Combined therapy targeting AR and EZH2 curbs castration-resistant prostate cancer enhancing anti-tumor T-cell response.

Aim: Castration-resistant prostate cancer (CRPC) eventually becomes resistant to androgen receptor pathway inhibitors like enzalutamide. Immunotherapy also fails in CRPC. We propose a new approach to simultaneously revert enzalutamide resistance and rewire anti-tumor immunity. Methods: We investigated in vitro and in subcutaneous and spontaneous mouse models the effects of combining enzalutamide and GSK-126, a drug inhibiting the epigenetic modulator EZH2. Results: Enzalutamide and GSK-126 synergized to reduce CRPC growth, also restraining tumor neuroendocrine differentiation. The anti-tumor activity was lost in immunodeficient mice. Indeed, the combination treatment awoke cytotoxic activity and IFN-γ production of tumor-specific CD8+ T lymphocytes. Conclusion: These results promote the combination of enzalutamide and GSK-126 in CRPC, also offering new avenues for immunotherapy in prostate cancer.

Prostate cancer depends on hormones called androgens for its growth. Therefore, hormonal therapies are commonly used. However, the tumor often does not respond to these treatments and new therapeutic approaches are needed. Here, using cell and mouse models, we have tested a new combination between hormone therapy and a drug that restrains an enzyme regulating gene expression. Our results have shown that this combination therapy not only reduces the growth of the tumor but also stops it from becoming more aggressive. This is really important because aggressive prostate cancer is much harder to treat. We have also found that this approach helps the immune system recognizing and attacking cancer cells. More research is needed to identify the mechanism of action of this treatment. However, our findings suggest that this approach could pave the way for new therapeutic strategies, including using immunotherapy, typically unsuccessful in treating prostate cancer.

Pulmonary Low Malignant Potential Adenocarcinoma: A Validation of the Proposed Criteria for This Novel Subtype.

Adenocarcinoma (ADC) is the most common histologic type of lung cancer, including in situ (lepidic), minimally invasive, and invasive forms. While the former 2 types are associated with a favorable outcome, the latter includes tumors with variable behavior, often tumor stage-related. A recent study proposed strict morphologic criteria defining a new subgroup of resected stage I invasive ADC (16% of cases) with favorable outcomes (100% disease-specific survival), named "ADC of low malignant potential (LMP-ADC)." The following criteria were met: ≤3 cm size, nonmucinous histotype, ≥15% lepidic growth, and the absence of the following: high-grade patterns, >1 mitosis/2 mm 2 , necrosis, and vascular/pleural invasion. The aim of the present study was to validate the performance of such criteria to identify LMP-ADC in a series of 274 stage IA resected lung ADCs from a single institution. Thirty-four tumors (12.4%) met the proposed criteria for LMP-ADC, as confirmed by additional stains for mitotic figures, Ki67 index, and elastic fibers (helpful to assess alveolar wall invasion). Minor differences between the lepidic and invasive components were observed regarding cell atypia and proliferation. p53 was normally expressed by invasive tumor cells. Mutations occurred in known lung cancer genes (mostly KRAS and EGFR). Five patients (14.7%) developed disease progression and 2 of them (5.9%) died of the disease. In our series, the disease-specific survival was 94.1%. In conclusion, in resected invasive lung ADC, a subgroup presenting low-grade morphologic features and associated with favorable prognosis does exist. Morphologic criteria for LMP-ADC supported by ancillary techniques represent a valid tool to better define this novel subgroup and to refine the stratification of invasive lung ADC, possibly suggesting modified follow-up protocols, based on the observed indolent behavior in most cases.

Gamma/delta T-cell lymphoma with mycosis fungoides-like clinical course transforming to "T-cell-receptor-silent" aggressive lymphoma: Description of one case.

Primary cutaneous γδ T-cell lymphomas (PCGDTLs) are a heterogeneous group of lymphomas representing about 1% of primary cutaneous T-cell lymphomas (CTCLs) and mostly regarded as clinically aggressive. Current WHO-EORTC classification recognizes different clinic-pathologic subsets of PCGDTL, but it suggests that cases showing a mycosis fungoides (MF)-like clinical presentation and histopathology should be classified as MF irrespective of phenotype for their indolent course. Herein, we describe a case of γδ-MF, featuring at onset a granulomatous pattern, with subsequent clinical worsening signaled by the development of an ulcero-necrotic lesion and systemic dissemination, leading to death in 5 months. Clinical progression was sustained by a shift to mature T-cell lymphoma composed of medium to large-sized blastoid T-cells featuring a T-cell receptor (TCR) silent immunophenotype.

