Coexistence of acute severe leukocytosis and anaplastic lymphoma kinase­positive histiocytic sarcoma, a rare entity with an unusual presentation: A case report.

Soft tissue sarcomas are rare cancers and most cases are metastatic at the time of diagnosis. Although the chances of survival are good with surgical treatment in the early stages, systemic treatment in the advanced stages is only associated with a survival duration of ~12 months. Alterations in the anaplastic lymphoma kinase (ALK) gene are becoming increasingly recognized as pan-cancer indicators in solid tumors. However, little is known regarding the molecular spectrum of ALK-positive histiocytosis. Molecular treatments, including ALK inhibitors, are potential treatment options. The present case report describes an aggressive ALK-positive soft tissue sarcoma with intracardiac metastases and severe leukocytosis responding to ALK inhibitors. The patient initially responded to crizotinib but required alectinib due to central nervous system progression. The patient has shown a near-complete response and remained stable for 2 years; however, there has been recent lymph node progression.

Papillary microcarcinoma of the thyroid gland: Evaluation of TERT and BRAFV-600E expression and their relationship with clinicopathological findings.

Papillary microcarcinomas (PMCs) are papillary carcinomas ≤1 cm in size, with an increasing incidence. Although generally indolent, some cases exhibit aggressive behavior. Recently, active surveillance has been recommended to avoid surgical treatment. Identifying molecular changes that predict aggressiveness in PMCs has gained importance, but studies are limited. We aimed to demonstrate TERT expression and BRAF V600E positivity immunohistochemically in PMCs and correlate them with histomorphological features, subtypes, and clinicopathological findings. We included 95 PMC cases diagnosed between 2010 and 2019 at the Department of Pathology, Faculty of Medicine, XXX University. We investigated TERT expression using RT-PCR. We evaluated BRAF V600E mutation immunohistochemically. We evaluated the relationship between genetic, histomorphological, and clinicopathological findings. In patients with multifocality and those with a tumor size ≥0.5 cm, the frequency of lymph node metastasis was significantly higher. A positive correlation was shown between BRAF V600E positivity and lymph node metastasis, lymphovascular invasion, advanced disease stage, and classical subtype by univariate analyses. We detected TERT expression in 18 of 95 patients (7.8 %). No relationship could be detected between TERT expression alone or combined with BRAF positivity and clinicopathological features. Although TERT mutations are associated with aggressiveness in thyroid cancers, this association was absent in PMCs. The presence of TERT expression was demonstrated in some cases. However, TERT expression could not be associated with clinicopathological findings, which is consistent with the literature suggesting that TERT plays a role in advanced stages of carcinogenesis.

Outcomes in Patients with Macrotrabecular-Massive Subtype Hepatocellular Carcinoma Treated with Yttrium-90 Transarterial Radioembolization.

PURPOSE: To compare the outcomes of yttrium-90 transarterial radioembolization (TARE) in patients with hepatocellular carcinoma (HCC) with and without macrotrabecular-massive (MTM) subtypes. MATERIALS AND METHODS: Forty-one consecutive patients with HCC (male, 90.3%; mean age, 65.3 years [SD ± 10.7]) who underwent yttrium-90 TARE between September 2014 and January 2022 were grouped into the MTM-HCC (n = 17, 41.5%) and non-MTM-HCC (n = 24, 58.5%) groups based on their histopathological subtypes. Demographic, clinical, and radiological characteristics were compared. Survival, univariate, and multivariate analyses were performed, and prognostic factors were evaluated. RESULTS: In MTM-HCC group, the rates of moderately to poorly differentiated tumors were significantly higher (13/17 vs 8/16, P = .007), and new intrahepatic/extrahepatic metastases were detected more frequently (12/17 vs 15/24, P = .038). Median overall survival (OS) in the cohort was 29 months (range, 17.1-40.9 months), whereas patients with MTM-HCC had a significantly shorter median OS (20 vs 44 months, P = .014). In univariate analysis, MTM-HCC subtype (hazard ratio [HR], 2.690; P = .021), the presence of satellite nodules (HR, 3.810; P = .004), and macrovascular invasion (HR, 3.321; P = .012) were identified as significant prognostic factors. In multivariate analysis, MTM-HCC subtype and macrovascular invasion were determined as independent poor prognostic factors (P = .038 and P = .012, respectively). CONCLUSIONS: In patients with HCC treated with yttrium-90 TARE, both the rates of moderately to poorly differentiated histopathological classes and the development of intrahepatic or extrahepatic metastases were significantly higher in the MTM-HCC subtype. OS was worse in patients with MTM-HCC, and macrovascular invasion and MTM-HCC subtype were identified as independent poor prognostic factors.

