Association of HOTAIR, MIR155HG, TERC, miR-155, -196a2, and -146a Genes Polymorphisms with Papillary Thyroid Cancer Susceptibility and Prognosis.

Polymorphisms in long non-coding RNA and microRNA genes may play a significant role in the susceptibility and progression of papillary thyroid carcinoma (PTC). The current study investigates the polymorphisms HOTAIR rs920778, MIR155HG rs1893650, TERC rs10936599, miR-155 rs767649, miR-196a2 rs11614913 and miR-146a rs2910164 in 102 PTC patients and 106 age- and sex-matched controls of the Caucasian Serbian population, using real-time PCR. We observed differences in genotype distributions of the HOTAIR rs920778 (p = 0.016) and MIR155HG rs1893650 (p = 0.0002) polymorphisms between PTC patients and controls. HOTAIR rs920778 was associated with increased PTC susceptibility (adjusted OR = 1.497, p = 0.021), with the TT variant genotype increasing the risk compared to the CC genotype (OR = 2.466, p = 0.012) and C allele carriers (CC + CT) (OR = 1.585, p = 0.006). The HOTAIR rs920778 TT genotype was associated with lymph node metastasis (p = 0.022), tumor recurrence (p = 0.016), and progression-free survival (p = 0.010) compared to C allele carriers. Multivariate Cox regression revealed that ATA risk (HR = 14.210, p = 0.000004) and HOTAIR rs920778 (HR = 2.811, p = 0.010) emerged as independent prognostic factors in PTC. A novel polymorphism, MIR155HG rs1893650, was negatively correlated with susceptibility to PTC, with TC heterozygotes exerting a protective effect (OR = 0.268, p = 0.0001). These results suggest that the polymorphisms HOTAIR rs920778 and MIR155HG rs1893650 could be potential prognostic and risk biomarkers in papillary thyroid carcinomas.

Application of Genomic Sequencing to Refine Patient Stratification for Adjuvant Therapy in Renal Cell Carcinoma.

PURPOSE: Patients with resected localized clear-cell renal cell carcinoma (ccRCC) remain at variable risk of recurrence. Incorporation of biomarkers may refine risk prediction and inform adjuvant treatment decisions. We explored the role of tumor genomics in this setting, leveraging the largest cohort to date of localized ccRCC tissues subjected to targeted gene sequencing. EXPERIMENTAL DESIGN: The somatic mutation status of 12 genes was determined in 943 ccRCC cases from a multinational cohort of patients, and associations to outcomes were examined in a Discovery (n = 469) and Validation (n = 474) framework. RESULTS: Tumors containing a von-Hippel Lindau (VHL) mutation alone were associated with significantly improved outcomes in comparison with tumors containing a VHL plus additional mutations. Within the Discovery cohort, those with VHL+0, VHL+1, VHL+2, and VHL+≥3 tumors had disease-free survival (DFS) rates of 90.8%, 80.1%, 68.2%, and 50.7% respectively, at 5 years. This trend was replicated in the Validation cohort. Notably, these genomically defined groups were independent of tumor mutational burden. Amongst patients eligible for adjuvant therapy, those with a VHL+0 tumor (29%) had a 5-year DFS rate of 79.3% and could, therefore, potentially be spared further treatment. Conversely, patients with VHL+2 and VHL+≥3 tumors (32%) had equivalent DFS rates of 45.6% and 35.3%, respectively, and should be prioritized for adjuvant therapy. CONCLUSIONS: Genomic characterization of ccRCC identified biologically distinct groups of patients with divergent relapse rates. These groups account for the ∼80% of cases with VHL mutations and could be used to personalize adjuvant treatment discussions with patients as well as inform future adjuvant trial design.

Peripheral Versus Intraparenchymal Papillary Thyroid Microcarcinoma: Different Morphologies and PD-L1 Expression.

