RESUMEN
BACKGROUND: Systemic mastocytosis (SM) encompasses a heterogeneous group of clonal disorders characterized by abnormal expansion of mast cells (MCs). Beyond KIT and other genes recurrently mutated in myeloid neoplasms, several genetic variants have been described as predisposing to the development of the disease and influencing its clinical phenotype. Increased copy number variants of the TPSAB1 gene were identified as a cause of nonclonal elevated tryptasemia and defined as hereditary α-tryptasemia (HαT). Moreover, HαT is enriched in patients with SM, where it can affect the incidence of mediator-related symptoms. OBJECTIVE: In a multicenter data set of 444 patients with MC disorders, we aimed to investigate the clinical correlates of germline TPSAB1 copy number gains. METHODS: Droplet digital PCR was performed in all cases to ascertain the presence of HαT. Clinical history along with blood values and bone marrow examination were analyzed. RESULTS: We confirmed a higher incidence of HαT+ cases (n = 59, 13.3%) in patients diagnosed with mastocytosis with respect to the general population (approximately 5%). HαT+ patients were characterized by a lower MC-associated disease burden and higher levels of tryptase. Several disease variables were coherent with this pattern, from bone marrow MC infiltration to MC-related histopathologic traits, which also accounted for a significantly higher incidence of clonal MC activation syndrome in HαT+ (10.2%) compared to HαT- (3.4%, P = .029) patients. We also confirmed that HαT+ carriers had a significantly higher frequency of anaphylaxis, without relevant differences for other clinical manifestations. CONCLUSION: These findings on a large patient series support and extend previous data, and suggest that knowledge of HαT status may be useful for personalized management of patients with SM.
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Mastocitosis Sistémica , Mastocitosis , Humanos , Mastocitosis Sistémica/genética , Mastocitosis Sistémica/diagnóstico , Relevancia Clínica , Mastocitosis/diagnóstico , Mastocitos/patología , Triptasas/genéticaRESUMEN
Although the benefit/risk profile for mRNA COVID-19 vaccines is recognised as extremely favourable, appendicitis is currently considered an adverse event (AE) of special interest. We describe the case of a 58-year-old female who presented with signs and symptoms of appendicitis approximately 48 hours after her first injection of the Pfizer-BioNTech vaccine. Abdominal ultrasound revealed fluid collection in the right iliac fossa and cecal wall thickening. Following the surgical visit, CT scan with contrast showed a distended appendix with thickened walls, suggestive of acute appendicitis. The patient tested negative to upper respiratory COVID-19 reverse transcription-polymerase chain reaction. Clinical trials and observational studies suggest a possible association between appendicitis and COVID-19 vaccines. Th-1 driven granulomatous inflammation reported in our case represents an infrequent nonspecific chronic inflammation of the appendix, especially in the setting of delayed or interval appendectomy. In view of the current paediatric vaccination campaign, we recommend monitoring the safety profile and potential gastrointestinal AEs associated with mRNA COVID-19 vaccines to swiftly manage subjects with gastrointestinal symptoms and prevent potential complications.
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Apendicitis , COVID-19 , Humanos , Niño , Femenino , Persona de Mediana Edad , Apendicitis/complicaciones , Apendicitis/diagnóstico , Apendicitis/cirugía , Vacunas contra la COVID-19/efectos adversos , COVID-19/diagnóstico , COVID-19/prevención & control , COVID-19/complicaciones , Inflamación , Enfermedad Aguda , ARN MensajeroRESUMEN
Several studies have investigated the role of inflammation in promoting tumorigenesis and cancer progression. Neoplastic as well as surrounding stromal and inflammatory cells engage in well-orchestrated reciprocal interactions to establish an inflammatory tumor microenvironment. The tumor-associated inflammatory tissue is highly plastic, capable of continuously modifying its phenotypic and functional characteristics. Accumulating evidence suggests that chronic inflammation plays a critical role in the development of urological cancers. Here, we review the origins of inflammation in urothelial, prostatic, renal, testicular, and penile cancers, focusing on the mechanisms that drive tumor initiation, growth, progression, and metastasis. We also discuss how tumor-associated inflammatory tissue may be a diagnostic marker of clinically significant tumor progression risk and the target for future anti-cancer therapies.
