Clinicopathological and molecular analyses of uterine carcinosarcomas using next-generation sequencing: A single-center experience.

Background: Uterine carcinosarcomas (UCS) constitute 3-4% of all uterine malignancies and 16% of deaths caused due to uterine neoplasms. Aim: In this study, we aimed to perform DNA-based mutation analysis in 12 genes (KRAS, NRAS, EGFR, C-KIT, BRAF, PDGFRA, ALK, ERBB2, ERBB3, ESR1, RAF1, PIK3CA) to determine the molecular subtypes of UCS using next-generation sequencing (NGS) in patients with aggressive UCS and poor prognosis. We aimed to compare the results of our analysis with clinicopathological data to contribute to the development of targeted therapy approaches related to the molecular changes of UCS. Materials and Methods: In this study, we included 12 cases diagnosed with uterine carcinosarcomas and examined the changes in oncogenes that play a role in UCS pathogenesis. For the analysis of mutation, the clinicopathological data were compared with the variations in the DNA-based gene panel consisting of 12 genes and 1237 variants in the UCS using the NGS method. Results: EGFR mutation was found in 91.7% of the cases, mutation in 41.7%, PDGFRA mutation in 25%, KRAS and PIK3CA mutation in 16.7%, and C-KIT mutation in 8.3% of the cases. Although no statistical significance was found between the detected mutation and clinicopathological data, it was concluded that PDGFRA mutation might be associated with advanced-stage disease development. Conclusion: This study's findings regarding different molecular types of UCS and information on oncogenesis of UCS can provide inferences for targeted therapies in the future by identifying targetable mutations representing early oncogenic events and thereby contribute toward further studies on this subject.

Serum Copeptin in Cardiooncology Practice: Review of Pathophysiological and Clinical Implications.

In cardiooncology practice, "early cardiotoxicity" refers to an emerging subclinical myocardial dysfunction/injury in response to certain chemotherapeutic regimens. This condition can progress to overt cardiotoxicity in time and hence warrants proper and timely diagnostic and preventive strategies. Current diagnostic strategies for "early cardiotoxicity" are largely based on conventional biomarkers and certain echocardiographic indices. However, a significant gap still exists in this setting, warranting further strategies to improve diagnosis and overall prognosis in cancer survivors. Copeptin (surrogate marker of the arginine vasopressine axis) might serve as a promising adjunctive guide for the timely detection, risk stratification, and management of early cardiotoxicity on top of conventional strategies largely due to its multifaceted pathophysiological implications in the clinical setting. This work aims to focus on serum copeptin as a marker of "early cardiotoxicity" and its general clinical implications in patients with cancer.

Cardiac myxoma as a potential trigger of takotsubo cardiomyopathy: A brief review on mechanistic and clinical perspectives.

In clinical practice, cardiac myxomas constitute the majority of benign cardiac neoplasms, and might potentially present with a variety of embolic, obstructive as well as constitutional symptoms. On the other hand, these neoplasms might be potentially associated with the evolution of takotsubo cardiomyopathy (TTC) that is universally considered as a transient form of acute myocardial dysfunction. Accordingly, the present paper primarily aims to focus on potential mechanisms and associated clinical implications of TTC evolution in the setting of cardiac myxomas.

Takotsubo syndrome in association with pheochromocytoma: clinical and practical considerations.

In clinical practice, pathophysiology of Takotsubo syndrome (TTS) has been attributed to adrenergic discharge mostly associated with a variety of stressors. Occasionally, organic sources of adrenergic discharge (including pheochromocytoma) might also account for this phenomenon and are not considered as exclusion criteria for the diagnosis of TTS (as opposed to previous suggestions). We read with great interest the recently published article by Maffè et al. that describes a case of fatal TTS due to a ruptured pheochromocytoma in a middle-aged male. In this context, we would like to comment on this interesting case and potential implications of TTS associated with pheochromocytoma....

BRAF V600 Mutation Profile of Metastatic Melanoma in the Thrace Region of Turkey.

