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In this study we evaluated both~ K- and N-RAS mutations in plasma samples from patients with metastatic colorectal cancer by means of the BEAMing technology, and we assessed their diagnostic performance compared to RAS analyses performed on tissue. The sensitivity of BEAMing in identifying KRAS mutations was of 89.5%, with a fair specificity. The agreement with tissue analysis was moderate. The sensitivity for NRAS was high with a good specificity, and the agreement between tissue analysis and BEAMing was fair. Interestingly, significantly higher mutant allele fraction (MAF) levels were detected in patients with G2 tumors, liver metastases, and in those who did not receive surgery. NRAS MAF level was significantly higher in patients with mucinous adenocarcinoma and for those with lung metastases. A sharp increase in the MAF values was observed in patients who moved towards disease progression. More strikingly, molecular progression always anticipated the radiological one in these patients. These observations pave the way to the possibility of using liquid biopsy to monitor patients during treatment, and to enable oncologists to anticipate interventions compared to radiological analyses. This will allow time to be saved and ensure a better management of metastatic patients in the near future.
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Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Humanos , Neoplasias Colorretais/patologia , Biópsia Líquida , Progressão da DoençaRESUMO
To date, few reports have evaluated the pneumococcal vaccination status in cirrhotic patients. No data are available for European countries. We have explored this topic and the potential independent predictors motivating lack of vaccination in Italy. Between January 1st and June 30th 2022, 1419 cirrhotic patients of any etiology were consecutively enrolled in an observational, prospective study at 8 referral centers in Italy. Adjusted odds ratios (ORs) for the association with lack of vaccination were evaluated by multiple logistic regression analysis. Overall vaccine coverage was 17.9% (8.9% in patients < 65 years of age and 27.1% in those aged ≥ 65 years; p < 0.001). Among the 1165 unvaccinated patients, 1068 (91.7%) reported lack of information regarding vaccination as the reason for not having undergone vaccination. Independent predictors associated with lack of vaccination were age < 65 years (OR 3.39, CI 95% 2.41-4.76) and a higher number of schooling years (OR 2.14, CI 95% 1.58-2.91); alcoholic etiology resulted only marginally associated (OR 1.91, CI 95% 1.03-3.52). These findings establish evidence on how pneumococcal vaccination status in Italy is largely suboptimal among cirrhotic patients. These results raise concern, considering the severe outcomes of pneumococcal infection in patients with chronic liver diseases.
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Infecções Pneumocócicas , Vacinas Pneumocócicas , Idoso , Humanos , Itália/epidemiologia , Cirrose Hepática/complicações , Cirrose Hepática/epidemiologia , Infecções Pneumocócicas/epidemiologia , Infecções Pneumocócicas/prevenção & controle , Estudos Prospectivos , Vacinação , Pessoa de Meia-IdadeRESUMO
Pancreatic cancer (PC) is one of the most lethal tumors in Europe with an overall 5-year survival rate of 5%. Since 1992, gemcitabine (Gem) has been the treatment of choice for metastatic disease with significant improvement in median overall survival (OS) compared to fluorouracil. A good performance status (PS) at diagnosis appears to be a strong predictive factor for better survival. Overall, 50% of PC are metastatic or locally advanced at diagnosis, and more than 70% of the resected patients will experience a recurrence, with a median OS ranging from 4 to 10 months (mos). FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) and Nab-paclitaxel (Nab-p) plus Gem have recently increased survival of patients with metastatic PC, over Gem. Treatment with FOLFIRINOX is generally considered more effective with respect to the doublet, with toxicity concerns, FOLFIRINOX achieves an overall response rate (ORR) of 31.6%, while for Nab-p plus Gem ORR is 23%; however, FOLFIRINOX was associated with higher rates of grade 3 and higher adverse events. Although the international guidelines indicate that both regimens can be used as first-line therapy for patients with metastatic PC, FOLFIRINOX is the most widely used; Nab-p plus Gem is more frequently used in patients with lower PS. In this review, we critically analyze these two regimens to give a pragmatic guide to treatment options.
