Asunto(s)
Linfoma de Células B , Linfoma de Células B Grandes Difuso , Neoplasias del Mediastino , Humanos , Linfoma de Células B/patología , Doxorrubicina/uso terapéutico , Polietilenglicoles/uso terapéutico , Neoplasias del Mediastino/patología , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
To compare FDG-PET/unenhanced MRI and FDG-PET/diagnostic CT in detecting infiltration in patients with newly diagnosed Hodgkin lymphoma (HL). The endpoint was equivalence between PET/MRI and PET/CT in correctly defining the revised Ann Arbor staging system. Seventy consecutive patients with classical-HL were prospectively investigated for nodal and extra-nodal involvement during pretreatment staging with same-day PET/CT and PET/MRI. Findings indicative of malignancy with the imaging procedures were regarded as lymphoma infiltration; in case of discrepancy, positive-biopsy and/or response to treatment were evidenced as lymphoma. Sixty of the 70 (86%) patients were evaluable having completed the staging program. Disease staging based on either PET/MRI or PET/CT was correct for 54 of the 60 patients (90% vs. 90%), with difference between proportions of 0.0 (95% CI, -9 to 9%; P=0.034 for the equivalence test). As compared with reference standard, invasion of lymph nodes was identified with PET/MRI in 100% and with PET/CT in 100%, of the spleen with PET/MRI in 66% and PET/CT in 55%, of the lung with PET/MRI in 60% and PET/CT in 100%, of the liver with PET/MRI in 67% and PET/CT in 100%, and of the bone with PET/MRI in 100% and PET/CT in 50%. The only statistically significant difference between PET/MRI and PET/CT was observed in bony infiltration detection rates. For PET/CT, iodinate contrast medium infusions' average was 86 mL, and exposure to ionizing radiation was estimated to be 4-fold higher than PET/MRI. PET/MRI is a promising safe new alternative in the care of patients with HL.
Asunto(s)
Enfermedad de Hodgkin/diagnóstico por imagen , Adulto , Anciano , Femenino , Fluorodesoxiglucosa F18/análisis , Enfermedad de Hodgkin/patología , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Imagen Multimodal/métodos , Invasividad Neoplásica/diagnóstico por imagen , Invasividad Neoplásica/patología , Estadificación de Neoplasias/métodos , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Tomografía de Emisión de Positrones/métodos , Estudios Prospectivos , Adulto JovenRESUMEN
BACKGROUND: The clinical impact of the positivity of the Deauville scale (DS) of positron emission tomography (PET) performed at the end of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) in patients with advanced Hodgkin lymphoma (HL), in terms of providing rationale to shift poor responders onto a more intensive regimen, remain to be validated by histopathology. PATIENTS AND METHODS: This prospective trial involved patients with stage IIB/IV HL who after six ABVD cycles underwent PET (PET6) and core-needle cutting biopsy (CNCB) of 2-deoxy-2[F-18] fluoro-d-glucose (FDG)-avid lymph nodes. Patients received high-dose chemotherapy/autologous haematopoietic stem cell rescue (HDCT/AHSCR) if CNCB was positive for HL, alternatively, if CNCB or PET was negative, received observation or consolidation radiotherapy (cRT) on residual nodal masses, as initially planned. The end-point was 5-year progression-free survival (PFS). RESULTS: In all, 43 of the 169 (25%) evaluable patients were PET6 positive (DS 4, 32; DS 5, 11). Among them, histology showed malignancy (HL) in 100% of DS 5 scores and in 12.5% of DS 4 scores. Fifteen patients with positive biopsy received HDCT/AHSCR, whereas 28 patients with negative biopsy, as well as 126 patients with negative PET6, continued the original plan (cRT, 78 patients; observation, 76 patients). The 5-year PFS in the negative PET6 group, negative biopsy group and positive biopsy group was 95.4%, 100% and 52.5%, respectively. CONCLUSION: DS positivity of end-of-ABVD PET in advanced HL carried a certain number of CNCB-proven non-malignant FDG-uptakes. The DS 4 scores which were found to have negative histology appeared to benefit from continuing the original non-intensive therapeutic plane as indicated by the successful outcome in more than 95% of them by obtaining similar 5-year PFS to the PET6-negative group. By contrast, the DS 5 score had consistently positive histology and was associated with unsuccessful conventional therapy, promptly requiring treatment intensification or innovative therapeutic approaches.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Fluorodesoxiglucosa F18/metabolismo , Glucosa/metabolismo , Enfermedad de Hodgkin/tratamiento farmacológico , Tomografía de Emisión de Positrones/métodos , Adolescente , Adulto , Bleomicina/administración & dosificación , Dacarbazina/administración & dosificación , Manejo de la Enfermedad , Doxorrubicina/administración & dosificación , Femenino , Estudios de Seguimiento , Enfermedad de Hodgkin/diagnóstico por imagen , Enfermedad de Hodgkin/metabolismo , Enfermedad de Hodgkin/patología , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Radiofármacos/metabolismo , Tasa de Supervivencia , Vinblastina/administración & dosificación , Adulto JovenRESUMEN
