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.

Risk factors for diabetic foot ulcers in metreleptin naïve patients with lipodystrophy.

AIM: Patients with lipodystrophy are at high risk for chronic complications of diabetes. Recently, we have reported 18 diabetic foot ulcer episodes in 9 subjects with lipodystrophy. This current study aims to determine risk factors associated with foot ulcer development in this rare disease population. METHODS: Ninety metreleptin naïve patients with diabetes registered in our national lipodystrophy database were included in this observational retrospective cohort study (9 with and 81 without foot ulcers). RESULTS: Patients with lipodystrophy developing foot ulcers had longer diabetes duration (p = 0.007), longer time since lipodystrophy diagnosis (p = 0.008), and higher HbA1c levels (p = 0.041). Insulin use was more prevalent (p = 0.003). The time from diagnosis of diabetes to first foot ulcer was shorter for patients with generalized lipodystrophy compared to partial lipodystrophy (p = 0.036). Retinopathy (p < 0.001), neuropathy (p < 0.001), peripheral artery disease (p = 0.001), and kidney failure (p = 0.003) were more commonly detected in patients with foot ulcers. Patients with foot ulcers tended to have lower leptin levels (p = 0.052). Multiple logistic regression estimated significant associations between foot ulcers and generalized lipodystrophy (OR: 40.81, 95% CI: 3.31-503.93, p = 0.004), long-term diabetes (≥ 15 years; OR: 27.07, 95% CI: 2.97-246.39, p = 0.003), and decreased eGFR (OR: 13.35, 95% CI: 1.96-90.67, p = 0.008). CONCLUSIONS: Our study identified several clinical factors associated with foot ulceration among patients with lipodystrophy and diabetes. Preventive measures and effective treatment of metabolic consequences of lipodystrophy are essential to prevent the occurrence of foot ulcers in these high-risk individuals.

Adult-onset still's disease, an unusual cause of severe acute liver injury: A case report.

Adult-onset Still's disease is a systemic inflammatory disease that often presents with spiking fever, typical rash, arthritis, and serositis. However, adult-onset-Still's-disease associated liver injury and acute liver failure are rare. Herein, we report a case of acute liver injury in a 23-year-old female patient with adult-onset Still's disease. She presented to the emergency department with a high fever and sore throat. She was then admitted to the department of infectious diseases with a preliminary diagnosis of an atypical respiratory infection. After being treated with antibiotics and antiviral agents, she was discharged. A few days later, she returned to the emergency department with jaundice and was rehospitalized. This time, she was admitted to the department of gastroenterology, where she was diagnosed with adult-onset Still's disease-associated acute liver injury. Eventually, the patient responded to immunosuppressive treatment with significant clinical improvement.

The impact of sarcopenia on morbidity and long-term survival among patients with peritoneal metastases of colorectal origin treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: a 10-year longitudinal analysis of a single-center experience.

BACKGROUND: The aim of this study was to evaluate the prognostic value of preoperative sarcopenia with regard to postoperative morbidity and long-term survival in patients with peritoneal metastasis from colorectal cancer treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: A longitudinal cohort study was conducted on patients with peritoneal metastases of colorectal origin treated with CRS-HIPEC between 2008 and 2018. Data on patient demographics, body mass index, operative characteristics, perioperative morbidity and survivorship status and oncological follow-up were obtained from the hospital registry. Sarcopenia was assessed using preoperative computed tomography (CT) findings. RESULTS: Sixty-five patients [mean (SD) age: 54.4 (13.4) years, 64.6% females] were included in the study. Sarcopenia was evident in 30.8% of patients, while mortality rate was 66.2% with median survival time of 33.6 months. Presence of sarcopenia was associated with older age (59.6 (9.2) vs. 52.1 (14.4) years, p = 0.038), higher likelihood of morbidity (70.0% vs. 35.6%, p = 0.015) and mortality (90.0% vs. 55.6%, p = 0.010) and shorter survival time (17.7 vs. 37.9 months, p = 0.005). Cox regression analysis revealed that the presence of sarcopenia (HR 2.245, 95% CI 0.996-5.067, p = 0.050) was a significant predictor of increased likelihood of mortality. CONCLUSIONS: Preoperative sarcopenia is an independent prognostic factor of postoperative morbidity and shorter survival in CRC peritoneal metastasis patients treated with CRS-HIPEC. Our findings support the importance of preoperative screening for sarcopenia as part of preoperative risk assessment for better selection of CRS-HIPEC candidates or treatment modifications in CRC patients with peritoneal metastasis.