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Neoplasias del Pene , Neoplasias Urológicas , Masculino , Humanos , Neoplasias Urológicas/etiología , Inflamación/complicaciones , Inflamación/patología , Carcinogénesis , Transformación Celular Neoplásica , Microambiente TumoralRESUMEN
AIMS: Burkitt lymphoma (BL) is an aggressive B-cell lymphoma that, in some instances, may show a granulomatous reaction associated with a favourable prognosis and occasional spontaneous regression. In the present study, we aimed to define the tumour microenvironment (TME) in four such cases, two of which regressed spontaneously. METHODS AND RESULTS: All cases showed aggregates of tumour cells with the typical morphology, molecular cytogenetics and immunophenotype of BL surrounded by a florid epithelioid granulomatous reaction. All four cases were Epstein-Barr virus (EBV)-positive with type I latency. Investigation of the TME showed similar features in all four cases. The analysis revealed a proinflammatory response triggered by Th1 lymphocytes and M1 polarised macrophages encircling the neoplastic cells with a peculiar topographic distribution. CONCLUSIONS: Our data provide an in-vivo picture of the role that specific immune cell subsets might play during the early phase of BL, which may be capable of maintaining the tumour in a self-limited state or inducing its regression. These novel results may provide insights into new potential therapeutic avenues in EBV-positive BL patients in the era of cellular immunotherapy.
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Linfoma de Burkitt/patología , Infecciones por Virus de Epstein-Barr/patología , Macrófagos/patología , Células TH1/patología , Microambiente Tumoral , Adolescente , Anciano , Femenino , Herpesvirus Humano 4 , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The diagnosis of systemic mastocytosis (SM) is based on various clinical, dermatological, serological, and hematological findings but essentially relies on histological evidence of an abnormal increase in tissue-localized mast cells (MCs). The extra-cutaneous organ most frequently affected is the bone marrow (BM), and therefore, histological examination of trephine biopsy specimens of the iliac crest is mandatory on suspicion of SM. At microscopic examination, neoplastic MCs show aberrant morphology, usually with prominent spindling. Immunohistochemistry is a useful tool in the diagnosis of SM because mast cell (MC) infiltrates may be slight and scarce, in a mixed background of lymphohistiocytic cells, eosinophils, and plasma cells. Moreover, neoplastic MCs exhibit an aberrant phenotype. Recent evidence, largely derived from molecular genetics, has enhanced the diagnostic capability of SM, also providing the basis for adequate prognostic and therapeutic evaluation. The cases herein reported illustrate the variable clinical manifestations and disease course of SM, focusing on diagnostic and therapeutic challenges. In accordance with the World Health Organization (WHO) classification and the International Consensus Classification (ICC) systems, our findings emphasize the importance of an integrated diagnostic approach for SM, with proper application of diverse assessment methodologies in order to improve SM classification and treatment effectiveness.
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Mastocitosis Sistémica , Médula Ósea/patología , Humanos , Inmunohistoquímica , Mastocitos , Mastocitosis Sistémica/diagnóstico , Mastocitosis Sistémica/genética , Mastocitosis Sistémica/patología , Biología Molecular , Proteínas Proto-Oncogénicas c-kit/genéticaRESUMEN
Background: Pheochromocytoma (Pheo) and paraganglioma (PGL) are rare tumors, mostly resulting from pathogenic variants of predisposing genes, with a genetic contribution that now stands at around 70%. Germline variants account for approximately 40%, while the remaining 30% is attributable to somatic variants. Objective: This study aimed to describe a new PHD2 (EGLN1) variant in a patient affected by metastatic Pheo and chronic myeloid leukemia (CML) without polycythemia and to emphasize the need to adopt a comprehensive next-generation sequencing (NGS) panel. Methods: Genetic analysis was carried out by NGS. This analysis was initially performed using a panel of genes known for tumor predisposition (EGLN1, EPAS1, FH, KIF1Bß, MAX, NF1, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, and VHL), followed initially by SNP-CGH array, to exclude the presence of the pathogenic Copy Number Variants (CNVs) and the loss of heterozygosity (LOH) and subsequently by whole exome sequencing (WES) comparative sequence analysis of the DNA extracted from tumor fragments and peripheral blood. Results: We found a novel germline PHD2 (EGLN1) gene variant, c.153G>A, p.W51*, in a patient affected by metastatic Pheo and chronic myeloid leukemia (CML) in the absence of polycythemia. Conclusions: According to the latest guidelines, it is mandatory to perform genetic analysis in all Pheo/PGL cases regardless of phenotype. In patients with metastatic disease and no evidence of polycythemia, we propose testing for PHD2 (EGLN1) gene variants. A possible correlation between PHD2 (EGLN1) pathogenic variants and CML clinical course should be considered.
