Aim: In this prospective study, the efficiency of imaging findings was investigated by comparing ... more Aim: In this prospective study, the efficiency of imaging findings was investigated by comparing the histopathological results of lymph nodes with Doppler and ultrasound features and elasticity scores. Material and method: A total of 100 cervical or axillary lymph nodes with a suspected malignancy or whose size did not decrease after treatment were examined. In addition to the demographic data of the patients, B-mode ultrasound, Doppler ultrasound, and elastography features of the lymph nodes were evaluated prospectively. The irregular shape, increased size, pronounced hypoechogenicity, presence of micro/macro calcification, short axis/long axis ratio >2, increased size of the short axis, increased cortex thickness, obliterated hilus or increased cortex thickness >3.5 mm were evaluated on ultrasound. Resistivity index, pulsatility index, acceleration rate and time were evaluated for intranodal arterial structures on color. Doppler ultrasound, strain ratio value and elasticity ...
ÖZET Amaç: Bu çalışmada, meme manyetik rezonans görüntülemede (MRG) patolojik görünümlü aksiller ... more ÖZET Amaç: Bu çalışmada, meme manyetik rezonans görüntülemede (MRG) patolojik görünümlü aksiller lenf nodlarının (ALN) MRG ve tekstür analizi (TA) özellikleri kullanılarak, daha önce meme lezyonlarında uygulanan noninvaziv, tekrarlanabilir kantitatif yöntemlerin malign ALN’leri ayırt etmedeki etkinliği araştırılmıştır. Gereç ve yöntemler: Çalışmaya 2018-2020 tarihleri arasında hastanemiz Girişimsel Radyoloji bölümünde ALN’lere yönelik ince iğne aspirasyon biyopsisi ve/veya kesici iğne biyopsisi işlemi yapılan, dinamik kontrastlı ve diffüzyon meme MRG’de patolojik görünümlü ALN’si olan 18 yaş üzeri kadın hastalar dahil edilmiştir. Bulgular: Benign ve malign lenf nodları arasında T2A yağlı hilus varlığı açısından istatistiksel olarak anlamlı farklılık vardı (p=0,008). MR tekstür analizi sonuçlarının değerlendirilmesinde; benign ve malign grupta T2 area ve T2 skewness değerleri arasında (sırasıyla p=0,006; 0,029), ADC area ve ADC kurtosis değerleri arasında (sırasıyla p=0,027;0,005), p...
Pankreas Duktal Adenokarsinomu (PDA), yüksek öldürücülük oranına sahip, en kötü prognozlu tümörle... more Pankreas Duktal Adenokarsinomu (PDA), yüksek öldürücülük oranına sahip, en kötü prognozlu tümörlerdendir. PDA’lu çoğu hastada, tanı anında lokal ileri yada metastatik hastalık bulunmaktadır. Kötü prognozunun nedenlerinden biri, kemoterapi, radyoterapi ve immunoterapi gibi çoğu tedaviye dirençli olmasıdır. Tek potansiyel kür şansı olarak cerrahi tedavi önerilmektedir. Apopitoz inhibitör proteinler (IAPs) apopitozda, sitokinler ve sinyal iletiminde anahtar rol oynayan proteinlerdir. Çeşitli tümörlerin gelişiminde ve tedavi direncinde, IAP’in fonksiyonunda yada ekspresyonunda artış olduğuna dair kanıtlar bulunmaktadır. Survivin ve Livin bu ailenin üyelerindendir. Bu çalışmada PDA’nda, Survivin ve Livin ekspresyonunun, klinikopatolojik parametreler ve sağkalım ile ilişkisi araştırılmıştır. Bu çalışmada, 2000-2008 yılları arasında pankreas tümörü nedeniyle opere edilen ve EÜTF Patoloji AD’nda PDA tanısı alan 117 olgu incelenmektedir. Yyaş, cinsiyet, tümör çapı, lokalizasyonu patoloji rap...
Background: Tumor budding is a histopathological finding that is accepted as an indicator of epit... more Background: Tumor budding is a histopathological finding that is accepted as an indicator of epithelial-mesenchymal transformation in many solid tumors. Axl is a Receptor Tyrosine Kinase (RTK) family member and contributes to epithelial-mesenchymal transformation. It has been reported that its overexpression in various solid cancer cells is associated with a poor prognosis. It is claimed that Axl RTK may be the targeted molecule in treating some cancers due to its location in the cell membrane. Aims: To investigate the relationship between immunohistochemical (IHC) Axl expression with tumor budding on the histopathological level and their prognostic significance in patients with gallbladder carcinoma. Thus, it is aimed to contribute to the emergence of a molecular option for targeted, personalized therapy in these patients. Study Design: A retrospective cross-sectional study Methods: Thirty-eight gallbladder cancer patients who underwent surgery between 2000 and 2017 were included in the study. The expressions of Axl RTK in tumor tissues were evaluated by the IHC method. Demographic data (age, sex) of patients, histopathological features (size, growth pattern), tumor differentiation, pathological T staging, lymphovascular invasion, perineural and serosal invasion, surgical margin, tumor infiltrated lymphocyte, and tumor budding were examined. The tumor budding of the tumor was made according to the International Tumor Budding Consensus Conference and was classified as low (0-4 buds), intermediate (5-9 buds), high (≥ 10 buds). The relationship between clinical pathologic features, the survival rate, and Axl expression was analyzed with Person's chi-square, Cox regression tests, and the Kaplan-Meier method. Results: Tumor budding was determined as low in 12, intermediate in 10, and high in 16 cases. The increased degree of tumor budding was associated with focal-diffuse Axl expression (p = 0.018), infiltrative growth patterns (p = 0.031), poor differentiation (p = 0.006), advanced pathological stage (p = 0.002), and serosal (p = 0.040), perineural (p = 0.008), and lymphovascular invasion (p < 0.0001). Overall survival time was shorter in patients with intermediate to high tumor budding compared with those with low tumor budding (p = 0.011). Conclusion: Axl expression appears to be associated with tumor budding capacity, which may be a poor prognostic criterion for patients with gallbladder cancer. It may be a good target to prevent tumor budding to reduce tumor invasion and metastasis.
