Nav1.7 as a chondrocyte regulator and therapeutic target for osteoarthritis.

Osteoarthritis (OA) is the most common joint disease. Currently there are no effective methods that simultaneously prevent joint degeneration and reduce pain1. Although limited evidence suggests the existence of voltage-gated sodium channels (VGSCs) in chondrocytes2, their expression and function in chondrocytes and in OA remain essentially unknown. Here we identify Nav1.7 as an OA-associated VGSC and demonstrate that human OA chondrocytes express functional Nav1.7 channels, with a density of 0.1 to 0.15 channels per µm2 and 350 to 525 channels per cell. Serial genetic ablation of Nav1.7 in multiple mouse models demonstrates that Nav1.7 expressed in dorsal root ganglia neurons is involved in pain, whereas Nav1.7 in chondrocytes regulates OA progression. Pharmacological blockade of Nav1.7 with selective or clinically used pan-Nav channel blockers significantly ameliorates the progression of structural joint damage, and reduces OA pain behaviour. Mechanistically, Nav1.7 blockers regulate intracellular Ca2+ signalling and the chondrocyte secretome, which in turn affects chondrocyte biology and OA progression. Identification of Nav1.7 as a novel chondrocyte-expressed, OA-associated channel uncovers a dual target for the development of disease-modifying and non-opioid pain relief treatment for OA.

Antigen identification and high-throughput interaction mapping by reprogramming viral entry.

Deciphering immune recognition is critical for understanding a broad range of diseases and for the development of effective vaccines and immunotherapies. Efforts to do so are limited by a lack of technologies capable of simultaneously capturing the complexity of adaptive immunoreceptor repertoires and the landscape of potential antigens. To address this, we present receptor-antigen pairing by targeted retroviruses, which combines viral pseudotyping and molecular engineering approaches to enable one-pot library-on-library interaction screens by displaying antigens on the surface of lentiviruses and encoding their identity in the viral genome. Antigen-specific viral infection of cell lines expressing human T or B cell receptors allows readout of both antigen and receptor identities via single-cell sequencing. The resulting system is modular, scalable and compatible with any cell type. These techniques provide a suite of tools for targeted viral entry, molecular engineering and interaction screens with broad potential applications.

Primary cutaneous lymphoma: recommendations for clinical trial design and staging update from the ISCL, USCLC, and EORTC.

The number of patients with primary cutaneous lymphoma (PCL) relative to other non-Hodgkin lymphomas (NHLs) is small and the number of subtypes large. Although clinical trial guidelines have been published for mycosis fungoides/Sézary syndrome, the most common type of PCL, none exist for the other PCLs. In addition, staging of the PCLs has been evolving based on new data on potential prognostic factors, diagnosis, and assessment methods of both skin and extracutaneous disease and a desire to align the latter with the Lugano guidelines for all NHLs. The International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous LymphomaConsortium (USCLC), and the Cutaneous Lymphoma Task Force of the European Organization for the Research and Treatment of Cancer (EORTC) now propose updated staging and guidelines for the study design, assessment, endpoints, and response criteria in clinical trials for all the PCLs in alignment with that of the Lugano guidelines. These recommendations provide standardized methodology that should facilitate planning and regulatory approval of new treatments for these lymphomas worldwide, encourage cooperative investigator-initiated trials, and help to assess the comparative efficacy of therapeutic agents tested across sites and studies.

Asian Cohort for Alzheimer's Disease (ACAD) pilot study on genetic and non-genetic risk factors for Alzheimer's disease among Asian Americans and Canadians.