We evaluated the impact on progression-free survival (PFS) of achieving a deep metabolic response at 2-deoxy-2[18F] fluoro-d-glucose positron emission tomography (FDG-PET) in patients with refractory or relapsed (R/R) classic Hodgkin lymphoma (cHL) following a new salvage regimen named Bv+Bs (brentuximab vedotin + bendamustine supercharge), from 2013 to 2017. In this real-life study, 20 consecutive patients (aged <60 years) with R/R cHL after failure of ≥1 salvage treatments received Bv+Bs regimen consisting of 3-days outpatient IV infusions of 1.8 mg/kg of Bv on day 1 of each 3-week cycle combined in sequence to bendamustine on days 2 and 3 of the treatment cycle at a fixed dose of 120 mg/m2 per day, for a total of 4 courses. A robust primary prophylaxis approach, including premedication, antimicrobials, stimulating factors, and cytomegalovirus monitoring, was systematically performed. The 20 patients (all evaluable) underwent 4 courses of Bv+Bs with a median dose intensity of 100% for both Bv and Bs. Ten patients (50%) experienced grade ≥3 treatment-related adverse events, without requiring hospitalization. At post-Bv+Bs reevaluation, 80% of patients had deep metabolic responses with Deauville 5-point scale scores ≤2. Thereafter, 14 patients (70%) received autologous hematopoietic stem cell transplantation (HSCT; peripheral blood stem cells previously harvested in 12 cases), and 4 patients (10%) received allogeneic HSCT. At a median follow-up of 27 months from Bv+Bs regimen initiation, the 2-year PFS of the entire population was 93.7% (95% confidence interval, 62.7% to 99.6%). Our data suggest that Bv+Bs regimen-driven strategy may be a promising salvage option to improve long-term control of high-risk Hodgkin lymphoma.
Asunto(s)
Antineoplásicos/uso terapéutico , Clorhidrato de Bendamustina/uso terapéutico , Brentuximab Vedotina/uso terapéutico , Enfermedad de Hodgkin/tratamiento farmacológico , Adulto , Antineoplásicos/efectos adversos , Clorhidrato de Bendamustina/efectos adversos , Brentuximab Vedotina/efectos adversos , Femenino , Estudios de Seguimiento , Trasplante de Células Madre Hematopoyéticas , Enfermedad de Hodgkin/diagnóstico , Enfermedad de Hodgkin/mortalidad , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Neutropenia/etiología , Tomografía de Emisión de Positrones , Supervivencia sin Progresión , Recurrencia , Trasplante Autólogo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Mycosis fungoides (MF) is the major subtype of cutaneous T-cell lymphomas (CTCL). It usually has a prolonged indolent clinical course with a minority of cases acquiring a more aggressive biological profile and resistance to conventional therapies, partially attributed to the persistent activation of nuclear factor-kappa B (NF-κB) pathway. In the last decade, several papers suggested an important role for the FK506-binding protein 51 (FKBP51), an immunophilin initially cloned in lymphocytes, in the control of NF-κB pathway in different types of human malignancies. OBJECTIVES: We aimed to investigate the possible value of FKBP51 expression as a new reliable marker of outcome in patients with MF. METHODS: We assessed by immunohistochemistry (IHC) FKBP51 expression in 44 patients with MF, representative of different stages of the disease. Immunohistochemical results were subsequently confirmed at mRNA level with quantitative PCR (qPCR) in a subset of enrolled patients. In addition, IHC and qPCR served to study the expression of some NF-κB-target genes, including the tumour necrosis factor receptor-associated factor 2 (TRAF2). RESULTS: Our results show that FKBP51 was expressed in all evaluated cases, with the highest level of expression characterizing MFs with the worst prognosis. Moreover, a significant correlation subsisted between FKBP51 and TRAF2 IHC expression scores. CONCLUSIONS: We hypothesize a role for FKBP51 as a prognostic marker for MF and suggest an involvement of this immunophilin in deregulated NF-κB pathway of this CTCL.