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Neoplasias de las Glándulas Suprarrenales , Leucemia Mielógena Crónica BCR-ABL Positiva , Paraganglioma , Feocromocitoma , Policitemia , Neoplasias de las Glándulas Suprarrenales/genética , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal/genética , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Paraganglioma/genética , Paraganglioma/patología , Feocromocitoma/genética , Policitemia/genéticaRESUMEN
Background and Objectives: The incidence of urothelial cancer in males is higher than in females; however, females have a higher risk of recurrence and progression. The aim of our study was to report the effect of gender on the oncological outcome in advanced urothelial cancer. Materials and Methods: In our retrospective study, all patients had undergone primary surgical treatment for urothelial cancer and were affected by stage IV disease at the time of chemotherapy. Response to therapy and toxicity were evaluated. Subgroups were analyzed for tumour presentation, first- and second-line treatment response, progression-free survival (PFS) and overall survival (OS). Results. Seventy-five patients, 18 (24%) females and 57 (76%) males, were considered. Investigation into the distribution of individual characteristics according to gender revealed a significant difference only for smoking, with a prevalence of smokers in women (p = 0.029). At the end of follow-up, OS was higher in females (27.5% vs. 17.4%; p = 0.047). Smoking did not significantly influence OS (p = 0.055), while univariate Cox regression analysis confirmed that males had a higher risk of death (HR = 2.28, 95% CI 0.99-129 5.25), with borderline statistical significance (p = 0.053). Men showed higher PFS than women both after first-line (p = 0.051) and second-line chemotherapy (p = 0.018), with a lower risk of progression (HR = 0.29, 95% CI 0.10-0.86; p = 0.026). No differences were found between genders with regard to toxicity. Conclusions. In our series, PFS rates following first- and second-line therapies for advanced urothelial carcinoma confirmed that females have a greater risk of progression than males.
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Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Carcinoma de Células Transicionales/tratamiento farmacológico , Femenino , Humanos , Masculino , Supervivencia sin Progresión , Estudios Retrospectivos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológicoRESUMEN
A 67-year-old woman presented with a 3-month history of patchy alopecia areata (AA)-like hair loss and multiple painful enlarged lymph nodes at cervical, nuchal, and left axillary site. The patient was on follow-up for IgM monoclonal gammopathy of undetermined significance, stable for many years. A punch biopsy from a patch of the temporal scalp revealed the presence of B-cell lymphoid infiltrates consistent with marginal zone B-cell lymphoma (MZL). Other staging examinations were conducted to make a definitive diagnosis of nodal MZL with secondary cutaneous involvement. The patient showed a complete remission of the alopecia, without evidence of scarring, after immunochemotherapy for lymphoma.
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Alopecia Areata/etiología , Linfoma de Células B de la Zona Marginal/complicaciones , Anciano , Femenino , HumanosRESUMEN
Wax models of normal and diseased organs were formerly essential medical teaching tools. The ceroplastic heart models from two 19th century pathology museums at the Universities of Florence (n = 8) and Coimbra (n = 10) were analysed. The Florentine collection comprised congenital malformations as well as infectious and inflammatory disorders. The Coimbra waxworks included congenital defects, cardiac hypertrophy and dilation, valvular pathology and cardiac adiposity. This study focuses on heart diseases and teaching resources in European university hospitals during the 19th century. It also highlights the importance of wax models in medical education both then and today, in an era of informatics and digital photography.