INTRODUCTION: Clinical research in Alzheimer's disease (AD) lacks cohort diversity despite being a global health crisis. The Asian Cohort for Alzheimer's Disease (ACAD) was formed to address underrepresentation of Asians in research, and limited understanding of how genetics and non-genetic/lifestyle factors impact this multi-ethnic population. METHODS: The ACAD started fully recruiting in October 2021 with one central coordination site, eight recruitment sites, and two analysis sites. We developed a comprehensive study protocol for outreach and recruitment, an extensive data collection packet, and a centralized data management system, in English, Chinese, Korean, and Vietnamese. RESULTS: ACAD has recruited 606 participants with an additional 900 expressing interest in enrollment since program inception. DISCUSSION: ACAD's traction indicates the feasibility of recruiting Asians for clinical research to enhance understanding of AD risk factors. ACAD will recruit > 5000 participants to identify genetic and non-genetic/lifestyle AD risk factors, establish blood biomarker levels for AD diagnosis, and facilitate clinical trial readiness. HIGHLIGHTS: The Asian Cohort for Alzheimer's Disease (ACAD) promotes awareness of under-investment in clinical research for Asians. We are recruiting Asian Americans and Canadians for novel insights into Alzheimer's disease. We describe culturally appropriate recruitment strategies and data collection protocol. ACAD addresses challenges of recruitment from heterogeneous Asian subcommunities. We aim to implement a successful recruitment program that enrolls across three Asian subcommunities.

Prevention of human milk-acquired cytomegalovirus infection in very-low-birth-weight infants.

BACKGROUND: The aim of the study was to determine the rate of cytomegalovirus virolactia in the human milk (HM) of mothers of VLBW infants, compare the CMV infection rates and the changes in CMV DNA viral load and nutrient profile among different HM preparation methods. METHODS: A prospective randomized controlled study was performed in infants with gestational age < 32 weeks or birth-weight < 1500 g admitted to neonatal intensive care unit of Asan Medical Center and Haeundae Paik Hospital who were given mother's own milk. Enrolled infants were randomized into three groups according to the HM preparation methods: freezing-thawing (FT), FT + low-temperature Holder pasteurization (FT + LP), and FT + high-temperature short-term pasteurization (FT + HP). Urine CMV culture and PCR were obtained at birth and at 4, 8, and 12 weeks. HM CMV culture and PCR were obtained at birth and at 3, 6, 9, and 12 weeks. Changes in macronutrients in HM was obtained at 4 ~ 6 weeks. RESULTS: Of 564 infants, 217 mothers (38.5%) produced CMV PCR positive milk. After exclusion, a total of 125 infants were randomized into the FT (n = 41), FT + LP (n = 42), and FT + HP (n = 42) groups, whose rate of HM-acquired CMV infection was 4.9% (n = 2), 9.5% (n = 4), and 2.4% (n = 1), respectively. Out of seven CMV infected infants, two infants fed with FT + LP HM developed CMV infection- associated symptoms. Ages at diagnoses were earlier (28.5 days after birth) and at younger post conceptional age (< 32 weeks) in comparison to infants with asymptomatic CMV infection. CMV DNA viral load significantly decreased after pasturizations, especially in FT + HP group. CONCLUSIONS: HM-acquired symptomatic CMV infection rate is low and its impact on clinical course was not serious in our VLBW infants. However, evidences showing poor neurodevelopmental outcome in later life, we need to generate a guideline to protect VLBW infant form HM transmitted CMV infection. Based on our small sized study, we did not find any superiority in pasteurizing HM with frequently used LP in comparison to frozen or HP HM. More research is needed to determine the method and duration of pasteurization to reduce the HM-acquired CMV infection.

Natural language processing of admission notes to predict severe maternal morbidity during the delivery encounter.

