Periodontal conditions and association of periodontitis with oral-health-related quality of life in patients experiencing different episodes of bipolar disorder compared with healthy controls.

AIM: The aim of the present cross-sectional study was to evaluate periodontal conditions and the association of periodontitis with oral-health-related quality of life (OHRQoL) in patients with a history of bipolar disorder. MATERIALS AND METHODS: A total of 160 participants were recruited in four groups for the study: 40 patients with euthymic episodes, 40 patients with depression, 40 patients with manic episodes and 40 systemically healthy individuals. Clinical periodontal parameters were recorded. Oral Health Impact Profile (OHIP-14) was used to measure the impact of oral health on the quality of life. RESULTS: Bipolar disorder groups exhibited generally higher clinical parameters compared with the control group (p < .05). OHIP-14 total score (ß = 3.32, 95% confidence interval [CI]: 0.08-6.56, p = .044), functional limitation (ß = .89, 95% CI: 0.27-1.49, p = .005) and physical pain (ß = .64, 95% CI: 0.01-1.27, p = .046) were associated with bipolar depression episodes. Psychological discomfort was associated with the presence of generalized periodontitis (ß = .76, 95% CI: 0.01-1.51, p = .047) and psychological disability was associated with the presence of stage III-IV (ß = .83, 95% CI: 0.07-1.59, p = .033) and generalized (ß = .75, 95% CI: 0.07-1.42, p = .029) periodontitis. CONCLUSIONS: According to this study, a history of bipolar disorder episodes (exposure) may be associated with increased prevalence and severity of periodontitis and related reported OHRQoL impacts (outcomes). Bipolar depression episodes had a higher impact on OHRQoL than other bipolar episodes.

Impact of tissue sampling on detection of venous invasion in colorectal cancer: a prospective analysis.

AIMS: Venous invasion (VI) is a powerful yet under-reported prognostic factor in colorectal cancer (CRC). Efforts to improve its detection have largely focused upon histological assessment, with less attention paid to tissue-sampling strategies. This study aimed to prospectively determine the number of tumour blocks required to optimise VI detection in CRC resections. In addition, the relationship between linear spiculation (LS) and extramural venous invasion (EMVI) was investigated. METHODS AND RESULTS: A standardised tissue sampling protocol was developed and applied prospectively to 217 CRC resections [AJCC 8th edition, stage 1 (n = 32); stage 2 (n = 84); stage 3 (n = 87); stage 4 (n = 14); and post-neoadjuvant therapy (n = 46)]. Elastin stains were performed on all tumour blocks. VI was identified in 55% of cases (EMVI = 37%; IMVI alone = 18%). The sensitivity of VI detection increased with increasing numbers of tumour blocks submitted [one block (35%), three blocks (66%), five blocks (84%), six blocks (95%) and seven blocks (97%)]. Similar findings were observed for EMVI [one block (35%), three blocks (73%), five blocks (89%), six blocks (96%) and seven blocks (96%)]. LS was identified macroscopically in 22% of specimens. In cases where no neoadjuvant therapy had been given, EMVI was significantly associated with LS (71% in LS+ cases versus 29% in LS- cases; P < 0.001). In addition, tumour blocks targeting LS were associated with a fivefold higher rate of EMVI compared with blocks that did not (P < 0.001). CONCLUSIONS: Our findings demonstrate the impact of tissue sampling and quality of gross examination on VI detection and may inform practices in future CRC protocols.

Molecular profiling of gingival crevicular fluid fails to distinguish between infrabony and suprabony periodontal defects.

AIM: To assess the differential molecular profiling of gingival crevicular fluid (GCF) from infrabony and suprabony periodontal defects compared with healthy sites. MATERIALS AND METHODS: Seventy-five samples from 25 patients with untreated periodontitis stage III-IV were included. Clinical and radiological parameters as well as GCF samples were collected from an infrabony defect, a suprabony defect and a periodontally healthy site per patient. A multiplex bead immunoassay was performed to assess the level of 18 biomarkers associated with inflammation, connective tissue degradation and regeneration/repair. RESULTS: GCF volume was higher in periodontal sites compared with healthy sites, with no significant difference between infrabony and suprabony defects. Fourteen biomarkers were elevated in infrabony and suprabony sites compared with healthy sites (p < .05). Only interleukin-1α levels were increased in infrabony compared with suprabony sites, whereas there was no difference in probing pocket depth. CONCLUSIONS: Although the GCF molecular profile clearly differentiates periodontally affected sites from healthy sites, the different architecture between infrabony and suprabony defects is not reflected in GCF biomarker changes.

