Brain metastases in adult patients with melanoma of unknown primary in the Netherlands (2011-2020).

BACKGROUND: Although patients with melanoma of unknown primary (MUP) have a better prognosis than similar-staged melanoma patients with known primary, the occurrence of brain metastases (BM) entails a serious complication. This study provides an overview of the incidence, treatment patterns, and overall survival (OS) of adult patients with BM-MUP in the Netherlands. METHODS: BM-MUP cases were retrieved from the Netherlands Cancer Registry. Patient, disease and treatment-related characteristics were summarised using descriptive statistics. Overall survival (OS) was calculated by the Kaplan-Meier method, and the impact of prognostic factors on OS was assessed using Cox proportional hazard regression analyses. RESULTS: Among 1779 MUP patients, 450 were identified as BM-MUP (25.3%). Of these patients, 381 (84.7%) presented with BM along with other metastases, while 69 (15.3%) had BM only. BM-MUP patients were predominantly male (68.2%), and had a median age of 64 years at diagnosis (interquartile range 54-71 years). Over time, the proportion of BM along other metastatic sites increased, and the occurrence of BM decreased (p = 0.01). 1-Year OS improved for the total population, from 30.0% (95% confidence interval (CI): 19.8-40.9%) in 2011-2012 to 43.6% (95%CI: 34.5-52.3%) in 2019-2020, and median OS more than doubled from 4.2 months (95%CI: 3.3-6.2 months) to 9.8 months (95%CI: 7.0-13.2 months). Patient's age, localisation of BM, presence of synchronous liver metastasis and treatment were identified as independent predictors of OS. CONCLUSION: Notwithstanding the progress made in OS for patients with BM-MUP in the past decade, their overall prognosis remains poor, and further efforts are needed to improve outcomes.

Prognostic factors among patients with brain metastases from cancer of unknown primary site.

PURPOSE: Cancers of an unknown primary site (CUPs) have a dismal prognosis, and the situation is even worse for CUPs patients with brain metastases (BM-CUPs). This study aims to give better insight into the occurrence and survival of BM-CUPs patients. METHODS: Cases were selected from the Netherlands Cancer Registry (1,430 BM-CUPs/17,140 CUPs). Baseline characteristics between CUPs patients with and without BM were tested using chi-square tests and Mann-Whitney U tests. Patients' overall survival (OS) times were estimated by the Kaplan-Meier method and prognostic factors on OS was assessed using Cox proportional hazards regression analyses. RESULTS: The proportion of BM-CUPs patients among CUPs increased from 8% in 2009-2010 to 10% in 2017-2018 (p < 0.001). Most patients presented with multiple brain lesions (53%). Survival of BM-CUPs improved over time: one-year OS increased from 10% for patients diagnosed in 2009-2010 to 17% (2017- 2018) (p < 0.01), and median survival times increased from 1.8 months to 2.2 months. Independent predictors of poor survival were multiple (HR 1.25; p < 0.01) or unknown (HR 1.48; p < 0.01) locations of BM, unknown/poorly/undifferentiated carcinoma histology (HR 1.53; p < 0.01), or clinical symptoms of BM (HR 1.74; p < 0.01), accompanying liver metastasis (HR 1.43; p < 0.01) and more than one metastatic site outside the brain compared to none (HR 1.52; p < 0.01). CONCLUSION: The incidence of patients with BM-CUPs is steadily increasing over time and overall prognosis remains dismal. Our results, however, show distinct patient subgroups that exhibit comparatively better outcomes, and more predictors may likely still be identified.

Endocrine disruptors: Challenges and future directions in epidemiologic research.

Public concern about the impact of endocrine disrupting chemicals (EDCs) on both humans and the environment is growing steadily. Epidemiologic research provides key information towards our understanding of the relationship between environmental exposures like EDCs and human health outcomes. Intended for researchers in disciplines complementary to epidemiology, this paper highlights the importance and challenges of epidemiologic research in order to present the key elements pertaining to the design and interpretation of an epidemiologic study on EDCs. The conduct of observational studies on EDCs derives from a thoughtful research question, which will help determine the subsequent methodological choices surrounding the careful selection of the study population (including the comparison group), the adequate ascertainment of exposure(s) and outcome(s) of interest, and the application of methodological and statistical concepts more specific to epidemiology. The interpretation of epidemiologic results may be arduous due to the latency occurring between EDC exposure and certain outcome(s), the complexity in capturing EDC exposure(s), and traditional methodological and statistical issues that also deserve consideration (e.g., confounding, effect modification, non-monotonic responses). Moving forward, we strongly advocate for an integrative approach of expertise in the fields of epidemiology, exposure science, risk assessment and toxicology to adequately study the health risks associated with EDCs while tackling their challenges.