Site specific genetic differences in colorectal cancer via Next-Generation-Sequencing using a multigene panel.

AIM: Next-generation sequencing (NGS) has been proposed as a comprehensive and efficient genomic profiling tool to guide personalized therapy for colorectal cancer. This study aimed to review the site-specific difference and the potential benefits of actionable mutation panel for colorectal cancer in relation to the clinicopathological features. MATERIAL AND METHODS: One hundred and six patients who underwent colorectal surgery with curative or palliative intent for histopathologically confirmed carcinoma between June 2016 and June 2018 were identified from a prospectively maintained database. Formalin-fixed, paraffin-embedded tumor tissues were analyzed for actionable variants in 11 genes via NGS (EGFR, ALK, KRAS, NRAS, KIT, BRAF, PDGFRA, ERBB2, ERBB3, ESR1, and RAF1). RESULTS: Most of the primary tumors were in the rectum (49 patients; 46.2%) followed by the right colon (32 patients; 30.1%) and left colon (25 patients; 23.5%), respectively. Of sequenced cases, 43 KRAS mutations, 7 EGFR mutations, 6 NRAS mutations, 6 BRAF mutations, 3 KIT mutations, 1 ERBB2 mutation, 1 PDGFRA mutation, and 1 RAF1 mutation were identified in 106 patients. The frequency of mutations is mostly concentrated on the right colon group. The highest drug resistance observed in all patients was against Cetuximab and Panitumumab, and the highest drug resistance was found in the right colon group (53.1%). CONCLUSIONS: The utility of actionable multigene panel revealed the value of a well-designed next-generation sequencing workflow in the practical use of clinical outcomes via the prediction of responsiveness to therapeutic agents or indications for novel treatment modalities in addition to prognosis estimate. KEY WORDS: Colorectal Cancer, Drug Resistance, Next-Generation Sequencing.

Pre-operative Neo-adjuvant Chemotherapy Related miRNAs as Key Regulators and Therapeutic Targets in Colorectal Cancer.

BACKGROUND: In colorectal cancer, the investigation of cancer pathogenesis and the determination of the relevant gene and gene pathways is particularly important to provide a basis for treatment-oriented studies. miRNAs which affect gene regulation in the molecular pathogenesis of cancer, have an active role in carcinogenesis. In the literature, miRNA expression levels have been associated with metastasis and prognosis in different cancers. OBJECTIVE: In our study, expression profiling of miRNAs involved in oncogenic and apoptotic pathways in patients with locally advanced colorectal cancer receiving neoadjuvant therapy was performed. METHODS: miRNAs were isolated from three different FFPE tissue samples taken at different times of the same patient (tumor tissue taken at the time of diagnosis, normal tissue samples, and after neoadjuvant therapy). The expression analysis of 84 miRNAs determined by PCR array (Fluidigm, USA) and mediated meta-analysis was performed comparatively to each study and non-cancerous control group. Evaluations were performed with ΔΔCT calculations. RESULTS: As a result of the miRNA PCR array study, in addition to differences were observed in miRNA expression between control and study groups. The potential biomarkers which were hsamiR- 215-5p, hsa-miR-9-59, hsa-miR-193a-5p, hsa-miR-206, hsa-miR-1, hsa-miR-96-5p have been detected for possible treatment resistance, prognosis and predispositions to cancers. CONCLUSION: In patients with colorectal cancer, miRNA expression in the tumoral regions before and after neoadjuvant therapy has represented a variable pattern. It has been shown that miRNA studies can be used to predict the clinical course and response to treatment with differences in expression levels. It has been concluded that specific miRNAs may be candidate biomarkers for colorectal cancer.