Association between periodontal diseases and COVID-19 infection: a case-control study with a longitudinal arm.

Some studies have suggested potential relationships between periodontal disease and COVID-19, explained by many possible pathological pathways. The aim of this case-control study with a longitudinal arm was to investigate this association. 80 systemically healthy individuals (apart from COVID-19) were involved in this study, divided into 40 patients who had recently had COVID-19 (test, divided into severe and mild/moderate cases) and 40 who had not had COVID-19 (control). Clinical periodontal parameters and laboratory data were recorded. Mann-Whitney U test, Wilcoxon test, and chi-square test were performed to compare variables. Multiple binary logistic regression method was used to estimate adjusted ORs and 95% confidence interval. Hs-CRP-1 and 2, Ferritin-1 and 2, lymphocyte count-1 values, and neutrophil/lymphocyte ratio-1 were higher in patients with severe COVID-19 than patients with mild/moderate COVID-19 (p < 0.05). All of these laboratory values significantly decreased after COVID-19 treatment (p < 0.05) in the test group. Presence of periodontitis (p = 0.015) was higher and periodontal health was lower (p = 0.002) in the test group than in the control group. All clinical periodontal parameters were significantly higher in the test group than in the control group (p < 0.05), except plaque index. Prevalence of periodontitis was associated with increased odds of having COVID-19 infection (PR = 1.34; 95% CI 0.23-2.45) in the multiple binary logistic regression. COVID-19 is associated with periodontitis prevalence, through a series of possible mechanisms including local and systemic inflammatory responses. Further studies should investigate whether the maintenance of periodontal health may be a factor in the reduction of the severity of COVID-19 infections.

Evaluation of IL-23p19/Ebi3 (IL-39) gingival crevicular fluid levels in periodontal health, gingivitis, and periodontitis.

OBJECTIVES: IL-23p19/Ebi3 (IL-39) was described as a new IL-12 family member. The aim of this study is to evaluate the gingival crevicular fluid (GCF) IL-39 levels in periodontal diseases and health and to correlate them to GCF levels of IL-1ß and periostin. MATERIALS AND METHODS: Sixty-six adult patients were included in the study. The study design was comprised of three groups, each containing 22 individuals: the periodontally healthy (PH), gingivitis (G), and periodontitis (P) groups. The clinical periodontal parameters were recorded and GCF samples were collected from the participants. GCF interleukin (IL)-39, IL-1ß, and periostin levels were examined using the enzyme-linked immunosorbent assay. RESULTS: GCF IL­1ß, periostin, and IL-39 levels were higher in the P and G groups than in the PH group (p < 0.001). Positive correlations were detected between all GCF biochemical parameters and clinical periodontal parameters (p < 0.05). In the multivariate generalized linear regression analysis, the P (ß = 37.6, 95% CI = 22.9-52.4) and G (ß = 28.4, 95% CI = 15.8-41) groups were associated with GCF IL-39 levels (p < 0.001). CONCLUSION: IL-39 levels were elevated in the presence of periodontal disease paralleling the increase in IL­1ß and periostin levels. IL-39 may have a role in the periodontal inflammation process. STATEMENT OF CLINICAL RELEVANCE: IL-39, a new cytokine from the IL-12 family, can be a possible predictor marker of periodontal diseases.

Effect of periodontal disease on oxidative stress markers in patients with atherosclerosis.

