Emerging Therapeutic Approaches to Target the Dark Side of Senescent Cells: New Hopes to Treat Aging as a Disease and to Delay Age-Related Pathologies.

Life expectancy has drastically increased over the last few decades worldwide, with important social and medical burdens and costs. To stay healthy longer and to avoid chronic disease have become essential issues. Organismal aging is a complex process that involves progressive destruction of tissue functionality and loss of regenerative capacity. One of the most important aging hallmarks is cellular senescence, which is a stable state of cell cycle arrest that occurs in response to cumulated cell stresses and damages. Cellular senescence is a physiological mechanism that has both beneficial and detrimental consequences. Senescence limits tumorigenesis, lifelong tissue damage, and is involved in different biological processes, such as morphogenesis, regeneration, and wound healing. However, in the elderly, senescent cells increasingly accumulate in several organs and secrete a combination of senescence associated factors, contributing to the development of various age-related diseases, including cancer. Several studies have revealed major molecular pathways controlling the senescent phenotype, as well as the ones regulating its interactions with the immune system. Attenuating the senescence-associated secretory phenotype (SASP) or eliminating senescent cells have emerged as attractive strategies aiming to reverse or delay the onset of aging diseases. Here, we review current senotherapies designed to suppress the deleterious effect of SASP by senomorphics or to selectively kill senescent cells by "senolytics" or by immune system-based approaches. These recent investigations are promising as radical new controls of aging pathologies and associated multimorbidities.

Colonic Malakoplakia: A Rare Finding in a Healthy Male.

Malakoplakia is a rare chronic granulomatous disease that may affect many organs, including the lung, brain, adrenal glands, pancreas, bone, and the genitourinary tract. The gastrointestinal tract is the most common site of involvement outside of the urinary tract. Herein, we present a case of a 65-year-old male who presented with abdominal pain and unintentional weight loss. Physical examination findings were unremarkable, but colonoscopy revealed an isolated large, flat, soft, and pale lesion in the transverse colon. Histopathological examination of the lesion showed expansion of the lamina propria due to numerous lymphocytes, plasma cells, neutrophils, and polygonal cells. Von Kossa stain showed small intracytoplasmic basophilic granular inclusions, and these histiocyte cells showed numerous Michaelis-Gutmann bodies, findings considered as diagnostic features of colonic malakoplakia. This is a rare case of isolated malakoplakia of the transverse colon diagnosed on endoscopic specimens. The majority of reported cases have shown an association between systemic diseases and colorectal adenocarcinoma. In addition, most reported cases of colonic involvement have been in the rectum, sigmoid, and right colon.

Results from a retrospective analysis of colonoscopies for Inflammatory bowel disease and colorectal cancer in a Lebanese tertiary care centre.

BACKGROUND AND AIMS: Inflammatory bowel diseases (IBDs) and colorectal cancer have an increased impact on the Lebanese population's morbidity and mortality. This study evaluated the situation of IBD and colorectal cancer at a tertiary hospital centre in Lebanon. METHODS: 1007 patients underwent colonoscopy over a period of 12 months by qualified physicians. 91 patients were excluded from the study. Biopsy results were divided into normal versus abnormal colonic tissue. The abnormal section was further subdivided into number of polyps, IBD, dysplasia and cancer. RESULTS: Out of 916 individuals included, 61 cases of Crohn's colitis (CC) (6.7%) and 24 cases of ulcerative colitis (UC) (2.7%) were identified. A total of 92 cases of colorectal cancer (10.04%) were also identified. There was a slight male predominance in both groups of IBD without any statistical significance. One statistical significance was reported in favour to age<50 years in both IBD groups with a mean age of 37.9±9.7 years and 34.4±6.4 years for CC and UC, respectively. The incidence of granuloma in the CC group was 8.9% without any correlation compared with age or gender. No correlation was made between colorectal cancer and the existence of any IBD type. The data showed that age >50 years and male gender significantly correlate with an increased incidence of precancerous and cancerous polyps in the colon. They significantly correlate with adenocarcinoma. The estimated incidence of colorectal cancer, CC and UC was 54.1, 35.8 and 14.1 per 100 000, respectively, with a denominator of 169 959 patients per year. CONCLUSION: Within the limitations of this study, the incidence of colorectal cancer and IBD falls in the high range compared with similar European and American studies. Our data are biased because of the tertiary centre setting but they can be considered as base for further investigations.

Idiopathic retroperitoneal fibrosis presenting as recurrent scrotal edema: Report of a case and review of the literature.

