RESUMO
The mechanism of action of natural killer (NK) cells in type 1 diabetes is still unknown. Here we show that the activating receptor NKp46 recognizes mouse and human ligands on pancreatic beta cells. NK cells appeared in the pancreas when insulitis progressed to type 1 diabetes, and NKp46 engagement by beta cells led to degranulation of NK cells. NKp46-deficient mice had less development of type 1 diabetes induced by injection of a low dose of streptozotocin. Injection of soluble NKp46 proteins into nonobese diabetic mice during the early phase of insulitis and the prediabetic stage prevented the development of type 1 diabetes. Our findings demonstrate that NKp46 is essential for the development of type 1 diabetes and highlight potential new therapeutic modalities for this disease.
Assuntos
Autoantígenos/imunologia , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 1/imunologia , Receptor 1 Desencadeador da Citotoxicidade Natural/imunologia , Animais , Antígenos Ly/genética , Antígenos Ly/imunologia , Antígenos Ly/metabolismo , Autoantígenos/genética , Autoantígenos/metabolismo , Degranulação Celular/imunologia , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Imunofluorescência , Humanos , Imuno-Histoquímica , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Receptor 1 Desencadeador da Citotoxicidade Natural/genética , Receptor 1 Desencadeador da Citotoxicidade Natural/metabolismoRESUMO
INTRODUCTION: The clinicopathologic characterization of tumoral intra-epithelial neoplasms of the gallbladder is fairly limited compared to that of similar tumors of the pancreatobiliary system. Until recently, pre-malignant lesions of the gallbladder were mostly reported as adenomas, which were microscopic and therefore regarded as benign and clinically inconsequential, whereas papillary lesions have been largely regarded as a papillary subtype of gallbladder invasive adenocarcinoma. In an attempt to create a unified terminology for these tumors, the term Intracholecystic papillary-tubular neoplasm (ICPN) was proposed to include all exophytic intra-epithelial tumors of the gallbladder measuring ≥1 cm under one category. A few studies which have retrospectively analyzed tumors fulfilling this category found them to be remarkable analogous to the more well-characterized intra-epithelial tumors of the pancreato-biliary system such as IPMN of the pancreas and IPNB of the bile ducts and as such they also represent an 'adenoma-carcinoma' sequence in the gallbladder. Since then a number of case series have been published which attempted to characterize the clinical and pathological features of these tumors and their relationship with invasive carcinoma. In this paper we report three cases of ICPN which represent different stages of the 'adenoma-carcinoma' sequence.
Assuntos
Adenocarcinoma , Adenoma , Neoplasias da Vesícula Biliar , Adenocarcinoma/patologia , Adenoma/patologia , Neoplasias da Vesícula Biliar/patologia , Humanos , Invasividade Neoplásica , Estudos RetrospectivosRESUMO
BACKGROUND: Progastrin-releasing peptide (ProGRP) is a potential marker for small-cell lung cancer (SCLC) in serum; however, it may be more stable in plasma. We investigated a new plasma assay (ProGRPp) and its usefulness in diagnosing and monitoring SCLC. METHODS: The marker concentrations were determined on the ARCHITECT i system. RESULTS: The assay could distinguish SCLC from non-small-cell lung cancer (NSCLC: area under the curve 0.931, 95% CI 0.893-0.969; cross-validated accuracy 0.813; sensitivity 84.0%, specificity 96.3%; at 140 pg ml(-1) cutoff). The probability of SCLC when ProGRPp was >140 pg ml(-1) was 91.8%, after adjusting for age, gender, and renal dysfunction. The NSCLC patients with ProGRPp >140 pg ml(-1) were at high risk (odds ratio=37.0, P<0.001) for tumours with neuroendocrine features. False negatives in SCLC were associated with a lack of thyroid transcription factor-1 (P<0.001). A decrease of ProGRPp to <140 pg ml(-1) during chemotherapy was significantly associated with the image-based response (P<0.001), and independently affected progression-free survival (PFS, relative risk=2.51, P=0.04) and overall survival (OS, relative risk=4.38, P=0.003), after adjustment for imaging response, performance status, and stage. CONCLUSIONS: The ProGRPp assay is specific and sensitive for diagnosing SCLC. Changes in ProGRPp during chemotherapy are significantly associated with image-based response, PFS, and OS.
Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Pulmonares/sangue , Fragmentos de Peptídeos/sangue , Carcinoma de Pequenas Células do Pulmão/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos de Casos e Controles , Diagnóstico Diferencial , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica/métodos , Proteínas Recombinantes , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológicoAssuntos
Neoplasias Pulmonares/diagnóstico por imagem , Embolia Pulmonar/diagnóstico por imagem , Carcinoma de Pequenas Células do Pulmão/diagnóstico por imagem , Feminino , Humanos , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Carcinoma de Pequenas Células do Pulmão/patologia , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: H syndrome is an autosomal recessive genodermatosis with multisystem involvement caused by mutations in SLC29A3. OBJECTIVE: We sought to investigate the clinical and molecular findings in 79 patients with this disorder. METHODS: A total of 79 patients were included, of which 13 are newly reported cases. Because of the phenotypic similarity and molecular overlap with H syndrome, we included 18 patients with allelic disorders. For 31 patients described by others, data were gathered from the medical literature. RESULTS: The most common clinical features (>45% of patients) were hyperpigmentation, phalangeal flexion contractures, hearing loss, and short stature. Insulin-dependent diabetes mellitus and lymphadenopathy mimicking Rosai-Dorfman disease were each found in approximately 20%. Additional systemic features were described in less than 15% of cases. Marked interfamilial and intrafamilial clinical variability exists. Twenty mutations have been identified in SLC29A3, with no genotype-phenotype correlation. LIMITATIONS: In the 31 patients described by others, data were collected from the medical literature. CONCLUSIONS: H syndrome is a multisystemic disease with clinical variability. Consequently, all SLC29A3-related diseases should be considered a single entity. Recognition of the pleomorphic nature of H syndrome is important for diagnosis of additional patients.
Assuntos
Contratura/genética , Hiperpigmentação/genética , Hipertricose/genética , Proteínas de Transporte de Nucleosídeos/genética , Dermatopatias Genéticas/genética , Adolescente , Adulto , Alelos , Criança , Pré-Escolar , Análise Mutacional de DNA , Diabetes Mellitus Tipo 1/genética , Feminino , Dedos , Perda Auditiva Neurossensorial/genética , Humanos , Hiperpigmentação/patologia , Hipertricose/patologia , Lactente , Doenças Linfáticas/genética , Masculino , Pessoa de Meia-Idade , Mutação , Dermatopatias Genéticas/patologia , Síndrome , Dedos do Pé , Adulto JovemRESUMO
OBJECTIVES: When performing CBCT sialography (sialo-CBCT), space-occupying lesions may be identified incidentally. The objective was to describe their radiologic-clinical-histopathologic correlations. METHOD AND MATERIALS: The archive of sialo-CBCT scans was retrospectively searched for suspected space-occupying lesions. Based on the scan and clinical-histopathologic data, the cases were divided into "pathologic" vs "normal," "intra-parenchymal" vs "extra-parenchymal," and "benign" vs "malignant." Two precalibrated, blinded radiologists performed a survey of the radiographic features of each scan. Cohen kappa, chi-square, Kruskal-Wallis, and Mann-Whitney tests assessed inter-observer agreement and radiologic-clinical-histopathologic correlations. RESULTS: In total, 27 (1.5%) suspected space-occupying lesions were found in 1,758 reports. Full follow-up data were available for 15 cases: four were "malignant," six were "benign," and the remaining five were "normal." Kappa showed substantial inter-observer agreement (0.8 to 1.0). Constant swelling correlated with "pathologic" cases (P = .003). Lesion diameter was greater in "pathologic" than "normal" (P < .001) cases, with a cut-off of 12.6 mm. Clinical and radiographic features were similar in "benign" and "malignant" lesions. "Intra-parenchymal" and "extra-parenchymal" space-occupying lesions correlated with "no-fill-region" (P = .01) and "main-duct-displacement" (P = .002), respectively. CONCLUSIONS: Suspected space-occupying lesions in sialo-CBCT with a diameter greater than 12.6 mm are likely to be "pathologic." No radiographic features were able to differentiate between "malignant" and "benign" space-occupying lesions.