Peripheral localisation of papillary thyroid microcarcinoma (PTMC), in comparison with intraparenchymal PTMC (i-PTMC) is related to some clinicopathological features related with biological aggressiveness, including lymph node metastasis (LNM). The expression of PD-L1 in tumour cell has been associated with increased tumour survival, progression, and potentially an aggressive clinical course. This study evaluates the relation between clinicopathological features of PTMC, including tumour localisation, with PD-L1 immunoexpression. The study included 99 patients with the histological diagnosis of PTMC (≥ 5 mm). PD-L1 protein expression was assessed by immunohistochemistry. PTMCs were divided into the four following groups: G1- peripherally localised PTMC (p-PTMC) with PD-L1 expression; G2-p-PTMC without PD-L1 expression; G3-i-PTMC with PD-L1 expression and G4-i-PTMC without PD-L1 expression. G1 was the most frequent (n = 46; 46.5%), followed by G4 (n = 25; 25.3%) and similar distribution of G3 (n = 15; 15.2%) and G2 (n = 13; 13.1%). In comparison with other groups, G1 was significantly associated with classical morphology, invasive growth, lymphatic invasion (LI), vascular invasion (VI), psammoma bodies, intratumoral fibrosis, PD-L1 positive tumour-infiltrating lymphocytes, and multinuclear giant cells (MGCs). G4 more commonly exhibited follicular morphology, expansive/circumscribed growth, and absence of the following: intratumoural fibrosis, LI, VI, psammoma bodies, PD-L1 positive tumour-infiltrating lymphocytes, and MGCs. LNMs were significantly more frequent in G1 in comparison with the other groups (p = 0.000). In conclusion, morphology and tumour microenvironment of p-PTMC with PD-L1 expression is different from i-PTMC without PD-L1 expression. The differences between these two groups of PTMC include clinicopathological features related with biological aggressiveness such as the occurrence of LNM.

EWSR1 rearrangement in papillary thyroid microcarcinoma is related to classic morphology and the presence of small-cell phenotype.

The EWSR1 rearrangements with unknown genes were detected in a high percentage of classic variants of papillary thyroid carcinoma. The small-cell carcinoma of the thyroid with Ewing family tumor elements (CEFTE) typically presents with EWSR1-FLI1 rearrangement suggesting the possible role of EWSR-FLI1 translocation in the loss of thyroid differentiation and acquisition of a small-cell phenotype. In order to determine the frequency and association of EWSR1 rearrangements, particularly the EWSR1-FLI1 fusion with clinicopathological features of papillary thyroid microcarcinoma (m-PTC) and the presence of small cells, we analyzed a series of 99 m-PTCs using the fluorescence in situ hybridization method.  Ninety cases (90.9%) of m-PTC were positive for small cells. This group of m-PTC has shown more often invasive growth, lymphatics invasion, and moderate/extended intratumoral fibrosis. Three cases out of 99 were inconclusive for EWSR1 rearrangement. Eighty-nine (92.7%) and twenty-seven (28.1%) out of 96 m-PTC cases were positive for EWSR1 rearrangement and EWSR1-FLI1 fusion, respectively. m-PTC with classical architectural pattern presented more frequently with EWSR1 rearrangement relative to m-PTC with other patterns (p = 0.005). Other clinicopathological features were not related to the presence of EWSR1 rearrangement or EWSR1-FLI1 fusion. The percentage of small cells present significantly correlated with the percentage of cells positive for EWSR1-FLI1 fusion (p = 0.05) and EWSR1 rearrangement (p <0.001). EWSR1-FLI1 fusion is not rare in m-PTC and it is associated with the acquisition of small-cell phenotype. The EWSR1 gene rearrangement is a frequent event in m-PTC and is related to the classical pattern of m-PTC.

Alopecia in preexisting autoimmune thyroid disease in family medicine practice: can hyperprolactinemia induce hair loss? A case report.

Management of hair loss in women presents several challenges for general practitioners, who are the first in identifying its cause and consequences in everyday clinical practice. It is usually associated with multiple secondary factors, including endocrine disorders, drug side effects, and physical or emotional stress. We report a possible pathophysiological link between hyperprolactinemia and alopecia in a patient with preexisting autoimmune thyroid disease, which has not been documented in a significant number in the literature. A 27-year-old female patient with a previous history of an autoimmune thyroid disease on hormone substitution therapy presented to a family doctor with signs of frontal alopecia that had started several months previously. On examination, frontal alopecia was confirmed. Laboratory results and thyroid ultrasound confirmed autoimmune thyroid disease, with reduced parathyroid hormone and elevated prolactin. Her female sex hormones were in the normal range. Due to elevated prolactin levels, computed tomography of the pituitary gland was performed, which excluded any brain pathology. Based on available data, there is no published systematic analysis on hyperprolactinemia-induced alopecia in previous autoimmune diseases (large cohort studies). This report indicates that, due to moderately elevated prolactin values, consideration of alternative causes and further diagnostics are necessary to exclude a prolactin-producing tumor of the pituitary gland.

