagnosis was associated with an increased risk of death from any cause (hazard ratio, 1.07; P=.01) but was not significantly associated with disease-specific death (P=.98). Sex was not significantly associated with death from any cause (P=.81) or death from disease (P=.23). No patient with malignant melanoma in situ died from disease. Patients with stage II, III, and IV disease were more than 14 times more likely to die from disease than were patients with stage 0 or I disease (P.001).The incidence of cutaneous melanoma among middle-aged adults increased over the past 4 decades, especially in middle-aged women, whereas mortality decreased.

Background Substance use by youth living with HIV (YLWH) is a concern, given potential interactions with virus-associated immune suppression and adverse effects on risk behaviors, neurocognition, and adherence. Self-report substance use measures provide efficient cost-effective assessments. Analyses describe self-reported substance use among YLWH and examine agreement with toxicology assays. Methods Seventy-eight youth age 18–24 years (87% male, 71% African–American) with behaviorally acquired HIV-1 infection and 55 uninfected youth completed the Alcohol, Smoking, and Substance Involvement Screening Test to assess drug use frequency, including tobacco, marijuana, cocaine, and alcohol, over the prior three months. Elisa-based toxicology assays were used to detect 27 substances in plasma. Chi-square tests compared substance use between YLWH and uninfected youth; Kappa statistics compared agreement between self-report and toxicology. Results YLWH reported marijuana (49%), tobacco (56%), and alcohol (87%) use, with 20%, 28% and 3% reporting daily use of each substance, respectively; other substance use was uncommon. Uninfected youth reported less tobacco use but otherwise similar substance use. All youth who reported daily use of marijuana or tobacco had positive plasma toxicology results, while concordance decreased with less frequent self-reported use. Among youth reporting no substance use, few tested positive (4% YLWH, 2% uninfected youth for cannabis; 8%YLWH for tobacco). Conclusions Youth report high rates of marijuana, tobacco, and alcohol use. Concordance between self-report and toxicology for marijuana and tobacco use, particularly for daily users, supports self-report as a valid indicator of substance use in research studies of youth with or without HIV-1 infection.