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hERG1 potassium channels are widely expressed in human cancers of different origins, where they affect several key aspects of cellular behaviour. The present study was designed to evaluate the expression and clinical relevance of hERG1 protein in cancer tissues from patients suffering from neuroendocrine tumours (NETs) of ileal (iNETs) and pancreatic (pNETs) origin, with available clinicopathological history and follow-up. The study was carried out by immunohistochemistry with an anti-hERG1 monoclonal antibody. In a subset of samples, a different antibody directed against the hERG1/ß1 integrin complex was also used. The analysis showed for the first time that hERG1 is expressed in human NETs originating from either the ileum or the pancreas. hERG1 turned out to have a prognostic value in NETs, showing (i) a statistically significant positive impact on OS of patients affected by ileal NETs, regardless the TNM stage; (ii) a statistically significant positive impact on OS of patients affected by aggressive (TNM stage IV) disease, either ileal or pancreatic; (iii) a trend to a negative impact on OS of patients affected by less aggressive (TNM stage I-III) disease, either ileal or pancreatic. Moreover, in order to evaluate whether ERG1 was functionally expressed in a cellular model of pNET, the INS1E rat insulinoma cell line was used, and it emerged that blocking ERG1 with a specific inhibitor of the channel (E4031) turned out in a significant reduction in cell proliferation.
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Canais de Potássio Éter-A-Go-Go , Tumores Neuroendócrinos , Animais , Anticorpos Monoclonais/metabolismo , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/genética , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Íleo/metabolismo , Integrina beta1/metabolismo , Pâncreas/metabolismo , Prognóstico , RatosRESUMO
Melanoma is a relatively rare disease worldwide; nevertheless, it has a great relevance in some countries, such as in Europe. In order to shed some light upon the transcriptional profile of skin melanoma, we compared the gene expression of six independent tumours (all progressed towards metastatic disease and with wild type BRAF) to the expression profile of non-dysplastic melanocytes (considered as a healthy control) in a pilot study. Paraffin-embedded samples were manually micro-dissected to obtain enriched samples, and then, RNA was extracted and analysed through a microarray-based approach. An exhaustive bioinformatics analysis was performed to identify differentially expressed transcripts between the two groups, as well as enriched functional terms. Overall, 50 up- and 19 downregulated transcripts were found to be significantly changed in the tumour compared to the control tissue. Among the upregulated transcripts, the majority belonged to the immune response group and to the proteasome, while most of the downregulated genes were related to cytosolic ribosomes. A Gene Set Enrichment Analysis (GSEA), along with the RNA-Seq data retrieved from the TCGA/GTEx databases, confirmed the general trend of downregulation affecting cytoribosome proteins. In contrast, transcripts coding for mitoribosome proteins showed the opposite trend.
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Melanoma , Proteínas Proto-Oncogênicas B-raf , Neoplasias Cutâneas , Humanos , Melanócitos/metabolismo , Melanoma/enzimologia , Melanoma/genética , Melanoma/metabolismo , Melanoma/patologia , Metástase Neoplásica , Projetos Piloto , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismoRESUMO
Because of its high incidence and poor prognosis, colorectal cancer (CRC) represents an important health issue in several countries. As with other carcinomas, the so-called tumour microenvironment (TME) has been shown to play key roles in CRC progression and related therapeutical outcomes, even though a deeper understanding of the underlying molecular mechanisms is needed to devise new treatment strategies. For some years now, omics technologies and consolidated bioinformatics pipelines have allowed scientists to access large amounts of biologically relevant information, even when starting from small tissue samples; thus, in order to shed new light upon the role of the TME in CRC, we compared the gene expression profiles of 6 independent tumour tissues (all progressed towards metastatic disease) to the expression profile of the surrounding stromata. To do this, paraffin-embedded whole tissues were first microdissected to obtain samples enriched with tumour and stromal cells, respectively. Afterwards, RNA was extracted and analysed using a microarray-based approach. A thorough bioinformatics analysis was then carried out to identify transcripts differentially expressed between the two groups and possibly enriched functional terms. Overall, 193 genes were found to be significantly downregulated in tumours compared to the paired stromata. The functional analysis of the downregulated gene list revealed three principal macro areas of interest: the extracellular matrix, cell migration, and angiogenesis. Conversely, among the upregulated genes, the main alterations detected by the functional annotation were related to the ribosomal proteins (rProteins) of both the large (60S) and small (40S) subunits of the cytosolic ribosomes. Subsequent gene set enrichment analysis (GSEA) confirmed the massive overexpression of most cytosolic-but not mitochondrial-ribosome rProteins.