Inter-rater reliability of occupational exposure assessment in a case-control study of female breast cancer.

The objective of this paper was to estimate the inter-rater reliability of expert assessments of occupational exposures. An inter-rater reliability sub-study was conducted within a population-based case-control study of postmenopausal breast cancer. Detailed information on lifetime occupational histories was obtained from participants and two industrial hygienists assigned exposures to 185 jobs using a checklist of 293 agents. Experts rated exposure for each job-agent combination according to exposure status (unexposed/exposed), confidence that the exposure occurred (possible/probable/definite), intensity (low/medium/high), and frequency (% time per week). The statistical unit of observation was each job-agent assessment (185 jobs × 293 agents = 54,205 assessments per expert). Crude agreement, Gwet AC1/2 statistics, and Cohen's Kappa were used to estimate inter-rater agreement for confidence and intensity; for frequency, the intra-class correlation coefficient (ICC) was used. The majority of job-agent combinations were evaluated by the two experts to be not exposed (crude agreement >98% of decisions). The degree of agreement between the experts for the confidence of exposure status was Gwet AC1/2 = 0.99 (95% CI: 0.99-0.99), and for intensity, a Gwet AC2 = 0.99 (95% CI: 0.99-0.99). For frequency, an ICC of 0.31 (95% CI: 0.26-0.35) was found. A sub-analysis restricted to job-agent combinations for which the two experts agreed on exposure status revealed a moderate agreement for confidence of exposure (Gwet AC2 = 0.66) and high agreement for intensity (Gwet AC2 = 0.96). For frequency, the ICC was 0.52 (95% CI: 0.47-0.57). A high level of inter-rater agreement was found for identifying exposures and for coding intensity, but agreement was lower for the coding of frequency of exposure.

Period-Prevalence and Risk Factors for Delirium in a Tertiary Referral ICU: A prospective cohort study.

BACKGROUND: Delirium is common in intensive care and leads to increases in morbidity, mortality, Intensive Care Unit (ICU) length of stay, and hospital length of stay. Certain risk factors predict the appearance of delirium. STUDY OBJECTIVES: To determine the rates of delirium, the rate of risk factors, and their relationship to the occurrence of delirium in an adult ICU. METHODS: Single-centre, prospective, observational study. Demographic and treatment data were collected. The Confusion Assessment Method for ICU (CAM-ICU) was performed twice daily to assess for delirium continuously during a 3-week period. Statistical analysis was used to determine the relationship between risk factors and the occurrence of delirium. RESULTS: 86 patients were screened, 44 patients were included, and 260 patient-days were analyzed. The incidence of delirium was 42.9%, the prevalence of delirium in ICU was 50%. Urinary catheters and use of opioids were the most common factors with a positive association for occurrence of delirium. Exposure to daylight and sleeping for more than 4 hours at night were the factors most commonly associated with a lack of delirium. CONCLUSION: The rates of delirium in ICU were high and risk factors occurred frequently. Addressing modifiable risk factors, including the promotion of adequate sleep, could improve outcomes.

Validation of the Chowdhury overall survival score in patients with melanoma brain metastasis treated with Gamma Knife Radiosurgery.

