Acromégalie : améliorer la prise en charge: Acromegaly: improving care.

Acromegaly is characterized by increased release of growth hormone (GH) and, consequently, Insulin-Like Growth Factor I (IGF-I), most often by a pituitary adenoma. Prolonged exposure to excess hormone leads to progressive somatic disfigurement and a wide range of systemic manifestations that are associated with increased mortality. Transsphenoidal adenomectomy is the treatment of choice of GH-secreting pituitary tumors but surgical cure is not achieved in around 50% of patients, then adjuvant treatment is necessary. Mortality in acromegaly is normalized with biochemical control and has decreased in the last decade with the increased use of adjuvant therapy. Both GH and IGF-I are currently biomarkers for assessing disease activity in patients with acromegaly. However, discordance between GH and IGF-I results is encountered in a quarter of treated patients. The impacts of such a discrepancy over mortality and morbidity and the risk of biochemical and/or clinical recurrence are unclear. Moreover, despite a good biochemical control, some symptoms persist, leading to a decreased quality of life. Back pain due to vertebral fractures seem to be frequent in these patients and underdiagnosed. In patients with acromegaly, bone mineral density is not a reliable predictor of fracture risk. A more accurate evaluation of bone microstructural alterations associated with GH hypersecretion and vertebral fractures may be provided by new radiological devices analyzing alteration of trabecular microarchitecture, leading to a better prevention. © 2019 Published by Elsevier Masson SAS. All rights reserved. Cet article fait partie du numéro supplément Les Must de l'Endocrinologie 2019 réalisé avec le soutien institutionnel de Ipsen-Pharma.

Effects of supplemental vitamin D and calcium on markers of proliferation, differentiation, and apoptosis in the normal colorectal mucosa of colorectal adenoma patients.

To clarify the roles of vitamin D and calcium as potential chemopreventive agents against colorectal cancer in humans, and to develop "treatable", pre-neoplastic, phenotypic biomarkers of risk for colorectal neoplasms, we estimated the effects of supplemental vitamin D3 (1,000 IU/day [25 µg/day]) and calcium (1,200 mg/day), alone and in combination, on biomarkers of proliferation (mib-1), differentiation (p21), and apoptosis (bax [apoptosis-promoting] and bcl-2 [apoptosis-inhibiting]), in the normal-appearing rectal mucosa in a subsample of participants (n = 104) in a larger randomized, double-blind, placebo-controlled clinical trial among colorectal adenoma patients. The biomarkers were measured in rectal biopsies at baseline and after one year of follow up, using automated immunohistochemistry and quantitative image analysis. In the vitamin D plus calcium group relative to control, in the crypt differentiation zone (upper 40% of crypts), mib-1 expression decreased 24% (P = 0.28); p21 expression alone and relative to mib-1 expression increased 29% (P = 0.06) and 73% (P = 0.06), respectively; and bax expression relative to mib-1 expression increased 58% (P = 0.21). The estimated vitamin D alone treatment effects were similar but of lesser magnitudes, and those for calcium alone were mixed. All estimated treatment effects on bcl-2 expression were close to the null. These pilot study results support further investigation of whether 1) vitamin D and calcium promote colorectal epithelial cell differentiation, reduce proliferation, and promote apoptosis in the normal-appearing human colorectal mucosa, 2) vitamin D and calcium act as chemopreventive agents against colorectal neoplasms, and 3) mib-1, p21, and bax are potential "treatable", pre-neoplastic, biomarkers of risk for colorectal neoplasms.

Minimally invasive follicular thyroid cancer: treat as a benign or malignant lesion?