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BACKGROUND: Relevant improvement in first-line treatment of metastatic pancreatic cancer (mPC) was provided by FOLFIRINOX and by gemcitabine (gem) plus nab-paclitaxel (Nab-p) regimens. Regardless of the first-line treatment survival benefit, most patients survive less than 1 year. AIM: The objectives of this multicenter phase I/II study were to evaluate as first-line chemotherapy (CT) two modified regimens of FOLFIRINOX, replacing either oxaliplatin (Oxa) or irinotecan with Nab-p, in patients with mPC. METHODS: The primary objectives of phase 1 were the definition of the dose limit binations, while for phase II they were the characterization of safety and activity of Nab-FOLFIRI and Nab-FOLFOX in mPC. RESULTS: Sixty-three patients received Nab-FOLFIRI or Nab-FOLFOX in phase I. We defined MTD at 120 mg/m2 for Nab-p with FOLFIRI and 160 mg/m2 with FOLFOX. In phase II, we randomized 42 patients for each arm with the following results: (1) overall response rate (ORR) was 31% for both schedules; (2) a clinical benefit rate (CBR) of 69% and 71%; (3) 1-year survival was 41% and 50%; (4) progression free survival (PFS) was 6 months and 5.6 months; (5) median overall survival (OS) was 10.2 and 10.4 months for Nab-FOLFIRI and Nab-FOLFOX, respectively. (6) Neutropenia was the most common grade ≥3 adverse event in our regimens, significantly lower than that reported for the FOLFIRINOX triplet. CONCLUSION: Nab-FOLFIRI and Nab-FOLFOX might be hopeful first-line CT options for mPC patients, with promising activity and a good safety profile.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Pancreáticas , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Desoxicitidina/uso terapêutico , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Intervalo Livre de ProgressãoRESUMO
BACKGROUND: Until now, no robust data supported the efficacy, safety and recommendation for influenza vaccination in patients with cancer receiving immune checkpoint inhibitors (ICIs). METHODS: The prospective multicenter observational INfluenza Vaccine Indication During therapy with Immune checkpoint inhibitors (INVIDIa-2) study investigated the clinical effectiveness of influenza vaccination in patients with advanced cancer receiving ICIs, enrolled in 82 Italian centers from October 2019 to January 2020. The primary endpoint was the time-adjusted incidence of influenza-like illness (ILI) until April 30, 2020. Secondary endpoints regarded ILI severity and vaccine safety. RESULTS: The study enrolled 1279 patients; 1188 patients were evaluable for the primary endpoint analysis. Of them, 48.9% (581) received influenza vaccination. The overall ILI incidence was 8.2% (98 patients). Vaccinated patients were significantly more frequently elderly (p<0.0001), males (p=0.004), with poor European Cooperative Oncology Group performance status (p=0.009), affected by lung cancer (p=0.01), and by other non-cancer comorbidities (p<0.0001) when compared with unvaccinated. ILI incidence was not different basing on influenza vaccination: the time-to-ILI was similar in vaccinated and unvaccinated patients (p=0.62). ILI complications were significantly less frequent for patients receiving the vaccination (11.8% vs 38.3% in unvaccinated, p=0.002). ILI-related intravenous therapies were significantly less frequent in vaccinated patients than in unvaccinated (11.8% vs 29.8%, p=0.027). ILI lethality was, respectively, 0% in vaccinated and 4.3% in unvaccinated patients. Vaccine-related adverse events were rare and mild (1.5%, grades 1-2). CONCLUSION: The INVIDIa-2 study results support a positive recommendation for influenza vaccination in patients with advanced cancer receiving immunotherapy.
