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Emel Öztürk Durmaz,1 Deniz Demircioğlu,1 Pınar Yalınay Dikmen,2 Yasemin Alanay,3 Ahmet Alanay,4 Cüyan Demirkesen,5 Fatma Tokat,5 Ercan Karaarslan6 1Department of Dermatology, Acıbadem Mehmet Ali Aydınlar University School of Medicine, İstanbul, Turkey; 2Department of Neurology, Acıbadem Mehmet Ali Aydınlar University School of Medicine, İstanbul, Turkey; 3Department of Pediatrics, Acıbadem Mehmet Ali Aydınlar University School of Medicine, İstanbul, Turkey; 4Department of Orthopedics, Acıbadem Mehmet Ali Aydınlar University School of Medicine, İstanbul, Turkey; 5Department of Pathology, Acıbadem Mehmet Ali Aydınlar University School of Medicine, İstanbul, Turkey; 6Department of Radiology, Acıbadem Mehmet Ali Aydınlar University School of Medicine, İstanbul, TurkeyCorrespondence: Emel Öztürk Durmaz, Acıbadem Maslak Hospital, Büyükdere Caddesi 40, Maslak, Istanbul, 34457, Turkey, Tel +90 (212) 304 46 19, Fax +90 (212) 286 15 66, Email emelerkek@yahoo.comAbstract: CLOVES syndrome is a novel sporadic mosaic segmental overgrowth syndrome, currently categorized under the canopy of PROS (PIK3CA-related overgrowth spectrum) disorders. All PROS disorders harbor heterozygous postzygotic activating somatic mutations involving the PIK3CA gene. As an upstream regulator of the PI3K/AKT/mTOR signal transduction pathway, activating mutations of PIK3CA gene commence in uncontrolled growth of cutaneous, vascular (capillaries, veins, and lymphatics), adipose, neural, and musculoskeletal tissues. The excessive growth is segmental, patchy, asymmetric, and confined to body parts affected by the mutation. The term ‘CLOVES’ is an acronym denoting congenital lipomatous overgrowth, vascular malformations, epidermal nevi and spinal (scoliosis) and/ or skeletal anomalies. The syndrome is characterized by an admixture of overgrown tissues, derived mainly from mesoderm and neuroectoderm. Among PROS disorders, CLOVES syndrome represents the extreme end of the spectrum with massive affection of almost the entire body. The syndrome might judiciously be treated with medications hampering with the PI3K/AKT/mTOR signal transduction pathway. This article aims at reviewing the cutaneous and musculoskeletal manifestations of CLOVES syndrome, as the paradigm for PROS disorders. CLOVES syndrome and other PROS disorders are still misdiagnosed, underdiagnosed, underreported, and undertreated by the dermatology community.Keywords: CLOVES syndrome, PIK3CA-related overgrowth spectrum, cutaneous manifestations, port wine stains, lymphangiomas, lipomas, epidermal nevi

Objective: The aim of this study is to categorize the risk groups of patients with oropharyngeal carcinoma (OPC) according to p16 and p53 status, smoking/alcohol consumption history, and other prognostic factors., Study Design: The immunostaining of p16 and p53 of 290 patients was retrospectively evaluated. The history of smoking/alcohol consumption of each patient was noted. p16 and p53 staining patterns were reviewed. The results were compared with demographic findings and prognostic factors. Risk groups have been classified for the p16 status of patients., Results: The median follow-up was 47 months (range 6-240). Five-year disease-free survival (DFS) rates for patients with p16 (+) and (-) were 76% and 36%, and overall survival rates were 83% vs 40%, respectively (HR = 0.34 [0.21-0.57], P < .0001), HR = 0.22 [0.12-0.40] P < .0001, respectively). p16(-), p53(+), heavy smoking/alcohol consumption, performance status; advanced T and N stages in patients with p16(-), and continuing smoking/alcohol consumption after treatment were found to be unfavorable risk factors. Five-year overall survival rates were 95%, 78%, and 36% for low, intermediate, and high-risk groups, respectively., Conclusions: The results of our study have shown that p16 negativity in patients with oropharyngeal cancer was found to be an important prognostic factor, especially for those with lower p53 expression and not smoking/consuming alcohol., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Rationale and Objectives: Adenoid cystic carcinoma (ACC) of the breast is a rare type of breast cancer with favorable prognosis. There is limited data on the radiological findings of this rare tumor in literature. The aim of this study is to determine the most common imaging features and review the literature., Materials and Methods: Pathological databases of seven institutions from 2009 to 2021 were retrospectively reviewed, and patients with a diagnosis of ACC of the breast were determined. Thirteen patients whose imaging studies could be recalled from the picture archiving systems (PACS) were included in the study. Clinical and pathological findings as well as follow-up data were recorded. Radiological findings were analyzed and categorized based on BI-RADS 5th edition., Results: There were 16 mass lesions in 13 patients (two multifocal cases, one case with recurrence). Mammography demonstrated 14 masses, while ultrasound (US) demonstrated all. MRI was available in only seven cases, with eight masses. The most common findings were round or oval shape on all modalities (78.57%-93.75%). Other frequent findings were parallel orientation (81.25%), isoechoic or hyperechoic echogenicity (62.5%), high T2 signal (87.5%), restricted diffusion (71.43%), and homogeneous enhancement (62.5%). Mammography, US and MRI showed circumscribed margins resembling a benign lesion in 35.71%, 37.5% and 50% of the lesions respectively. Three patients had a cyst-like echogenicty on US. Half of the lesions were avascular on Doppler US (6/12) and half were soft (2/4) on strain elastography. Although there were benign features on all imaging modalities seperately, all lesions could be categorized as BI-RADS 4 or 5 when the findings were combined. However 9/16 masses were BI-RADS 4A, emphasizing the subtlety of the malignant features., Conclusion: ACC of the breast can present with findings resembling a benign lesion on different imaging modalities. Although combination of all imaging findings correctly indicated the suspicious nature of the lesions in all cases, final classification was BI-RADS 4A in most of them. Radiologists should be aware of the more frequent findings of ACC of the breast for early diagnosis. US findings of isoechoic or hyperechoic appearance, and cyst-like echogenicity have not been reported previously in literature., (Copyright © 2022 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