Cancer Diagnostic Delay in Northern and Central Italy During the 2020 Lockdown Due to the Coronavirus Disease 2019 Pandemic.

OBJECTIVES: We performed data collection concerning the coronavirus disease 2019 (COVID-19) pandemic-related delay in the diagnosis of cancers to individuate proper corrective procedures. METHODS: A comparison was made among the number of first pathologic diagnoses of malignancy made from weeks 11 to 20 of 2018, 2019, and 2020 at seven anatomic pathology units serving secondary care hospitals in northern-central Italy. RESULTS: Cancer diagnoses fell in 2020 by 44.9% compared with the average number recorded in 2018 and 2019. Melanoma and nonmelanoma skin cancer represented 56.7% of all missing diagnoses. The diagnostic decrease in colorectal (-46.6%), prostate (-45%), and bladder (-43.6%) cancer was the most relevant among internal malignancies; for prostate, however, high-grade tumors were only moderately affected (-21.7%). CONCLUSIONS: Diagnosis of cutaneous malignancies was mostly affected by the lockdown; among internal malignancies, corrective actions were mostly needed for colorectal cancer and invasive bladder cancer.

Human endogenous retroviruses env gene expression and long terminal repeat methylation in colorectal cancer patients.

Human endogenous retroviruses (HERV) are remnants of exogenous retroviral infections, representing 8% of the human genome. Their regulation is based on the DNA methylation of promoters, the long terminal repeats (LTRs). Transcripts from HERV have been associated with cancers, but reports concerning HERV expression in colorectal cancer remain sporadic. Sixty-three patients with advanced stages of colorectal cancer were enrolled in this study. The expressions of HERV env gene, and HERV-H, -K, -R and -P LTRs and Alu, LINE-1 methylation levels, were investigated in the tumor, normal adjacent tissues, and, where possible, blood and plasmatic extracellular vesicles (EVs). Associations among HERV env expression, methylation status and clinical characteristics were evaluated. No differences were observed in HERV env gene expression levels among the clinical specimens, while Alu, LINE-1, HERV-H and -K LTRs were demethylated in the tumor compared to the normal adjacent tissues (p < 0.05).The HERV env gene was expressed in the EVs at of 54% (-H), 38% (-K), 31% (-R) patients. Association was not found between HERV env expression and LTR methylation, but significant higher expression of HERV-P and -R env was found in tumor tissues arising from the right colon. Our findings do not demonstrate significant overexpression of the studied HERV in colorectal cancer, but their association with tumor localization and specificity of the changes in DNA methylation of retroelements are shown. HERV sequences were packaged in the EVs and might be transferred from one cell to another.

Activated-cytotoxic TCRαß+CD4+ peripheral T-cell lymphoma with hypodermal localization: Case report of a lymphoproliferative disorder probably evolved from the CD4+ cytotoxic T-cell subpopulation.

The World Health Organization (WHO) classification of hematopoietic and lymphoid tumors identifies distinctive subtypes of peripheral T-cell lymphoma (PTCL), and, additionally, some PTCLs involving mostly extranodal sites like the skin. The difficulty of classifying PTCLs according to the normal stages of T-cell differentiation and the lack of definitive diagnostic markers for most of the subtypes make the diagnosis of these diseases challenging. PTCL cases which do not fit into any of the specifically defined entities are categorized as PTCL not otherwise specified (PTCL-NOS). PTCLs-NOS represent less than 2% of the total cases of T-cell lymphoma involving the skin. This article illustrates a case of a PTCL-NOS in which tumor cells have an activated cytotoxic TCRαß+CD3+CD4+CD56+ T-cell phenotype and histopathologic features of subcutaneous panniculitis-like T-cell lymphoma, leading to a fatal outcome.

Neuroendocrine Differentiation, Microsatellite Instability, and Tumor-infiltrating Lymphocytes in Advanced Colorectal Cancer With BRAF Mutation.

