New Emerging Chemokine Receptors: CCR5 or CXCR5 on Tumor Is Associated with Poor Response to Chemotherapy and Poor Prognosis in Locally Advanced Triple-Negative Breast Cancer.

BACKGROUND: We aim to investigate any possible associations between chemokine receptor expression and responses to neoadjuvant chemotherapy (NAC) along with outcomes in patients with triple-negative breast cancer (TNBC) with locally advanced disease. METHOD: Expressions of chemokine receptors were examined immunohistochemically after staining archival tissue of surgical specimens (n = 63) using specific antibodies for CCR5, CCR7, CXCR4, and CXCR5. RESULTS: Patients with high CCR5, CCR7, CXCR4, and CXCR5 expression on tumors and high CXCR4 expression on tumor-infiltrating lymphocytes (TILs) were less likely to have a pathological complete response (pCR) or Class 0-I RCB-Index compared to others. Patients with residual lymph node metastases (ypN-positive), high CCR5TM(tumor), and high CXCR4TM expressions had an increased hazard ratio (HR) compared to others (DFS: HR = 2.655 [1.029-6.852]; DSS: HR = 2.763 [1.008-7.574]), (DFS: HR = 2.036 [0.805-5.148]; DSS: HR = 2.689 [1.020-7.090]), and (DFS: HR = 2.908 [1.080-7.829]; DSS: HR = 2.132 (0.778-5.846)), respectively. However, patients without CXCR5TIL expression had an increased HR compared to those with CXCR5TIL (DFS: 2.838 [1.266-6.362]; DSS: 4.211 [1.770-10.016]). CONCLUSIONS: High expression of CXCR4TM and CCR5TM was found to be associated with poor prognosis, and CXCR5TM was associated with poor chemotherapy response in the present cohort with locally advanced TNBC. Our results suggest that patients with TNBC could benefit from a chemokine receptor inhibitor therapy containing neoadjuvant chemotherapy protocols.

Distinguishing Pituitary Metastasis and Pituitary Neuroendocrine Tumors through Conventional MR Imaging and Clinical Features.

BACKGROUND AND PURPOSE: Given their overlapping features, pituitary metastases frequently imitate pituitary neuroendocrine tumors in neuroimaging studies. This study aimed to distinguish pituitary metastases from pituitary neuroendocrine tumors on the basis of conventional MR imaging and clinical features as a practical approach. MATERIALS AND METHODS: In this 2-center retrospective study, backward from January 2024, preoperative pituitary MR imaging examinations of 22 pituitary metastases and 74 pituitary neuroendocrine tumors were analyzed. Exclusion criteria were as follows: absence of a definitive histopathologic diagnosis, history of pituitary surgery or radiation therapy before MR imaging, and pituitary neuroendocrine tumors treated with medical therapy. Two radiologists systematically evaluated 13 conventional MR imaging features that have been reported more commonly as indicative of pituitary metastases and pituitary neuroendocrine tumors in the literature. Age, sex, history of cancer, and maximum tumor size constituted the clinical/epidemiologic features. The primary cancer origin for this study was also noted. Univariable and multivariable logistic regression was used for the selection of variables, determining independent predictors, and modeling. Interobserver agreement was evaluated for all imaging parameters using the Cohen κ statistic or intraclass correlation coefficient. RESULTS: A total of 22 patients with pituitary metastases (8 women; mean age, 49.5 [SD, 13] years) and 74 patients with pituitary neuroendocrine tumors (36 women; mean age, 50.1 [SD, 11] years) were enrolled. There was no statistically significant distributional difference in age, sex, or maximum tumor size between the 2 groups. Lung cancer (9/22; 41%) was the most commonly reported primary tumor, followed by breast (3/22; 13.6%) and unknown cancer (3/22; 13.6%). Logistic regression revealed 3 independent predictors: rapid growth on control MR imaging, masslike or nodular expansion of the pituitary stalk, and a history of cancer. The model based on these 3 features achieved an area under the curve, accuracy, sensitivity, specificity, and Brier score of 0.987 (95% CI, 0.964-1), 97.9% (95% CI, 92.7%-99.8%), 95.5% (95% CI, 77.2%-99.9%), 98.6% (95% CI, 92.7%-100%), and 0.025, respectively. CONCLUSIONS: Two conventional features based on pituitary MR imaging with the clinical variable of history of cancer had satisfying predictive performance, making them potential discriminators between pituitary metastases and pituitary neuroendocrine tumors. In cases in which differentiation between pituitary metastases and pituitary neuroendocrine tumors poses a challenge, the results of this study may help with the diagnosis.

