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.

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.

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.

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.

Chronic hemolytic anemia associated with glucose 6-phosphate dehydrogenase (Guadalajara)1 159 C --> T (387 Arg --> Cys) deficiency associated with Gilbert syndrome in a Turkish patient.

The case of an 8-year-old male child with severe kernicterus sequelae is presented in this paper. The child's hemoglobin value varied between 6.0 and 10.8 g/dL and his reticulocyte count ranged between 3.4 and 46.0% during the steady-state condition and hyperhemolytic crisis, respectively. A chronic hemolytic type of red cell G6PD deficiency was diagnosed. DNA studies indicate that the mutation was G6PD Guadalajara 1159 C --> T (387 Arg --> Cys) that is situated at the NADP binding site. Additionally, extra nucleotides of (TA) in the A(TA)n TAA motif of the promoter region of the uridine diphosphate-glucuronosyltransferase gene (UGT-1 A) were found to be homozygous in the patient. The coexistence of Gilbert syndrome with a chronic type of G6PD deficiency was suggested as a cause of neonatal hyperbilirubinemia leading to kernicterus.

Association of complementation group and mutation type with clinical outcome in fanconi anemia. European Fanconi Anemia Research Group.

Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder. Clinical care is complicated by variable age at onset and severity of hematologic symptoms. Recent advances in the molecular biology of FA have allowed us to investigate the relationship between FA genotype and the nature and severity of the clinical phenotype. Two hundred forty-five patients from all 7 known complementation groups (FA-A to FA-G) were studied. Mutations were detected in one of the cloned FANC genes in 169 patients; in the remainder the complementation group was assigned by cell fusion or Western blotting. A range of qualitative and quantitative clinical parameters was compared for each complementation group and for different classes of mutation. Significant phenotypic differences were found. FA-G patients had more severe cytopenia and a higher incidence of leukemia. Somatic abnormalities were less prevalent in FA-C, but more common in the rare groups FA-D, FA-E, and FA-F. In FA-A, patients homozygous for null mutations had an earlier onset of anemia and a higher incidence of leukemia than those with mutations producing an altered protein. In FA-C, there was a later age of onset of aplastic anemia and fewer somatic abnormalities in patients with the 322delG mutation, but there were more somatic abnormalities in patients with IVS4 + 4A --> T. This study indicates that FA patients with mutations in the FANCG gene and patients homozygous for null mutations in FANCA are high-risk groups with a poor hematologic outcome and should be considered as candidates both for frequent monitoring and early therapeutic intervention. (Blood. 2000;96:4064-4070)

Myelodysplastic syndrome (MDS) associated with increased hemoglobin F and trisomy 8: presentation of a patient.

A 7.5 year old boy with myelodysplastic syndrome (MDS) of CMML type associated with trisomy 8 and elevated hemoglobin F (Hb F) value is presented. Hematological evaluation of the patient revealed that the Hb was 10 g/dl, MCV 110 FL, platelets 58 X 10(9)/l, WBC 5.4 X 10(9)/l with 24% atypical monocytes. Karyotype analysis revealed 47, XY, +8. Hb F value was 21% which was distributed heterogeneously among red cells. PCR amplified cDNA copies of circulating reticulocyte mRNA were used to measure the relative amounts of alpha-, beta-, and gamma- globin. There was marked increases in both alpha/beta mRNA ratio (20%) and gamma/(gamma+beta) mRNA ratio (35%) in the patient compared to normal subjects. The study indicated that increased transcription of alpha and gamma genes are partly responsible for the elevation of Hb F in MDS.

The Fanconi anemia group E gene, FANCE, maps to chromosome 6p.

Fanconi anemia (FA) is a genetically heterogeneous autosomal recessive disease with bone marrow failure and predisposition to cancer as major features, often accompanied by developmental anomalies. The cells of patients with FA are hypersensitive to DNA cross-linking agents in terms of cell survival and chromosomal breakage. Of the eight complementation groups (FA-A to FA-H) distinguished thus far by cell fusion studies, the genes for three-FANCA, FANCC, and FANCG-have been identified, and the FANCD gene has been localized to chromosome 3p22-26. We report here the use of homozygosity mapping and genetic linkage analysis to map a fifth distinct genetic locus for FA. DNA from three families was assigned to group FA-E by cell fusion and complementation analysis and was then used to localize the FANCE gene to chromosome 6p21-22 in an 18.2-cM region flanked by markers D6S422 and D6S1610. This study shows that data from even a small number of families can be successfully used to map a gene for a genetically heterogeneous disorder.