OBJECTIVES: The aim of this study was to investigate the effect of periodontal inflammation on oxidative stress in patients with atherosclerosis by considering serum and saliva total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI). MATERIALS AND METHODS: In the study, there were 4 groups, with 20 individuals in each group. These groups consisted of individuals who had periodontitis with atherosclerosis (group A-P), were periodontally healthy with atherosclerosis (group A-C), were systemically healthy with periodontitis (group P), and were systemically and periodontally healthy (group C). Clinical periodontal parameters were recorded. PISA values were calculated. Atherosclerosis severity was determined by the Gensini score. The ratio of TAS/TOS resulting in the OSI levels of the serum and saliva samples was examined biochemically. RESULTS: Group A-P serum TAS and group C saliva OSI values were lower than those of the other groups (p < 0.05). Group A-P serum TOS and OSI values were higher than those of the other groups (p < 0.05). Groups A-C and P serum TOS and OSI values were higher than those of group C (p < 0.05). In the multivariate linear regression analysis, group A-P and PISA values were independently associated with serum TOS and OSI values (p < 0.05). Group A-P, group P, and PISA values were independently associated with saliva OSI values (p < 0.05). CONCLUSIONS: Periodontitis and atherosclerosis may have systemic oxidative stress-increasing effects. The coexistence of periodontitis and atherosclerosis increases oxidative stress beyond that seen in either condition alone. Periodontitis can be associated with increased systemic TOS and OSI values in patients with atherosclerosis. STATEMENT OF CLINICAL RELEVANCE: Oxidative status is affected more severely when periodontitis and atherosclerosis coexist rather than when either exists alone. Periodontitis can cause increasing effect on serum TOS and OSI and decreasing effect on TAS in patients with atherosclerosis. The increase in oxidative stress markers with the presence of periodontal disease in patients with atherosclerosis emphasizes that controlling periodontal diseases, a treatable disease, may contribute to the prognosis of atherosclerosis.

Neoadjuvant Cytoreductive Treatment With BRAF/MEK Inhibition of Prior Unresectable Regionally Advanced Melanoma to Allow Complete Surgical Resection, REDUCTOR: A Prospective, Single-arm, Open-label Phase II Trial.

OBJECTIVE: To evaluate the potency of short-term neoadjuvant cytoreductive therapy with dabrafenib plus trametinib (BRAF and MEK inhibitor) to allow for radical surgical resection in patients with unresectable locally advanced melanoma. SUMMARY BACKGROUND DATA: Approximately 5% of stage III melanoma patients presents with unresectable locally advanced disease, making standard of care with resection followed by adjuvant systemic therapy impossible. Although neoadjuvant targeted therapy has shown promising results in resectable stage III melanoma, its potency to enable surgical resection in patients with primarily unresectable locally advanced stage III melanoma is still unclear. METHODS: In this prospective, single-arm, phase II trial, patients with unresectable BRAF-mutated locally advanced stage IIIC or oligometastatic stage IV melanoma were included. After 8 weeks of treatment with dabrafenib and trametinib, evaluation by positron emission tomography/computed tomography and physical examination were used to assess sufficient downsizing of the tumor to enable resection. The primary objective was the percentage of patients who achieved a radical (R0) resection. RESULTS: Between August 2014 and March 2019, 21 patients (20/21 stage IIIC American Joint Committee on Cancer staging manual 7th edition) were included. Planned inclusion of 25 patients was not reached due to slow accrual and changing treatment landscape. Despite this, the predefined endpoint was successfully met. In 18/21 (86%) patients a resection was performed, of which 17 were R0 resections. At a median follow-up of 50 months (interquartile range 37.7-57.1 months), median recurrence-free survival was 9.9 months (95% confidence interval 7.52-not reached) in patients undergoing surgery. CONCLUSIONS: This prospective, single-arm, open-label phase II trial, shows neoadjuvant dabrafenib plus trametinib as a potent cytoreductive treatment, allowing radical resection of metastases in 17/21 (81%) patients with prior unresectable locally advanced melanoma.

Clinicopathological analysis of invasive cribriform carcinoma of the breast, with review of the literature.

Invasive cribriform carcinoma (ICC) is a rare type of a primary breast carcinoma. It is subdivided into two groups as pure and mixed types. There are limited studies comparing the pure and mixed ICC at present. We aim to investigate the clinicopathological, radiological, prognostic features, and survival outcomes of two types with reviewing the published literature. 16 pure ICC and 26 mixed ICC cases were evaluated. The population consisted of 41 female and 1 male patients. The only male patient was a pure ICC case. The median age was for pure and mixed type, 46.5 and 54 years, respectively. All ICCs were ER positive. All ICCs except one mixed ICC, were positive for PR. Only one mixed ICC was accepted HER2 positive (3+). Pure ICCs showed more favorable features than mixed ICCs such as lesser axillary lymph node involvement, lower grade, and proliferation index. Twenty-five patients had one of the following imaging methods; ultrasonography (US), mammography (MG), and magnetic resonance imaging (MRI). Irregular shape, hypoechogenicity, and spiculated margins were the most common US findings. Similarly, irregular shape+spiculated margin is the most common MG findings. The median follow-up time for pure and mixed ICC was 88 and 56.5 months, respectively. One mixed ICC case developed bone metastasis. One death occurred in each group. Reasons of death were unknown. The 5-year OS for both ICC groups was 100%. 10-year OS for pure and mixed ICCs was 100% and 90%, respectively. 5-year DFS was 100% for pure ICC, and 94% for mixed ICC.