Melanoma brain metastases (MBM) are common in patients with stage IV disease. For Gamma Knife radiosurgery (GKRS) on MBM, risk scores such as RPA and melanoma-GPA aid to identify prognostic subgroups. This study aimed to validate the overall survival (OS) risk score developed by Chowdhury et al. in our center's patient cohort. A total of 104 MBM patients were treated with GKRS between 1/1/2002 and 31/12/2014 in our institution. Patients were categorized according to RPA, melanoma-GPA and Chowdhury OS score. The Kaplan-Meier method was used to estimate overall survival, and predicted survival probabilities were calculated for calibration. Cox proportional hazards regressions were performed to identify additional risk factors. Overall, median follow-up time was 80 months, while median OS (mOS) after GKRS was 6 months. Stratified according to the Chowdhury OS score, mOS in the high, medium and low risk group was 3.4, 7.1, and 10.0 months, respectively. The addition of other patient or disease characteristics to the Chowdhury OS model did not improve its performance. The C-index of the melanoma-GPA was 0.46 while the Chowdhury OS had an index of 0.67. In comparison with the RPA and melanoma-GPA, the Chowdhury OS score more accurately distinguished between separate risk groups among patients with MBM treated with GKRS. Contrary to the original study by Chowdhury, follow-up time was sufficient here for the low-risk group to reach the mOS time of 10 months.

Monte Carlo ray-trace diffraction based on the Huygens-Fresnel principle.

The goal of this effort is to establish the conditions and limits under which the Huygens-Fresnel principle accurately describes diffraction in the Monte Carlo ray-trace (MCRT) environment. This goal is achieved by systematic intercomparison of dedicated experimental, theoretical, and numerical results. We evaluate the success of the Huygens-Fresnel principle by predicting and carefully measuring the diffraction fringes produced by both single slit and circular apertures. We then compare the results from the analytical and numerical approaches with each other and with dedicated experimental results. We conclude that use of the MCRT method to accurately describe diffraction requires that careful attention be paid to the interplay among the number of aperture points, the number of rays traced per aperture point, and the number of bins on the screen. This conclusion is supported by standard statistical analysis, including the adjusted coefficient of determination, Radj2, the rms deviation, and the reduced chi-square statistic, χv2.

Decision analysis supports the use of drain amylase-based enhanced recovery method after esophagectomy.

Postesophagectomy anastomotic leak is a common postsurgical complication. The current standard method of detecting leak is esophagram usually late in the postoperative period. Perianastomotic drain amylase level had shown promising results in early detection anastomosis leak. Previous studies have shown that postoperative day 4 amylase level is more specific and sensitive than esophagram. The purpose of this study is to determine if implementing a drain amylase-based screening method for anastomotic leak can reduce length of stay and hospital cost relative to a traditional esophagram-based pathway. The drain amylase protocol we propose uses postoperative day 4 drain amylase level to direct the initiation of PO intake and discharge. We designed a decision analysis tree using TreeAge Pro software to compare the drain amylase-based screening method to the standard of care, the esophagram. We performed a retrospective review of postesophagectomy patients from a tertiary academic medical center (University hospital Cleveland medical center) where amylase level was measured routinely postoperatively. The patients were separated into amylase-based pathway group and the standard of care group based on their postop management. The length of stay, costs, complications, and leak rate of these two groups were used to inform the decision analysis tree. In the base-case analysis, the decision analysis demonstrated that an amylase-based screening method can reduce the hospital stay by one day and reduced costs by ∼$3,000 compared to esophagram group. To take the variability of the data into consideration, we performed a Monte Carlo simulation. The result showed again a median saving of 0.71 days and ∼$2,500 per patient in hospital cost. A ballistic sensitivity analysis was performed to show that the sensitivity of postoperative day 4 amylase level in detecting a leak was the most important factor in the model. We conclude that implementing an amylase-based screening method for anastomotic leak in postesophagectomy patient can significantly reduce hospital cost and length of stay. This study demonstrates a novel protocol to improve postesophagectomy care. Based on this result, we believe a prospective multicenter study is appropriate.

Adjuvant Chemoradiotherapy for Non-Pretreated Gastric Cancer.

