scholarly journals High Inter- and Intratumoral Variability of Ki67 Labeling Index in Newly Diagnosed Prostate Cancer with High Gleason Scores

Pathobiology ◽  
2021 ◽  
pp. 1-7
Author(s):  
Tatjana Vlajnic ◽  
Patrik Brunner ◽  
Serenella Eppenberger-Castori ◽  
Cyrill A. Rentsch ◽  
Tobias Zellweger ◽  
...  
Keyword(s):  
Gleason Score ◽  
Treatment Strategies ◽  
Progression Free Survival ◽  
Labeling Index ◽  
High Grade ◽  
Newly Diagnosed ◽  
Ki67 Labeling Index ◽  
The Status ◽  
Underlying Mechanisms

<b><i>Background:</i></b> The majority of studies investigating the role of Ki67 labeling index (LI) in prostate carcinoma (PC) focused on localized PC treated radically, where Ki67 LI is regarded as a prognostic marker. The relevance of Ki67 in advanced PC remains largely unexplored. While Gleason score is still one of the best indicators of clinical outcomes in PC, differences in progression-free survival and overall survival in patients with high Gleason scores suggest that additional factors are involved in tumor progression. Understanding the underlying mechanisms could help to optimize treatment strategies for an individual patient. Here, we aimed to determine the inter- and intratumoral distribution of Ki67 LI in patients with PC with high Gleason scores and to correlate Ki67 LI with the status of ERG, PTEN, and Bcl-2. <b><i>Methods:</i></b> Immunohistochemistry for Ki67, ERG, PTEN, and Bcl-2 was performed on core needle biopsies from 112 patients with newly diagnosed PC Gleason score 8, 9, and 10. <b><i>Results:</i></b> Using a cutoff of ≥10%, 17/112 cases (15%) had a homogeneously low and 95/112 cases (85%) a high Ki67 LI. 41% of cases showed intratumoral heterogeneity containing areas with low and high proliferation. There was no association between Ki67 LI and ERG, PTEN, or Bcl-2 status. <b><i>Conclusions:</i></b> Our data demonstrate major inter- and intratumoral variability of Ki67 LI in high-grade PC with a surprisingly low Ki67 LI in a subset of cases. Further studies are necessary to explore the molecular basis and potential clinical implications of a paradoxically low proliferation rate in high-grade PC.

scholarly journals Mebendazole and temozolomide in patients with newly diagnosed high-grade gliomas: Results of a phase 1 clinical trial

2020 ◽  
Author(s):  
Gary L Gallia ◽  
Matthias Holdhoff ◽  
Henry Brem ◽  
Avadhut D Joshi ◽  
Christine L Hann ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Plasma Levels ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
High Grade ◽  
Newly Diagnosed ◽  
Kaplan Meier ◽  
High Grade Gliomas ◽  
Expansion Cohort

Abstract Background Mebendazole is an anthelmintic drug introduced for human use in 1971 that extends survival in preclinical models of glioblastoma and other brain cancers. Methods A single center dose escalation and safety study of mebendazole in 24 patients with newly diagnosed high-grade gliomas (HGG) in combination with temozolomide was conducted. Patients received mebendazole in combination with adjuvant temozolomide after completing concurrent radiation plus temozolomide. Dose escalation levels were 25, 50, 100 and 200 mg/kg/day of oral mebendazole. A 15-patient expansion cohort was conducted at the maximum tolerated dose of 200 mg/kg/day. Trough plasma levels of mebendazole were measured at 4, 8 and 16 weeks. Results Twenty-four patients (18 glioblastoma, 6 anaplastic astrocytoma) were enrolled with median age of 49.9 years. Four patients (at 200 mg/kg) developed elevated grade 3 ALT and/or AST after one month, which reversed with lower dosing or discontinuation. Plasma levels of mebendazole were variable but generally increased with dose. Kaplan Meier analysis showed a 21-month median survival with 43% of patients alive at two years and 25% at 3 and 4 years. Median progression free survival (PFS) from the date of diagnosis for 17 patients taking more than one month of mebendazole was 13.1 months (95% Confidence Interval: 8.8 to 14.6 months) but for seven patients who received less than one month of mebendazole PFS was 9.2 months (95% CI: 5.8 -13.0 months). Conclusion Mebendazole at doses up to 200 mg/kg demonstrated long-term safety and acceptable toxicity. Further studies are needed to determine mebendazole’s efficacy in patients with HGG.

