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PURPOSE: To identify predictive factors of nivolumab sensitivity, peripheral blood NKs and Tregs were evaluated in patients with metastatic renal cell carcinoma (mRCC) enrolled in the REVOLUTION trial. EXPERIMENTAL DESIGN: 57 mRCCs being treated with nivolumab, as at least second-line of therapy (REV), and 62 healthy donors (HDs) were longitudinally evaluated (0-1-3-6-12 months) for peripheral NKs and Tregs, phenotype and function. Multivariable logistic regression were conducted to identify the independent predictors. The .632+ internal cross-validation was used to avoid overfitting. The best cut-off value based on three-months clinical-response was applied to progression-free survival (PFS) and overall survival (OS). Kaplan-Meier-curves for PFS and OS were produced. RESULTS: At pre-treatment, mRCCs displayed high frequency of NKp46+NKs, NKp30+NKs, KIR2DL1+NKs, KIR2DL2/DL3+NKs, and PD-1+NKs with reduced NK degranulation; as well as high frequency of Tregs, PD-1+Tregs, Helios+Tregs and ENTPD-1+Tregs. Responder patients (R), identified as a clinical response after three-months of treatment, presented at pre-treatment significantly low CD3+, high KIR2DL2/DL3+NKs, high PD-1+Tregs and high Helios+Tregs. Upon multivariate analysis, only KIR2DL2/DL3NKs and Helios+Tregs held as independent predictors of nivolumab responsiveness. The KIR2DL2/DL3+NKs >35.3% identified patients with longer OS while the Helios+Tregs >34.3% displayed significantly longer PFS. After 1-month of nivolumab, R patients showed low CD3+, high NKs, KIR2DL2/DL3+NKs and ICOS+Tregs. Among these subpopulations, CD3+ and KIR2DL2/DL3+NKs held as independent predictors of nivolumab efficacy. Low CD3+ (≤71%) significantly associated with longer PFS while high KIR2DL2/DL3+NKs (>23.3%) associated with both PFS and OS. CONCLUSIONS: Pre-treatment evaluation of Helios+Tregs/KIR2DL2/DL3+NKs and one-month post-treatment CD3+/ KIR2DL2/DL3+NKs will predict nivolumab response in mRCCs.
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BACKGROUND: Tregs trafficking is controlled by CXCR4. In Renal Cell Carcinoma (RCC), the effect of the new CXCR4 antagonist, R54, was explored in peripheral blood (PB)-Tregs isolated from primary RCC patients. METHODS: PB-Tregs were isolated from 77 RCC patients and 38 healthy donors (HDs). CFSE-T effector-Tregs suppression assay, IL-35, IFN-γ, IL-10, TGF-ß1 secretion, and Nrp-1+Tregs frequency were evaluated. Tregs were characterised for CTLA-4, PD-1, CD40L, PTEN, CD25, TGF-ß1, FOXP3, DNMT1 transcriptional profile. PTEN-pAKT signalling was evaluated in the presence of R54 and/or triciribine (TCB), an AKT inhibitor. Methylation of TSDR (Treg-Specific-Demethylated-Region) was conducted. RESULTS: R54 impaired PB-RCC-Tregs function, reduced Nrp-1+Tregs frequency, the release of IL-35, IL-10, and TGF-ß1, while increased IFN-γ Teff-secretion. The CXCR4 ligand, CXCL12, recruited CD25+PTEN+Tregs in RCC while R54 significantly reduced it. IL-2/PMA activates Tregs reducing pAKT+Tregs while R54 increases it. The AKT inhibitor, TCB, prevented the increase in pAKT+Tregs R54-mediated. Moreover, R54 significantly reduced FOXP3-TSDR demethylation with DNMT1 and FOXP3 downregulation. CONCLUSION: R54 impairs Tregs function in primary RCC patients targeting PTEN/PI3K/AKT pathway, reducing TSDR demethylation and FOXP3 and DNMT1 expression. Thus, CXCR4 targeting is a strategy to inhibit Tregs activity in the RCC tumour microenvironment.