Minimal Change Nephrotic Syndrome with Acute Kidney Injury after the Administration of Pfizer-BioNTech COVID-19 Vaccine.

Nephrotic syndrome progresses with various metabolic disturbances, such as proteinuria over 3.5 grams in 24 hours, hypoalbuminemia, and hypercoagulability. Patients usually complain about diffuse edema throughout the body, which is secondary to hypoalbuminemia. It has many primary and secondary causes. Patients may require a renal biopsy to confirm the diagnosis. Besides, many secondary causes of nephrotic syndrome should be examined and excluded. Although many vaccines were developed due to the COVID-19, many side effects are still reported because of the Pfizer-BioNTech COVID-19 vaccine (COVID-19 mRNA and BNT162b2), which is widely used in Turkey. This study examines a case of nephrotic syndrome with acute renal injury after Pfizer-BioNTech vaccine.

Correlation between the tissue ghrelin presence, disease activity and laboratory parameters in ulcerative colitis patients; immunohistochemical study.

BACKGROUND: The aim of the study was to determine the differences in terms of ghrelin presence in the colon between the patients with ulcerative colitis (UC) and control patients. METHODS: Sixty-one UC and 15 control patients were included in the study. Immunohistochemical staining for ghrelin was investigated in colonic biopsy samples of UC and control patients. UC patients were subdivided into Group A (absence of ghrelin staining) and Group B (presence of staining for ghrelin in biopsy samples). Disease activity scores, laboratory parameters and quantitative ghrelin staining were compared in both groups of UC patients, as well as with the observations in control patients. RESULTS: Cells in colonic mucosa stained for ghrelin were identified in twenty-three (37.7%) UC patients, while this proportion in control patients was 6/15(40%). A significant difference was found between Groups A and B for serum albumin concentration but not for erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), hemoglobin concentration or leucocyte count. Mayo score/disease activity index (DAI) for UC were significantly higher in Group A than in Group B (p = 0.03). CONCLUSIONS: There were no differences in the amount of colonic ghrelin staining between healthy individuals and UC patients. Colonic ghrelin staining in UC patients seems to be associated with the increased activity of this disease.

Sarcoma - correlation between CD73 and PD-L1 and their relationship with prognosis.

This study aimed to evaluate CD73 and PD-L1 and determine their relationship with each other and with overall survival (OS) in sarcoma patients. The paraffin blocks of 101 patients were analysed. 56.4% were female, and the mean age was 51.39 years. The mean OS was 20.73 months, and the Ki-67 proliferative index was 41.45. A positive correlation was found between CD73 tumour and CD73 tumour-infiltrating lymphocyte (TIL) findings. CD73 tumour and TIL findings were also positively correlated with PD-L1 percentages and PD-L1 intensity. An inverse correlation was detected between OS and CD73 tumour and TIL groups of 5-25%, 25-50%, 50-75%, 75-90%, and > 90%, but no such correlation was found for the ≤ 5% group. There was an inverse correlation between OS and the PD-L1 percentages of  50% and the PD-L1 intensity of weak-moderate and strong, but no correlation was found for the negative values. Lastly, an inverse correlation was found between OS and the Ki-67 proliferative index. We found CD73 and PD-L1 positivity to be associated with decreased OS in sarcoma patients and determined a significant correlation between these parameters. This result is promising in terms of achieving better survival and disease control with anti-CD73 and anti-PD-L1 therapy in selected patients.

More than tubular dysfunction: cystinosis and kidney outcomes.