The role of rare breast cancers in the false negative strain elastography results.

PURPOSE: Elastography was primarily used as an adjunctive method along with ultrasonography in differentiation between benign from malignant lesions. Occasionally, overlaps can occur which are caused by some rare invasive breast cancers. Our aim is to analyze the role of rare breast cancers in false negative strain elastography results and to assess the relation among false negative results and tumor size, lesion distance to skin, and tumor grade. METHODS: Patients with BI-RADS 5 category underwent strain elastography and core biopsy. All those with confirmed invasive breast cancer were included. For each rare breast cancer, four usual invasive breast cancer cases were taken as a control group. The cut-off value of strain ratio was considered as 2.3. The true positive and the false negative groups were compared in terms of histological type (rare carcinomas and the others) and the other parameters. Pearson Chi-square and Fisher's exact test were used for statistical analyses. P values < 0.05 were considered statistically significant. RESULTS: One hundred-thirteen patients were defined as true positive (70.6%), and 47 patients were defined as false negative (29.4%). Strain ratio values of the rare breast cancers were significantly lower than those of the other breast cancers (p = 0.012). There was no statistically significant difference between the groups with respect to tumor size, distance to skin, and tumor grade (p > 0.05). CONCLUSION: The rare breast cancers are an important cause of false negativity in elastographic evaluation of invasive breast cancers. The results should be interpreted in combination with grayscale US findings.

The prognostic significance of cyclin D1 expression in patients with triple-negative breast cancer.

PURPOSE: Breast cancer (BC) is the most common cancer and the second leading cause of cancer death among women. While receptor-targeted therapies are used for other subtypes due to the presence of such receptors, studies are still continuing on receptor expression in order to identify new therapeutic targets as the triple-negative breast cancer (TNBC) lacks a target receptor and its prognosis is worse than the other subtypes. Cyclin D1 (CycD1) is a cell cycle regulator protein. It is stated that its overexpression plays a role in carcinogenesis. With the present study, we aimed to evaluate the prognostic significance of immunohistochemical expression of CycD1 in patients with TNBC. METHODS: The study included 56 operated patients with TNBC who were diagnosed between 2006 and 2011 at Izmir Katip Celebi University, Ataturk Research and Training Hospital, Department of Pathology. In tumor paraffin-embedded sections, CycD1 was immunohistochemically (IHC) studied. Demographic and survival data of the patients were obtained from the Department of Medical Oncology follow-up files. ROC curve analysis was used to calculate the cutoff value for CycD1 staining density. Patients were divided into two groups using 11.5 cutoff value for the expression of CycD1, obtained by ROC analysis. Kaplan-Meier analysis was utilized for survival analyses, and log rank test for comparisons between the two groups. RESULTS: Of the patients, 62.5% had CycD1 expression (37.5% had not). In the whole group, the 5-year disease-free survival (DFS) was 51%, and the 5-year overall survival (OS) was 65%. No difference in DFS between the two groups was noticed (p=0.37). The 5-year DFS was 47% in the group with CycD1 expression below 11.5, while it was 57% in the group above the 11.5 value. The difference in OS between the groups was statistically significant (p=0.044). The 5-year OS was 55% in the group with a CycD1 expression below 11.5, while it was 79% in the group above the 11.5 value (p=0.044). CONCLUSION: OS differed significantly between the high and low-CycD1 expression. It was also demonstrated that CycD1 may have prognostic significance in TNBC. Further studies with larger populations are required to confirm the prognostic significance of CycD1.

How to approach phyllodes tumors of the breast?

