Checkpoint-blocker-induced autoimmunity is associated with favourable outcome in metastatic melanoma and distinct T-cell expression profiles

Background Immune checkpoint blockers (ICBs) activate CD8⁺ T cells, eliciting both anti-cancer activity and immune-related adverse events (irAEs). The relationship of irAEs with baseline parameters and clinical outcome is unclear.Methods Retrospective evaluation of irAEs on survival was performed across primary (N = 144) and secondary (N = 211) independent cohorts of patients with metastatic melanoma receiving single agent (pembrolizumab/nivolumab—sICB) or combination (nivolumab and ipilimumab—cICB) checkpoint blockade. RNA from pre-treatment and post-treatment CD8⁺ T cells was sequenced and differential gene expression according to irAE development assessed.Results 58.3% of patients developed early irAEs and this was associated with longer progression-free (PFS) and overall survival (OS) across both cohorts (log-rank test, OS: P < 0.0001). Median survival for patients without irAEs was 16.6 months (95% CI: 10.9–33.4) versus not-reached (P = 2.8 × 10⁻⁶). Pre-treatment monocyte and neutrophil counts, but not BMI, were additional predictors of clinical outcome. Differential expression of numerous gene pathway members was observed in CD8⁺ T cells according to irAE development, and patients not developing irAEs demonstrating upregulated CXCR1 pre- and post-treatment.Conclusions Early irAE development post-ICB is associated with favourable survival in MM. Development of irAEs is coupled to expression of numerous gene pathways, suggesting irAE development in-part reflects baseline immune activation.Subject terms: Immunotherapy, Melanoma     

Single parent women

Summary While there has been considerable interest in the problems of single parent families, no study has yet determined if the problems are due to increased risk of specific psychiatric disorders in single parents as compared to their married counterparts. Data collected as part of the National Institute of Mental Health Epidemiologic Catchment Area (ECA) Project are presented to compare the psychiatric as well as economic and social functioning of single vs. married parent women ages 18–44, based on a probability sample of members of the greater New Haven community. The major finding between groups is their relative similarity in psychiatric as well as social functioning. The major difference is economic. Single parents, both Black and White, more frequently are less educated and poorer. While many are on welfare, single compared to married female parents are more likely to be working and to report insufficient income to meet their needs. There are no appreciable differences in social contacts, use of health services or six-month prevalence rates of psychiatric disorders including major depression, alcohol or drug abuse. The data suggest that the problems faced by single parent women and their children may be a reflection of poverty and stress in families and not of psychiatric disorders or poor social relations in mothers.     

Development of bariatric surgery-specific risk assessment tool.

BACKGROUND: Administrative databases have increasingly been used to assess bariatric surgery outcomes, resulting in policy recommendations about bariatric practice. However, surgical outcomes must be risk adjusted to compare patients of varying potential risk fairly with those to whom the policies will apply. To date, the risk adjustment tools used for database analysis of bariatric surgical outcomes have been those designed for other purposes, and their sensitivity for bariatric outcomes has not been established. METHODS: Bariatric surgical procedures contained in the National Hospital Discharge Summary for 1993-2003 were assembled into a database. The standard set of Elixhauser co-morbidity variables used by the Agency for Healthcare Research and Quality were entered into the database. Those variables that were significantly associated with adverse outcomes were entered into a stepwise-elimination logistic regression equation, yielding a set of variables related to adverse outcomes from bariatric surgery. These were then prospectively applied to another database (the National Inpatient Survey) to determine their sensitivity for predicting outcomes and were compared with the commonly used Charlson score. RESULTS: The variables significantly correlating with bariatric adverse events included chronic pulmonary disease, hypertension, diabetes with chronic complications, fluid and electrolyte disorders, deficiency anemias, and depression. Age and male gender were also signficantly related to adverse events. The c-index (a correlative index, with .5 showing no, and 1, a perfect, relationship) for bariatric surgery mortality with the Charlson index is .52. For the Elixhauser-based system we developed, it is .72. CONCLUSIONS: We have developed a new risk-adjustment tool for bariatric surgery outcomes studies that use administrative databases. Its performance was clearly better than that of the commonly used Charlson co-morbidity score. Bariatric studies that have used the Charlson index should not be considered adequately risk adjusted.     

Rehabilitation in neuropsychiatry

Patients with neuropsychiatric disorders may present with multiple functional deficits. A rehabilitation approach tends to focus on problems presented and involve multidisciplinary assessment and therapeutic programmes. Ideally the programme should be flexible and tailored to the needs of the individual and his or her family.     

Biopsy excision through a fiberoptic bronchoscope in the palliative management of airway obstruction

Simple biopsy resection through the rigid bronchoscope has been described in the past. We successfully performed such resection through a flexible bronchoscope in six patients with symptomatic and relatively less vascular lesions without complications. In selected patients simple biopsy resection of endobronchial lesion can be safely performed through flexible bronchoscope.     

The experiential impact of head injury on adolescents: individual perspectives on long term outcome

Thirty one young people, who were experiencing chronic sequelae of a head injury sustained at least 1 year previously, were interviewed in depth about the impact head injury had had on their lives. Their functioning was also assessed using the Offer Self Image Questionnaire OSIQ R . The main theme raised by subjects was that they had not received adequate explanation of the emotional problems associated with head injury and relevant support in coming to terms with their condition. Head injury had had a devastating effect on their lives, causing limitations in day to day activities, employment, education and relationships, and they scored significantly below norms on the OSIQ R scale of Self Confidence. However, these young people had a predominantly positive attitude towards life, which appeared to be related to their appreciation of how fortunate they had been to survive. They scored significantly above norms on the OSIQ R scale of Social Functioning. Markers of poor functioning were identified and, in clinical practice, could be used as a method of highlighting those head injured young people who potentially are most in need of support. The findings have implications for future research directions, service delivery and planning, in that particular weaknesses of current provision are demonstrated and recommendations made for improvements.     

Thyroid growth immunoglobulins in feline hyperthyroidism.

Feline hyperthyroidism bears a strong clinical and pathologic resemblance to toxic nodular goiter in humans. To evaluate whether the observed thyroid growth might be due to circulating thyroid antibodies, as has been postulated in humans, we studied the effect of purified immunoglobulin (Ig) G preparations on a rat thyroid follicular (FRTL-5) cell line. When compared with control, hyperthyroid cat IgG caused significantly increased [3H]-thymidine (Tdr) incorporation into DNA (p less than 0.02) and stimulated cellular proliferation 15-fold. Stimulation of 3H-Tdr incorporation tended to be biphasic and could be inhibited completely by a potent, specific TSH receptor blocking antibody. Hyperthyroid cat IgG also significantly inhibited 125I-bTSH binding to porcine thyroid membranes, an effect that could be reproduced using electrophoretically pure IgG and normal cat thyroid membranes. Unlike its effect on growth, hyperthyroid cat IgG did not stimulate intracellular cAMP, and there was no correlation between thyroid function in vivo and IgG growth-promoting activity in vitro. These data suggest that elevated titers of thyroid growth IgGs, probably acting through the TSH receptor, are present in feline hyperthyroidism and may play a role in goiter formation. Unlike growth, the thyroid hyperfunction observed is not IgG dependent. Further study of feline hyperthyroidism may contribute important insights into human nodular goiter and into the mediation of thyroid growth in general.