Rejection and graft outcomes in kidney transplant recipients with and without angiotensin II receptor type 1 antibodies.

AIM: Angiotensin II type 1 receptor antibody (AT1R Ab) is a non-Human Leucocyte Antigen (HLA) antibody that is maybe associated with early severe kidney transplant rejection and worse graft outcomes. This study aimed to assess the association between AT1R Ab and kidney transplant rejection and graft outcomes. METHODS: We performed a retrospective analysis of all adult kidney transplant recipients in an Australian centre who had an AT1R Ab test between 1 January 2015 to 30 June 2020. AT1R Ab positive patients were compared to AT1R Ab negative patients. Primary outcomes were rejection risk, type and histopathological severity scores. Secondary outcomes were 8-week graft function and graft loss. RESULTS: Of 965 kidney transplants that were performed during the study period, 73 patients had AT1R Ab tested; 16 (22%) were positive and 57(78%) were negative. Positive patients were on average younger and had higher level of donor-specific HLA antibodies. Rejection occurred in 13 (81%) positive patients and 41 (72%) negative patients (P = 0.45). No significant differences in rejection type or severity were found. HLA mismatch and peak panel reactive antibody ≥80%, but not AT1R Ab, independently predicted rejection. Average (132 vs. 177 mmol/L, P = 0.302) and graft loss were not significantly different between groups. CONCLUSION: The study found no evidence that AT1R Ab is associated with rejection type, severity or worse graft function. Future studies should assess its relationship with graft outcomes to help complement immunological risk assessment and potentially provide therapeutic options to alter outcomes.

Metaplastic breast cancers frequently express immune checkpoint markers FOXP3 and PD-L1.

BACKGROUND: Metaplastic breast carcinoma encompasses a heterogeneous group of tumours with differentiation into squamous and/or spindle, chondroid, osseous or rhabdoid mesenchymal-looking elements. Emerging immunotherapies targeting Programmed Death Ligand 1 (PD-L1) and immune-suppressing T cells (Tregs) may benefit metaplastic breast cancer patients, which are typically chemo-resistant and do not express hormone therapy targets. METHODS: We evaluated the immunohistochemical expression of PD-L1 and FOXP3, and the extent of tumour infiltrating lymphocytes (TILs) in a large cohort of metaplastic breast cancers, with survival data. RESULTS: Metaplastic breast cancers were significantly enriched for PD-L1 positive tumour cells, compared to triple-negative ductal breast cancers (P < 0.0001), while there was no significant difference in PD-L1 positive TILs. Metaplastic breast cancers were also significantly enriched for TILs expressing FOXP3, with FOXP3 positive intra-tumoural TILs (iTILs) associated with an adverse prognostic outcome (P = 0.0226). Multivariate analysis identified FOXP3 iTILs expression status as an important independent prognostic factor for patient survival. CONCLUSIONS: Our findings indicate the clinical significance and prognostic value of FOXP3, PD-1/PD-L1 checkpoint and TILs in metaplastic breast cancer and confirm that a subset of metaplastics may benefit from immune-based therapies.

Phenotypic and molecular dissection of metaplastic breast cancer and the prognostic implications.

Metaplastic breast carcinoma (MBC) is relatively rare but accounts for a significant proportion of global breast cancer mortality. This group is extremely heterogeneous and by definition exhibits metaplastic change to squamous and/or mesenchymal elements, including spindle, squamous, chondroid, osseous, and rhabdomyoid features. Clinically, patients are more likely to present with large primary tumours (higher stage), distant metastases, and overall, have shorter 5-year survival compared to invasive carcinomas of no special type. The current World Health Organisation (WHO) diagnostic classification for this cancer type is based purely on morphology - the biological basis and clinical relevance of its seven sub-categories are currently unclear. By establishing the Asia-Pacific MBC (AP-MBC) Consortium, we amassed a large series of MBCs (n = 347) and analysed the mutation profile of a subset, expression of 14 breast cancer biomarkers, and clinicopathological correlates, contextualising our findings within the WHO guidelines. The most significant indicators of poor prognosis were large tumour size (T3; p = 0.004), loss of cytokeratin expression (lack of staining with pan-cytokeratin AE1/3 antibody; p = 0.007), EGFR overexpression (p = 0.01), and for 'mixed' MBC, the presence of more than three distinct morphological entities (p = 0.007). Conversely, fewer morphological components and EGFR negativity were favourable indicators. Exome sequencing of 30 cases confirmed enrichment of TP53 and PTEN mutations, and intriguingly, concurrent mutations of TP53, PTEN, and PIK3CA. Mutations in neurofibromatosis-1 (NF1) were also overrepresented [16.7% MBCs compared to ∼5% of breast cancers overall; enrichment p = 0.028; mutation significance p = 0.006 (OncodriveFM)], consistent with published case reports implicating germline NF1 mutations in MBC risk. Taken together, we propose a practically minor but clinically significant modification to the guidelines: all WHO_1 mixed-type tumours should have the number of morphologies present recorded, as a mechanism for refining prognosis, and that EGFR and pan-cytokeratin expression are important prognostic markers. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Cystic neutrophilic granulomatous mastitis associated with Corynebacterium including Corynebacterium kroppenstedtii.

