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LESSONS LEARNED: The use of sodium levofolinate (Na-Lev) is safe in combination with continuous infusion 5-fluorouracil in patients with gastrointestinal tumors treated with the FOLFIRI regimen. A comparison with calcium levofolinate (Ca-Lev) showed a similar toxicity profile. The advantages of Na-Lev over Ca-Lev might be the faster drug preparation and the shorter time of drug administration. BACKGROUND: The objectives of this study were to compare the safety profiles of sodium levofolinate (Na-Lev) and calcium levofolinate (Ca-Lev) in combination with 5-fluorouracil (5-FU) in the FOLFIRI regimen and to measure the organizational impact of the introduction of Na-Lev on drug production and administration. METHODS: The study opened in November 2015 and closed in August 2019. Patients with gastrointestinal cancers who were candidates for treatment with the FOLFIRI regimen were included in this nonrandomized study. Age ≥18 years, life expectancy >3 months, adequate bone marrow reserve, adequate hepatic and renal function, and an ECOG performance status of 0-2 were required. Patients in the Ca-Lev arm received a 2-hour infusion of Ca-Lev followed by 5-FU, whereas those in the Na-Lev arm received Na-Lev and 5-FU administered in a single 48-hour pump. RESULTS: Sixty patients were enrolled, 30 in each arm. Patient characteristics were balanced. Grade (G)1-2 adverse events occurred in 18 (60.0%) and 19 (63.4%) patients of Na-Lev and Ca-Lev cohorts, respectively, whereas G3-4 adverse events occurred in 12 (40.0%) and 11 (36.6%) patients, respectively. The use of Na-Lev enabled us to save approximately 13 minutes for drug preparation and 2 hours for treatment administration, per patient per cycle. CONCLUSION: Na-Lev showed a reassuring toxicity profile and a favorable impact on drug preparation and administration.
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Cálcio , Neoplasias Colorretais , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/efeitos adversos , Humanos , Leucovorina/efeitos adversos , Sódio/uso terapêuticoRESUMO
BACKGROUND AND AIMS: In the last few years, there has been increasing interest in non-cancer medications and their potential anti-cancer activity. Data are not available in cholangiocarcinoma (CCA) patients. The aim of this study is to fill this gap by investigating the potential impact in terms of clinical outcome of the common non-cancer medications. METHODS: All consecutive patients with CCAs were retrospectively identified from 7 Italian medical institutions. We investigated the role of intake of vitamin D, aspirin, metformin, statins, and diuretics. RESULTS: A total of 537 patients with CCAs were identified; 197 patients undergoing surgery were evaluated for disease-free survival (DFS), and 509 patients with an advanced stage were evaluated for overall survival (OS). A longer DFS was found in patients with intake of vitamin D versus never users (HR 0.55, 95% CI 0.32-0.92, p = 0.02). In an advanced stage an association with OS was found in patients with intake of metformin versus never users (HR 0.70, 95% CI 0.52-0.93, p = 0.0162), and in patients who have started taking metformin after chemotherapy versus before chemotherapy and never users (HR 0.44, 95% CI 0.26-0.73, p = 0.0016). CONCLUSIONS: Our results highlighted that vitamin D intake improves DFS in patients undergoing surgery. Metformin intake after starting chemotherapy can improve the clinical outcome in advanced disease. These results could open up new therapeutic strategies in cholangiocarcinoma patients. We are planning to undertake a prospective study to validate these data.
