Keith A. Sacco

The role of prostaglandin E2 in endometriosis

Endometriosis is a leading cause of infertility in women of reproductive age. It involves the occurrence of endometrial tissue outside the uterine endometrium, mainly in the peritoneal cavity. Prostaglandin E2 is up regulated in the peritoneal cavity in endometriosis and is produced by macrophages and ectopic endometrial cells. This prostaglandin is involved in the pathophysiology of the disease and elicits cell signals via four receptor types. Prostaglandin E2 increases estrogen synthesis by up regulating steroidogenic acute regulatory protein (StAR) and aromatase. It inhibits apoptosis and up regulates fibroblast growth factor-9 (FGF-9) promoting cell proliferation. Prostaglandin E2 affects leukocyte populations and promotes angiogenesis through its effect on estrogen and up regulation of vascular endothelial growth factor (VEGF). Dienogest is a synthetic progestin targeting expression of genes involved in prostaglandin synthesis.

Leptin signalling, obesity and prostate cancer: molecular and clinical perspective on the old dilemma

The prevalence of global obesity is increasing. Obesity is associated with general cancer-related morbidity and mortality and is a known risk factor for development of specific cancers. A recent large systematic review of 24 studies based on meta-analysis of 11,149 patients with prostate cancer showed a significant correlation between obesity and the risk of advanced prostate cancer. Further, a sustained reduction in BMI correlates with a decreased risk of developing aggressive disease. On the other hand, the correlation between consuming different products and prostate cancer occurrence/risk is limited. Here, we review the role of adipose tissue from an endocrine perspective and outline the effect of adipokines on cancer metabolism, with particular focus on leptin. Leptin exerts its physiological and pathological effects through modification of intracellular signalling, most notably activating the Janus kinase (JAK) 2/signal transducer and activator of transcription (STAT) 3 pathway and recently shown sphingolipid pathway. Both high levels of leptin in circulation and leptin receptor mutation are associated with prostate cancer risk in human patients; however, the in vivo mechanistic evidence is less conclusive. Given the complexity of metabolic cancer pathways, it is possible that leptin may have varying effects on prostate cancer at different stages of its development, a point that may be addressed by further epidemiological studies.

Molecular links between endometriosis and cancer

Endometriosis is the leading cause of morbidity among premenopausal women affecting about 1 in 10 females. The features shared by endometriosis and cancer include the ability to evade apoptosis, the stem cell-like ability and angiogenic potential. As such characteristics are encoded by the cell’s genetic constitution, acquired mutations are responsible for the malignant transformation of endometriosis. Indeed, a number of tumour-suppressor genes and proto-oncogenes, such as protein 53 (P53) and B-cell lymphoma 2 (BCL-2) respectively, are mutated and as a result differentially expressed between endometriotic and malignant tissue associated with endometriosis. Moreover, cytokines and macrophages, both of which are inflammatory mediators have been implicated in the transformation process. The angiogenic properties possessed by cancer arising from endometriosis signifies a bad prognosis, while the stem cell-like activity possessed by both endometriosis and cancer has been attributed to the effect of oestrogen. A number of differences between endometriosis and cancer are found at the molecular level. Considering the link between these two pathologies, the three components which fuel the malignant transformation of endometriosis can be embodied in the endometriosis-induced carcinoma (EIC) triangle which shows the intricate relationship between endocrinologic, immunologic and genetic components.

Histone deacetylases as new therapy targets for platinum-resistant epithelial ovarian cancer

IntroductionIn developed countries, ovarian cancer is the fourth most common cancer in women. Due to the non-specific symptomatology associated with the disease many patients with ovarian cancer are diagnosed late, which leads to significantly poorer prognosis. Apart from surgery and radiotherapy, a substantial number of ovarian cancer patients will undergo chemotherapy and platinum based agents are the mainstream first-line therapy for this disease. Despite the initial efficacy of these therapies, many women relapse; therefore, strategies for second-line therapies are required. Regulation of DNA transcription is crucial for tumour progression, metastasis and chemoresistance which offers potential for novel drug targets.MethodsWe have reviewed the existing literature on the role of histone deacetylases, nuclear enzymes regulating gene transcription.Results and conclusionAnalysis of available data suggests that a signifant proportion of drug resistance stems from abberant gene expression, therefore HDAC inhibitors are amongst the most promising therapeutic targets for cancer treatment. Together with genetic testing, they may have a potential to serve as base for patient-adapted therapies.