Primary or idiopathic retroperitoneal fibrosis, first described by Ormond in 1948, is a rare and elusive diagnosis, requiring a high level of suspicion. Patients usually present with entrapment of retroperitoneal organs, the most common being the ureters, causing hydronephrosis and acute kidney injury. Here, we present the case of a 56-year-old male presenting for recurrent and intermittent scrotal edema. Upon routine laboratory workup, he was found to have an elevated creatinine level. Imaging showed encasement of bilateral ureters. Bilateral ureteral stents were placed with relief of his obstructive uropathy, followed by normalization of creatinine. The patient later underwent laparoscopic release of retroperitoneal adhesions. Biopsies taken from the operative site showed fibroblast proliferation and elements of acute and chronic inflammation. With further workup of etiologies being negative, he was diagnosed with idiopathic retroperitoneal fibrosis.

Myxedema ascites with high CA-125: Case and a review of literature.

Ascites appearing in a previously healthy female patient is usually ascribed to a variety of causes, among which, is a cancerous process, especially if it comes with a raised CA-125 level. Although the CA-125 antigen is present on more than 80% of malignant epithelial ovarian tissue of non-mucinous type, it is also found on both healthy and malignant cells of mesothelial and non-mesothelial origin. Myxedema ascites which is caused by hypothyroidism is a rare entity, but on the other hand is easy to treat. It is one of the differential diagnoses when the ascites is refractory to treatment and no other obvious cause can be identified. If the diagnosis is delayed, patients will frequently receive unnecessary procedures, while treatment has very good response rates and ascites resolve with serum CA-125 normalization after adequate hormonal treatment.

Efficiency and tolerance of mitotane in Cushing's disease in 76 patients from a single center.

CONTEXT: Alternatives to transsphenoidal pituitary surgery may be required in Cushing's disease (CD) as a first- or second-line treatment. Mitotane is a potent anti-cortisolic drug but has been rarely investigated in the treatment of CD. OBJECTIVE: Evaluation of the efficacy and tolerance of mitotane in CD patients. DESIGN AND SETTING: Retrospective analysis of 76 patients treated with mitotane from 219 patients diagnosed with CD between 1993 and 2009 in a single center. MAIN OUTCOME MEASURE: Remission was defined as normalization of 24-h urinary free cortisol (24-h-UFC). RESULTS: Remission was achieved in 48 (72%) of the 67 long-term treated patients, after a median time of 6.7 (5.2-8.2) months. Mean plasma mitotane concentration at the time of remission was 10.5 ± 8.9 mg/l, with a mean daily dose of 2.6 ± 1.1 g. A negative linear relationship was observed between plasma mitotane concentration and 24-h-UFC (P<0.0001). Seventeen of 24 (71%) patients with durable remission subsequently experienced recurrence, after a median time of 13.2 (5.0-67.9) months. At the time of treatment discontinuation, ACTH concentration was statistically associated with a lower recurrence probability (hazard ratios 0.57 (0.32-1.00), P=0.05). Intolerance leading to treatment discontinuation occurred in 19 patients (29%). A pituitary adenoma became identifiable during mitotane treatment in 12 (25%) of the 48 patients with initial negative pituitary imaging allowing subsequent transsphenoidal surgery. CONCLUSION: Mitotane is useful at different stages of CD. Mitotane dose adjustment based on plasma concentration monitoring and side effects could control hypercortisolism in the majority of CD patients.

Sequential hormonal changes in 21 patients with recurrent Cushing's disease after successful pituitary surgery.

OBJECTIVE: To describe the sequence of hormonal changes during recurrence of Cushing's disease (CD) after successful transsphenoidal surgery (TSS). DESIGN: Retrospective study in a single center. PATIENTS AND METHODS: We studied 101 of the 127 patients treated by TSS for CD between 1996 and 2009, who had hypocortisolism or eucortisolism for at least 3 months post-TSS. We arbitrarily defined 'overt recurrence', as presence of two classical parameters of excess cortisol (increased midnight--either serum or salivary--and 24  h urinary cortisol (UC)), leading to further specific therapeutic action, and 'mild recurrence', as presence of a single classical parameter, leading to simple surveillance. RESULTS: Of the 101 patients, 21 (20.8%) presented with recurrence, 'mild' or 'overt', during long-term follow-up (median 50.4 months, range 7-99). Recurrence occurred less frequently (16.8 vs 50%, P=0.02), and later (mean 44.7 months, median 43, range 7-94 vs mean 21.5 months, median 17, range 3-61, P=0.05), in patients with early post-TSS hypocortisolism compared with those with eucortisolism. Increase in midnight cortisol occurred in a mean time of 38.2 months, while UC elevation was observed at 50.6 months. Vasopressin analogs and CRH tests were eventually positive in 85 and 93% of all patients respectively; a positive response to one of the two dynamic tests preceded the increase in midnight cortisol or UC in 71 and 64% of the patients respectively. CONCLUSION: A positive response to vasopressin analogs and/or CRH tests occurs early in recurrence, followed by an increase in midnight cortisol, while UC elevation is at a later stage.