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1.
Int J Biol Markers ; : 1724600820919969, 2020 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-32389051

RESUMO

BACKGROUND: The PreImplantation Factor (PIF)-a peptide secreted by viable embryos-exerts autotrophic protective effects, promotes endometrial receptivity and controls trophoblast invasion. Synthetic PIF (sPIF) has both immune-protective and regenerative properties, and reduces oxidative stress and protein misfolding. PIF is detected by immunohistochemistry (IHC) in hyperplastic endometriotic lesions and advanced uterine cancer. sPIF reduces graft-versus-host disease while maintaining a graft-versus-leukemia effect. METHODS: PIF detection in prostate cancer was assessed in 50 human prostate samples following radical prostatectomy using tumor-microarray-based IHC correlating PIF immune staining with Gleason score (GS) and cancer aggressiveness. RESULTS: PIF was detected in moderate-to-high risk prostate cancer (GS 4+3 and beyond, prognostic groups 3 to 5). In prostate cancer (GS (WHO Grade Group (GG)5), PIF was detected in 50% of cases; in prostate cancer (GS 4+4 GG4), PIF was observed in 62.5% of cases; in prostate cancer (GS 4+3 GG3), PIF immunostaining was observed in 57.1% of cases. In prostate cancer, (GS 3+4 GG2) and (GS 3+3 GG1) cases where PIF staining was negative to weak, membranous staining was observed in 20% of cases (staining pattern considered negative). High-grade prostate intraepithelial neoplasia PIF positive stain in 28.57% of cases (6 of 21) was observed. In contrast, PIF was not detected in normal prostate glands. Importantly, sPIF added to the PC3 cell line alone or combined with prostate cancer fibroblast feeder-cells did not affect proliferation. Only when peripheral blood mononuclear cells were added to the culture, a minor increase in cell proliferation was noted, reflecting local proliferation control. CONCLUSIONS: Collectively, PIF assessment could be a valuable, simple-to-use immunohistochemical biomarker to evaluate aggressiveness/prognosis in specimens from prostate cancer patients.

3.
Cells ; 9(5)2020 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-32344931

RESUMO

The term aggressive variant prostate cancer (AVPCa) refers to androgen receptor (AR)-independent anaplastic forms of prostate cancer (PCa), clinically characterized by a rapidly progressive disease course. This involves hormone refractoriness and metastasis in visceral sites. Morphologically, AVPCa is made up of solid sheets of cells devoid of pleomorphism, with round and enlarged nuclei with prominent nucleoli and slightly basophilic cytoplasm. The cells do not show the typical architectural features of prostatic adenocarcinoma and mimic the undifferentiated carcinoma of other organs and locations. The final diagnosis is based on the immunohistochemical expression of markers usually seen in the prostate, such as prostate-specific membrane antigen (PSMA). A subset of AVPCa can also express neuroendocrine (NE) markers such as chromogranin A, synaptophysin and CD56. This letter subset represents an intermediate part of the spectrum of NE tumors which ranges from small cell to large cell carcinoma. All such tumors can develop following potent androgen receptor pathway inhibition. This means that castration-resistant prostate cancer (CRPCa) transdifferentiates and becomes a treatment-related NE PCa in a clonally divergent manner. The tumors that do not show NE differentiation might harbor somatic and/or germline alterations in the DNA repair pathway. The identification of these subtypes has direct clinical relevance with regard to the potential benefit of platinum-based chemotherapy, poly (ADP-ribose) polymerase inhibitors and likely further therapies.