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Carcinoma de Células Renais , Neoplasias Renais , PTEN Fosfo-Hidrolase , Receptores CXCR4 , Linfócitos T Reguladores , Humanos , Linfócitos T Reguladores/imunologia , PTEN Fosfo-Hidrolase/metabolismo , Receptores CXCR4/metabolismo , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/metabolismo , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/metabolismo , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Adulto , Transdução de Sinais , Fatores de Transcrição Forkhead/metabolismoRESUMO
Non-clear cell renal cell carcinoma (nccRCC) is a heterogeneous group representing 15-30% of renal tumors. They are mostly excluded from immunotherapy trials due to their rarity and worse prognosis. This, alongside nccRCC misdiagnosis/misclassification, lack of immune-biomarker expression rate data, lack of homogeneous data reporting, the retrospective nature of many studies, small sample sizes, and the fact that high-grade evidence only stems from trials mostly addressing the clear cell subtype, result in poorly defined treatments. We thus reviewed available data from several clinical trials, retrospective studies, and meta-analyses on immunotherapy responses and their correlation with histological subtypes and prognostic biomarkers. The papillary and unclassified subtypes are the best candidate for immunotherapy, showing response rates up to â¼35%. Chromophobe cancers, on the other end, have mostly null response rates. Cancers with sarcomatoid features respond very well to immunotherapy, regardless of their histology. Available data for translocation, medullary, collecting duct, and other nccRCCs are inconclusive. Regarding PD-L1, its expression correlates with better responses, but its prognostic value remains to be determined due to small sample sizes hindering direct statistical comparisons. It is necessary to involve a larger number of nccRCC patients and centers in clinical trials and report tumor response rates and PD-(L)1 and other markers' expression rates divided by nccRCC subtypes and not just for the whole cohorts. This will allow us to collect more robust data to best identify patients who can benefit from immunotherapy and ultimately define the standard of treatment. AVAILABILITY OF DATA AND MATERIAL: N/A.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/terapia , Carcinoma de Células Renais/tratamento farmacológico , Estudos Retrospectivos , Neoplasias Renais/tratamento farmacológico , Prognóstico , ImunoterapiaRESUMO
BACKGROUND: The Italian Register of Actionable Mutations (RATIONAL) is a multicentric, observational study collecting next-generation sequencing (NGS)-based tumour profiling data of patients with advanced solid tumours. METHODS: The study enrols patients who had available an NGS-based tumour profiling (Pathway-A) or undergo comprehensive genomic profiling (CGP) with FoundationOne CDx assays within the trial (Pathway-B). The primary endpoint was the rate of actionable mutations identified. RESULTS: Sequencing data were available for 738 patients in Pathway-A (218) and -B (520). In Pathway-A, 154/218 (70.6%) tests were performed using NGS panels ≤52 genes, and genomic alterations (GAs) were found in 164/218 (75.2%) patients. In Pathway-B, CGP revealed GAs in 512/520 (98.5%) patients. Levels I/II/III actionable GAs according to the European Society of Medical Oncology Scale for Clinical Actionability of molecular Targets (ESCAT) were identified in 254/554 (45.8%) patients with non-small-cell lung cancer, cholangiocarcinoma, colorectal, gastric, pancreatic and breast cancer. The rate of patients with level I GAs was similar in Pathways A and B (69 versus 102). CGP in Pathway-B revealed a higher number of patients with level II/III GAs (99 versus 20) and potentially germline pathogenic/likely pathogenic variants (58 versus 15) as compared with standard testing in Pathway-A. In patients with cancer of unknown primary, CGP detected OncoKB levels 3B/4 GAs in 31/58 (53.4%) cases. Overall, 67/573 (11.7%) of patients received targeted therapy based on genomic testing. CONCLUSION: The Italian Register of Actionable Mutations represents the first overview of genomic profiling in Italian current clinical practice and highlights the utility of CGP for identifying therapeutic targets in selected cancer patients.
