Prognostic Role of OX40, LAG-3, TIM-3 and PD-L1 Expression in Bone and Soft Tissue Sarcomas.

Introduction: The current study aims to evaluate the OX40, TIM-3, LAG-3, and PD-L1 targeted pathways in the regulation of T-cell activity in sarcoma patients to determine their relationship with overall survival (OS). Method: This study included one hundred and eleven patients with bone and soft tissue sarcoma diagnosed in two centers between 2010 and 2020. OX40, LAG-3, TIM-3 and PD-L1 expression levels were evaluated immunohistochemically from pathology preparations. Results: PD-L1 staining was detected in tumor cells, OX40, LAG-3, TIM-3 staining was detected in inflammatory cells in tumor tissue. In univariate analysis, no significant relationship was found between OX40, TIM-3, LAG-3, and PD-L1 staining and overall survival (respectively: p = 0.12, p = 0.49, p = 0.31, p = 0.95). When grade and stage at diagnosis, which were found to be significant in univariate analysis, along with OX-40, TIM-3, LAG-3, and PD-L1, were evaluated in multivariate analysis, a positive effect of OX-40 staining on overall survival was determined (p = 0.009). Considering the correlation between PDL-1 and OX40, TIM-3, and LAG-3 staining, a significant positive correlation was found between PDL-1 and TIM-3 and LAG-3 staining (respectively; p = 0.002, p = 0.001). Conclusions: There was no significant relationship between the PDL-1 staining percentage of tumor cells and OX40, TIM-3, and LAG-3 staining in inflammatory cells with the OS of sarcoma patients. However, detecting a significant positive correlation between PDL-1 staining and TIM-3 and LAG-3 staining also holds promise for finding effective targetable combination therapies that can prolong survival in sarcoma patients in the future.

Analysis of Treatment Strategies and Outcomes in Malignant Peritoneal Mesothelioma: Insights From a Multi-Center Study.

BACKGROUND: This study aimed to evaluate the demographic," clinicopathologic, and prognostic characteristics of malignant peritoneal mesothelioma (MPeM), as well as the treatment options for the rare and heterogeneous MPeM population. METHODS: A retrospective multi-center observational cohort study was conducted to evaluate patients with MPeM. Due to the heterogeneity of the study population, the study divided them into two main groups in terms of treatments, follow-up periods, and prognostic features. The first group comprised the patients who underwent cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), and the second group included the patients with metastatic disease for whom curative intent surgery was not possible. The patients' diagnostic procedures and treatments were identified from medical records. Patients older than 18 years old were included in the study regardless of asbestos exposure. Well-differentiated papillary and multicystic mesothelioma histologic types were not included in the study. RESULTS: The study evaluated 118 patients from five centers. Survival times, prognosis, and treatment responses were analyzed in both groups. The study showed that CRS-HIPEC was associated with longer overall survival (OS) and progression-free survival (PFS). Perioperative therapy was evaluated in subgroup analyses of this population and shown to provide survival benefits. The patients treated with chemotherapy (metastatic and medically inoperable patients and those for whom complete cytoreduction was not achievable) had a poorer prognosis than the surgery group. The study showed that life expectancy decreased significantly for the patients not suitable to undergo surgery for any reason. CONCLUSIONS: According to data from experienced centers, CRS-HIPEC is a treatment option recognized as effective, cost-effective, and safe, with better OS and PFS , as well as low morbidity and mortality rates similar to those in the literature. In addition, the platinum-pemetrexed combination continues to be an effective and acceptable treatment option for metastatic patients, those who are medically inoperable, and those for whom complete or near-complete cytoreduction is not achievable.

Clinicopathological Features and First-Line Treatment Outcomes of Geriatric Patients With Extensive-Stage Small Cell Lung Cancer: A Multicenter Study.