Expression of different functional isoforms in haematopoiesis

Haematopoiesis is a complex process regulated at various levels facilitating rapid responses to external factors including stress, modulation of lineage commitment and terminal differentiation of progenitors. Although the transcription program determines the RNA pool of a cell, various mRNA strands can be obtained from the same template, giving rise to multiple protein isoforms. The majority of variants and isoforms co-occur in normal haematopoietic cells or are differentially expressed at various maturity stages of progenitor maturation and cellular differentiation within the same lineage or across lineages. Genetic aberrations or specific cellular states result in the predominant expression of abnormal isoforms leading to deregulation and disease. The presence of upstream open reading frames (uORF) in 5′ untranslated regions (UTRs) of a transcript, couples the utilization of start codons with the cellular status and availability of translation initiation factors (eIFs). In addition, tissue-specific and cell lineage-specific alternative promoter use, regulates several transcription factors producing transcript variants with variable 5′ exons. In this review, we propose to give a detailed account of the differential isoform formation, causing haematological malignancies.

Actionable pharmacogenetic markers for prediction and prognosis in breast cancer

Breast cancer is a heterogeneous disease that necessitates proper patient classification to direct surgery, pharmacotherapy, and radiotherapy. Despite patients within the same subgroup receiving similar pharmacotherapy, substantial variation in clinical outcomes is observed. Pharmacogenetic variations with direct effect on pharmacokinetics and pharmacodynamics play a central role in clinical outcomes. Pharmacogenetic markers associated with clinical outcome are known as biomarkers. They are termed prognostic biomarkers when their presence is associated with a specific clinical outcome. If the presence of such biomarkers guides treatment, they are termed predictive biomarkers. A number of pharmacogenetic markers have been described in relation to breast cancer pharmacotherapy both in the adjuvant and neoadjuvant setting. CYP2D6 allelic variants produce variable rates of tamoxifen metabolism and are associated with survival outcomes. Other biomarkers have been described in relation to other forms of endocrine therapy and trastuzumab. In neoadjuvant and adjuvant breast cancer chemotherapy, specific biomarkers were correlated with clinical outcomes and risk of drug toxicity. This review highlights key biomarkers in breast cancer pharmacotherapy with the potential of translating such study outcomes into clinical practice.

60-Year-Old Woman With Headache and Fatigue

Resident in Internal Medicine, Mayo Clinic School of Graduate Medical Education, Jacksonville, FL (L.F.C., K.A.S.); Advisor to residents and Consultant in Consultative and Diagnostic Medicine, Mayo Clinic, Jacksonville, FL (R.M.C.). A 60-year-old woman presented with a 6-month history of progressive fatigue and frequent headache. The fatigue was worse in the afternoon and prevented the patient from performing her regular daily activities. She reported occasional bloodtinged urine and hematochezia, and no hematemesis or melena. Her medical history was notable for an unprovoked lower-extremity deep vein thrombosis (DVT) 1 year earlier, for which she had completed 6 months of warfarin therapy. Medications included omeprazole, zolpidem, and a daily calcium/vitamin D supplement. On physical examination, she appeared to be in no distress. Her vital signs included the following: temperature 36.7 C; pulse rate 67 beats/minute; respiratory rate 18 breaths/ minute; blood pressure 160/85 mm Hg; and oxygen saturation 97%, breathing room air. Lung auscultation revealed normal breath and heart sounds, without murmurs. Abdominal examination revealed marked tenderness in the left upper quadrant with no organomegaly. Tone, power, reflexes, and sensation were intact on neurologic examination, with no evidence of lateralizing. No evidence was found of petechiae, purpura, ecchymosis, or frank lymphadenopathy. The remainder of the physical examination was unremarkable. Laboratory studies revealed the following (reference ranges provided parenthetically): leukopenia (white blood cell count 2.8 10/L [3.5-10.5 10/L]) with normal differential; macrocytic anemia (hemoglobin 10.9 g/dL [12.0-15.5 g/dL]); mean corpuscular volume 101.2 fL (81.6-98.3 fL); and a platelet count of 160 10/L (150-450 10/L). An electrolyte panel revealed a sodium level of 144 mmol/L (135-145 mmol/L); a potassium level of 4.0 mmol/L (3.6-5.2 mmol/L); a random glucose concentration of 81 mg/dL (70-140 mg/dL); a blood urea nitrogen level of 19 mg/dL (0.84-1.21 mg/dL); and a