Granulomatous (lobular) mastitis is a rare inflammatory breast disease affecting parous reproductive-aged women. Once considered idiopathic, there is growing evidence of an association with corynebacteria infection, especially in the setting of a distinct histological pattern termed cystic neutrophilic granulomatous mastitis (CNGM). We describe 15 cases with histological features either confirming (n = 12) or suggesting (n = 3) CNGM, and concurrent microbiological evidence of Corynebacterium species. The organism was detected by culture or 16S rRNA gene sequencing of specimens obtained at surgery or fine needle aspiration. In seven cases, Gram-positive organisms were seen within vacuolated spaces. Speciation was performed in nine cases, with Corynebacterium kroppenstedtii subsequently identified. These cases provide further evidence in support of this association and in doing so highlight the importance of recognising these histological clues as well as the limitations of Gram stain and microbiological culture in detecting this previously under-recognised disease process.

Inhaled corticosteroids for subacute and chronic cough in adults.

BACKGROUND: Persistent cough is a common clinical problem. Despite thorough investigation and empirical management, a considerable proportion of those people with subacute and chronic cough have unexplained cough, for which treatment options are limited. While current guidelines recommend inhaled corticosteroids (ICS), the research evidence for this intervention is conflicting. OBJECTIVES: To assess the effects of ICS for subacute and chronic cough in adults. SEARCH METHODS: We searched the Cochrane Airways Group Register of Trials, Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and ClinicalTrials.gov in December 2012 and conducted handsearches. SELECTION CRITERIA: Two authors independently assessed all potentially relevant trials. All published and unpublished randomised comparisons of ICS versus placebo in adults with subacute or chronic cough were included. Participants with known chronic respiratory disease and asthma were excluded. Studies of cough-variant asthma and eosinophilic bronchitis were eligible. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data pertaining to pre-defined outcomes. The primary outcome was the proportion of participants with clinical cure or significant improvement (over 70% reduction in cough severity measure) at follow up (clinical success). The secondary outcomes included proportion of participants with clinical cure or over 50% reduction in cough severity measure at follow up, mean change in cough severity measures, complications of cough, biomarkers of inflammation and adverse effects. We requested additional data from study authors. MAIN RESULTS: Eight primary studies, including 570 participants, were included. The overall methodological quality of studies was good. Significant clinical heterogeneity resulting from differences in participants and interventions, as well as variation in outcome measures, limited the validity of comparisons between studies for most outcomes. Data for the primary outcome of clinical cure or significant (> 70%) improvement were available for only three studies, which were too heterogeneous to pool. Similarly, heterogeneity in study characteristics limited the validity of meta-analysis for the secondary outcomes of proportion of participants with clinical cure or over 50% reduction in cough severity measure and clinical cure. One parallel group trial of predominantly chronic cough with 'cough-variant asthma' identified a significant treatment effect and contributed to the majority of statistical heterogeneity for these outcomes. While ICS treatment resulted in a mean decrease in cough score of 0.34 standard deviations (SMD -0.34; 95% CI -0.56 to -0.13; 346 participants), the quality of evidence was low. Heterogeneity also prevented meta-analysis for the outcome of mean change in visual analogue scale score. Meta-analysis was not possible for the outcomes of pulmonary function, complications of cough or biomarkers of inflammation due to insufficient data. There was moderate quality evidence that treatment with ICS did not significantly increase the odds of experiencing an adverse event (OR 1.67; 95% CI 0.92 to 3.04). AUTHORS' CONCLUSIONS: The studies were highly heterogeneous and results were inconsistent. Heterogeneity in study design needs to be addressed in future research in order to test the efficacy of this intervention. International cough guidelines recommend that a trial of ICS should only be considered in patients after thorough evaluation including chest X-ray and consideration of spirometry and other appropriate investigations.

The value of care provided by student doulas: an examination of the perceptions of women in their care.

This study provides an examination of women's perceptions of care provided by student doulas undertaking a formal qualification in doula support services. Feedback forms completed by women attended by student doulas undertaking a formal qualification in doula support services were analyzed. The women (N = 160) consistently rated the student doulas' contribution to their experience of birth favorably. Qualitative analysis revealed that women value the presence of their student doulas highly with reference to the student doulas' demeanor, support provided to family, interface with other health professionals, and learned skills. Within the Australian context, this study suggests that the support provided by student doulas that have completed a formal training course is held in positive regard by the women receiving their care.