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Neoplasias dos Ductos Biliares/mortalidade , Colangiocarcinoma/mortalidade , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Vitamina D/uso terapêutico , Vitaminas/uso terapêutico , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/patologia , Feminino , Seguimentos , Humanos , Masculino , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: Pancreatic cancer (PC) is a major cause of cancer death. In an effort to improve treatment strategies and outcomes, DNA damage repair (DDR) pathways have been introduced as a new target in PC and in other cancers, through the exploitation of synthetic lethality. Furthermore, genes involved in DDR are among the major determinants of cancer susceptibility. In addition to the well-known BRCA1 and BRCA2 genes, a plethora of other targets in the same pathways are now emerging. METHODS: We analyzed samples from 60 patients, affected by PC and already tested for BRCA, using a panel with 24 other cancer susceptibility genes. RESULTS: We detected 8 pathogenic or likely pathogenic mutations (13.3% of samples analyzed), 4 of which were found in non-BRCA genes (2 in ATM, 1 each in PALB2 and RAD50). Furthermore, 4 pathogenic or likely pathogenic mutations were found in patients without a personal or familial history of cancer. CONCLUSIONS: Our results suggest that genetic testing with a comprehensive gene panel should be perfomed in all patients with PC, in order to allow screening for PC and other gene-related cancers in all at risk family members and to assess patients' eligibility for emerging therapeutic options.
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Biomarcadores Tumorais/genética , Reparo do DNA , Detecção Precoce de Câncer/métodos , Testes Genéticos/métodos , Neoplasias Pancreáticas/diagnóstico , Hidrolases Anidrido Ácido/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Dano ao DNA , Análise Mutacional de DNA/estatística & dados numéricos , Proteínas de Ligação a DNA/genética , Detecção Precoce de Câncer/estatística & dados numéricos , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Feminino , Testes Genéticos/estatística & dados numéricos , Humanos , Masculino , Anamnese , Pessoa de Meia-Idade , Neoplasias Pancreáticas/genéticaRESUMO
PURPOSE: Early palliative care (EPC) has shown a positive impact on quality of life (QoL), quality of care, and healthcare costs. We evaluated such effects in patients with advanced gastric cancer. METHODS: In this prospective, multicenter study, 186 advanced gastric cancer patients were randomized 1:1 to receive standard cancer care (SCC) plus on-demand EPC (standard arm) or SCC plus systematic EPC (interventional arm). Primary outcome was a change in QoL between randomization (T0) and T1 (12 weeks after T0) in the Trial Outcome Index (TOI) scores evaluated through the Functional Assessment of Cancer Therapy-Gastric questionnaire. Secondary outcomes were patient mood, overall survival, and family satisfaction with healthcare and care aggressiveness. RESULTS: The mean change in TOI scores from T0 to T1 was - 1.30 (standard deviation (SD) 20.01) for standard arm patients and 1.65 (SD 22.38) for the interventional group, with a difference of 2.95 (95% CI - 4.43 to 10.32) (p = 0.430). The change in mean Gastric Cancer Subscale values for the standard arm was 0.91 (SD 14.14) and 3.19 (SD 15.25) for the interventional group, with a difference of 2.29 (95% CI - 2.80 to 7.38) (p = 0.375). Forty-three percent of patients in the standard arm received EPC. CONCLUSIONS: Our results indicated a slight, albeit not significant, benefit from EPC. Findings on EPC studies may be underestimated in the event of suboptimally managed issues: type of intervention, shared decision-making process between oncologists and PC physicians, risk of standard arm contamination, study duration, timeliness of assessment of primary outcomes, timeliness of cohort inception, and recruitment of patients with a significant symptom burden. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT01996540).
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Enfermagem de Cuidados Paliativos na Terminalidade da Vida/métodos , Cuidados Paliativos/métodos , Qualidade de Vida/psicologia , Neoplasias Gástricas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Gástricas/patologiaRESUMO
BACKGROUND: Appropriate cessation of chemotherapy and timely referral of patients to hospice services are crucial for the quality of care near death. We investigated the quality of care in our Cancer Institute in very advanced metastatic colorectal cancer patients treated in real life. PATIENTS AND METHODS: We performed a retrospective analysis of electronic medical data of patients with metastatic colorectal cancer who were candidates for chemotherapy during the study period (1 January 2007-30 June 2014) and died before 31 December 2014. Quality-of-cancer-care indicators were calculated for the overuse of chemotherapy and referral to hospice. Predictive factors of chemotherapy discontinuation and hospice referral in end-of life care were investigated using parametric and nonparametric methods. RESULTS: Of the 365 patients who died before 31 December 2014, 26 (7.1%) received chemotherapy in the last 14 days of life and 36 (9.8%) started a new chemotherapy regimen in the last 30 days of life. Factors associated with the overuse of chemotherapy were being < 70 years of age for both indicators and not having received advanced chemotherapy treatments for the former indicator. The majority of patients (74.7%) had access to hospice services, of whom only a small percentage (7.2%) accessed them very near to death. CONCLUSIONS: According to the criteria used, our Institute provides a good quality of cancer care for dying colorectal cancer patients, measured by the use of chemotherapy and referral to hospice in their last days of life.