scholarly journals Emerging Roles of Exosomes in T1DM

2020 ◽  
Vol 11 ◽  
Author(s):  
Haipeng Pang ◽  
Shuoming Luo ◽  
Yang Xiao ◽  
Ying Xia ◽  
Xia Li ◽  
...  
Keyword(s):  
Autoimmune Disorder ◽  
Elevated Blood Glucose Level ◽  
The Status ◽  
Life Threatening ◽  
Novel Biomarkers ◽  
Therapeutic Tools ◽  
Underlying Mechanisms ◽  
The Relationship

Type 1 diabetes mellitus (T1DM) is a complex autoimmune disorder that mainly affects children and adolescents. The elevated blood glucose level of patients with T1DM results from absolute insulin deficiency and leads to hyperglycemia and the development of life-threatening diabetic complications. Although great efforts have been made to elucidate the pathogenesis of this disease, the precise underlying mechanisms are still obscure. Emerging evidence indicates that small extracellular vesicles, namely, exosomes, take part in intercellular communication and regulate interorgan crosstalk. More importantly, many findings suggest that exosomes and their cargo are associated with the development of T1DM. Therefore, a deeper understanding of exosomes is beneficial for further elucidating the pathogenic process of T1DM. Exosomes are promising biomarkers for evaluating the risk of developingty T1DM, monitoring the disease state and predicting related complications because their number and composition can reflect the status of their parent cells. Additionally, since exosomes are natural carriers of functional proteins, RNA and DNA, they can be used as therapeutic tools to deliver these molecules and drugs. In this review, we briefly introduce the current understanding of exosomes. Next, we focus on the relationship between exosomes and T1DM from three perspectives, i.e., the pathogenic role of exosomes in T1DM, exosomes as novel biomarkers of T1DM and exosomes as therapeutic tools for T1DM.

scholarly journals Pursuing a Curative Approach in Multiple Myeloma: A Review of New Therapeutic Strategies

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 2015 ◽  
Author(s):  
Mattia D'Agostino ◽  
Luca Bertamini ◽  
Stefania Oliva ◽  
Mario Boccadoro ◽  
Francesca Gay
Keyword(s):  
Multiple Myeloma ◽  
Residual Disease ◽  
Treatment Strategies ◽  
Progression Free Survival ◽  
Hematologic Cancer ◽  
Focus On Results ◽  
Individualize Treatment ◽  
New Generation ◽  
Effective Drugs

Multiple myeloma (MM) is still considered an incurable hematologic cancer and, in the last decades, the treatment goal has been to obtain a long-lasting disease control. However, the recent availability of new effective drugs has led to unprecedented high-quality responses and prolonged progression-free survival and overall survival. The improvement of response rates has prompted the development of new, very sensitive methods to measure residual disease, even when monoclonal components become undetectable in patients’ serum and urine. Several scientific efforts have been made to develop reliable and validated techniques to measure minimal residual disease (MRD), both within and outside the bone marrow. With the newest multidrug combinations, a good proportion of MM patients can achieve MRD negativity. Long-lasting MRD negativity may prove to be a marker of “operational cure”, although the follow-up of the currently ongoing studies is still too short to draw conclusions. In this article, we focus on results obtained with new-generation multidrug combinations in the treatment of high-risk smoldering MM and newly diagnosed MM, including the potential role of MRD and MRD-driven treatment strategies in clinical trials, in order to optimize and individualize treatment.

scholarly journals Prognostic role of primary tumor, nodal neck, and retropharyngeal GTVs for unresectable sinonasal cancers treated with IMRT and chemotherapy

2019 ◽  
Vol 106 (1) ◽  
pp. 39-46
Author(s):  
Letizia Ferella ◽  
Anna Cavallo ◽  
Rosalba Miceli ◽  
Nicola Alessandro Iacovelli ◽  
Tommaso Giandini ◽  
...  
Keyword(s):  
Primary Tumor ◽  
Locally Advanced ◽  
Treatment Strategies ◽  
Intensity Modulated Radiotherapy ◽  
Progression Free Survival ◽  
Nodal Metastasis ◽  
Rank Test ◽  
Prognostic Role ◽  
Sinonasal Cancer