Bu calismanin amaci, merkezimizde US esliginde tiroid nodullerine uygulanan IIAS yeterlilik ve si... more Bu calismanin amaci, merkezimizde US esliginde tiroid nodullerine uygulanan IIAS yeterlilik ve sitolojik tani dagilimini degerlendirmek, ayrica hastanemizde ameliyat olmus hastalarin preoperatif sitoloji ve postoperatif doku tanilari arasindaki uyumu arastirmaktir. Calismamiza Agustos 2013 ile Eylul 2015 tarihleri arasinda, Izmir Bozyaka Egitim ve Arastirma Hastanesinde, cesitli kliniklerden girisimsel radyoloji unitesine US kilavuzlugunda TIIAS icin gonderilen, toplam 1114 IIAS yapilan 1089 hasta dahil edildi. Butun IIAS islemleri ayni girisimsel radyolog tarafindan yapildi. Sitoloji sonuclari 1) benign sitoloji (benign), 2) malignite yonunden supheli sitoloji (supheli), 3) malign sitoloji (malign), 4) tanisal olmayan sitoloji (yetersiz) olarak dort gruba ayrildi. Ayrica IIAS sonrasi opere edilen 116 hastada, sitoloji ve histopatoloji sonuclari karsilastirilarak, istatistiksel olarak, IIAS’nin duyarliligi, ozgullugu, pozitif prediktif degeri, negatif prediktif degeri, dogrulugu (accuracy), yanlis pozitif ve yanlis negatiflik orani hesaplandi. Toplam 1114 IIAS’nin 963’u (% 86.5) benign, 79’u (% 7.1) supheli, 26’si (% 2.3) malign ve 46’si (% 4.1) yetersiz grupta yer aldi. IIAS’de duyarlilik, %82.7 (43/52); ozgulluk, %87.5 (56/64); yanlis pozitif orani, %12.5 (8/64); yanlis negatif orani, %17.3 (9/52); pozitif prediktif degeri, %84.3 (43/51); negatif prediktif degeri, %86.1 (56/65); ve dogrulugu %85.4 (99/116) olarak bulundu. Ince igne aspirasyon sitolojisi, tiroid nodullerinin tani ve takibinde kendisine verilen onemi hak eden degerli bir yontemdir. Ancak yanlis negatif ve yanlis pozitif vakalarin oldugu goz onunde bulundurularak nodule yaklasimda en uygun karara hastanin klinik, radyolojik ve laboratuvar sonuclariyla birlikte bir butun olarak degerlendirilerek varilmalidir. Anahtar kelimeler: Ince igne aspirasyon, sitoloji, tiroid nodulu, ultrasonografi esligi
A comprehensive molecular classification was published in 2014 within The Cancer Genome Atlas (TC... more A comprehensive molecular classification was published in 2014 within The Cancer Genome Atlas (TCGA) to guide clinical approaches and treatment strategies. This study aimed to investigate the clinicopathological and prognostic importance of the classification using immunohistochemistry (IHC) and chromogenic in situ hybridization (CISH) to identify potential surrogate markers of molecular changes in gastroesophageal junction (GEJ) adenocarcinomas. A total of 52 GEJ adenocarcinomas were divided into five groups using IHC with MLH-1, E-cadherin, p53 and CISH with EBER: 1) microsatellite unstable (MSI: negative with MLH-1), 2) genomically stable tumors (GS: positive with p53), 3) chromosomally unstable tumors (CUN: negative with e-cadherin), 4) EBV+ tumors (EBV+: positive with EBER) and 5) unclassifiable (G-NOS: MLH-1 and e-cadherin positive with p53 and negative with EBER). The largest group consisted of 24 (46.2%) cases of CUN tumors. This group was followed by groups of GS with 14 (26.9%) cases, MSI with 7 (13.5%) cases, and EBV + with 3 (5.8%) cases, respectively. Although this classification was not associated with pathological features, it was found to be closely related to prognosis (p = 0.029). Patients with EBV+ tumors had the longest overall survival, followed by the G-NOS, MSI, CUN, GS groups.
Journal of Environmental Pathology, Toxicology and Oncology, 2021
AIM In our study, a new grading model (e-GM) including nuclear membrane irregularity highlighted ... more AIM In our study, a new grading model (e-GM) including nuclear membrane irregularity highlighted by emerin expression was proposed for renal cell carcinomas (RCC). It was aimed to investigate the relationship of this model with WHO/ISUP grading system, histopathological features, and prognosis. METHODS AND RESULTS 86 RCC cases were included in the study. The mean age of the patients was 59.65, and the mean tumor size was 6.36 cm. According to pTNM staging, 45 of the cases were stage 1, 11 were stage 2, 26 were stage 3, and 4 were stage 4. According to e-GM grading, advanced tumor grade was found to be associated with perirenal tissue extension, necrosis, lymphovascular invasion, distant metastasis, advanced pT and TNM stage. Nuclear membrane irregularity caused an increase in tumor grade in 17 wi-GS grade 1 cases, 14 WHO/ISUP grading system (wi-GS) grade 2 cases, and 1 wi-GS grade 3 case. In the stepwise statistical analysis, it was determined that the most important prognostic factor was the TNM stage, followed by age and tumor size. CONCLUSIONS Statistical analyses showed that nuclear membrane irregularity should be a criterion for classification according to e-GM in wi-grade 2 cases, but not necessarily in wi-grade 1 cases. Nuclear membrane irregularity was a prominent feature at high tumor grades, and its expression in RCCs suggests that it may be a target for tumor-specific treatments.
Bu calismanin amaci, merkezimizde US esliginde tiroid nodullerine uygulanan IIAS yeterlilik ve si... more Bu calismanin amaci, merkezimizde US esliginde tiroid nodullerine uygulanan IIAS yeterlilik ve sitolojik tani dagilimini degerlendirmek, ayrica hastanemizde ameliyat olmus hastalarin preoperatif sitoloji ve postoperatif doku tanilari arasindaki uyumu arastirmaktir. Calismamiza Agustos 2013 ile Eylul 2015 tarihleri arasinda, Izmir Bozyaka Egitim ve Arastirma Hastanesinde, cesitli kliniklerden girisimsel radyoloji unitesine US kilavuzlugunda TIIAS icin gonderilen, toplam 1114 IIAS yapilan 1089 hasta dahil edildi. Butun IIAS islemleri ayni girisimsel radyolog tarafindan yapildi. Sitoloji sonuclari 1) benign sitoloji (benign), 2) malignite yonunden supheli sitoloji (supheli), 3) malign sitoloji (malign), 4) tanisal olmayan sitoloji (yetersiz) olarak dort gruba ayrildi. Ayrica IIAS sonrasi opere edilen 116 hastada, sitoloji ve histopatoloji sonuclari karsilastirilarak, istatistiksel olarak, IIAS’nin duyarliligi, ozgullugu, pozitif prediktif degeri, negatif prediktif degeri, dogrulugu (ac...