Assuntos
Tomografia Computadorizada de Feixe Cônico , Glândulas Salivares , Sialografia , Humanos , Tomografia Computadorizada de Feixe Cônico/métodos , Estudos Retrospectivos , Glândulas Salivares/diagnóstico por imagem , Sialografia/métodos , Tomografia Computadorizada de Feixe Cônico EspiralAssuntos
Infecções por Citomegalovirus/diagnóstico , Gastrite Hipertrófica/diagnóstico , Dor Abdominal/diagnóstico , Dor Abdominal/virologia , Adulto , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/tratamento farmacológico , Gastrite/patologia , Gastrite/virologia , Gastrite Hipertrófica/tratamento farmacológico , Gastrite Hipertrófica/virologia , Humanos , Hipoalbuminemia/diagnóstico , Hipoalbuminemia/virologia , Ibuprofeno/administração & dosagem , Ibuprofeno/efeitos adversos , Masculino , Esplenomegalia/diagnóstico , Esplenomegalia/virologia , Estômago/patologia , Estômago/virologiaRESUMO
PURPOSE: To examine the ex- vivo ability of explanted human tumors and normal tissue to activate liposomal mitomycin C lipidic prodrug (MLP) by releasing the active free drug form, mitomycin C (MMC). METHODS: We tested conversion of MLP to MMC in an ex vivo assay using explanted tissues obtained during routine surgery to remove primary tumors or metastases. Tumor and adjacent normal tissue were obtained from freshly explanted tumors and were immediately deep frozen at - 70 °C. On test day, the fragments were thawed, homogenized and incubated in the presence of a fixed amount of liposomal MLP at 37 °C for 1 h. We measured MLP and its rate of conversion to MMC by HPLC. Controls included plasma, malignant effusions, red blood cells, tumor cell lines, mouse liver, and buffer with dithiothreitol, a potent reducing agent. RESULTS: Most patients tested (16/20) were diagnosed with colo-rectal carcinoma. The average fraction of MLP cleaved per 100-mg tumor tissue (21.1%, SEM = 1.8) was greater than per 100-mg normal tissue (16.6%, SEM = 1.3). When the tumor and normal tissue samples were paired by patient, the difference was statistically significant (p = 0.022, paired t test). Biological fluids did not activate liposomal MLP, while normal liver tissue strongly does. Interestingly, the omental fatty tissue also greatly activated MLP. CONCLUSIONS: Tumor tissue homogenates activate MLP with greater efficiency than the surrounding normal tissues, but far less than liver and adipose tissue. These observations demonstrate the bioavailability of liposomal MLP in human tumors, and its pharmacologic potential in cancer therapy.
Assuntos
Mitomicina , Pró-Fármacos , Animais , Linhagem Celular Tumoral , Humanos , Lipídeos , Lipossomos , Camundongos , Mitomicina/farmacologia , Pró-Fármacos/farmacologiaRESUMO
OBJECTIVE: Glucagonoma is a pancreatic neuroendocrine tumour that arises from alpha cells in the pancreas and is often accompanied by a characteristic clinical syndrome. DESIGN: In this report, we present the cumulative experience and clinical characteristics of six patients diagnosed with glucagonoma and the glucagonoma syndrome and treated at our centre during the past 25 years. RESULTS: Although the course of the disease was variable, some features were similar. The median age at diagnosis was 53·5 years; the median time from onset of symptoms to diagnosis was 39 months. Presenting symptoms were as follows: weight loss 5/6 (83%), necrotizing migratory erythema (NME) 5/6 (83%), diabetes mellitus 4/6 (66%) and diarrhoea, weakness and thrombosis 2/6 (33%). Plasma glucagon was elevated in all patients upon diagnosis (range 200-10,000 pm; N < 50). Skin biopsy was diagnostic only in 1/6 specimens obtained, even after revision. Metastatic disease developed in all patients; 4/6 initially presented with hepatic metastasis. All patient symptoms responded to somatostatin analogue therapy. In 4/6, the NME responded to amino acid solutions. Other modes of therapy were as follows: surgery in 3/6 patients, peptide receptor radioligand therapy with (90) Y-DOTATOC (PRRT) in 3/6 patients (two responses) and chemotherapy in three patients (two responded). Four out of six patients died of the disease, and median survival time was 6·25 years (range 2-11) from diagnosis and 8 years (range 8-16) from initial symptoms. Five-year survival was 66%. CONCLUSION: Our data indicate that somatostatin analogues and an aggressive surgical approach offer symptom relief and tumour control. Among other available treatment modalities, PRRT seems to hold the most promise.