BACKGROUND: Severe maternal morbidity and mortality remain public health priorities in the United States, given their high rates relative to other high-income countries and the notable racial and ethnic disparities that exist. In general, accurate risk stratification methods are needed to help patients, providers, hospitals, and health systems plan for and potentially avert adverse outcomes. OBJECTIVE: Our objective was to understand if machine learning methods with natural language processing of history and physical notes could identify a group of patients at high risk of maternal morbidity on admission for delivery without relying on any additional patient information (eg, demographics and diagnosis codes). STUDY DESIGN: This was a retrospective study of people admitted for delivery at 2 hospitals (hospitals A and B) in a single healthcare system between July 1, 2016, and June 30, 2020. The primary outcome was severe maternal morbidity, as defined by the Centers for Disease Control and Prevention; furthermore, we examined nontransfusion severe maternal morbidity. Clinician documents designated as history and physical notes were extracted from the electronic health record for processing and analysis. A bag-of-words approach was used for this natural language processing analysis (ie, each history or physical note was converted into a matrix of counts of individual words (or phrases) that occurred within the document). The least absolute shrinkage and selection operator models were used to generate prediction probabilities for severe maternal morbidity and nontransfusion severe maternal morbidity for each note. Model discrimination was assessed via the area under the receiver operating curve. Discrimination was compared between models using the DeLong test. Calibration plots were generated to assess model calibration. Moreover, the natural language processing models with history and physical note texts were compared with validated obstetrical comorbidity risk scores based on diagnosis codes. RESULTS: There were 13,572 delivery encounters with history and physical notes from hospital A, split between training (Atrain, n=10,250) and testing (Atest, n=3,322) datasets for model derivation and internal validation. There were 23,397 delivery encounters with history and physical notes from hospital B (Bvalid) used for external validation. For the outcome of severe maternal morbidity, the natural language processing model had an area under the receiver operating curve of 0.67 (95% confidence interval, 0.63-0.72) and 0.72 (95% confidence interval, 0.70-0.74) in the Atest and Bvalid datasets, respectively. For the outcome of nontransfusion severe maternal morbidity, the area under the receiver operating curve was 0.72 (95% confidence interval, 0.65-0.80) and 0.76 (95% confidence interval, 0.73-0.79) in the Atest and Bvalid datasets, respectively. The calibration plots demonstrated the bag-of-words model's ability to distinguish a group of individuals at a substantially higher risk of severe maternal morbidity and nontransfusion severe maternal morbidity, notably those in the top deciles of predicted risk. Areas under the receiver operating curve in the natural language processing-based models were similar to those generated using a validated, retrospectively derived, diagnosis code-based comorbidity score. CONCLUSION: In this practical application of machine learning, we demonstrated the capabilities of natural language processing for the prediction of severe maternal morbidity based on provider documentation inherently generated at the time of admission. This work should serve as a catalyst for providers, hospitals, and electronic health record systems to explore ways that artificial intelligence can be incorporated into clinical practice and evaluated rigorously for their ability to improve health.

Management of relapsed cutaneous T-Cell lymphoma following allogeneic hematopoietic stem cell transplantation: Review with representative patient case.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment option for patients with refractory cutaneous T-cell lymphoma (CTCL) through replacement of the bone marrow responsible for lymphoma cells and possibly induction of a graft-versus-lymphoma effect. However, allo-HSCT is not always curative; relapse of CTCL occurs in about half of patients post-transplant. Treatment of relapsed CTCL after allo-HSCT is challenging because post-transplant patients are at high risk of graft-versus-host disease, and this condition may be precipitated or exacerbated by standard CTCL therapies. The benefit of each potential therapy must therefore be weighed against its risk of graft versus host disease (GVHD). In this article, we review the management of relapsed CTCL after allo-HSCT. We begin with an exemplative patient whose relapsed Sezary syndrome was successfully treated without development of GVHD. We also report high-throughput T-cell receptor sequencing data obtained during the patient's disease relapse and remission. We then review general guidelines for management of relapsed CTCL and summarize all reported cases and outcomes of relapsed CTCL after transplant. We conclude by reviewing the current CTCL therapies and their risk of GVHD.

Prenatal prognostic factors for isolated right congenital diaphragmatic hernia: a single center's experience.