Introduction The geriatric patient population diagnosed with extensive stage small cell lung cancer (SCLC) is underrepresented in clinical studies. We aimed to evaluate the clinicopathological characteristics, first-line treatment patterns and treatment outcomes of patients aged 65 years or older with extensive stage SCLC. Material and methods In this multicenter, retrospective cohort study, patients aged 65 years or older, diagnosed with extensive-stage SCLC, between January 2009 and December 2021 were included. Patients who were under 65 years of age at the time of diagnosis and did not develop progression after curative treatment and patients with a second malignancy were excluded from the study. The clinicopathological characteristics, first-line treatment patterns and treatment outcomes were analyzed. Results A total of 132 patients were included in the study. The median age was 70 years (range:65-91), and 118 (89.4%) patients were male. There were 77 (58.3%) patients with eastern cooperative oncology group (ECOG) performance status (PS) of 0-1. There were 26 (19.7%) patients in the limited stage disease and 106 (80.3%) patients in the extensive stage disease at the time of diagnosis. First-line chemotherapy was given to 86 (65.2%) patients. Of the patients who could not receive treatment, 18 patients (13.6%) due to patient refusal, and 28 patients (21.2%) due to comorbid diseases and poor performance status with organ dysfunctions. The most common treatment regimen used as first-line treatment was cisplatin+etoposide (n=47, 54.7%), and followed by carboplatin+etoposide (n=39, 45.3%). First-line chemotherapy responses were complete response in 4 (4.7%) patients, partial response in 35 (40.7%) patients, stable disease in 13 (15.1%) patients, and progressive disease in 34 (39.5%) patients. The most common grade 3-4 adverse events was neutropenia in 33 (38.4%) patients. Forty nine patients (57.0%) completed the planned first-line treatment. The mPFS was 6.1 months and the mOS was 8.2 months with first-line treatment. We found that ECOG PS status was the most important negative prognostic factor for both PFS and OS. There was no difference between carboplatin+etoposide and cisplatin+etoposide regimens in terms of PFS, OS, adverse events and treatment compliance. Conclusion Thus, it may be an appropriate approach not to give up chemotherapy treatment easily in elderly patients with a diagnosis of extensive stage SCLC. It should be kept in mind that finding factors that might affect the prognosis and tailoring the tretment precisely on case-by-case basis in geriatric cancer patients have an impact on survival.

Alexithymia May Be Associated With Depression in Early-Stage Breast Cancer Patients.

Background Depression, anxiety, or both are common in women with early-stage breast cancer (BC). A relationship is known between low perceived social support (PSS) and depression. We aimed to investigate the relationships between alexithymia, PSS, and Beck Depression Inventory (BDI) score in patients diagnosed with early-stage BC. Materials and methods A demographic and medical information form, BDI, the 20-item Toronto Alexithymia Scale (TAS-20), and the Multidimensional Scale of PSS (MSPSS) were given to 200 early-stage BC patients to respond. Two subgroups were created as group A (BDI score < 17) and group B (BDI score ≥ 17) and compared in terms of sociodemographic characteristics, TAS-20, and MSPSS scores. Results Twenty-six (18.1%), 48 (33.3%), and 26 (18.1%) patients were with high BDI scores, in low PSS status, and alexithymic, respectively. The median ages of the participants in group A and group B were 53.4 (interquartile range (IQR): 46-60.7) and 46 (IQR: 41.5-59) years, respectively (p = 0.083). The rates of single participants (26.9% versus 11%, p = 0.055), alexithymic participants (42.3% versus 12.7%, p = 0.001), low PSS levels (57.7% versus 28%, p = 0.018), psychiatric treatment history (46.2% versus 22%, p = 0.025), and patients with low income (57.7% versus 22.9%, p = 0.001) were higher in group B than in group A. In the multivariate regression model that contains the parameters mentioned above, psychiatric treatment history (odds ratio (OR): 2.758, 95% confidence interval (CI): 1.034-7.356, p = 0.043), low-income status (OR: 3.503, 95% CI: 1.336-9.182, p = 0.011), and alexithymia (OR: 3.482, 95% CI: 1.229-9.867, p = 0.019) were independent predictive factors for a high BDI. Conclusion Alexithymia and low PSS are significantly common in patients with prominent depressive symptoms in early-stage BC patients. Alexithymia may be associated with depression and may also have a role in depression pathogenesis in early-stage BC patients. New studies are needed to investigate whether there is a causal relationship between alexithymia and depression.

The Relationship Between Caregiver Burden and Posttraumatic Growth in Caregivers of Patients With Metastatic Cancer.