Prevalence and diagnostic challenges of thyroid lymphoma: a multi-institutional study in non-Western countries.

Research on the primary thyroid lymphoma (PTL) diagnosis is limited, with only a few large sample size studies, reported from Asian countries. The aim of the present study was to clarify the current prevalence and challenges in PTL diagnosis, and recommended ancillary studies for PTL in non-Western countries. PTL (n = 153) cases were retrieved from 10 institutions in non-Western countries and analyzed. Ultrasound examination (UE) and fine needle aspiration cytology (FNAC) were used as main preoperative diagnostic tools in all participating institutions. Flow cytometry (FCM) was performed in the 5 institutions (50%). Lobectomy was the most common histological procedure to confirm the PTL diagnosis. All institutions routinely performed immuno-histochemical analysis. PTL was 0.54% of malignant thyroid tumor cases, with mucosa-associated lymphoid tissue lymphoma (MALTL) and diffuse large B-cell lymphoma (DLBCL) being 54.9% and 38.6%, respectively. Kuma Hospital, where the frequency of MALTL was highest (83.7%), routinely performed FCM using the materials obtained by FNAC. UE and FNAC sensitivities were 62.5% and 57.8%, respectively. In both UE and FNAC, sensitivity of MALTL was lower than of DLBCL. The study elucidated that the prevalence of PTL in non-Western countries was lower than previously reported. We propose that FCM should be more actively used to improve the preoperative diagnosis of MALTL. Our data predicted that the MALTL proportion will increase with improved diagnostic tools, while observation of PTL-suspected nodules without histological examination remains a viable option.

The physiological range of the Böhler's angle in the adult Croatian population.

BACKGROUND: To examine the relationship of the Böhler's angle with age, sex, and laterality, and to analyze the interrater agreement. METHODS: After 248 digital lateral radiographs of the foot were submitted to exclusion criteria, three raters independently measured the Böhler's angle on the remaining 130 X-rays in PACS. The variables were analyzed with correlation coefficients, and one-way ANOVA. The repeated measures of ANOVA were computed across age groups (30-39, 40-49, 50-59, and 60-69 years). The interrater agreement was calculated using intraclass correlation coefficient (ICC). RESULTS: The mean value of the Böhler's angle was 34±5° (21-46°). It was not related to age (in general [p=0.057], and across groups [p from 0.107 to 0.122]), sex (p=0.344; p=0.342), and laterality (p=0.618; p=0.617). The interrater reliability was almost perfect (ICC=0.94). CONCLUSIONS: The Böhler's angle was not related to age, sex, and laterality, whereas the interrater agreement was almost perfect.

Tissue and urinary KIM-1 relate to tumor characteristics in patients with clear renal cell carcinoma.

The objective of this prospective follow-up trial was to ascertain whether the urinary kidney injury molecule-1 (uKIM-1) associates with tumor tissue (tKIM-1) expression and with the pathological characteristics of clear renal cell carcinoma (cRCC) in radically nephrectomized (RN) and/or in partially nephrectomized (PN) patients with cRCC, pre- and postoperatively. This clinical study included 40 patients subjected to RN/PN (cRCC group) and 30 healthy volunteers (control group). Urinary KIM-1 was determined by ELISA TIM-1/KIM-1 kit and normalized by urinary creatinine. Immunohistochemical staining (monoclonal anti-human anti-TIM-1/KIM-1/HAVCR antibody) was used for semiquantitative analysis of the tKIM-1 expression and expressed as a score (% KIM-1 positively stained tubules). Both markers were interpreted in terms of the tumor characteristics comprising tumor size, Fuhrman grade, pathological (pT) stage, tumor/nodes/metastasis (TNM) stage, lymphovascular invasion and type of surgery RN/PN. Preoperative uKIM-1 was significantly higher in the cRCC group compared to controls, such as uKIM-1 was statistically higher in RN than in PN patients. Postoperatively, uKIM-1 decreased to control values. Expression of tKIM-1 was documented in all nephrectomized patients. Significant associations were achieved between uKIM-1 and tKIM-1 and with considered tumor characteristics, especially with tumor size and grade. Based on the accomplished associations, we found uKIM-1 as a highly sensitive marker for cRCC diagnosis. The clinical trial registration number: 1110-2012.