BACKGROUND: Cystinosis is a lysosomal storage disease that affects many tissues. Its prognosis depends predominantly on kidney involvement. Cystinosis has three clinical forms: nephropathic infantile, nephropathic juvenile and non-nephropathic adult. Proximal tubular dysfunction is prominent in the infantile form, whereas a combination of glomerular and tubular alterations are observed in the juvenile form. METHODS: Thirty-six children with nephropathic cystinosis were included in the study. Clinical features, molecular genetic diagnoses, and kidney outcomes of the patients were evaluated. RESULTS: Twenty-one children (58.3%) were male. The median age at diagnosis was 18.5 months. Twenty-eight patients (77.8%) had infantile nephropathic cystinosis, while eight (22.2%) had juvenile nephropathic cystinosis. An acute rapid deterioration of the kidney function with proteinuria, hypoalbuminemia, and nephrotic syndrome, was observed in 37.5% of patients with the juvenile form. The mean estimated glomerular filtration rate (eGFR) was 82.31 ± 37.45 ml/min/1.73m2 at diagnosis and 63.10 ± 54.60 ml/min/1.73m2 at the last visit (p = 0.01). Six patients (16.6%) had kidney replacement therapy (KRT) at the last visit. The median age of patients with kidney failure was 122 months. Patients with a spot urine protein/creatinine ratio < 6 mg/mg at the time of diagnosis had better kidney outcomes (p = 0.01). The most common allele was c.451A>G (32.6%). The patients with the most common mutation tended to have higher mean eGFR and lower leukocyte cystine levels than patients with other mutations. CONCLUSION: Glomerulonephritis may be a frequent finding in addition to the well-known tubular dysfunction in patients with cystinosis. Furthermore, our results highlight that the presence of severe proteinuria at the time of diagnosis is a relevant prognostic factor for kidney survival.

Whole tumor volumetric ADC analysis: relationships with histopathological differentiation of hepatocellular carcinoma.

PURPOSE: The aim of this study was to investigate the relationships between values obtained from whole tumor volumetric apparent diffusion coefficient (ADC) measurements and histopathological grade in patients with hepatocellular carcinoma (HCC). METHODS: Fifty-one naïve patients with HCC were included in the study. The tumors were classified according to the Edmondson-Steiner grade and separated as well-differentiated and non-well-differentiated (moderately and poorly differentiated). The ADC parameters of groups were compared by applying Mann-Whitney U test. The correlation between tumors' histopathological stage and whole tumor ADC parameters was investigated using Spearman's Rank Correlation Coefficient. The receiver operating characteristic curve analysis (ROC) was applied to calculate the area under curve (AUC) with intersection point of ADC parameters and curve. RESULTS: Mean and percentile ADC values of well-differentiated tumors were significantly higher than those of non-well-differentiated tumors (p < 0.05). The strongest correlation between histopathological grade and ADC parameters was 75th percentile ADC (r = - 0.501), 50th percentile ADC (r = - 0.476) and mean ADC (r = - 0.465). Mean, 75th and 50th percentile ADC values used for the distinction of groups gave the highest AUC at ROC analysis (0.781, 0.781, 0.767, respectively). When threshold values of mean, 75th and 50th percentile ADC values were applied (1516 mm2/s, 1194 mm2/s, and 1035 mm2/s) sensitivity was calculated as 0.73, 0.91, 0.83, respectively, and specificity was calculated as 0.82, 0.61, and 0.68, respectively. CONCLUSIONS: A correlation between whole tumor volumetric ADC values and HCCs' histopathological grade was detected in this study. 75th percentile, 50th percentile and mean ADC values are determined as highly sensitive and specific tests when the threshold values are applied for distinguishing between well-differentiated tumors and moderately/poorly differentiated tumors. When all these findings are evaluated together, HCCs' volumetric ADC values might be a useful noninvasive predictive parameters for histopathological grade in patients with HCC.

The effect of preferentially expressed antigen in melanoma (PRAME) expression status on survival in stage II and stage III colon cancer.

PURPOSE: There are no studies showing PRAME expression in stage II and III colon adenocarcinoma. In this study, we aimed to determine the frequency of PRAME expression and the relationship with survival and clinicopathological data in stage II and III colon adenocarcinoma that need adjuvant therapy. METHODS: Included were 81 patients with stage II and III colon cancer with adjuvant therapy without a second malignancy and systemic inflammatory diseases. RESULTS: A statistically significant relationship was detected between PRAME expression and disease progression and survival (p=0.01 and p=0.003, respectively). Shorter disease-free survival (DFS) and overall survival (OS) were detected in right colon tumors in patients with lymph node metastasis, metastatic lymph node >3, N1 or N2 according to the TNM staging system, with lymphovascular invasion, perineural invasion and PRAME expression (p=0.004, p=0.023, p=0.002, p=0.004, p=0.001, p=0.006, p=0.01, respectively and p=0.009, p=0.037, p=0.001, p=0.004, p=0.003, p=0.004, p=0.006, respectively). In multivariate analysis, it was determined that right colon tumor (HR: 0.488, 95% CI, 0.201-0.998, p=0.049) and PRAME expression (HR: 0.423, 95% CI, 0.170-1.052, p=0.046) were independent risk factors for short DFS. For the OS, only the presence of PRAME expression was determined as an independent risk factor. (HR:0.332, 95%CI, 0.129-0.856, p=0.022). CONCLUSION: PRAME can be a potential target in immunotherapy in colon cancer treatment.