The tubule index is a vital prognostic measure in breast cancer tumor grading and is visually evaluated by pathologists. In this paper, a computer-aided patch-based deep learning tubule segmentation framework, named Tubule-U-Net, is developed and proposed to segment tubules in Whole Slide Images (WSI) of breast cancer. Moreover, this paper presents a new tubule segmentation dataset consisting of 30820 polygonal annotated tubules in 8225 patches. The Tubule-U-Net framework first uses a patch enhancement technique such as reflection or mirror padding and then employs an asymmetric encoder-decoder semantic segmentation model. The encoder is developed in the model by various deep learning architectures such as EfficientNetB3, ResNet34, and DenseNet161, whereas the decoder is similar to U-Net. Thus, three different models are obtained, which are EfficientNetB3-U-Net, ResNet34-U-Net, and DenseNet161-U-Net. The proposed framework with three different models, U-Net, U-Net++, and Trans-U-Net segmentation methods are trained on the created dataset and tested on five different WSIs. The experimental results demonstrate that the proposed framework with the EfficientNetB3 model trained on patches obtained using the reflection padding and tested on patches with overlapping provides the best segmentation results on the test data and achieves 95.33%, 93.74%, and 90.02%, dice, recall, and specificity scores, respectively., (© 2023. The Author(s).)

Background: Recent studies have shown a lower likelihood of locoregional recurrences in patients with a low 21-gene recurrence score (RS). In this single-institution study, we investigated whether there are any associations between different cutoff values of 21-gene RS, histopathological factors, and outcome in patients with long-term follow-up., Methods: The study included 61 patients who had early-stage (I-II) clinically node-negative hormone receptor-positive and HER2-negative breast cancer and were tested with the 21-gene RS assay between February 2010 and February 2013. Demographic, clinicopathological, treatment, and outcome characteristics were analyzed., Results: The median age was 48 years (range, 29-72 years). Patients with high histologic grade (HG), Ki-67 ≥ 25%, or Ki-67 ≥ 30% were more likely to have intermediate/high RS (≥ 18). Based on the 21-gene RS assay, only 19 patients (31%) received adjuvant chemotherapy. At a median follow-up of 112 months, 3 patients developed locoregional recurrences (4.9%), which were treated with endocrine therapy alone. Among patients treated with endocrine treatment alone (n = 42), the following clinicopathological characteristics were not found to be significantly associated with 10-year locoregional recurrence free survival (LRRFS): age < 40 years, age < 50 years, high histological or nuclear grade, high Ki-67-scores (≥ 15%, ≥ 20%, ≥ 25%, ≥ 30%), presence of lymphovascular invasion, luminal-A type, multifocality, lymph node positivity, tumor size more than 2 cm, RS ≥ 18, and RS > 11. However, patients with RS ≥ 16 had significantly poorer 10-year LRRFS compared to those with RS < 16 (75% vs. 100%, respectively; p = 0.039)., Conclusions: The results suggest that patients with clinically node-negative disease and RS ≥ 16 are more likely to benefit from adjuvant chemotherapies. However, those with RS < 16 have an excellent outcome and local control in long-term follow-up with endocrine treatment alone., (© 2022. The Author(s).)

Objective: Vascular endothelial growth factor (VEGF) is an angiogenic factor that plays an important role in physiological and pathological angiogenesis of the thyroid. The aim of the current study was to determine the expression characteristics of VEGF in follicular cell-derived lesions of the thyroid and to assess whether a new entity noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is precancerous. Material and Methods: Patients diagnosed with 33 follicular adenomas (FA), 41 invasive follicular variant papillary thyroid cancer (IN-FVPTC), and 40 NIFTP in surgical resection materials were evaluated retrospectively. Immunostaining was performed on 5-μm paraffin tissue sections. The percentages of immunostaing for VEGF were evaluated on pathological materials. We used a percentage of labeled thyrocytes score (0, no labeling; 1, <30%; 2, 31-60%; 3, >60%) and an intensity score (0, no staining; 1, weak; 2, intermediate; 3, strong). The sum of two scores were accepted as the total score. Results: Mean ages of the FA, IN-FVPTC, and NIFTP groups were 44.7 ± 11.7 years, 46.9 ± 13.6 years, 43.2 ± 15.4 years, respectively and the mean VEGF immunostaining scores were 44.7 ± 29.3, 50.2 ± 32.54, 4 ± 26.3 respectively. Although there was no statistically significant difference (p= 0.347), the total score of the NIFTPs was higher than the scores of the FA (mean= 3.9 ± 1.8) and IN-FVPTC(mean= 4.3 ± 1.9) groups with a mean value of 4.6 ± 1.7. This result was remarkable. There was no statistically significant difference between tumor diameters and staining percentages (p= 0.750). Conclusion: Even if there were no statistical differences for VEGF immunostaining, it was high in NIFTPs. Since we know the role of VEGF in tumorigenesis, we can hypothesize that NIPTP can be precancerous. Our argue should be corroborated by a large prospective study., Competing Interests: Conflict of Interest: The authors have no conflicts of interest to declare., (Copyright © 2022, Turkish Surgical Society.)