BACKGROUND: Approximately 10% of metastatic colorectal cancer (mCRC) cases will harbor the BRAF p.V600E mutation (BRAF-mCRC) and have been associated with a poor prognosis. Although they are usually considered a unique clinical entity, biologic heterogeneity has been described. We performed an extensive clinicopathologic study of a multicenter series of BRAF-mCRC to highlight differences between tumors with microsatellite instability (MSI) and microsatellite stable tumors, focusing on both inflammatory profiles and neuroendocrine differentiation. METHODS: We included 59 BRAF-mCRC cases and collected the clinical data (ie, surgery, treatment, and follow-up). We evaluated MSI status, budding, lympho-angioinvasion, neuroinvasion, extent of active stroma, CD3+ and CD8+ intratumoral and peritumoral lymphocytes, programmed cell death ligand 1, p53, Ki-67, synaptophysin, and CDX2 expression. RESULTS: The 22 MSI BRAF-mCRC cases were associated with the right side (P < .0001), an expansive grown pattern (P < .01), programmed cell death ligand 1 expression (P < .0001), high CD8 T-cell content (P = .0001), and lymph node metastases (P < .029). The 37 MSS BRAF-mCRC cases were characterized by a greater stromal component (P = .0002), pulmonary metastases (P = .095), and p53 and synaptophysin immunoreactivity (P = .004 and P = .001, respectively). Univariate analysis demonstrated that MSI and a high CD8 T-cell content were associated with a 34% (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.34-1.28; P = .2) and 33% (HR, 0.67; 95% CI, 0.45-0.99; P = .04) reduction in the risk of death, respectively. The combined presence of MSI and CD8 T-cell content decreased the hazard of mortality ≤ 63% (HR, 0.37; 95% CI, 0.14-0.97; P = .2), which was slightly reduced after multivariate analysis. CONCLUSION: A simultaneous evaluation of MSI, CD8 T-cell content, and neuroendocrine markers could allow for the identification of subsets of BRAF-mCRC with a different prognosis and potential eligibility for specific treatments.

18F-FDG PET/CT in Metastatic Pilomatrix Carcinoma.

We describe the FDG PET/CT findings in an exceedingly rare case of metastatic pilomatrix carcinoma (PC). A 76-year-old man, who underwent incisional biopsy of a soft-tissue mass in the frontal scalp that revealed PC, was referred for an F-FDG PET/CT scan for staging purposes. PET/CT showed areas of increased radiotracer uptake corresponding to frontal mass and unsuspected lung lesions, which were later confirmed as metastases from PC at histological analysis. Clinical condition deteriorated rapidly, and the patient died 3 months after the initial diagnosis.

Expression of Translationally Controlled Tumor Protein in Human Kidney and in Renal Cell Carcinoma.

Translationally controlled tumor protein is a multifaceted protein involved in several physiological and biological functions. Its expression in normal kidney and in renal carcinomas, once corroborated by functional data, may add elements to elucidate renal physiology and carcinogenesis. In this study, translationally controlled tumor protein expression was evaluated by quantitative real time polymerase chain reaction and western blotting, and its localization was examined by immunohistochemistry on 84 nephrectomies for cancer. In normal kidney protein expression was found in the cytoplasm of proximal and distal tubular cells, in cells of the thick segment of the loop of Henle, and in urothelial cells of the pelvis. It was also detectable in cells of renal carcinoma with different pattern of localization (membranous and cytoplasmic) depending on tumor histotype. Our data may suggest an involvement of translationally controlled tumor protein in normal physiology and carcinogenesis. However, functional in vitro and in vivo studies are needed to verify this hypothesis.

Lymphatic Vascularization in Prostate Adenocarcinoma: Correlation with Tumor Grade, Androgen Withdrawal and Prognosis.

BACKGROUND/AIM: The lymphatic system plays an active role in the metastatic process by directly facilitating recruitment of cancer cells into the vessels. The present study aimed to assess the lymphatic vessel area and the lymphatic vessel density in prostate adenocarcinoma and to correlate these parameters with patients prognosis and outcome. PATIENTS AND METHODS: The lymphatic vessel area and the lymphatic vessel density were evaluated using the D2-40 monoclonal antibody in 153 patients with prostate adenocarcinoma who had been treated by radical prostatectomy, in comparison to 152 non-neoplastic controls. We also estimated the lymphatic vessel area in a set of 139 patients who had undergone radical prostatectomy after neoadjuvant treatment with combined androgen blockade. RESULTS: Lymphatic vessel area was higher in periglandular than in interglandular stroma, inversely correlated with tumor differentiation (in untreated patients) and was influenced by hormonal treatment. Lymphatic vessel density was not significantly different between the non-tumoral and the high-grade prostate intraepithelial neoplasm compartment, whereas it was higher in tumoral than in non-tumoral compartments, mainly in periglandular stroma. In addition, it increased in parallel to the tumor grade progression and positively correlated with all the main prognostic factors of prostate adenocarcinoma. CONCLUSION: The evaluation of lymphatic vessel density on radical prostatectomy with positive nodes may help to discriminate those patients at higher risk of developing an aggressive disease, which may need early androgen deprivation therapy to delay the worsening of clinical disease.