Objective In this study, we aimed to examine the effect of post-traumatic growth and depressive symptoms on caregiver burden in caregivers of cancer patients. Methods This was a single-center cross-sectional observational descriptive study conducted at a medical oncology clinic. The study included 214 caregivers of cancer patients. Participants were assessed with a sociodemographic information form, the Turkish versions of the Zarit Caregiver Burden Scale (ZCBS), the Posttraumatic Growth Inventory (PTGI), and the Beck Depression Inventory (BDI). Results The mean ZCBS, PTGI, and BDI scores were 42.7 ±13.8, 67.8 ±22.3, and 13.5 ±9.8, respectively. There was a negative correlation (r=-0.407, p<0.001) between the ZCBS and the PTGI total scores, a positive correlation (r=0.636, p<0.001) between the ZCBS total and BDI scores, and a negative correlation (r=-0.426, p<0.001) between the PTGI total and BDI scores. Age, gender, income level, and history of psychiatric treatment were not independent predictive factors for the ZCBS total scores. PTGI total score (B=-0.107, 95% CI: -0.178 to -0.037, p=0.003) and BDI score (B=0.776, 95% CI: 0.602-0.950, p<0.001) were independent predictive factors for ZCBS total scores. Conclusions Our study revealed a significant negative relationship between caregiver burden and PTGI in caregivers of metastatic cancer patients, and it was found that depression negatively affects burden in caregivers. Posttraumatic growth can be a protective buffer against the burden of care and depression among caregivers.

Does docetaxel matter in metastatic gastric cancer? FOLFOX versus FLOT regimens as first-line treatment.

We aimed to compare the efficacy and the safety of the FOLFOX and the FLOT regimens in metastatic gastric cancer (mGC) as first-line treatment. It was a retrospective multicenter observational study. The comparisons between groups were conducted in terms of progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and hematologic adverse events. Seventy-nine patients, diagnosed with mGC between March 2012 and December 2019, treated with FOLFOX (n = 43) or FLOT (n = 36) regimens as first-line treatment were included in the study. The mPFS was 10.9 months [95% confidence interval (CI), 5.8-16.1] in the FLOT arm and 7.1 months (95% CI, 5.1-9.1) in the FOLFOX arm (P < 0.001). The ORR was 63.9% in the FLOT arm and 30.2% in the FOLFOX arm (P = 0.003). The mOS was 13.3 months (95% CI, 11.3-15.4) in the FLOT arm and 10.9 months (95% CI, 8.2-13.5) in the FOLFOX arm (P = 0.103). The hematologic adverse events in all grades were 88.4% (n = 38) in the FOLFOX arm compared with 80.6% (n = 29) in the FLOT arm (P = 0.335). The FLOT regimen might be a preferred option in mGC with an improved PFS and ORR compared with the FOLFOX regimen.

Thirty-day mortality rates after immunotherapy initiation.

Background: The aim of this study was to determine the cause of death in patients who died within 30 days after the first dose of immunotherapy. Methods: The data of 1432 patients treated with immunotherapy in six tertiary referral hospitals were retrospectively analyzed. Results: It was determined that 34 (2%) of the patients died within 30 days after the first dose of immunotherapy. Death occurred in all patients who received palliative therapy, and most patients (88%) received immunotherapy as second- or subsequent-line of therapy. The most common cause of death was disease progression and thromboembolic events. Conclusion: Preliminary results of the current study might give some clues to define the patient population in whom the fatal side effects of immunotherapy might be encountered.

The Need for Effective Adjuvant Therapy in Uterine Leiomyosarcoma: A Single-centre Experience.

OBJECTIVE: To evaluate the efficacy of adjuvant chemotherapy (ACTx) in completely resected uterine leiomyosarcoma (ULMS) in terms of survival outcomes. STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Department of Medical Oncology, Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, Ankara, Turkey from February 2009 to November 2019. METHODOLOGY: Patients older than 18 years, who underwent complete surgical resection with a diagnosis of non-metastatic ULMS were evaluated retrospectively. The patients were divided into two groups: patients who received ACTx (group I) and patients who received only surgical treatment (group II). Both groups were compared in terms of main patient and tumour characteristics, relapse rates, relapse-free survival (RFS) and overall survival (OS). RESULTS: Forty-five patients with a median age of 52.1 years (IQR, 45.8-58.2) were included in the study. Group I consisted of 26 (57.8%) patients and group II consisted of 19 (42.2%) patients. Median RFS was 43.8 months (95% CI, 7.4-80.2) and the median OS was 81.3 months (95% CI, 39.4-123.1) for all patients (N = 45). Median RFS was 27.1 months (95% CI, 6.8-47.4) in group I (n = 26) and 43.8 months (95% CI, 11.8-75.8) in group II (n = 19) (p = 0.985). Median OS was 85.6 months (95% CI, 38.3-132.9) in group I (n = 26) and 81.2 months (95% CI, 62.1-100.4) in group II (n = 19) (p = 0.699).  Conclusion: There was no survival benefit of ACTx in completely resected ULMSs, in accordance with the literature data. There is a need for prospective randomised clinical trials evaluating the role of ACTx in ULMSs. Key Words: Uterine leiomyosarcoma, Complete resection, Adjuvant chemotherapy, Relapse, RFS, OS.