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Inibidores de Checkpoint Imunológico/uso terapêutico , Vacinas contra Influenza/administração & dosagem , Influenza Humana/prevenção & controle , Neoplasias/tratamento farmacológico , Vacinação , Eficácia de Vacinas , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Incidência , Vacinas contra Influenza/efeitos adversos , Influenza Humana/diagnóstico , Influenza Humana/epidemiologia , Influenza Humana/imunologia , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico , Neoplasias/epidemiologia , Neoplasias/imunologia , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Vacinação/efeitos adversos , Adulto JovemRESUMO
BACKGROUND: Within the OMITERC prospective study (OMIcs application from solid to liquid biopsy for a personalised ThERapy of Cancer), we explored the prognostic role of liquid biopsy encompassing cell-free DNA (cfDNA) and circulating tumour cells (CTCs) in KRAS mutated metastatic colorectal cancer (mCRC). METHODS: We defined a workflow including pre-analytical and analytical procedures collecting blood before therapy and every 3 months until disease progression (PD). CTCs were counted by CellSearch® and isolated by DEPArray™. NGS sequencing of CTCs and cfDNA was performed using a panel of cancer/CRC related genes respectively. RESULTS: KRAS mutational status was mostly concordant between tumour tissues and liquid biopsy. The percentage of cfDNA samples with mutations in CRC driver genes was in line with literature. In longitudinal monitoring circulating biomarkers anticipated or overlapped conventional diagnostic tools in predicting PD. The presence of CTCs at baseline was confirmed a negative prognostic marker. CONCLUSIONS: Cell-free DNA and CTCs are readily available candidates for clinical application in mCRC. While CTCs demonstrated a prognostic significance at baseline, cfDNA was confirmed an easily accessible material for monitoring the mutational status of the tumour over time. Moreover, in the longitudinal study, the two markers emerged as complementary in assessing disease progression.
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Biomarcadores Tumorais/genética , Ácidos Nucleicos Livres/genética , Neoplasias Colorretais/patologia , Células Neoplásicas Circulantes/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Análise de Sequência de DNA/métodos , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/genética , Progressão da Doença , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Prognóstico , Estudos ProspectivosRESUMO
BACKGROUND & AIMS: Patients with advanced hepatocellular carcinoma (aHCC) and Child-Pugh B liver function are often excluded from clinical trials. In previous studies, overall survival for these patients treated with sorafenib was â¼3-5 months; thus, new treatments are needed. Nivolumab, alone or in combination with ipilimumab, is conditionally approved in the United States to treat patients with aHCC who previously received sorafenib. We describe nivolumab monotherapy outcomes in patients with Child-Pugh B status. METHODS: This phase I/II, open-label, non-comparative, multicentre trial (27 centres) included patients with Child-Pugh B (B7-B8) aHCC. Patients received intravenous nivolumab 240 mg every 2 weeks until unacceptable toxicity or disease progression. Primary endpoints were objective response rate (ORR) by investigator assessment (using Response Evaluation Criteria in Solid Tumors v1.1) and duration of response. Safety was assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v4.0. RESULTS: Twenty-five sorafenib-naive and 24 sorafenib-treated patients began treatment between November 2016 and October 2017 (median follow-up, 16.3 months). Investigator-assessed ORR was 12% (95% CI 5-25%) with 6 patients responding; disease control rate was 55% (95% CI 40-69%). Median time to response was 2.7 months (interquartile range, 1.4-4.2), and median duration of response was 9.9 months (95% CI 9.7-9.9). Treatment-related adverse events (TRAEs) were reported in 25 patients (51%) and led to discontinuation in 2 patients (4%). The most frequent grade 3/4 TRAEs were hypertransaminasemia (n = 2), amylase increase (n = 2), and aspartate aminotransferase increase (n = 2). The safety of nivolumab was comparable to that in patients with Child-Pugh A aHCC. CONCLUSIONS: Nivolumab showed clinical activity and favourable safety with manageable toxicities, suggesting it could be suitable for patients with Child-Pugh B aHCC. LAY SUMMARY: In patients with advanced hepatocellular carcinoma, almost all systemic therapies require very good liver function, i.e. Child-Pugh A status. The evidence from this study suggests that nivolumab shows clinical activity and an acceptable safety profile in patients with hepatocellular carcinoma with Child-Pugh B status who have mild to moderate impairment of liver function or liver decompensation that might rule out other therapies. Further studies are warranted to assess the safety and efficacy of nivolumab in this patient population. CLINICAL TRIAL NUMBER: NCT01658878.