4.
Virchows Arch ; 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32296929

RESUMO

Most patients with bladder carcinoma are diagnosed with non-muscle-invasive disease, stage Ta, and pT1. Stage remains as the single most important prognostic indicator in urothelial carcinoma. Among the pT1 bladder cancer patients, recurrence and progression of disease occur in 50% and 10%, respectively. The identification of high-risk patients within the pT1 subgroup remains an important clinical goal and an active field of research. Substaging of pT1 disease has been claimed as important histologic discriminator by the 2016 World Health Organization (WHO) classification of the genitourinary tract tumors and by the 8th edition of the American Joint Committee on Cancer (AJCC) staging manual supporting its implementation in clinical practice. Interobserver variation in pT1 diagnosis and the associated pitfalls in pT1 assessment are the critical pathological issues. The aim of this review paper is to provide the practicing pathologist with the state of the art of morphological and immunohistochemical features useful for the diagnosis of early invasive bladder carcinomas, including practical clues on how to avoid relevant interpretative pitfalls, and to summarize the current status of pT1 substaging.

5.
Curr Drug Targets ; 2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-32160846

RESUMO

AIMS: The aim of our review is to explore the current knowledge on the relationship between immunotherapy and radiotherapy in renal cell carcinoma. BACKGROUND: The management of renal cell carcinoma is rapidly evolving and immunotherapy, mostly consisting in immune checkpoint inhibitors, are revolutionizing the treatment scenario of metastatic patients. Novel fractionation schedules of radiotherapy, consisting of high doses in few fractions, are able to overcome the radioresistance of this tumor. Localized radiotherapy is associated with a systemic effect, known as abscopal effect. This immune mediated effect can be enhanced with association of radiotherapy with immunotherapy. OBJECTIVE: In this review, we explore the role of radiotherapy and immunotherapy in RCC, the rationale of combining these strategies and the on-going clinical trials investigating combinations of these two treatment modalities. METHOD: We conducted a review of the recent evidences of the literature on the role of immunotherapy and radiotherapy and their relationship in the management of renal cell carcinoma. RESULT: Immunotherapy is a new cornerstone in the management of metastatic RCC. Radiotherapy can stimulate an abscopal effect. The combination of immunotherapy and radiotherapy can increase the immune response against the tumor. CONCLUSION: Combining immunotherapy and radiotherapy has a strong rationale and pre-clinical studies support their association because it can overcome the immunosuppression of the tumor microenvironment and increase the anti-tumor immune response. Other: More clinical evidences, deriving from on-clinical trials, are needed to prove the efficacy and safety of these treatments combined.

8.
Curr Drug Targets ; 2020 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-32208115

RESUMO

BACKGROUND: Immune checkpoint inhibitors targeting the programmed death receptor ligand 1 (PD-L1)/programmed death receptor 1 (PD-1) pathway represents a drastic change in the treatment landscape of RCC resulting in a dynamic and evolving scenario. There is an urgent need for predictive biomarkers of response to provide a personalized therapeutic strategy for individual patients. OBJECTIVE: In this review we focused on trials that investigated the use of a PD-1 and PD-L1 inhibitor alone or in combination with another agent and compared the different assays applied in each trial to evaluate the role of PD-L1 as prognostic and predictive biomarker. Conclusion So far, data on the use of PD-L1 expression alone is not sufficient to predict treatment response and present many limitations: the lack of consensus between different methodologies on biomarker assessment, the heterogeneity of PD-L1 between primary tumors and metastatic sites, different criteria of response to therapy (RECIST vs. irRECIST), the complex interplay with inflammatory components, previous treatments, administration of an antibiotic therapy. Combinations of different biomarkers and biological features such as gene expression associated with angiogenesis, immune response and myeloid inflammation are promising biological variables that need to be validated in the context of prospective clinical trials.

10.
Indian J Pathol Microbiol ; 63(Supplement): S53-S55, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32108629

RESUMO

Paratesticular tumours are relatively rare and mostly of the mesenchymal origin. Due to its rarity, general surgical pathologists might have limited experience on the diagnostic entities and relevant differential diagnoses related to mesenchymal paratesticular tumours. This may likely cause diagnostic difficulties in a daily pathology practice. Paratesticular liposarcoma is a highly heterogeneous tumour and may be misdiagnosed as a benign fibromatous lesion. Herein we present a case of well-differentiated paratesticular liposarcoma of the sclerosing type initially diagnosed as a fibrous pseudotumour. Main differential diagnostic considerations are highlighted.

