Utility of immunology, microbiology, and helminth investigations in clinical assessment of severe asthma.

OBJECTIVE: Systematic assessment of patients with potential severe asthma is key to identification of treatable traits and optimal management. Assessment of antimicrobial immune function is part of that assessment at many centers although there is little evidence-base on its added value in clinical assessment of this patient group. As part of reviewing our local pathway, we have retrospectively reviewed these tests in 327 consecutive referrals to our severe asthma service, in an evaluation to describe the utility of these tests and allow refinement of the local guideline for patient assessment. METHODS AND RESULTS: Serum immunoglobulin concentrations were in the normal range in most patients though 12 patients had serum IgG < 5.5 g/L and many had suboptimal anti-Haemophilus (127 of 249 patients tested) and anti-Pneumococcal (111 of 239) immune responses. As expected many patients had evidence of sensitization to Aspergillus although specific IgG was not confined to those with evidence of allergic sensitization/allergic bronchopulmonary aspergillosis (ABPA). Eighteen of 277 patients tested had serological evidence of Strongyloides infection. Bacteria and/or yeast were cultured from the sputum in 76 out of 110 patients productive of sputum, and the most common microbes cultured were Candida sp. (44 patients), Staphylococcus aureus (21 patients), Haemophilus influenzae (18 patients). CONCLUSIONS: Many patients had evidence of infection, colonization, or sensitization to potential pathogens relevant to asthma. Strongyloides infection was evident in several patients, which may be a major issue when considering the risk of hyper-infection following immunosuppression and supports our local screening strategy.

Paratesticular rhabdomyosarcoma in children and adolescents-Outcome and patterns of relapse when utilizing a nonsurgical strategy for lymph node staging: Report from the International Society of Paediatric Oncology (SIOP) Malignant Mesenchymal Tumour 89 and 95 studies.

PURPOSE: To report the results from International Society of Pediatric Oncology (SIOP) Malignant Mesenchymal Tumors studies (MMT 89 and 95) of males with nonmetastatic paratesticular rhabdomyosarcoma. METHODS: From 1989 to 2003, 159 patients were included. Radical inguinal orchidectomy was recommended, but retroperitoneal lymph node (LN) assessment was based on imaging alone. The treatment was stratified by stage (SIOP tumor-node-metastasis staging system) and histology. RESULTS: Median age at presentation was 5.6 years (range 0.3-17.6) and 120 patients were of <10 years (75%). Patients ≥10 years had tumors of >5 cm more frequently compared to patients of <10 years (54% vs. 22%, P = 0.0004). The 5- year overall and progression-free survivals were 94% and 83%, respectively. Seventy-eight percent of relapses occurred in the retroperitoneal LN. Thirty-one percent of stage N0 patients of age ≥10 years developed node relapse, compared with 8% of N0 patients aged <10 years (P = 0.0005). CONCLUSIONS: Older patients with paratesticular rhabdomyosarcoma have a significant risk of LN relapse. These results support a surgical approach to LN staging in this subgroup of patients.

Sparing strategy does not compromise prognosis in pediatric localized synovial sarcoma: experience of the International Society of Pediatric Oncology, Malignant Mesenchymal Tumors (SIOP-MMT) Working Group.

BACKGROUND: The aim of this analysis was to identify if the modified indications of radiotherapy (RT) or radical surgery compromised survival in pediatric synovial sarcoma (SS). PROCEDURE: Children with non-metastatic SS, prospectively enrolled in three trials, were analyzed. After primary surgery or biopsy, they received chemotherapy. RT was planned after chemotherapy in patients who had not achieved a complete response (CR). The considered outcome was 5-year overall survival (OS) and event-free survival (EFS). RESULTS: Eighty-eight patients were identified. Primary tumors were mainly located in limbs (66%). The first-line therapy for 65 patients was primary resection. Of the 49 patients who had gross tumor resection, 43 received adjuvant chemotherapy, and 8 had RT. All of the 39 patients with macroscopic residual disease received chemotherapy, then only surgery (n = 12) ± RT (n = 22). The 5-year EFS and OS rates were 68% and 85%, respectively. The TNM stage was a prognostic factor for relapse, whereas primary site of the tumor and TNM stage were prognostic factors for death. CONCLUSIONS: Only 32% of survivors received RT. OS was similar to published data. Omission of RT may be considered in younger children, to limit the potential sequelae in patients with tumors less than 5 cm in size initially submitted to marginal resection. This strategy may also be considered in initially unresected cases, when the tumor is resected at delayed surgery with microscopically free margins, and in patients in complete remission after primary chemotherapy.

Initial seronegative immune-mediated necrotising myopathy with subsequent anti-HMGCR antibody development and response to rituximab: case report.

