Associations of CTCF and FOXA1 with androgen and IGF pathways in men with localized prostate cancer.

AIMS: To examine associations between the transcription factors CCCTC-binding factor (CTCF) and forkhead box protein A1 (FOXA1) and the androgen receptor (AR) and their association with components of the insulin-like growth factor (IGF)-pathway in a cohort of men with localized prostate cancer. METHODS: Using prostate tissue samples collected during the Prostate cancer: Evidence of Exercise and Nutrition Trial (PrEvENT) trial (N = 70 to 92, depending on section availability), we assessed the abundance of CTCF, FOXA1, AR, IGFIR, p-mTOR, PTEN and IGFBP-2 proteins using a modified version of the Allred scoring system. Validation studies were performed using large, publicly available datasets (TCGA) (N = 489). RESULTS: We identified a strong correlation between CTCF and AR staining with benign prostate tissue. CTCF also strongly associated with the IGFIR, with PTEN and with phospho-mTOR. FOXA1 was also correlated with staining for the IGF-IR, with IGFBP-2 and with staining for activated phosphor-mTOR. The staining for the IGF-IR was strongly correlated with the AR. CONCLUSION: Our findings emphasise the close and complex links between the endocrine controls, well known to play an important role in prostate cancer, and the transcription factors implicated by the recent genetic evidence.

Significant ketoacidosis at autopsy: a single-centre systematic review.

AIM: To examine the value of vitreous beta-hydroxybutyrate and serum acetone in the investigation of sudden unexpected death. METHODS: Coroners' autopsy reports from a provincial UK city, with a population of approximately 900 000, over a 24-month period with significant ketoacidosis were studied. Demographic features, medical history, anatomical and histological findings, and biochemical parameters, including renal function, vitreous glucose, serum and vitreous alcohol, were analysed. RESULTS: Forty-two cases (28 males and 14 females) were identified; 55% had a history of alcohol and/or substance misuse, and mental health problems, particularly depression and anxiety, and 16% were diabetic. In all, 50% of subjects had alcoholic ketoacidosis (AKA), 19% had diabetic ketoacidosis (DKA) and 12% had a history of both diabetes and alcohol abuse. In 19% of cases, an exact cause of ketoacidosis was established. In AKA, the subjects typically had low vitreous glucose and low or undetected blood alcohol levels. All of the subjects with raised vitreous glucose levels had DKA. CONCLUSION: Ketoacidosis is relatively common and should be considered as a cause of sudden death, especially in alcoholic patients and patients with diabetes with no clear cause of death at autopsy.

Paraneoplastic pemphigus caused by pre-existing stroma-rich variant of Castleman disease: from a pathologist's point of view.

A young woman presented with mucocutaneous blisters and ulcerating lesions, and was diagnosed with erythrodermic pemphigus complicated by bronchiolitis obliterans. Her clinical condition did not improve on immunosuppressive therapy. She had a history of an asymptomatic retroperitoneal mass, presumed to be a dermoid cyst, followed up clinically. Due to the pre-existing nature of the retroperitoneal mass, the paraneoplastic nature of the pemphigus was initially not recognised, but after a multidisciplinary team meeting a biopsy was performed. Histology revealed a rare stroma-rich variant of Castleman disease with a prominent stroma demonstrating a myoid phenotype. Resection of the retroperitoneal tumour resulted in resolution of the cutaneous blisters. This emphasises the importance to consider paraneoplastic disease in treatment-resistant pemphigus as surgical removal of the tumour forms the mainstay of therapy. The differential diagnosis should include Castleman disease and careful evaluation of histology is essential with the awareness of this rare stroma-rich variant.

Alteration of Metabolic Conditions Impacts the Regulation of IGF-II/H19 Imprinting Status in Prostate Cancer.

