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     

The history of ideas of Nordic midwives’ excursions from the early 19th century to the millennium

The midwifery art has emphasised the uniqueness of human beings throughout its Nordic history. The educated Nordic midwife has in the last decade celebrated several hundred years of memories. This article studies how the key ideas of the midwifery art and patterns of ideas become evident in the zeitgeist from the beginning of the 19th century to the millennium in the Nordic countries. The legacy and pattern of ideas of the art of midwifery are interpreted in relation to the texts of the selected historical sources and based on Ricoeur's phenomenological-hermeneutic approach to the text and further to the dedication of understanding and interpretation. The historical sources refer to unprinted primary sources from historical archives and printed secondary and tertiary sources. The patterns of ideas include a tripartite whole: the true cultivation of the head, the philosophy and aesthetics of the hand, the strength of the heart and the drive of calling. These ideas open for unique visions and attest to the evident in modern midwives. Today's midwives have academic training with examinations, and the education is based on scientific evidence. The midwife profession is authorised by the state and supervised by the authorities.     

Spatial restriction of light adaptation and mutation-induced inactivation in fly photoreceptors

The spatial spread within fly photoreceptors of 2 forms of desensitization by bright light have been investigated: the natural process of light adaptation in normal Musca photoreceptors and a receptor-potential inactivation in the no-steady-state (nss) mutant of the sheep blowfly Lucilia. The suction-electrode method used for recording from vertebrate rods was applied to fly ommatidia. A single ommatidium in vitro was partially sucked into a recording pipette. Illumination of the portion of the ommatidium within the pipette resulted in a flow of current having a wave form similar to that of the receptor potential and polarity consistent with current flow into the illuminated region of the photoreceptors. Two 5-microns slits of light, positioned at right angles to the ommatidial axis, were employed to determine the spread of light adaptation or inactivation along the ommatidium. The intensity of a flash of light delivered to one (adapting) slit was adjusted until it produced a criterion fractional reduction in the response to the other (test) slit. The reciprocal of this intensity of the adapting slit was taken as a measure of the effectiveness of the slit in causing light adaptation or inactivation. The effectiveness of the slit in causing light adaptation in normal Musca ommatidia fell as the adapting and test slits were moved farther apart along the ommatidial axis, declining to half its maximal value at a distance of 13 +/- 2 microns. Similar measurements of the effectiveness of a slit in causing light-induced inactivation in the nss mutant of Lucilia also demonstrated localization, declining to half its maximal value at a distance between the slits of 9 +/- 1 microns. Neither light adaptation nor inactivation by the nss mutation, therefore, appear to be mediated by voltage or by a highly diffusible agent. The results are consistent with the idea that inactivation by the nss mutation replaces adaptation in the mutant photoreceptors.     

Flow measurement by the development of phase differences during slice formation in MR imaging

A method for measuring flow based on the shifting of the rephasing pulse following slice selection in partial saturation is described. The technique is based on a partial saturation sequence and retains much of the high signal which is a feature of the use of this sequence. Images obtained while encoding for the flow signal compated with those when not encoding appear very similar.     

Isolation of Stomatococcus mucilaginosus from drug user with endocarditis.

Stomatococcus mucilaginosus was isolated from the blood of a patient with endocarditis and a past history of drug abuse and aortic valve replacement. At autopsy, Gram stain of the aortic valve revealed gram-positive cocci. Our isolate was atypical for S. mucilaginosus in that colonies were nonmucoid and nonadherent to agar surfaces. Cellular capsules were demonstrated by light and electron microscopy. Phenotypic characteristics identified by conventional methods as well as profile numbers obtained by using two commercial identification systems for staphylococci, the API Staph-Ident and the dms Staph Trac, are presented. Practical tests that differentiate S. mucilaginosus from the genera Micrococcus and Staphylococcus include growth on nutrient agar containing salt and lysostaphin susceptibility. Additional tests that helped differentiate our isolate from group D streptococci included hydrolysis of L-pyrrolidonyl-beta-naphthylamide and streptococcal serogrouping.     

Retrospective review of pemetrexed with or without platinum in malignant mesothelioma: The Australian 'Special Access Scheme' experience

Background: Pemetrexed and cisplatin have recently been shown to significantly improve survival compared with cisplatin alone. However, there are only limited data reflecting teaching hospital experience outside a clinical trial. Pemetrexed has only been available in Australia on a restricted basis since 2002. We reviewed our experience of patients treated on the Australian ‘Special Access Scheme’ at three major thoracic oncology units. Methods: Charts were reviewed for all patients enrolled on the scheme. Data was extracted on age, World Health Organization (WHO) performance status, histology, prior therapy, time from diagnosis to starting pemetrexed, chemotherapy (pemetrexed alone or with a platinum), cycle number, response rate, actuarial progression‐free and overall survival. Doses were cisplatin 75 mg/m² or carboplatin AUC = 5 and pemetrexed 500 mg/m² every 21 days. Results: 52 patients (32 male and 20 female) were reviewed. Median age was 58 years and 88% were WHO 0–1. Histology included 54% epithelial, 17% biphasic (epithelial and sarcomatoid) and 21% undefined. The median time from diagnosis to administration of pemetrexed was 145 days. Sixty‐five percent had minimal surgical intervention with video assisted thoracoscopy, pleurodesis and biopsy, while 19% had received prior palliative radiation. Seventy‐one percent were chemotherapy naïve, the remaining 29% having received previous platinum and/or gemcitabine regimens. Twenty‐three percent had pemetrexed alone, 35% in combination with carboplatin and 42% with cisplatin. The median number of cycles was 4 (range 1–13). The response rate was 33%. No toxicity was observed in 20% grade 3–4 toxicity in 10% (majority nausea/vomiting). The median progression‐free and overall survival times from starting pemetrexed were 184 days and 298 days, respectively. Conclusions: Pemetrexed‐based regimens are safe and effective in a community setting in malignant mesothelioma.     

Lung Transplant Metalloproteinase Levels Are Elevated Prior to Bronchiolitis Obliterans Syndrome

Parenchymal disease in the allograft lung is associated with interstitial remodeling believed to be mediated by matrix metalloproteinases (MMPs). Recent studies suggest high levels of MMP-9 are associated with bronchiolitis obliterans syndrome (BOS) in lung transplant recipients. Since BOS occurs late in the posttransplant period and may be preceded by episodes of acute rejection or infection, which are associated with interstitial remodeling, we examined MMP profiles in allograft bronchoalveolar lavage (BAL) fluid in the early posttransplant period (preceding BOS). Gelatin zymography, protein array analysis and specific ELISA on BAL fluids from transplanted lungs indicated that MMP-8, MMP-9 and TIMP-1 were strongly expressed in allograft BAL fluid from stable patients, or those with infection or rejection compared to BAL fluid from normal volunteers. Elevated expression of MMP-8, MMP-9 and TIMP-1 occurred early, and was sustained for the 3.2 years covered in this study. Elevations of MMP-8, MMP-9 and TIMP-1 in the first 2 years posttransplant appear to be associated with lung transplantation itself, and not infection or rejection. These data suggest that ongoing and clinically silent MMP activity could perpetuate progressive disease in the allograft lung.