BACKGROUND: Follicular thyroid cancer is the second most common thyroid cancer, accounting for 10%-15% of all cases. Follicular thyroid carcinomas (FTCs) can be classified into two subtypes: classic (C), which exhibit both vascular and capsular invasion and minimally invasive (MI), which only has limited capsular invasion. Both types, like most well-differentiated thyroid cancers, are traditionally treated the same: a completion thyroidectomy usually followed by radioiodine ablation. We hypothesize that MI-FTC may behave more like a benign follicular adenoma rather than C-FTC and may not require total thyroidectomy and radioiodine. METHODS: A prospective thyroid database was screened for patients with follicular cell tumors. Data on recurrence rates, disease-free survival, and requirement for follow-up surgery and/or radioiodine were compared. Disease-free survival was determined by the Kaplan-Meier method. Analysis of variance and chi-square test were used to evaluate other factors. RESULTS: In total, there were 419 benign adenomas (87%), 21 MI-FTCs (4.5%), and 41 C-FTCs (8.5%). Patients with adenomas were younger (P = 0.035) and were more likely to be female (P = 0.001). Importantly, the 16-y disease-free survival was 100% in the adenoma group, 100% in the MI-FTC group, and 36.6% in the C-FTC group (P < 0.0001). CONCLUSIONS: MI-FTCs behave similar to adenomas with 100% disease-free survival with up to 16 y of follow-up. These data suggest MI-FTCs could be potentially treated by thyroid lobectomy alone like follicular adenomas and perhaps should be classified as a distinct clinical entity.

Somatostatin Analogue Treatment of a TSH-Secreting Adenoma Presenting With Accelerated Bone Metabolism and a Pericardial Effusion: A Case Report.

Increased bone turnover and other less frequent comorbidities of hyperthyroidism, such as heart failure, have only rarely been reported in association with central hyperthyroidism due to a thyrotropin (TSH)-secreting pituitary adenoma (TSHoma). Treatment is highly empirical and relies on eliminating the tumor and the hyperthyroid state.We report here an unusual case of a 39-year-old man who was initially admitted for management of pleuritic chest pain and fever of unknown origin. Diagnostic work up confirmed pericarditis and pleural effusion both refractory to treatment. The patient had a previous history of persistently elevated levels of alkaline phosphatase (ALP), indicative of increased bone turnover. He had also initially been treated with thyroxine supplementation due to elevated TSH levels. During the diagnostic process a TSHoma was revealed. Thyroxine was discontinued, and resection of the pituitary tumor followed by treatment with a somatostatin analog led to complete recession of the effusions, normalization of ALP, and shrinkage of pituitary tumor.Accelerated bone metabolism and pericardial and pleural effusions attributed to a TSHoma may resolve after successful treatment of the tumor. The unexpected clinical course of this case highlights the need for careful long-term surveillance in patients with these rare pituitary adenomas.

[Up-to-date on the treatment of benign prostatic hyperplasia. Which adenoma to treat and how to do it?]. / Actualités sur la prise en charge de l'hyperplasie bénigne de la prostate. Quel adénome traiter et comment ?

Benign prostatic hyperplasia is a state of the nature rather than a disease. It affects mainly men over 50 years and represents a public health problem. A literature review on the therapeutic management of benign prostatic hyperplasia was carried out from a selection of publications with the highest level of evidence. Medical treatment is based on herbal medicine, alpha-blockers and 5-alpha-reductase inhibitors. Surgical treatment is used in case of complications or failure of medical management. Surgical options are numerous. Transurethral prostate resection and prostate adenomectomy are the most usual procedures. Due to their significant morbidity, other less invasive procedures have recently been developed. The choice of treatment will depend on prostate volume and anatomy and patient's comorbidities.

Photoselective vaporization combined with bipolar transurethral resection for the treatment of large prostate adenoma in high-risk patients.

OBJECTIVE: To evaluate the safety and effectiveness of the combined photoselective vaporization of the prostate (PVP) and bipolar transurethral resection of the prostate (TURP) in high-risk symptomatic patients with large prostates. METHODS: Between January 2007 and January 2010, a prospective study was performed in Shandong Provincial Hospital, Shandong University, Jinan, Shandong Province, China. One hundred and one patients presenting with various kinds of systematic diseases, and with an American Society of Anesthesiologists score of 3 or greater underwent PVP plus bipolar TURP for severe lower urinary tract symptoms due to benign prostatic hyperplasia with prostatic volume greater than 80 ml. The International Prostate Symptom Score (IPSS) and quality-of-life questionnaire (IPPS-QoL), maximum flow rates (Qmax), postvoid urine residues (PVR), and MRI prostatic volumes were recorded. Perioperative data, functional outcome, and complications were evaluated. Patients were reassessed at 3, 6, and 12 months. RESULTS: The mean operation time was 68.5 ± 23.9 minutes. The mean pre- and post- operative prostate volumes were 102.2 ± 33.1 ml and 40.4 ± 15.6 ml. No severe complications were observed. Significant differences in IPSS, Qmax, and PVR values were recorded within the follow-up period. CONCLUSION: The results of our study show that PVP plus bipolar TURP have an excellent efficiency and low morbidity in high-risk patients with large prostates.