BACKGROUND: Right-sided congenital diaphragmatic hernia (RCDH) is relatively rare compared with left-sided congenital diaphragmatic hernia (LCDH). Clinical data of RCDH, especially with respect to antenatal prediction of neonatal outcome, are lacking. The aim of this study was to report the treatment outcomes of patients with antenatally diagnosed RCDH and to evaluate the predictability of observed-to-expected lung area-to-head circumference ratio (O/E LHR) for perinatal outcomes, focused on mortality or extracorporeal membrane oxygenation (ECMO) requirement. METHODS: We retrospectively reviewed the medical records of newborn infants with isolated RCDH. We analyzed and compared the clinical and prenatal characteristics including the fetal lung volume, which was measured as the O/E LHR, between the survivors and the non-survivors. RESULTS: A total of 26 (66.7%) of 39 patients with isolated RCDH survived to discharge. The O/E LHR was significantly greater in survivors (64.7 ± 21.2) than in non-survivors (40.5 ± 23.4) (P =.027). It was greater in survivors without ECMO requirement (68.3 ± 15.1) than non-survivors or those with ECMO requirement (46.3 ± 19.4; P = .010). The best O/E LHR cut-off value for predicting mortality in isolated RCDH was 50. CONCLUSIONS: The findings in this study suggest that O/E LHR, a well-characterized prognostic indicator in LCDH, could be applied to a fetus with antenatally diagnosed RCDH. A large cohort study is required to verify the association between O/E LHR values and the graded severity of RCDH.

Functional and structural evaluation in the lungs of children with repaired congenital diaphragmatic hernia.

BACKGROUND: To evaluate the long-term functional and structural pulmonary development in children with repaired congenital diaphragmatic hernia (CDH) and to identify the associated perinatal-neonatal risk factors. METHODS: Children with repaired CDH through corrective surgery who were born at gestational age ≥ 35 weeks were included in this analysis. Those who were followed for at least 5 years were subjected to spirometry and chest computed tomography for evaluation of their functional and structural growth. Main bronchus diameters and lung volumes (total, left/right) were measured. According to total lung volume (TLV) relative to body surface area, children were grouped into TLV ≥ 50 group and TLV < 50 group and the associations with perinatal-neonatal factors were analyzed. RESULTS: Of the 28 children (mean age, 6.2 ± 0.2 years) with left-sided CDH, 7 (25%) had abnormal pulmonary function, of whom 6 (87%) showed restrictive patterns. All pulmonary functions except FEF25-75% were worse than those in matched healthy control group. Worse pulmonary function was significantly associated with small head and abdominal circumferences at birth. The mean TLV was 1339.1 ± 363.9 mL and LLV/TLV was 47.9 ± 2.5 mL. Children with abnormal pulmonary function were more likely to have smaller lung volumes. In multivariate analysis, abdominal circumference at birth was significantly associated with abnormal lung volume. CONCLUSIONS: A quarter of children with repaired CDH showed abnormal pulmonary function. Small abdominal circumference at birth was associated with abnormal pulmonary function and lower TLV. .

Survival and Morbidities in Infants with Birth Weight Less than 500 g: a Nationwide Cohort Study.

BACKGROUND: This study aimed to investigate the survival and morbidities of infants in the Korean Neonatal Network (KNN) with birth weight (BW) < 500 g. METHODS: The demographic and clinical data of 208 live-born infants with a BW < 500 g at a gestational age of ≥ 22 weeks who were treated in the neonatal intensive care units of the KNN between 2013 and 2017 were reviewed. RESULTS: The survival rate of the infants was 28%, with a median gestational age and BW of 243/7 weeks (range, 220/7-336/7) and 440 g (range, 220-499), respectively. Multivariable Cox proportional hazards analysis demonstrated that survival to discharge was associated with longer gestation, higher BW, female sex, singleton gestation, use of any antenatal corticosteroids, and higher Apgar scores at 5 minutes. The overall survival rates were significantly different between the BW categories of < 400 g and 400-499 g. However, there was no significant difference in the incidence of any morbidity between the BW groups. Half of the deaths of infants with BW < 500 g occurred within a week of life, mainly due to cardiopulmonary and neurologic causes. The major causes of death in infants after 1 week of age were infection and gastrointestinal disease. Among the surviving infants, 79% had moderate to severe bronchopulmonary dysplasia, 21% underwent surgical ligation of patent ductus arteriosus, 12% had severe intraventricular hemorrhage (grade III-IV), 38% had sepsis, 9% had necrotizing enterocolitis (stage ≥ 2), and 47% underwent laser treatment for retinopathy of prematurity. The median length of hospital stay was 132 days (range, 69-291), and 53% required assistive devices at discharge. CONCLUSION: Despite recent advances in neonatal intensive care, the survival and morbidity rates of infants with BW < 500 g need further improvement.