Prostate cancer is the second major cause of male cancer deaths. Obesity, type 2 diabetes, and cancer risk are linked. Insulin-like growth factor II (IGF-II) is involved in numerous cellular events, including proliferation and survival. The IGF-II gene shares its locus with the lncRNA, H19. IGF-II/H19 was the first gene to be identified as being "imprinted"-where the paternal copy is not transcribed-a silencing phenomenon lost in many cancer types. We disrupted imprinting behaviour in vitro by altering metabolic conditions and quantified it using RFLP, qPCR and pyrosequencing; changes to peptide were measured using RIA. Prostate tissue samples were analysed using ddPCR, pyrosequencing and IHC. We compared with in silico data, provided by TGCA on the cBIO Portal. We observed disruption of imprinting behaviour, in vitro, with a significant increase in IGF-II and a reciprocal decrease in H19 mRNA; the increased mRNA was not translated into peptides. In vivo, most specimens retained imprinting status apart from a small subset which showed reduced imprinting. A positive correlation was seen between IGF-II and H19 mRNA expression, which concurred with findings of larger Cancer Genome Atlas (TGCA) cohorts. This positive correlation did not affect IGF-II peptide. Our findings show that type 2 diabetes and/or obesity, can directly affect regulation growth factors involved in carcinogenesis, indirectly suggesting a modification of lifestyle habits may reduce cancer risk.

Two cases of rare HHV8-driven intravascular lymphoma with synchronous Kaposi sarcoma, both diagnosed at autopsy in renal transplant recipients.

We present the first report of two rare yet remarkably similar autopsy cases of Kaposi sarcoma (KS) and intravascular human herpesvirus 8 (HHV8) positive lymphoproliferative disorder in renal transplant patients. It is well established that HHV8 infection causes Kaposi sarcoma (KS). More recently, it is recognized that HHV8 is also related to several lymphoproliferative conditions. These are poorly characterized and often difficult to diagnose. In both cases described herein, the diagnoses of multifocal hepatic KS and intravascular HHV8 positive (EBV negative) systemic diffuse large B-cell lymphoma, NOS were made at autopsy. Given the findings we describe in cases with fatal outcomes, we discuss the implications of HHV8 screening in solid allograft recipients.

Cell block processing is optimal for assessing endoscopic ultrasound fine needle aspiration specimens of pancreatic mucinous cysts.

AIMS: The cell block technique for assessing endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) specimens from pancreatic mucinous cystic lesions (MCLs) was systematically evaluated for the first time, including comparisons with three traditional methods of assessing such specimens. METHODS: The prospective arm comprised EUS-FNA specimens from EUS-suspected pancreatic MCLs. The retrospective arm comprised EUS-FNA specimens from pancreatic MCLs surgically resected before the study start. For each specimen, these data points were collected: macroscopic likelihood of mucin, cyst fluid carcinoembryonic antigen (CEA) level and presence of mucin in air-dried, direct smears and in cell block preparations. RESULTS: The prospective and retrospective arms of the study comprised 80 and 30 EUS-FNA specimens, respectively. Seven prospective cases led to surgical resections during the study, and therefore, 37 EUS-FNA specimens were confirmed to have originated from MCLs. In the prospective arm, macroscopic mucin was suspected, cyst fluid CEA level exceeded 192 ng/mL, mucin was detected in direct smears and cell block preparations in 78%, 30%, 39% and 73% of cases, respectively. Of the 37 specimens confirmed to originate from MCLs, macroscopic mucin assessment, cyst fluid CEA level, direct smear mucin assessment and cell block mucin assessment had sensitivities for diagnosing MCL of 87%, 45%, 45% and 81%, respectively. CONCLUSIONS: Cell block preparations are as likely to identify mucin from pancreatic MCLs as macroscopic assessment but are twice as likely to diagnose MCL than direct smears and fluid CEA biochemistry. The cell block technique is easy for sample collection and processing especially because these are identical for solid and cystic pancreatic lesions.

Two cases of rare HHV8-driven intravascular lymphoma with synchronous Kaposi sarcoma, both diagnosed at autopsy in renal transplant recipients

We present the first report of two rare yet remarkably similar autopsy cases of Kaposi sarcoma (KS) and intravascular human herpesvirus 8 (HHV8) positive lymphoproliferative disorder in renal transplant patients. It is well established that HHV8 infection causes Kaposi sarcoma (KS). More recently, it is recognized that HHV8 is also related to several lymphoproliferative conditions. These are poorly characterized and often difficult to diagnose. In both cases described herein, the diagnoses of multifocal hepatic KS and intravascular HHV8 positive (EBV negative) systemic diffuse large B-cell lymphoma, NOS were made at autopsy. Given the findings we describe in cases with fatal outcomes, we discuss the implications of HHV8 screening in solid allograft recipients.