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Carcinoma Hepatocelular/tratamento farmacológico , Nivolumabe/farmacologia , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Nivolumabe/uso terapêuticoRESUMO
Patients with metastatic colorectal cancer (mCRC) are routinely screened for either K- and N-RAS to select the appropriate treatment. The present study aimed to evaluate the concordance between K- and NRAS status in the tissue (either primary tumor or metastasis) and the plasma of patients with mCRC and to identify the associations between K- and NRAS mutations in ctDNA and the clinicopathological parameters. Samples from a total of 31 patients with mCRC with measurable disease according to the Response Evaluation Criteria in Solid Tumors were analyzed. For all patients, K- and NRAS status was determined in the tissue by matrix-assisted laser desorption/ionization time of flight mass spectrometry. For the detection of RAS mutations in cell-free tumor DNA also defined as circulating tumor DNA (ctDNA), the OncoBEAM® RAS CRC kit (Sysmex Inostics) was used. A total of 6/31 tissue samples expressed wild-type KRAS, whereas 25/31 presented mutations. In addition, 7/31 plasma samples expressed wild-type KRAS, mutations were detected in 22/31 patients, and for 2/31 patients, the test did not provide a conclusive result. A total of 24/31 patients expressed wild-type NRAS, 6/31 had mutations and 1/21 was not informative. For the KRAS mutational status, a moderate concordance (agreement, 85.18%; Cohen's k, 0.513) between the tissue and plasma analysis was observed; for NRAS, a fair agreement (agreement, 83.33%; Cohen's k, 0.242) was obtained. In conclusion, both tissue and plasma analyses should be performed for the management of patients with mCRC. To better exploit the beads, emulsions, amplification, magnetics (BEAMing) technique in the clinical setting, studies aimed at determining the RAS status to monitor therapy and during follow-up are warranted.
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Since the introduction of antiepidermal growth factor receptor (anti-EGFR) monoclonal antibodies (moAbs), the treatment of metastatic colorectal cancer (mCRC) has become crucially dependent on the mutation profile of the tumour over the last two decades. Recently, rechallenge strategy with cetuximab-based chemotherapy has demonstrated to be active in a subgroup of patients whose tumour maintained wild-type RAS and RAF status. In this setting, liquid biopsy may replace tissue sample for the identification of specific subgroups of pretreated patients that may benefit from the reintroduction of anti-EGFR moAbs. In November 2014, a 64-year-old man with IVB stage BRAF, KRAS and NRAS wild-type mCRC was admitted in our hospital. He received FOLFIRI cetuximab as first-line treatment with deep and long-lasting partial response (PR), followed by cetuximab maintenance therapy until January 2016. At the time of disease progression, FOLFIRI cetuximab regimen was reintroduced resulting in stabilization of disease and he continued with capecitabine cetuximab therapy until disease progression in October 2016. Then, the patient consecutively received FOLFOX bevacizumab, TAS-102, regorafenib and FOLFIRI followed by de Gramont maintenance treatment. Finally, he was retreated with FOLFIRI cetuximab with disease progression within 3 months and died in May 2019. During his clinical course, liquid biopsy detected two mutations: one in KRAS Cd.12 and one in NRAS Cd. 61. The longitudinal assessment of RAS status offers considerable advantages in order to avoid side effects and economic costs for ineffective treatment choices. Liquid biopsy could help better monitor the disease and provide molecularly guided treatments.
