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To the Editor Sodium-glucose co-transporter 2 (SGLT2) inhibitor therapy is a specific mode of anti-diabetic strategy that significantly improves cardiovascular outcomes.1 The recently published article by Joshi et al 1 has focused on beneficial effects of SGLT2 inhibitors in the setting of heart failure (HF). We fully agree that complex cellular mechanisms, beyond diuresis,1 seem to underlie pleitrophic actions of these agents. More specifically, it also seems likely that SGLT2 inhibitors might potentiate favourable effects of certain metabolic agents including cellular anti-ischaemics (and vice versa) in patients with diabetes with cardiovascular disease. Accordingly, combination of SGLT2 inhibitors with cellular anti-ischaemic regimens might have important implications in these …

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.

Bickerstaff’s brainstem encephalitis (BBE) has been regarded as a specific form of post-infectious and potentially autoimmune neurological disorder with a relatively favorable prognosis and usually presents with sensorial changes, ophthalmoplegia, and ataxia WOS:000572704600002 32975674 Q2

Over recent decades, systemic inflammation as quantified with inflammation markers or indices has been extensively investigated in the setting of various cardiovascular conditions including heart failure (HF), acute coronary syndromes (ACS). In contrast, systemic inflammation in patients with takotsubo syndrome (TTS) has been an underrated phenomenon in clinical practice. On the other hand, experimental and clinical data have been rapidly accumulating in the recent years regarding pathogenetic, prognostic as well as therapeutic implications of systemic inflammation in TTS. Accordingly, the present article aims to provide a general perspective on mechanistic and clinical aspects of systemic inflammation in the setting of TTS.

The present paper aims to highlight clinical implications of elevated cardiac biomarkers and associated myocardial dysfunction in a variety of cardiac and non-cardiac scenarios in patients with an asthma exacerbation, and to propose a basic algorithm for cardiovascular evaluation and triage (and hence, for further management) of these patients primarily based on evaluation of cardiac biomarkers along with basic diagnostic modalities and specific cardiac symptoms in the hospital setting. Elevation of cardiac biomarkers in the setting of an asthma exacerbation mostly signifies a new-onset subclinical myocardial dysfunction/injury generally associated with certain asthma-related factors including acute hypoxemia and bronchodilator therapy, and usually has a limited prognostic value in these patients. On the other hand, elevation of these biomarkers in patients with an asthma exacerbation might also denote a variety of certain life-threatening cardiac or non-cardiac conditions associated with significant myocardial dysfunction (acute coronary syndromes (ACSs), sepsis, etc.) that might be masked by the rampant course of the asthma exacerbation, and hence, might possibly go undetected potentially aggravating the prognosis in a portion of these patients. In patients with an asthma exacerbation, it seems imperative to timely diagnose and manage emerging diverse clinical conditions particularly through the guidance of cardiac biomarkers and associated myocardial dysfunction patterns in an effort to improve overall prognosis in these patients.

Yetkin, Ertan (isu author) Takotsubo cardiomyopathy (TTC) has been widely recognized as a specific form of transient myocardial dysfunction, and is well known to have a potential recurrence risk following the index event [1-11]. In a recent systematic review [3], certain factors in-cluding female gender, temporal proximity to the first TTC event, lower body mass index (BMI) and an existing mid-ventricular gra-dient (MVG) (potentially suggestive of a mechanical basis for TTC evolution) have been suggested as fundamental predictors of TTC recurrence. On the other hand, extreme adrenergic discharge in the setting of index TTC (regardless of its association with these sug-gested predictors) might potentially be regarded as central to the evolution of future TTC recurrences, and might present with in-direct clinical signs including left ventricular outflow tract (LVOT) gradient and coronary slow flow (CSF) in this setting [5-7]. In their recently published article [1], Ahmadjee A, et al have reported a female patient who had suffered a recurrent TTC episode with a completely different morphological pattern compared with the in-dex TTC (classical followed by a reverse TTC pattern). Accordingly; we would like to make a few comments on this interesting case and potential implications of morphological patterns in the setting of TTC recurrences WOS:000545794500008 32460038 Q3

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.