Comparison of Patients With and Without Anterior Sector Venous Drainage in Right Lobe Liver Transplantation From Live Donors in Terms of Complications, Rejections, and Graft Survival: Single-Center Experience.

AIM: The issue of performing an anastomosis of the anterior sector veins to the vena cava in living donor liver transplantation is still controversial. We aimed to research whether there was any difference in terms of complications, rejections, and graft survival between patients with and without anterior sector venous drainage to the vena cava. PATIENTS AND METHODS: Patients were retrospectively investigated for demographic data and ratio of graft needed to available graft weight. Donors had volumetric calculations and middle hepatic vein anterior sector drainage documented in detail. RESULTS: Seventy-three donors with middle hepatic vein drainage were included. Thirty-five had anterior sector venous drainage performed and 38 patients did not have drainage procedures performed. The incidence of general complications was higher in the group without anterior sector drainage (78.3% and P = .002). Biloma linked to bile leaks were observed in 8 patients without drainage (72.8%) and 3 patients with drainage (27.2%). Late acute rejection occurring during follow up after transplantation was identified in 28 patients (11.6%). Of these, 1 (14.3%) had anterior sector drainage and 6 (85.7%) were in the patient group without drainage (P = .067). CONCLUSION: As a result of this study, for patients with grafts at the volume limit (graft weight to receiver weight ratio <0.8) and with congestion observed in the anterior sector after liver implantation and for patients with outflow problems identified on Doppler ultrasonography, anterior sector veins >5 mm should definitely be drained into the vena cava. Hence, both complication and rejection rates will reduce, and we can lengthen the graft, and thus patient, survival.

The Analysis of Posthepatectomy Liver Failure Incidence and Risk Factors Among Right Liver Living Donors According to International Study Group of Liver Surgery Definition.

AIM: There is a well-known risk of the emergence of hepatic failure in living donor transplant cases on whom are performed a right donor hepatectomy (RDH). There are different prevalence ratios in literature on this phenomenon. In our study, we aim to depict the prevalence of hepatic failure and risk factors in our cases regarding the most recent description criteria related to hepatic failure. PATIENTS AND METHODS: We included right liver donor hepatectomy cases who fit the donor evaluation algorithm at the Dokuz Eylul University Liver Transplantation Unit between the period of June 2000 and September 2017. The patients were evaluated regarding preoperative data. Liver failure was defined according to the International Study Group of Liver Surgery (ISGLS) criteria. We also included statistical analysis of risk factors that are potentially related to liver failure. RESULTS: We included a total of 276 patients. In 27 (9.7%) patients, we observed posthepatectomy liver failure (PHLF). In 26 (9.4%) patients, we observed Grade A liver failure; in 1 (0.3%) patient, we observed Grade B liver failure. We did not observe any Grade C hepatic failure. In patients with hepatic failure, we observed a significantly longer period of hospitalization (P = .007). Old age (odds ratio = 1.065, 95% confidence interval, 1.135-29.108, P = .035) and preoperatory red blood cell (RBC) transfusion (odds ratio = 5.749, 95% confidence interval, 1.019-1.113, P = .005) were shown as independent risk factors for PHLF. CONCLUSION: Posthepatectomy liver failure is a vital complication of RDH. The risk can be decreased by careful selection of donor candidates. Elderly donor candidates and intraoperative RBC are independent risk factors for PHLF.

Preventing parastomal hernia with modified stapled mesh stoma reinforcement technique (SMART) in patients who underwent surgery for rectal cancer: a case-control study.