Polarization of cytokine profile from Th1 into Th2 along colorectal adenoma-carcinoma sequence: implications for the biotherapeutic target?

The development of colorectal carcinoma (CRC) has been hypothesized to be raised mostly from the precancerous lesion of colorectal adenoma (CRA) through a multistep process and defined as the adenoma-carcinoma sequence. In response to the tumorigenesis, host cellular immunity acts as the most important defense factor with cytokines as the main regulator molecules. Therefore, changes of cytokines of the T helper 1 (Th1)/T helper 2 (Th2) type immune responses along this sequence may therefore reflect a functional switch of host anti-tumor immunity. This minireview focused on the recent knowledge of the Th1/Th2 balance in the adenoma-carcinoma sequence and its potential clinical and therapeutical significance.

Aspirin and folic acid for the prevention of recurrent colorectal adenomas.

BACKGROUND & AIMS: Although observational studies have found regular aspirin use to be associated with a reduced risk of colorectal neoplasia, results from randomized trials using aspirin have been inconsistent. Dietary folate intake also has been found to be associated with a reduced risk of colorectal neoplasms in observational studies. METHODS: A multicenter, randomized, double-blind trial of aspirin (300 mg/day) and folate supplements (0.5 mg/day) to prevent colorectal adenoma recurrence was performed using a 2 x 2 factorial design. All patients had an adenoma (>/=0.5 cm) removed in the 6 months before recruitment and were followed-up at 4-month intervals with a second colonoscopy after approximately 3 years. The primary outcome measure was a colorectal adenoma diagnosed after baseline. RESULTS: A total of 945 patients were recruited into the study, of whom 853 (90.3%) underwent a second colonoscopy. In total, 99 (22.8%) of 434 patients receiving aspirin had a recurrent adenoma compared with 121 (28.9%) of 419 patients receiving placebo (relative risk, 0.79; 95% confidence interval [CI], 0.63-0.99). A total of 104 patients developed an advanced colorectal adenoma; 41 (9.4%) of these were in the aspirin group and 63 (15.0%) were in the placebo group (relative risk, 0.63; 95% CI, 0.43-0.91). Folate supplementation was found to have no effect on adenoma recurrence (relative risk, 1.07; 95% CI, 0.85-1.34). CONCLUSIONS: Aspirin (300 mg/day) but not folate (0.5 mg/day) use was found to reduce the risk of colorectal adenoma recurrence, with evidence that aspirin could have a significant role in preventing the development of advanced lesions.

[Hyperparathyroidism--new aspects]. / Neue Aspekte bei Hyperparathyreoidismus.

Hyperparathyroidism is generally classified into a primary and secondary form. The primary form is caused by an autonomous adenomatous hypertrophy and/or hyperplasia of parythyroideal glands without known cause in most of the patients. Resulting elevated levels of parathyroid hormone cause elevation of serum calcium, subsequently followed by cerebral symptoms, fatigue and calcinosis of vessels and kidneys. The mainstay of secondary HPT is the initial vitamin D deficiency such as associated with kidney failure. Via an increased PTH secretion, calcium homeostasis will be maintained together with ongoing hyperplasia of the parathyroidea. Therapeutic approaches are related to pathophysiological mechanisms. While surgical removal of adenomatous glands is the mainstay of therapy in primary and late secondary forms, during the still regulated initial period of secondary HPT supplementation of vitamin D and/or sensitation of parathyroideal Calcium-sensing-receptors are therapy of choice.

Feasibility of transcatheter arterial chemoembolization for hepatic adenoma.