Hepatocellular carcinomas (HCCs) with steatohepatitis and steatosis are reported with varying def... more Hepatocellular carcinomas (HCCs) with steatohepatitis and steatosis are reported with varying definitions and clinicopathologic features. We aimed to search the attributes of steatohepatitic hepatocellular carcinoma (SH-HCC) and steatotic-HCC in our series. A retrospective clinicopathologic analyses of 150 HCCs and immunostaining for C-reactive protein (CRP) and serum amyloid A (SAA) were performed. Tumors were reclassified as all SH-HCC, limited SH-HCC, typical SH-HCC (steatohepatitic features in >5%, 5% to 50%, and ≥50% of the tumor, respectively), steatotic-HCC, and classic HCC (C-HCC). Group comparisons were made using Kruskal-Wallis and Kaplan-Meier tests. The background etiology in all SH-HCCs was pure viral in 51.4%, nonalcoholic steatohepatitis (NASH)/alcoholic liver disease (ALD) alone/mixed in 34.3%, and unidentified in normal liver in 14.3%. All SH-HCCS (n=35, 23.3%) and typical SH-HCCs (n=13, 8.6%) had higher NASH/ALD. Limited SH-HCCs (n=22, 14.6%) had higher ALD (all P<0.05). Typical SH-HCCs tended to have more NASH (P=0.054). Steatotic-HCCs (n=13, 9%) and C-HCCs (n=102, 68%) had higher pure viral etiology and serum CRP (all P<0.05). CRP and SAA were positive in 69% and 27% of the tumors, respectively. SAA positivity correlated with ALD (P=0.026). In the overall group disease-free survival rates at 1, 5, 10, and 20 years were 97.0%, 82.3%, 79.6%, and 77.2%, respectively. Demographics, tumor characteristics, CRP and SAA positivity, and survival were similar between the groups (P>0.05). SH-HCC is heterogenous in terms of underlying etiologies, and can be seen in NASH/ALD, pure viral and noncirrhotic/normal background. The ≥50% cutoff for the definition of SH-HCC can lead to overlook ALD-related SH-HCC. Steatotic-HCC seems more similar to C-HCC rather than SH-HCC, but none of them feature as a different prognostic group.
Acinar cystic transformation (ACT) or acinar cell cystadenoma is a rare benign tumor of the pancr... more Acinar cystic transformation (ACT) or acinar cell cystadenoma is a rare benign tumor of the pancreas. Their clinical presentation is nonspecific, thus hampering their detection and frequently leading to misdiagnosis. In this report, we present a case of ACT of the pancreas in a 54-year-old man that was vague abdominal symptoms. A magnetic resonance imaging was shown a well-defined cystic mass located in the head of the pancreas, measuring 57×47×23 mm. Our patient was treated by pancreaticoduodenectomy. In the macroscopic examination of the mass, a multicystic lesion was found in cream-colored pancreatic tissue. Histological and immunohistochemical studies examination revealed a cystic mass containing multiple cysts at varying sizes, lined by epithelial cells without atypia and positive staining of CK7, CK8/18, and CK19. A high index of clinical suspicion is required to diagnose this tumor. The surgical approach is to ensure accurate diagnosis and to avoid complications
AIM: To investigate the effects of different magnesium forms on tissue damage, cognitive and emot... more AIM: To investigate the effects of different magnesium forms on tissue damage, cognitive and emotional behavioural impairment after mild traumatic brain injury (TBI). MATERIAL and METHODS: Rats were divided into 5 groups (control, trauma, magnesium sulphate, magnesium citrate, magnesium acetyl taurate) and following head trauma, empathy-like behaviour, anxiety-like behaviour (elevated plus maze and open field tests), and depression (forced swim test) were measured. The rats were then sacrificed 12 days later. Oxytocin, vasopressin and receptors levels in the amygdala and prefrontal cortex regions were measured. Histopathological damage (with haematoxylin-eosin staining) and apoptosis (with caspase-3 immunohistochemistry) was evaluated. RESULTS: Following head trauma, anxiety-like behaviour and depression tests did not change; empathy-like behaviour deteriorated on the 3 rd day and improved gradually on the 6 th and 12 th days. Oxytocin, vasopressin and vasopressin v1b receptor levels decreased in the amygdala; morphological damage and apoptosis were significant. Magnesium acetyl taurate effectively ameliorated histopathological deteriorations and improved vasopressin and v1b receptor levels in the amygdala. Transient deterioration of empathy-like behaviour was impeded only in magnesium taurate treatment. CONCLUSION: Magnesium acetyl taurate can be a promising candidate agent to prevent structural and functional damage in traumatic brain injury.
Vascular endothelial growth factor (VEGF) is the most important regulator of angiogenesis which s... more Vascular endothelial growth factor (VEGF) is the most important regulator of angiogenesis which serves to provide sufficient blood supply, and can trigger both physiological and pathological angiogenesis. Recent studies have shown that VEGF increases in gynecological diseases (such as endometriosis, ovarian, and endometrial cancers) and is a prognostic factor in these pathologies. Therefore, VEGF should be maintained at appropriate levels. Magnesium is used in many gynecological practices (such as eclampsia, preeclampsia, dysmenorrhea, and climacteric symptoms) and the mechanisms of action are still under investigation. Redox status, which can be regulated by magnesium, was shown to affect VEGF expression. The aim of this study was to evaluate the effects of chronic magnesium use on VEGF and oxidative status in the uterus. Magnesium sulfate was administered to rats at doses of 30 mg/kg (intramuscular) for 2 weeks. VEGF, Superoxide dismutase (SOD), Glutathione peroxidase (GPx), and Malondialdehyde (MDA) levels were measured using ELISA; vascular and cellular alterations were determined by histology in the uterine tissue at the metoestrus phase. In the uterine tissue of Mg-treated subjects, magnesium levels increased while VEGF, SOD, GPx, and MDA levels decreased without histological changes. There was a negative correlation between uterine tissue magnesium levels and VEGF, SOD, GPx, and MDA levels. Consequently, the results of this study demonstrated that regular magnesium use decreased VEGF levels in uterus. Decreased VEGF levels were associated with decreased uterine oxidative stress. Chronic magnesium usage may protect the uterine tissue from certain diseases in which angiogenesis is critical.