Background: This study investigates the effects of COVID-19 on the breast cancer stage and the volume of breast cancer surgery in a specialized breast institute., Methods: Data of 332 patients who were diagnosed and treated for breast cancer between December 2019 and November 2020 were evaluated retrospectively according to periods of pandemic., Results: A significant decrease in the number of operations, especially upfront surgeries rather than surgeries after neoadjuvant chemotherapy, was detected in the early period of the COVID-19 pandemic. It was found that patients with complaints were mostly admitted during this period ( p = 0.024). No statistical significance was found for age, sex, side of the tumor, type of tumor, surgery to breast, and axilla. Following the early period of the pandemic, it was observed that patients with mostly luminal, early-stage, and less axillary nodal involvement ( p < 0.05) were admitted, and as a result, it was founded that upfront surgeries increased, although no change in TNM staging was observed. However, it did affect the decision of initial treatment. Thus, the number of upfront surgeries was significantly higher than the NCT group ( p = 0.027) following the early period., Conclusion: Surgical volume is significantly affected in the early period of the COVID-19 pandemic. To overcome overload due to delayed surgeries related to pandemics, some hospitals should be spared for oncological treatments. Following the early period, mostly luminal type, early-stage patients were admitted, probably because of increased self-awareness and short wave duration, but the breast cancer stage was not affected., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kara, Arikan, Dulgeroglu, Tutar, Tokat and Uras.)

Background: The progression to gastric cancer has been linked to chronic infection with Helicobacter pylori (H. pylori). Immune checkpoint inhibitors (programmed cell death -1, PD-1; programmed cell death -ligand 1, PD-L1) have a role in cancer immune escape. The relationship between H. pylori virulence factors with PD-1, PD-L1 T helper 1 (Th1), T helper 17 (Th17), and regulatory T cell (Treg) response genes, has not been thoroughly investigated in the development of gastric cancer. Therefore, we evaluated how H. pylori virulence factors influence the expression levels of immune-related genes in the development of gastric immunopathology., Methods: A total of 92 gastric tissues of normal controls and patients with gastritis, gastric ulcer, and gastric cancer were examined for the expression of immune-checkpoint inhibitor genes (PD-1 PD-L1), Th1 (interferon- γ, IFN-γ), Th17 (interleukin- 17, IL-17, Retinoic-acid-receptor- related orphan nuclear receptor gamma t, RORγ-t), and Treg (Forkhead box P3, FOXP3) response genes with quantitative real-time PCR (qRT-PCR). Furthermore, correlation of H. pylori virulence factors' (cytotoxin-associated gene A, cagA; vacuolating cytotoxin gene A, vacA (s1,s2,m1,m2); blood group antigen-binding adhesin gene A, babA, duodenal ulcer promoting gene A, dupA; the putative neuraminyllactose-binding hemagglutinin homolog, hpaA; neutrophil-activating protein A napA; outer inflammatory protein A, oipA; urease A, ureA; and urease B, ureB) genotypes with a degree of inflammation and density of H. pylori were investigated. Next, the relationship between H. pylori virulence factors and immune-checkpoint inhibitor genes, and T-cell response genes was evaluated. Eventually, a decision tree model was developed to determine the clinical outcome of patients using expression data., Results: The intensity of PD-1 and PD-L1 mRNA expression was increased significantly in gastric tissue of patients with gastric ulcer (PD-1: 2.3 fold, p=0.01; PD-L1: 2.1 fold, p=0.004), and gastric cancer (PD-1: 2 fold, p= 0.04; PD-L1: 1.8 fold, p=0.05) compared with control subjects. Also, PD-1: PD-L1 expression was significantly higher in patients with gastritis, who were infected with a marked density of H. pylori compared with its mildly infected counterparts. Furthermore, a novel negative correlation was found between PD-1 (r= -0.43) and PD-L1 (r= -0.42) with FOXP3 in patients with gastritis. CagA-positive H. pylori strain's negative association with PD-L1 expression (r=-0.34) was detected in patients with gastritis. Interestingly, PD-1 mRNA expression correlated positively with vacA s2/m2, in gastritis (r=0.43) and ulcer (r=0.43) patients. Furthermore, PD-1: PDL1 expression negatively correlated with vacA m1/m2 (r=-0.43 for PD-1; r=-0.38 for PD-L1) in gastritis patients. Moreover, an inverse correlation of PDL1 was present with vacA m1 (r=0.52) and vacA s1/m1 (r=0.46) versus vacA m2 (r=-0.44) and vacA m1 (r=0.52) and vacA s1/m2 (r=-0.14) in ulcer patients, respectively. Also, a correlation of vacA m2 (r=-0.47) and vacA s1/s2 (r= 0.45) with PD-1 was detected in ulcer patients. In addition, a novel negative correlation between FOXP3 mRNA levels and napA was shown in patients with gastritis and ulcer (r=-0.59). Finally, a computer-based model that was developed showed that knowing the expression levels of PD-L1, RORγ-t, and vacA s1/m2 would be useful to detect the clinical outcome of a patient., Conclusion: Our results suggested that PD-1:PD-L1 immune checkpoint inhibitors were increased in gastric pre-cancerous lesions that progress to gastric cancer. Herein, we report the relationship between H. pylori virulence factors and expression of host immune checkpoint inhibitors for diagnostic prediction of gastric malignancies using computer-based models., (Copyright © 2021. Published by Elsevier B.V.)

