RESUMO
We report on the efficacy of the non-attenuated HER2-retargeted oHSV named R-337 against the immunologically hot CT26-HER2 tumor, and an insight into the basis of the immune protection. Preliminarily, we conducted an RNA immune profiling and immune cell content characterization of CT26-HER2 tumor in comparison to the immunologically cold LLC1-HER2 tumor. CT26-HER2 tumor was implanted into HER2-transgenic BALB/c mice. Hallmarks of R-337 effects were the protection from primary tumor, long-term adaptive vaccination directed to both HER2 and CT26-wt cell neoantigens. The latter effect differentiated R-337 from OncoVEXGM-CSF. As to the basis of the immune protection, R-337 orchestrated several changes to the tumor immune profile, which cumulatively reversed the immunosuppression typical of this tumor (graphical abstract). Thus, Ido1 (inhibitor of T cell anticancer immunity) levels and T regulatory cell infiltration were decreased; Cd40 and Cd27 co-immunostimulatory markers were increased; the IFNγ cascade was activated. Of note was the dampening of IFN-I response, which we attribute to the fact that R-337 is fully equipped with genes that contrast the host innate response. The IFN-I shut-down likely favored viral replication and the expression of the mIL-12 payload, which, in turn, boosted the antitumor response. The results call for a characterization of tumor immune markers to employ oncolytic herpesviruses more precisely.
Assuntos
Genótipo , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 1/patogenicidade , Imunidade , Imunoterapia/métodos , Neoplasias/imunologia , Vírus Oncolíticos/imunologia , Animais , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Vírus Oncolíticos/patogenicidade , Receptor ErbB-2/genética , Receptor ErbB-2/imunologia , Replicação ViralRESUMO
OBJECTIVES: Bone is a common location for lung cancer metastasis. Clinicians are often reluctant to biopsy bone metastases, as they are known to require a decalcification process that damages nucleic acids, which makes it incompatible with molecular testing. We performed this study to assess the diagnostic performance of histopathology and molecular testing of computed tomography (CT)-guided percutaneous bone biopsies of lytic bone lesions during the initial assessment or during the progression of lung cancer. MATERIALS AND METHODS: This retrospective study included all patients suspected of having or known to have primary lung cancer and CT-guided percutaneous bone biopsies of lytic bone from January 2010 to June 2017. The main judgment criterion was the diagnostic performance of the pathological analysis. Secondary endpoints were the diagnostic performance of molecular testing and incidence of complications. RESULTS: Fifty patients were included. The yield of CT-guided percutaneous bone biopsies for pathological analysis was 100 %, allowing for a diagnosis of certainty in all cases. The percentage of tumor cells in samples was higher than the 20 % threshold in 83.9 % of cases. The yield of molecular analysis was 94.6 %. A mutation was found in 60 % of cases; most frequently in KRAS (Kirsten rat sarcoma viral oncogene homolog) (28.6 %) and EGFR (epidermal growth factor receptor) (14.3 %). The complication rate was 2 %, i.e. a minor undrained pneumothorax. CONCLUSION: CT-guided percutaneous biopsies of lytic bone is associated with a very low complication rate and high diagnostic performance for histopathology and mutation testing.