PURPOSE: Parastomal hernia is a frequent complication of an abdominal wall stoma. Surgical repairs have high complication and recurrence rates. Several different techniques have been suggested to prevent parastomal hernia during stoma creation. The aim of the present case-control study was to evaluate the efficacy of modified Stapled Mesh stomA Reinforcement Technique (SMART) for prevention of parastomal hernia compared with conventional colostomy formation in patients who underwent open or laparoscopic rectal resection and end colostomy for cancer. METHODS AND MATERIALS: Between January 2014 and May 2016, all consecutive patients who underwent open or laparoscopic resection and end colostomy for primary or recurrent rectal cancer were identified from a prospectively collected database. Since January 2014, one surgeon in our team has routinely offered modified SMART procedure to all patients who are candidates for permanent terminal colostomy. In the SMART group patients, while creating an end colostomy, we placed a standard polypropylene mesh in the retromuscular position, fixed and cut the mesh by firing a 31- or 33-mm-diameter circular stapler and constructed the stoma. In the control group, a stoma was created conventionally by a longitudinal or transverse incision of the rectus abdominis sheath sufficiently large for the colon to pass through. RESULTS: Twenty-nine patients underwent parastomal hernia prophylaxis with modified SMART and 38 patients underwent end-colostomy formation without prophylaxis (control group). Groups were similar in terms of age, sex and underlying conditions predisposing to herniation. Median follow-up time is 27 (range 12-41) months. Nineteen patients (28.4%) developed parastomal herniation. In the SMART group, 4 patients (13.8%) developed parastomal herniation which is significantly lower than the control group in which 15 patients (39.5%) developed parastomal herniation (p = 0.029). We did not observe mesh infection, stenosis, erosion or fistulation in the SMART group. One patient in the control group underwent surgical correction of stoma stricture, another patient underwent surgery for stoma prolapse and four patients underwent surgery for parastomal herniation. CONCLUSION: New systemic reviews and meta-analysis support parastomal hernia prevention with the use of a prophylactic mesh. Until more evidence is available, prophylactic mesh should be routinely offered to all patients undergoing permanent stoma formation. SMART is easy to use, safe and effective for paracolostomy hernia prophylaxis.

Evaluation of ureteral jet dynamics in pediatric kidney stone formers: A cross-sectional study.

INTRODUCTION: The risk of kidney stone formation increases with urinary stasis, which is associated with decreased peristaltism. The relationship between nonobstructive kidney stone formation and ureteral jet dynamics, which can be measured with Doppler ultrasonography (US) and provide information about ureteral peristaltism, has been demonstrated in adults. OBJECTIVE: To investigate the relationship between ureteral jet dynamics, which provide information about ureteral peristaltism, and stone formation in children. STUDY DESIGN: Children admitted to Dokuz Eylul University Hospital with flank pain, and asymptomatic age-matched children for the control group, were prospectively enrolled and underwent Doppler US for diagnostic reasons and bilateral ureteral jet flow measurements. Children diagnosed with unilateral nonobstructive lower pole kidney stones formed Group 1, and the control group, without any evidence of stone disease, formed Group 2. Ureteral jet dynamics were compared between the affected renal units in Group 1, and healthy renal units in Group 1 and Group 2. RESULTS: A total of 32 children were included for each group. The mean average jet flow-rate (JETave (cm/second)) in affected renal units in Group 1 was found to be significantly lower than in the healthy renal units in Group 1 and left and right healthy renal units in Group 2 (P < 0.05). The continuous JETpattern rate in affected renal units in Group 1 was found to be significantly higher compared with healthy renal units in Groups 1 and 2 (P = 0.012) (Table). The odds ratio for kidney stone formation was 5.6 for renal units with JETave <9.5 cm/s when compared with renal units with JETave ≥9.5 cm/s. DISCUSSION: In a recent study, it was demonstrated in adults that low ureteral jet flow-rate and continuous JETpattern were significantly higher in affected renal units. The findings in children were also similar to adults: the mean JETave was significantly lower and determination rate of continuous flow pattern was significantly higher in affected renal units. CONCLUSIONS: Children with low JETave and continuous JETpattern as a sign of decreased ureteral peristaltism are at an increased risk of kidney stone formation. However, it is vital that further studies are conducted to elaborate on this topic.

Familial partial lipodystrophy linked to a novel peroxisome proliferator activator receptor -γ (PPARG) mutation, H449L: a comparison of people with this mutation and those with classic codon 482 Lamin A/C (LMNA) mutations.

AIMS: To describe the phenotype associated with a novel heterozygous missense PPARG mutation discovered in a Turkish family and to compare the fat distribution and metabolic characteristics of subjects with the peroxisome proliferator activator receptor -γ (PPARG) mutation with those of a cluster of patients with familial partial lipodystrophy with classic codon 482 Lamin A/C (LMNA) mutations. METHODS: The study involved four subjects with familial partial lipodystrophy who had a novel PPARG mutation (H449L) and six subjects with classic codon 482 LMNA mutations (R482W). RESULTS: Compared with subjects with LMNA R482W mutation, fat loss was generally less prominent in subjects with the PPARG H449L mutation. Partial fat loss was limited to the extremities, whilst truncal fat mass was preserved. The PPARG H449L mutation was associated with insulin resistance, hypertriglyceridaemia and non-alcoholic fatty liver disease in all affected subjects, but the severity was variable. Three out of four mutation carriers had overt diabetes or impaired glucose tolerance. Pioglitazone therapy in these three individuals resulted in a modest improvement in their metabolic control, and regular menstrual cycles in the two female subjects. CONCLUSIONS: We suggest that relatively modest fat loss in patients with PPARG mutations may render the recognition of the syndrome more difficult in routine clinical practice. The PPARG H449L mutation is associated with insulin resistance and metabolic complications, but their severity is variable among the affected subjects.