Assuntos
Glucagonoma/diagnóstico , Glucagonoma/terapia , Eritema Migratório Necrolítico , Neoplasias Pancreáticas , Neoplasias das Glândulas Endócrinas/diagnóstico , Neoplasias das Glândulas Endócrinas/terapia , Glucagonoma/diagnóstico por imagem , Glucagonoma/tratamento farmacológico , Glucagonoma/cirurgia , Humanos , Pessoa de Meia-Idade , Eritema Migratório Necrolítico/diagnóstico , Eritema Migratório Necrolítico/terapia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/terapia , Cintilografia , Estudos Retrospectivos , Somatostatina/uso terapêutico , Taxa de Sobrevida , Síndrome , Resultado do TratamentoRESUMO
Capillaria hepatica (syn. Calodium hepaticum) is a parasitic nematode of rodents, rarely infecting humans. An asymptomatic Israeli adult male with extensive travel history was diagnosed with a liver mass on routine post-thymectomy follow-up. Imaging and computer tomography (CT) guided biopsy were inconclusive. Surgical excision revealed an eosinophilic granuloma with fragments of a nematode suspected to be C. hepatica. Molecular methods verified the diagnosis, and the patient was treated empirically. This is the first case of hepatic capillariasis described in Israel, and the first to be diagnosed using molecular methods.
Assuntos
Doenças Assintomáticas/terapia , Infecções por Enoplida/diagnóstico , Enoplídios/isolamento & purificação , Granuloma/diagnóstico por imagem , Granuloma/diagnóstico , Granuloma/cirurgia , Hepatopatias Parasitárias/diagnóstico , Animais , Humanos , Israel , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
OBJECTIVES: Nontuberculous mycobacteria (NTM) infections pose a diagnostic challenge in peritoneal dialysis (PD) patients. In this study, we sought to identify findings that are suggestive of NTM infection in PD adult patients. METHODS: All patients with NTM exit-site infection (ESI) with/without tunnel infection and peritonitis identified during the last decade in eight medical centers in Israel were included. Clinical, microbiological, and outcome data were collected and analyzed. RESULTS: Thirty patients were identified; 16 had ESI (53%) and 14 had peritonitis (47%). Median age was 65 years (interquartile range 52-76). Abdominal pain and cloudy PD fluid were reported in all patients with peritonitis, whereas exit-site discharge and granulation tissue were common in patients with ESI. Fourteen patients (47%) had negative cultures prior NTM diagnosis, and isolation of diphtheroids or Corynebacterium spp. was reported in 9 of 30 patients (30%). Antimicrobial treatment prior to diagnosis was documented in 13 of 30 patients (43%). Delayed diagnosis was frequent. Treatment regimens and duration of therapy varied widely. In 26 of 30 (87%) patients, catheter was removed and 19 of 30 patients (63%) required permanent transition to hemodialysis. Two patients with peritonitis (2 of 14, 14%) and seven with ESI (7 of 16, 44%) were eligible for continuation of PD. CONCLUSIONS: Culture negative peritonitis, isolation of diphtheroids or Corynebacterium spp., previous exposure to antibiotics, and/or a refractory infection should all prompt consideration of PD-related NTM infection and timely workup. Catheter removal is recommended aside prolonged antimicrobial therapy. In select patients with ESI, continuation of PD may be feasible.
Assuntos
Infecções por Mycobacterium não Tuberculosas , Diálise Peritoneal , Peritonite , Adulto , Idoso , Antibacterianos/uso terapêutico , Humanos , Infecções por Mycobacterium não Tuberculosas/diagnóstico , Infecções por Mycobacterium não Tuberculosas/epidemiologia , Infecções por Mycobacterium não Tuberculosas/etiologia , Micobactérias não Tuberculosas , Diálise Peritoneal/efeitos adversos , Peritonite/diagnóstico , Peritonite/epidemiologia , Peritonite/etiologiaRESUMO
Haptides are a family of 19-21-mer cell-binding and permeating peptides homologous to sequences in the C termini on both fibrinogen ß- and γ-chain (Cß and preCγ, respectively). The effect of the Haptides on the cardiovascular system was studied by different assays, including the activity of isolated perfused rat heart and blood vessels in the organ bath. Haptides (50-80 µg/ml) decreased the hemodynamic functions of perfused rat hearts by up to 60% (p < 0.05) in a dose-dependent manner. Whole fibrinogen or a control nonrelated peptide (Cα) did not show such an effect. The NO donor, sodium nitroprusside, reversed the inhibitory effects of Haptides. L-NAME, an endothelial nitric oxide synthase (eNOS) inhibitor, did not further augment the effect of the Haptides. Perfused (FITC)Haptides were attached to the coronary endothelium. In myocardial homogenates and HUVEC, Haptides significantly decreased eNOS activity, but had no effect on the contraction of isolated cultured adult cardiomyocytes. Haptides also significantly enhanced the contraction of rings of rat aorta and human mammary artery vessels ex vivo only when the endothelium was intact. Haptides seem to affect the coronary endothelium, but not the cardiomyocytes, by inhibiting eNOS activity, causing vasoconstriction, temporary ischemia and impaired myocardial function that seem to be related to the amino acid composition of the Haptides.
