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     

Results From a Large,Multicenter, Retrospective Analysis On Radium223 Use in Metastatic Castration-resistant Prostate Cancer (mCRPC) in the Triveneto Italian Region

Background

Radium 223 was introduced for metastatic castration-resistant prostate cancer based on the results of a randomized controlled trial showing risk reduction for death and skeletal events. Our aim was to evaluate the outcome of patients receiving radium 223 in a real-world setting.

Intracranial tumors of the first year of life

The introduction of new diagnostic tools for neuroimaging has resulted in the early recognition of congenital brain tumors. In the present report we describe a personal series of 39 children and an International Multicenter Series of 876 children with brain tumors, in whom the diagnosis was obtained during the first 12 months of life. Most of the tumors were located within the supratentorial compartment. In spite of a relatively high operative mortality, surgery still appears to be the more effective therapy. Radiotherapy in this age group is of a scarce value, due to the vulnerability of the infantile brain. At the present time, chemotherapy still plays a controversial role.     

Hemolytic anemia during pegylated IFN-alpha2b plus ribavirin treatment for chronic hepatitis C: ribavirin is not always the culprit.

A 53-year-old woman admitted to our department for histologically proven chronic hepatitis C had previously been treated with pegylated interferon-alpha2b (PEG-IFN) plus ribavirin. Combination therapy had been withdrawn after 5 weeks because of severe anemia (hemoglobin 8.2 g/dl) despite a reduction in ribavirin dose. A second liver biopsy showed moderate chronic hepatitis with portoportal and portocentral bridges (Ishak score: grading 14/18, staging 4-5/6). Consequently, the patient was retreated with 1.5 microg/kg body weight weekly PEG-IFN and 1000 mg/day ribavirin. Ribavirin was withdrawn about 3 months later because of anemia. After 1 month of PEG-IFN alone, hemoglobin had decreased further to reach 7.9 g/dl; consequently IFN was stopped. An elevated reticulocyte count, indirect bilirubin concentration, and lactic dehydrogenase (LDH) concentration, and a positive direct Coombs test (IgG3, C3d also for panagglutinant irregular antibodies on eluate) led us to diagnose autoimmune hemolytic anemia (AHA). The patient received 1 mg/kg body weight/day prednisone, and all parameters normalized within 20 days. This is the first case of IFN-related AHA during PEG-IFN plus ribavirin therapy. Physicians should be aware that PEG-IFN can be the cause of AHA during a ribavirin-containing regimen for chronic hepatitis C.     

Uniportal vs standard three-port VATS technique for spontaneous pneumothorax: comparison of post-operative pain and residual paraesthesia.

OBJECTIVE: VATS using the conventional three ports is currently the technique of choice for blebectomy/bullectomy for spontaneous pneumothorax. However, the procedure has recently been shown to have neurological complications related to the port sites. Uniportal VATS has recently been proposed as an alternative to conventional three-port VATS. It is anticipated that the single incision will predispose to a lower incidence of neurological complications. METHODS: We report our initial single surgeon experience of uniportal VATS (n = 16) and provide a comparison of post-operative pain and residual paraesthesia to conventional three-port procedures (n = 19) for the same pathology. RESULTS: In both groups, the pneumothorax pathology was principally primary. There was no difference between the groups in terms of age, spirometry, tissue resected, drainage time and inpatient stay. A difference was, however, noted in inpatient pain scores. The uniportal group had a lower median score of 0.4 (visual analogue range 0-4) while the three-port technique reported 0.8 (P = 0.06, Mann-Whitney test). The maximum score trend was similar (1.4 vs. 2.6, respectively, P < 0.001, Mann-Whitney test). Follow-up for uniportal and three-port VATS averaged 9.4+/-6.6 and 32.1+/-9.9 months, respectively. One patient in the three-port group had a pneumothorax recurrence. Three-port VATS also had a higher residual pain score (0.5) compared to uniportal VATS (0.3). Of clinical significance was the incidence of neurological complications. Eighty-six percent of uniportal patients reported no symptoms. The remaining experienced only mild 'numbness' or 'swelling'. However, in the three-port group, only 42% reported no symptoms. A similar number experienced 'numbness'. Two females described sexual dysfunction due to altered breast sensitivity. Seventeen percent (2/12) reported 'pins and needles'. CONCLUSIONS: Uniportal VATS appears to be tolerable, safe and efficient in treating spontaneous pneumothorax in our series. Moreover, post-operative pain and paraesthesia incidence was lower than three-port VATS. Prospective randomised trials are important to evaluate this technique.