The cost trajectory of the diagnostic care pathway for children with suspected genetic disorders.

PURPOSE: This study describes the cost trajectory of the standard diagnostic care pathway for children with suspected genetic disorders in British Columbia, Canada. METHODS: Average annual per-patient costs were estimated using medical records review and a caregiver survey for a cohort of 498 children referred to BC Children's and Women's Hospitals (C&W) with unexplained intellectual disability (the TIDE-BC study) and families enrolled in the CAUSES study, which offered diagnostic genome-wide sequencing (GWS; exome and genome sequencing) to 500 families of children with suspected genetic disorders. RESULTS: Direct costs peaked in the first year of patients' diagnostic odyssey, with an average of C$2257 per patient (95% confidence interval [CI] C$2074, C$2441) for diagnostic testing and C$631 (95% CI C$543, C$727) for specialist consultations at C&W. In subsequent years, direct costs accrued at a constant rate, with an estimated annual per-patient cost of C$511 (95% CI C$473, C$551) for diagnostic testing and C$334 (95% CI C$295, C$369) for consultations at C&W. Travel costs and caregiver productivity loss associated with attending diagnosis-related physician appointments averaged C$1907/family/year. CONCLUSIONS: The continuing long-term accrual of costs by undiagnosed patients suggests that economic evaluations of diagnostic GWS services should use longer time horizons than have typically been used.

Neonatal exchange transfusion: Experience in Korea.

BACKGROUND: Exchange transfusion (ET) is an established, efficacious, and reliable practice for severe neonatal hyperbilirubinemia, hemolytic disease of the newborn, and neonatal sepsis. This study assessed the indications and clinical outcomes of ET performed in a tertiary hospital in Korea. MATERIALS AND METHODS: We studied 64 ET sessions performed on 23 neonates between March 1999 and March 2018. ET was performed based on estimated double volume exchange transfusion using fresh red blood cells and fresh frozen plasma. Patients' clinical information, including demographic data and ET indication, and laboratory data were collected pre- and post-ET. RESULTS: The most common ET indication was hyperbilirubinemia with hemolytic anemia due to non-ABO maternal blood group discrepancies. In three preterm babies, ETs were performed for severe anemia, leukocytosis, and hyperkalemia cases. Before ET, the patients showed slightly high WBC counts, low hemoglobin levels, and low platelet counts. After ET, blood examination revealed normal WBC counts, increased hemoglobin levels, and decreased platelet counts (all P < 0.001). Bilirubin levels decreased immediately after ET (P < 0.001). Electrolyte and C-reactive protein levels showed no significant changes after ETs. Adverse events occurred in 11 (47.8 %) patients; the most common were hypoxemia and hypotension. One infant experienced cardiorespiratory arrest due to hypercalcemia and was successfully resuscitated. No one died within 24 h of ET. However, five infants showed hyperbilirubinemia aggravation. CONCLUSIONS: ET is an effective treatment modality for leukocytosis and hyperbilirubinemia with low mortality but involves common adverse events post-ET. This report provides an overview of current ET practices in Korea.

Challenges of acute peritoneal dialysis in extremely-low-birth-weight infants: a retrospective cohort study.