Evaluación de los conocimientos, actitudes y prácticas de los estudiantes de escuelas vocacionales de servicios de salud respecto a COVID-19 / Evaluation of knowledge, attitudes and practices of health services vocational schools’ students with regard to COVID-19

Resumen Introducción: La intervención más crítica para controlar la infección por SARS-CoV-2 requiere el conocimiento y la actitud correctos hacia el virus. Objetivo: Determinar el conocimiento, las actitudes y las prácticas de los estudiantes de una escuela vocacional de servicios de salud respecto a COVID-19. Métodos: Estudio transversal realizado entre mayo y junio de 2020 en una universidad de la región de Turquía. Los datos se recopilaron mediante un portal de encuestas en línea. Resultados: Se completaron y devolvieron 454 cuestionarios. Los estudiantes de técnicas de laboratorio médico y primeros auxilios y emergencias tuvieron puntuaciones de conocimiento significativamente más altas (p < 0.001). Más de 43 % de los estudiantes (n = 201) usaron televisores como su principal fuente de información sobre COVID-19. Se manifestó una actitud positiva hacia las aplicaciones, así como evitar lugares concurridos y mantener la higiene de las manos y la distancia social. Conclusiones: Los estudiantes de la escuela vocacional de servicios de salud tienen buen conocimiento y actitud positiva hacia COVID-19. Las principales fuentes de información fueron la televisión y las redes sociales, por lo que se debe prestar más atención a estos temas en el plan de estudios para utilizar fuentes de información basadas en la ciencia.

Abstract Introduction: The most critical intervention to control SARS-CoV-2 infection requires appropriate knowledge and attitude towards the virus. Objective: To determine the level of knowledge, attitudes and practices of students of a health services’ vocational school with regard to COVID-19. Methods: Cross-sectional study carried out between May and June 2020 in a university of the Turkish region. Data were collected through an online survey portal. Results: Four hundred and fifty-four questionnaires were completed and returned. Students of medical laboratory techniques and first aid and emergency medicine had significantly higher knowledge scores (p < 0.001). More than 43 % of the students (n = 201) used the TV as their main source of information on COVID-19. There was a positive attitude towards preventive measures such as avoiding crowded places and maintaining hand hygiene and social distance. Conclusions: Health services vocational school students have good knowledge and positive attitude towards COVID-19. The main sources of information were the TV and social media. For this reason, more attention should be given to these issues in the curriculum in order for science-based information sources to be used.

Real-life comparison of the afatinib and first-generation tyrosine kinase inhibitors in nonsmall cell lung cancer harboring EGFR exon 19 deletion: a Turk Oncology Group (TOG) study.

BACKGROUND: The new second-generation tyrosine kinase inhibitors (TKIs) have superior survival outcome and worse toxicity profile when compared with first-generation TKIs according to the results of clinical trials. However, there are limited studies that investigate the efficacy and safety of the new generation TKIs in real-world patients. Thus, we aimed to compare the efficacy and safety of the afatinib, an irreversible inhibitor of ErbB family receptor, and first-generation TKIs in real-world patients. MATERIALS AND METHODS: We included advanced nonsmall cell lung cancer (NSCLC) patients who had EGFR exon 19del mutation and treated with afatinib or first-generation TKIs as upfront treatment between 2016 and 2020. All patient's information was collected retrospectively. The study cohort was divided as afatinib arm and erlotinib/gefitinib arm. RESULTS: A total of 283 patients at the 24 oncology centers were included. The 89 and 193 of whom were treated with afatinib and erlotinib/gefitinib, respectively. After 12.9 months (mo) of follow-up, the median PFS was statistically longer in the afatinib arm than erlotinib/gefitinib arm (19.3 mo vs. 11.9 mo, p: 0.046) and the survival advantage was more profound in younger patients (< 65 years). The 24-mo overall survival rate was 76.1% and 49.5% in the afatinib arm and erlotinib/gefitinib arm, respectively. Although all-grade adverse event (AE) rates were similar between the two arms, grade 3-4 AE rates were higher in the afatinib arm (30.7% vs. 15.2%; p: 0.004). DISCUSSION: In our real-world study, afatinib has superior survival outcomes despite worse toxicity profile as inconsistent with clinical study results and it is the good upfront treatment option for younger patients and elderly patients who have good performance status.