Vitamin B12 absorption test and oral treatment in 14 children with selective vitamin B12 malabsorption.

Oral vitamin B12 (VB12) absorption was studied in 12 patients with selective VB12 malabsorption and in 6 age-matched healthy controls. Serum VB12 level was measured before and 3 h after oral administration of VB12 100 or 1000 micrograms. After administration of 1000 micrograms of VB12 an appreciable increase in the serum VB12 level was observed in patients as well as in controls. The mean of the increase in the serum VB12 level did not differ between patients and the controls (273 +/- 203 pg/mL, 180 +/- 71 pg/mL, respectively P > .05). Twelve patients previously treated by parenteral VB12 were switched to, and 2 newly diagnosed patients were started on, oral VB12 treatment of 1000 micrograms given every 2 weeks. Hematological parameters and serum VB12 levels remained stable after switching to oral therapy in the 12 patients. In the two newly diagnosed patients anemia was cured by orally administrated VB12. This study lends further support to the use of megadoses of VB12 as an alternative treatment for selective VB12 malabsorption.

Transferrin receptor on peripheral blood lymphocytes in iron deficiency anaemia.

The effect of iron deficiency anaemia (IDA) on CD71 expression by peripheral blood lymphocytes was studied in 43 children with iron deficiency anaemia. 18 healthy age-matched children were selected as the control group. 11 children with beta-thalassaemia trait were also studied. Lymphocytes bearing CD71 were enumerated by flow cytometric analysis of peripheral blood. At diagnosis, CD71+ peripheral lymphocytes (mean+/-SE) was 5.90+/-0-76% in patients with IDA and 12.60+/-0.98% in healthy controls (P=0.000). In beta-thalassaemia trait patients the peripheral blood CD71+ lymphocytes were 7.80+/-1.20%. In IDA patients there was a statistically significant correlation between the levels of CD71+ peripheral lymphocytes and haemoglobin value (P = 0.000). In 19 patients studied at days 0 and 30 of oral iron therapy, the number of peripheral blood CD71+ lymphocytes was shown to be increased from 5.90+/-0.76% to 12.11+/-1.21%. In severe IDA presence of a limited number of CD71+ peripheral blood lymphocytes indicated that severe IDA should be borne in mind when considering conditions responsible for the suppression of lymphocyte proliferation.

Heterogeneous spectrum of mutations in the Fanconi anaemia group A gene.

Fanconi anaemia (FA) is a genetically heterogeneous autosomal recessive disorder associated with chromosomal fragility, bone-marrow failure, congenital abnormalities and cancer. The gene for complementation group A (FAA), which accounts for 60-65% of all cases, has been cloned, and is composed of an open reading frame of 4.3 kb, which is distributed among 43 exons. We have investigated the molecular pathology of FA by screening the FAA gene for mutations in a panel of 90 patients identified by the European FA research group, EUFAR. A highly heterogeneous spectrum of mutations was identified, with 31 different mutations being detected in 34 patients. The mutations were scattered throughout the gene, and most are likely to result in the absence of the FAA protein. A surprisingly high frequency of intragenic deletions was detected, which removed between 1 and 30 exons from the gene. Most microdeletions and insertions occurred at homopolymeric tracts or direct repeats within the coding sequence. These features have not been observed in the other FA gene which has been cloned to date (FAC) and may be indicative of a higher mutation rate in FAA. This would explain why FA group A is much more common than the other complementation groups. The heterogeneity of the mutation spectrum and the frequency of intragenic deletions present a considerable challenge for the molecular diagnosis of FA. A scan of the entire coding sequence of the FAA gene may be required to detect the causative mutations, and scanning protocols will have to include methods which will detect the deletions in compound heterozygotes.