12.
Virchows Arch ; 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31950242

RESUMO

We report on the clinicopathologic features of 115 cases of high-grade urothelial carcinoma of the upper urinary tract with variant histology present in 39 (34%). Variant histology was typically seen in high pathological stage (pT2-pT4) (82%, 32 cases) patients with lower survival rate (70%, 27 cases, median survival 31 months) and consisted in urothelial with one (23%), two (3%), and three or more variants (3%); 4% of cases presented with pure variant histology. Squamous divergent differentiation was the most common variant (7%) followed by sarcomatoid (6%) and glandular (4%), followed by 3% each of micropapillary, diffuse-plasmacytoid, inverted growth, clear cell glycogenic, or lipid-rich. The pseudo-angiosarcomatous variant is seen in 2%, and 1% each of nested, giant-cell, lymphoepithelioma-like, small-cell, trophoblastic, rhabdoid, microcystic, lymphoid-rich stroma, or myxoid stroma/chordoid completed the study series. Loss of mismatch repair protein expression was identified in one case of upper urinary tract carcinoma with inverted growth variant (3.6%). Variant histology was associated to pathological stage (p = 0.007) and survival status (p = 0.039). The univariate survival analysis identified variant histology as a feature of lower recurrence-free survival (p = 0.046). Our findings suggest that variant histology is a feature of aggressiveness in urothelial carcinoma of the upper urinary tract worth it to be reported.

15.
Expert Rev Mol Diagn ; 20(2): 255-264, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31608720

RESUMO

Introduction: The use of liquid biopsy on the blood from solid malignancies provides a convenient way of detecting actionable mutations, monitoring treatment response, detecting early recurrence and prognosticating outcomes. The aim of this review is to discuss the current status and future direction of serum biomarkers in the clinical management of urinary bladder cancer.Areas covered: This review provides an overview of blood liquid biopsy and bladder cancer using methods of circulating tumors cells, circulating RNA, serum metabolites and cell-free DNA. Recent clinical studies and advances in methodology are emphasized. We performed a literature search using PMC/PubMed with keywords including 'liquid biopsy', 'circulating tumor DNA', 'cell-free DNA', 'biomarkers', 'bladder cancer' 'precision medicine'. Additional articles were obtained from the cited references of key articles. An emphasis was placed on recent studies published since 2018.Expert opinion: Liquid biopsies represent a potential biomarker using cell-free DNA, metabolomic profiles of altered cellular metabolism, circulating cancer cells and RNA. Despite displaying tremendous clinical promise, the current status of the blood liquid biopsies has not reached fruition. However, future investigations should lead the evolution of liquid biomarker into clinical utility for the management of bladder cancer.

17.
Expert Rev Mol Diagn ; 20(2): 231-243, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31795775

RESUMO

Introduction: Bladder cancer detection typically requires unpleasant and costly cystoscopy, a procedure potentially harmful and often accompanied by variable adverse effects. The use of urine analysis as a noninvasive method is of great scientific interest since it is enriched in tumor-related proteins, DNA and RNA which can provide a molecular landscape with multiple alterations identified in bladder cancer.Areas covered: Current sensitivity, specificity and diagnostic accuracy of FDA approved urine-based assays are still suboptimal with none of them routinely used by clinics. The recent introduction of RNA/DNA based bladder cancer tests, some of them commercially available, establishes a promising new horizon of clinical applicability.Expert opinion: There is growing evidence toward the use of minimally invasive 'liquid biopsies' to identify biomarkers in urothelial malignancy. Urine has been identified as an optimal noninvasive source of proteins, DNA and RNA; therefore, it has been identified as a type of liquid biopsy likely to soon be routine clinical practice. Cell-free proteins and peptides, exosomes, cell-free DNA, methylated DNA and DNA mutations, circulating tumor cells, miRNA, lncRNA, rtRNA and mRNAs, have been assessed in urine specimens. However, lack of well-designed multicenter clinical studies remain as important limitation, and therefore, precludes their use in clinical practice.