OBJECTIVE: Phyllodes tumor of the breast is a rare fibroepithelial breast tumor that comprise 0.3-0.9% of primary breast neoplasms. In this study, we aimed to present clinicopathologic symptoms of our patients along with their treatment modality. MATERIAL AND METHODS: Clinicopathologic properties and treatment modality of 20 phyllodes tumor patients who underwent surgery between January 2008 and January 2013 were retrospectively evaluated. RESULTS: Median patient age was 47 years (22-75). Fine-needle aspiration biopsy was applied to 19 patients. Biopsy results were reported as suspicious in four, malignant in three, benign in 11, and as non-diagnostic in one patient. Final histopathology reports revealed two benign, one malignant and one borderline tumor out of the four patients with suspicious findings on fine needle aspiration biopsy; all patients with malignant cytology had malignancy. There were two borderline and nine benign lesions within the benign biopsy group. Sixteen patients underwent segmental mastectomy, four patients underwent mastectomy with/without axillary dissection. The median tumor size was 6 (1-13) cm. Histopathologically, 11 (55%) tumors were benign, 5 (25%) were borderline, and 4 (20%) were malignant. Two of the four patients with malignancy underwent radiotherapy and chemotherapy, and one patient only received chemotherapy as adjuvant treatment. CONCLUSION: Phyllodes tumors are rare, mix-type breast tumors. Due to high rates of local recurrence and potential for malignancy, preoperative diagnosis and accurate management are important.

Primary mucinous cystadenocarcinoma of the breast with amplification of the HER2 gene confirmed by FISH - case report and review of the literature.

Fifty five-years-old woman was presented to the general surgery upon the palpation of a mass in her left breast. In the excisional biopsy performed, partially cystic tumor of 2 × 1 cm with solid areas was macroscopically observed. After through microscopic examination, the patient was diagnosed as invasive mucinous cystadenocarcinoma and the tumor was found to be ER- and PR-negative and C-erbB2 (2+). In the fluorescent in situ hybridization, HER2/neu gene amplification was observed. Here, we present the clinical, cytological, morphological and immunohistochemical features of a very rare type of breast carcinoma, mucinous cystadenocarcinoma of the breast, with the review of the relevant literature.

The prognostic significance of CD117-positive mast cells and microvessel density in colorectal cancer.

The prognostic significance of angiogenesis has been demonstrated in various types of cancer. However, in colorectal cancer (CRC), there are conflicting results regarding the relationship between angiogenesis and clinical-histopathological prognostic factors. Mast cells are immune system cells found in the inflammatory microenvironment; their role in carcinogenesis and prognosis remains unclear although they are considered to cause cancer development and progression. The present study aims to evaluate the prognostic significance of mast cell accumulation and angiogenesis assessed by microvessel density (MVD) in patients with CRC. Patients who underwent curative resection and who were not treated with neoadjuvant chemotherapy were included. The anti-CD34 antibody and anti-CD117 antibody were utilized for the immunohistochemical assessment of MVD and the mast cell count (MCC) in the tissue samples, respectively. The relationship between MCC, MVD, survival and clinical-histopathological prognostic factors were evaluated. A total of 94 patients were enrolled to the study. In a median 49-month follow-up, 65 patients (69.1%) died. The 5-year disease-free survival was 61.1% and 31.3% for the group with CD34 < 18.3% and CD34 > 18.3%, respectively (P = .001). The same groups presented 5-year overall survival rates of 77, 1% and 51, 4%, respectively (P, .012). The MVD was found to be associated with the pathological T stage, lymph node metastasis and distant metastasis (P < .05). Although the MCC was positively correlated with MVD, there was no association between the MCC and clinical-histopathological prognostic factors. MVD-assessed angiogenesis was significantly related to survival and the clinical-histopathological prognostic factors in patients diagnosed with CRC.

Development of a Voice Handicap Index for Clergymen: An Investigation of Its Validation and Reliability.

OBJECTIVE: This study aims to is to develop a disorder-specific patient-reported outcome measure to be used in Islamic clergymen with voice disorders and to investigate its validity and reliability. METHODS AND PROCEDURES: Employing an exploratory sequential mixed-methods design, this study conducted in two phases. Initially, semistructured interviews were conducted with 10 clergymen experiencing voice disorders. Subsequently, the questionnaire underwent rigorous validation, encompassing content, construct, and criterion validity assessments, in addition to test-retest reliability and internal consistency analyses. The index was administered to a sample of 110 male clergy, including imams, muezzins, and Quran course teachers, with an age range from 19 to 61years. RESULTS: Construct validity was established through factor analysis, resulting in a final 23-item scale categorized into two factors: physical-functional and emotional. Known group validity demonstrated a significant distinction between the study and control groups. Criterion validity reinforced the index's validity, displaying a correlation coefficient of 0.758 between the Voice Handicap Index for Clergymen and the well-established Voice Handicap Index. The questionnaire exhibited commendable internal consistency, with a Cronbach's Alpha (α) coefficient value of 0.971. Test-retest reliability analysis exhibited strong consistency, with a Pearson correlation coefficient of 0.863. CONCLUSIONS: It is recommended that the developed valid and reliable handicap index in the present study be included in the voice assessment batteries of Islamic clergymen with voice complaints with the clinical and research purposes. In future studies, the validity of the questionnaire can be investigated more by examining the difference between the Voice Handicap Index for Islamic Clergymen (CVHI) scores obtained before and after treatment. Identifying a cut-off point that discriminates between dysphonic and normophonic clergymen may allow the use of the CVHI as a screening tool for this population.

