Search

PTEN is one of the most commonly inactivated tumour suppressor genes in sporadic cancer. Germline heterozygous PTEN gene alterations also underlie PTEN hamartoma tumour syndrome (PHTS), a rare human cancer-predisposition condition. A key feature of systemic PTEN deregulation is the inability to adequately dampen PI3-kinase (PI3K)/mTORC1 signalling. PI3K/mTORC1 pathway inhibitors such as rapamycin are therefore expected to neutralise the impact of PTEN loss, rendering this a more druggable context compared with those of other tumour suppressor pathways such as loss of TP53. However, this has not been explored in cancer prevention in a model of germline cancer predisposition, such as PHTS. Clinical trials of short-term treatment with rapamycin have recently been initiated for PHTS, focusing on cognition and colon polyposis. Here, we administered a low dose of rapamycin from the age of 6 weeks onwards to mice with heterozygous germline Pten loss, a mouse model that recapitulates most characteristics of human PHTS. Rapamycin was well tolerated and led to a highly significant improvement of survival in both male and female mice. This was accompanied by a delay in, but not full blockade of, the development of a range of proliferative lesions, including gastro-intestinal and thyroid tumours and endometrial hyperplasia, with no impact on mammary and prostate tumours, and no effect on brain overgrowth. Our data indicate that rapamycin may have cancer prevention potential in human PHTS. This might also be the case for sporadic cancers in which genetic PI3K pathway activation is an early event in tumour development, such as endometrial cancer and some breast cancers. To the best of our knowledge, this is the first report of a long-term treatment of a germline cancer predisposition model with a PI3K/mTOR pathway inhibitor. © 2022 The Authors. The Journal of Pathology published by John WileySons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Objectives: Cystic neutrophilic granulomatous mastitis (CNGM) is a rare cause of destructive inflammatory breast disease which has been linked to the presence of lipophilic Corynebacteria which often show broad resistance to antibiotics. Antibiotic therapy is frequently utilised as an adjunct to surgical management however there is a lack of reported data on optimal antimicrobial strategies and recovery is often prolonged. Methods: We developed a management strategy in a tertiary infectious diseases unit to identify potential Corynebacteria-related CNGM pathology and took a targeted antibiotic-led approach to treatment. Clinical, laboratory, imaging, and therapeutic data were collected retrospectively from patients seen in our clinic between 2016-2020. Results: Thirteen patients were identified who met criteria for the diagnosis of CNGM. The mean age was 42.6 years and all patients were female. All had bacteriological evidence of Corynebacteria infection or granulomatous findings on histology. Microbiological evidence of Corynebacteria was present in 76.9%. Antibiotics were used as first line therapy in 92.6%, with a variety of agents used. Steroids were used as an adjunctive therapy in 53.8%. Most patients underwent surgical drainage or clinic-based aspiration of an abscess as part of their treatment. Eleven of thirteen patients (84.6%) experienced complete resolution of symptoms however recovery was protracted with a median time to resolution of >6 months. Conclusions: We present a case series of a rare clinical entity, CNGM, and highlight the outcomes of implementation of an antibiotic and infection service-led clinical approach in these patients.