The SARS-CoV-2 virus caused the most severe pandemic around the world, and vaccine development for urgent use became a crucial issue. Inactivated virus formulated vaccines such as Hepatitis A and smallpox proved to be reliable approaches for immunization for prolonged periods. In this study, a gamma-irradiated inactivated virus vaccine does not require an extra purification process, unlike the chemically inactivated vaccines. Hence, the novelty of our vaccine candidate (OZG-38.61.3) is that it is a non-adjuvant added, gamma-irradiated, and intradermally applied inactive viral vaccine. Efficiency and safety dose (either 10 13 or 10 14 viral RNA copy per dose) of OZG-38.61.3 was initially determined in BALB/c mice. This was followed by testing the immunogenicity and protective efficacy of the vaccine. Human ACE2-encoding transgenic mice were immunized and then infected with the SARS-CoV-2 virus for the challenge test. This study shows that vaccinated mice have lowered SARS-CoV-2 viral RNA copy numbers both in oropharyngeal specimens and in the histological analysis of the lung tissues along with humoral and cellular immune responses, including the neutralizing antibodies similar to those shown in BALB/c mice without substantial toxicity. Subsequently, plans are being made for the commencement of Phase 1 clinical trial of the OZG-38.61.3 vaccine for the COVID-19 pandemic., (© 2021. The Author(s).)

Microsatellite instability (MSI) is present in 15-20% of primary colorectal cancers. MSI status is assessed to detect Lynch syndrome, guide adjuvant chemotherapy, determine prognosis, and use as a companion test for checkpoint blockade inhibitors. Traditionally, MSI status is determined by immunohistochemistry or molecular methods. The Idylla™ MSI Assay is a fully automated molecular method (including automated result interpretation), using seven novel MSI biomarkers (ACVR2A, BTBD7, DIDO1, MRE11, RYR3, SEC31A, SULF2) and not requiring matched normal tissue. In this real-world global study, 44 clinical centers performed Idylla™ testing on a total of 1301 archived colorectal cancer formalin-fixed, paraffin-embedded (FFPE) tissue sections and compared Idylla™ results against available results from routine diagnostic testing in those sites. MSI mutations detected with the Idylla™ MSI Assay were equally distributed over the seven biomarkers, and 84.48% of the MSI-high samples had ≥ 5 mutated biomarkers, while 98.25% of the microsatellite-stable samples had zero mutated biomarkers. The concordance level between the Idylla™ MSI Assay and immunohistochemistry was 96.39% (988/1025); 17/37 discordant samples were found to be concordant when a third method was used. Compared with routine molecular methods, the concordance level was 98.01% (789/805); third-method analysis found concordance for 8/16 discordant samples. The failure rate of the Idylla™ MSI Assay (0.23%; 3/1301) was lower than that of referenced immunohistochemistry (4.37%; 47/1075) or molecular assays (0.86%; 7/812). In conclusion, lower failure rates and high concordance levels were found between the Idylla™ MSI Assay and routine tests.

Background: Signs of inflammation including epidermal interface changes, spongiosis, and dermal inflammation as well as pagetoid dyskeratosis are rarely described in fibrous papule (FP). We aimed to describe the inflammatory parameters, the rate of pagetoid dyskeratosis, along with CD163 immunohistochemical staining as an adjunctive diagnostic tool in FP., Methods: Histopathology samples of all biopsy-proven FP cases were retrieved from archives and investigated for inflammatory parameters, presence of pagetoid dyskeratosis, as well as CD163, CD10, and CD34 immunostaining pattern of dermal spindle/stellate or multinucleate cells (graded from 0 to 4)., Results: Thirty-two cases of FP were identified. A high rate of inflammatory parameters including interface changes (20/32), spongiosis (31/32), and dermal lymphocytic inflammation (31/32) were detected. Pagetoid dyskeratosis was identified in eight out of 32 cases (25%). A grade 4 staining revealing a strong dendritic pattern was confirmed in all FP cases with CD163 immunohistochemistry including atypical variants such as granular FP, compared with CD10 (11/32) and CD34 (3/32)., Conclusion: The dendritic cellular proliferation in FP may represent an inflammatory response to various stimuli; pagetoid dyskeratosis is a relatively common and underrecognized epidermal feature and CD163 immunostaining may be used as an adjunctive diagnostic tool in unusual histopathological subtypes., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Relapsed and refractory CD19-positive B-cell acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) are the focus of studies on hematological cancers. Treatment of these malignancies has undergone recent transformation with the development of new gene therapy and molecular biology techniques, which are safer and well-tolerated therapeutic approaches. The CD19 antigen is the most studied therapeutic target in these hematological cancers. This study reports the results of clinical-grade production, quality control, and in vivo efficacy processes of ISIKOK-19 cells as the first academic clinical trial of CAR-T cells targeting CD19-expressing B cells in relapsed/refractory ALL and NHL patients in Turkey., Materials and Methods: We used a lentiviral vector encoding the CD19 antigen-specific antibody head (FMC63) conjugated with the CD8-CD28-CD3ζ sequence as a chimeric antigen receptor (CAR) along with a truncated form of EGFR (EGFRt) on human T-lymphocytes (CAR-T). We preclinically assessed the efficacy and safety of the manufactured CAR-T cells, namely ISIKOK-19, from both healthy donors’ and ALL/NHL patients’ peripheral blood mononuclear cells., Results: We showed significant enhancement of CAR lentivirus transduction efficacy in T-cells using BX-795, an inhibitor of the signaling molecule TBK1/IKKƐ, in order to cut the cost of CAR-T cell production. In addition, ISIKOK-19 cells demonstrated a significantly high level of cytotoxicity specifically against a CD19+ B-lymphocyte cancer model, RAJI cells, in NOD/SCID mice., Conclusion: This is the first report of preclinical assessment of efficacy and safety analysis of CAR-T cells (ISIKOK-19) targeting CD19-expressing B cells in relapsed/refractory ALL and NHL patients in Turkey.