Pagetoid reticulosis tumor cells with double expression of TCRγδ and TCRαß: an off-target phenomenon or genuine expression?

Pagetoid reticulosis (PR) is a low-grade primary cutaneous T-cell lymphoma showing localized patches or plaques with an intrapeidermal proliferation of neoplastic T-cells with heterogeneous immunophenotype. We describe a 73-year-old woman with a 8-year history of gluteal lesions of PR, whom large blast cells were CD4/CD8 double negative T-cells with an activated cytotoxic profile. The case was investigated using a broad panel of monoclonal antibodies including TCRγM1, a new available antibody that recognizes the γ chain subunit of the T-cell receptor (TCR) in formalin-fixed paraffin-embedded tissue. Large blast cells were simultaneously positive for TCRαß and TCRγδ with an activated cytotoxic phenotype. It is worldwide accepted the mutual exclusive expression of TCRαß and TCRγδ but six different studies, dealing with TCRγδ expression in various types of extra-nodal lymphomas, reported cases whom tumor cells expressed simultaneously TCRαß and TCRγδ. Our data and those of similar reports, suggest the possibility of existence of a subset of extra-nodal T-cell lymphomas showing simultaneous expression by tumor cells of TCRγδ and TCRαß with an immunoprofile consistent with an origin from TCRγδ+ T lymphocytes. This unusual subset has preferential, but not exclusive, skin localization and variable epidermotropism.

Translationally controlled tumor protein in prostatic adenocarcinoma: correlation with tumor grading and treatment-related changes.

Prostate cancer is the second leading cause of cancer-related death. The androgen deprivation therapy is the standard treatment for advanced stages. Unfortunately, virtually all tumors become resistant to androgen withdrawal. The progression to castration-resistance is not fully understood, although a recent paper has suggested translationally controlled tumor protein to be implicated in the process. The present study was designed to investigate the role of this protein in prostate cancer, focusing on the correlation between its expression level with tumor differentiation and response to treatment. We retrieved 292 prostatic cancer specimens; of these 153 had been treated only by radical prostatectomy and 139 had undergone radical prostatectomy after neoadjuvant treatment with combined androgen blockade therapy. Non-neoplastic controls were represented by 102 prostatic peripheral zone specimens. In untreated patients, the expression of the protein, evaluated by RT-qPCR and immunohistochemistry, was significantly higher in tumor specimens than in non-neoplastic control, increasing as Gleason pattern and score progressed. In treated prostates, the staining was correlated with the response to treatment. An association between protein expression and the main clinicopathological factors involved in prostate cancer aggressiveness was identified. These findings suggest that the protein may be a promising prognostic factor and a target for therapy.

Hydrogel for cell housing in the brain and in the spinal cord.

PURPOSE: Neurons in the adult mammalian central nervous system do not proliferate or renew themselves and consequently strong interest in cell replacement therapies to repair brain and spinal cord damages has emerged in the last decade. METHODS: An injectable resorbable hydrogel with a controlled nanostructure, specifically designed for neural cell housing, was developed together with a new protocol for building three-dimensional (3D) biohybrid cell/hydrogel constructs: cells are housed within the polymeric matrix which is directly built with a specific cell culture media. This matrix was tested with standard glial populations, primary astrocytes and mesenchymal stem cells. RESULTS: Physico-chemical characterization of the hydrogel matrix confirmed a 2- week (+ 2 days) stability before massive degradation; mean mesh size of about 5 nm and thixotropic behavior with transition yield stress at 60+5 Pa. Cell survival within the hydrogel resulted in about 55 ± 5% (minimum value) survivals, data also confirmed by optical assessments. Cell viability also remained high after extraction from the gel, indicating survival to inclusion latency period. CONCLUSIONS: Since the intimate structure of the gel mimics extracellular matrix cells as would be expected to be found in an in vivo context, this polymeric formulation is a promising base for building 3D constructs for neural cell housing, in which cells are embedded and kept alive directly from the time of polycondensation.