Anaplastic carcinoma of the pancreas (ACP) is a very rare histologic subtype of pancreatic cancer... more Anaplastic carcinoma of the pancreas (ACP) is a very rare histologic subtype of pancreatic cancer and associated with more aggressive and poor prognosis than pancreatic ductal adenocarcinoma. We aimed to review this rare entity and discuss its clinical features, diagnosis and therapy. We presented a case of a 63-year-old male patient that diagnosed as ACP with cyst formation at a tertiary medical center with a detailed review of the current medical literature. We performed pancreaticoduodenectomy operation with lymph node dissection after diagnosis. Any complication after surgery was not observed. Anaplastic pancreas carcinomas are associated with poor survival when compared to invasive ductal adenocarcinomas. Clinical, radiological, laboratory and histological features may be helpful in making differential diagnosis and should be kept in mind in the diagnosis of this rare pancreatic malignancy.
Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer, 2017
Oncocytic neoplasms of the adrenal gland are extremely rare tumors. These tumors differ from thei... more Oncocytic neoplasms of the adrenal gland are extremely rare tumors. These tumors differ from their nononcocytic counterparts in some respects. The aim of this study was to review and discuss the clinical, histological, and immunohistochemical features of as well as the prognosis for these rare tumors. In total, 16 cases diagnosed as adrenocortical oncocytic neoplasms between January 2011 and December 2016 were included in the study. The demographic data, gross characteristics, histological data, and immunohistochemical data (Chromogranin-A, Synaptophysin, α-Inhibin, Melan-A, Ki67, PHH3) were reevaluated. The follow-up data for these patients were added in January 2017. Of the 16 cases, 12 were adrenocortical adenoma, 1 was borderline adrenocortical tumor, and 3 were adrenocortical carcinoma. The tumors equally affected both genders. The tumors were not generally large. Tumor cells had pleomorphic nuclei in ten cases, but it was more obvious in one case. The mitotic figure count was ...
Objective: As there is continuing disagreement among the observers on the differential diagnosis ... more Objective: As there is continuing disagreement among the observers on the differential diagnosis between the epithelial changes/lesions and neoplasms of the gallbladder, this multicentre study was planned in order to assess the rate of the epithelial gallbladder lesions in Turkey and to propose microscopy and macroscopy protocols. Material and Method: With the participation of 22 institutions around Turkey that were included in the Hepato-Pancreato-Biliary Study Group, 89,324 cholecystectomy specimens sampled from 2003 to 2016 were retrospectively evaluated. The numbers of adenocarcinomas, dysplasias, intracholecystic neoplasms/adenomas, intestinal metaplasias and reactive atypia were identified with the review of pathology reports and the regional and countrywide incidence rates were presented in percentages. Results: epithelial changes/lesions were reported in 6% of cholecystectomy materials. Of these epithelial lesions, 7% were reported as adenocarcinoma, 0.9% as high-grade dysplasia, 4% as low-grade dysplasia, 7.8% as reactive/regenerative atypia, 1.7% as neoplastic polyp, and 15.6% as intestinal metaplasia. The remaining lesions (63%) primarily included non-neoplastic polypoids/hyperplastic lesions and antral/pyloric metaplasia. There were also differences between pathology laboratories. Conclusion: The major causes of the difference in reporting these epithelial changes/lesions and neoplasms include the differences related to the institute's oncological surgery frequency, sampling protocols, geographical dissimilarities, and differences in the diagnoses/interpretations of the pathologists. It seems that the diagnosis may change if new sections are taken from the specimen when any epithelial abnormality is seen during microscopic examination of the cholecystectomy materials.
The term intracholecystic papillary-tubular neoplasm (ICPN) is suggested by some authors for a gr... more The term intracholecystic papillary-tubular neoplasm (ICPN) is suggested by some authors for a group of exophytic lesions of the gallbladder. In our study, demographic, pathological, and immunohistochemical features of 45 ICPN cases and their relationship with invasive carcinoma were analyzed. A total of 45 ICPN cases were retrieved out of 7334 cholecystectomies performed between1996 and 2014. Cases were evaluated with regard to demographic, pathological, and immunohistochemical features. Correlation between the clinical and histopathological data and occurrence of invasion was sought. The incidence of ICPN was 0.61% in our series. Invasive carcinoma was observed in 56% of cases. Factors associated with invasion were diffuse high-grade dysplasia (P = .002), papillary growth pattern (P = .001), greatest diameter of the lesion, and high Ki67 proliferation index (P < .0001). Some authors have reported that small intracholecystic exophytic lesions without high-grade dysplasia are con...
Journal of Environmental Pathology, Toxicology and Oncology, 2016
Recent studies report that tumor microenvironment effects prognosis of colorectal cancers. We ana... more Recent studies report that tumor microenvironment effects prognosis of colorectal cancers. We analyzed the densities of FoxP3 + cells and CD8 + cells, the ratio of FoxP3 + /CD8 + cells and the relationship between these parameters, clinicopathological features, and prognosis. A total of 186 colorectal adenocarcinoma were evaluated in terms of clinicopathological features. Immunohistochemically, densities of intratumoral (IT; IT-FoxP3) and nontumoral (NT; NT-FoxP3) FoxP3 + cells and IT-CD8 and NT-CD8 CD8 + cells were calculated. The ratio of Foxp3/CD8 was recorded. IT-FoxP3 and the ratio of IT-FoxP3/IT-CD8 were higher than NT-FoxP3 and the ratio of NT-FoxP3/NT-CD8, respectively. In multivariate analysis, high FoxP3 + cell density is the most important predictive marker after clinical stage and surgical margin positivity in disease-free survival and the most important predictive marker after clinical stage in overall survival (OS). Short OS time was correlated with clinical stage, decrease in IT-FoxP3, increasing age, number of metastatic lymph nodes, surgical margin positivity, satellite tumor nodule, medullary carcinoma, and the number of pericolorectal lymph nodes. The ratio of FoxP3/CD8 increased noticeably in the IT area, but no relationship was found with survival. The relationships of the cells with one another in the tumor microenvironment seem to have many secrets. Studies in large series supported by molecular techniques can illuminate those secrets to some extent.