BACKGROUND: Peritoneal dialysis (PD) has been used occasionally in extremely-low-birth-weight (ELBW) infants with acute kidney injury (AKI). This study aimed to evaluate the clinical characteristics and outcomes of ELBW infants with AKI treated with PD. METHODS: In this retrospective cohort study, the medical records of ELBW infants with AKI, who underwent PD from January 2008 to February 2018, were reviewed. A PD catheter (7.5-9.0 Fr) or central venous catheter (4 Fr) was used for the peritoneal access. Treatment with PD solutions (2.5 or 4.25%) was started at 10 mL/kg, which was increased to 20-30 mL/kg for 60-120 min/cycle continuing for 24 h. RESULTS: Twelve ELBW infants (seven male and five female infants) were treated, and their mean (±SD) gestational age and birth weight were 27.2 (±3.3) weeks and 706.5 (±220.5) g, respectively. Two patients had severe perinatal asphyxia (5-min Apgar score ≤ 3). The most important indication for starting PD was AKI due to sepsis. The average (±SD) duration of PD was 9.4 (± 7.7) days. The potassium levels in the ELBW infants with hyperkalemia decreased from 6.8 to 5.0 mg/mL after 9.3 (± 4.4) days. The most common complication of PD was mechanical dysfunction of the catheters, such as dialysate leakage (75%). Two patients were successful weaned off PD. The mortality rate of the infants treated with PD was 91.7%. CONCLUSIONS: In this series, the mortality rate of ELBW infants with AKI treated with PD was relatively high because of their incompletely developed organ systems. Therefore, the use of PD should be carefully considered for the treatment of ELBW infants with AKI in terms of decisions regarding resuscitation.

Prenatal sonographic markers of the outcome in fetuses with bronchopulmonary sequestration.

PURPOSE: To evaluate the prenatal sonographic predictive markers of the outcome in fetuses with bronchopulmonary sequestration (BPS). METHODS: BPS size and diameter of the feeding artery (FA) were measured prenatally and postnatally. Velocity of the FA and the left ventricular-modified myocardial performance index (LV mod-MPI) were also evaluated prenatally. RESULTS: Forty-seven women were included in the study. Mean gestational age, mass size, diameter and velocity of the FA, and LV mod-MPI at prenatal diagnosis were 23.5 ± 2.2 weeks, 3.6 ± 8.3 cm, 2.3 ± 0.6 mm, 46.6 ± 15.4 cm/s, and 0.46 ± 0.06, respectively. Mean mass diameter and FA diameter measured on postnatal CT examinations were 3.8 ± 1.0 cm and 2.3 ± 0.7 mm, respectively. Five patients had respiratory symptoms after birth. Twenty children (43%) underwent or were scheduled to undergo mass excision, and the remaining 27 (57%) were doing well without any intervention. There was no neonatal death. LV mod-MPI at diagnosis, the FA diameter after birth and the serial change in the FA size were significantly associated with postnatal mass excision. CONCLUSION: The FA diameter and LV mod-MPI may be additional markers for predicting whether fetuses with BPS should undergo mass excision in early childhood or conservative care.

Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): an international, open-label, randomised, controlled phase 3 trial.