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Modelos Anatómicos , Ceras , Humanos , Museos/historia , Universidades , Ceras/historiaRESUMEN
Background and objectives: Angiosarcomas are uncommon and extremely aggressive malignancies derived from vascular endothelial cells. Although they can occur anywhere in the body and at any age, they are more frequently found in the skin of the head and neck regions and in the elderly. Few cases have been recorded in deep soft tissues and in parenchymal organs. Angiosarcomas of the urinary bladder are exceedingly rare. They usually arise in adult patients with a history of radiation therapy, cigarette smoking, or exposure to chemical agents (e.g., vinyl chloride). Despite multidisciplinary treatment approaches combining surgery, radiotherapy, and chemotherapy, prognosis is dismal. Materials and Methods: We describe a case of a 78-year-old Caucasian man presenting with a vesical mass incidentally discovered with abdominal computerized tomography (CT). He underwent transurethral resection of the bladder (TURB), and histology was compatible with angiosarcoma. Results: The patient had been a heavy smoker and his medical history included therapeutic irradiation for prostate cancer eight years previously. Radical cystoprostatectomy was feasible, and pathologic examination of the surgical specimen confirmed angiosarcoma involving the urinary bladder, prostate, and seminal vesicles. Post-operative peritonitis resulted in progressive multi-organ failure and death. Conclusions: Angiosarcoma primary to the urinary bladder is seldom encountered, however, it should be considered in the differential diagnosis of vesical tumors, especially in elderly men with a history of pelvic radiotherapy.
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Hemangiosarcoma , Neoplasias de la Vejiga Urinaria , Adulto , Anciano , Células Endoteliales , Hemangiosarcoma/diagnóstico , Hemangiosarcoma/etiología , Humanos , Masculino , Pronóstico , Neoplasias de la Vejiga Urinaria/etiologíaRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
The Epstein-Barr virus (EBV) is linked to various B-cell lymphomas, including Burkitt lymphoma (BL), classical Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL) at frequencies ranging, by routine techniques, from 5 to 10% of cases in DLBCL to >95% in endemic BL. Using higher-sensitivity methods, we recently detected EBV traces in a few EBV-negative BL cases, possibly suggesting a "hit-and-run" mechanism. Here, we used routine and higher-sensitivity methods (qPCR and ddPCR for conserved EBV genomic regions and miRNAs on microdissected tumor cells; EBNA1 mRNA In situ detection by RNAscope) to assess EBV infection in a larger lymphoma cohort [19 BL, 34 DLBCL, 44 cHL, 50 follicular lymphomas (FL), 10 T-lymphoblastic lymphomas (T-LL), 20 hairy cell leukemias (HCL), 10 mantle cell lymphomas (MCL)], as well as in several lymphoma cell lines (9 cHL and 6 BL). qPCR, ddPCR, and RNAscope consistently documented the presence of multiple EBV nucleic acids in rare tumor cells of several cases EBV-negative by conventional methods that all belonged to lymphoma entities clearly related to EBV (BL, 6/9 cases; cHL, 16/32 cases; DLBCL, 11/30 cases), in contrast to fewer cases (3/47 cases) of FL (where the role of EBV is more elusive) and no cases (0/40) of control lymphomas unrelated to EBV (HCL, T-LL, MCL). Similarly, we revealed traces of EBV infection in 4/5 BL and 6/7 HL cell lines otherwise conventionally classified as EBV negative. Interestingly, additional EBV-positive cases (1 DLBCL, 2 cHL) relapsed as EBV-negative by routine methods while showing EBNA1 expression in rare tumor cells by RNAscope. The relapse specimens were clonally identical to their onset biopsies, indicating that the lymphoma clone can largely loose the EBV genome over time but traces of EBV infection are still detectable by high-sensitivity methods. We suggest EBV may contribute to lymphoma pathogenesis more widely than currently acknowledged.
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Infecciones por Virus de Epstein-Barr/virología , Antígenos Nucleares del Virus de Epstein-Barr/genética , Herpesvirus Humano 4/genética , Enfermedad de Hodgkin/virología , Linfoma no Hodgkin/virología , ARN Mensajero/genética , ARN Viral/genética , Infecciones por Virus de Epstein-Barr/diagnóstico , Enfermedad de Hodgkin/diagnóstico , Humanos , Italia , Linfoma no Hodgkin/diagnóstico , Técnicas de Diagnóstico Molecular , Células U937 , Carga ViralAsunto(s)
Eosinofilia , Trastornos Mieloproliferativos , Neoplasias , Humanos , Eosinofilia/diagnóstico , Eosinofilia/genética , Mesilato de Imatinib , Factores de Escisión y Poliadenilación de ARNm/genética , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/genética , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismoRESUMEN
Urothelial bladder cancer is one of the most lethal cancers worldwide with barely 5% five-year survival in patients with metastatic disease. Intravesical immunotherapy with Bacillus Calmette-Guérin and platinum-based chemotherapy are currently the standard of care for non-muscle invasive and advanced or metastatic urothelial cancer (mUC), respectively. Recently, a subset of patients with locally advanced or mUC has shown to be responsive to immune checkpoint inhibitors (ICIs), e.g., the anti-cytotoxic T-lymphocyte-associated protein 4 and programmed cell death -1/programmed death-ligand1 (PD-1/PD-L1) antibodies. Due to the relevant clinical benefit of immunotherapy for mUC, in 2016, the United States Food and Drug Administration (FDA) approved five immunotherapeutic agents as second-line or first-line treatments for patients with advanced bladder cancer who did not profit from or were ineligible for standard therapy. In this review, we discuss the role of immunotherapy in bladder cancer and recent clinical applications of PD-1/PD-L1 blockade in mUC. Furthermore, we evaluate a variable response rate to ICIs treatment and outline potential biomarkers predictive of immunotherapy response.
