The role of microglia in neuropsychiatric disorders and suicide.

This narrative review examines the possible role of microglial cells, first, in neuroinflammation and, second, in schizophrenia, depression, and suicide. Recent research on the interactions between microglia, astrocytes and neurons and their involvement in pathophysiological processes of neuropsychiatric disorders is presented. This review focuses on results from postmortem, positron emission tomography (PET) imaging studies, and animal models of schizophrenia and depression. Third, the effects of antipsychotic and antidepressant drug therapy, and of electroconvulsive therapy on microglial cells are explored and the upcoming development of therapeutic drugs targeting microglia is described. Finally, there is a discussion on the role of microglia in the evolutionary progression of human lineage. This view may contribute to a new understanding of neuropsychiatric disorders.

The impact of low volume lymph node metastases and stage migration after pathologic ultrastaging of non-sentinel lymph nodes in early-stage cervical cancer: a study of 54 patients with 4.2 years of follow up.

OBJECTIVES: To assess the significance of pathologic ultrastaging (PU) of sentinel (SLN) and non-sentinel (nSLN) lymph nodes (LNs) and the influence on cancer staging in patients with International Federation of Gynecology and Obstetrics (FIGO) stage IA2-IB1 cervical cancer. MATERIAL AND METHODS: A retrospective study was conducted with 54 patients divided into two equal-sized groups. In test group (n1), at least one SLN/patient was detected with blue dye. All excised LNs in this group were subjected to PU (4 µm slices/150 µm intervals) with hematoxylin-eosin staining and immunohistochemistry (AE1-AE3 antibodies). In none of the control group (n2) was PU performed, but in 2 patients SLN concept was performed. Patients in both groups underwent radical hysterectomy and lymphadenectomy. The effect of PU was expressed in puTNM and compared with both standard pTNM and FIGO systems. The influence of PU on patients' disease-free survival (DFS) and overall survival (OS) was assessed using Kaplan-Meier curves. RESULTS: In total, 516 LNs were extracted (66 SLNs, 36% bilaterally). Micrometastases (MIC) or isolated tumor cells (ITC) were detected in 34 of the 482 LNs (7.1%), including 16 MICs and 9 ITC in non-SLNs. False negative rates were: 3.7%/side-specific, and 7.4%/both sides. The use of PU resulted in stage change in 2 cases (N and M status change), FIGO stage did not changed. No PU impact on DFS or OS was observed. CONCLUSIONS: The risk of TNM stage migration in early cervical cancer is low, is more likely in inattentively evaluated patients, and has indeterminate prognostic and predictive value. Selection of cases with cT ≤ 2 cm and cN0 is sufficient to avoid the risk of improper staging.

[Micrometastases in sentinel lymph node in endometrial cancer patients]. / Mikroprzerzuty w wartowniczym wezle chlonnym u chorych na raka endometrium.

BACKGROUND: Detection of micrometastases in sentinel lymph nodes (SLN) extends our knowledge of lymphatic spread in endometrial cancer, although its clinical significance has not yet been confirmed. OBJECTIVES: The aim of study was to determine the incidence of SLN micrometastases and to analyze the association between micrometastases and disease relapse. MATERIAL AND METHODS: Fifty-four patients with endometrioid endometrial cancer underwent routine surgical therapy and sentinel lymph node biopsy (SLNB). SLNB was performed using two techniques: cervical injection of 99mTc-labelled albumin or blue dye and fundal injection of blue dye. SLNs were subjected to ultrastaging with immunohistochemistry (AE1/AE3, 150µm). RESULTS: At least one SLN was detected in 51 patients (94.4%) and bilateral SLN detection was achieved in 80.4%. Nodal macrometastases were found in 3 patients (6.3%). SLNB enabled us to detect nodal macrometastases in 2 out of those 3 patients. In the third case, detection of SLN micrometastasis allowed to correctly determine the nodal status, thus avoiding the false negative result of SLNB. In 48 patients with detected 184 SLNs, there were 4 patients (8.3%) with micrometastases and 4 (8.3%) with ITC foci. No significant associations between the presence of risk factors (grade, myometrial invasion, cervical invasion, lymphovascular space invasion) and incidence of micrometastases and/or ITC foci in SLNs were found. CONCLUSIONS: Detection of micrometastases may result in lower false-negative rate, thus increasing SLNB safety.

Clinical feasibility and diagnostic accuracy of detecting micrometastatic lymph node disease in sentinel and non-sentinel lyph nodes in cervical cancer: outcomes and implications.