Clinicopathological Correlates of PIT1 and SF1-Multilineage Pituitary Neuroendocrine Tumors and the Diagnostic Utility of NKX2.2 Immunohistochemistry in Pituitary Pathology.

CONTEXT.­: PIT1 and SF1-multilineage pituitary neuroendocrine tumors (PitNETs) have been defined since the classification of adenohypophysial tumors based on the PIT1, SF1, and TPIT transcription factors. OBJECTIVE.­: To describe the clinicopathologic features of PIT1 and SF1-multilineage PitNETs and to contribute to the pituitary pathology practice by questioning the expression of NKX2.2 in PitNETs. DESIGN.­: We reviewed 345 PitNETs and described the clinicopathologic features of 8 PIT1 and SF1-multilineage tumors. NKX2.2 positivity and staining pattern were compared to those of 45 PitNETs from the control group. RESULTS.­: PIT1 and SF1-multilineage PitNET patients had a mean age of 41.13 (range, 14-58 years) and a mean diameter of 14.0 mm (range, 8-20 mm). The most common clinical presentation was acromegaly (6 of 8), and postoperative remission was achieved in all patients. On histomorphologic examination, a pseudopapillary pattern was seen in 5 of the tumors, either focally or diffusely. In addition to PIT1 and SF1, there was a diffuse staining with growth hormone and a predominantly perinuclear staining with cytokeratin 18. With NKX2.2, all multilineage tumors were positive, of which 5 were diffuse and 3 were focal. In the control group, 8 tumors (8 of 45) were positive, of which only 1 was diffuse and 7 were focal. CONCLUSIONS.­: In conclusion, NKX2.2 is a transcription factor that can be used as an additional tool in pituitary pathology, and PIT1 and SF1-multilineage PitNETs are specific tumors that usually present with acromegaly, show signs of a nonaggressive clinical course, have a pseudopapillary histomorphology, and express NKX2.2.

Diverging prognostic effects of CD155 and CD73 expressions in locally advanced triple-negative breast cancer.

Background: Immune checkpoint inhibition, combined with novel biomarkers, may provide alternative pathways for treating chemotherapy-resistant triple-negative breast cancer (TNBC). This study investigates the expression of new immune checkpoint receptors, including CD155 and CD73, which play a role in T and natural killer (NK) cell activities, in patients with residual TNBC after neoadjuvant chemotherapy (NAC). Methods: The expression of biomarkers was immunohistochemically examined by staining archival tissue from surgical specimens (n = 53) using specific monoclonal antibodies for PD-L1, CD155, and CD73. Results: Of those, 59.2% (29/49) were found to be positive (>1%) for PD-L1 on the tumour and tumour-infiltrating lymphocytes (TILs), while CD155 (30/53, 56.6%) and CD73 (24/53, 45.3%) were detected on tumours. Tumour expressions of CD155 and CD73 significantly correlated with PD-L1 expression on the tumour (p = 0.004 for CD155, p = 0.001 for CD73). Patients with CD155 positivity ≥10% were more likely to have a poor chemotherapy response, as evidenced by higher MDACC Residual Cancer Burden Index scores and Class II/III than those without CD155 expression (100% vs 82.6%, p = 0.03). At a median follow-up time of 80 months (range, 24-239), patients with high CD73 expression showed improved 10-year disease-free survival (DFS) and disease-specific survival (DSS) rates compared to those with low CD73 expression. In contrast, patients with CD155 (≥10%) expression exhibited a decreasing trend in 10-year DFS and DSS compared to cases with lower expression, although statistical significance was not reached. However, patients with coexpression of CD155 (≥10%) and low CD73 were significantly more likely to have decreased 10-year DFS and DSS rates compared to others (p = 0.005). Conclusion: These results demonstrate high expression of CD73 and CD155 in patients with residual tumours following NAC. CD155 expression was associated with a poor response to NAC and poor prognosis in this chemotherapy-resistant TNBC cohort, supporting the use of additional immune checkpoint receptor inhibitor therapy. Interestingly, the interaction between CD155 and CD73 at lower levels resulted in a worse outcome than either marker alone, which calls for further investigation in future studies.

