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SummaryNon‐Hodgkin lymphoma (NHL) is the third most common malignancy in children, adolescents and young adults (CAYA). NHL is a diverse set of diseases that arise at key regulatory checkpoints during B or T cell development in the bone marrow, germinal centre or thymus. While advances in the use of conventional cytotoxic agents have led to dramatic improvements in survival, these cures are associated with significant acute and long‐term toxicities. Moreover, the prognosis for CAYA patients with relapsed or refractory NHL remains dismal, with the vast majority dying of their disease. Thanks to a large number of candidate‐based biological studies, together with large‐scale sequencing efforts, there has been an explosion of knowledge regarding the molecular pathophysiology of B‐ and T‐NHL. This has ushered development of a flurry of novel therapeutic approaches that may simultaneously provide new hope for relapsed patients and an opportunity to reduce the therapeutic burden in newly diagnosed CAYA. Here we review a selection of the most promising new therapeutic approaches to these diseases. While the vast majority of these agents are untested in children, on‐going work from many cooperative groups will soon explore their use in paediatric disease, in hope of further improving outcomes while maximizing quality of life.

Hypothermia/rewarming (H/R) is poorly tolerated by the myocardium; however, the underlying intracellular basis of H/R-induced cardiac dysfunction remains elusive. We hypothesized that in cardiomyocytes, H/R disrupts excitation-contraction coupling by reducing myofilament Ca2+sensitivity due to an increase in cardiac troponin I (cTnI) phosphorylation. To test this hypothesis, isolated rat cardiomyocytes (13–15 cells from 6 rats per group) were electrically stimulated to evoke both cytosolic Ca2+([Ca2+]cyto) and contractile (sarcomere shortening) responses that were simultaneously measured using an IonOptix system. Cardiomyocytes were divided into two groups: 1) those exposed to hypothermia (15°C for 2 h) followed by rewarming (35°C; H/R); or 2) time-matched normothermic (35°C) controls (CTL). Contractile dysfunction after H/R was indicated by reduced velocity and extent of sarcomere length (SL) shortening compared with time-matched controls. Throughout hypothermia, basal [Ca2+]cytoincreased and the duration of evoked [Ca2+]cytotransients was prolonged. Phase-loop plots of [Ca2+]cytovs. contraction were shifted rightward in cardiomyocytes during hypothermia compared with CTL, indicating a decrease in Ca2+sensitivity. Using Western blot, we found that H/R increases cTnI phosphorylation. These results support our overall hypothesis and suggest that H/R disrupts excitation-contraction coupling of cardiomyocytes due to increased cTnI phosphorylation and reduced Ca2+sensitivity.Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/hypothermiarewarming-disrupts-e-c-coupling/ .

Although the occurrence of sudden cardiac death (SCD) in a young person is a rare event, it is traumatic and often widely publicized. In recent years, SCD in this population has been increasingly seen as a public health and safety issue. This review presents current knowledge relevant to the epidemiology of SCD and to strategies for prevention, resuscitation, and identification of those at greatest risk. Areas of active research and controversy include the development of best practices in screening, risk stratification approaches and postmortem evaluation, and identification of modifiable barriers to providing better outcomes after resuscitation of young SCD patients. Institution of a national registry of SCD in the young will provide data that will help to answer these questions.

AbstractObjective:To develop clinical practice guidelines for the management of patients with primary aldosteronism.Participants:The Task Force included a chair, selected by the Clinical Guidelines Subcommittee of the Endocrine Society, six additional experts, a methodologist, and a medical writer. The guideline was cosponsored by American Heart Association, American Association of Endocrine Surgeons, European Society of Endocrinology, European Society of Hypertension, International Association of Endocrine Surgeons, International Society of Endocrinology, International Society of Hypertension, Japan Endocrine Society, and The Japanese Society of Hypertension. The Task Force received no corporate funding or remuneration.Evidence:We searched for systematic reviews and primary studies to formulate the key treatment and prevention recommendations. We used the Grading of Recommendations, Assessment, Development, and Evaluation group criteria to describe both the quality of evidence and the strength of recommendations. We used “recommend” for strong recommendations and “suggest” for weak recommendations.Consensus Process:We achieved consensus by collecting the best available evidence and conducting one group meeting, several conference calls, and multiple e-mail communications. With the help of a medical writer, the Endocrine Society's Clinical Guidelines Subcommittee, Clinical Affairs Core Committee, and Council successfully reviewed the drafts prepared by the Task Force. We placed the version approved by the Clinical Guidelines Subcommittee and Clinical Affairs Core Committee on the Endocrine Society's website for comments by members. At each stage of review, the Task Force received written comments and incorporated necessary changes.Conclusions:For high-risk groups of hypertensive patients and those with hypokalemia, we recommend case detection of primary aldosteronism by determining the aldosterone-renin ratio under standard conditions and recommend that a commonly used confirmatory test should confirm/exclude the condition. We recommend that all patients with primary aldosteronism undergo adrenal computed tomography as the initial study in subtype testing and to exclude adrenocortical carcinoma. We recommend that an experienced radiologist should establish/exclude unilateral primary aldosteronism using bilateral adrenal venous sampling, and if confirmed, this should optimally be treated by laparoscopic adrenalectomy. We recommend that patients with bilateral adrenal hyperplasia or those unsuitable for surgery should be treated primarily with a mineralocorticoid receptor antagonist.