BACKGROUND: While the curative approach to gastric cancer includes perioperative regimens in several countries, a substantial proportion of patients may not receive treatment prior to surgery. This study examines the adjuvant provision of chemoradiotherapy (CRT) for non-pretreated patients with cancer of the stomach including the gastric cardia. METHODS: All surgically treated patients with primary adenocarcinoma of the stomach and gastric cardia diagnosed between January 2004-December 2013 were selected from the Netherlands Cancer Registry. Patients who did not receive neoadjuvant treatment were included. Early gastric cancers (cT1), postoperative deaths within 90 days, patients with metastatic disease (M1), patients who received adjuvant chemotherapy and patients with macroscopic tumor after surgery (R2) were excluded. RESULTS: Some 3277 patients underwent surgery, and 99 patients (3%) received adjuvant CRT. Treatment was more often administered in patients with a younger age (<65 years) and a high socioeconomic status (SES), in case of non-cardia cancer, positive lymph nodes, and positive resection margins (R1). Median survival time was 28 months (95% CI 17-39), compared to 35 months (95% CI 33-38) in CRT-naïve patients. After adjustment for confounders, a small net benefit for adjuvant CRT was found (hazard ratio, HR: 0.75, 95% CI 0.58-0.96). In subgroup analyses, benefit was most pronounced for patients with seven or more lymph metastases. CONCLUSIONS: Marginal survival benefit was observed for adjuvant CRT in gastric cancer patients who did not receive neoadjuvant treatment. Treatment could be considered for patients with disease involving nodal invasion and those left with microscopic residual disease after surgery.

Socioeconomic status and lifestyle behaviours in cancer survivors: smoking and physical activity.

PURPOSE: Smoking cessation and increased physical activity (pa) have been linked to better outcomes in cancer survivors. We assessed whether socioeconomic factors influence changes in those behaviours after a cancer diagnosis. METHODS: As part of a cross-sectional study, a diverse group of cancer survivors at the Princess Margaret Cancer Centre (Toronto, ON), completed a questionnaire about past and current lifestyle behaviours and perceptions about the importance of those behaviours with respect to their health. The influence of socioeconomic indicators on smoking status and physical inactivity at 1 year before and after diagnosis were assessed using multivariable logistic regression with adjustment for clinico-demographic factors. RESULTS: Of 1222 participants, 1192 completed the smoking component. Of those respondents, 15% smoked before diagnosis, and 43% of those smokers continued to smoke after. The proportion of survivors who continued to smoke increased with lower education level (p = 0.03). Of the 1106 participants answering pa questions, 39% reported being physically inactive before diagnosis, of whom 82% remained inactive afterward. Survivors with a lower education level were most likely to remain inactive after diagnosis (p = 0.003). Lower education level, household income, and occupation were associated with the perception that pa had no effect or could worsen fatigue and quality of life (p ≤ 0.0001). CONCLUSIONS: In cancer survivors, education level was a major modifier of smoking and pa behaviours. Lower socioeconomic status was associated with incorrect perceptions about pa. Targeting at-risk survivors by education level should be evaluated as a strategy in cancer survivorship programs.

Gold nanocrystal arrays as a macroscopic platform for molecular junction thermoelectrics.

Efficiencies of bulk thermoelectric systems have been limited because the Seebeck coefficient and electrical conductivity are typically inversely correlated in traditional materials. Decoupling of these properties has been demonstrated in molecular junctions by capitalizing on the unique electronic transport at organic-inorganic interfaces. In this work, the thermoelectric properties of gold nanocrystal arrays with varying thiol-terminated ligands are compared to molecular junction experiments. The experimental results and supporting theory demonstrate that gold nanocrystal arrays are a valuable model system for mapping the applicability of molecular junction design rules to the design of macroscale organic-inorganic hybrid thermoelectric materials.

Canavan disease - unusual imaging features in a child with mild clinical presentation.

Canavan disease is a rare hereditary leukodystrophy that manifests in early childhood. Associated with rapidly progressive clinical deterioration, it usually results in death by the third year of life. The predominant MRI appearance is diffuse and symmetrical white matter disease. We discuss an atypical, late presentation of Canavan disease with a benign clinical course and uncharacteristic imaging features. This case introduces a previously unreported pattern of diffuse cortical abnormality without significant white matter involvement.

New insights into the aetiology of scrotal cancer, a nationwide case-control study in the Netherlands.