Assuntos
Vasos Coronários/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Fibrinogênio/farmacologia , Artéria Torácica Interna/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Peptídeos/farmacologia , Animais , Células Cultivadas , Vasos Coronários/enzimologia , Relação Dose-Resposta a Droga , Células Endoteliais/enzimologia , Fibrinogênio/química , Hemodinâmica/efeitos dos fármacos , Humanos , Técnicas In Vitro , Masculino , Artéria Torácica Interna/enzimologia , Miócitos Cardíacos/efeitos dos fármacos , Óxido Nítrico/metabolismo , Doadores de Óxido Nítrico/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Perfusão , Estrutura Terciária de Proteína , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Vasoconstrição/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
This study analyzes the histopathological findings in H syndrome, a recently recognized autosomal recessive genodermatosis characterized by indurated, hyperpigmented, and hypertrichotic skin in well-defined anatomical areas accompanied by various systemic manifestations. So far, descriptions of the histopathological skin changes in this disorder, as reported in a few small case series, were inconsistent, leading to diverse clinical interpretations. In an attempt to define standardized, diagnostic, morphological criteria that will distinguish this disorder from other fibrosing conditions, we studied skin biopsies from 10 patients with H syndrome. The characteristic morphology included widespread fibrosis (moderate in dermis and severe in subcutis); striking mononuclear infiltrates consisting mainly of monocyte-derived cells (small CD68 histiocytes and CD34 and FXIIIa dendrocytes) and plasma cells; and thickened, fragmented, and partially calcified elastic fibers, admixed with well-formed psammoma bodies, a previously unrecognized feature in nonneoplastic skin and subcutaneous conditions. In addition, the ultrastructure of CD68 small histiocytes exhibited distended endoplasmic reticulum and scarcity of lysosomes, features typical for fibroblasts but unusual for histiocytes. These unusual findings in the histiocytes pose a question as to their possible role in the fibrotic cascade in this disorder. We conclude that the above findings are essential for the diagnosis of H syndrome and that incisional biopsies are mandatory for recognition of the full spectrum of histopathological findings.
Assuntos
Hiperpigmentação/patologia , Hipertricose/patologia , Escleroderma Sistêmico/patologia , Dermatopatias/patologia , Adolescente , Adulto , Antígenos CD/metabolismo , Antígenos CD34/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Biópsia , Criança , Tecido Elástico/ultraestrutura , Retículo Endoplasmático/ultraestrutura , Feminino , Histiócitos/metabolismo , Histiócitos/patologia , Histiócitos/ultraestrutura , Humanos , Hiperpigmentação/diagnóstico , Hiperpigmentação/metabolismo , Hipertricose/diagnóstico , Hipertricose/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Lisossomos/ultraestrutura , Masculino , Plasmócitos/metabolismo , Plasmócitos/patologia , Plasmócitos/ultraestrutura , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/metabolismo , Pele/metabolismo , Pele/patologia , Pele/ultraestrutura , Dermatopatias/diagnóstico , Dermatopatias/metabolismo , Síndrome , Adulto JovemRESUMO
Cystic lymphangioma is an uncommon benign tumor that occurs primarily in children in the cervical region. We report the first case of a pleural-based cystic lymphangioma in an infant. The patient was admitted for RUL pneumonia. Because of the persistence of the radiographic findings despite clinical improvement, a computed tomography (CT) and a magnetic resonance imaging (MRI) scan were performed. They showed a multiloculated cystic lesion in the superior posterior right hemithorax. A surgical procedure was performed with complete resection of the tumor. Histopathological examination showed a pleural-based intrathoracic multicystic lymphangioma. One year after the surgery, the patient feels well without any sign of recurrence.