18.
Expert Rev Mol Diagn ; 20(2): 141-150, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31498685

RESUMO

Introduction: Over the past 6 years, important genomic and transcriptomic studies performed on RCC reported a comprehensive molecular description of RCC pathogenic alterations. Such molecular findings pave the way for an integrated classification, based on histopathology aspects and molecular alterations in order to personalize the clinical management of RCC.Areas covered: The aim of this review is to evaluate the current knowledge and the potential value of liquid biopsy in RCC. Studies on presence and analysis of circulating tumor DNA (ctDNA), circulating RNA, specific microRNA, long non-coding RNA, and circulating tumor cells are reported for each phase of disease, from the diagnostic setting to the localized disease and, lastly, in the metastatic stage.Expert opinion: Advantages of liquid biopsies compared to serial tissue sampling are numerous. However, some limitations must be addressed before considering liquid biopsy as a noninvasive biomarker of clinical utility. The suboptimal sensitivity depends on the assessment technique and genetic platforms used, the tumor organ, the tumor stage, tumor heterogeneity, and clonality. The rate of discordance with tumor tissue genotyping may depends on temporal heterogeneity, spatial heterogeneity, and/or assay error (false-negative or false-positive genotyping).

19.
Expert Rev Mol Diagn ; 20(2): 207-217, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31640441

RESUMO

Introduction: Knowledge of the complex biology of prostate cancer is constantly growing, opening the field up to new therapeutic advances. The selection of patients on the basis of prognostic and predictive biomarkers is a challenging and emerging clinical need, not yet completely fulfilled. In this scenario, liquid biopsy offers a noninvasive and attractive approach to give important information about tumor biology and eventual resistance to treatments.Areas covered: The aim of this review of the literature is to evaluate the current knowledge and the promising value of liquid biopsy in prostate cancer. Circulating tumor cells and circulating tumor DNA identified by liquid biopsies are currently under evaluation to guide therapeutic decisions in prostate cancer management, even though practical applications of these approaches are still very limited. We examined the current areas of interest in which circulating tumor cells and circulating tumor DNA are being investigated, such as their prognostic and predictive role in response to chemotherapy or androgen receptor signaling inhibition, especially in the castration-resistant setting.Expert opinion: As the body of knowledge on liquid biopsy rapidly grows, we need to identify which can be the real applications of this technique in clinical practice and to overcome the problems that are limiting its routinely use.

20.
Expert Rev Cardiovasc Ther ; 17(12): 917-927, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31829045

RESUMO

Objective: Hypertension is a common adverse event with targeted agents in cancer patients and can lead to serious and sometimes lethal cardiovascular complications. The authors performed a meta-analysis of clinical trials aiming to evaluate the incidence and Relative Risk (RR) of developing all-grade and high-grade Hypertension Events (HE) in patients with solid tumors receiving targeted therapy.Methods: A review of citations from PubMed was performed and studies were selected based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The search was limited to randomized phase III trials published in English focused on the efficacy and safety of targeted agents in cancer patients, reporting data on HE. Incidence, RR and relative 95% CIs were analyzed using random or fixed-effects models. Overall incidences were calculated and further compared with the chi-squared test for proportions.Results: Ninety-three phase III trials were included, with a total of 68,077 patients. Prostate cancer was the most represented (18.9%), followed by breast cancer (17.3%) and colorectal cancer (16.4%). The incidence of all- and high-grade HE was 23.47% and 8.57%, respectively, with the highest incidence of serious HE reported by adjuvant Sunitib/Sorafenib (29.03%). The highest RR of high-grade HE was observed with Bevacizumab in patients with advanced cervical cancer. By drug category, the highest RR of high-grade HE was reported by VEGFR/EGFR TKIs.Conclusion: According to these data, monitoring this class of toxicities is of primary importance to avoid hypertension worsening and, thus, the risk of major cardiovascular events.

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