Aim: To determine whether performing incision on the surface of the ovarian cortex in rats advances follicular development., Methods: Five to seven separate superficial incisions were performed on the surface of right ovaries of 6-7-month-old albino Wistar rats. Daily 40 IU of gonadotropins were administered for 14 days. On the 15th day, both ovaries of the rats were removed. The right (incised) ovaries were compared with the contralateral ovaries in terms of ovary's weight, numbers of primordial, primary, secondary and antral follicles, their mean percentages and mean Ki-67 proliferation indices., Results: A total of 22 ovaries were evaluated, with 11 right ovaries (incised) and 11 left ovaries (non-incised). The mean weight of ovaries was greater in the right ovaries than in the left ovaries; however, no statistical difference was found between them (0.77 ± 1.22 vs. 0.22 ± 0.08 gr, P = 0.159). The numbers of secondary and antral follicle were statistically higher in the right ovaries than in the left ovaries (4.4 ± 1.5 vs. 2.1 ± 1.6, P = 0.003 and 18.6 ± 8.7 vs. 11.3 ± 7.5, P = 0.046, respectively). The right ovaries also significantly differed from the left ovaries in terms of mean percentages of primordial and antral follicles (P < 0.05 for both). The mean Ki-67 proliferation index had a marginal difference between the groups (P = 0.064)., Conclusion: Performing incisions on the surface of the ovarian cortex in rats may advance the ovarian follicular development. Future animal studies may provide more evidence regarding potential benefits of mechanical stimulation to the ovaries., (© 2020 Japan Society of Obstetrics and Gynecology.)

The underlying mechanisms of aggressive pituitary neuroendocrine tumors (pitNETs) are still unclear. The p16 protein, encoded by the CDKN2A tumor suppressor gene on chromosome 9p21, is commonly reported to be lost in numerous types of cancer. For this reason, this study examined to examine the status of homozygous deletion of CDKN2A in high-risk pitNETs. Thirty-eight high-risk pitNETs (30 male, 8 female) were analyzed for CDKN2A deletion by fluorescent in situ hybridization (FISH). Demographic characteristics such as sex, patient age at operation, and sellar magnetic resonance imaging findings including tumor size and invasion status were recorded. The frequency of CDKN2A homozygous deletion by FISH was 3/38 (7.89%) in the high-risk pitNET group. All of these three cases with CDKN2A homozygous deletion were invasive densely granulated lactotroph tumors (p = 0.000). CDKN2A deletion was not correlated with patient age, sex, cavernous sinus invasion (CSI), and tumor size (p > 0.05). The Ki-67 proliferation index was significantly correlated with CDKN2A homozygous deletion (p = 0.003). The mean Ki-67 proliferation index was 10.7% in pitNETs with CDKN2A homozygous deletion and the Ki-67 proliferation index in the whole study group was 4.1%. CSI was significantly correlated with the morphofunctional tumor types including lactotroph tumor, invasive null cell tumor, and invasive gonadotroph tumor (p = 0.021). These findings suggest a close correlation between inactivation of p16 gene and invasive lactotroph tumors. Further investigations are needed to expand on the mechanism of p16 (CDKN2A) gene deletion in high-risk pitNETs.

Telomeres, and telomere length in particular, have broad significance for genome biology and thus are prime research targets for complex diseases such as cancers. In this context, BRCA1 and BRCA2 gene mutations have been implicated in relationship to telomere length, and breast cancer susceptibility. Yet, the linkages among human genetic variation and telomere length in persons with high hereditary cancer risk are inadequately mapped. We report here original findings in 113 unrelated women at high hereditary risk for breast cancer, who were characterized for the BRCA1 and BRCA2 mutations using next-generation sequencing. Thirty-one BRCA2 and 21 BRCA1 mutations were identified in 47 subjects (41.6%). The women with a mutation in BRCA1 and/or BRCA2 genes had, on average, 12% shorter telomere compared to women with no BRCA1 or BRCA2 mutation ( p  = 0.0139). Moreover, the association between telomere length and BRCA mutation status held up upon stratified analysis in those with or without a breast cancer diagnosis. We also indentified two rare mutations, c.536&#95;537insT and c.10078A>G, and a novel mutation c.8680C>G in BRCA2 that was studied further by homology modeling of the DNA binding tower domain of BRCA2 and the structure of the protein. These data collectively lend evidence to the idea that BRCA1 and BRCA2 mutations play a role in telomere length in women at high hereditary risk for breast cancer. Further clinical and diagnostics discovery research on BRCA1 and BRCA2 variation, telomere length, and breast cancer mechanistic linkages are called for in larger study samples.