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Neoplasias dos Ductos Biliares , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/patologia , Mutação , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Ductos Biliares Intra-Hepáticos/patologiaRESUMO
Breast cancer is the most commonly diagnosed cancer and registers the highest number of deaths for women. Advances in diagnostic activities combined with large-scale screening policies have significantly lowered the mortality rates for breast cancer patients. However, the manual inspection of tissue slides by pathologists is cumbersome, time-consuming and is subject to significant inter- and intra-observer variability. Recently, the advent of whole-slide scanning systems has empowered the rapid digitization of pathology slides and enabled the development of Artificial Intelligence (AI)-assisted digital workflows. However, AI techniques, especially Deep Learning, require a large amount of high-quality annotated data to learn from. Constructing such task-specific datasets poses several challenges, such as data-acquisition level constraints, time-consuming and expensive annotations and anonymization of patient information. In this paper, we introduce the BReAst Carcinoma Subtyping (BRACS) dataset, a large cohort of annotated Hematoxylin and Eosin (H&E)-stained images to advance AI development in the automatic characterization of breast lesions. BRACS contains 547 Whole-Slide Images (WSIs) and 4539 Regions Of Interest (ROIs) extracted from the WSIs. Each WSI and respective ROIs are annotated by the consensus of three board-certified pathologists into different lesion categories. Specifically, BRACS includes three lesion types, i.e., benign, malignant and atypical, which are further subtyped into seven categories. It is, to the best of our knowledge, the largest annotated dataset for breast cancer subtyping both at WSI and ROI levels. Furthermore, by including the understudied atypical lesions, BRACS offers a unique opportunity for leveraging AI to better understand their characteristics. We encourage AI practitioners to develop and evaluate novel algorithms on the BRACS dataset to further breast cancer diagnosis and patient care. Database URL: https://www.bracs.icar.cnr.it/.
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Inteligência Artificial , Neoplasias da Mama , Algoritmos , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Amarelo de Eosina-(YS) , Feminino , Hematoxilina , HumanosRESUMO
In the last recent years, the introduction in the clinical setting of treatment combinations having immune checkpoint inhibitors as the backbone has dramatically improved the outcomes of patients suffering from advanced/metastatic renal cell carcinoma (RCC). Here we report the clinical course of a patient with a rapid and bulky bone recurrence of RCC after nephrectomy, experiencing long-term benefit from nivolumab-ipilimumab administered as first-line treatment.
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Carcinoma de Células Renais , Neoplasias Renais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Humanos , Ipilimumab/efeitos adversos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Nivolumabe/uso terapêuticoRESUMO
Background: Penile cancer (PC) is an extremely rare malignancy, and the patients at advanced stages have currently limited treatment options with disappointing results. Immune checkpoint inhibitors anti-programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) are currently changing the treatment of several tumors. Furthermore, the microsatellite instability (MSI) and the deficient mismatch repair system (dMMR) proteins represent predictive biomarkers for response to immune checkpoint therapy. Until present, few data have been reported related to PD-L1 expression and MSI in PC. The main aim of our study was the evaluation of PD-L1 expression in tumor cells (TCs) and tumor-infiltrating lymphocytes (TILs) in immune cells and the analysis of dMMR/MSI status in a large series of PCs. Methods: A series of 72 PC, including 65 usual squamous cell carcinoma (USCC), 1 verrucous, 4 basaloid, 1 warty, and 1 mixed (warty-basaloid), was collected. Immunohistochemistry (IHC) was performed to assess PD-L1 expression using two different anti-PD-L1 antibodies (clone SP263 and SP142 Ventana) and MMR proteins expression using anti-MLH1, anti-PMS2, anti-MSH2, and anti-MSH6 antibodies. PCR analysis was performed for the detection of MSI status. Results: Of the 72 PC cases analyzed by IHC, 45 (62.5%) cases were TC positive and 57 (79%) cases were combined positive score (CPS) using PDL1 SP263. In our cohort, TILs were present in 62 out of 72 cases (86.1%), 47 (75.8%) out of 62 cases showed positivity to PDL1 clone SP142. In our series, 59 cases (82%) had pMMR, 12 cases (16.7%) had lo-paMMR, and only 1 case (1.3%) had MMR. PCR results showed that only one case lo-paMMR was MSI-H, and the case dMMR by IHC not confirmed MSI status. Conclusion: Our findings showed that PD-L1 expression and MSI status represent frequent biological events in this tumor suggesting a rationale for a new frontier in the treatment of patients with PC based on the immune checkpoint inhibitors.