Aim: In this prospective study, the efficiency of imaging findings was investigated by comparing ... more Aim: In this prospective study, the efficiency of imaging findings was investigated by comparing the histopathological results of lymph nodes with Doppler and ultrasound features and elasticity scores. Material and method: A total of 100 cervical or axillary lymph nodes with a suspected malignancy or whose size did not decrease after treatment were examined. In addition to the demographic data of the patients, B-mode ultrasound, Doppler ultrasound, and elastography features of the lymph nodes were evaluated prospectively. The irregular shape, increased size, pronounced hypoechogenicity, presence of micro/macro calcification, short axis/long axis ratio >2, increased size of the short axis, increased cortex thickness, obliterated hilus or increased cortex thickness >3.5 mm were evaluated on ultrasound. Resistivity index, pulsatility index, acceleration rate and time were evaluated for intranodal arterial structures on color. Doppler ultrasound, strain ratio value and elasticity ...
ÖZET Amaç: Bu çalışmada, meme manyetik rezonans görüntülemede (MRG) patolojik görünümlü aksiller ... more ÖZET Amaç: Bu çalışmada, meme manyetik rezonans görüntülemede (MRG) patolojik görünümlü aksiller lenf nodlarının (ALN) MRG ve tekstür analizi (TA) özellikleri kullanılarak, daha önce meme lezyonlarında uygulanan noninvaziv, tekrarlanabilir kantitatif yöntemlerin malign ALN’leri ayırt etmedeki etkinliği araştırılmıştır. Gereç ve yöntemler: Çalışmaya 2018-2020 tarihleri arasında hastanemiz Girişimsel Radyoloji bölümünde ALN’lere yönelik ince iğne aspirasyon biyopsisi ve/veya kesici iğne biyopsisi işlemi yapılan, dinamik kontrastlı ve diffüzyon meme MRG’de patolojik görünümlü ALN’si olan 18 yaş üzeri kadın hastalar dahil edilmiştir. Bulgular: Benign ve malign lenf nodları arasında T2A yağlı hilus varlığı açısından istatistiksel olarak anlamlı farklılık vardı (p=0,008). MR tekstür analizi sonuçlarının değerlendirilmesinde; benign ve malign grupta T2 area ve T2 skewness değerleri arasında (sırasıyla p=0,006; 0,029), ADC area ve ADC kurtosis değerleri arasında (sırasıyla p=0,027;0,005), p...
Pankreas Duktal Adenokarsinomu (PDA), yüksek öldürücülük oranına sahip, en kötü prognozlu tümörle... more Pankreas Duktal Adenokarsinomu (PDA), yüksek öldürücülük oranına sahip, en kötü prognozlu tümörlerdendir. PDA’lu çoğu hastada, tanı anında lokal ileri yada metastatik hastalık bulunmaktadır. Kötü prognozunun nedenlerinden biri, kemoterapi, radyoterapi ve immunoterapi gibi çoğu tedaviye dirençli olmasıdır. Tek potansiyel kür şansı olarak cerrahi tedavi önerilmektedir. Apopitoz inhibitör proteinler (IAPs) apopitozda, sitokinler ve sinyal iletiminde anahtar rol oynayan proteinlerdir. Çeşitli tümörlerin gelişiminde ve tedavi direncinde, IAP’in fonksiyonunda yada ekspresyonunda artış olduğuna dair kanıtlar bulunmaktadır. Survivin ve Livin bu ailenin üyelerindendir. Bu çalışmada PDA’nda, Survivin ve Livin ekspresyonunun, klinikopatolojik parametreler ve sağkalım ile ilişkisi araştırılmıştır. Bu çalışmada, 2000-2008 yılları arasında pankreas tümörü nedeniyle opere edilen ve EÜTF Patoloji AD’nda PDA tanısı alan 117 olgu incelenmektedir. Yyaş, cinsiyet, tümör çapı, lokalizasyonu patoloji rap...
Background: Tumor budding is a histopathological finding that is accepted as an indicator of epit... more Background: Tumor budding is a histopathological finding that is accepted as an indicator of epithelial-mesenchymal transformation in many solid tumors. Axl is a Receptor Tyrosine Kinase (RTK) family member and contributes to epithelial-mesenchymal transformation. It has been reported that its overexpression in various solid cancer cells is associated with a poor prognosis. It is claimed that Axl RTK may be the targeted molecule in treating some cancers due to its location in the cell membrane. Aims: To investigate the relationship between immunohistochemical (IHC) Axl expression with tumor budding on the histopathological level and their prognostic significance in patients with gallbladder carcinoma. Thus, it is aimed to contribute to the emergence of a molecular option for targeted, personalized therapy in these patients. Study Design: A retrospective cross-sectional study Methods: Thirty-eight gallbladder cancer patients who underwent surgery between 2000 and 2017 were included in the study. The expressions of Axl RTK in tumor tissues were evaluated by the IHC method. Demographic data (age, sex) of patients, histopathological features (size, growth pattern), tumor differentiation, pathological T staging, lymphovascular invasion, perineural and serosal invasion, surgical margin, tumor infiltrated lymphocyte, and tumor budding were examined. The tumor budding of the tumor was made according to the International Tumor Budding Consensus Conference and was classified as low (0-4 buds), intermediate (5-9 buds), high (≥ 10 buds). The relationship between clinical pathologic features, the survival rate, and Axl expression was analyzed with Person's chi-square, Cox regression tests, and the Kaplan-Meier method. Results: Tumor budding was determined as low in 12, intermediate in 10, and high in 16 cases. The increased degree of tumor budding was associated with focal-diffuse Axl expression (p = 0.018), infiltrative growth patterns (p = 0.031), poor differentiation (p = 0.006), advanced pathological stage (p = 0.002), and serosal (p = 0.040), perineural (p = 0.008), and lymphovascular invasion (p < 0.0001). Overall survival time was shorter in patients with intermediate to high tumor budding compared with those with low tumor budding (p = 0.011). Conclusion: Axl expression appears to be associated with tumor budding capacity, which may be a poor prognostic criterion for patients with gallbladder cancer. It may be a good target to prevent tumor budding to reduce tumor invasion and metastasis.