Introduction: The lack of papillary structures and faint and/or unclear core features of follicular variant of papillary thyroid carcinoma (FV-PTC) may hamper the definitive fine needle aspiration biopsy -based diagnosis. Recently, the nomenclature of noninvasive encapsulated FV-PTC was revised to "noninvasive follicular thyroid neoplasms with papillary-like nuclear features" (NIFTP). However, it remains inconclusive whether or not the peptide patterns differ between NIFTP and encapsulated FV-PTC. The main objectives of this study were to investigate the viability of matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) in the pathological assessment of NIFTP and to evaluate the discriminatory power of MALDI MSI for the classification of classical variant of PTC (CV-PTC), NIFTP, and encapsulated FV-PTC. Methods: MALDI MSI was employed to investigate the changes in peptide profiles from 21 formalin-fixed paraffin-embedded (FFPE) tissue samples ( n  = 7 from each group of CV-PTC, NIFTP, and FV-PTC). Six out of seven FV-PTC FFPE tissue samples were encapsulated FV-PTC; only one was infiltrative FV-PTC. Liquid chromatography-tandem mass spectrometry was used for the identification of the peptide signals detected in MALDI MSI. Results: Using receiver operating characteristics analysis, 10 peptide signals distinguished NIFTP from normal thyroid parenchyma (area under the curve [AUC] >0.80). To evaluate the discriminatory power of MALDI MSI, statistically significant peptide signals ( n  = 88) within three groups were used for hierarchical clustering. The method had high discriminatory power for distinguishing CV-PTC from NIFTP and FV-PTC (encapsulated and infiltrative). The majority of the NIFTP and encapsulated FV-PTC were clustered together, indicating that NIFTP could not be distinguished from encapsulated FV-PTC. However, infiltrative FV-PTC FFPE tissue samples had the furthest distance from all the NIFTP cases. High signal intensities of S100-A6, vimentin, and cytoplasmic actin 1 were detected in FV-PTC, prelamin A/C in CV-PTC, and 60S ribosomal protein L6 and L8 in NIFTP tissues. Conclusions: MALDI MSI, a powerful tool combining histological and mass spectrometric data, enabled the differentiation of NIFTP from normal thyroid parenchyma. Although NIFTP is a recent definition that replaces noninvasive encapsulated FV-PTC, the peptide profiles of NIFTP and encapsulated FV-PTC were found to be similar.

The recent description of noninvasive follicular tumor with papillary-like nuclear features (NIFTP) creates several diagnostic and therapeutic challenges for both the pathologist and the attending clinician. Given the concern about overtreatment of these neoplasms, the best way to manage the patients by a surgical procedure and postsurgical follow-up is still under discussion. We aimed to identify predictors of synchronous disease (eg, bilateral cancers) that can influence the appropriate type of surgery and long-term surveillance. We reevaluated the original diagnosis and the presence of contralateral lesions in 94 cases retrieved from our archives that were seen between 2010 and 2017. In 74 cases, the diagnosis was NIFTP, and in 20 cases, the diagnosis was infiltrative follicular variant of papillary thyroid carcinoma (IFVPTC). Bilateral disease was found in 17% of the cases. In 13 (18%) of those cases, NIFTP was the primary lesion, and in 3 (15%), it was IFVPTC. The contralateral disease was predominantly invasive: 6 cases of micropapillary carcinoma, 5 of papillary thyroid carcinoma, 3 of IFVPTC, and 2 of NIFTP. Despite the higher frequency of contralateral disease in NIFTP, there was no statistically significant difference with IFVPTC. In the patients with multifocal NIFTP, 2 (15%) of the contralateral malignancies showed microscopic extrathyroidal extension (P < .05). We conclude that close monitoring of the contralateral lobe is appropriate in patients with FVPTC, particularly NIFTP, if they are not submitted to total thyroidectomy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Lipomatous tumors accompanied by spindle cell component are not frequently encountered, and there are still problems regarding their differential diagnosis, nature, and nomenclature. To contribute to ongoing efforts, we present the clinical, histologic, and immunohistochemical characteristics of 20 cases of spindle cell lipomatous tumors with atypical features that may also be called atypical spindle cell/pleomorphic lipomatous tumors. Of the patients, 13 were men and 7 were women with an average age of 57.5 years. The most commonly affected site was the extremities. Twelve tumors arose in the subcutaneous tissue, while eight cases were located in the deep soft tissues. Tumor margins were often ill-defined with invasion into the surrounding tissues. Microscopic examination revealed a wide spectrum of histologic features. All cases consisted of poorly marginated proliferation of mildly atypical spindle cells set in a fibrous or myxoid stroma with a variable amount of adipocytic component showing variation in adipocyte size and scattered nuclear atypia and frequent univacuolated or multivacuolated lipoblasts. Tumor cellularity and the relative proportion of the components were highly variable. One tumor showed morphologic features evocative of dedifferentiation and another one exhibited histological features resembling pleomorphic liposarcoma. None of the patients had recurrence or metastasis at follow-up., (© 2018 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Background: In 2016, the Papanicolaou Society of Cytopathology (PSC) issued a new classification scheme for respiratory cytology. We aim to evaluate our samples according to this classification and to assess risk of malignancy and diagnostic yield of different cytological modalities., Methods: Respiratory specimens (sputum, bronchial wash/brush, BAL and FNA) obtained between 2007 and 2016 were reclassified according to PSC guidelines. Risk of malignancy for each diagnostic category was determined. Diagnostic yield was evaluated based on three-categorical approach., Results: One thousand, two hundred and ninety respiratory specimens were retrieved, of which 280 had histologic follow-up. Samples were reclassified as nondiagnostic 16%, negative for malignancy 53%, atypical 5.4%, neoplastic (benign neoplasm/low-grade carcinoma) 0.4%, suspicious for malignancy 2.1% and malignant 23.1%. Risk of malignancy for each category was 64.01% for ND, 48.27% for NM, 59.09% for A, 100% for N-B-LG; 90% for SM and 89.74% for M. When only malignant cases were considered positive tests, cytology sensitivity was 55% and specificity 88%., Conclusion: Our results were in line with PSC guidelines, but the use of multiple cytological techniques may cause some discrepancies in overall diagnostic yield and in estimated risks of malignancy, which is important due to the widespread utilization of different cytological procedures., (© 2018 Wiley Periodicals, Inc.)