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The diagnosis of myoid gonadal stromal tumor (MSGT) can represent a difficult challenge, both for the extreme rarity of this neoplasm and for the clinical-radiological characteristics similar to other neoplasms of the testicle. The case management we present suggests how a complete differential diagnosis can be obtained by integrating ultrasonographic and pathological data.
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Tumores do Estroma Gonadal e dos Cordões Sexuais , Diagnóstico Diferencial , Humanos , Masculino , Radiografia , Tumores do Estroma Gonadal e dos Cordões Sexuais/diagnóstico por imagem , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologia , Testículo/diagnóstico por imagem , Testículo/patologiaRESUMO
Cancer diagnosis, prognosis, and therapy response predictions from tissue specimens highly depend on the phenotype and topological distribution of constituting histological entities. Thus, adequate tissue representations for encoding histological entities is imperative for computer aided cancer patient care. To this end, several approaches have leveraged cell-graphs, capturing the cell-microenvironment, to depict the tissue. These allow for utilizing graph theory and machine learning to map the tissue representation to tissue functionality, and quantify their relationship. Though cellular information is crucial, it is incomplete alone to comprehensively characterize complex tissue structure. We herein treat the tissue as a hierarchical composition of multiple types of histological entities from fine to coarse level, capturing multivariate tissue information at multiple levels. We propose a novel multi-level hierarchical entity-graph representation of tissue specimens to model the hierarchical compositions that encode histological entities as well as their intra- and inter-entity level interactions. Subsequently, a hierarchical graph neural network is proposed to operate on the hierarchical entity-graph and map the tissue structure to tissue functionality. Specifically, for input histology images, we utilize well-defined cells and tissue regions to build HierArchical Cell-to-Tissue (HACT) graph representations, and devise HACT-Net, a message passing graph neural network, to classify the HACT representations. As part of this work, we introduce the BReAst Carcinoma Subtyping (BRACS) dataset, a large cohort of Haematoxylin & Eosin stained breast tumor regions-of-interest, to evaluate and benchmark our proposed methodology against pathologists and state-of-the-art computer-aided diagnostic approaches. Through comparative assessment and ablation studies, our proposed method is demonstrated to yield superior classification results compared to alternative methods as well as individual pathologists. The code, data, and models can be accessed at https://github.com/histocartography/hact-net.
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Técnicas Histológicas , Redes Neurais de Computação , Benchmarking , Humanos , PrognósticoRESUMO
Oligometastatic prostate cancer is an intermediate state between localized disease and widespread metastasis. Its biological and clinical peculiarities are still to be elucidated. New imaging techniques contribute to the detection of patients with oligometastatic disease. PET/CT scanning with prostate-specific membrane antigen can improve the selection of men with true early, low-volume oligometastatic disease, who are candidates for metastasis-directed therapy. Clinical studies demonstrated that androgen deprivation therapy can be delayed in oligometastatic patients with a low tumor burden, although no survival benefit has been demonstrated at present. This article presents available evidence on the treatment strategies for oligometastatic prostate cancer.
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Neoplasias da Próstata/terapia , Antagonistas de Androgênios/uso terapêutico , Antígenos de Superfície , Glutamato Carboxipeptidase II , Humanos , Masculino , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologiaRESUMO
Monoclonal antibodies targeting the checkpoint inhibitors (CPIs), programmed cell death protein-1 or programmed cell death ligand-1, are changing the landscape of urothelial carcinoma therapeutics. Overall, clinical studies in metastatic or advanced urothelial cancer showed that CPIs provided a slight improvement in survival and a relevant advantage in safety, compared with chemotherapy. After reviewing published and ongoing trials, the authors discuss expected answers to unmet needs, with a special attention to the research of biological markers for patients with urothelial cancer eligible for treatment with CPIs in this article.