Bu calismanin amaci, merkezimizde US esliginde tiroid nodullerine uygulanan IIAS yeterlilik ve si... more Bu calismanin amaci, merkezimizde US esliginde tiroid nodullerine uygulanan IIAS yeterlilik ve sitolojik tani dagilimini degerlendirmek, ayrica hastanemizde ameliyat olmus hastalarin preoperatif sitoloji ve postoperatif doku tanilari arasindaki uyumu arastirmaktir. Calismamiza Agustos 2013 ile Eylul 2015 tarihleri arasinda, Izmir Bozyaka Egitim ve Arastirma Hastanesinde, cesitli kliniklerden girisimsel radyoloji unitesine US kilavuzlugunda TIIAS icin gonderilen, toplam 1114 IIAS yapilan 1089 hasta dahil edildi. Butun IIAS islemleri ayni girisimsel radyolog tarafindan yapildi. Sitoloji sonuclari 1) benign sitoloji (benign), 2) malignite yonunden supheli sitoloji (supheli), 3) malign sitoloji (malign), 4) tanisal olmayan sitoloji (yetersiz) olarak dort gruba ayrildi. Ayrica IIAS sonrasi opere edilen 116 hastada, sitoloji ve histopatoloji sonuclari karsilastirilarak, istatistiksel olarak, IIAS’nin duyarliligi, ozgullugu, pozitif prediktif degeri, negatif prediktif degeri, dogrulugu (accuracy), yanlis pozitif ve yanlis negatiflik orani hesaplandi. Toplam 1114 IIAS’nin 963’u (% 86.5) benign, 79’u (% 7.1) supheli, 26’si (% 2.3) malign ve 46’si (% 4.1) yetersiz grupta yer aldi. IIAS’de duyarlilik, %82.7 (43/52); ozgulluk, %87.5 (56/64); yanlis pozitif orani, %12.5 (8/64); yanlis negatif orani, %17.3 (9/52); pozitif prediktif degeri, %84.3 (43/51); negatif prediktif degeri, %86.1 (56/65); ve dogrulugu %85.4 (99/116) olarak bulundu. Ince igne aspirasyon sitolojisi, tiroid nodullerinin tani ve takibinde kendisine verilen onemi hak eden degerli bir yontemdir. Ancak yanlis negatif ve yanlis pozitif vakalarin oldugu goz onunde bulundurularak nodule yaklasimda en uygun karara hastanin klinik, radyolojik ve laboratuvar sonuclariyla birlikte bir butun olarak degerlendirilerek varilmalidir. Anahtar kelimeler: Ince igne aspirasyon, sitoloji, tiroid nodulu, ultrasonografi esligi
A comprehensive molecular classification was published in 2014 within The Cancer Genome Atlas (TC... more A comprehensive molecular classification was published in 2014 within The Cancer Genome Atlas (TCGA) to guide clinical approaches and treatment strategies. This study aimed to investigate the clinicopathological and prognostic importance of the classification using immunohistochemistry (IHC) and chromogenic in situ hybridization (CISH) to identify potential surrogate markers of molecular changes in gastroesophageal junction (GEJ) adenocarcinomas. A total of 52 GEJ adenocarcinomas were divided into five groups using IHC with MLH-1, E-cadherin, p53 and CISH with EBER: 1) microsatellite unstable (MSI: negative with MLH-1), 2) genomically stable tumors (GS: positive with p53), 3) chromosomally unstable tumors (CUN: negative with e-cadherin), 4) EBV+ tumors (EBV+: positive with EBER) and 5) unclassifiable (G-NOS: MLH-1 and e-cadherin positive with p53 and negative with EBER). The largest group consisted of 24 (46.2%) cases of CUN tumors. This group was followed by groups of GS with 14 (26.9%) cases, MSI with 7 (13.5%) cases, and EBV + with 3 (5.8%) cases, respectively. Although this classification was not associated with pathological features, it was found to be closely related to prognosis (p = 0.029). Patients with EBV+ tumors had the longest overall survival, followed by the G-NOS, MSI, CUN, GS groups.
Journal of Environmental Pathology, Toxicology and Oncology, 2021
AIM In our study, a new grading model (e-GM) including nuclear membrane irregularity highlighted ... more AIM In our study, a new grading model (e-GM) including nuclear membrane irregularity highlighted by emerin expression was proposed for renal cell carcinomas (RCC). It was aimed to investigate the relationship of this model with WHO/ISUP grading system, histopathological features, and prognosis. METHODS AND RESULTS 86 RCC cases were included in the study. The mean age of the patients was 59.65, and the mean tumor size was 6.36 cm. According to pTNM staging, 45 of the cases were stage 1, 11 were stage 2, 26 were stage 3, and 4 were stage 4. According to e-GM grading, advanced tumor grade was found to be associated with perirenal tissue extension, necrosis, lymphovascular invasion, distant metastasis, advanced pT and TNM stage. Nuclear membrane irregularity caused an increase in tumor grade in 17 wi-GS grade 1 cases, 14 WHO/ISUP grading system (wi-GS) grade 2 cases, and 1 wi-GS grade 3 case. In the stepwise statistical analysis, it was determined that the most important prognostic factor was the TNM stage, followed by age and tumor size. CONCLUSIONS Statistical analyses showed that nuclear membrane irregularity should be a criterion for classification according to e-GM in wi-grade 2 cases, but not necessarily in wi-grade 1 cases. Nuclear membrane irregularity was a prominent feature at high tumor grades, and its expression in RCCs suggests that it may be a target for tumor-specific treatments.
Bu calismanin amaci, merkezimizde US esliginde tiroid nodullerine uygulanan IIAS yeterlilik ve si... more Bu calismanin amaci, merkezimizde US esliginde tiroid nodullerine uygulanan IIAS yeterlilik ve sitolojik tani dagilimini degerlendirmek, ayrica hastanemizde ameliyat olmus hastalarin preoperatif sitoloji ve postoperatif doku tanilari arasindaki uyumu arastirmaktir. Calismamiza Agustos 2013 ile Eylul 2015 tarihleri arasinda, Izmir Bozyaka Egitim ve Arastirma Hastanesinde, cesitli kliniklerden girisimsel radyoloji unitesine US kilavuzlugunda TIIAS icin gonderilen, toplam 1114 IIAS yapilan 1089 hasta dahil edildi. Butun IIAS islemleri ayni girisimsel radyolog tarafindan yapildi. Sitoloji sonuclari 1) benign sitoloji (benign), 2) malignite yonunden supheli sitoloji (supheli), 3) malign sitoloji (malign), 4) tanisal olmayan sitoloji (yetersiz) olarak dort gruba ayrildi. Ayrica IIAS sonrasi opere edilen 116 hastada, sitoloji ve histopatoloji sonuclari karsilastirilarak, istatistiksel olarak, IIAS’nin duyarliligi, ozgullugu, pozitif prediktif degeri, negatif prediktif degeri, dogrulugu (ac...