Background: Angiolymphoid hyperplasia with eosinophilia (ALHE) is a rare vascular proliferative disorder mainly located in the periauricular region. The etiopathogenesis of ALHE is unknown, and it is still controversial as to whether the entity represents a benign vascular neoplasm or an inflammatory process., Aim: Recently, the intracytoplasmic staining pattern of Wilms tumor 1 (WT1) on immunohistochemistry has highlighted true vascular neoplasms, such as microvenular hemangioma, tufted angioma, and spindle cell hemangioma, which has made it helpful to distinguish ALHE from vascular malformations, as there is a negative staining pattern in the other entities. We aimed to investigate the immunoreactivity of ALHE specimens for WT1 as well as glucose transporter protein 1 (GLUT1) immunohistochemistry, an important and sensitive marker for the diagnosis of infantile hemangioma, which recently has been described to label other hemangiomas, such as verrucous hemangioma., Material and Methods: Clinical data and histopathological specimens from patients diagnosed with ALHE were reviewed, and immunohistochemical staining and microscopic analysis for WT-1 and GLUT1 were performed., Results: Intracytoplasmic endothelial staining of WT1 was detected in 19 of 20 ALHE specimens. GLUT1 was not detected in any ALHE specimen., Conclusions: We conclude that ALHE may represent a true hemangioma (i.e., benign vascular neoplasia) characterized by an eosinophil- and lymphocyte-rich inflammatory component as opposed to the reactive inflammatory dermatosis with a positive intracytoplasmic staining pattern for WT1. As far as we are aware, WT1 staining for ALHE has not been described to date., Competing Interests: Competing interests: The authors have no conflicts of interest to disclose.

Introduction: Fine Needle Aspiration Biopsy (FNAB) allows the cytological differentiation of benign and malignant thyroid nodules. However, the method itself is not adequate in determining some cases. For example, the diagnosis of Follicular Variant Papillary Thyroid Carcinoma (FV-PTC) can be challenging. In the current study we investigate the protein profiles of FV-PTC and classical variant PTC (CV-PTC) with no lymph node metastasis and compare it with benign thyroid tissue., Method: We used CV-PTC (n = 6), FV-PTC (n = 6) and benign thyroid tissues (n = 6) to prepare tissue lysates. Proteins from each group were trypsin and lys-C digested. The samples were analyzed on a Q Exactive Orbitrap mass spectrometer., Results: We identified 2560 proteins across all 18 specimens. Protein profiles revealed that there was no clear distinction between benign and FV-PTC samples. However, further examination of our data showed that proteins in energy metabolism have altered in FV-PTC. Proteomic pathway analysis showed marked alteration of the actin cytoskeleton proteins, especially several members of Arp2/3 complex were significantly increased in CV-PTC. We made the novel observation that IQGAP1 protein was significantly increased in CV-PTC, whereas IQGAP2 protein was highly expressed in FV-PTC lesions, suggesting differential roles of IQGAP proteins in thyroid pathology., Conclusion: In the present study, mass spectrometry based label free quantification approach was applied to investigate the protein profiles of FV-PTC, CV-PTC and benign thyroid tissues. This study pointed out that actin cytoskeleton proteins, IQGAP proteins and changes in energy metabolism play predominant roles in thyroid pathology.

Objective: To investigate the effect of azoospermia type on fertilization and clinical pregnancy rates when microdissection testicular sperm extraction (TESE) is performed for sperm retrieval in nonobstructive azoospermia (NOA)., Study Design: STUDY DESIGN: Patients who underwent microdissection TESE for NOA and conventional TESE for obstructive azoospermia (OA) were included in the study. Intracytoplasmic sperm injection (ICSI) results were compared between groups., Results: The mean ages in the 2 groups were similar. FSH and LH levels in the NOA group were significantly higher than those of the OA group. Between groups there was no statistically significant difference in testosterone levels. The sperm retrieval rate was 58.56% in NOA. Fertilization and clinical pregnancy rates were similar for patients with NOA and OA., Conclusion: In patients with NOA, microdissection TESE accurately determines active spermatogenesis areas via the high identification power of the operative microscope. From these areas surgeons can collect healthier spermatozoa, which can result in better ICSI outcomes, the results of which are similar to those with OA.