The effect of hydrogen sulfide on ischemi̇a /reperfusion injury in an experimental testicular torsion model.

INTRODUCTION: Testicular torsion is an acute pediatric surgical emergency requiring rapid diagnosis to prevent the permanent ischaemic damage of the testicles. Hydrogen Sulfide (H2S) have shown to cure tissue damage and has a role in the prevention of I/R damage. We aimed to evaluate the effect of H2S in testicular torsion. MATERIALS AND METHODS: Eighteen male, Wistar albino rats were divided into 3 groups. The sham group which is applied surgical stress. The ischemia/reperfusion group (I/R) which detorsion performed 1 h later than testicular torsion application. I/R + NaHS treatment group, NaHS solution was injected intraperitoneally for 1 week. On the 7th day of the detorsion all left testes were fixed in Bouin solution and sent to Pathology Department for histopathological examination. All right testes were washed with normal saline, dried in a sterile way and stored in - 80 °C deepfreeze up to the date of biochemical processes. Testicular tissues were obtained for the detection of myeloperoxidase (MPO), malondialdehyde (MDA), AOPP (advanced oxidation protein product) for oxidant markers and ferric reducing antioxidant power (FRAP) levels, superoxide dismutase (SOD),glutathione peroxidase (GSH-Px) activities for antioxidant markers and histopathological exploration. RESULTS: The effects of NaHs administration on oxidation were evaluated by determination of testicular MPO, MDA and AOPP levels. Increased testicular MPO (58.6%) activity was observed in the I/R group compared to the sham group. Following NaHS treatment, MPO (26.7%) activity was significantly decreased in rats exposed to I/R injury (Figure 1). MDA levels did not alter. Increases in AOPP (20.9%) levels were observed in the I/R group. NaHS treatment resulted in significant decreases in AOPP (25.1%) levels in testes tissues of rats exposed to I/R injury. The effects of NaHS treatment on antioxidant system FRAP, SOD, GSH and GSH-Px activities were evaluated. GSH levels were significantly increased in the IR + NaHS group compared to the I/R group. In histopathological examination degeneration of seminiferous tubules and spermatogenic cells were observed in the I/R group. After NaHS treatment, normal spermatogenic activity with many spermatozoa in the lumen of most seminiferous tubules were observed in the I/R injured rats. According to Johnsen's scoring (JS), the I/R group was significantly decreased compared to the sham group. JS values for the I/R + NaHS group were significantly increased compared to the I/R group. CONCLUSION: Our study supports that ischemia/reperfusion injury plays an important role in the testicular torsion injury, and it is a pioneer study showing that H2S may have a potential for therapeutic effect. The limitation of this work is this is an experimental study with limited number of animals. According to the results of our study, hydrogen sulfide treatment has beneficial effects on biochemical and histopathological results of testicular injury in testic torsion.

Diagnostic accuracy of core biopsies of renal masses: Experience in a real-life setting from a tertiary center.