BACKGROUND: Lymph node (LN) micrometastatic disease has come to prominence since ultrastaging was shown to improve the quality of LN procedures in epithelial cancers. The aim of the study was to evaluate the feasibility and diagnostic usefulness of detecting micrometastases in sentinel (SLN) and non-sentinel LNs (nSLN) in cervical cancer MATERIAL AND METHODS: Twelve consecutive patients with cervical cancer stages IA to IIA, classified according to the Union for International Cancer Control (UICC) and divided into two groups: A (7) and B (5), with and without SLN procedure with methylene blue dye, who underwent radical hysterectomy and lymph nodes removal, were recruited for the study. All LNs were evaluated in hematoxylin-eosin (HE) staining and immunohistochemically (IHC) in ultrastaging with anti-cytokeratin AE1/AE3 antibodies. A detailed analysis was performed with regard to the technical and histopathological aspects of the procedure. RESULTS: More LNs could be extracted and studied in group A as compared to group B (210 vs. 70, mean 30 vs. 14, respectively p < 0.0005). A total of 13 SLNs were extracted, and the identification rate was 71% (5/7 in group A). One micrometastatic LN was found in each of the groups (16% cases), but the preliminary classification of the advancement stage was changed only in 1 case from the labeled nodes group (group A--from pN0 with HE to pN1 with IHC). CONCLUSIONS: Presence or absence of metastases in SLN(s) should not be sufficient amount of information for a surgeon or an oncologist, who ought to have data about all of the removed lymph nodes (sent to ultrastaging). In order for the surgery to be performed properly it is vital to ensure that SLNs were removed. Assessment of the N status ought to be taken into consideration in the classification according to the International Federation of Gynecology and Obstetrics (FIGO).

Tertiary prevention strategies for micrometastatic lymph node cervical cancer: A systematic review and a prototype of an adapted model of care.

PURPOSE: We found a need for balancing the application of clinical guidelines and tailored approaches to follow-up of cervical cancer (CC) patients in the lymph node micrometastatic (MICs) setting. This review aimed to determine the current knowledge of management of MIC-positive CC cases. METHODOLOGY: We addressed prognostic and risk of recurrence monitoring impacts associated with MIC+ cases. The electronic databases for literature and relevant articles were analysed. RESULTS: Fifteen studies, (4882 patients), were included in our systematic review. While the results show that MICs significantly worsen prognosis in early CC. A tertiary prevention algorithm for low volume lymph node disease may stratify follow-up according to the burden of nodal disease and provide data that helps improve follow-up performance. CONCLUSION: MICs worsen prognosis and should be managed as suggested by the algorithm. However, this algorithm must be externally validated. The clinical impact of isolated tumor cells (ITC) remains unclear.

[Clinical significance of lymph node micrometastases in cervical cancer]. / Kliniczne znaczenie mikroprzerzutów w wezlach chlonnych w raku szyjki macicy.

In most cancers of epithelial origin, metastases to the lymph nodes constitute the most important prognostic factor and are predictive of the results of the surgical and adjuvant therapies. Data on the lymph node status allows to design an appropriate treatment plan. Despite advances in gynecologic oncology the importance of lymph node micrometastases in cervical cancer especially in nonsentinel lymph nodes which are detected by ultrastaging, has not been fully elucidated. The purpose of the article is to familiarize the reader with the state of current knowledge on cervical cancer micrometastases. The authors attempt to answer the question about the benefits of lymph node assessment in the search for micrometastases in cervical cancer as well as to address emerging doubts.

Assessment of Cytological Changes in the Oral Mucosa in Young Hematological Patients Treated with Systemic Chemotherapy.

BACKGROUND AND OBJECTIVES: The primary objective of the undertaken study was to determine the morphological changes that occur within the oral epithelium in children undergoing chemotherapy following a diagnosis of hematological malignancies. MATERIALS AND METHODS: The study group consisted of 18 patients diagnosed with leukemia or lymphoma undergoing treatment with chemotherapy. Swabs (liquid-based cytology) were collected from the oral cavity for microscopic evaluation at baseline, during the chemotherapy cycle with oral mucositis symptoms present, and upon completion of the cycle. Both the neutrophil count and oral mucositis (OM) were registered using the WHO (World Health Organization) scale. The control group included 41 children who were generally healthy. All samples underwent microscopical analyses at the Department of Pathology, Medical University of Gdansk, Poland. RESULTS: A total of 190 cytological preparations were evaluated. The baseline preparations revealed similar cytological images, and the superficial cells of the epithelial layers were seen. A significant (p < 0.01) increase in the number of cells in the intermediate layer of the oral epithelium, as well as a decrease (p < 0.01) in the volume of cells in the superficial layers, was observed in further stages of cytostatic treatment. CONCLUSIONS: A decrease in the percentage of superficial epithelial cells with a corresponding increase in the number of intermediate epithelial cells is considered to be a result of toxic damage to the oral mucosa during chemotherapy.