Asunto(s)
Micosis Fungoide/metabolismo , ARN Mensajero/metabolismo , Factor 2 Asociado a Receptor de TNF/metabolismo , Proteínas de Unión a Tacrolimus/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/metabolismo , Dermatitis/metabolismo , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Micosis Fungoide/genética , Pronóstico , Piel/metabolismo , Factor 2 Asociado a Receptor de TNF/genética , Proteínas de Unión a Tacrolimus/genética , Timo/metabolismoRESUMEN
This study analysed the immunohistochemical expression of the CAF-1/p60 protein in laryngeal cancers. CAF-1/p60 assumes an independent discriminative and prognostic value in laryngeal neoplasms; the presence of this protein in carcinoma in situ compared with laryngeal precancerous and larynx infiltrating tumours. We assessed the immunohistochemical expression of CAF-1/p60 in 30 cases of moderate and/or severe dysplasia, 30 cases of carcinoma in situ and 30 cases of laryngeal squamous cell carcinoma (LSCCs). CAF-1/p60 expression increased significantly according to the high index of neoplastic cellular replication; therefore, CAF-1/p60 was overexpressed in neoplastic cells and its moderate-severe expression is correlated with poorer prognosis compared to less expression. In conclusion, overexpression of the CAF-1/p60 protein is related to a risk of higher morbidity and mortality and is a reliable independent prognostic index of laryngeal carcinoma. CAF1-p60 protein overexpression can be used in cancer management as an indicator of malignant evolution, especially in carcinoma in situ.
Asunto(s)
Carcinoma in Situ/metabolismo , Carcinoma de Células Escamosas/metabolismo , Factor 1 de Ensamblaje de la Cromatina/biosíntesis , Neoplasias Laríngeas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana EdadAsunto(s)
Mejilla/patología , Citodiagnóstico , Frente/patología , Piel/patología , Dermoscopía , Humanos , Masculino , Persona de Mediana EdadAsunto(s)
Duramadre/patología , Linfoma de Células B Grandes Difuso/patología , Neoplasias Craneales/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/análisis , Biopsia , Diagnóstico Diferencial , Diagnóstico por Imagen , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Neoplasias Craneales/tratamiento farmacológicoRESUMEN
Intrinsic and acquired drug resistance of tumor cells still causes the failure of treatment regimens in advanced human cancers. It may be driven by intrinsic tumor cells features, or may also arise from micro environmental influences. Hypoxia is a microenvironment feature associated with the aggressiveness and metastasizing ability of human solid cancers. Hypoxic cancer cells overexpress Carbonic Anhydrase IX (CA IX). CA IX ensures a favorable tumor intracellular pH, while contributing to stromal acidosis, which facilitates tumor invasion and metastasis. The overexpression of CA IX is considered an epiphenomenon of the presence of hypoxic, aggressive tumor cells. Recently, a relationship between CA IX overexpression and the cancer stem cells (CSCs) population has been hypothesized. CSCs are strictly regulated by tumor hypoxia and drive a major non-mutational mechanism of cancer drug-resistance. We reviewed the current data concerning the role of CA IX overexpression in human malignancies, extending such information to the expression of the stem cells markers CD44 and nestin in solid cancers, to explore their relationship with the biological behavior of tumors. CA IX is heavily expressed in advanced tumors. A positive trend of correlation between CA IX overexpression, tumor stage/grade and poor outcome emerged. Moreover, stromal CA IX expression was associated with adverse events occurrence, maybe signaling the direct action of CA IX in directing the mesenchymal changes that favor tumor invasion; in addition, membranous/cytoplasmic co-overexpression of CA IX and stem cells markers were found in several aggressive tumors. This suggests that CA IX targeting could indirectly deplete CSCs and counteract resistance of solid cancers in the clinical setting.
