NIVOLUMAB ASSOCIATED ENDOCRINE ABNORMALITIES: CHALLENGING CASES FROM A REFERENCE CLINIC.

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced cancers. Antibodies directed against programmed cell death receptor 1 (PD-1) interrupt the ability of the cancerous cell to depress the immune system. Methods and results: We report three patients who developed different endocrine abnormalities after treatment with nivolumab, a monoclonal antibody directed against PD-1. First, we report a 76-year-old male presenting with generalized fat loss after treatment with nivolumab which predominantly affected his face and trunk. Second, we described the development of thyroiditis that presented with thyrotoxicosis and the expression of thyroid-stimulating hormone receptor antibodies (TRAb). Finally, we observed the emergence of adrenal insufficiency due to hypophysitis in another case. Conclusion: Although immune checkpoint inhibitors are an effective anticancer treatment modality, adverse effects are evident that can affect the endocrine system. These adverse events may relate to different endocrine systems that include the thyroid and pituitary glands. Also, acquired generalized lipodystrophy should be suspected in patients developing unusual fat loss after treatment with ICIs.

Seroprevalence of hepatitis B and C virus infections and risk factors in Turkey: a fieldwork TURHEP study.

The present study was designed to determine the seroprevalence of hepatitis B and C virus (HBV, HCV) infections and risk factors in the Turkish general population. Participants were enrolled from urban and rural areas of the predetermined 23 EUROSTAT NUTS 2 region. A two-stage stratified sampling method was used to select participants from these regions (n = 5460; 50.9% females; mean (SD) age: 40.8 (14.7) years). Sociodemographics, clinical characteristics and risk factors were recorded at home visits. The seropositivity rates for hepatitis B surface antigen (HBsAg), anti-HCV, anti-HBs and anti-HBc total were 4.0%, 1.0%, 31.9% and 30.6%, respectively. Among HBsAg-positive cases, 94.5% were anti-HBe-positive, 70.2% were HBV-DNA-positive and 2.8% were anti-HDV total positive; 99.1% of HBV infections were of genotype D. Close contact with a hepatitis patient (OR 3.24; 95% CI 2.25-4.66; p < 0.001), living in the southeastern region (OR 2.74; 95% CI 1.7-4.45; p < 0.001), male gender (OR 1.77; 95% CI 1.28-2.46; p < 0.001), being married (OR 1.62; 95% CI 1.02-2.57; p 0.038), educational level less than high school (OR 1.53; 95% CI 1.04-2.26; p 0.03), orodental interventions (OR 1.54; 95% CI 1.01-2.35; p 0.047) and a history of non-disposable syringe use (OR 1.4; 95% CI 1.01-1.96; p 0.045) were significant determinants of HBsAg positivity. Age ≥50 years (OR 2; 95% CI 1.09-4.3; p 0.026) was the only significant predictor of anti-HCV positivity. In conclusion, our findings revealed an HBsAg positivity in 4% and anti-HCV positivity in 1% of the adult population and at least one-third of the population has been exposed to HBV infection in Turkey.

Evaluation of epithelial chimerism after bone marrow mesenchymal stromal cell infusion in intestinal transplant patients.

Intestinal transplantation is the most effective treatment for patients with short bowel syndrome and small bowel insufficiencies. We evaluated epithelial chimerism after infusion of autologous bone marrow mesenchymal stromal cells (BMSCs) in patients undergoing cadaveric donor isolated intestinal transplantation (I-ITx). BMSCs were isolated from patients' bone marrow via iliac puncture and expanded in vitro prior to infusion. Two out of the 3 patients were infused with autologous BMSCs, and small intestine tissue biopsies collected post-operatively were analyzed for epithelial chimerism using XY fluorescent in situ hybridization and short tandem repeat polymerase chain reaction. We observed epithelial chimeric effect in conditions both with and without BMSC infusion. Although our results suggest a higher epithelial chimerism effect with autologous BMSC infusion in I-ITx, the measurements in multiple biopsies at different time points that demonstrate the reproducibility of this finding and its stability or changes in the level over time would be beneficial. These approaches may have potential implications for improved graft survival, lower immunosuppressant doses, superior engraftment of the transplanted tissue, and higher success rates in I-ITx.