The Influence of Innate and Adaptive Immunity on Crohn’s Disease Severity

Stricturing and penetrating disease are classified as severe Crohn’s disease types and are frequently associated with an increased risk for bowel surgery. Research has shown that early treatment with aggressive immunosuppression (including biological and thiopurine therapies – the so-called “top-down approach”) results in a diminished risk of developing these complicated disease types. However, these therapies carry significant risks and cost. Being able to predict which patients are at an increased risk of developing severe Crohn’s disease may enable us to treat patients individually, with the aggressive “top-down approach” started at diagnosis in patients with a significantly increased risk of developing complicated disease types. Defects of innate and adaptive immunity both play a role in Crohn’s disease pathophysiology. Identifying whether defects of innate immunity (through gene mutations) or adaptive immunity (through antibodies to microbial antigens) are associated with stricturing/penetrating disease types may enable us to predict the course of the disease and therefore decide on who would benefit most from the “top-down approach”. This review discusses the role of NOD2 and other gene polymorphisms in predicting Crohn’s disease severity. It also highlights the evidence linking the role of the various antibodies involved in adaptive immunity (ASCA, OmpC, GM-CSF) and complicated Crohn’s disease types.

Evaluation of medication list accuracy from hospital discharge to first outpatient follow-up

Medication discrepancies are common between transitions in healthcare and are associated with higher healthcare utilisation and hospital readmission following discharge. Medication reconciliation is a key intervention to reduce medication list discrepancy. The transition between discharge and first outpatient appointment is critical for patient recovery. The proportion of medication discrepancies during this interval is not well characterised.

Renal Disease in Chronic Granulomatous Disease: Data from the USIDNET Registry

To the editor: Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in genes encoding NADPH oxidase complex protein subunits, which leads to skin and soft tissue infection, pneumonia, abscesses, and granulomatous inflammation all of which could be life-threatening [1]. Prophylactic antimicrobials are the mainstay of treatment for CGD. Some of these antimicrobials are nephrotoxic and may lead to end-stage renal disease (ESRD) [2]. The aim of our study was to assess the prevalence of ESRD in CGD patients using the USIDNET registry. We queried the USIDNET database on 28 March 2017 requesting demographic data on CGD patients, number of CGD patients who required renal replacement therapy (hemodialysis and transplant) and timeline to renal replacement therapy from CGD diagnosis. A second query on 02 May 2017 requested all antimicrobials (drug, indication, dose, outcome, complications) received by patients identified in the first query to have had a diagnosis of medical renal disease. Queries of a case inclusion were resolved by consensus between the two authors. Five hundred sixteen patients with CGD were entered in the database of which 435 (84.3%) were male (Table 1). Twelve patients were Caucasian while two were of AfricanAmerican descent. Median age of CGD diagnosis was 3.55 years (IQR 0.7–13.25). Renal disease was identified in 14 patients (2.7%), with equal gender distribution. Ten patients had a diagnosis of BRenal Failure,^ 2 patients had chronic kidney disease, 1 patient had acute kidney injury, 1 patient had non-specific ‘kidney disease’. Etiology for renal failure was identified in 2 patients (glomerulonephritis and polycystic kidneys). Pneumonia with lung abscesses was the most common documented infection in this cohort (9 patients). Genitourinary infection was documented in 2 patients (pyelonephritis and urinary tract infection). Patients 2 and 12 received amphotericin B; however, no diagnosis of aspergillosis was documented. Patient 1 was documented to have BFungal infection of central nervous system^ while patient 4 had Bfungal infection of lung^. No other fungal infections were documented. X-linked CGD with CYBB gene mutation was present in 11 of 343 patients with the mutation (3.2%). Three patients had autosomal recessive CGD with NCF1 mutation (of a total 18 patients with the mutation). Walther et al. described a cohort of CGD patients with renal manifestations. Seven of 60 (11.7%) patients had decreased renal function while 3 patients had bladder granulomas [3]. Nephrotoxic antimicrobials (particularly amphotericin) are thought to be the main etiologic agent for chronic kidney disease in CGD [4]. We attempted to cross reference fungal infection as a surrogate for amphotericin use; however, only 2 patients were documented to have such a diagnosis (patients 1 and 4). Chronic urinary tract infections can also contribute to ESRD [5]. Renal replacement therapy has been shown to be successful in patients with CGD [2]. This is the first report using the USIDNET registry data on the prevalence of ESRD in CGD patients. This retrospective dataset review has many limitations including the inability to measure temporality of onset of renal disease from diagnosis of CGD. Further there were no formal standard coding renal diagnoses. This dataset was not sufficient to enable assessing the relationship between antimicrobial prescription and * Keith A. Sacco sacco.keith@mayo.edu