Asunto(s)
Anhidrasas Carbónicas/metabolismo , Neoplasias/enzimología , Hipoxia de la Célula , Resistencia a Antineoplásicos , Humanos , Inmunohistoquímica , Neoplasias/patología , Células Madre Neoplásicas/enzimologíaRESUMEN
Eosinophils participate in the immune response against Helicobacter pylori, but little is known about their role in the gastritis associated to the infection. We recently demonstrated that the Hp(2-20) peptide derived from H. pylori accelerates wound healing of gastric mucosa by interacting with N-formyl peptide receptors (FPRs) expressed on gastric epithelial cells. The aim of the present study was to investigate whether eosinophils play a role in the repair of gastric mucosa tissue during H. pylori infection. Immuno-histochemistry and transmission electron microscopy were used to detect eosinophils in gastric mucosal biopsies. Eosinophil re-distribution occurred in the gastric mucosa of H. pylori-infected patients: their density did not change in the deep mucosal layer, whereas it increased in the superficial lamina propria just below the foveolar epithelium; eosinophils entered the epithelium itself as well as the lumen of foveolae located close to the area harboring bacteria, which in turn were also engulfed by eosinophils. The H. pylori-derived peptide Hp(2-20) stimulated eosinophil migration through the engagement of FPR2 and FPR3, and also induced production of VEGF-A and TGF-beta, two key mediators of tissue remodelling. We also demonstrate that Hp(2-20) in vivo induced eosinophil infiltration in rat gastric mucosa after injury brought about by indomethacin. This study suggests that eosinophil infiltrate could modulate the capacity of gastric mucosa to maintain or recover its integrity thereby shedding light on the role of eosinophils in H. pylori infection.
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Proteínas Bacterianas/metabolismo , Eosinófilos/metabolismo , Mucosa Gástrica/metabolismo , Gastritis/metabolismo , Infecciones por Helicobacter/metabolismo , Helicobacter pylori/metabolismo , Fragmentos de Péptidos/metabolismo , Receptores de Formil Péptido/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Estudios de Casos y Controles , Células Cultivadas , Quimiotaxis de Leucocito , Enfermedad Crónica , Modelos Animales de Enfermedad , Eosinófilos/inmunología , Eosinófilos/microbiología , Eosinófilos/ultraestructura , Mucosa Gástrica/inmunología , Mucosa Gástrica/microbiología , Mucosa Gástrica/ultraestructura , Gastritis/inmunología , Gastritis/microbiología , Gastritis/patología , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/patología , Helicobacter pylori/inmunología , Humanos , Inmunohistoquímica , Indometacina , Masculino , Microscopía Electrónica de Transmisión , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Receptores de Lipoxina/metabolismo , Transducción de Señal , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/inmunología , Úlcera Gástrica/metabolismo , Úlcera Gástrica/microbiología , Factor de Crecimiento Transformador beta/genética , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
Melanoma is the most aggressive skin cancer; there is no cure in advanced stages. Identifying molecular participants in melanoma progression may provide useful diagnostic and therapeutic tools. FK506 binding protein 51 (FKBP51), an immunophilin with a relevant role in developmental stages, is highly expressed in melanoma and correlates with aggressiveness and therapy resistance. We hypothesized a role for FKBP51 in melanoma invasive behaviour. FKBP51 promoted activation of epithelial-to-mesenchymal transition (EMT) genes and improved melanoma cell migration and invasion. In addition, FKBP51 induced some melanoma stem cell (MCSC) genes. Purified MCSCs expressed high EMT genes levels, suggesting that genetic programs of EMT and MCSCs overlap. Immunohistochemistry of samples from patients showed intense FKBP51 nuclear signal and cytoplasmic positivity for the stem cell marker nestin in extravasating melanoma cells and metastatic brains. In addition, FKBP51 targeting by small interfering RNA (siRNA) prevented the massive metastatic substitution of liver and lung in a mouse model of experimental metastasis. The present study provides evidence that the genetic programs of cancer stemness and invasiveness overlap in melanoma, and that FKBP51 plays a pivotal role in sustaining such a program.