Dear Editor, Takotsubo cardiomyopathy (TTC) has been universally regarded as a unique form of reversible myocardial dysfunction associated with a variety of emotional and physical stressors. In their recently published elegant article, Dell'Aquila et al. have reported an interesting case of TTC triggered by an exacerbation of relapsing-remitting multiple sclerosis (MS). However, we would like to comment on this interesting case and its particular implications... WOS:000587752100020 32724231

In the recent decades, systemic inflammation, as a clinical phenomenon, has been the focus of extensive research particularly with regard to its potential association with a variety of cardiovascular diseases including atherogenesis and acute coronary syndromes. Within this context, there also exists a potential link between systemic inflammation and cardiac arrhythmogenesis in various aspects. Accordingly, systemic inflammation response as measured with inflammation markers (cytokines, etc) has been investigated in the setting of well-known cardiac arrhythmias including atrial fibrillation and ventricular tachycardia. Based on current literature, clinical utility of these markers might potentially yield important prognostic implications in the setting of certain arrhythmogenic conditions. On the other hand, there exists limited data regarding therapeutic implications including clinical benefit of primary anti-inflammatory agents (corticosteroids, colchicine, etc) in the setting of arrhythmia management. The present review primarily aims to discuss potential triggers and fundamental mechanisms of inflammation-related arrhythmias along with a particular emphasis on clinical implications of systemic inflammation in the setting of cardiac arrhythmogenesis.

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.

Neurohormones (NHs) in the cascade of the arginine vasopressin (AVP) system have drawn particular attention in the recent years. Copeptin, the C-terminal portion of provasopressin, is a novel NH of the AVP system, and is known to be co-released with AVP from hypothalamus (neurohypophysis). As a surrogate marker of the AVP system, copeptin has gradually replaced AVP in several clinical studies largely due to its structural and methodological advantages. Copeptin has been regarded as a marker of non-specific stress response, and has also been suggested to have clinical implications in a variety of non-cardiovascular (pneumonia, sepsis, etc.) and cardiovascular conditions (heart failure and acute coronary syndromes (ACSs, etc.)). However, current data on relation of copeptin with other cardiovascular conditions ( arrhythmias, etc.) are still insufficient. The present review primarily focuses on general features of copeptin, its general clinical implications, and specifically aims to cover its potential clinical value in a variety of cardiovascular conditions.

Erdogan, Kivilcim Eren/0000-0002-4951-8703; kilic bagir, Emine/0000-0002-1447-1060; Celik, Betul/0000-0001-9731-9939; Tatli Dogan, Hayriye/0000-0003-4318-2775; Cakir, Asli/0000-0003-0128-6947 WOS: 000414649400006 PubMed: 28272675 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.

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.

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.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.Mean survival for classical vascular pattern was longer than bizarre vascular pattern (p0.001). The survival time of patients decreased with increasing score of survivin staining. There was a significant correlation between survivin and survival time (p0.001). There was no significant correlation between microvessel density and survival time (p0.05).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.

Malignant skin tumors are known to occur on various forms of scars, chronic ulcerations, inflammations, fistulas and mainly on burn scars after a long latent period [1,2]. The term ‘‘Marjolin’s ulcer’’ is used for these malignant skin tumors arising on chronic wound and irritation sites [3]. The relation between malignant degeneration and thermal burn scars is known to have been defined by Celsus in the first century A.D., for the first time. This situation is named after the French surgeon Jean-Nicholas Marjolin who demonstrated the cellular changes of the ulcerated lesions in the scarred tissue in 1828, but it is claimed that Dupuytren also reported the malignant degeneration in 1839 [3,4]. The latent period between the initial injury and the diagnosis of the malignancy is quite long. Though various time periods have been reported, it is accepted to be longer than 20 years [2,5]. On the other hand, there is a reported case of Marjolin’s ulcer occurring a few months after the initial injury [2,3,6]. The pathogenesis of Marjolin’s ulcer is controversial [3,5,7–11]. The incidence of malignant skin tumors on scarred tissues is 0.1–2.5% and squamous cell cancers constitute the majority [2]. Though half of the cases (49%) are due to burn scars, physical and chemical frostbites, stasis ulcers, osteomyelitic sinuses, amputation stumps, syphilis, lupus vulgaris, hidradenitis suppurativa, vesicovaginal fistulas and lymphogranuloma venereum are among the reported rare causes of Marjolin’s ulcers [12]. Frostbite of the lower extremity, also known as ‘‘trench foot’’, is one of the etiologic factors of Marjolin’s ulcer, but