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Neoplasias Colorretais/terapia , Tratamento Farmacológico/psicologia , Tratamento Farmacológico/normas , Cuidados Paliativos/métodos , Academias e Institutos/organização & administração , Adulto , Idoso , Idoso de 80 Anos ou mais , Registros Eletrônicos de Saúde , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Estatísticas não Paramétricas , Suspensão de Tratamento/normasRESUMO
Targeting angiogenesis in the treatment of colorectal cancer (CRC) is a common strategy, for which potential predictive biomarkers have been studied. miRNAs are small non-coding RNAs involved in several processes including the angiogenic pathway. They are very stable in biological fluids, which turns them into potential circulating biomarkers. In this study, we considered a case series of patients with metastatic (m) CRC treated with a bevacizumab (B)-based treatment, enrolled in the prospective multicentric Italian Trial in Advanced Colorectal Cancer (ITACa). We then analyzed a panel of circulating miRNAs in relation to the patient outcome. In multivariate analysis, circulating basal levels of hsa-miR-20b-5p, hsa-miR-29b-3p and hsa-miR-155-5p resulted in being significantly associated with progression-free survival (PFS) (p = 0.027, p = 0.034 and p = 0.039, respectively) and overall survival (OS) (p = 0.044, p = 0.024 and p = 0.032, respectively). We also observed that an increase in hsa-miR-155-5p at the first clinical evaluation was significantly associated with shorter PFS (HR 3.03 (95% CI 1.06-9.09), p = 0.040) and OS (HR 3.45 (95% CI 1.18-10.00), p = 0.024), with PFS and OS of 9.5 (95% CI 6.8-18.7) and 15.9 (95% CI 8.4-not reached), respectively, in patients with an increase ≥30% of hsa-miR-155-5p and 22.3 (95% CI 10.2-25.5) and 42.9 (24.8-not reached) months, respectively, in patients without such increase. In conclusion, our results highlight the potential usefulness of circulating basal levels of hsa-miR-20b-5p, hsa-miR-29b-3p and hsa-miR-155-5p in predicting the outcome of patients with mCRC treated with B. In addition, the variation of circulating hsa-miR-155-5p could also be indicative of the patient survival.
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Biomarcadores Tumorais , MicroRNA Circulante , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , MicroRNAs/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/tratamento farmacológico , Terapia Combinada , Feminino , Regulação Neoplásica da Expressão Gênica , Genes ras , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida , Resultado do TratamentoRESUMO
LESSONS LEARNED: Difficulties in translating in vitro results into clinical practice are inevitable.Further efforts to verify the efficacy of alternative schedules of pemetrexed in solid tumors are encouraged. BACKGROUND: We investigated the cytotoxic activity of pemetrexed in combination with several drugs (gemcitabine, carboplatin, vinorelbine, and mitomycin C) using different exposure schedules in three colon cancer cell lines. The best results were obtained with the following schedule: a prolonged pemetrexed exposure followed by a 48-hour wash-out and then gemcitabine. This combination was then advanced to a phase II clinical trial. METHODS: Patients with metastatic colorectal cancer in progression after standard treatment were included in the study. Adequate bone marrow reserve, normal hepatic and renal function, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were required. Treatment consisted of an 8-hour intravenous infusion of pemetrexed 150 mg/m2 on day 1 and a 30-minute intravenous infusion of gemcitabine 1,000 mg/m2 on day 3 of each cycle, repeated every 14 days. RESULTS: Fourteen patients were enrolled onto the study (first step). No objective responses were seen, and evidence of stable disease was observed in only one of the 12 evaluable patients. The most important grade 3-4 side effects were hematological toxicity (neutropenia 64.2%, thrombocytopenia 71.4%, anemia 28.7%), fatigue (50.0%), and stomatitis (21.5%). Median overall survival and time to progression were 5.8 months (95% confidence interval [CI]: 3.9-7.1) and 2.1 months (95% CI: 1.7-2.8), respectively. CONCLUSION: The experimental pemetrexed-gemcitabine combination proved to be inactive and moderately toxic.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Desoxicitidina/análogos & derivados , Pemetrexede/administração & dosagem , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Progressão da Doença , Intervalo Livre de Doença , Esquema de Medicação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Pemetrexede/efeitos adversos , GencitabinaRESUMO