Outcomes of Autologous Stem Cell Transplantation (ASCT) in Relapsed/Refractory Germ Cell Tumors: Single Center Experience from Turkey.

PURPOSE: Germ cell tumors (GCTs) are rare and highly curable malignancies. However, salvage treatments for relapsed or refractory disease are needed in approximately 20-60% of the patients. As salvage therapy, autologous stem cell transplantation (ASCT) administered after high-dose chemotherapy (HDCT) may be a feasible option as well as standard dose chemotherapy (SDCT). This study aimed to evaluate the efficacy and toxicity of ASCT in salvage therapy of GCTs retrospectively.  Materials and Methods: Male patients older than 18 years of age who underwent ASCT due to a relapsed/refractory GCT were included in the study. RESULTS: The median age of 18 patients included in the study was 28 (19-46). The majority of patients (n:16, 88.8%) had non-seminomatous GCT histology. All of the patients had relapsed or refractory GCTs and received bleomycin, etoposide, cisplatin (BEP) combination therapy previously. Half of the patients were in the poor risk group. ASCT was administered as a second-line therapy in 14 (77.7%) patients and third-line therapy in four (22.2%) patients. There is no ASCT-related exitus. Febrile neutropenia (FN) developed in almost all patients. Complete response (CR) was obtained in 7 (38.8%) patients, partial response (PR) in four (22.2%) patients after ASCT. The 2-year PFS was 44.4% and the median PFS was 8.7 (2.7-12.6) months. Median OS was 22.7 (3.9-41.7) months and 3 years OS was 50.0%. CONCLUSION: In conclusion, ASCT was found to be an effective and safe treatment option in salvage therapy of GCT patients in our study.

The investigation of the prenatal and postnatal alcohol exposure-induced neurodegeneration in rat brain: protection by betaine and/or omega-3.

PURPOSE: We aim to study the effect of neurodegeneration on the brain of rat pups caused by prenatal and postnatal ethanol exposure with modified liquid diet to elucidate protective effects of betaine and omega-3 supplementation. When ethanol is consumed during prenatal and postnatal periods, it may result in fetal alcohol syndrome (FAS) in the offspring. METHODS: Rats were divided into control, ethanol, ethanol + betaine, ethanol + omega-3, ethanol + omega-3 + betaine groups. The effect of betaine and omega-3 in response to ethanol-induced changes on the brain, by biochemical analyses cytochrome c, caspase-3, calpain, cathepsin B and L, DNA fragmentation, histological and morfometric methods were evaluated. RESULTS: Caspase-3, calpain, cathepsin B, and cytochrome c levels in ethanol group were significantly higher than control. Caspase-3, calpain levels were decreased in ethanol + betaine, ethanol + omega-3, and ethanol + omega-3 + betaine groups compared to ethanol group. Cathepsin B in ethanol + omega-3 + betaine group was decreased compared to ethanol, ethanol + betaine groups. Cathepsin L and DNA fragmentation were found not statistically significant. We found similar results in histological and morfometric parameters. CONCLUSION: We found that pre- and postnatal ethanol exposure is capable of triggering necrotic cell death in rat brains, omega-3, and betaine reduce neurodegeneration. Omega-3 and betaine may prove beneficial for neurodegeneration, particularly in preventing FAS.

Diabetic polyneuropathy relates to bone metabolism and markers of bone turnover in elderly patients with type 2 diabetes: greater effects in male patients.