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Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Antineoplásicos Inmunológicos/farmacología , Antígeno B7-H1/metabolismo , Antígeno CTLA-4/metabolismo , Carcinoma de Células Transicionales/metabolismo , Ensayos Clínicos como Asunto , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Metástasis de la Neoplasia , Receptor de Muerte Celular Programada 1/metabolismo , Resultado del Tratamiento , Estados Unidos , United States Food and Drug Administration , Neoplasias de la Vejiga Urinaria/metabolismoRESUMEN
The Pathology Museum of the University of Florence houses a rich collection of anatomical specimens and over a hundred waxworks portraying pathological conditions occurring in the nineteenth century, when the museum was established. Clinical and autopsy findings of these cases can still be retrieved from the original museum catalogue, offering a rare opportunity for retrospective palaeo-pathological diagnostics. We present a historical case of severe hydrocephalus backed by modern-day anthropological, radiological and molecular analyses conducted on the skeleton of an 18-month-old male infant deceased in 1831. Luigi Calamai (1796-1851), a wax craftsman of La Specola workshop in Florence, was commissioned to create a life-sized wax model of the child's head, neck and upper thorax. This artwork allows us to appreciate the cranial and facial alterations determined by 30 lb of cerebrospinal fluid (CSF) accumulated within the cerebral ventricular system. Based on the autopsy report, gross malformations of the neural tube, tumours and haemorrhage could be excluded. A molecular approach proved helpful in confirming sex. We present this case as the so-far most compelling case of hydrocephalus in palaeo-pathological research.
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Hidrocefalia/genética , Hidrocefalia/patología , Modelos Anatómicos , ADN Antiguo , Historia del Siglo XIX , Humanos , Hidrocefalia/diagnóstico por imagen , Hidrocefalia/historia , Lactante , Italia , Masculino , Museos , Escultura , CerasRESUMEN
Our understanding of aetiological factors associated with urinary bladder cancer has radically improved over the last decades. Cigarette smoking is considered the most important risk factor, even in the industrialised world, while various occupational and environmental exposures to chemicals are also held responsible. The link between bladder cancer and schistosomiasis, highly prevalent in sub-Saharan Africa, Sudan, Egypt, and Yemen, provides input for investigating and potentially preventing bladder carcinogenesis. Growing concern regarding environmental diseases prompts investigation into the historical milestones that have helped disentangle the relationships between health and environment.
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Fumar Cigarrillos/efectos adversos , Exposición a Riesgos Ambientales/efectos adversos , Esquistosomiasis/complicaciones , Neoplasias de la Vejiga Urinaria/complicaciones , Neoplasias de la Vejiga Urinaria/etiología , Humanos , Factores de RiesgoRESUMEN
Inflammation is inherent in prostatic diseases and it is now accepted that it may facilitate cellular proliferation in both benign and malignant conditions. The strong relationship between prostatic inflammation and pathogenesis of benign prostatic hyperplasia (BPH) is supported by epidemiologic, histopathologic and molecular evidence. Contrariwise, the role of inflammation in prostate carcinogenesis is still controversial, although current data indicate that the inflammatory microenvironment can regulate prostate cancer (PCa) growth and progression. Knowledge of the complex molecular landscape associated with chronic inflammation in the context of PCa may lead to the introduction and optimization of novel targeted therapies. In this perspective, evaluation of the inflammatory component in prostate specimens could be included in routine pathology reports.