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Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/terapia , Ensaios Clínicos como Assunto , Humanos , Neoplasias da Bexiga Urinária/secundárioRESUMO
Pleomorphic rhabdomyosarcoma (PRMS) is a rare but highly aggressive soft tissue tumor, accounting for 3% of soft tissue sarcomas. PRMS is the most frequent subtype of RMS in adulthood and it is mainly located in the large muscles of the extremities, particularly the lower limbs and the trunk, more rarely in other locations especially in the bladder. At our knowledge, only six cases of adult pleomorphic rhabdomyosarcoma of the bladder have been reported in the literature. In this study, we report a case of PRMS of bladder with a very poor prognosis. In fact, the patient died a month after surgery. The tumor was characterized by poorly differentiated, medium-sized sometimes rhabdoid cells, mixed with large-sized and pleomorphic elements with evident anisonucleosis, and with large areas of necrosis. We used an extensive immunohistochemical panel to exclude other tumors much more frequently reported at this site. The positivity for myogenic markers such as actin, desmin, myogenin and MyoD1 allowed the correct diagnosis. Furthermore, since preliminary studies highlighted a series of specific molecular alterations in PMRS cell lines, we analyzed a panel of specific mutations and gene rearrangements by RT-PCR and FISH methods. We showed a copy gains of CCND1 and MALT genes in our samples, suggesting an accurate molecular characterization of PRMS to establish a better management of patients and new therapeutic opportunities.
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Rabdomiossarcoma/genética , Rabdomiossarcoma/patologia , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Biomarcadores Tumorais/análise , Ciclina D1/genética , Análise Mutacional de DNA , Evolução Fatal , Humanos , Masculino , Pessoa de Meia-Idade , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/genéticaRESUMO
BACKGROUND: Narrow Band Imaging is a noninvasive optical diagnostic tool. It allows the visualization of sub-mucosal vasculature; four patterns of shapes of submucosal capillaries can be recognized, increasingly associated with neoplastic transformation. With such characteristics, it has showed high effectiveness for detection of Oral Squamous Cell Carcinoma. Still, scientific literature highlights several bias/confounding factors, such as Oral Lichen Planus. We performed a retrospective observational study on patients routinely examined with Narrow Band Imaging, investigating for bias, confounding factors and conditions that may limit its applicability. METHODS: Age, sex, smoking, use of dentures, history of head & neck radiotherapy, history of Oral Squamous Cell Carcinoma, site of the lesion and thickness of the epithelium of origin were statistically evaluated as possible bias/confounding factors. Pearson's Chi-squared test, multivariate logistic regression, Positive Predictive Value, Negative Predictive Value, Sensitivity, Specificity, Positive Likelihood Ratio, Negative Likelihood Ratio and accuracy were calculated, normalizing the cohort with/without patients affected by Oral Lichen Planus, to acknowledge its role as bias/confounding factor. RESULTS: Five hundred fifty-six inspections were performed on 106 oral cavity lesions from 98 patients. Age, sex, smoking, use of dentures and anamnesis of Oral Squamous Cell Carcinoma were not found to influence Narrow Band Imaging. History of head & neck radiotherapy was not assessed due to insufficient sample. Epithelium thickness does not seem to interfere with feasibility. Presence of Oral Lichen Planus patients in the cohort led to false positives but not to false negatives. Among capillary patterns, number IV was the most significantly associated to Oral Squamous Cell Carcinoma (p < 0.001), not impaired by the presence of Oral Lichen Planus patients in the cohort (accuracy: 94.3, 95% confidence interval: 88.1-97.9%; odds ratio: 261.7, 95% confidence interval: 37.7-1815.5). CONCLUSION: Narrow Band Imaging showed high reliability in detection of Oral Squamous Cell Carcinoma in a cohort of patients with oral cavity lesions not normalized for bias/confounding factors. Still, Oral Lichen Planus may lead to false positives. Narrow Band Imaging could help in the follow-up of patients with multiple lesions through detection of capillary pattern IV, which seems to be the most significantly associated to neoplastic epithelium.