Purpose: To determine the effects of corneal collagen cross-linking (CXL) on the penetration of topical 0.5% moxifloxacin, on the number of colony-forming units (CFUs) in the cornea, and on the clinical course in a rabbit eye model of experimentally induced Pseudomonas aeruginosa keratitis., Methods: In this prospective animal study, experimental Pseudomonas corneal ulcers were induced in 56 corneas of 28 albino New Zealand rabbits. The corneas were randomly divided into the following 4 groups: the control group (14 eyes), the MOX group (moxifloxacin) (14 eyes), the MOX + CXL group (14 eyes), and the CXL group (14 eyes). On day 4 of the experiment, the eyes in the control group were enucleated and CFU counting was performed. On day 10 of the experiment, all eyes were enucleated and CFU counting was performed. In the MOX and MOX + CXL groups, the moxifloxacin level in the cornea, aqueous humor, iris, plasma, and serum was measured by reverse-phase high-performance liquid chromatography., Results: The difference in the corneal CFU count between the MOX group and the MOX + CXL group was not significant (P = 0.317). Clinical improvement was greatest in the MOX + CXL group (P < 0.001). The mean corneal moxifloxacin level was 0.391 ± 0.09 μg·mg in the MOX group versus 0.291 ± 0.09 μg·mg in the MOX + CXL group; as such, CXL did not have a significant effect on antibiotic penetrance (P = 0.386)., Conclusions: Clinical improvement was greatest in the MOX + CXL group. The synergistic effect of CXL on corneal ulcer treatment is not through antibiotic penetrance.

Background: Differentiation of psoriasis from non-psoriasis psoriasiform dermatitis (NPPD) may be difficult for dermatopathologists, as lack of distinctive histopathological features in a subset of cases may cause confusion in diagnosis., Objective: As the prototype of psoriasiform dermatitis, psoriasis is a hyperproliferative skin disorder with increased epidermal turnover compared with NPPD, we investigated the role of proliferation markers, Ki-67 and Cyclin D1 as diagnostic tools to differentiate psoriasis from other psoriasiform dermatitis., Methods: Histopathological specimens of psoriasis (n = 35) and NPPD (n = 36, 14 pityriasis rubra pilaris, 12 pityriasis rosea and 10 lichen simplex) cases were reviewed and immunohistochemically stained for Ki-67 and Cyclin D1. Ki-67 and Cyclin D1 positive cells were counted for suprabasal, and total epidermal immunostaining per mm(2)., Results: Suprabasal and total epidermal cell counts for Ki-67 were found to be significantly higher in the psoriasis group compared with the NPPD group (p < 0.05). An important and interesting feature was the presence of a cut-off value for the suprabasal/total epidermal cell count ratio of 75% for Ki-67 immunostaining, which was higher in all patients having psoriasis (range, 77.1% - 92.4%) and lower in all NPPD cases (range, 21.0% - 73.3%). However, suprabasal Cyclin D1 cell counts were higher in the psoriasis group compared with the NPPD group (p < 0.05), total epidermal Cyclin D1 cell counts were not statistically significant in either group (p = 0.167), and a cut-off value for suprabasal/total epidermal cell count ratio to distinguish these two entities was not detected using this immunostain., Conclusions: We suggest that Ki-67 is a more sensitive marker than Cyclin D1 in terms of having a cutoff value of 75% for the suprabasal/total epidermal immunoreactive cell count ratio, which we believe could be useful for dermatopathologists in differentiating psoriasis from other psoriasiform dermatitis.

Gastrointestinal stromal tumors (GISTs) are the most prevalent mesenchymal tumors of the gastrointestinal tract. GISTs are considered to originate from the interstitial cells of Cajal, the pacemakers of the peristaltic activity of the gastrointestinal tract. More than 95% of GISTs express KIT protein and discovered on GIST-1. GISTs may also be encountered in locations outside the gastrointestinal tract, in which case they are referred to as extra-GISTs (EGISTs) and often behave more aggressively. This is the case report of a primary pericardial EGIST in a 53-year-old male patient, confirmed by immunohistochemistry. To the best of our knowledge, this is the third case of EGIST diagnosed above the diaphragm, without being associated with the esophageal wall. Two cases of primary EGIST arising from the pleura were reported previously. In addition, this is the first reported case of an EGIST originating from the pericardium.

Objective: To define the accuracy and acceptability of ultrasonography-guided percutaneous needle core biopsy in diagnosis of renal masses., Methods: The data of 42 consecutive patients on whom needle biopsies were performed and were surgically treated for suspicious renal masses in our clinic between January 2001 and April 2008 were evaluated. In all patients, needle biopsies were done percutaneously with an 18-gauge needle under local anesthesia in prone position with ultrasonography guidance. Two cores were taken from each tumor. The pathology results of biopsy and surgical specimens were compared., Results: The mean age was 56.1 years (range, 21-77 years). The mean follow-up period was calculated as 44.8 months (range, 10-85 months). The abdominal computed tomography imaging showed that the mean mass size was 63.9 mm (range, 25-140 mm). Of 42 patients, 39 were diagnosed (92.8%) after the first biopsy. The accuracy of percutaneous needle biopsy in differentiating between malignant and benign masses was calculated as 90% (36/40).The accuracy of histopathological diagnostic typing as against the postsurgical pathologic examination results was 77.5% (31/40) and the accuracy in the Fuhrman grade was 51.5% (17/33). The sensitivity was calculated as 91.4% and specificity as 60%. Its negative predictive value was 50% and positive predictive value was 94.1%., Conclusions: In conclusion, percutaneous renal needle core biopsy has an acceptable sensitivity and specificity in the diagnosis of renal masses. The major limitation of percutaneous core biopsy is the technical failure that leads to insufficient material for accurate diagnosis., (Copyright © 2010 Elsevier Inc. All rights reserved.)