Hepatocellular carcinomas (HCCs) with steatohepatitis and steatosis are reported with varying def... more Hepatocellular carcinomas (HCCs) with steatohepatitis and steatosis are reported with varying definitions and clinicopathologic features. We aimed to search the attributes of steatohepatitic hepatocellular carcinoma (SH-HCC) and steatotic-HCC in our series. A retrospective clinicopathologic analyses of 150 HCCs and immunostaining for C-reactive protein (CRP) and serum amyloid A (SAA) were performed. Tumors were reclassified as all SH-HCC, limited SH-HCC, typical SH-HCC (steatohepatitic features in >5%, 5% to 50%, and ≥50% of the tumor, respectively), steatotic-HCC, and classic HCC (C-HCC). Group comparisons were made using Kruskal-Wallis and Kaplan-Meier tests. The background etiology in all SH-HCCs was pure viral in 51.4%, nonalcoholic steatohepatitis (NASH)/alcoholic liver disease (ALD) alone/mixed in 34.3%, and unidentified in normal liver in 14.3%. All SH-HCCS (n=35, 23.3%) and typical SH-HCCs (n=13, 8.6%) had higher NASH/ALD. Limited SH-HCCs (n=22, 14.6%) had higher ALD (all P<0.05). Typical SH-HCCs tended to have more NASH (P=0.054). Steatotic-HCCs (n=13, 9%) and C-HCCs (n=102, 68%) had higher pure viral etiology and serum CRP (all P<0.05). CRP and SAA were positive in 69% and 27% of the tumors, respectively. SAA positivity correlated with ALD (P=0.026). In the overall group disease-free survival rates at 1, 5, 10, and 20 years were 97.0%, 82.3%, 79.6%, and 77.2%, respectively. Demographics, tumor characteristics, CRP and SAA positivity, and survival were similar between the groups (P>0.05). SH-HCC is heterogenous in terms of underlying etiologies, and can be seen in NASH/ALD, pure viral and noncirrhotic/normal background. The ≥50% cutoff for the definition of SH-HCC can lead to overlook ALD-related SH-HCC. Steatotic-HCC seems more similar to C-HCC rather than SH-HCC, but none of them feature as a different prognostic group.
Acinar cystic transformation (ACT) or acinar cell cystadenoma is a rare benign tumor of the pancr... more Acinar cystic transformation (ACT) or acinar cell cystadenoma is a rare benign tumor of the pancreas. Their clinical presentation is nonspecific, thus hampering their detection and frequently leading to misdiagnosis. In this report, we present a case of ACT of the pancreas in a 54-year-old man that was vague abdominal symptoms. A magnetic resonance imaging was shown a well-defined cystic mass located in the head of the pancreas, measuring 57×47×23 mm. Our patient was treated by pancreaticoduodenectomy. In the macroscopic examination of the mass, a multicystic lesion was found in cream-colored pancreatic tissue. Histological and immunohistochemical studies examination revealed a cystic mass containing multiple cysts at varying sizes, lined by epithelial cells without atypia and positive staining of CK7, CK8/18, and CK19. A high index of clinical suspicion is required to diagnose this tumor. The surgical approach is to ensure accurate diagnosis and to avoid complications
AIM: To investigate the effects of different magnesium forms on tissue damage, cognitive and emot... more AIM: To investigate the effects of different magnesium forms on tissue damage, cognitive and emotional behavioural impairment after mild traumatic brain injury (TBI). MATERIAL and METHODS: Rats were divided into 5 groups (control, trauma, magnesium sulphate, magnesium citrate, magnesium acetyl taurate) and following head trauma, empathy-like behaviour, anxiety-like behaviour (elevated plus maze and open field tests), and depression (forced swim test) were measured. The rats were then sacrificed 12 days later. Oxytocin, vasopressin and receptors levels in the amygdala and prefrontal cortex regions were measured. Histopathological damage (with haematoxylin-eosin staining) and apoptosis (with caspase-3 immunohistochemistry) was evaluated. RESULTS: Following head trauma, anxiety-like behaviour and depression tests did not change; empathy-like behaviour deteriorated on the 3 rd day and improved gradually on the 6 th and 12 th days. Oxytocin, vasopressin and vasopressin v1b receptor levels decreased in the amygdala; morphological damage and apoptosis were significant. Magnesium acetyl taurate effectively ameliorated histopathological deteriorations and improved vasopressin and v1b receptor levels in the amygdala. Transient deterioration of empathy-like behaviour was impeded only in magnesium taurate treatment. CONCLUSION: Magnesium acetyl taurate can be a promising candidate agent to prevent structural and functional damage in traumatic brain injury.
Vascular endothelial growth factor (VEGF) is the most important regulator of angiogenesis which s... more Vascular endothelial growth factor (VEGF) is the most important regulator of angiogenesis which serves to provide sufficient blood supply, and can trigger both physiological and pathological angiogenesis. Recent studies have shown that VEGF increases in gynecological diseases (such as endometriosis, ovarian, and endometrial cancers) and is a prognostic factor in these pathologies. Therefore, VEGF should be maintained at appropriate levels. Magnesium is used in many gynecological practices (such as eclampsia, preeclampsia, dysmenorrhea, and climacteric symptoms) and the mechanisms of action are still under investigation. Redox status, which can be regulated by magnesium, was shown to affect VEGF expression. The aim of this study was to evaluate the effects of chronic magnesium use on VEGF and oxidative status in the uterus. Magnesium sulfate was administered to rats at doses of 30 mg/kg (intramuscular) for 2 weeks. VEGF, Superoxide dismutase (SOD), Glutathione peroxidase (GPx), and Malondialdehyde (MDA) levels were measured using ELISA; vascular and cellular alterations were determined by histology in the uterine tissue at the metoestrus phase. In the uterine tissue of Mg-treated subjects, magnesium levels increased while VEGF, SOD, GPx, and MDA levels decreased without histological changes. There was a negative correlation between uterine tissue magnesium levels and VEGF, SOD, GPx, and MDA levels. Consequently, the results of this study demonstrated that regular magnesium use decreased VEGF levels in uterus. Decreased VEGF levels were associated with decreased uterine oxidative stress. Chronic magnesium usage may protect the uterine tissue from certain diseases in which angiogenesis is critical.