Diffusion-weighted MR imaging: role in the differential diagnosis of breast lesions.

PURPOSE: To evaluate the diagnostic value of magnetic resonance diffusion-weighted imaging (DWI) using apparent diffusion coefficient (ADC) values to the characterization of breast lesions and differentiation of benign and malignant lesions. MATERIALS AND METHODS: Thirty-seven women (mean age, 38 years) with 37 enrolled in the study. DWI and ADC maps in the axial plane were obtained using a 1.5 Tesla MRI device. Mean ADC measurements were calculated among cysts, normal fibroglandular tissue, benign lesions and malignant lesions were evaluated. RESULTS: Out of 37 women, 4 had normally breast MRI findings. The diagnosis of remaining 33 patients with 37 breast lesions were as follows; malign lesions (n = 23), benign lesions (n = 10) and simple breast cyst (n = 4). The ADC values were as follows (in units of 10(-3) mm2/s): Normal fibroglandular tissue (range: 1.39-2.06; mean: 1.61 ± 0.23), benign breast lesions (range: 1.09-1.76; mean: 1.47 ± 0.25), cyts (range: 2.27-2.46, mean: 2.37 ± 0.07) and malignant breast lesions (range: 0.78-1.26, mean: 0.96 ± 0.25). The mean ADC obtained from malignant breast lesions was statistically different from that observed in benign solid lesions (p < < 0.01) and normal fibroglandular breast tissue (p < 0.01). Furthermore, the mean ADC values of benign breast lesions was not statistically different from cyst (p ≥ 0.01) and normal fibroglandular breast tissue (p ≥ 0.01). A ADC value of 1.1 x 10(-3) mm'/s as a treshold value provided differantiation for malign and benign lesions, with a sensitivity of 91.3% and a specificity of 85.7% compared with conventional breast MRI values. CONCLUSION: DWI with quantitative ADC measurements is a reliable tool for differentiation of benign and malignant breast lesions.

MDCT findings in neuroendocrine carcinoma of the gallbladder: case report.

Neuroendocrine tumors are commonly seen in the gastrointestinal tract, but they are extremely rare in the gallbladder. In this study, sonographic and multidetector-row computed tomographic findings of a patient with neuroendocrine tumors of the gallbladder are presented.

Impaired endothelial function in patients with ankylosing spondylitis.

OBJECTIVE: In recent years, accelerated atherosclerosis and increased risk of cardiovascular events have been described in patients with rheumatic disease, particularly for rheumatoid arthritis and systemic lupus erythematosus. However, the link between inflammation, atherosclerosis and ankylosing spondylitis is controversial. We evaluated the degree of atherosclerosis and endothelial function of ankylosing spondylitis patients ultrasonographically. METHODS: Fifty-four patients with ankylosing spondylitis (37 +/- 11 yr, 29 males, 25 females) and 31 healthy controls (35 +/- 9 yr, 16 males, 15 females) were consecutively enrolled in the study. Serum lipids, creatinine, glucose, and acute-phase proteins were assessed. The Bath Ankylosing Spondylitis Metrology Index (BASMI), Bath Ankylosing Spondylitis Functional Index (BASFI) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) were also evaluated. Flow-mediated dilatation and endothelium-independent dilatation of the brachial artery and intima-media thickness of the common carotid artery were measured sonographically. RESULTS: Left, right and averaged intima-media thickness of the common carotid artery did not show a statistically significant difference between the ankylosing spondylitis and control groups. However, flow-mediated dilatation was significantly lower in the ankylosing spondylitis patients (14.1 +/- 6.7 vs 17.6 +/- 8%; P = 0.03). Likewise, nitroglycerin-induced dilatation was lower in the patient group, but the difference was not significant (16.4 +/- 6.8 vs 19.8 +/- 10%; P = 0.07). No correlation was detected between flow-mediated dilatation and age, sex, serum lipids, CRP, ESR, smoking habits and disease activity scores. Intima-media thickness of the common carotid artery was positively correlated with age and BASMI score (r = 0.55, P = 0.00; r = 0.22, P = 0.04, respectively). CONCLUSION: This study demonstrates impairment of endothelial function in ankylosing spondylitis.