PURPOSE: To assess the efficacy of transcatheter arterial chemoembolization (TACE) for hepatic adenoma (HA). MATERIALS AND METHODS: Between July 1989 and June 2006, TACE was performed in seven patients with HA (five male and two female patients; mean age, 25 years). The therapeutic results were evaluated by reviewing the clinical records and radiologic studies. The causes of HA were hormonal therapy for aplastic anemia (n = 4) and glycogen storage disease type I (n = 2); in one patient, the cause was unknown. The presenting symptoms were abdominal pain (n = 4) and lower-extremity edema (n = 1). Two patients had no symptoms at presentation. Rupture (n = 1) or impending rupture (n = 3) of the tumors was detected on computed tomographic (CT) scans obtained before TACE. Clinical results were assessed at subsequent TACE sessions and follow-up CT. The mean follow-up duration after the first TACE session was 88 months (range, 16-200 months). The change in tumor size at CT was measured to evaluate the therapeutic results. RESULTS: The preexisting symptoms were relieved and no procedural-related complications were observed in all patients. Hemostasis and no further bleeding episodes were achieved in patients with rupture or impending rupture with intratumoral hemorrhage. The treatment results were complete remission (n = 2), tumor regression in size by more than 50% (n = 4), and progression (n = 1) at follow-up CT. CONCLUSION: TACE is a feasible therapeutic modality for HA.

Benign adult brain tumors: an evidence-based medicine review.

BACKGROUND: Benign adult brain tumors can be managed conservatively or using surgery, radiation, or medicines. While randomized comparisons assessing tumor recurrence, quality of life, or survival are the ideal means of comparing treatments, it can be difficult to recruit patients to such trials and lengthy follow-up periods are needed because of the slowly progressive natural history of these tumors. METHODS: Review of the literature on benign adult brain tumors using evidence-based standards and focusing on meningiomas, pituitary adenomas, and vestibular schwannomas, which together represent the majority of WHO grade 1 adult brain tumors. RESULTS: Nearly all studies of benign adult brain tumors were of relatively poor quality (level 3 or poorer). These studies enable grade C recommendations. The safety of meningioma surgery in the elderly varies with institution, radiosurgery is a reliable alternative to surgery in small to medium-sized meningiomas, and the efficacy of drugs in therapy of meningiomas recurring after surgery is difficult to interpret due to a lack of uniform criteria in the studies. Radiosurgery is effective in nonfunctional pituitary adenomas recurring after surgery, while phototherapy is a newer treatment modality with potential benefits in pituitary adenomas that fail surgery or radiation. Vestibular schwannomas can be conservatively managed, but there are no reliable predictors of growth, so serial imaging is important. Radiosurgery has proven to be a reliable alternative to surgery for small to medium-sized vestibular schwannomas, but followup has been relatively short in most studies to date. CONCLUSIONS: While randomized clinical trials comparing conservative management, surgery, radiation, and medical management of benign adult benign tumors are unlikely to occur, there is some level 3 evidence that can assist in their treatment.

Gene therapy for pituitary tumors.

Pituitary tumors are the most common primary intracranial neoplasms. Although most pituitary tumors are considered typically benign, others can cause severe and progressive disease. The principal aims of pituitary tumor treatment are the elimination or reduction of the tumor mass, normalization of hormone secretion and preservation of remaining pituitary function. In spite of major advances in the therapy of pituitary tumors, for some of the most difficult tumors, current therapies that include medical, surgical and radiotherapeutic methods are often unsatisfactory and there is a need to develop new treatment strategies. Gene therapy, which uses nucleic acids as drugs, has emerged as an attractive therapeutic option for the treatment of pituitary tumors that do not respond to classical treatment strategies if the patients become intolerant to the therapy. The development of animal models for pituitary tumors and hormone hypersecretion has proven to be critical for the implementation of novel treatment strategies and gene therapy approaches. Preclinical trials using several gene therapy approaches for the treatment of anterior pituitary diseases have been successfully implemented. Several issues need to be addressed before clinical implementation becomes a reality, including the development of more effective and safer viral vectors, uncovering novel therapeutic targets and development of targeted expression of therapeutic transgenes. With the development of efficient gene delivery vectors allowing long-term transgene expression with minimal toxicity, gene therapy will become one of the most promising approaches for treating pituitary adenomas.

Neuroendocrine research models.