[1] Ravnskov U. The doubtful association between blood lipid changes and progression of atherosclerosis. Int J Cardiol 2011;153(1):95. [2] Tenenbaum A, Shemesh J, Koren-Morag N, et al. Long-term changes in serum cholesterol level does not influence the progression of coronary calcification. Int J Cardiol 2011;150:130–4. [3] Cowell SJ, Newby DE, Prescott RJ, et al. Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression (SALTIRE) investigators. A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis. N Engl J Med 2005;352:2389–97. [4] Chan KL, Teo K, Dumesnil JG, Ni A, Tam J. ASTRONOMER investigators. Effect of lipid lowering with rosuvastatin on progression of aortic stenosis: results of the aortic stenosis progression observation: measuring effects of rosuvastatin (ASTRONOMER) trial. Circulation 2010;121:306–14. [5] Rossebo AB, Pedersen TR, Boman K, et al, SEAS investigators. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008;359:1343–56. [6] Nissen SE, Nicholls SJ, Sipahi I, et al, ASTEROID investigators. Effect of very highintensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006;295:1556–65. [7] Nissen SE, Tuzcu EM, Schoenhagen P, et al. Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) Investigators. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 2005;352:29–38. [8] Ayaori M, Momiyama Y, Fayad ZA, et al. Effect of bezafibrate therapy on atherosclerotic aortic plaques detected by MRI in dyslipidemic patients with hypertriglyceridemia. Atherosclerosis 2008;196:425–33. [9] Villines TC, Stanek EJ, Devine PJ, et al. The ARBITER 6-HALTS Trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies in Atherosclerosis): final results and the impact of medication adherence, dose, and treatment duration. J Am Coll Cardiol 2010;55:2721–6.

thickening and stiffening [2–4]. In our case, the disease involved predominantly the lungs and airways thus requiring lung transplantation after cardiac evaluation. Since pectus excavatum is common in this pathology, echogenicitymay not be optimalwith difficulty to assess cardiac abnormality. In such case, we think that cardiac MRI is an excellent solution to accurately assess both ventricular function and valvular disease as demonstrated in this case. Interestingly, recent studies also described the ability of cMRI to assess myocardial lipid content by spectroscopy [5,6]. Although late enhancement imagingwas normal in our case, whether cardiac spectrometry could detect cardiac accumulation of glycosaminoglycans and proteoglycans, and could help to detect myocardial involvement in patients with MPS would be of interest. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [7,8]. Supplementary data to this article can be found online at doi:10.1016/j.ijcard.2010.10.089. References

WOS: 000272607700014, PubMed ID: 19996625, Objectives: To report a case of signet ring cell adenoma of the thyroid which is an extremely rare thyroid lesion. Clinical Presentation and Intervention: A 25-year-old female patient presented with a goiter and dysphagia that had been present for the last 1 year before admission. Physical examination revealed a palpable solitary nodule in the right lobe of the thyroid. The ultrasonogram demonstrated multiple nodules among which the most remarkable one was 15 ! 24 mm in size, in the right lobe of the thyroid. After surgical excision, the lesion was found to be consistent with signet ring cell adenoma characterized by the presence of round to oval signet ring cells with large cytoplasmic vacuoles and hyperchromatic eccentric nuclei. Intracytoplasmic thyroglobulin, periodic acid-Schiff (PAS) with and without diastase and combined Alcian-blue-PAS were all positive. Conclusions: Pathologists should keep this rare primary tumor of the thyroid in mind when examining thyroid lesions and should not confound it with metastatic signet ring cell carcinoma of the thyroid. Copyright (C) 2009 S. Karger AG, Basel

This study examined the frequency of E-cadherin expression in endometrial biopsy or hysterectomy specimens from patients diagnosed with endometrial adenocarcinoma and in normal endometrial tissue specimens. E-cadherin expression was detected by immunohistochemistry using monoclonal antibody to E-cadherin. Specimens were classified as positive when ≥ 5% of the tumour cells showed staining for E-cadherin, irrespective of the pattern of staining. Twenty-three endometrioid carcinomas and nine non-endometrioid (four papillary serous and five clear cell) carcinomas were studied, along with 10 normal endometrial tissue specimens as controls. E-cadherin expression was significantly less frequent in non-endometrioid carcinomas compared with endometrioid carcinomas and controls. There was no statistically significant difference in the frequency of E-cadherin expression between endometrioid carcinomas and controls. In conclusion, this study demonstrated that uterine non-endometrioid (papillary serous and clear cell) carcinomas were less likely to express E-cadherin compared with endometrioid carcinomas and normal endometrial tissue. This may help to explain the more aggressive behaviour of non-endometrioid carcinomas.