BACKGROUND: Although scrotal cancer is traditionally regarded as an occupational disease, there is increasing evidence that factors which are involved in cutaneous and genital carcinogenesis might play a role in the carcinogenesis of scrotal cancer. OBJECTIVE: This exploratory study aimed to detect exposures that might have an aetiological relation with scrotal cancer. METHODS: A nationwide population-based case-control study was conducted in the Netherlands. The patients were identified through the Netherlands cancer registry. Controls were recruited among acquaintances of the cancer registry registrars. The participants completed a questionnaire that included questions on occupational exposures, naked sunbathing, use of sunbeds, skin diseases and their treatments, treatments for cancer and sexually transmitted diseases. Age-adjusted odds-ratios (ORs) were calculated. RESULTS: Forty-seven scrotal cancer patients and 125 controls completed the questionnaire. The patients were categorized according to histology of the scrotal tumours. Having had a skin disease (OR = 6.3, 95% CI = 1.8-22), especially psoriasis (OR = 8.7), increased the risk of squamous cell carcinomas (SCC) of the scrotum. A previous cancer diagnosis may affect the risk of scrotal basal cell carcinomas (BCC; OR = 4.9, 95% CI = 0.9-27.3). Furthermore, an association between the number of sexual partners and the occurrence of scrotal sarcoma was found. CONCLUSION: Scrotal SCCs may be related with skin diseases or skin disease treatments. Having had cancer may be a risk factor for a BCC of the scrotum. Scrotal sarcomas seem to be correlated with the number of sexual partners. This study suggests that scrotal cancer has characteristics of both cutaneous and genital carcinogenesis.

Outcomes of a population-based series of early breast cancer patients with micrometastases and isolated tumour cells in axillary lymph nodes.

BACKGROUND: Axillary lymph node staging is traditionally important to provide prognostic information to guide further treatment. However, the relevance of isolated tumour cells (ITC) or micrometastases in axillary nodes and the need for adjuvant treatment remain uncertain. PATIENTS AND METHODS: Data from 18 370 patients with pT1-2 breast cancer with pN0, pN0i+ or pN1mi were analysed. The primary end point was 5-year disease-free survival (locoregional recurrence, distant metastases or contralateral breast cancer). RESULTS: Five-year disease-free survival was 89.9% [95% confidence interval 89.5% to 90.4%]; and did not differ significantly between groups. After adjusting for prognostic factors (including treatment), patients with ITC had a comparable risk (hazard ratio = 1.12) as patients with node-negative disease, while patients with micrometastases had a 38% higher risk of recurrence. CONCLUSION(S): Patients with ITC and node-negative breast cancer appear to have similar prognosis, and those with micrometastases have a 38% higher risk of tumour recurrence. However, considering that disease-free survival is already high, we are reluctant to advise chemotherapy in all patients with ITC or micrometastases. In future, genomic tumour characteristics might predict the propensity of dissemination from the primary cancer better than the status of the axillary lymph nodes.

Disease progression and patient survival are significantly influenced by BRAF protein expression in primary melanoma.

BACKGROUND: Mutation of BRAF is a prevalent event in melanoma. Despite much attention to the role of BRAF mutation in melanoma, the status of BRAF protein expression and its significance in melanoma progression are unknown. OBJECTIVES: We investigated the BRAF expression level in different stages of melanocytic lesions and evaluated its correlation with clinicopathological features and patient survival. METHODS: Using tissue microarray, BRAF expression and its correlation with patient outcome was evaluated in 49 naevi samples and 370 patients with melanoma. We also evaluated the correlation of BRAF protein expression and V600E mutation using direct sequencing. RESULTS: Compared with naevi samples, BRAF expression was remarkably increased in primary melanomas and further increased in metastatic melanomas (P = 1·8 × 10(-11) ). High BRAF expression was significantly correlated with thicker tumours, ulceration and higher American Joint Committee on Cancer stages (P = 1·5 × 10(-7) , 1·5 × 10(-5) and 3·6 × 10(-13) , respectively). In cases of primary melanoma, patients with high BRAF expression had significantly worse overall (P = 0·009) and disease-specific 5-year survival (P = 0·007). While there was a trend for higher prevalence of BRAF V600E mutation in patients with high BRAF protein expression, no significant correlation was observed between protein expression and BRAF mutation. Furthermore, univariate Cox regression analysis confirmed high BRAF protein expression as a strong risk factor for poor patient survival in primary melanoma [hazard ratio (HR) 2·08 for overall survival; HR 2·39 for disease-specific survival]. CONCLUSIONS: Our data demonstrate that BRAF protein expression is significantly increased during melanoma progression. In addition, we revealed a novel prognostic value for BRAF protein expression in primary melanoma as it is significantly correlated with poor patient survival.