BACKGROUND: Immune-mediated necrotising myopathy (IMNM) is characterised by severe muscle weakness and necrosis with a paucity of inflammation on muscle biopsy. Around 60% of cases are associated with antibodies to the signal recognition particle (SRP) or 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR); the remainder are seronegative. IMNM is more treatment resistant than inflammatory myopathies. CASE PRESENTATION: A 69-year-old woman with previous statin exposure presented aged 63 with muscle weakness and raised creatinine kinase (CK). Anti-SRP and anti-HMGCR antibodies were not detected, but muscle biopsy revealed changes consistent with necrotising myopathy. Statins were discontinued, and she was treated with prednisolone and methotrexate achieving disease remission. Clinical and biochemical parameters were largely stable until 6 years after diagnosis she experienced a rapid deterioration. This was found to be associated with new development of anti-HMGCR antibody. Rituximab was commenced, resulting rapidly in remission. She has remained in remission since, following 2 cycles of rituximab. CONCLUSIONS: To our knowledge, this is the first reported case of serologically negative IMNM whose subsequent rapid deterioration was associated with development of anti-HMGCR antibody. The response to rituximab and subsequent sustained remission suggests a role for early use of rituximab in aggressive cases of anti-HMGCR myopathy.

The relevance of transdiagnostic shared networks to the severity of symptoms and cognitive deficits in schizophrenia: a multimodal brain imaging fusion study.

Schizophrenia (SZ) is frequently concurrent with substance use, depressive symptoms, social communication and attention deficits. However, the relationship between common brain networks (e.g., SZ vs. substance use, SZ vs. depression, SZ vs. developmental disorders) with SZ on specific symptoms and cognition is unclear. Symptom scores were used as a reference to guide fMRI-sMRI fusion for SZ (n = 94), substance use with drinking (n = 313), smoking (n = 104), major depressive disorder (MDD, n = 260), developmental disorders with autism spectrum disorder (ASD, n = 421) and attention-deficit/hyperactivity disorder (ADHD, n = 244) respectively. Common brain regions were determined by overlapping the symptom-related components between SZ and these other groups. Correlation between the identified common brain regions and cognition/symptoms in an independent SZ dataset (n = 144) was also performed. Results show that (1): substance use was related with cognitive deficits in schizophrenia through gray matter volume (GMV) in anterior cingulate cortex and thalamus; (2) depression was linked to PANSS negative dimensions and reasoning in SZ through a network involving caudate-thalamus-middle/inferior temporal gyrus in GMV; (3) developmental disorders pattern was correlated with poor attention, speed of processing and reasoning in SZ through inferior temporal gyrus in GMV. This study reveals symptom driven transdiagnostic shared networks between SZ and other mental disorders via multi-group data mining, indicating that some potential common underlying brain networks associated with schizophrenia differently with respect to symptoms and cognition. These results have heuristic value and advocate specific approaches to refine available treatment strategies for comorbid conditions in schizophrenia.

Are survival and mortality rates associated with recruitment to clinical trials in teenage and young adult patients with acute lymphoblastic leukaemia? A retrospective observational analysis in England.

OBJECTIVE: Participation rates in clinical trials are low in teenagers and young adults (TYA) with cancer. Whilst the importance of clinical trials in informing best practice is well established, data regarding individual patient benefit are scarce. We have investigated the association between overall survival and trial recruitment in TYA patients with acute lymphoblastic leukaemia (ALL). DESIGN: Retrospective. SETTING: National (England) TYA patients treated for ALL. PARTICIPANTS: 511 patients aged 15-24 years diagnosed with ALL between 2004 and 2010 inclusive, of whom 239 (46.7%) participated in the UKALL2003 trial. OUTCOME MEASURES: Patients were identified using National Clinical Trial (UKALL2003) and Cancer Registry (National Cancer Data Repository, English National Cancer Online Registration Environment) Databases. Relative survival rates were calculated for trial and non-trial patients and observed differences were modelled using a multiple regression approach. The numbers and percentages of deaths in those patients included in the survival analysis were determined for each 3-month period, p values were calculated using the two-tailed z-test for difference between proportions and 95% CIs for percentage deaths were derived using the binomial distribution based on the Wilson Score method. RESULTS: Patients treated on the trial had a 17.9% better 2-year survival (85.4% vs 67.5%, p<0.001) and 8.9% better 1-year survival (90.8% vs 81.9%, p=0.004) than those not on the trial. 35 (14.6%) patients recruited to the trial died in the 2 years following diagnosis compared with 86 (32.6%) of those not recruited (p<0.001). CONCLUSIONS: TYA patients recruited to the clinical trial UKALL 2003 in England had a lower risk of mortality and a higher overall survival than contemporaneous non-trial patients. These data underline the potential for individual patient benefit in participating in a clinical trial and the importance of international efforts to increase trial participation in the TYA age group. TRIAL REGISTRATION NUMBER: ISRCTN07355119.

Hippocampus function predicts severity of post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is often accompanied by memory problems and abnormal brain structure, particularly within the hippocampus. We implemented a cross-species, hippocampal-dependent task--the virtual Morris Water task--to assess hippocampal function in people with PTSD and age-matched controls during functional magnetic resonance imaging (fMRI). Performance on the task was equivalent between the groups. However, when correlating fMRI-derived hippocampal activity during this task with PTSD severity, we observe a -0.84 correlation, indicating that those with reduced hippocampal activity show more severe PTSD symptoms. This correlation is not explained by differences in task performance, IQ, duration since trauma, nor time with PTSD. Hence, PTSD severity is predicted by functionally assessing the hippocampus using the virtual Morris water task, suggesting that this task may be used to identify those at risk for developing PTSD following a trauma.