OBJECTIVE: BRAF is the most common mutation in melanoma. The most common subtype is BRAF V600E, followed by V600K. Initially, the authors aimed to investigate whether clinicopathological features of melanoma are associated with BRAF mutations. We then aimed to present the relationships between the clinicopathological features and the mutated subtype (V600E vs V600K). MATERIAL AND METHOD: 61 patients with metastatic malignant melanoma (affecting the lymph node or other distant sites) were selected. Patient data regarding age at the time of diagnosis, sex, metastatic site (lymph node, distant metastasis or both) and primary tumour site were obtained from the hospital's database. Tissue samples containing at least 30% tumour cells were isolated from the specimens of 61 patients (24 samples from primary tumours and 37 from metastatic foci) for BRAF analysis. Comparisons between the BRAF V600 mutation and clinicopathological and histopathological features were performed. RESULTS: BRAF V600 mutation was detected in 34 (55.7%) patients. The subtype was BRAF V600E in 22 (64.7%) patients, BRAF V600K in 11(32.4%) patients and BRAF V600R in 1(2.9%) patient. The crucial results of the present study may be summarized as follows: i) BRAF V600 mutation was more common in older patients and tumors with BRAF V600 mutation revealed necrosis and LVI more commonly than wild-type tumors, ii) BRAF V600K mutation was more common in older patients and BRAF V600K mutated tumors exhibited ulceration more commonly than tumors with BRAF V600E mutation (close to significant). CONCLUSION: The BRAF V600 mutation may have interactions with prognostic clinicoptahological features of melanoma including necrosis and lymphovascular invasion. V600K mutation may be more common than expected and may have different associations with properties of the tumor such as tumor ulceration and patient age. Investigation of the mutated subtype of the BRAF gene may therefore reveal more detailed data about the management of melanoma and may also prevent missing of candidates for BRAF inhibitor therapies.

What does the Data of 354,725 Patients from Turkey Tell Us About Cervical Smear Epithelial Cell Abnormalities? - The Epithelial Cell Abnormality Rate is Increasing - Quality Control Studies and Corrective Activity are Musts.

OBJECTIVE: There is no other screening program close to the success rate of PAP test. Cervical cytology constitutes a large workload so that quality control in cervical cytology is important for the quality assurance of pathology laboratories. MATERIAL AND METHOD: In this study, we collected the cervical cytology results from all over Turkey and discussed the parameters influencing the quality of the PAP test. The study was conducted with Turkish gynaecopathology working group and 38 centers (totally 45 hospitals) agreed to contribute from 24 different cities. The study was designed to cover the cervical cytology results during 2013. The results were evaluated from the data based on an online questionnaire. RESULTS: The total number of Epithelial Cell Abnormality was 18,020 and the global Epithelial Cell Abnormality rate was 5.08% in the total 354,725 smears and ranging between 0.3% to 16.64% among centers. The Atypical squamous cells /Squamous intraepithelial lesion ratios changed within the range of 0.21-13.94 with an average of 2.61. When the centers were asked whether they performed quality assurance studies, only 14 out of 28 centers, which shared the information, had such a control study and some quality parameters were better in these centers. CONCLUSION: There is an increase in the global Epithelial Cell Abnormality rate and there are great differences among centers. Quality control studies including the Atypical squamous cells/Squamous intraepithelial lesion ratio are important. Corrective and preventive action according to quality control parameters is a must. A cervical cytology subspecialist in every center can be utopic but a dedicated pathologist in the center is certainly needed.

TERT Expression in Pituitary Adenomas.

OBJECTIVE: Although pituitary adenomas have benign histomorphological features, some of them may present in an aggressive manner. To predict the behaviour of these tumours, telomerase reverse transcriptase (TERT) activity in pituitary adenomas has been the subject of a few studies with contradictory results. This study aims to investigate whether immunohistochemical expression of TERT differs in neoplastic and nonneoplastic pituitary tissues and aims to investigate whether TERT expression is related to clinicopathological features of pituitary adenomas. MATERIAL AND METHOD: The study included 48 patients who had been diagnosed with pituitary adenomas and had clinical follow-ups. Nonneoplastic pituitary tissues were obtained from autopsy specimens (n=20). Immunohistochemistry for TERT antibody was performed. Both the nuclear and cytoplasmic expression of TERT antibody was noted, and total combined TERT staining was evaluated according to nuclear and cytoplasmic stainings. RESULTS: TERT expression did not differ between neoplastic and nonneoplastic pituitary tissues. Neither total (combined nuclear and cytoplasmic) TERT nor nuclear TERT expression revealed any statistically significant relationship with any of the clinicopathological features. Higher cytoplasmic TERT expression was observed in adenomas with recurrence than adenomas without recurrence (p=0.035). CONCLUSION: This study introduces the notion that immunohistochemical expression of TERT does not differ in neoplastic and nonneoplastic pituitary tissues. Pituitary adenomas with cytoplasmic immunohistochemical expression of TERT have significantly higher rates of recurrence. Further studies, including combined methods of immunohistochemistry and molecular analyses in larger groups, may reveal applicable results for the clinical significance of TERT in pituitary adenomas.

