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Purpose:Cancer susceptibility and mortality are higher in males, and the mutational and transcriptomic landscape of cancer differs by sex. The current assumption is that men are at higher risk of epithelial cancers as they expose more to carcinogens and accumulate more damage than women. We present data showing women present with less aggressive primary cutaneous squamous cell carcinoma (cSCC) and early strong immune activation.Experimental Design:We explored clinical and molecular sexual disparity in immunocompetent and immunosuppressed patients with primary cSCC (N = 738, N = 160), advanced-stage cSCC (N = 63, N = 20) and FVB/N mice exposed to equal doses of DMBA, as well as in human keratinocytes by whole-exome, bulk, and single-cell RNA sequencing.Results:We show cSCC is more aggressive in men, and immunocompetent women develop mild cSCC, later in life. To test whether sex drives disparity, we exposed male and female mice to equal doses of carcinogen, and found males present with more aggressive, metastatic cSCC than females. Critically, females activate cancer immune-related expression pathways and CD4 and CD8 T-cell infiltration independently of mutations, a response that is absent in prednisolone-treated animals. In contrast, males increase the rate of mitosis and proliferation in response to carcinogen. Women's skin and keratinocytes also activate immune-cancer fighting pathways and immune cells at UV radiation–damaged sites. Critically, a compromised immune system leads to high-risk, aggressive cSCC specifically in women.Conclusions:This work shows the immune response is sex biased in cSCC and highlights female immunity offers greater protection than male immunity.

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Introduction There is a recognised need to improve the quality of discharge documentation to facilitate the safe and effective ongoing care of patients once they leave hospital. Previous studies have focused on individual interventions, such as teaching or feedback. Our continuous quality improvement project aims to improve the quality of discharge documentation at our hospital by providing a comprehensive overhaul of the education and feedback around discharge documentation. Methods We designed a comprehensive data analysis tool to analyse the performance of our discharge summaries. We presented at clinical governance sessions and arranged numerous teaching sessions for junior doctors. We developed a live-feedback system based on the content of a sample set of the previous month9s summaries, which included poster-based feedback and group teaching. Results Our interventions have significantly improved the quality of our discharge documentation across a broad range of categories, including the summary of the stay, actions for general practitioners and information given to patients in lay terminology. Conclusion Our comprehensive quality improvement project has improved the quality of our discharge documentation. Further work aims to expand this project into a regional setting, as well as designing a strategy to maintain engagement of key stakeholders to ensure continued progress.

Summary: Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor and bi-functional lipid and protein phosphatase. We report that the metabolic regulator pyruvate dehydrogenase kinase1 (PDHK1) is a synthetic-essential gene in PTEN-deficient cancer and normal cells. The PTEN protein phosphatase dephosphorylates nuclear factor κB (NF-κB)-activating protein (NKAP) and limits NFκB activation to suppress expression of PDHK1, a NF-κB target gene. Loss of the PTEN protein phosphatase upregulates PDHK1 to induce aerobic glycolysis and PDHK1 cellular dependence. PTEN-deficient human tumors harbor increased PDHK1, a biomarker of decreased patient survival. This study uncovers a PTEN-regulated signaling pathway and reveals PDHK1 as a potential target in PTEN-deficient cancers. : The tumor suppressor PTEN is widely inactivated in cancers and tumor syndromes. Currently, there is no effective therapeutic strategy in the clinic for PTEN-deficient cancers. Chatterjee et al. found that PTEN-deficient cells and cancers are uniquely sensitive to PDHK1 inhibition and propose PDHK1 as a potential therapeutic target in PTEN-deficient cancers. Keywords: PTEN, protein phosphatase, PDHK1, NKAP, NF-κB, synthetic lethality, metabolism, signaling, cancer

Cytotoxic therapies, besides directly inducing cancer cell death, can stimulate immune-dependent tumor growth control or paradoxically accelerate tumor progression. The underlying mechanisms dictating these opposing outcomes are poorly defined. Here, we show that cytotoxic therapy acutely upregulates cyclooxygenase (COX)-2 expression and prostaglandin E