From struma ovarii to Hashimoto disease--an unusual diagnosis of primary hypothyroidism: case report.

CAPSULE: Authors report a case of a 52-year-old woman after struma ovarii with chronic lymphocytic inflammation excision. Finally thyroxin treatment was started and patient's hypothyroidism symptoms diminished. CASE SUMMARY: Struma ovarii is a type of mature teratoma in which thyroid tissue forms the main component. In most cases struma ovarii is composed of normal thyroid tissue while lymphocytic thyroiditis in struma ovarii occurs very rarely. The authors report a case of a 52-year-old woman after ovarian tumor excision. In histopatholgical examination struma ovarii with chronic lymphocytic inflammation was diagnosed. Additional studies revealed a typical ultrasonographic picture of Hashimoto disease in the thyroid gland and an increased concentration of thyroglobulin antibodies. A final diagnosis of Hashimoto disease was confirmed. Initially, thyroid gland function was normal but 11 months after surgery, supplementation therapy with thyroxin was administered. In this case, an early diagnosis of Hashimoto disease resulted from excision of struma ovarii with chronic lymphocytic inflammation. It induced early thyroxin treatment and allowed to reduce hypothyroidism symptoms.

Incorporation of Tumor-Free Distance and Other Alternative Ultrasound Biomarkers into a Myometrial Invasion-Based Model Better Predicts Lymph Node Metastasis in Endometrial Cancer: Evidence and Future Prospects.

Myometrial invasion (MI) is a parameter currently used in transvaginal ultrasound (TVS) in endometrial cancer (EC) to determine local staging; however, without molecular diagnostics, it is insufficient for the selection of high-risk cases, i.e., those with a high risk of lymph node metastases (LNM). The study's objective was to answer the question of which TVS markers, or their combination, reflecting the molecular changes in EC, can improve the prediction of LNM. Methods: The TVS examination was performed on 116 consecutive EC patients included in this prospective study. The results from the final histopathology were a reference standard. Univariate and multivariate logistic models of analyzed TVS biomarkers (tumor [T] size, T area [AREA], T volume [SPE-VOL], MI, T-free distance to serosa [TFD], endo-myometrial irregularity, [EMIR], cervical stromal involvement, CSI) were evaluated to assess the relative accuracy of the possible LNM predictors., Spline functions were applied to avoid a potential bias in assuming linear relations between LNM and continuous predictors. Calculations were made in R using libraries splines, glmulti, and pROC. Results: LNM was found in 20 out of the 116 (17%) patients. In univariate analysis, only uMI, EMIR, uCSI and uTFD were significant predictors of LNM. The accuracy was 0.707 (AUC 0.684, 95% CI 0.568−0.801) for uMI (p < 0.01), 0.672 (AUC 0.664, 95% CI 0.547−0.781) for EMIR (p < 0.01), 0.776 (AUC 0.647, 95% CI 0.529−0.765) for uCSI (p < 0.01), and 0.638 (AUC 0.683, 95% CI 0.563−0.803) for uTFD (p < 0.05). The cut-off value for uTFD was 5.2 mm. However, AREA and VOL revealed a significant relationship by nonlinear analysis as well. Among all possible multivariate models, the one comprising interactions of splines of uTFD with uMI and splines of SPE-VOL with uCSI showed the most usefulness. Accuracy was 0.802 (AUC 0.791, 95% CI 0.673−0.91) Conclusions: A combination of uTFD for patients with uMI > 50%, and SPE-VOL for patients with uCSI, allows for the most accurate prediction of LNM in EC, rather than uMI alone.

Analysis of PTEN, estrogen receptor α and progesterone receptor expression in endometrial hyperplasia using tissue microarray.