Prognostic Value of Angiogenesis and Survivin Expression in Patients with Glioblastoma.

AIM: Glioblastoma (GBM) is the most common and the most aggressive primary brain tumor with poor prognosis. We aimed to evaluate the association between immunohistochemical expression of survivin and angiogenic parameters (microvessel density and vascular pattern) in patients who underwent surgery for GBM. MATERIAL AND METHODS: The pathology reports and also clinical and follow-up data of patients with GBM were retrospectively evaluated. Control tissues were obtained from the archive for each antibody (Survivin, CD 34). Then, control staining of these antibodies was performed. Vessels were evaluated according to the standardized assessment of vascular pattern. RESULTS: Mean survival for classical vascular pattern was longer than bizarre vascular pattern (p < 0.001). The survival time of patients decreased with increasing score of survivin staining. There was a significant correlation between survivin and survival time (p < 0.001). There was no significant correlation between microvessel density and survival time (p > 0.05). CONCLUSION: With these findings, it is considered that high expression of survivin, bizarre vascular pattern and development of secondary GBM correlates with the low survival rates, however microvessel density has no correlation with the survival rates. Since only malignant cells express survivin, it might be a target protein for the development of novel therapies.

A giant ancient schwannoma mimicking an adnexal mass: Case report.

INTRODUCTION: Ancient schwannoma is a rare tumor of the peripheral nerve sheath. As degenerative properties are defined histologically, it can be wrongly interpreted as malignant. CASE PRESENTATION: The case presented here is of a giant ancient schwannoma with a pelvic retroperitoneal location, which was mimicking an adnexal mass. CONCLUSION: In the rarely seen cases in the retroperitoneum, it may reach very large dimensions.

Importance of Ki-67 in human epidermal growth factor receptor 2 positive breast cancer.

PURPOSE: The aim of this study was to evaluate the importance of Ki-67 in Human Epidermal Growth Factor Receptor 2 (Her-2) positive breast cancer patients. METHODS: We reviewed the records of patients diagnosed with Her-2-positive non-metastatic breast cancer between 2005 and 2011. Paraffin-embedded tissue samples were stained with MIB-1 mouse monoclonal antibody to find Ki-67 levels. Patients were grouped as low Ki-67<20% and high Ki-67≥20%. Demographic and clinical features were compared. RESULTS: One hundred and six patients were included in the study. Median follow up time was 41 months (range 15-100). Median age was 49.5 years (range 29-79). Twenty-nine patients (27.4%) were in the Ki-67 low group. Demographic features were similar in both groups. Lymphovas cular invasion was more frequent in the Ki-67 high group, and hormone receptor (HR) positivity was more frequent in the Ki-67 low group (p=0.03, p=0.03, respectively). Recurrence rate was not significantly different in both groups (p=0.36). T stage (p=0.02), stage (p<0.01), lymphovascular invasion (p=0.02), ER status (p=0.02), and HR status (p<0.01) were related with recurrence. In multivariate analysis, stage and HR negativity were independent factors for recurrence (p<0.01, p=0.01, respectively). Recurrence sites were also similar in both groups. Survival rates at the third year for Ki-67 low group and Ki-67 high group were 94% and 92%, respectively. CONCLUSION: Her-2 positive patients with low Ki-67 and high Ki-67 had similar demographic and pathologic features except lymphovascular invasion and HR status. HR status was an important factor for disease course. Clinical course was determined by HR status rather than Ki-67.

Effect of leptin and apelin preconditioning on hepatic ischemia reperfusion injury in rats.