Assuntos
Neoplasias Ósseas/secundário , Carcinoma Pulmonar de Células não Pequenas/patologia , Biópsia Guiada por Imagem/métodos , Neoplasias Pulmonares/patologia , Tomografia Computadorizada por Raios X/métodos , Adenocarcinoma de Pulmão/diagnóstico por imagem , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/cirurgia , Idoso , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/cirurgia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Carcinoma de Células Escamosas/diagnóstico por imagem , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Diagnóstico Diferencial , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular , Estadiamento de Neoplasias , Estudos RetrospectivosRESUMO
We report an interesting clinical case of a patient carrying a specific BRCA2 germline variant affected by bone and hepatic metastases from a high grade uterine stromal sarcoma who obtained a complete metabolic response after only 3 cycles of trabectedin treatment (1.5 mg/m2 given intravenously over 24 hours every 21 days). Molecular investigations linked this outstanding positive pharmacological response with the loss of heterozygosity (LOH) of the mutated BRCA2 gene. These data support the hypothesis that the response to trabectedin may be positively conditioned by the different DNA repair defects present in the neoplasm and that BRCAness tumor genotype is important in determining the efficacy of trabectedin-based chemotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteína BRCA2/genética , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/genética , Mutação de Sentido Incorreto , Sarcoma do Estroma Endometrial/tratamento farmacológico , Sarcoma do Estroma Endometrial/genética , Sequência de Bases , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética , Neoplasias Ósseas/secundário , Dioxóis/administração & dosagem , Neoplasias do Endométrio/diagnóstico por imagem , Neoplasias do Endométrio/patologia , Epirubicina/administração & dosagem , Feminino , Genes BRCA2 , Mutação em Linhagem Germinativa , Humanos , Ifosfamida/administração & dosagem , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Pessoa de Meia-Idade , Sarcoma do Estroma Endometrial/diagnóstico por imagem , Sarcoma do Estroma Endometrial/patologia , Tetra-Hidroisoquinolinas/administração & dosagem , TrabectedinaRESUMO
Renal-cell carcinomas (RCC) are often resistant to conventional cytotoxic agents. Xenograft models are used for in vivo preclinical studies and drug development. The validity of these studies is highly dependent on the phenotypic and genotypic stability of the models. Here we assessed the stability of six aggressive human RCC xenografted in nude/NMRI mice. We compared the initial samples (P0), first (P1) and fifth (P5) passages for the following criteria: histopathology, immunohistochemistry for CK7, CD10, vimentin and p53, DNA allelic profiles using 10 microsatellites and CGH-array. Next we evaluated the response to sunitinib in primary RCC and corresponding xenografted RCC. We observed a good overall stability between primary RCC and corresponding xenografted RCC at P1 and P5 regarding histopathology and immunohistochemistry except for cytokeratin 7 (one case) and p53 (one case) expression. Out of 44 groups with fully available microsatellite data (at P0, P1 and P5), 66% (29 groups) showed no difference from P0 to P5 while 34% (15 groups) showed new or lost alleles. Using CGH-array, overall genomic alterations at P5 were not different from those of initial RCC. The xenografted RCC had identical response to sunitinib therapy compared to the initial human RCC from which they derive. These xenograft models of aggressive human RCC are clinically relevant, showing a good histological and molecular stability and are suitable for studies of basic biology and response to therapy.
Assuntos
Carcinoma de Células Renais/patologia , Modelos Animais de Doenças , Neoplasias Renais/patologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Idoso , Animais , Carcinoma de Células Renais/genética , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Renais/genética , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: Identification of some somatic molecular alterations in non-small-cell lung cancer (NSCLC) has become evidence-based practice. The success and failure rate of using commercially available tumor genotyping techniques in routine day-to-day NSCLC pathology samples is not well described. We sought to evaluate the success and failure rate of EGFR mutation, KRAS mutation, and ALK FISH in a cohort of lung cancers subjected to routine clinical tumor genotype. METHODS: Clinicopathologic data, tumor genotype success and failure rates were retrospectively compiled and analyzed from 381 patient-tumor samples. RESULTS: From these 381 patients with lung cancer, the mean age was 65 years, 61.2% were women, 75.9% were white, 27.8% were never smokers, 73.8% had advanced NSCLC and 86.1% had adenocarcinoma histology. The tumor tissue was obtained from surgical specimens in 48.8%, core needle biopsies in 17.9%, and as cell blocks from aspirates or fluid in 33.3% of cases. Anatomic sites for tissue collection included lung (49.3%), lymph nodes (22.3%), pleura (11.8%), bone (6.0%), brain (6.0%), among others. The overall success rate for EGFR mutation analysis was 94.2%, for KRAS mutation 91.6% and for ALK FISH 91.6%. The highest failure rates were observed when the tissue was obtained from image-guided percutaneous transthoracic core-needle biopsies (31.8%, 27.3%, and 35.3% for EGFR, KRAS, and ALK tests, respectively) and bone specimens (23.1%, 15.4%, and 23.1%, respectively). In specimens obtained from bone, the failure rates were significantly higher for biopsies than resection specimens (40% vs. 0%, p=0.024 for EGFR) and for decalcified compared to non-decalcified samples (60% vs. 5.5%, p=0.021 for EGFR). CONCLUSIONS: Tumor genotype techniques are feasible in most samples, outside small image-guided percutaneous transthoracic core-needle biopsies and bone samples from core biopsies with decalcification, and therefore expansion of routine tumor genotype into the care of patients with NSCLC may not require special tissue acquisition or manipulation.