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Carcinoma de Células Escamosas/diagnóstico por imagem , Líquen Plano Bucal/diagnóstico por imagem , Mucosa Bucal/diagnóstico por imagem , Neoplasias Bucais/diagnóstico por imagem , Imagem de Banda Estreita/métodos , Carcinoma de Células Escamosas/patologia , Humanos , Líquen Plano Bucal/patologia , Mucosa Bucal/patologia , Neoplasias Bucais/patologia , Projetos Piloto , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
Noncoding RNAs (ncRNAs) identify a large family of RNAs that do not encode proteins and represent an important group of tumor biomarkers, directly involved in the process of tumor pathogenesis and progression. Many of them have also been identified in biological fluids of patients with cancer, especially blood, suggesting their role as an emerging class of circulating biomarkers. Many ncRNAs, both miRNAs and lncRNAs, are deregulated in sarcoma tissues, with the most consistent data in osteosarcomas. In patients with osteosarcoma, the role of ncRNAs as circulating biomarkers is taking enormous value, above all for their ability to vary expression levels during disease progression and in response to therapy. In this mini-review, we summarize the main studies supporting the role of circulating ncRNAs in monitoring disease status in patients with osteosarcoma.
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Biomarcadores Tumorais/sangue , Osteossarcoma/genética , RNA Longo não Codificante/sangue , RNA não Traduzido/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , MicroRNAs/sangue , MicroRNAs/genética , Osteossarcoma/sangue , Osteossarcoma/patologia , RNA Longo não Codificante/genética , RNA não Traduzido/sangueRESUMO
Kaposi's sarcoma (KS) is the most common human immunodeficiency virus (HIV) infection disease-associated malignancy. It consists of an angiosarcomatous change of the epithelial and mucous membrane-associated connective tissue not only in various sites, for example, skin, gastrointestinal system, lungs, and so on, but may also involve nonepithelial organs, such as lymphnodes. An unusual localization of KS to an intramammary lymphnode is reported here. The patient, an HIV-negative 69-year-old woman with a clinical history of rheumatoid arthritis treated with hydrocortisone, had an 8-month pathological history of biopsy-proven Kaposi sarcoma of the skin with visceral extension (stomach and duodenum). The appearance of a well-defined 23 × 20 mm(2) breast nodule during chemotherapy elicited fine-needle cytology to exclude breast carcinoma. Surgical excision confirmed the cytopathological diagnosis of Kaposis's sarcoma.
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Neoplasias da Mama/patologia , Mama/patologia , Linfonodos/patologia , Sarcoma de Kaposi/patologia , Idoso , Biópsia por Agulha Fina , Feminino , Humanos , Imuno-HistoquímicaRESUMO
Canine anal sac gland carcinoma (ASGC) is a frequently described neoplasm that is highly aggressive and can frequently lead to metastatic spread. In this paper, we describe the successful treatment of an incompletely excised ASGC by using cisplatin selectively driven within the tumor cells by trains of biphasic pulses. The dog received two courses of electrochemotherapy 14 days apart. Neither systemic nor local toxicities were detected during the whole course of therapy. The dog is still in complete remission after 18 months. Electrochemotherapy is a safe and efficacious adjuvant therapy for ASGC and warrants further investigation in order to standardize its protocols.
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Neoplasias das Glândulas Anais/tratamento farmacológico , Sacos Anais/efeitos dos fármacos , Antineoplásicos/uso terapêutico , Cisplatino/uso terapêutico , Doenças do Cão/tratamento farmacológico , Eletroquimioterapia , Neoplasias das Glândulas Anais/patologia , Neoplasias das Glândulas Anais/cirurgia , Sacos Anais/patologia , Sacos Anais/cirurgia , Animais , Terapia Combinada , Intervalo Livre de Doença , Doenças do Cão/patologia , Doenças do Cão/cirurgia , Cães , Masculino , Indução de RemissãoRESUMO
Cystic nephroma is a rare benign cystic renal tumor, which has been only recently recognized as an exclusively adult histological entity. We present a case of cystic nephroma, together with clinical, radiological, histopathological and immunohistochemical findings. The histopathological differential diagnosis and immunohistochemical features that are potentially useful for refining this tumor are discussed.
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Doenças Renais Císticas/patologia , Adulto , Humanos , Masculino , Tomógrafos ComputadorizadosRESUMO
Electrochemotherapy (ECT) is a novel anticancer therapy that is currently being evaluated in human and pet cancer patients. ECT associates the administration of an anti-tumor agent to the delivery of trains of appropriate waveforms. The increased uptake of chemotherapy leads to apoptotic death of the neoplasm thus resulting in prolonged local control and extended survival. In this paper we describe the histological features of a broad array of spontaneous tumors of companion animals receiving pulse-mediated chemotherapy. Multivariate statistical analysis of the percentage of necrosis and apoptosis in the tumors before and after ECT treatment, shows that only a high percentage of necrosis and apoptosis after the ECT treatment were significantly correlated with longer survivals of the patients (p < 0.0001 and p = 0.004, respectively). Further studies on this topic are warranted in companion animals with spontaneous tumors to identify new molecular targets for electrochemotherapy and to the develop new therapeutical protocols to be translated to humans.