Leptin and apelin are important adipocytokines involved in a variety of endocrine and paracrine functions. The aim of this study was to evaluate the effect of exogenous leptin and apelin preconditioning on hepatic ischemia reperfusion (I/R) injury in rats. Forty mice were assigned to four groups (n = 10): sham-operated control (sham), I/R injury, I/R + leptin (I/R + L), and I/R + apelin (I/R + A). Leptin 100 µg/kg/day and apelin 2 µg/kg/day were delivered intraperitoneally starting 3 days prior to surgical procedure in I/R + L and I/R + A groups, respectively. All I/R groups underwent 45 min of warm ischemia, followed by 30 min of reperfusion. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), liver malondialdehyde (MDA) and glutathione (GSH), and liver histopathology were compared between groups. MDA was elevated in I/R, but stayed similar in I/R + L and I/R + A compared to sham. I/R + A had significantly lower MDA compared to I/R. GSH levels did not differ significantly between the groups. ALT and AST were elevated in all I/R groups, but significant reduction was observed in I/R + L and I/R + A compared to I/R. Liver histopathology was mostly mild in I/R + L and I/R + A, in contrast to severe injury observed in the I/R group. Leptin and apelin preconditioning significantly reduced hepatic I/R injury in rats.

Protective effect of everolimus on renal ischemia reperfusion injury in rats.

The aim of this study was to determine the effect of everolimus and tacrolimus pretreatments on renal morphology and function in a rat ischemia reperfusion (I/R) model. Twenty-eight male Sprague-Dawley rats were randomly assigned to saline + sham operation, saline + I/R (IR), tacrolimus + I/R (TRL + I/R) and everolimus + I/R (ERL + I/R) groups. Saline and active treatments were administered intraperitoneally for seven consecutive days before the surgery. The suprarenal aorta was clamped to achieve warm ischemia, except in the sham group. Right nephrectomy was performed in all animals and histology was examined. Renal function was assessed on post-operative Day 7 by Tc-99m dimercaptosuccinic acid (DMSA) scintigraphy, glomerular filtration rate (GFR) and serum biochemistry. Both everolimus and tacrolimus preserved serum creatinine and blood urea nitrogen levels, but only everolimus preserved GFR (0.74 ± 0.36, 1.20 ± 0.37 and 2.24 ± 0.32 mL/min for I/R, TRL + I/R and ERL + I/R, respectively, P < 0.001). %ID values for sham, I/R, TRL + I/R and ERL + I/R were 55 ± 3, 47 ± 4, 45 ± 6 and 62 ± 7 (P < 0.001). On histologic evaluation, ERL + I/R showed less tubular damage and necrosis than I/R, as well as TRL + I/R. Within the confines of this rat warm ischemia model, everolimus pre-treatment was useful in preserving renal function following I/R injury. The possibility of using everolimus as a pre-conditioning agent for I/R injury in kidney transplantation should be further explored.

An experimental model of aortic surgery and the effect of Iloprost on lung injury.

OBJECTIVES: Ischemia/reperfusion (I/R) damage of the lung is a frequently encountered complication following aortic surgery. The aim of the present study is to investigate the histopathological effects of Iloprost on pulmonary damage developed after I/R. DESIGN: Twenty-four Sprague-Dawley rats were randomly divided into 3 groups. In the control group, aortas were not clamped. In the I/R group, aortas were occluded, and after 1 h of ischemia, clamps were removed. After 2 h of reperfusion period, lungs of the rats were extracted. In the I/R + Iloprost group after 1 h of ischemia, Iloprost infusion was initiated, and maintained for the duration of 2 h reperfusion period. For histopathological scoring, density of polymorphonuclear leucocytes, congestion, interstitial edema, and bleeding were semiquantitatively evaluated, and histopathological changes were scored. RESULTS: In the I/R group, multifocal-marked histopathological changes in 5 (62.5%), and multifocal-moderate histopathological changes in 3 (37.5%) rats were detected. In the I/R + Iloprost group, multifocal-moderate histopathological changes in 4 (50%), and multifocal-mild changes in 4 (50%) rats were detected. CONCLUSIONS: In the experimental rat model, administration of Iloprost has been shown to have preventive effects for pulmonary damage occurring after I/R generated by infrarenal aortic occlusion.