AbstractBackgroundThe optimal treatment for respiratory syncytial virus (RSV) infection in adult immunocompromised patients is unknown. We assessed the management of RSV and other non‐influenza respiratory viruses in Midwestern transplant centers.MethodsA survey assessing strategies for RSV and other non‐influenza respiratory viral infections was sent to 13 centers.ResultsMultiplex polymerase chain reaction assay was used for diagnosis in 11/12 centers. Eight of 12 centers used inhaled ribavirin (RBV) in some patient populations. Barriers included cost, safety, lack of evidence, and inconvenience. Six of 12 used intravenous immunoglobulin (IVIG), mostly in combination with RBV. Inhaled RBV was used more than oral, and in the post‐stem cell transplant population, patients with lower respiratory tract infection (LRTI), graft‐versus‐host disease, and more recent transplantation were treated at higher rates. Ten centers had experience with lung transplant patients; all used either oral or inhaled RBV for LRTI, 6/10 treated upper respiratory tract infection (URTI). No center treated non‐lung solid organ transplant (SOT) recipients with URTI; 7/11 would use oral or inhaled RBV in the same group with LRTI. Patients with hematologic malignancy without hematopoietic stem cell transplantation were treated with RBV at a similar frequency to non‐lung SOT recipients. Three of 12 centers, in severe cases, treated parainfluenza and metapneumovirus, and 1/12 treated coronavirus.ConclusionsTreatment of RSV in immunocompromised patients varied greatly. While most centers treat LRTI, treatment of URTI was variable. No consensus was found regarding the use of oral versus inhaled RBV, or the use of IVIG. The presence of such heterogeneity demonstrates the need for further studies defining optimal treatment of RSV in immunocompromised hosts.

AbstractAimSurgery aims to prevent cancer‐related morbidity for patients with ulcerative colitis (UC) associated dysplasia. The literature varies widely regarding the likelihood of dysplastic progression to higher grades of dysplasia or cancer. The aim of this study was to characterize the likelihood of the development of colorectal cancer (CRC) of patients with UC‐associated dysplasia who chose to defer surgery.MethodA retrospective review was carried out of patients undergoing surgery for UC at the Mayo Clinic, who were diagnosed to have dysplasia between August 1993 and July 2012. The relationships between grade of dysplasia, time to surgery and the detection of unsuspected carcinoma were investigated.ResultsIn all, 175 patients underwent surgery at a median of 4.9 (interquartile range 2.5–8.9) months after a diagnosis of dysplasia. Their median age was 52 (interquartile range 43−59) years. An initial diagnosis of indeterminate dysplasia was not associated with CRC [0/23; 17.7 (8.1−29.6) months]. Thirty‐six patients who had an initial diagnosis of dysplasia progressed from indeterminate to low‐grade dysplasia [24.2 (11.0−30.4) months]. Low‐grade dysplasia was associated with a 2% (1/56; T2N0M0) risk of CRC when present in random surveillance biopsies and a 3% (2/61; T1N0M0, T4N0M0) risk if detected in endoscopically visible lesions [7.4 (5.2−33.3) months]. Eighteen patients progressed from indeterminate to high‐grade dysplasia [19.1 (9.2−133.9) months]. Seventeen patients progressed from low to high‐grade dysplasia [11.0 (5.8−30.1) months]. None of the patients with high‐grade dysplasia (0/35) progressed to CRC [4.5 (1.7−9.9) months].ConclusionDysplasia was associated with a low incidence of node negative CRC if surgery was deferred for up to 5 years. These findings may help inform the decision‐making process for asymptomatic patients who are having to decide between intensive surveillance or surgery for UC‐associated dysplasia.

BACKGROUNDThe objective of the current study was to establish a process for validating immunohistochemistry (IHC) protocols for use on the Cellient cell block (CCB) system.METHODSThirty antibodies were initially tested on CCBs using IHC protocols previously validated on formalin‐fixed, paraffin‐embedded tissue (FFPE). Cytology samples were split to generate thrombin cell blocks (TCB) and CCBs. IHC was performed in parallel. Antibody immunoreactivity was scored, and concordance or discordance in immunoreactivity between the TCBs and CCBs for each sample was determined. Criteria for validation of an antibody were defined as concordant staining in expected positive and negative cells, in at least 5 samples each, and concordance in at least 90% of the samples total. Antibodies that failed initial validation were retested after alterations in IHC conditions.RESULTSThirteen of the 30 antibodies (43%) did not meet initial validation criteria. Of those, 8 antibodies (calretinin, clusters of differentiation [CD] 3, CD20, CDX2, cytokeratin 20, estrogen receptor, MOC‐31, and p16) were optimized for CCBs and subsequently validated. Despite several alterations in conditions, 3 antibodies (Ber‐EP4, D2‐40, and paired box gene 8 [PAX8]) were not successfully validated.CONCLUSIONSNearly one‐half of the antibodies tested in the current study failed initial validation using IHC conditions that were established in the study laboratory for FFPE material. Although some antibodies subsequently met validation criteria after optimization of conditions, a few continued to demonstrate inadequate immunoreactivity. These findings emphasize the importance of validating IHC protocols for methanol‐fixed tissue before clinical use and suggest that optimization for alcohol fixation may be needed to obtain adequate immunoreactivity on CCBs. Cancer (Cancer Cytopathol) 2016;124:89‐99. © 2016 American Cancer Society.