Usefulness of ß-catenin expression in the differential diagnosis of osteosarcoma, osteoblastoma, and chondroblastoma.

The aim of this study is to assess the usefulness of beta-catenin immunohistochemical expression in the differential diagnosis of osteoid-producing primary tumors of bone. Seventy cases of osteoid-producing tumors of bone (24 conventional osteosarcomas, 18 osteoblastomas, 13 osteoblastoma-like osteosarcomas, 10 chondroblastomas, and 5 chondroblastoma-like osteosarcomas) diagnosed at Istituto Ortopedico Rizzoli were reviewed and evaluated for the intensity, extension, and subcellular distribution of immunohistochemical expression of beta-catenin. A majority of cases (73%, 51 cases) exhibited cytoplasmic and/or membranous positivity in varied degrees of intensity and proportion of positive cells, in the absence of nuclear staining. Fifteen cases (21%) were completely negative, including two osteoblastomas, five chondroblastomas, three conventional osteosarcomas, four osteoblastoma-like osteosarcomas, and one chondroblastoma-like osteosarcoma. A minority of cases (6%) including three osteoblastoma-like osteosarcomas and one osteoblastoma showed focal nuclear beta-catenin positivity with or without concomitant cytoplasmic staining. In the current series, beta-catenin showed not to be useful in the differential diagnosis of osteoid-producing primary bone tumors.

Aggressive angiomyxoma of the pelvis presenting as an obturator hernia.

INTRODUCTION : Angiomyxoma is a rare slow-growing soft tissue myxoid cell tumor that usually arises in the pelvis and perineal regions and occurs predominantly in women in the fourth decade. Angiomyxomas usually present as often initially misdiagnosed asymptomatic masses. Most common clinical early diagnoses of aggressive angiomyxomas are in form Of Vulvar Masses, Vulvar Lipomas, Bartholin's Cysts, Levator Hernias, Inguinal Hernias Or Cervical Polyps. PATIENTS AND METHODS: This paper presents the case of the pelvic angiomyxoma diagnosis of a 41 year old with early findings of suspicious obturator hernia during the initial physical examination. RESULTS: The dissection was extended from the right retrorectal area to the ischiorectal cavity and the mass was reached. The capsulated mass of 10*15 cm with soft consistency was completely released and unblocked, it was excised from the abdomen through the incision using wound protection The obturator defect was repaired with interrupted sutures. CONCLUSIONS: Angiomyxoma is a rare, benign and locally aggressive tumor, which can infiltrate locally and present unusually as perineal hernia. Due to its rarity and lack of specific diagnostic requirements, it's difficult to diagnose preoperatively KEY WORDS: Angiomyxoma, Obturator hernia, Pelvic mass.

Therapy-Induced Neural Differentiation in Ewing's Sarcoma: A Case Report and Review of the Literature.

Ewing's sarcoma (ES) is a small round cell tumor of adolescents or young adults that usually arises in the deep soft tissues of the extremities. The tumor cells have uniform round nuclei, fine powdery chromatin and indistinct nucleoli. CD99 (O13) is a product of the MIC 2 gene that is highly sensitive to ES but not specific. A panel of markers should be used for the differential diagnosis of small round cell tumors because nearly all others, on occasion, show membranous staining for CD99. One of the defining feature of ES is the presence of 22q12 gene rearrangement. The presented case is a 6 year-old boy complaining of swelling on his right leg. The biopsy was compatible with classic ES in terms of histopathological, immunohistochemical and cytogenetic criteria. Wide surgical resection was performed after chemotherapy. The posttreatment specimen was composed of uniformly small round cells mixed with areas of ganglion cells embedded in neurophil-like fibrillary background. Immunohistochemically, neoplastic cells revealed strong CD99 (O13) and NSE staining and the tumor had EWSR1 gene rearrangement. Morphologic alterations due to treatment are commonly seen in pediatric tumors. Single case reports have defined neural differentiation in ES but to the best of our knowledge this is the first report of ES in the literature with all histopathological, immunohistochemical, and cytogenetic criteria evaluated in both pretreatment and posttreatment specimens.