Heart rate variability in ß-thalassaemia major with or without cardiac siderosis.

OBJECTIVES: Iron cardiomyopathy remains the major cause of death in ß-thalassaemia major. Excessive iron loading could lead to cardiac dysfunction and arrhythmias. Reduced heart rate variability is associated with a higher risk of arrhythmia and sudden death after myocardial infarction and heart failure. Previous data have reported on reduced heart rate variability in patients with marked cardiac iron accumulation. In this study, we compared heart rate variability among ß-thalassaemia major (TM) patients with or without cardiac siderosis. METHODS: Out of 70 ß-thalassaemia major patients with preserved ejection fractions, 38 patients with cardiac T2* magnetic resonance imaging assessment were included in our study. Time domain heart rate variability parameters were analysed from 24-hour recorded electrocardiograms and were compared with the control group. RESULTS: The mean T2* magnetic resonance imaging value was 22.9 ± 13.3 (4.7-47.5). In 21 patients with ß-thalassaemia major, the T2* magnetic resonance imaging values were greater than 20 ms and these patients were considered to be in the early stage of the disease. When we compare these patients with control subjects, the standard deviation of all NN intervals was still significantly lower (133.0 ± 32.2 versus 162.8 ± 32.9, p = 0.001) in ß-thalassaemia major patients despite normal T2* magnetic resonance imaging values. On the contrary, the standard deviation of all NN intervals was not correlated with haemoglobin levels in these patients (p > 0.05). CONCLUSIONS: Heart rate variability parameters were reduced even in ß-thalassaemia major patients without evident cardiac siderosis, as specified by magnetic resonance imaging data. The results of this study show that reduction of heart rate variability may start before cardiac iron loading is demonstrated by T2* magnetic resonance imaging in ß-thalassaemia major.

Serum N-terminal-pro-brain natriuretic peptide (NT-pro-BNP) and homocysteine levels in type 2 diabetic patients with asymptomatic left ventricular diastolic dysfunction.

AIMS: : The aim of this study was to determine serum NT-proBNP and plasma Hcy levels and to explore the relationship between serum NT-proBNP and plasma Hcy levels in type 2 diabetic patients with and without asymptomatic LVDD. METHODS: : NT-proBNP and Hcy levels were measured 31 patients with type 2 diabetes mellitus. According to echocardiographic data, diabetic patients were divided into two groups: normal LV function or LV diastolic dysfunction. RESULTS: : Serum NT-proBNP levels in diabetic patients with LVDD were significantly higher than in diabetic patients with normal LV function and controls. The area under the receiver-operating characteristic (ROC) curve for NT-proBNP to separate normal vs. diastolic dysfunction was 0.96 in type 2 diabetic patients. Plasma Hcy levels were significantly higher in both diabetic groups than in controls. Positive correlation was noted between NT-proBNP and Hcy levels in diabetic patients with LVDD (r=0.881, p=0.0001). CONCLUSIONS: : The correlation between elevated NT-proBNP and Hcy levels in diabetic patients with LVDD suggest an association between homocysteinemia and increased NT-proBNP secretion. Our data indicate that NT-proBNP may be a simple screening tool to select diabetic patients with LVDD requiring further examination with echocardiography.

Recurrent Cushing's syndrome after adrenal autotransplantation.

Adrenalectomy with adrenal autotransplantation used to be performed frequently for Cushing's disease in the past because of the limitations of conventional radiological techniques and the lack of adequate neurosurgical techniques. Today, however, bilateral adrenalectomy may be still required for selective patients with Cushing's syndrome when partial hypophysectomy has failed to control hypercortisolism or the source for ectopic ACTH syndrome could not be determined. Here, we report a case of recurrent Cushing's syndrome due to a pituitary adenoma, who was treated with bilateral adrenalectomy and autotransplantation for her Cushing's syndrome. Having determined pituitary adenoma as the cause of recurrent Cushing's syndrome after endocrinological investigations and imaging, we were able to treat the patient with transsphenoidal adenomectomy. We suggest that transsphenoidal resection of the adenoma rather than excision of the autotransplants and adrenal remnants should be the preferred treatment method for recurrent Cushing's disease.