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Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Análise Mutacional de DNA/métodos , Proteínas ras/genética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/administração & dosagem , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Capecitabina/administração & dosagem , Cetuximab/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/cirurgia , Progressão da Doença , Combinação de Medicamentos , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Biópsia Líquida/métodos , Masculino , Pessoa de Meia-Idade , Mutação , Compostos de Fenilureia/administração & dosagem , Piridinas/administração & dosagem , Pirrolidinas/administração & dosagem , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Timina/administração & dosagem , Trifluridina/administração & dosagemRESUMO
This retrospective observational study aimed to provide insights on the use of clinical nutrition (CN) (enteral and parenteral feeding) and outcomes in an Italian real-world setting. The data source comes from administrative databases of 10 Italian Local Health Units. Patients diagnosed with malignant neoplasms from 1 January 2010 to 31 December 2015 were included. Metastasis presence was ascertained by discharge diagnosis in the hospitalization database. CN was identified by specific codes from pharmaceutical and hospitalization databases. Two cohorts were created-one for metastatic patients (N = 53,042), and one for non-metastatic patients (N = 4379) receiving CN. Two survival analyses were set for the cohort of metastatic patients-one included patients receiving CN and the second included malnourished patients. Our findings show that (1) administration of CN is associated with positive survival outcomes in metastatic patients with gastrointestinal, respiratory, and genitourinary cancer; (2) CN in malnourished metastatic patients with gastrointestinal and genitourinary cancer was associated with significant improvement in survival; (3) early administration of CN was associated with improvement in survival in non-metastatic patients with gastrointestinal cancer (HR 95%CI: 0.5 (0.4-0.6), p-value < 0.05). This study highlights the need to improve the assessment of nutritional status in oncologic patients and suggests a potential survival benefit of CN treatment in metastatic disease.
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BACKGROUND: In search of novel biomarkers of response to bevacizumab in metastatic colorectal cancer (mCRC), we analyzed the expression and prognostic role of several proteins related to angiogenesis. METHODS: A retrospective, multicenter study on 80 surgical samples from mCRC patients treated in first line with bevacizumab plus chemotherapy was accomplished. The following proteins were analyzed by immunohistochemistry: hERG1 potassium channel, ß1-integrin, pAKT, NFkB, HIF-1α, HIF-2α, p53, VEGF-A, GLUT-1, and CA-IX. Data were analyzed in conjunction with the clinicopathological characteristics of the patients, KRAS status, response to bevacizumab, and follow-up. RESULTS: (1) All the proteins were expressed in the samples, with statistically significant associations between HIF-1α and gender, HIF-2α and left colon, hERG1 and VEGF-A, ß1-integrin and HIF-2α, GLUT-1 and both HIF-1α and HIF-2α, and CA-IX and VEGF-A. (2) At the univariate analysis, positivity for hERG1, VEGF-A, and the active form of HIF-2α (aHIF-2α), and the G3 histological grade showed a positive impact on progression-free survival (PFS). (3) hERG1 and aHIF-2α maintained their positive impact on PFS at the multivariate analysis. (4) hERG1 behaved as a protective factor for PFS independently on KRAS status. CONCLUSIONS: hERG1 and aHIF-2α might help to identify patients who would benefit from bevacizumab treatment.
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INTRODUCTION: Exocrine pancreatic cancers include common type pancreatic ductal adenocarcinoma and cystic neoplasms, which account for 85% and 10% of cases, respectively. The remaining 5% are rare histotypes, comprising adenosquamous carcinoma, acinar cell carcinoma, signet ring cell carcinoma, medullary carcinoma, pancreatoblastoma, hepatoid carcinoma, undifferentiated carcinoma and its variant with osteoclast-like giant cells, solid pseudopapillary carcinoma, and carcinosarcoma. Due to their low incidence, little knowledge is available on their clinical and molecular features as well as on treatment choices. The national initiative presented here aims at the molecular characterization of series of rare histotypes for which therapeutic and follow-up data are available. METHODS: A nationwide Italian Rare Pancreatic Cancer (IRaPaCa) task force whose first initiative is a multicentric retrospective study involving 21 Italian cancer centers to retrieve histologic material and clinical and treatment data of at least 100 patients with rare exocrine pancreatic cancers has been created. After histologic revision by a panel of expert pathologists, DNA and RNA from paraffin tissues will be investigated by next-generation sequencing using molecular pathway-oriented and immune-oriented mutational and expression profiling panels constructed availing of the information from the International Cancer Genome Consortium. Bioinformatic analysis of data will drive validation studies by immunohistochemistry and in situ hybridization, as well as nanostring assays. CONCLUSIONS: We expect to gather novel data on rare pancreatic cancer types that will be useful to inform the design of therapeutic choices.