Long-term safety of ustekinumab in patients with moderate-to-severe psoriasis: final results from 5 years of follow-up.

BACKGROUND: Long-term safety evaluations of biologics are needed to inform patient management decisions. OBJECTIVES: To evaluate the safety of ustekinumab in patients with moderate-to-severe psoriasis treated for up to 5 years. METHODS: Safety data were pooled from four studies of ustekinumab for psoriasis. Rates of adverse events (AEs), serious AEs (SAEs) and AEs of interest [infections, nonmelanoma skin cancers (NMSCs), other malignancies and major adverse cardiovascular events (MACE)] per 100 patient-years (PY) of follow-up were analysed by ustekinumab dose (45 or 90 mg) and by year of follow-up (years 1-5) to evaluate the dose response and impact of cumulative exposure. Observed rates of overall mortality and other malignancies were compared with those expected in the general U.S. population. RESULTS: Analyses included 3117 patients (8998 PY) who received one or more doses of ustekinumab, with 1482 patients treated for ≥4 years (including 838 patients ≥5 years). At year 5, event rates (45 mg, 90 mg, respectively) for overall AEs (242·6, 225·3), SAEs (7·0, 7·2), serious infections (0·98, 1·19), NMSCs (0·64, 0·44), other malignancies (0·59, 0·61) and MACE (0·56, 0·36) were comparable between dose groups. Year-to-year variability was observed, but no increasing trend was evident. Rates of overall mortality and other malignancies were comparable with those expected in the general U.S. population. CONCLUSIONS: No dose-related or cumulative toxicity was observed with increasing duration of ustekinumab exposure for up to 5 years. Rates of AEs reported in ustekinumab psoriasis trials are generally comparable with those reported for other biologics approved for the treatment of moderate-to-severe psoriasis.

Comprehensive microRNA expression profiling of the hematopoietic hierarchy.

The hematopoietic system produces a large number of highly specialized cell types that are derived through a hierarchical differentiation process from a common stem cell population. miRNAs are critical players in orchestrating this differentiation. Here, we report the development and application of a high-throughput microfluidic real-time quantitative PCR (RT-qPCR) approach for generating global miRNA profiles for 27 phenotypically distinct cell populations isolated from normal adult mouse hematopoietic tissues. A total of 80,000 RT-qPCR assays were used to map the landscape of miRNA expression across the hematopoietic hierarchy, including rare progenitor and stem cell populations. We show that miRNA profiles allow for the direct inference of cell lineage relations and functional similarity. Our analysis reveals a close relatedness of the miRNA expression patterns in multipotent progenitors and stem cells, followed by a major reprogramming upon restriction of differentiation potential to a single lineage. The analysis of miRNA expression in single hematopoietic cells further demonstrates that miRNA expression is very tightly regulated within highly purified populations, underscoring the potential of single-cell miRNA profiling for assessing compartment heterogeneity.

Harmonizing Definitions for Diagnostic Criteria and Prognostic Assessment of Transplantation-Associated Thrombotic Microangiopathy: A Report on Behalf of the European Society for Blood and Marrow Transplantation, American Society for Transplantation and Cellular Therapy, Asia-Pacific Blood and Marrow Transplantation Group, and Center for International Blood and Marrow Transplant Research.