Sirtuins (SIRT), first described as nicotinamide adenine dinucleotide (NAD+)-dependent type III histone deacetylases, are produced by cells to support in the defense against chronic stress conditions such as metabolic syndromes, neurodegeneration, and cancer. SIRT-3 is one of the most studied members of the mitochondrial sirtuins family. In particular, its involvement in metabolic diseases and its dual role in cancer have been described. In the present review, based on the evidence of SIRT-3 involvement in metabolic dysfunctions, we aimed to provide an insight into the multifaceted role of SIRT-3 in many solid and hematological tumors with a particular focus on hepatocellular carcinoma (HCC). SIRT-3 regulatory effect and involvement in metabolism dysfunctions may have strong implications in HCC development and treatment. Research literature widely reports the relationship between metabolic disorders and HCC development. This evidence suggests a putative bridge role of SIRT-3 between metabolic diseases and HCC. However, further studies are necessary to demonstrate such interconnection.
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Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Sirtuína 3/fisiologia , Proteínas Supressoras de Tumor/fisiologia , Carcinoma Hepatocelular/etiologia , Humanos , Neoplasias Hepáticas/etiologia , Doenças Metabólicas/complicações , Neoplasias/etiologia , Neoplasias/metabolismoRESUMO
Anti-tumor immunity is a new line of research for the treatment of patients with solid tumors. In this field, negative regulators of the immune system called immune checkpoints play a key role in limiting antitumor immunologic responses. For this reason, immune checkpoint-inhibiting agents, such as those directed against cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death-1 receptor (PD1) and its ligand PD-L1, have been developed as antitumor drugs, producing interesting results in preclinical and clinical studies. We present an updated review of the biological background and clinical development of immune checkpoint inhibitors in colorectal cancer (CRC). Early trial results on PD1 and PD-L1 blockade appear promising, especially in CRC patients with microsatellite instability (MSI). Clinical trials are ongoing to confirm these preliminary results, evaluate combination strategies and identify biomarkers to predict which patients are most likely to benefit from, or show resistance to, the effects of checkpoint inhibition.
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Antineoplásicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Neoplasias Colorretais/tratamento farmacológico , Imunidade/efeitos dos fármacos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Antígeno B7-H1/imunologia , Colo/efeitos dos fármacos , Colo/imunologia , Colo/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Descoberta de Drogas , Humanos , Instabilidade de Microssatélites , Terapia de Alvo Molecular , Receptor de Morte Celular Programada 1/imunologia , Reto/efeitos dos fármacos , Reto/imunologia , Reto/metabolismoRESUMO
There is evidence of a different response to treatment with regard to the primary tumor localization (right-sided or left-sided) in patients with metastatic colorectal cancer (mCRC). We analyzed the different outcomes and biomolecular characteristics in relation to tumor localization in 122 of the 370 patients with metastatic colorectal cancer enrolled onto the phase III prospective multicenter "Italian Trial in Advanced Colorectal Cancer (ITACa)", randomized to receive first-line chemotherapy (CT) or CT plus bevacizumab (CT + B). RAS and BRAF mutations; baseline expression levels of circulating vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), cyclooxygenase-2 (COX2), ephrin type-B receptor 4 (EPHB4), hypoxia-inducible factor 1-alpha (HIF-1α), lactate dehydrogenase (LDH), and high-sensitivity C reactive protein (hs-CRP); and inflammatory indexes such as the neutrophil-to-lymphocyte ratio, platelet-lymphocyte rate and systemic immune-inflammation index were evaluated. Patients with right-sided tumors showed a longer median progression-free survival in the CT + B arm than in the CT group (12.6 vs. 9.0 months, respectively, p = 0.017). Baseline inflammatory indexes were significantly higher in left-sided tumors, whereas eNOS and EPHB4 expression was significantly higher and BRAF mutation more frequent in right-sided tumors. Our data suggest a greater efficacy of the CT + B combination in right-sided mCRC, which might be attributable to the lower inflammatory status and higher expression of pro-angiogenic factors that appear to characterize these tumors.