Purpose Cancer susceptibility and mortality are higher in males, and the mutational and transcriptomic landscape of cancer differs by sex. The current assumption is that men are at higher risk of epithelial cancers as they expose more to carcinogens and accumulate more damage than women. We present data showing women are more protected from aggressive cutaneous squamous cell carcinoma (cSCC) due to strong immune activation. Methods We explored clinical and molecular sexual disparity in immunocompetent and immunosuppressed patients (N= 738, N=160) with carcinoma cSCC, in FVB/N mice exposed to equal doses of DMBA, and in human keratinocytes by whole exome sequencing, bulk and single cell RNA sequencing. Results We show cSCC is more aggressive in men, and immunocompetent women develop mild cSCC, later in life. To test if sex drives disparity, we exposed male and female mice to equal doses of carcinogen, and found males present more aggressive, metastatic cSCC than females. Critically, females activate cancer immune-related expression pathways and CD4 and CD8 T cell infiltration independently of mutations. In contrast, males increase the rate of mitoses and proliferation in response to carcinogen. Human female skin and keratinocytes also activate immune-cancer fighting pathways and immune cells at ultraviolet radiation-damaged sites. Critically, a compromised immune system leads to high-risk, aggressive cSCC specifically in women. Conclusions This work shows the immune response is sex biased in cSCC, and highlights female immunity offers greater protection than male immunity. Translational relevance Sex bias affects cancer incidence, mortality and therapy response; and the molecular landscape of cancer differs by sex. However, it is not known if the sex discrepancy is due to a difference in behaviour and exposure to carcinogens, or due to sex-linked susceptibility. This work reveals men are inherently more susceptible to cutaneous aggressive squamous cell carcinoma, in contrast to women who activate stronger immune responses when challenged with the same carcinogens. The loss of immunity particularly affects women. Personalised medicine approaches stratify cancer patients by genotype; however, to date, the potential for cancer stratification, prevention strategies and therapy by sex and immune competency has not been explored. These data indicate men require targeted prevention programs and increased monitoring. Furthermore, we provide a rationale to prioritise men and immunosuppressed women for adjuvant therapy and immunotherapy.

Aims and methodAdmissions of patients to secure forensic hospitals are often lengthy. Previous research has examined factors associated with prolonged admission, but studies analysing admission data at a single medium secure unit (MSU) over a prolonged time period are lacking. We compared admission data for all patients admitted to a MSU in England during the years 1985, 1995, 2005 and 2012.ResultsThe median length of admission increased from 167 days in 1985 to 580 days in 2012, though not in the intervening cohorts. There have been changes in the discharge destination of patients, away from independent accommodation in the community towards further care or supported accommodation.Clinical implicationsThe results suggest a change in the delivery of care. Further studies should be performed to assess whether the same trends exist at other sites. If these trends are also found elsewhere, this should trigger a specialty-wide discussion about admission length and its effects on bed availability.Declaration of interestNone.

Melanoma is a clinically heterogeneous disease, and current strategies for treatment of the primary tumour are based on pathological criteria alone. In the recent past, several DNA-sequencing and RNA-sequencing studies of primary and advanced melanoma samples have identified unique relationships between somatic mutations, genomic aberrations, and the genetic fingerprint of ultraviolet radiation (UVR). The recurrent patterns of genomic alterations reveal different disease pathways, drug targets and mechanisms limiting drug response. Here, we examine the known associations between the molecular categories of melanoma and the multidimensional UVR damage. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Objectives The fate of all manuscripts rejected from the journal Clinical Otolaryngology over a three-year period was investigated. The aim was to review publication rate, delay, and the impact factors of the journals that the papers went on to be published in. Design 917 papers were rejected from Clinical Otolaryngology between 2011 and 2013. The fate of these manuscripts was determined by searching for the corresponding author's surname, and if necessary key words from the manuscript title, in both PubMed and Google Scholar. Main outcome measures The main outcome measures recorded were: the subsequent publication of the article, delay to publication, and journal of publication Results 511 papers were subsequently published in journals, representing 55.7% of all rejected manuscripts. The average delay was 15.1 months (Standard Deviation (SD) = 8.8). The impact factor of Clinical Otolaryngology was found to be higher than the average of the journals that accepted the rejected manuscripts in all three years. Only 41 (8%) papers were published in journals with a higher impact factor than Clinical Otolaryngology. Of all subsequently accepted manuscripts 60 (11.7%) were found only on Google Scholar (and not on PubMed). Conclusions Rejection from Clinical Otolaryngology certainly does not prevent subsequent publication, although the papers tend to be published after a lengthy delay and in journals with a lower impact factor than Clinical Otolaryngology. When performing literature searches, it is important to search more than one database to ensure as many of the relevant articles are found as possible. This article is protected by copyright. All rights reserved.

Melanoma is a clinically heterogeneous disease, and current strategies for treatment of the primary tumour are based on pathological criteria alone. In the recent past, several DNA-sequencing and RNA-sequencing studies of primary and advanced melanoma samples have identified unique relationships between somatic mutations, genomic aberrations, and the genetic fingerprint of ultraviolet radiation (UVR). The recurrent patterns of genomic alterations reveal different disease pathways, drug targets and mechanisms limiting drug response. Here, we examine the known associations between the molecular categories of melanoma and the multidimensional UVR damage. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John WileySons, Ltd.

Hedgehog View to a Kill Hedgehog (Hh) signaling is best known for its role in development and is a key signaling component of primary cilia. Hh signaling plays a role in T cell development, but whether Hh signaling plays a role in the function of mature effector T cells is unclear. De la Roche et al. (p. 1247 ; see the Perspective by Le Borgne and Shaw ) now show that T cell receptor signaling triggers Hh signaling. When Hh signaling is disrupted, centrosome polarization to the immunological synapse is reduced, and cytotoxic T cell–mediated killing is impaired.