BACKGROUND: Cutaneous T-cell lymphomas are rare non-Hodgkin lymphomas with substantial morbidity and mortality in advanced disease stages. We compared the efficacy of mogamulizumab, a novel monoclonal antibody directed against C-C chemokine receptor 4, with vorinostat in patients with previously treated cutaneous T-cell lymphoma. METHODS: In this open-label, international, phase 3, randomised controlled trial, we recruited patients with relapsed or refractory mycosis fungoides or Sézary syndrome at 61 medical centres in the USA, Denmark, France, Italy, Germany, the Netherlands, Spain, Switzerland, the UK, Japan, and Australia. Eligible patients were aged at least 18 years (in Japan, ≥20 years), had failed (for progression or toxicity as assessed by the principal investigator) at least one previous systemic therapy, and had an Eastern Cooperative Oncology Group performance score of 1 or less and adequate haematological, hepatic, and renal function. Patients were randomly assigned (1:1) using an interactive voice web response system to mogamulizumab (1·0 mg/kg intravenously on a weekly basis for the first 28-day cycle, then on days 1 and 15 of subsequent cycles) or vorinostat (400 mg daily). Stratification was by cutaneous T-cell lymphoma subtype (mycosis fungoides vs Sézary syndrome) and disease stage (IB-II vs III-IV). Since this study was open label, patients and investigators were not masked to treatment assignment. The primary endpoint was progression-free survival by investigator assessment in the intention-to-treat population. Patients who received one or more doses of study drug were included in the safety analyses. This study is ongoing, and enrolment is complete. This trial was registered with ClinicalTrials.gov, number NCT01728805. FINDINGS: Between Dec 12, 2012, and Jan 29, 2016, 372 eligible patients were randomly assigned to receive mogamulizumab (n=186) or vorinostat (n=186), comprising the intention-to-treat population. Two patients randomly assigned to mogamulizumab withdrew consent before receiving study treatment; thus, 370 patients were included in the safety population. Mogamulizumab therapy resulted in superior investigator-assessed progression-free survival compared with vorinostat therapy (median 7·7 months [95% CI 5·7-10·3] in the mogamulizumab group vs 3·1 months [2·9-4·1] in the vorinostat group; hazard ratio 0·53, 95% CI 0·41-0·69; stratified log-rank p<0·0001). Grade 3-4 adverse events of any cause were reported in 75 (41%) of 184 patients in the mogamulizumab group and 76 (41%) of 186 patients in the vorinostat group. The most common serious adverse events of any cause were pyrexia in eight (4%) patients and cellulitis in five (3%) patients in the mogamulizumab group; and cellulitis in six (3%) patients, pulmonary embolism in six (3%) patients, and sepsis in five (3%) patients in the vorinostat group. Two (67%) of three on-treatment deaths with mogamulizumab (due to sepsis and polymyositis) and three (33%) of nine on-treatment deaths with vorinostat (two due to pulmonary embolism and one due to bronchopneumonia) were considered treatment-related. INTERPRETATION: Mogamulizumab significantly prolonged progression-free survival compared with vorinostat, and could provide a new, effective treatment for patients with mycosis fungoides and, importantly, for Sézary syndrome, a subtype that represents a major therapeutic challenge in cutaneous T-cell lymphoma. FUNDING: Kyowa Kirin.

National Registry Data from Korean Neonatal Network: Two-Year Outcomes of Korean Very Low Birth Weight Infants Born in 2013-2014.

BACKGROUND: The aim of this study was to observe long-term outcomes of very low birth weight infants (VLBWIs) born between 2013 and 2014 in Korea, especially focusing on neurodevelopmental outcomes. METHODS: The data were collected from Korean Neonatal Network (KNN) registry from 43 and 54 participating units in 2013 and 2014, respectively. A standardized electronic case report form containing 30 items related to long-term follow up was used after data validation. RESULTS: Of 2,660 VLBWI, the mean gestational age and birth weight were 291/7 ± 26/7 weeks and 1,093 ± 268 g in 2013 and 292/7 ± 26/7 weeks and 1,125 ± 261 g in 2014, respectively. The post-discharge mortality rate was 1.2%-1.5%. Weight < 50th percentile was 46.5% in 2013 and 66.1% in 2014. The overall prevalence of cerebral palsy among the follow up infants was 6.2% in 2013 and 6.6% in 2014. The Bayley Scales of Infant Developmental Outcomes version II showed 14%-25% of infants had developmental delay and 3%-8% of infants in Bayley version III. For the Korean developmental screening test for infants and children, the area "Further evaluation needed" was 5%-12%. Blindness in both eyes was reported to be 0.2%-0.3%. For hearing impairment, 0.8%-1.9% showed bilateral hearing loss. Almost 50% were readmitted to hospital with respiratory illness as a leading cause. CONCLUSION: The overall prevalence of long-term outcomes was not largely different among the VLBWI born between 2013 and 2014. This study is the first large national data study of long-term outcomes.

Primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphomas: reappraisal of a provisional entity in the 2016 WHO classification of cutaneous lymphomas.