Neuromuscular hamartoma is a rare benign tumor consisted of well-differentiated striated muscle fibers within mature neural elements. Though most cases are composed of solitary masses associated with major peripheral nerves, multiple tumors or subcutaneous tumors without any association with peripheral nerves have also been reported. Twenty-three neuromuscular hamartomas of various anatomical locations have been reported in English literature. There have been no reports of this tumor in association with the occipital nerve. An interesting case of neuromuscular hamartoma of the occipital nerve is presented and previous reports about this rare pathology is reviewed.

Neurohormones have drawn particular attention in the recent years possiblyduetotheirpotentialdiagnosticandprognosticvalues inavarietyof clinical conditions includingcongestiveheart failure(CHF), acutemyocardial infarction (AMI), etc. Among neurohormones, arginine vasopressin (AVP) has been known to be secreted by hypothalamus in response to hypovolemia and increased plasma osmolality [1], and was also demonstrated to be a marker of the presence and severity of CHF [2]. However as described below, the potential association between AVP system and arrhythmogenesis may also confer some important therapeutic and prognostic implications in arrhthmia-prone patients. In the recent years, due to the instability and rapid clerance [1], the clinical utility of AVP has beengraduallyabandonedtosomedegree, andcopeptin(CP), anothernovel neurohormone of the AVP system, has come into use in the clinical practice. CP, the C-terminal portion of provasopressin [1], is co-released with AVP from hypothalamus. CP is structurally more stable, and hence may mirror the stable levels of AVP associated with the severity of the related disease [1]. CP was recently demonstrated to be a strong predictor of mortality and morbidity in patients suffering heart failure after an AMI [1]. In another study [3], CP was found to be associated with left ventricular dysfunction (inverse correlation between copeptin levels and left ventricular ejection fraction (LVEF)) in the early (at discharge) and late stages (on follow-up) of AMI indicating that hyperactivation of the AVPsystemseems tobea contributor (via inducing remodelling) and/or a consequence in the process of heart failure development. However, as an absolute clinical implication inCHF, substantial levels of CPmay indirectly denotepoor systemicperfusionassociatedwithdepressed left ventricular systolic function (a notion consistent with a previous study that demonstrated a negative correlation between AVP and cardiac index [2]). CHF is a well known trigger for malign ventricular arrhythmias through various mechanisms including structural alterations of myocardium, increased myocardial wall tension, adrenergic activation, enhanced effects of the AVP system on the heart, etc. AVP (co-secreted with CP) was suggested to induce protein synthesis, cardiac hypertrophy [4] and collagen synthesis in cardiac fibroblasts [5] in rats that may not only induce myocardial remodelling but may also create an arrhythmogenic substrate for malign ventricular arrhythmias indicating direct arrhythmogenic effects of AVP on myocardium in patients with CHF. It may be suggested that the association between CP levels and arrhythmogenesis may be dependent on left ventricular function, to some extent. However, this association may still persist even after adjustment for parameters of left ventricular function (LVEF, etc.) suggesting CP as an arrhythmogenic marker in arrhythmia-prone patients without heart failure as well. In the absence of heart failure, CP may still remain associated with arrhythmogenesis through various potentialmechanisms: CPwas found to be associatedwith the individual stress level [6]. In a very recently published study, CP was reported to have an additional diagnostic value in AMI (for rapid rule out) as an endogenous stress marker [7]. Hyperactivation of the adrenergic system is generally suggested to trigger malign ventricular arrhythmias and sudden cardiac death (SCD) in arrhythmia-prone subjects [8], and iswell known to be associated with the endogenous stress level. Therefore, CP may be regarded as a promising biochemical marker of arrhythmogenesis in arrhytmia-prone patients with and without heart failure. It may be suggested that besides conventional indices of arrhythmogenesis (QT dispersion, T wave alternance (TWA), heart rate variability (HRV), etc.), clinicians are in need of novel biochemicalmarkers thatmay rapidly and reliably predict the risk for arrhythmogenesis and arrhythmic mortality in arrhythmia-prone patients. CP, the novel and promising marker with strong predictive values, may help predict arrhythmia risk, and may help determine the therapeutic strategy in these patients. However, future large scale studies particularly focusing on the link between arrhythmogenesis and CP in arrhythmia-prone subjects are still warranted to confirm the clinical utility of CP in these patients. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [9].