BACKGROUND: There is evidence that diabetic polyneuropathy (PNP) is associated with reduced bone mineral density (BMD) in type 1 diabetes but little is known about the impact of diabetic PNP on bone metabolism in type 2 diabetes. OBJECTIVES: The aim of this study was to evaluate differences in bone metabolism by measuring markers of bone turnover and BMD in men and postmenopausal women with type 2 diabetes and diabetic PNP compared with those without PNP. Gender differences were analyzed for both groups of patients. METHODS: One hundred twenty patients with type 2 diabetes, 68 without PNP (43 men, 25 women, mean age 62 [8] years) and 52 with PNP (28 men, 24 women, mean age 64 [8] years) were studied. Clinical parameters with bone turnover biomarkers such as osteocalcin, bone alkaline phosphatase, procollagen type 1 amino-terminal propeptide, and carboxy-terminal telopeptide of type 1 collagen were measured in all patients. Dual energy x-ray absorptiometry to evaluate BMD was performed in a subgroup of patients. RESULTS: After controlling for age, body mass index, duration of diabetes, smoking, glycosylated hemoglobin, homeostasis model assessment index for insulin resistance, serum C-reactive protein, creatinine, calcium, gamma-glutamyltransferase, parathyroid and sex hormones levels, presence of micro/macrovascular complications, statin- as well as diabetes-related therapies, levels of carboxy-terminal telopeptide of type 1 collagen and procollagen type 1 amino-terminal propeptide were significantly higher among patients with PNP when compared with patients without PNP (P = 0.01 and P = 0.03, respectively). Differences in bone biomarkers were more pronounced among men with diabetes. BMD did not differ significantly between patients with and without PNP, independent of gender. CONCLUSIONS: Male patients with PNP exhibit a higher rate of bone turnover than men without PNP. High rate of bone turnover increases the susceptibility for developing osteoporosis. Prevention of diabetic PNP might also reduce the incidence of osteoporosis and fractures in patients with type 2 diabetes.

Levels of fetuin-A relate to the levels of bone turnover biomarkers in male and female patients with type 2 diabetes.

OBJECTIVE: To evaluate the relationship of plasma fetuin-A levels with markers of bone turnover in male and female type 2 diabetic subjects. BACKGROUND: Fetuin-A, which is a serum protein produced by the liver and promotes bone mineralization, is an independent risk factor for type 2 diabetes, whilst type 2 diabetes is associated with an increased incidence of osteoporosis or fractures. It is not known how fetuin-A levels relate to parameters of bone metabolism in type 2 diabetes. DESIGN AND PATIENTS: Eighty patients with type 2 diabetes [40 men and 40 women matched for age, body mass index (BMI) and time since diagnosis of diabetes] were studied. Fetuin-A together with metabolic parameters and levels of serum carboxy-terminal telopeptide of type 1 collagen (C-telopeptide), osteocalcin, procollagen type 1 amino-terminal propeptide (P1NP), bone alkaline phosphatase (ALP) and sex hormones was determined in all participants. RESULTS: Fetuin-A levels did not differ significantly between male and female diabetic subjects. In a model adjusted for age, BMI, fatty liver index (FLI), time since diagnosis of diabetes, HbA(1c) , antidiabetic and lipid-lowering drug therapies, smoking, total serum protein, creatinine, gamma glutamyl-transferase, parathyroid hormone, C-reactive protein, glomerular filtration rate, and presence of micro-, cardio-, and peripheral vascular diabetic complications, fetuin-A showed a significant positive association with levels of bone ALP (r = 0·71, P = 0·006) in men. In women, fetuin-A was significantly negatively associated with C-telopeptide (r = -0·60, P = 0·03) levels. CONCLUSIONS: Results suggest an independent association of fetuin-A levels with markers of bone turnover in male and female patients with type 2 diabetes. More studies are needed to determine whether fetuin-A could serve as a new marker for fracture risk or osteoporosis in type 2 diabetes and to explore its potential sexually dimorphic effects.

Immunohistochemical testing of BRAF V600E status in 1,120 tumor tissue samples of patients with brain metastases.