The neuroendocrine system has always been a main research area for neuroscience. The distinctiveness of this system is due to its diverse anatomical and physiological properties, which modulates the homeostasis and reproductivity of the organism. For decades, generated research models have served to elucidate the complex properties of this system and provided invaluable data on the physiology and mechanism. Currently, the basic research has concentrated on the mechanisms of neuropeptide secretion, carriage and transportation with neurotransmitters and mechanisms operative during various physiological or pathological states. Comparable to the basic research, neuroendocrine models also help to investigate certain clinical aspects of neurological neurosurgical diseases. Pituitary adenomas have been induced by several methods in rats to elucidate adenoma morphology, characteristics and treatment options. More recently, experimental studies are concentrated on the effectiveness of therapeutic gene transfer in neuroendocrine disorders and tumors. Moreover, animal models are of great importance for both to investigate the role of hypothalamus in aging and the potential of correcting age-related neurodegenerative processes in this setting.

Lifestyle-related factors and colorectal polyps: preliminary results from a Norwegian follow-up and intervention study.

Lifestyle-related variables are suggested to play a major role in the development of colorectal cancer (CRC). Within a 3-year follow-up and intervention study with calcium and antioxidants against growth and recurrence of colorectal polyps, supplementary studies were performed in which different aspects of lifestyle were examined. Instead of polypectomy at diagnosis, polyps <9 mm were left in situ in 116 polyp patients (50-76 years, 50% men). After 3 years, all polyps were removed and subjected to histology. Two different sets of control groups were included (all controls were age- and sex-matched and proven to be free of polyps). We applied two different methods in order to assess most exposure variables. Generally, in case-control studies, the validity of the study outcomes is high if they are similar regardless of choice of controls and methods, since bias due to these choices may affect the risk estimates. In contrast, the validity of the study outcomes is low if dependent upon these choices. Our preliminary data support the theory that different factors may be of importance in different stages of the neoplastive formation, and that lifestyle-related factors are likely to play a major role in CRC development.

Invasive ductal carcinoma associated with tubular adenoma of the breast.

We report an extremely rare case of the colocalization of a tubular adenoma and an invasive ductal carcinoma occurring in a 55-year-old woman. Following radiographical evaluation, fine-needle aspiration cytology of the left breast tumor was undertaken. Because cytological examination revealed malignancy, a partial mastectomy was performed. Histologically, the tumor (measuring 1.7 x 1.3 cm) comprised two distinct parts: tubular adenoma and invasive ductal carcinoma. The invasive ductal carcinoma showed a solid pattern, high nuclear and structural atypia and frequent mitotic figures, while the tubular adenoma consisted of a proliferation of small ducts lined by single layers of epithelial and myoepithelial cells with bland nuclei and inconspicuous nucleoli. The histological boundary was clearly defined between the tubular adenoma and the invasive ductal carcinoma, and between the tubular adenoma and the surrounding breast tissue. The current case might be a collision between separate tubular adenoma and invasive ductal carcinoma, but the malignant transformation of a tubular adenoma cannot be ruled out. Both the long-term observation of this case and analysis of more cases may enable us to determine the histological characteristics and clinical significance of invasive ductal carcinoma associated with tubular adenoma.

Rationale and study design of dietary intervention in patients polypectomized for tumors of the colorectum.

We have implemented a randomized controlled dietary intervention in patients polypectomized for tumors of the colorectum to elucidate potential beneficial effects of n-3 polyunsaturated fatty acids (PUFAs) on the development of colorectal tumors. Those individuals in the experimental group were advised not only to decrease their consumption of fats/oils as a whole and foods supplying n-6 PUFAs but also to increase intake of foods and supplements containing n-3 PUFAs, while those in the comparison group were cautioned to reduce intake of fats/oils as a whole. Patients' compliance/adherence was monitored with a semi-quantitative food frequency questionnaire and by assessment of fatty acid concentrations in plasma, membranes of red blood cells and sigmoid colon samples. As for endpoints to assess tumor suppressive effects of n-3 PUFAs, the number/multiplicity, sizes and incidence rates of colorectal tumors were compared between the experimental and comparison groups after 12 and 24 months of the dietary intervention. On the specified assumption, the number of pairs needed for achieving statistical significance was calculated to be approximately 60-80. A randomized controlled trial is under way to secure enough patients, sustain compliance/adherence and minimize dropouts.