Urinary KIM-1 and AQP-1 in patients with clear renal cell carcinoma: Potential noninvasive biomarkers.

BACKGROUND/AIM: Kidney injury molecule-1 (KIM-1) and aquaporin-1 (AQP-1) are potential early urinary biomarkers of clear renal cell carcinoma (cRCC). The aim of this study was to ascertain relationship between the urine concentrations KIM-1 and AQP-1 with tumor size, grade, pT stage and type of operation (radical or partial nephrectomy) in patients with cRCC. METHODS: Urinary concentrations of urinary KIM-1 (uKIM-1) and urinary AQP-1 (uAQP-1) were determined by commercially available ELISA kits. The analysis included 40 patients undergoing partial or radical nephrectomy for cRCC and 40 age- and sex-matched healthy adult volunteers. RESULTS: The median preoperative concentrations of KIM-1 in the cRCC group [0.724 ? 1.120 ng/mg urinary creatinine (Ucr)] were significantly greater compared with controls (healthy volunteers) (0.210 +/- 0.082 ng/mgUcr) (p = 0.0227). Postoperatively, uKIM-1 concentration decreased significantly to control values (0.177 +/- 0.099 ng/mgUcr vs 0.210 + 0.082 ng/mgUcr, respectively). The size, grade and stage of tumor were correlated positively with preoperative uKIM-1 concentrations. Contrary to these results, concentrations of uAQP-1 in the cRCC group were significantly lower (0.111 +/- 0.092 ng/mgUcr) compared with the control group (0.202 +/- 0.078 ng/mgUcr) (p = 0.0014). Postoperatively, the concentrations of uAQP-1 increased progressively up to control values, approximately. We find no significant correlation between preoperative uAQP-1 concentrations and tumor size, grade and stage. CONCLUSION: uKIM-1 was found to be a reliable diagnostic marker of cRCC, based on its significantly increased values before and decreased values after the nephrectomy.

Neobladder "Belgrade pouch": Metabolic consideration.

Background/Aim: The ileal neobladder should be a lowpressure reservoir with acceptable volume and relatively small resorptive surface. A larger inner surface of the ileal pouch is associated with the high resorption of urine metabolites through intestinal mucosa and systemic metabolic disturbances, while a too small pouch results in a higher frequency of voiding and incontinency. The aim of this study was to investigate it is possible to create a neobladder from a shorter ileal segment compared to standard surgical techniques, and reduce metabolic complications. Methods: This prospective study included 77 male patients, scheduled for radical cystectomy and orthotopic neobladder derivation. The patients were divided into two groups: the standard pouch (SP) group of 37 patients scheduled for standard orthotopic neobladder, using a 50−70 cm long terminal ileum segment; the "Belgrade pouch" (BP) group of 40 patients scheduled for original, orthotopic urinary reservoir, using a 25−35 cm long terminal ileum segment. We measured neobladder capacity, acidosis, base excess and bicarbonate concentration in the postoperative month 3rd, 6th, 12th and 15th. Results: At the end of the study, the patients from the SP group had much higher neobladder capacity than the natural bladder − 750 mL (range 514−2,050 mL); in contrast, the patients from the BP group had average capacity of 438 mL (range 205−653 mL) (p < 0.001). At the end of the study, there were more patients with acidosis (37.8% : 2.5%), base excess (35.1% : 7.5%) and low bicarbonate level (40.5% : 20.0%) in the SP group, than in the BP group, respectively (p < 0.001). Conclusion: "Belgrade pouch", make from 25−35 cm long terminal ileum segment may obtain adequate capacity and lower rate of metabolic disturbances than standard, high capacity orthotopic neobladders.

Acquired cystic disease and renal cell carcinoma in hemodialysis patients--A case report on three patients.