Tc-99m HMPAO scintigraphy in amiodarone-induced acute lung toxicity: comparison with Tc-99m DTPA inhalation scintigraphy.

PURPOSE: This case demonstrates the use of Tc-99m HMPAO scintigraphy in amiodarone (AD)-induced lung toxicity. The aim of this presentation is also to discuss different scintigraphic modalities in the diagnosis and follow up in AD-induced lung toxicity. MATERIALS AND METHODS: A 77-year-old man, with a suspicious AD-induced acute lung toxicity, underwent Tc-99m DTPA aerosol inhalation scintigraphy and Tc-99m HMPAO scintigraphy. RESULTS: Rapid alveolar clearance of Tc-99m DTPA was found during AD therapy and increased lung uptake of Tc-99m HMPAO was also demonstrated. These findings supported the diagnosis AD lung toxicity. After cessation of therapy, Tc-99m DTPA alveolar clearance was decreased. Although there was some decrease in L/H and L/B ratios of Tc-99m HMPAO after 3 weeks of stopping therapy, Tc-99m HMPAO uptake in the lungs was still continued. This finding may be the result of ongoing pulmonary inflammation as a result of the long half-life of AD. CONCLUSION: Compared with Tc-99m DTPA aerosol inhalation scintigraphy, Tc-99m HMPAO scintigraphy may have a role in the diagnosis of AD lung toxicity. Nevertheless, there is a need for longitudinal studies investigating patients under AD therapy using follow-up Tc-9m HMPAO scintigraphy.

Epidemiology of viral hepatitis in the Mediterranean basin.

The prevalence of viral hepatitis is high and remains a serious public health challenge throughout the world. New molecular biology techniques provided a better understanding of the viruses over the last decades. Novel therapeutic options seem to be promising but preventing measures including donor screening, immunization against hepatitis A virus (HAV) and hepatitis B virus (HBV), universal use of disposable syringes and implementation of better hygienic conditions play a major role in the control of viral hepatitis. The Mediterranean basin has special demographic and socioeconomic features. We reviewed in this article the seroepidemiological features of viral hepatitis in this particular region. Improving general conditions led to a tendency to be infected in older ages with HAV. Hepatitis B and C virus still remain to be the major causes of chronic hepatitis. The seroprevalence of hepatitis D virus, which was once endemic in the Mediterranean region seem to decrease nowadays whereas hepatitis E virus is still prevalent in some areas. Other viruses such as hepatitis G virus (HGV), TT virus (TTV) and SEN virus do not seem to be a major problem and their clinical importance remains to be determined in further studies.

Technetium-99m DTPA inhalation scintigraphy in patients treated with fluoxetine and maprotiline: preliminary results.

Drug-metabolising enzymatic activities have been detected in tracheobronchiolar, bronchiolar and alveolar regions in the lungs. Induction of phospholipidosis by amine drugs such as clorphentermine has also been shown. This study aimed to investigate the effect of fluoxetine and maprotiline, which contain amine groups in their structure, on pulmonary epithelial membrane permeability. Twenty-seven patients (mean age 36+/-12 years) with various psychiatric problems, of whom 17 were treated with fluoxetine and 10 with maprotiline, were included in this study. Technetium-99m diethylene triamine penta-acetic acid (DTPA) aerosol inhalation scintigraphy was performed before and after 4-6 weeks of therapy. Following the inhalation of 1480 MBq 99mTc-DTPA for 3 min, lung images in a 64x64 matrix were obtained every minute for 30 min. Regions of interest were drawn around the periphery of the lungs and on the major airways. Clearance half-times (T 1/2) were calculated by placing a mono-exponential fit on the curves. Penetration index (PI) was calculated on the first-minute image. There was no difference between the clearance rates of 99mTc-DTPA before and after therapy for either the fluoxetine or the maprotiline group. After therapy, a significant decrease in PI was found in patients treated with fluoxetine (PI values before and after therapy: 0.53+/-0.03 and 0.49+/-0.05 respectively, P< or =0.05). This finding might have been due to the induction of increased synaptic serotonin (5-HT) by fluoxetine, which acts by inhibiting the re-uptake of 5-HT on presynaptic membranes. Bronchoconstriction of small and medium airways may be caused by direct and indirect effects of 5-HT on smooth muscle contraction.