High cystine in platelets from patients with nephropathic cystinosis: a chemical, ultrastructural, and functional evaluation.

AIM: To investigate the morphology and function of platelets in nephropathic cystinosis (NC). METHODS: Seven patients (mean age, 6.5 years; SD, 20 months) with NC were investigated. Their platelets were examined by transmission electron microscopy (TEM) and the characteristics of the dense granules (DGs) were determined by mepacrine labelling and the uranaffin reaction. Bleeding time, turbidometric aggregation, and luminescence aggregation were studied and intraplatelet cystine was measured. RESULTS: Increased intraplatelet cystine, primary and secondary aggregation defects, and the absence of ATP release were demonstrated. TEM revealed DGs of various shapes and sizes and lamellary or amorphous cytoplasmic inclusions. Viscous material had been released into the vacuolar spaces and enlarged open canalicular system. Mepacrine labelling revealed that the numbers of DGs/platelet were comparable between the patients and the controls (mean, 2.9 (SD, 0.22) v 3.32 (0.18); p = 0.34). The uranaffin reaction revealed that the numbers of type 1, 3, and 4 DGs were comparable between the patients and the controls, but that there were fewer type 2 DGs in the patients (mean, 8.5 (SD, 1.95) v 17.22 (1.58); p = 0.01). TEM for platelet aggregation revealed a lack of induction and/or defective execution and/or delayed transmission. The patients' intraplatelet cystine concentrations were higher than the controls (mean, 1.56 (SD, 0.84) v 0.08 (0.01) nmol/mg protein; p = 0.009). CONCLUSIONS: This is the first report to demonstrate raised intraplatelet cystine, abnormal platelet ultrastructural findings, and defective aggregation in NC.

Severe hemolytic anemia associated with Hb Volga [beta27(B9)Ala-->Asp]: GCC-->GAC at codon 27 in a Turkish family.

A boy presented at age 4 years with severe congenital hemolytic anemia characterized by highly elevated reticulocyte count (30-50%) and prominent basophilic stippling. Hb had been 4 g/dL at age 7 months. The patient was on a monthly transfusion regimen up to the age of 7 years, when he underwent splenectomy. After removal of the spleen, his Hb stabilized at 11 g/dL. No abnormal pattern was detected in hemoglobin electrophoresis at pH 9 and 6. In-vitro globin synthesis revealed the presence of an abnormal beta-chain in front of the gamma-chain. The beta(A)/beta(X) ratio was 0.77 at 30 min and 0.74 at 2 hr of incubation. Molecular analysis revealed that the patient had GCC-->GAC alteration at codon 27 (beta27(B9)Ala-->Asp) causing the abnormal hemoglobin Volga. The beta-cDNA derived from the beta-Hb Volga allele could be differentiated from HbA beta-cDNA on silver-stained gel. No imbalance in the mRNA of beta(A)/beta(Hb Volga) ratio was observed.

Importance of RDW value in differential diagnosis of hypochrome anemias.

Red cell distribution width (RDW) was studied in adults carrying delta-beta thalassemia traits (deltabeta-TT) who were 20-40 years of age (n = 29), beta thalassemia traits (beta-TT) with an age range of 18-60 years (n = 49), iron deficiency anemia (IDA) in individuals aged 1-18 years (n = 27), and in controls with an age range of 20-40 years (n = 20). Although red blood cell count, MCV, and MCH values showed no statistically significant differences between deltabeta-TT and beta-TT, the mean RDW value was significantly higher in deltabeta-TT (20.14 +/- 1.21) compared to beta-TT (14.88 +/- 1.77) (P < 0.001). No difference was observed between the means of RDW in deltabeta-TT and IDA (18.00 +/- 1.94) (P > 0.05). A significant rise in RDW in IDA 5-7 days after initiation of iron therapy (P = 0.00) which was continued to rise up to the 4(th) week of therapy was suggested as an important tool in differentiation of IDA from deltabeta-TT. These observations could be kept in mind in the differential diagnosis of deltabeta-TT from beta-TT and IDA by determining the red blood cell count, red cell indices, and RDW only.