OBJECTIVE: To document and analyze diagnostic accuracy of renal core biopsy (RCB), its diagnostic correlation with resection specimens, and to question the need for immunohistochemistry (IHC) in the preoperative diagnosis of renal masses. MATERIAL AND METHOD: RCBs performed at a reference center between 2007 and 2017 were included. Pathological, clinical, and radiological data were obtained from medical records. RESULTS: Among 302 biopsies included in this study, 274 (90.7%) were diagnostic. Two hundred sixty-six were neoplastic and 179 were of primary renal origin. The most common secondary neoplasms were hematolymphoid (n = 35) and metastatic (n = 17). Sixty-nine tumors were classified as small renal masses (SRMs) (≤4 cm in diameter) and 53 of them were malignant. Nephrectomy was performed in 58 patients. Overall diagnostic accuracy between resections and RCBs was 88.7%. IHC was performed in 160 (53%) cases. In 15 of those, a definite diagnosis could not be rendered. Renal cell origin and subtype were determined by histomorphology alone in 81 and 75 cases, respectively. Sixty primary neoplasms of renal cell origin required IHC for diagnosis. CONCLUSION: RCB is a safe and highly accurate method for the diagnosis of both primary and secondary renal neoplasms. IHC is mostly required for the diagnosis of secondary tumors. Histomorphology is still the primary diagnostic tool, highly dependent on the experience of the surgical pathologist.

Clinical impact of PD-L1 expression in triple-negative breast cancer patients with residual tumor burden after neoadjuvant chemotherapy.

BACKGROUND: Studies on PD-L1 expression in breast cancer have gained importance in recent years, especially in triple-negative breast cancer (TNBC). Our aim was to analyze the differential expression of PD-L1 to explore its correlation with response to neoadjuvant chemotherapy (NACT) and patient survival. METHODS: PD-L1 expression was evaluated immunohistochemically (Ventana SP263 clone kit) by staining tumor specimen. PD-L1 positivity was defined as membranous staining > 1%, > 5%, > 10%, and > 20% on either tumor cell (TC) and /or immune cell (IC). RESULTS: Fifty patients with locally advanced TNBC, who had a partial response to NACT, were included in the study. PD-L1 staining was observed in TCs in 25 patients (50%) and in ICs in 23 patients (46%) when PD-L1 > 1% was considered positive. Patients with PD-L1 positivity on ICs were more likely to respond to chemotherapy as measured by "MD Anderson Cancer Center Residual Cancer Burden Index" (14/22, 63.6% vs. 10/27, 37%, p = 0.064). The 5-year disease-free survival (DFS) and disease-specific survival (DSS) rates were 46.3% and 51.4%, respectively. A high (> 20%) tumoral PD-L1 positivity was associated with a better DFS and DSS. CONCLUSIONS: Studies in the literature mostly focused on PD-L1 expression in inflammatory cells. However, our results suggest that patients with a high PD-L1 expression on TCs were more likely to have a better outcome. Since patients with residual tumor burden who express PD-L1 on TILs were more likely to respond to NACT, an immune checkpoint inhibitor therapy in addition to NACT would be an important option for TNBC with locally advanced disease.

Immunoexpression of SDHB, FH, and CK20 among eosinophilic renal tumors: A tissue microarray study.

BACKGROUND: Differential diagnosis can be a challenge for eosinophilic subtypes of renal cell tumors due to their overlapping histomorphological and immunohistochemical features. We aimed to investigate the frequency of rare variants of renal cell carcinomas (RCCs) such as succinate dehydrogenase-deficient RCC (SDDRCC), hereditary leiomyomatosis and RCC (HLRCC)-associated RCC, and eosinophilic, solid, and cystic RCC (ESCRCC) in our population. MATERIALS AND METHODS: Renal tumors which could be considered in the eosinophilic tumor category were included: 91 conventional clear cell RCCs with eosinophilic cytoplasm, 72 papillary RCCs, 74 chromophobe RCCs, 88 oncocytomas, and 37 other rare subtypes. Using the tissue microarray method, succinate dehydrogenase B (SDHB), fumarate hydratase (FH), and cytokeratin 20 (CK20) antibodies were performed by immunohistochemistry. Immunohistochemistry was repeated on whole block sections for selected cases. The utility of these antibodies in the differential diagnosis was also investigated. RESULTS: Loss of SDHB expression was detected in three tumors, two of which showed typical morphology for SDDRCC. In additional two tumors, SDHB showed weak cytoplasmic expression without a mitochondrial pattern (possible-SDHB deficient). None of the tumors showed loss of FH expression. Heterogeneous reactions were observed with SDHB and FH antibodies. Only one ESCRCC was detected with diffuse CK20 positivity. CONCLUSION: SDDRCCs, HLRCC-associated RCCs, and ESCRCCs are very rare tumors depending on the population. Possible weak staining and focal loss of SDHB and FH expression should be kept in mind and genetic testing must be included for equivocal results.