Background: We evaluated the prognostic role of gross tumor volumes (GTVs) of primary tumor and positive lymph nodes on overall survival (OS) and progression-free survival (PFS) in locally advanced unresectable sinonasal cancer (SNC) treated with definitive intensity-modulated radiotherapy (IMRT) with or without chemotherapy. Methods: Primary tumor GTV (GTV-T), pathologic neck nodes GTV (GTV-N), and positive retropharyngeal nodes GTV (GTV-RPN) of 34 patients with epithelial nonglandular SNC receiving IMRT with or without chemotherapy were retrospectively measured. The GTV variables were analyzed in relation with OS and PFS. Survival curves were estimated using the Kaplan-Meier method and compared with the log-rank test. We also estimated the crude cumulative incidence of locoregional relapses only. The optimal volume cutoff value was determined using an outcome-oriented method among the observed values. Results: GTV-T was significantly associated with decreased OS ( P=0.003) and PFS ( P=0.003). Moreover, patients with disease total volumes (GTV) smaller than 149.44 cm³ had better OS and PFS than patients with higher volumes ( P<0.0001 for both). Neck nodal metastasis impacted on OS and PFS ( P=0.030 and P=0.033, respectively), but GTV-N did not ( P=0.961; P=0.958). Retropharyngeal nodes metastasis was not associated with prognosis (OS: P=0.400; PFS: P=0.104). When GTV-RPN was added to GTV-N (GTV-TN), a relation with PFS ( P=0.041) and a trend toward significance for OS ( P=0.075) were found. Conclusions: Our results show that tumor volume is a powerful predictor of outcome in SNC. This could be useful to identify patients with worse prognosis deserving different treatment strategies.

p53 Expression in Canine Liposarcoma Correlates With Myxoid Variant and Higher Proliferative Activity

2020 ◽  
Vol 57 (5) ◽  
pp. 620-622
Author(s):  
Giancarlo Avallone ◽  
Luisa V. Muscatello ◽  
Alessandro Leoni ◽  
Paola Roccabianca ◽  
Elvio Lepri ◽  
...  
Keyword(s):  
Proliferative Activity ◽  
Mitotic Count ◽  
Labeling Index ◽  
P53 Expression ◽  
Ki67 Labeling Index ◽  
Mdm2 Expression ◽  
Morphological Variants ◽  
Well Differentiated

Canine liposarcoma is classified as well differentiated (WDL), dedifferentiated (DDL), myxoid (ML), and pleomorphic (PL). Overexpression of the protooncogene MDM2 has been reported in WDL and DDL, but little is known regarding the role of p53 in their tumorigenesis. The aim of this study was to assess p53 expression in canine liposarcoma and compare it with subtype, grade, mitotic count (MC), Ki67 labeling index (LI), and MDM2 expression. Forty-seven cases were included (13 WDL, 3 DDL, 7 ML, and 24 PL); 17 were MDM2-positive (13 WDL, 3DDL, and 1ML). Five were p53-positive (4 ML and 1 WDL) but DDL and PL were consistently negative. p53 expression correlated with higher Ki67-LI, higher MC, and myxoid histotype. No correlation was found with grade and MDM2 expression. Based on these results canine liposarcoma seems to embody a group of neoplasms whose subtypes, especially ML, may represent distinct diseases rather than morphological variants of the same entity.

scholarly journals Low RAP80 mRNA Expression Correlates with Shorter Survival in Sporadic High-Grade Serous Ovarian Carcinoma

2017 ◽  
Vol 32 (1) ◽  
pp. 90-95 ◽  
Author(s):  
Margarita Romeo ◽  
Niki Karachaliou ◽  
Imane Chaid ◽  
Cristina Queralt ◽  
Itziar De Aguirre ◽  
...  
Keyword(s):  
Ovarian Carcinoma ◽  
Mrna Expression ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Figo Stage ◽  
High Grade ◽  
Platinum Compounds ◽  
Serous Ovarian Carcinoma ◽  
Platinum Based Chemotherapy

Objective Homologous recombination (HR) is frequently impaired in sporadic high-grade serous ovarian carcinoma (sHGSOC) due to deficiencies in BRCA1/2 genes, a situation associated with hypersensitivity to platinum compounds. Alterations in other genes can also cause HR deficiency. Preclinical data show that RAP80 is an HR–pathway-related gene that influences BRCA1 activity. RAP80 has been reported to affect outcome in some solid neoplasms. This study investigates the role of RAP80 in sHGSOC survival. Methods mRNA expression of RAP80 was analyzed in tumor samples from 35 patients who postoperatively received standard platinum-based chemotherapy. The effects of RAP80 expression on progression-free survival (PFS) and overall survival (OS) were examined by means of Cox regressions. The clinical variables known to have prognostic value (FIGO stage, residual disease at surgery, and debulking surgery) were included as covariates in the analysis. BRCA1 was analyzed given the moderate correlations with RAP80. Results Median follow-up, PFS and OS were 61.3, 20.2 and 62.8 months, respectively. Low RAP80 expression levels were associated with shorter PFS ( HR = 1.449, p = 0.007) and OS ( HR = 1.331, p = 0.047). Conclusions This is the first study to show a potential prognostic role of RAP80 expression in patients with HGSOC. The results suggest that HR deficiency due to low RAP80 expression is not associated with hypersensitivity to platinum compounds in sHGSOC.

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