We compared the immunohistochemical expression of PTEN, estrogen receptor α (ER-α) and progesterone receptor (PR) in a series of endometrial hyperplasia (EH) and in disordered proliferative endometrium (DPE) by tissue microarray (TMA). The material consisted of 141 endometrial curretings including 98 cases (study group) diagnosed as EH [59-simple (SH), 20-complex (CH), 19 atypical (AEH)] and 43 cases (control group) with DPE due to anovulation. The mean PTEN expression index decreased in order DPE-EH-AEH groups (p < 0.05). The mean value of the ER-α index increased in order DPE-SH-CH and decreased in AEH group, whereas the PR expression index decreased in order DPE-EH-AEH (p > 0.05 and p > 0.05, respectively). These results show that steroid hormone receptor status influences the architectural changes of endometriumrather than cytological ones. On the other hand, decreased PTEN expression correlates more closely with the cytological atypia in endometrial cells. In our opinion ER-α and PR may be useful markers predicting therapy response in EH. PTEN presents as a strong prognosticator which may help in determining the risk of progression in advanced stages of EH, especially those with atypical cytological features.

Factors limiting the detection of sentinel lymph nodes in early-stage cervical cancer.

OBJECTIVES: Sentinel lymph node detection (SLND) has not yet displaced lymphadenectomy, but it is a desired supplementary technique in cervical cancer surgery. The aim of our study was to identify the sources of SLND failure while performing the procedure by injecting blue dye (BD) into the cervix in cases of early-stage cervical cancer (ECC). MATERIAL AND METHODS: We analyzed 27 consecutive ECC patients (FIGO IA2-IB1) who underwent hysterectomy with SLND and systematic lymphadenectomy between October 2011 and June 2014. The main inclusion criterion was at least unilateral SLND by BD. Predictors of either unilateral or bilateral staining were identified using multinomial logit models and a decision tree. RESULTS: Overall, bilateral staining was achieved in nine patients (33%). Among the factors analyzed, BMI > 23.5 kg/m2 was the only factor negatively affecting the quality of SLND using BD (p < 0.02) in the univariable multinomial logit model. All patients with BMI < 23.5 kg/m2 and depth of invasion ≥ 15 mm had unilateral mapping. CONCLUSIONS: Both obese and overweight patients are unlikely to achieve optimal SLN staining with BD alone. Although some possible reasons are discussed, we believe that further studies are needed to clarify the specific limitations of other dyes currently in use.

Ultrasound Measurement of Tumor-Free Distance from the Serosal Surface as the Alternative to Measuring the Depth of Myometrial Invasion in Predicting Lymph Node Metastases in Endometrial Cancer.

BACKGROUND: Ultrasonography's usefulness in endometrial cancer (EC) diagnosis consists in its roles in staging and prediction of metastasis. Ultrasound-measured tumor-free distance from the tumor to the uterine serosa (uTFD) is a promising marker for these diagnostic and prognostic variables. The aim of the study was to determine the usefulness of this biomarker in locoregional staging, and thus in the prediction of lymph node metastasis (LNM). METHODS: We conducted a single-institutional, prospective study on 116 consecutive patients with EC who underwent 2D transvaginal ultrasound examination. The uTFD marker was compared with the depth of ultrasound-measured myometrial invasion (uMI). Univariable and multivariable logit models were evaluated to assess the predictive power of the uTFD and uMI in regard to LNM. The reference standard was a final histopathology result. Survival was assessed by the Kaplan-Meier method. RESULTS: LNM was found in 17% of the patients (20/116). In the univariable analysis, uMI and uTFD were significant predictors of LNM. The accuracy was 70.7%, and the NPV was 92.68% (OR 4.746, 95% CI 1.710-13.174) for uMI (p = 0.002), and they were 63.8% and 89.02% (OR 0.842, 95% CI 0.736-0.963), respectively, for uTFD (p = 0.01). The cutoff value for uTFD in the prediction of LNM was 5.2 mm. The association between absence of LNM and biomarker values of uMI < 1/2 and uTFD ≥ 5.2 mm was greater than that between the presence of metastases and uMI > 1/2 and uTFD values <5.2 mm. In the multivariable analysis, the accuracy of the uMI-uTFD model was 74%, and its NPV was 90.24% (p = non-significant). Neither uMI nor uTFD were surrogates for overall and recurrence-free survivals in endometrial cancer. CONCLUSIONS: Both uMI and uTFD, either alone or in combination, were valuable tools for gaining additional preoperative information on expected lymph node status. Negative lymph nodes status was better described by ultrasound biomarkers than a positive status. It was easier to use the uTFD rather than the uMI measurement as a biomarker of EC invasion, and the former still maintained a similar predictive value for lymph node metastases to the latter at diagnosis.