TIM3 expression on TILs is associated with poor response to neoadjuvant chemotherapy in patients with locally advanced triple-negative breast cancer.

BACKGROUND: The expression of immune checkpoint receptors (ICRs) on tumor-infiltrating lymphocytes (TILs) is associated with better response to immunotherapies via immune checkpoint inhibitors. Therefore, we investigated various ICR expressions on TILs in patients with locally advanced triple-negative breast cancer (TNBC) after neoadjuvant chemotherapy (NAC). METHODS: Expressions of ICRs were examined immunohistochemically in surgical specimens (n = 61) using monoclonal antibodies for PDL-1, PD-1, TIM-3, LAG-3, and CTLA-4. Positivity was defined as staining > 1% on TILs. RESULTS: The median age was 49 (24-76) years. The majority of patients were clinically T3-4 (n = 31, 50.8%) and clinically N1-3 (n = 58, 95.1%) before NAC. Of those, 82% were found to have CTLA-4 positivity, whereas PD1, PDL-1, LAG3, and TIM-3 expressions on TILs were 62.3, 50.9, 26.2, and 68.9%. A high expression of CTLA-4 was found to be associated with a better chemotherapy response (OR = 7.94, 95% CI: 0.9-70.12, p = 0.06), whereas TIM-3 positivity was contrarily associated with a worse chemotherapy response (OR = 0.253, 95% CI: 0.066-0.974, p = 0.047) as measured by the MDACC Residual Cancer Burden Index. At a 47-month follow-up, ypN0 (DFS; HR = 0.31, 95% CI: 0.12-0.83, p = 0.02 and DSS; HR = 0.21, 95% CI: 0.07-0.62, p = 0.005) and CTLA-4 high expression on TILs (DFS; HR = 0.38, 95% CI: 0.17-0.85, p = 0.019 and DSS; HR = 0.34, 95% CI: 0.15-0.78, p = 0.01) were found to be associated with improved survival. CONCLUSIONS: These findings demonstrate that CTLA-4, PD-1, PDL-1, and TIM-3 were highly expressed in TNBC. Based on these high expression patterns, further studies directed towards combined therapies are warranted in advanced TNBC in future.

Promoter region mutations of the telomerase reverse transcriptase (TERT) gene in head and neck squamous cell carcinoma.

OBJECTIVE: The aim of the present study was to assess the prevalence of TERT promoter region mutations in tumor samples of patients with squamous cell carcinoma at different sites of the head and neck region and correlate it with patients' clinicopathologic data. STUDY DESIGN: Mutations in promoter region of the TERT gene were analyzed with polymerase chain reaction-based direct sequencing method using formalin-fixed, paraffin-embedded tumor samples of 189 HNSCCs. TERT promoter region mutations were assessed in terms of age, gender, location, smoking, alcohol consumption, and overall survival. RESULTS: TERT promoter region mutations were detected in the oral cavity (75%); larynx (8.4%), hypopharynx (16.6%), and oropharynx (0%). TERT promoter region mutations are associated with younger age and female gender and have a reverse relationship with smoking and alcohol consumption. CONCLUSIONS: We found statistically significant higher rates of TERT promoter region mutations in tumor samples of patients with squamous cell carcinoma in the oral cavity compared with other locations in the head and neck region.