Brain metastases (BM) are frequent and carry a dismal prognosis. BRAF V600E mutations are found in a broad range of tumor types and specific inhibitors targeting BRAF V600E protein exist. We analyzed tumoral BRAF V600E-mutant protein expression using the novel mutation-specific antibody VE1 in a series of 1,120 tumor specimens (885 BM, 157 primary tumors, 78 extra-cranial metastases) of 874 BM patients. In 85 cases, we performed validation of immunohistochemical results by BRAF exon 15 gene sequencing. BRAF V600E protein was expressed in BM of 42/76 (55.3%) melanomas, 1/15 (6.7%) ovarian cancers, 4/72 (5.5%) colorectal cancers, 1/355 (0.3%) lung cancers, 2/6 thyroid cancers and 1/2 choriocarcinomas. BRAF V600E expression showed high intra-tumoral homogeneity and was similar in different tumor manifestations of individual patients. VE1 immunohistochemistry and BRAF exon 15 sequencing were congruent in 68/70 (97.1%) cases, but VE1 immunostaining identified small BRAF V600E expressing tumor cell aggregates in 10 cases with inconclusive genetic results. Melanoma patients with BRAF V600E mutant protein expressing tumors were significantly younger at diagnosis of the primary tumor and at operation of BM than patients with non-mutated tumors. In conclusion, expression of BRAF V600E mutant protein occurs in approximately 6% of BM and is consistent in different tumor manifestations of the same patient. Thus, BRAF V600E inhibiting therapies seem feasible in selected BM patients. Immunohistochemical visualization of V600E-mutant BRAF protein is a promising tool for patient stratification. An integrated approach combining both, VE1 immunohistochemistry and genetic analysis may increase the diagnostic accuracy of BRAF mutation analysis.

Age related changes in pancreatic beta cells: A putative extra-cerebral site of Alzheimer's pathology.

Frequent concomitant manifestation of type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) has been recently demonstrated by epidemiological studies. This might be due to functional similarities between ß-cells and neurons, such as secretion on demand of highly specific molecules in a tightly controlled fashion. An additional similarity represents the age-related alteration of hyperphosphorylated tau in AD patients. Similarly, alterations have been identified in ß-cells of T2DM patients. The islet amyloid polypeptide has been associated with ß-cell apoptosis. As a consequence of increasing age, the accumulation of highly modified proteins together with decreased regenerative potential might lead to increasing rates of apoptosis. Moreover, reduction of ß-cell replication capabilities results in reduction of ß-cell mass in mammals, simultaneously with impaired glucose tolerance. The new challenge is to learn much more about age-related protein modifications. This can lead to new treatment strategies for reducing the incidence of T2DM and AD.

Expression of secretagogin in clear-cell renal cell carcinomas is associated with a high metastasis rate.

Renal cell carcinomas are divided into several subgroups according to their histopathologic characteristics. The outcome, therapy responses, and the applicability of molecular-targeted therapies depend on the tumor classification and on the tumor stage. Recent advances within the biomarker research facilitated the exact classification of the molecular character of the renal tumor. For example, the calcium-binding proteins parvalbumin and S-100A1 are characteristically expressed in renal cell carcinoma subgroups. This led us to investigate the expression of the novel calcium-binding protein secretagogin in renal cell carcinomas. Tissue microarray cylinders including 94 clear-cell renal cell carcinomas, 61 non-clear-cell renal cell carcinomas (37 papillary renal cell and 24 chromophobe carcinomas), and 30 oncocytomas were analyzed by immunohistochemistry. This showed remarkable secretagogin expression in 37% of the clear-cell renal cell carcinomas. Non-clear-cell renal cell carcinomas and oncocytomas were completely negative. Consequently performed immunoblotting analyses confirmed this expression profile. Because publicly available data direct toward a formation of a hierarchical cluster of secretagogin overexpressing clear-cell renal cell carcinomas, we conducted a clinical follow-up of the patients with clear-cell renal cell carcinoma. This revealed significantly more metastasis within the secretagogin-positive clear-cell renal cell carcinoma subgroup (49% versus 28%; P < .05). In conclusion, we report on detection of the novel calcium-binding protein secretagogin within a subgroup of clear-cell renal cell carcinomas. The increased metastasis rates within the secretagogin-positive subgroup of clear-cell renal cell carcinomas direct toward a clinical impact of our findings.

Elevated blood markers 1 year before manifestation of malignant glioma.

We detected distinct plasma concentration profiles of S100B, neuropeptide Y, and secretagogin in 3 of 191 patients enrolled in a previous study investigating brain-tissue-related markers in the blood of patients with atrial fibrillation. Intriguingly, 2 of these 3 patients, both of whom were without neurological symptoms at the time of blood sampling, were diagnosed with malignant glioma (MG) approximately 1 year later. To our knowledge, this is the first report indicating that distinct blood biomarker profiles may be detected long before clinical manifestation of MG.