Anaplastic carcinoma of the pancreas (ACP) is a very rare histologic subtype of pancreatic cancer... more Anaplastic carcinoma of the pancreas (ACP) is a very rare histologic subtype of pancreatic cancer and associated with more aggressive and poor prognosis than pancreatic ductal adenocarcinoma. We aimed to review this rare entity and discuss its clinical features, diagnosis and therapy. We presented a case of a 63-year-old male patient that diagnosed as ACP with cyst formation at a tertiary medical center with a detailed review of the current medical literature. We performed pancreaticoduodenectomy operation with lymph node dissection after diagnosis. Any complication after surgery was not observed. Anaplastic pancreas carcinomas are associated with poor survival when compared to invasive ductal adenocarcinomas. Clinical, radiological, laboratory and histological features may be helpful in making differential diagnosis and should be kept in mind in the diagnosis of this rare pancreatic malignancy.
Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer, 2017
Oncocytic neoplasms of the adrenal gland are extremely rare tumors. These tumors differ from thei... more Oncocytic neoplasms of the adrenal gland are extremely rare tumors. These tumors differ from their nononcocytic counterparts in some respects. The aim of this study was to review and discuss the clinical, histological, and immunohistochemical features of as well as the prognosis for these rare tumors. In total, 16 cases diagnosed as adrenocortical oncocytic neoplasms between January 2011 and December 2016 were included in the study. The demographic data, gross characteristics, histological data, and immunohistochemical data (Chromogranin-A, Synaptophysin, α-Inhibin, Melan-A, Ki67, PHH3) were reevaluated. The follow-up data for these patients were added in January 2017. Of the 16 cases, 12 were adrenocortical adenoma, 1 was borderline adrenocortical tumor, and 3 were adrenocortical carcinoma. The tumors equally affected both genders. The tumors were not generally large. Tumor cells had pleomorphic nuclei in ten cases, but it was more obvious in one case. The mitotic figure count was ...
Objective: As there is continuing disagreement among the observers on the differential diagnosis ... more Objective: As there is continuing disagreement among the observers on the differential diagnosis between the epithelial changes/lesions and neoplasms of the gallbladder, this multicentre study was planned in order to assess the rate of the epithelial gallbladder lesions in Turkey and to propose microscopy and macroscopy protocols. Material and Method: With the participation of 22 institutions around Turkey that were included in the Hepato-Pancreato-Biliary Study Group, 89,324 cholecystectomy specimens sampled from 2003 to 2016 were retrospectively evaluated. The numbers of adenocarcinomas, dysplasias, intracholecystic neoplasms/adenomas, intestinal metaplasias and reactive atypia were identified with the review of pathology reports and the regional and countrywide incidence rates were presented in percentages. Results: epithelial changes/lesions were reported in 6% of cholecystectomy materials. Of these epithelial lesions, 7% were reported as adenocarcinoma, 0.9% as high-grade dysplasia, 4% as low-grade dysplasia, 7.8% as reactive/regenerative atypia, 1.7% as neoplastic polyp, and 15.6% as intestinal metaplasia. The remaining lesions (63%) primarily included non-neoplastic polypoids/hyperplastic lesions and antral/pyloric metaplasia. There were also differences between pathology laboratories. Conclusion: The major causes of the difference in reporting these epithelial changes/lesions and neoplasms include the differences related to the institute's oncological surgery frequency, sampling protocols, geographical dissimilarities, and differences in the diagnoses/interpretations of the pathologists. It seems that the diagnosis may change if new sections are taken from the specimen when any epithelial abnormality is seen during microscopic examination of the cholecystectomy materials.
The term intracholecystic papillary-tubular neoplasm (ICPN) is suggested by some authors for a gr... more The term intracholecystic papillary-tubular neoplasm (ICPN) is suggested by some authors for a group of exophytic lesions of the gallbladder. In our study, demographic, pathological, and immunohistochemical features of 45 ICPN cases and their relationship with invasive carcinoma were analyzed. A total of 45 ICPN cases were retrieved out of 7334 cholecystectomies performed between1996 and 2014. Cases were evaluated with regard to demographic, pathological, and immunohistochemical features. Correlation between the clinical and histopathological data and occurrence of invasion was sought. The incidence of ICPN was 0.61% in our series. Invasive carcinoma was observed in 56% of cases. Factors associated with invasion were diffuse high-grade dysplasia (P = .002), papillary growth pattern (P = .001), greatest diameter of the lesion, and high Ki67 proliferation index (P < .0001). Some authors have reported that small intracholecystic exophytic lesions without high-grade dysplasia are con...
Journal of Environmental Pathology, Toxicology and Oncology, 2016
Recent studies report that tumor microenvironment effects prognosis of colorectal cancers. We ana... more Recent studies report that tumor microenvironment effects prognosis of colorectal cancers. We analyzed the densities of FoxP3 + cells and CD8 + cells, the ratio of FoxP3 + /CD8 + cells and the relationship between these parameters, clinicopathological features, and prognosis. A total of 186 colorectal adenocarcinoma were evaluated in terms of clinicopathological features. Immunohistochemically, densities of intratumoral (IT; IT-FoxP3) and nontumoral (NT; NT-FoxP3) FoxP3 + cells and IT-CD8 and NT-CD8 CD8 + cells were calculated. The ratio of Foxp3/CD8 was recorded. IT-FoxP3 and the ratio of IT-FoxP3/IT-CD8 were higher than NT-FoxP3 and the ratio of NT-FoxP3/NT-CD8, respectively. In multivariate analysis, high FoxP3 + cell density is the most important predictive marker after clinical stage and surgical margin positivity in disease-free survival and the most important predictive marker after clinical stage in overall survival (OS). Short OS time was correlated with clinical stage, decrease in IT-FoxP3, increasing age, number of metastatic lymph nodes, surgical margin positivity, satellite tumor nodule, medullary carcinoma, and the number of pericolorectal lymph nodes. The ratio of FoxP3/CD8 increased noticeably in the IT area, but no relationship was found with survival. The relationships of the cells with one another in the tumor microenvironment seem to have many secrets. Studies in large series supported by molecular techniques can illuminate those secrets to some extent.
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