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Neoplasias Pancreáticas/patologia , Carcinoma de Células Acinares/patologia , Carcinoma Adenoescamoso/patologia , Carcinoma Ductal Pancreático/patologia , Feminino , Humanos , Imuno-Histoquímica/métodos , Itália , Masculino , Estudos Retrospectivos , Neoplasias PancreáticasRESUMO
BACKGROUND: Platinum/fluoropyrimidine regimens are the backbone of first-line chemotherapy for advanced gastric cancer (AGC). However response rates to first line chemotherapy range from 30 to 50% and disease progression occurs after 4-6 cycles. The optimal duration of first-line therapy is still unknown and its continuation until disease progression represents the standard. However this strategy is often associated with cumulative toxicity and rapid development of drug resistance. Moreover, only about 40% of AGC pts. are eligible for second-line treatment. METHODS: This is a randomized, open-label, multicenter phase III trial. It aims at assessing whether switch maintenance to ramucirumab plus paclitaxel will extend the progression-free survival (PFS) of subjects with HER-2 negative AGC who have not progressed after 3 months of a first-line with a platinum/fluoropyrimidine regimen (either FOLFOX4, mFOLFOX6 or XELOX). The primary endpoint is to compare Progression-Free Survival (PFS) of patients in ARM A (switch maintenance to ramucirumab and placlitaxel) versus ARM B (continuation of the same first-line therapy with oxaliplatin/fluoropyrimidine). Secondary endpoints are: overall survival, time-to-treatment failure, overall response rate, duration of response, percentage of patients that will receive a second line therapy according to arm treatment, safety, quality of life. Exploratory studies including Next-Generation Sequencing (NGS) in archival tumor tissues are planned in order to identify potential biomarkers of primary resistance and prognosis. DISCUSSION: The ARMANI study estimates if patients treated with early swich with ramucirumab plus paclitaxel received benefit when compared to those treated with continuation of first line therapy. The hypothesis is that the early administration of an active, non-cross resistant second-line regimen such as ramucirumab plus paclitaxel may prolong the time in which patients are progression-free, and consequently have a better quality of life. Moreover, this strategy may rescue all those subjects that become ineligible for second-line therapy due to the rapid deterioration of health status after the first disease progression. TRIAL REGISTRATION: ARMANI is registered at ClinicalTrials.gov ( NCT02934464 , October 17, 2016) and EudraCT(2016-001783-12, April 202,016).
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Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Junção Esofagogástrica/patologia , Paclitaxel/administração & dosagem , Neoplasias Gástricas/tratamento farmacológico , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Esquema de Medicação , Junção Esofagogástrica/metabolismo , Feminino , Humanos , Quimioterapia de Manutenção , Masculino , Paclitaxel/efeitos adversos , Intervalo Livre de Progressão , Qualidade de Vida/psicologia , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Neoplasias Gástricas/psicologia , Resultado do Tratamento , RamucirumabRESUMO
BACKGROUND: Aerobic and resistance exercises have been promoted recently to improve quality of life in cancer patients. Most cancer survivorship rehabilitation programs consist of supervised exercise programs; however, less data is available on the effects of unsupervised or home-based exercise interventions. The study aimed to compare the physical and physiologic changes in a group of cancer survivors (CS) and a control group of non-cancer, health controls (HC) who participated in individualized home-based aerobic and resistance exercises for 12 months. METHODS: Thirty-three surviving cancer survivors (CS) aged 55.6±3 years were enrolled for 1 year of unsupervised exercise prescription programs. Anthropometric parameters hydration status, fitness, and echocardiographic examination were measured every six month and compared to10 HC (aged 52.6±7.7 years) individuals prior to starting the program (t0) and at 6 (t6) and 12 (t12) months. RESULTS: Among the CS subjects, a significant reductions in waist circumference (t0: 97.5±15.2 cm, t6: 86.6±13.5 cm, t12: 85.8±13.9 cm; P<0.05), body cell mass (t0: 50.9±4.7%, t6: 52.3±4.4%, t12: 53.7±3.7%; P<0.05), and extracellular mass (t0: 49.1±4.7%, t6: 47.6±4.4%, t12: 46.2±3.7%; P<0.05) were observed, as well significant improvements in lower body muscle strength (chair test t0: 13.3±4.1, t6: 14.2±3.5, t12: 15.1±3.2; P<0.05). Changes in functionality and heart function were similar between CS and HC. CONCLUSIONS: Individually-prescribed home-based exercise programs were cost effective, safe and resulted in modest improvements in body composition, strength, and total body water distribution with little to no adverse effect on cardiac function.