[How to plan the treatment of prostatic adenoma today?]. / Comment concevoir aujourd'hui le traitement de l'adénome prostatique?

Surgical treatment, mainly transurethral resection of the prostate, still remains the reference treatment for benign prostatic hyperplasia (BPH). Two studies conducted in the Urology Department of the Pitié-Salpêtrière Hospital have tried to define certain characteristics of this surgery. The first study tried to evaluate the long-term outcome of patients operated for benign prostatic hyperplasia. Analysis of 881 replies to a questionnaire sent to 3,147 patients operated for BPH (between 1976 and 1989) assessed functional status (by Madsen's symptom score), quality of life (by Fowler's method), and sex life (by two specific questions), with a follow-up ranging from 5 to 14 years. At this follow-up, 90% of patients declared to be satisfied with their voiding status, 95% considered their quality of life to be excellent and about 50% had maintained a sex life. The second study was designed to evaluate the morbidity of this treatment in elderly patients. A group of 33 operated patients over the age of 80 was compared to a control group composed of 66 patients between the ages of 60 and 70 years, treated in a similar way, in the same centre and in the same year. Morbidity was higher in the first group, but age itself did not appear to constitute a poor prognostic factor for surgery; it only intervenes by allowing certain complications of benign prostatic hyperplasia (acute retention) to create emergency situations complicating the perioperative period. Following demonstration of the short-term and long-term efficacy of this conventional surgery, many new technologies were subsequently developed in order to reduce perioperative discomfort, anaesthetic requirements, duration of catheterization and hospital stay. Some of them constitute a new approach to endoscopic surgery, such as prostatic tissue vaporization techniques (electrovaporization, laser contact vaporization), which have a comparable efficacy to that of TURP, while reducing bleeding, catheterization time and hospital stay. However, the duration of postoperative irritative symptoms is much longer. Other techniques use a thermal effect to obtain coagulation necrosis of prostatic tissue, using various energy sources: microwaves (thermotherapy), laser (interstitial laser), radiofrequency waves (TUNA). These techniques are perfectly adapted to outpatient surgery with local or regional anaesthesia. They do not interfere with continence, sexual function, but may be followed by high dysuria or retention rates, with a variable cathererization time, sometimes several weeks. Finally, urethroprostatic stents are easy to insert, provide a solution in critical situations and have replaced old indwelling catheters. The current choice of treatment therefore comprises several approaches: more effective, but still purely symptomatic medical treatment, safe conventional surgery providing excellent long-term results, but generating a certain perioperative discomfort and a certain morbidity, or, on the contrary "minimally invasive" techniques, greatly simplifying the therapeutic procedure, but whose morbidity has not yet been determined and whose results are still uncertain.

Severe thyrotoxicosis due to hyperfunctioning liver metastasis from follicular carcinoma: treatment with (131)I and interstitial laser ablation.

Liver metastases from differentiated thyroid tumors are unusual clinical findings, and are only rarely hyperfunctioning. We report a case of thyrotoxicosis caused by a huge and surgically unresectable liver metastasis from follicular thyroid cancer, unresponsive to treatment with large doses of thionamides. To avoid the hazardous side effects of (131)I treatment in a severely thyrotoxic patient, a preliminary debulking of the liver mass was performed by means of percutaneous interstitial laser photocoagulation. Three treatments (total energy delivery: 7200 J) were performed under ultrasound guidance, with no serious complications, during a 2-week period. One month later, serum thyroid hormones had decreased, general condition was improved, and magnetic resonance evaluation revealed large and well-defined areas of necrosis of metastatic tissue. During the following 10 months, the patient underwent 3 radioiodine treatments. Eighteen months after diagnosis, thyroid hormones were within normal levels, liver mass decreased, and the clinical condition markedly improved. The combination of percutaneous interstitial laser photocoagulation treatment and radioiodine therapy made possible the effective management of a hyperfunctioning and surgically untreatable liver metastasis from thyroid follicular carcinoma, avoiding the side effects of (131)I therapy in a thyrotoxic patient and increasing the effectiveness of radioiodine-induced neoplastic tissue ablation.