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Antineoplásicos/uso terapêutico , Doenças do Gato/tratamento farmacológico , Doenças do Cão/tratamento farmacológico , Eletroquimioterapia/métodos , Neoplasias/tratamento farmacológico , Neoplasias/veterinária , Animais , Animais Domésticos , Biópsia , Doenças do Gato/mortalidade , Doenças do Gato/patologia , Gatos , Doenças do Cão/mortalidade , Doenças do Cão/patologia , Cães , Eletroquimioterapia/veterinária , Humanos , Neoplasias/mortalidade , Neoplasias/patologia , Análise de SobrevidaRESUMO
OBJECTIVES: The aim of the study was to analyze the molecular mechanisms activated during postinfarction remodeling in human hearts. BACKGROUND: The molecular mechanisms of initial response to ischemic insult in the heart and the pathways involved in compensation and remodeling are still largely unknown. METHODS: Up-regulation or down-regulation of gene expression in the human viable peri-infarct (vs. remote) myocardial region was investigated by complementary deoxyribonucleic acid array technology and confirmed at a single-gene/protein level with reverse transcriptase polymerase chain reaction and immunohistochemistry. An in vitro model of cardiomyocyte hypoxia in HL1 cells was used to validate anti-apoptotic effects of the candidate gene/protein and to assess the associated downstream cascade. Finally, a mouse model of myocardial infarction was used to test the in vivo effects of exogenous transfection with the candidate gene/protein. RESULTS: Protein disulfide isomerase (PDI), a member of the unfolded protein response, is 3-fold up-regulated in the viable peri-infarct myocardial region, and in a postmortem model, its expression is significantly inversely correlated with apoptotic rate and with presence of heart failure (HF) and biventricular dilatation. Induced PDI expression in HL1 cells conferred protection from hypoxia-induced apoptosis. Adenoviral-mediated PDI gene transfer to the mouse heart resulted in 2.5-fold smaller infarct size, significantly reduced cardiomyocyte apoptosis in the peri-infarct region, and smaller left ventricular end-diastolic diameter versus mice treated with a transgene-null adenoviral vector. CONCLUSIONS: These results suggest that PDI promotes survival after ischemic damage and that zinc-superoxide dismutase is one of the PDI molecular targets. Pharmacological modulation of this pathway might prove useful for future prevention and treatment of HF.
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Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/patologia , Miócitos Cardíacos/fisiologia , Isomerases de Dissulfetos de Proteínas/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose/fisiologia , Técnicas de Cultura de Células , Hipóxia Celular/fisiologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Isomerases de Dissulfetos de Proteínas/genética , RNA Mensageiro/metabolismo , Remodelação Ventricular/fisiologiaRESUMO
During the last 20 years, an increasing incidence of basal cell carcinoma (BCC) has been demonstrated by several studies. A ten-year retrospective analysis on 7,266 cases of primary BCC of the Department of Dermatology and Plastic Surgery of the University of Rome La Sapienza and the Department of Dermatology of the University of Naples "Federico If' is reported. Among a population aged over 35 years, BCC cases increased from 618 in 1994 up to 749 cases in 2003, while among the younger population (<35 years), BCC cases increased from 30 in 1994 to 47 cases in 2003. Anatomic site distribution of BCC among people aged <35 years was: head and neck=51.54%, trunk=41.40%, limbs=5.91%, others= 1.12%. On histological examination aggressive-growth BBC was recorded in 48 out of 355 cases (13.52%) among people aged <35 years and in 841 out of 6,755 cases (12.45%) among patients >35 years. In conclusion, an increasing incidence of basal cell carcinoma among young people over the past 20 years was reported. No significant difference in tumour aggressiveness between the young and the elderly patients was observed.