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Sobreviventes de Câncer , Terapia por Exercício , Aptidão Física , Composição Corporal , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Força Muscular , Qualidade de VidaRESUMO
AIM: This analysis evaluated the efficacy and safety of nivolumab, an immune checkpoint inhibitor, in elderly patients with stage IIIB or IV squamous non-small-cell lung cancer (NSCLC) enrolled in the expanded access programme (EAP) in Italy. METHODS: Nivolumab was available on physician request. Safety data included adverse events (AEs). Efficacy data included investigator-assessed tumour response, progression date and survival information. Results were analysed for patients aged <65, 65-<75 and ≥75 years and for the overall population. RESULTS: A total of 371 patients with squamous NSCLC were enrolled at 96 centres between April 2015 and September 2015; 34% (n = 126), 47% (n = 175) and 19% (n = 70) were aged <65, 65-<75 and ≥75 years, respectively. Efficacy was similar among patients aged <65, 65-<75 and ≥75 years and the overall population (objective response rates: 18%, 18%, 19% and 18%, respectively; disease control rates: 49%, 47%, 43% and 47%, respectively). Median overall survival was reduced in patients aged ≥75 years (5.8 months) versus patients aged <65; years (8.6 months), patients aged 65-<75 years (8.0 months) and the overall population (7.9 months). The incidence of grade 3-4 treatment-related AEs was low in patients aged 65, 65-<75 and ≥75 years and the overall population (3%, 9%, 3%, 6%, respectively). Discontinuation rates due to treatment-related AEs were low irrespective of age (4-5%). CONCLUSIONS: These EAP results suggest that elderly patients with advanced squamous NSCLC benefit from nivolumab, with tolerability similar to that in the overall population.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Nivolumabe/uso terapêutico , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Ensaios de Uso Compassivo , Feminino , Humanos , Itália , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Nivolumabe/efeitos adversos , Fatores de Tempo , Resultado do TratamentoRESUMO
Afatinib, a second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is effective as first-line treatment in patients with EGFR-mutated non-small cell lung cancer (NSCLC). We report 2 cases of EGFR-mutated locally advanced NSCLC treated in neoadjuvant setting with EGFR tyrosine kinase inhibitor at University of Florence/Careggi Hospital. In both cases, afatinib was used for up to 3 months, until 1 week before surgery. Both patients achieved significant reduction (downstaging) of the pulmonary mass and lymphadenopathies and after surgery, it was decided for both cases to restore afatinib treatment up to a further 4 months. Both patients experienced local and distant disease relapses after 9 and 10 months, respectively, and then we restored the afatinib treatment.
Assuntos
Afatinib/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/cirurgia , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Masculino , Mutação/genética , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
AIM: We report the outcomes observed with nivolumab in metastatic renal cell carcinoma patients with poor prognostic features enrolled in the Italian expanded access program. PATIENTS & METHODS: Nivolumab was available for patients who relapsed after at least one prior systemic treatment in the advanced or metastatic setting. RESULTS: Of 389 patients, 32 (8%) had brain metastasis, 129 (33%) had liver and 193 (50%) had bone metastasis. These subpopulations achieved a disease control rate of 53, 45 and 47%, respectively. Fifty-one patients had G4 tumor, and they showed 23% objective response rate. The safety profile of the subgroups was in line with the expanded access program population. No new safety signals were reported. CONCLUSION: Patients with poor prognostic features may derive relevant benefits from nivolumab.