[Karyometric evaluations of the seminal tubule cells in men with azoospermia]. / Badania kariometryczne komórek kanalika jadra u mezczyzn z azoospermia.

OBJECTIVES: The aim of the study is to confirm that karyometric evaluations of the seminal tubule cells in men with azoospermia indicate stimulating influence of the Leydig cell and testosterone on the functions of Sertoli cells, whereas serum LH concentration may in fact lead to regressive changes in the wall of the seminal tubule. MATERIAL AND METHODS: Material consists of 75 patients with azoospermia and hypospermatogenesis. In all patients surgical biopsy of the testes was done, prior to an assessment of serum LH and testosterone levels. In histopathology, sperminal epithelium, basal membrane, myoid cells of the tubular wall and interstitial cells have been examined. Karyometry in Sertoli cells, spermatogonia and myoid cells was performed. Also, the thickness of the tubular wall was assessed quantitatively. RESULTS: The size of Sertoli cells nuclei was significantly bigger in hypospermatogenesis associated with hyperplasia of Leydig cells than in hypospermatogenesis alone (p = 0.01). Regression analysis revealed positive correlations between serum testosterone and the size of Sertoli cells nuclei (p = 0.02), between the size of Sertoli cell nuclei and of spermatogonia and between nuclear size of myoid cells and spermatogonia (p = 0.0001). Serum LH correlated positively with the thickness of tubular wall (p = 0.01). CONCLUSIONS: Leydig cell hyperplasia and testosterone stimulate the functions of Sertoli cells whereas Sertoli cells activate spermatogonia. The Sertoli cell function is positively interrelated with the function of myoid cells. There is a close interrelationship between LH and the thickness of tubular wall, which may suggest that hippersecretion of LH causes the enlarged thickness of tubular wall, observed in hipergonadotropizm.

FGFR1 mRNA and protein expression, not gene copy number, predict FGFR TKI sensitivity across all lung cancer histologies.

PURPOSE: FGFR1 gene copy number (GCN) is being evaluated as a biomarker for FGFR tyrosine kinase inhibitor (TKI) response in squamous cell lung cancers (SCC). The exclusive use of FGFR1 GCN for predicting FGFR TKI sensitivity assumes increased GCN is the only mechanism for biologically relevant increases in FGFR1 signaling. Herein, we tested whether FGFR1 mRNA and protein expression may serve as better biomarkers of FGFR TKI sensitivity in lung cancer. EXPERIMENTAL DESIGN: Histologically diverse lung cancer cell lines were submitted to assays for ponatinib sensitivity, a potent FGFR TKI. A tissue microarray composed of resected lung tumors was submitted to FGFR1 GCN, and mRNA analyses and the results were validated with The Cancer Genome Atlas (TCGA) lung cancer data. RESULTS: Among 58 cell lines, 14 exhibited ponatinib sensitivity (IC50 values ≤ 50 nmol/L) that correlated with FGFR1 mRNA and protein expression, but not with FGFR1 GCN or histology. Moreover, ponatinib sensitivity associated with mRNA expression of the ligands, FGF2 and FGF9. In resected tumors, 22% of adenocarcinomas and 28% of SCCs expressed high FGFR1 mRNA. Importantly, only 46% of SCCs with increased FGFR1 GCN expressed high mRNA. Lung cancer TCGA data validated these findings and unveiled overlap of FGFR1 mRNA positivity with KRAS and PIK3CA mutations. CONCLUSIONS: FGFR1 dependency is frequent across various lung cancer histologies, and FGFR1 mRNA may serve as a better biomarker of FGFR TKI response in lung cancer than FGFR1 GCN. The study provides important and timely insight into clinical testing of FGFR TKIs in lung cancer and other solid tumor types.

Ovarian thecoma with androgenic manifestations in a postmenopausal woman.

A 50-year-old woman, who presented with progressive androgenization, central obesity and severe hypertension, was initially suspected to have an adrenal virilizing tumor. Her serum testosterone level was in the male range (9.3-11.6 ng/ml) and was not suppressed with dexamethasone. Although no pathological abdominal or pelvic mass was detected, total hysterectomy and bilateral salpingo-oophorectomy was performed. Histopathological examination revealed a theca-cell tumor of the right ovary. Postoperatively the testosterone level returned to normal and the patient had regression of virilism. Our case illustrates that a virilizing ovarian tumor can be small and elude imaging studies, but may be detected by means of well-considered clinical management.