Primary cutaneous CD8-positive aggressive epidermotropic T-cell lymphoma is a rare and poorly characterized variant of cutaneous lymphoma still considered a provisional entity in the latest 2016 World Health Organization Classification of Cutaneous lymphomas. We sought to better characterize and provide diagnostic and therapeutic guidance of this rare cutaneous lymphoma. Thirty-four patients with a median age of 77 years (range 19-89 years) presented primarily with extensive annular necrotic plaques or tumor lesions with frequent mucous membrane involvement. The 5-year survival was 32% with a median survival of 12 months. A subset of 17 patients had a prodrome of chronic patches prior to the development of aggressive ulcerative lesions. We identified cases with lack of CD8 or αß T-cell receptor expression yet with similar clinical and pathological presentation. Allogeneic stem cell transplantation provided partial or complete remissions in 5/6 patients. We recommend the term primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphoma as this more broad designation better describes this clinical-pathologic presentation, which allows the inclusion of cases with CD8 negative and/or αß/γδ T-cell receptor chain double-positive or double-negative expression. We have identified early skin signs of chronic patch/plaque lesions that are often misdiagnosed as eczema, psoriasis, or mycosis fungoides. Our experience confirms the poor prognosis of this entity and highlights the inefficacy of our standard therapies with the exception of allogeneic stem cell transplantation in selected cases.

Topical resiquimod can induce disease regression and enhance T-cell effector functions in cutaneous T-cell lymphoma.

Early-stage cutaneous T-cell lymphoma (CTCL) is a skin-limited lymphoma with no cure aside from stem cell transplantation. Twelve patients with stage IA-IIA CTCL were treated in a phase 1 trial of 0.03% and 0.06% topical resiquimod gel, a Toll-like receptor 7/8 agonist. Treated lesions significantly improved in 75% of patients and 30% had clearing of all treated lesions. Resiquimod also induced regression of untreated lesions. Ninety-two percent of patients had more than a 50% improvement in body surface area involvement by the modified Severity-Weighted Assessment Tool analysis and 2 patients experienced complete clearing of disease. Four of 5 patients with folliculotropic disease also improved significantly. Adverse effects were minor and largely skin limited. T-cell receptor sequencing and flow cytometry studies of T cells from treated lesions demonstrated decreased clonal malignant T cells in 90% of patients and complete eradication of malignant T cells in 30%. High responses were associated with recruitment and expansion of benign T-cell clones in treated skin, increased skin T-cell effector functions, and a trend toward increased natural killer cell functions. In patients with complete or near eradication of malignant T cells, residual clinical inflammation was associated with cytokine production by benign T cells. Fifty percent of patients had increased activation of circulating dendritic cells, consistent with a systemic response to therapy. In summary, topical resiquimod is safe and effective in early-stage CTCL and the first topical therapy to our knowledge that can induce clearance of untreated lesions and complete remissions in some patients. This trial was registered at www.clinicaltrials.gov as #NCT813320.

Extralobar pulmonary sequestration in neonates: The natural course and predictive factors associated with spontaneous regression.

PURPOSE: To describe the natural course of extralobar pulmonary sequestration (EPS) and identify factors associated with spontaneous regression of EPS. MATERIALS AND METHODS: We retrospectively searched for patients diagnosed with EPS on initial contrast CT scan within 1 month after birth and had a follow-up CT scan without treatment. Spontaneous regression of EPS was assessed by percentage decrease in volume (PDV) and percentage decrease in sum of the diameter of systemic feeding arteries (PDD) by comparing initial and follow-up CT scans. Clinical and CT features were analysed to determine factors associated with PDV and PDD rates. RESULTS: Fifty-one neonates were included. The cumulative proportions of patients reaching PDV > 50 % and PDD > 50 % were 93.0 % and 73.3 % at 4 years, respectively. Tissue attenuation was significantly associated with PDV rate (B = -21.78, P < .001). The tissue attenuation (B = -22.62, P = .001) and diameter of the largest systemic feeding arteries (B = -48.31, P = .011) were significant factors associated with PDD rate. CONCLUSION: The volume and diameter of systemic feeding arteries of EPS spontaneously decreased within 4 years without treatment. EPSs showing a low tissue attenuation and small diameter of the largest systemic feeding arteries on initial contrast-enhanced CT scans were likely to regress spontaneously. KEY POINTS: • Extralobar pulmonary sequestration (EPS) could show spontaneous regression. • Initial CT features may predict spontaneous regression of EPS. • The tissue attenuation and diameter of systemic feeding artery are important factors.