Tumor Budding Assessment in Colorectal Carcinoma: Normalization Revisited.

Tumor budding (TB) is a powerful prognostic factor in colorectal cancer (CRC). An internationally standardized method for its assessment (International Tumor Budding Consensus Conference [ITBCC] method) has been adopted by most CRC pathology protocols. This method requires that TB counts are reported by field area (0.785 mm 2 ) rather than objective lens and a normalization factor is applied for this purpose. However, the validity of this approach is yet to be tested. We sought to validate the ITBCC method with a particular emphasis on normalization as a tool for standardization. In a cohort of 365 stage I-III CRC, both normalized and non-normalized TB were significantly associated with disease-specific survival and recurrence-free survival ( P <0.0001). Examining both 0.95 and 0.785 mm 2 field areas in a subset of patients (n=200), we found that normalization markedly overcorrects TB counts: Counts obtained in a 0.95 mm 2 hotspot field were reduced by an average of 17.5% following normalization compared with only 3.8% when counts were performed in an actual 0.785 mm 2 field. This resulted in 45 (11.3%) cases being downgraded using ITBCC grading criteria following normalization, compared with only 5 cases (1.3%, P =0.0007) downgraded when a true 0.785 mm 2 field was examined. In summary, the prognostic value of TB was retained regardless of whether TB counts in a 0.95 mm 2 field were normalized. Normalization resulted in overcorrecting TB counts with consequent downgrading of most borderline cases. This has implications for risk stratification and adjuvant treatment decisions, and suggests the need to re-evaluate the role of normalization in TB assessment.

IMPemBra: a phase 2 study comparing pembrolizumab with intermittent/short-term dual MAPK pathway inhibition plus pembrolizumab in patients with melanoma harboring the BRAFV600 mutation.

BACKGROUND: Continuous combination of MAPK pathway inhibition (MAPKi) and anti-programmed death-(ligand) 1 (PD-(L)1) showed high response rates, but only limited improvement in progression-free survival (PFS) at the cost of a high frequency of treatment-related adverse events (TRAE) in patients with BRAFV600-mutated melanoma. Short-term MAPKi induces T-cell infiltration in patients and is synergistic with anti-programmed death-1 (PD-1) in a preclinical melanoma mouse model. The aim of this phase 2b trial was to identify an optimal regimen of short-term MAPKi with dabrafenib plus trametinib in combination with pembrolizumab. METHODS: Patients with treatment-naïve BRAFV600E/K-mutant advanced melanoma started pembrolizumab 200 mg every 3 weeks. In week 6, patients were randomized to continue pembrolizumab only (cohort 1), or to receive, in addition, intermittent dabrafenib 150 mg two times per day plus trametinib 2 mg one time per day for two cycles of 1 week (cohort 2), two cycles of 2 weeks (cohort 3), or continuously for 6 weeks (cohort 4). All cohorts continued pembrolizumab for up to 2 years. Primary endpoints were safety and treatment-adherence. Secondary endpoints were objective response rate (ORR) at week 6, 12, 18 and PFS. RESULTS: Between June 2016 and August 2018, 33 patients with advanced melanoma have been included and 32 were randomized. Grade 3-4 TRAE were observed in 12%, 12%, 50%, and 63% of patients in cohort 1, 2, 3, and 4, respectively. All planned targeted therapy was given in 88%, 63%, and 38% of patients in cohort 2, 3, and 4. ORR at week 6, 12, and 18 were 38%, 63%, and 63% in cohort 1; 25%, 63%, and 75% in cohort 2; 25%, 50%, and 75% in cohort 3; and 0%, 63%, and 50% in cohort 4. After a median follow-up of 43.5 months, median PFS was 10.6 months for pembrolizumab monotherapy and not reached for patients treated with pembrolizumab and intermittent dabrafenib and trametinib (p=0.17). The 2-year and 3-year landmark PFS were both 25% for cohort 1, both 63% for cohort 2, 50% and 38% for cohort 3 and 75% and 60% for cohort 4. CONCLUSIONS: The combination of pembrolizumab plus intermittent dabrafenib and trametinib seems more feasible and tolerable than continuous triple therapy. The efficacy is promising and appears to be favorable over pembrolizumab monotherapy. TRIAL REGISTRATION NUMBER: NCT02625337.