INTRODUCTION: Renal cell carcinoma (RCC) is derived from renal tubular epithelial cells and represents approximately 3.8% of all malignancies in adults. The incidence of renal cell carcinoma has been growing steadily and ranging from 0.6 to 14.7 for every 100,000 inhabitants. Patients with end-stage renal disease and acquired cystic kidney disease are at increased risk of developing RCC while undergoing dialysis treatment or after renal transplantation. CASE REPORT: We presented 3 patients undergoing hemodialysis, with acquired cystic kidney disease accompanied by the development of RCC. In all the patients tumor was asymptomatic and discovered through ultrasound screening in 2 patients and in 1 of the patients by post-surgery pathohistological analysis of the tissue of the kidney excised using nephrectomy. All the three patients had organ-limited disease at the time of the diagnosis and they did not require additional therapy after surgical treatment. During the follow-up after nephrectomy from 6 months to 7 years, local recurrence or metastasis of RCC were not diagnosed. CONCLUSION: Acquired cystic kidney disease represents a predisposing factor for the development of renal cell carcinoma in dialysis patients and requires regular ultrasound examinations of the abdomen aimed at early diagnosis of malignancies. Prognosis for patients with end-stage renal disease and RCC is mostly good because these tumors are usually of indolent course.

Unrecognised adrenergic symptoms and the delayed diagnosis of urinary bladder paraganglioma.

INTRODUCTION: Paraganglioma is a rare neuroendocrine neoplasm that may arise from the extra-adrenal autonomic paraganglia. Urinary bladder paraganglioma is typically presented as repeated episodes of palpitations, headache or blood pressure rise immediately after micturition. Management of these tumors includes radical surgical treatment with preoperative antihypertensive preparation, and a life-long follow-up. CASE REPORT: We presented a middle-age female patient with functional urinary bladder paraganglioma, with a 3-year history of repeated episodes of abdominal pain, dysuria and hematuria. After obtaining more precise anamnestic data, the patient reported occasional simultaneous presence of mild adrenergic symptoms, that did not cause any particular attention at first. Morphological and biohumoral examinations suggested paraganglioma of the urinary bladder. Open partial cystectomy was performed, detecting a submucosal mass, while immunohistochemical analysis confirmed the presence of chromaffin tissue. Clinical manifestations, diagnostic approach, management and histopathological findings of urinary bladder paraganglioma are discussed. CONCLUSION: Since the prognosis with localized paraganglioma is good, we underlined the importance of a well-timed, accurate and detailed medical history in all the patients with even mild, inexplicable micturition-provoked adrenergic symptomatology.

The clinical course of non-muscle invasive bladder cancer after transurethral resection of the tumor with or without subsequent intravesical application of bacillus Calmette-Guérin: The influence of patients gender and age.

UNLABELLED: BACGROUND/AIM: The therapy with intravesical instillation of bacillus Calmette-Guérin (BCG) after transurethral resection (TUR) of tumor is the gold standard of treatment of non-muscle invasive bladder cancer (NMIBC). The role and importance of BCG intravesical therapy in various shape of tumors, were confirmed by our previous investigation. The aim of this study was to examine whether incidence of recurrence and tumor regression differs depending on sex and age of patients. METHODS: This study included a total of 899 patients suffering from NIMBC, treated at our institution from January 1, 2007 to March 1, 2013. Two groups of patients were formed: patients underwent TUR + BCG therapy (the group I) and the group II with patients in whom TUR was performed as only therapy. These two groups of patients were divided into subgroups of respondents male and female, age 60 years or younger and older than 60 years. Statistical analysis was performed using χ2 test and the Kolmogorov-Smirnov test. RESULTS: This research suggests that if the frequency of recurrence is seen as the only parameter, considering all the subjects, the lowest recurrence rate was determined in the male subjects, aged 60 years and younger who had received BCG after TUR. A high statistical significance was found in the incidence of recurrence in patients younger than 60 years, depending on the response to the therapy, while in those older than 60 years, the difference was at the level of statistical significance. This can be attributed to a certain degree of infravesical obstruction in older men. CONCLUSIONS: Sex and age of patients may have a significant influence on the course and outcome of NMIBC. The disease has the most malignant and most aggressive behavior when present in males older than 60 years.

Difference in recurrence frequencies of non-muscle-invasive-bladder tumors depending on optimal usage of intravesical immunotherapy of bacillus Calmette-Guérin.