Liver tissue trace element levels in HepB patients and the relationship of these elements with histological injury in the liver and with clinical parameters.

AIM: In this study, the relationship of liver tissue trace element concentrations with hepatitis B disease and the effects of several environmental factors were analysed. METHOD: The liver tissue concentrations of Al, Fe, Cd, Mn, Cr, Cu, Pb, Ni, Zn, Ag, and Co were evaluated in 92 patients with hepatitis B using the Inductively Coupled Plasma - Mass Spectrometry (ICP/MS) method in the analyses. The patients were divided into the following two groups: low-high Ishak histologic activity index (HAI) (0-6: Low Histologic Activity, 7-18: High Histologic Activity) and low-high fibrosis (FS) (Fibrosis 1,1,2 and Fibrosis 3,4,5,6). The metal levels were compared between the groups. RESULTS: The Cd concentration was found to be statistically higher in the group with low HAI scores (p=0.019). The hepatic Cu concentration was found to be higher in women than in men (p=0.046). The hepatic Fe concentration was found to be higher in the group with increased FS compared to the group with decreased FS (p=0.033). Cd was found to be higher in patients who worked in positions involving exposure to heavy metals and in individuals with an ALT level above 40 IU/L (p=0.008). Several correlations have been found between the hepatic tissue metal levels in our study. In a linear regression analysis, Fe and Zn were found to be correlated with the fibrosis scores (p=<0.001 and p=0.029), and Cu was correlated with HAI (p=0.023). In the linear regression model, Ni (p=0.018) and Cr (p=0.011) were correlated with gender. There was a correlation between the hepatic Fe level and the location where hepatitis B patients were living (village/city) (p=0.001), frequency of fish consumption (p=0.045) and smoking (p=0.018) according to the linear regression analysis. Using a logistic regression analysis, Cr (p=0.029), Ni (p=0.031) and Pb (p=0.027) were found to be correlated with smoking habit, and Zn (p=0.010), Ag (p=0.026), Cd (p=0.007) and Al (p=0.005) were correlated with fish consumption. CONCLUSION: The liver tissue trace element levels are correlated with disease activity and histologic damage in patients with HepB disease. Additionally, smoking, the environment in which the patient works and the amount of fish consumption affect the accumulation of trace elements in the liver.

Protective effect of alpha-linolenic acid on gentamicin-induced ototoxicity in mice.

Alpha-linolenic acid is one of the fatty acids known as omega 3. Previous studies have shown the antioxidant and anti-inflammatory effects of alpha-linolenic acid, which prevented cell damage by inhibiting apoptotic pathway. Also, it is known that gentamicin activates apoptotic mediators and causes necrosis in the kidney. Due to this reason, we planned a study to evaluate the protective effects of alpha-linolenic acid on gentamicin induced ototoxicity by evaluating inflammation and apoptotic mediators. For this purpose, 100 mg/kg gentamicin (i.p; intraperitoneally) and 200 mg/kg alpha-linolenic acid (gavage) are administered to mice for 9 days. On 9th and 10th days, rotarod performance was assessed to test the effect of gentamicin and alpha-linolenic acid treatment on the motor coordination of mice. Gentamicin treatment decreased fall latency of mice and gentamicin treatment together with alpha-linolenic acid increased fall latency of mice. Gentamicin treatment also increased expression of phospholipase A2(plA2), cyclooxygenase-2(COX-2) and inducible nitric oxide syntheses (iNOS). Furthermore, it increased Bax and caspase-3, which are proapoptotic proteins and decreased bcl-2 that is an antiapoptotic protein. Gentamicin treatment together alpha-linolenic acid recovered the change of expression of these enzymes. In conclusion, this study showed that alpha-linolenic acid will be useful to prevent gentamicin-induced ototoxicity by inhibiting apoptosis and inflammation.