Effect of intraluminal temperature on human oesophageal motor function.

Oesophageal motor activity is altered by bolus temperature. The effects of sustained cold or warm intraluminal temperature on oesophageal motility have not been documented in detail. Oesophageal manometry was performed in 11 normal subjects after intraluminal room, cold- and warm-water treatments. The intraluminal temperatures were 34.2 +/- 0.8, 30.6 +/- 1.7 and 39.7 +/- 0.9 degrees C respectively during room temperature, cold and warm applications. Low-temperature treatment prolonged the duration of lower oesophageal sphincter relaxation and the duration of oesophageal peristaltic contraction wave compared with the room temperature and warm treatments. Low temperature also attenuated the mean pressure slope of oesophageal contraction waves and resulted in an increased percentage of non-transmitted and simultaneous contractions. The effects of low-temperature application remained constant and there was no adaptation. Cooling oesophageal lumen temperature alters oesophageal motor activity, and this effect is not adaptive.

The distribution of HLA-DRB alleles in ulcerative colitis patients in Turkey.

Recently described distinct associations of HLA class II genes with ulcerative colitis (UC) suggest a genetic heterogeneity for disease susceptibility. In this study, HLA-DRB alleles of UC patients (n = 59) from Turkey were investigated and compared with healthy controls (n = 244). Using molecular genotyping by polymerase chain reaction (PCR) and sequence-specific oligonucleotide hybridization, we have shown a positive association of UC patients with the HLA-DRB1*1502 allele (10/59 vs. 16/244; P = 0.02; OR: 2.9) and a negative association with the DRB1*13 allele (7/59 vs. 64/244; P = 0.03; OR: 0.38) compared to controls. HLA-DRB1*0701 was significantly increased in perinuclear antineutrophil cytoplasmic antibody (pANCA)-positive UC patients compared to pANCA-negative patients (8/32 vs. 0/27; P = 0.005), whereas DRB1*1502 was observed more frequently in pANCA-negative patients (8/27 vs. 2/32; P = 0.03). These results extended the reported positive association of DRB1*1502 with UC to another population and supported the genetic susceptibility associated with HLA genes for disease development.

Effect of diltiazem on renal function in patients with liver cirrhosis.

Calcium channel blockers have strong vasodilator, natriuretic and diuretic actions in normal and hypertensive subjects. The aim of this study was to evaluate the effect of diltiazem on renal function, renin-angiotensin-aldosterone axis (RAA) and atrial natriuretic factor (ANF) in patients with liver cirrhosis. Seven patients (3 females and 4 males) with a mean age of 56.3 +/- 11.1 years (36-68) entered the trial. All of the patients had HBV (6 cases) or HCV (1 case) related Child A (3 cases) or Child B (4 cases) liver cirrhosis proven by liver biopsy. Patients were given placebo for 15 days followed by p.o. diltiazem 30 mg t.i.d. for 15 days. Urinary volume, natriuresis, creatinine clearance, plasma renin activity (PRA), ANF and aldosterone (ALD) levels were determined after the washout period and during the first and second weeks of drug treatment. Urinary volume increased by 25-170% in 5 cases but this difference did not reach statistical significance. Slight increases in natriuresis occurred in some cases on the 3rd day of the trial but the overall results were not statistically significant (191.50 +/- 26.85 vs 204.07 +/- 39.83 mmol/l). Diltiazem induced no significant changes in PRA, ALD and ANF levels or creatinine clearance during the first or second weeks of the trial. There was a significant drop in the pulse rate on the first or second weeks of the treatment (p less than 0.01 and p less than 0.05, respectively). No significant changes were noted on mean arterial pressure (MAP).(ABSTRACT TRUNCATED AT 250 WORDS)