BACKGROUND/AIM: The therapy with intravesical instillation of bacillus Calmette-Guérin (BCG) after transurethral resection (ITJR) of the tumor is the gold standard of treatment of non-muscle invasive bladder cancer (NMIBC). The aim of this study was to compare the frequencies of reccurence between a group of patients submitted to TUR + BCG therapy (group I) and a group of patients submitted only to TUR (group II). METHODS: The patients with NMIBC, a total of 899, treated in our Institution from January 1, 2007 to March, 2013, were included in this study and divided into two groups: group I and group II. These two groups were divided into three subgroups: solitary first diagnosed tumor ≤ 3 cm (SFDGT), solitary first diagnosed tumor > 3 cm and multiple first diagnosed tumors (MFDGT), and recedive tumors (RCT). Statistical analysis was performed by using χ2-test and Kolmogorov-Smirnov test. RESULTS: In the group I a total of 133 cases had reccurence contrary to 75 in the group II, making a statistically highly significant difference. Analysis of recurrences through the subgroups revealed: in the group I SFDGT recurrence occured in 27 of the cases vs 9 cases in the group II; in the group I MFDGT recurrence occured in 49 of the cases vs 31 in the group II (p < 0.001), and finally, in the group I RCT recurrence occured in 57 cases vs 35 cases in the group II (p < 0.001). CONCLUSION: The obtained results indicate no difference in the frequency of reccurence between the group I and group II regarding SFDGT, but a very high significant difference regarding those with MFDGT and RCT. These results should be taken into consideration in everyday clinical practise.

Radical cystectomy in eldery.

BACKGROUND/AIM: Radical cystectomy is the method of choice for the treatment of muscle invasive bladder cancer. This major surgery is associated with many complications, especially in older patients. The aim of this study was to analyze preoperative comorbidity, and intraoperative and postoperative complicatons in patients older than 75 years. METHODS: This clinical, retrospective study included 46 patients over 75 years, who underwent radical cystectomy. Indications for surgery, and complications during and after the surgery were followed up. RESULTS: Preoperatively, anemia caused by hematuria was registered in 76% of the patients. In 52% of the patients urine derivation was performed by ileal conduit, in 35% by ureterocutaneostomy and in 13% orthotopic ileal neobladder was created. The average duration of surgery was 190 (120-300) min. A total of 76% of the patients were treated by blood supstitution intraoperatively, average 630 (310-1230) mL. Concerning pathological stage of transitional cell carcinoma of urinary bladder, 26% of the patients had T2, 4% T3a, 52% T3b, and 14% T4a stage. In one case, planocellular carcinoma was diagnosed by patohistological examination, and in 2 cases prostate carcinoma was incidentally found. The average duration of hospitalization was 16 (8-35) days. CONCLUSION: The main reason for cystectomy in patients over 70-and 80 years was gross hematuria caused by bladder cancer, with consecutive anemia which could not be solved using endoscopic treat- ment or blood supstitution. As expected, a prolonged stay in hospital after cystectomy, and a higher rate of complications were recorded in this population.

A new reference line in diagnosing a high-riding patella on routine digital lateral radiographs of the knee.

OBJECTIVE: To propose a new reference line in diagnosing a high-riding patella (patella alta) on routine digital lateral radiographs of the knee. MATERIALS AND METHODS: On 64 routine digital lateral radiographs of adult knees with no bone pathology or surgery and over the range of knee flexion between 1.6° and 79.1° (34.4°± 16.6°), the long axis of the superimposed egg-shaped femoral condyles was drawn and moved upward to pass through the point where the posterior contours of the femoral diaphysis and the femoral condyles meet-the posterior reference point-to become a new reference line. Any part of the patella crossing the new reference line indicated a high-riding patella. The new reference line was compared with the four most common patellar height ratios (Insall-Salvati, Grelsamer-Meadows or the modified Insall-Salvati, Caton Deschamps, and Blackburne-Peel) for the drawing time, accuracy, and reproducibility (intra- and interobserver agreement). RESULTS: The new reference line required approximately one-third to one-half of the drawing time compared to the most common patellar height ratios, with equal accuracy and complete reproducibility. On the contrary, the reproducibility of the most common patellar height ratios ranged from poor to moderate, with the best results for the Insall-Salvati ratio. CONCLUSIONS: The new reference line proved to be a very simple, accurate, and reproducible tool in diagnosing a high-riding patella. We believe that our preliminary results are an encouraging impetus to more complex research.