Association of mast cells with microvessel density in urothelial carcinomas of the urinary bladder.

This study aims to investigate the relation of mast cell (MC) accumulation with tumor grade and stage in urothelial carcinomas of the urinary bladder and to determine its relationship with angiogenesis. A total of 78 urothelial carcinomas obtained by transurethral resection were investigated immunohistochemically by using c-Kit (CD117) and anti-CD34. The correlation between MC counts and microvessels was evaluated and compared with histopathologic parameters including tumor stage and grade. There were significant correlations between MC counts, grade, and stage (P < .05; r = 0.69 and 0.63, respectively). However, MC counts in adjacent nontumoral bladder mucosa significantly were higher than the MC counts in tumoral zone (P < .001). On the other hand, significant correlation was found between the number of MCs in tumoral zone and the microvessel density (P < .05, r = 0.56). The results of our study suggest that c-Kit positive MCs in tumoral zone may contribute to tumor angiogenesis and play a significant role in tumor growth and invasion. Further studies are needed to support these observations.

Epithelioid schwannoma of soft tissue: unusual morphological variant causing a diagnostic dilemma.

Epithelioid variant of peripheral nerve sheath tumors is a rare but, at the same time, a well-known entity especially in the malignant counterpart. However, peculiar epithelioid morphology in soft tissue schwannomas is unusual and has been defined recently. These tumors may cause diagnostic errors owing to their increased cellularity and epithelioid morphology. Typical histologic features of classic schwannoma such as Antoni A and B areas, Verocay bodies, and hyalinized vessels are either absent or only present in focal areas. Furthermore, strong and diffuse S-100 protein expression is seen in both benign and malignant counterparts of epithelioid schwannoma. The findings that are suggestive of the benign nature of the lesion are long-term clinical history, small size, superficial localization, encapsulation, bland morphology, lack of mitosis and necrosis, and a benign clinical course after complete excision. Pathologists should be aware of the epithelioid variant of schwannoma to avoid false diagnosis of malignancy. We hereby report 3 cases of unusual benign epithelioid schwannoma of the soft tissue with special regard to problems in differential diagnosis.

Association between periodontal inflamed surface area and serum acute phase biomarkers in patients with sickle cell anemia.

OBJECTIVES: The aim of the present cross-sectional study was to investigate the association between periodontal inflamed surface area (PISA) and serum inflammatory biomarkers in patients with sickle cell anemia. DESIGN: Patients with sickle cell anemia (n = 80) and systemically healthy individuals (n = 80) were enrolled in the study. Crisis episodes were recorded and blood samples were collected from patients with sickle cell anemia. Clinical periodontal parameters and PISA values were calculated from all patients. Ferritin and high sensitivity C-reactive protein (hs-CRP) levels were analyzed biochemically. RESULTS: In sickle cell anemia group, presence of periodontitis (p < 0.001) was more frequent than periodontal health (p < 0.001). All clinical periodontal recordings and PISA values were higher in the sickle cell anemia group compared to controls (p < 0.001). Patients with PISA > 776 mm² had 6.06-fold greater chances of having hs-CRP levels above 10 mg/L (OR = 6.06; 95 % CI: 1.9-19.26) and had 31.41-fold greater chances of having ferritin levels above 1000 ng/L (OR = 31.41; 95 % CI: 6.62-149.16). Also, they had 3.27-fold greater risk of having crisis frequency above three times per year (OR = 3.27; 95 % CI: 1.05-10.23) after adjusting for confounders. CONCLUSION: In patients with sickle cell anemia, positive association was evident between PISA values and serum acute phase biomarkers levels as well as the frequency of acute painful crisis. Patients with increased inflammatory burden may have a higher likelihood of developing periodontitis in the presence of sickle cell anemia. PISA value could be a candidate disease activity indicator in patients with an underlying hematological condition.