RESUMO
BACKGROUND: The association of cutaneous hyperpigmented, hypertrichotic, and indurated patches associated with hearing loss, short stature, cardiac anomalies, hepatosplenomegaly, scrotal masses, and hypogonadism has not, to our knowledge, been previously recognized as a disease entity. OBJECTIVE: We describe 10 patients with the above-mentioned findings. METHODS: Patients were clinically examined and extensive laboratory evaluation was performed. RESULTS: We describe 10 patients from 6 Arab consanguineous families with hyperpigmented, hypertrichotic, and indurated cutaneous patches involving the middle and lower parts of their bodies. In addition, patients displayed short stature, sensorineural hearing loss, cardiac anomalies, hepatosplenomegaly, and scrotal masses. Laboratory evaluation revealed growth hormone deficiency and hypergonadotropic hypogonadism with azoospermia. Cutaneous histopathologic examination showed hyperpigmentation of the basal layer with seborrheic-keratosis-like acanthosis, histiocytic infiltration, and a perivascular mononuclear infiltrate with plasma cells and mast cells throughout the dermis and subcutaneous fat. Comparison with several patients, recently reported in the medical literature, with similar cutaneous findings is made. LIMITATIONS: Laboratory evaluation in some patients was incomplete because of lack of cooperation. CONCLUSIONS: We suggest that our patients represent a novel multisystemic autosomal recessive inherited disorder. We call this constellation of symptoms the "H syndrome."
Assuntos
Perda Auditiva Neurossensorial/diagnóstico , Hiperpigmentação/diagnóstico , Hipertricose/diagnóstico , Dermatopatias Genéticas/diagnóstico , Adolescente , Adulto , Biópsia , Consanguinidade , Feminino , Fibrose , Doenças dos Genitais Masculinos/diagnóstico , Cardiopatias Congênitas/diagnóstico , Hepatomegalia/diagnóstico , Humanos , Linfonodos/patologia , Masculino , Fenótipo , Pele/patologia , Esplenomegalia/diagnóstico , SíndromeRESUMO
Patients with neuroendocrine neoplasms (NENs) often require systemic treatment, which is frequently limited by the emergence of drug resistance. mTOR inhibitors (mTORi), such as RAD001 (everolimus), have been shown to inhibit neoplasm progression. mTORi stimulates autophagy, a degradation pathway that might promote the survival of neoplasm cells that are exposed to anti-cancer therapy. Chloroquine (CQ), a well-known anti-malarial and anti-rheumatic drug, suppresses autophagy. Based on our previous results, we hypothesized that CQ may enhance the anti-tumorigenic effects of mTORi by inhibiting autophagy and we aimed to examine the anti-tumorigenic effect of CQ, alone or in combination with RAD001. We established a NEN subcutaneous xenograft mouse model and evaluated the effect of the drugs on tumor growth, mTOR pathway, autophagy and apoptosis. CQ alone and in combination with RAD001 significantly decreased neoplasm volume. Histopathological analysis revealed that the combination of CQ and RAD001 markedly inhibited mTOR activity and neoplasm cell growth, along with accumulation of autophagosomes and increased apoptosis. In conclusion, CQ enhances the anti-tumorigenic effect of RAD001 in vivo by inhibiting autophagy. Clinical trials addressing the effects of CQ therapy on neoplasm progression in patients with NENs, mainly in those treated with mTORi, are warranted.
Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cloroquina/uso terapêutico , Everolimo/uso terapêutico , Imunossupressores/uso terapêutico , Tumores Neuroendócrinos/tratamento farmacológico , Animais , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos Nus , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The aim of the present study was to evaluate the toxicity of biodegradable hydrogels in the rat with a future aim of utilizing this hydrogel as a vehicle for brachytherapy delivery in cancer patients. Two types of chitosan hydrogels: fast degrading and slow degrading; were prepared and surgically implanted in rats. The adjacent tissue response to the gels after subcutaneous and intraperitoneal implantation was examined histologically and found to be identical to typical foreign body response and was milder than the response to absorbable surgical sutures (Vicril). Neither tissue damage nor gel fragments could be detected in distant organs (brain, heart, lungs, liver, spleen, kidney, and sternal bone marrow) after implantation of the hydrogels. The degradation mechanism of the gels was studied in vivo, and it was deduced that an oxidative process degraded the chitosan. Loading the hydrogels with a radioisotope (131I-norcholesterol) caused a severe tissue response and necrosis in adjacent tissues only at a distance of several microns. It is concluded that crosslinked chitosan implants could serve as alternative, biocompatible, and safe biodegradable devices for radioisotope delivery in brachytherapy for cancer.