Transplantation-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of hematopoietic cell transplantation (HCT) associated with significant morbidity and mortality. However, TA-TMA is a clinical diagnosis, and multiple criteria have been proposed without universal application. Although some patients have a self-resolving disease, others progress to multiorgan failure and/or death. Poor prognostic features also are not uniformly accepted. The lack of harmonization of diagnostic and prognostic markers has precluded multi-institutional studies to better understand incidence and outcomes. Even current interventional trials use different criteria, making it challenging to interpret the data. To address this urgent need, the American Society for Transplantation and Cellular Therapy, Center for International Bone Marrow Transplant Research, Asia-Pacific Blood and Marrow Transplantation, and European Society for Blood and Marrow Transplantation nominated representatives for an expert panel tasked with reaching consensus on diagnostic and prognostic criteria. The panel reviewed literature, generated consensus statements regarding diagnostic and prognostic features of TA-TMA using the Delphi method, and identified future directions of investigation. Consensus was reached on 4 key concepts: (1) TA-TMA can be diagnosed using clinical and laboratory criteria or tissue biopsy of kidney or gastrointestinal tissue; however, biopsy is not required; (2) consensus diagnostic criteria are proposed using the modified Jodele criteria with additional definitions of anemia and thrombocytopenia. TA-TMA is diagnosed when ≥4 of the following 7 features occur twice within 14 days: anemia, defined as failure to achieve transfusion independence despite neutrophil engraftment; hemoglobin decline by ≥1 g/dL or new-onset transfusion dependence; thrombocytopenia, defined as failure to achieve platelet engraftment, higher-than-expected transfusion needs, refractory to platelet transfusions, or ≥50% reduction in baseline platelet count after full platelet engraftment; lactate dehydrogenase (LDH) exceeding the upper limit of normal (ULN); schistocytes; hypertension; soluble C5b-9 (sC5b-9) exceeding the ULN; and proteinuria (≥1 mg/mg random urine protein-to-creatinine ratio [rUPCR]); (3) patients with any of the following features are at increased risk of nonrelapse mortality and should be stratified as high-risk TA-TMA: elevated sC5b-9, LDH ≥2 times the ULN, rUPCR ≥1 mg/mg, multiorgan dysfunction, concurrent grade II-IV acute graft-versus-host disease (GVHD), or infection (bacterial or viral); and (4) all allogeneic and pediatric autologous HCT recipients with neuroblastoma should be screened weekly for TA-TMA during the first 100 days post-HCT. Patients diagnosed with TA-TMA should be risk-stratified, and those with high-risk disease should be offered participation in a clinical trial for TA-TMA-directed therapy if available. We propose that these criteria and risk stratification features be used in data registries, prospective studies, and clinical practice across international settings. This harmonization will facilitate the investigation of TA-TMA across populations diverse in race, ethnicity, age, disease indications, and transplantation characteristics. As these criteria are widely used, we expect continued refinement as necessary. Efforts to identify more specific diagnostic and prognostic biomarkers are a top priority of the field. Finally, an investigation of the impact of TA-TMA-directed treatment, particularly in the setting of concurrent highly morbid complications, such as steroid-refractory GVHD and infection, is critically needed.

The safety of ustekinumab treatment in patients with moderate-to-severe psoriasis and latent tuberculosis infection.

BACKGROUND: Ustekinumab is a monoclonal antibody that targets interleukin (IL)-12/23 p40 to treat psoriasis. The IL-12 pathway is also important in regulating immunity to Mycobacterium tuberculosis. OBJECTIVES: To evaluate the safety of isoniazid (INH) prophylaxis for newly identified latent tuberculosis infection (LTBI) in ustekinumab-treated patients with psoriasis. METHODS: Safety data from 3177 psoriasis patients evaluated across five phase III trials of ustekinumab (45 or 90 mg) conducted in North America, Europe and Asia were analysed. LTBI was diagnosed based on positive tuberculin skin test or QuantiFERON(®) -TB test (Cellestis, Carnegie, Vic., Australia) without evidence of active tuberculosis. RESULTS: At baseline, 101/2898 (3·5%) non-Asian and 66/279 (23·7%) Asian patients were newly identified with LTBI, and all were treated with INH. Through week 12, among patients who received INH, rates of adverse events (AEs) representative of INH toxicity were generally comparable between control and ustekinumab-treated patients, as well as between ustekinumab dose groups. Markedly abnormal alanine transaminase values occurred with comparable incidences between control and ustekinumab-treated patients. The rate of study agent discontinuation due to INH toxicity was low (5/167, 3·0%) and comparable between control and ustekinumab groups through week 12. The rate of INH-related AEs did not increase disproportionately through week 28. No cases of active tuberculosis were reported in patients who received concomitant INH starting at baseline. CONCLUSIONS: Across five trials of ustekinumab-treated patients with psoriasis, no cases of LTBI reactivation were observed in patients receiving concomitant INH prophylaxis for LTBI. INH prophylaxis was generally well tolerated by these patients with psoriasis.