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Colo/patologia , Neoplasias Colorretais/patologia , Antineoplásicos Imunológicos/uso terapêutico , Bevacizumab/uso terapêutico , Biomarcadores , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/mortalidade , Terapia Combinada , Feminino , Genes ras , Humanos , Mediadores da Inflamação , Masculino , Mutação , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Óxido Nítrico Sintase Tipo III/genética , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
BACKGROUND: Small-cell lung cancer (SCLC) is known to express antigens of both the neural crest and epithelium, and to secrete polypeptide hormones and enzymes. Anecdotal reports correlate lung cancer with marked hyperamylasemia, and a review of the literature reveals only one case of metastatic SCLC linked to high paraneoplastic lipase production. CASE PRESENTATION: We present the case of a patient with metastatic SCLC who showed both lipase and pancreatic isoamylase elevation in the absence of acute pancreatitis. Chemotherapy resulted in a rapid reduction in serum lipase and in pancreatic isoamylase which was correlated with the radiological response of the tumor to therapy. Lipase and pancreatic isoamylase expression in tumor cells from the lung biopsy was confirmed by immunohistochemical staining. CONCLUSIONS: This is a very rare case of paraneoplastic syndrome linked to metastatic SCLC. The enzymes secreted could be used as markers of response to treatment until clonal selection mechanisms and intratumor heterogeneity induce changes in biochemical characteristics and consequently in tumor behavior.
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Amilases/sangue , Lipase/sangue , Neoplasias Pulmonares/enzimologia , Síndromes Paraneoplásicas/enzimologia , Carcinoma de Pequenas Células do Pulmão/enzimologia , Evolução Fatal , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
PURPOSE: We aimed to investigate the prognostic role of baseline and longitudinal levels of neutrophil-to-lymphocyte ratio (NLR) in patients with metastatic colorectal cancer (mCRC) treated with chemotherapy + bevacizumab (CT + B) or chemotherapy only. Additionally, we investigated whether treatment outcomes were mediated by the longitudinal biomarker. METHODS: Data from an Italian randomized phase III trial were used. The main end point was progression-free survival (PFS). To address research questions, a series of joint models of longitudinal and survival data were specified, and the direct and indirect treatment effects were quantified. RESULTS: Data for 239 patients, 113 (47.3%) treated with CT + B and 126 (52.7%) with CT only, were included in the analyses. The effect of NLR seemed to be mediated by the longitudinal trajectory of the biomarker. Only in the patient subgroup treated with CT + B, the baseline NLR retained a direct effect on PFS. Regarding the effect of treatment on PFS, two scenarios were observed. In the subgroup of patients with low baseline, NLR bevacizumab showed a direct protective effect only (hazard ratio [HR], 0.66 [95% CI, 0.45 to 0.98]), whereas in the subgroup with high baseline NLR, there was evidence for an adverse direct effect (HR, 1.63 [95% CI, 1.03 to 2.57]) and a protective indirect-which is mediated by the longitudinal biomarker-effect (HR, 0.71 [95% CI, 0.55 to 0.90]). CONCLUSION: In our study, inflammatory indexes collected longitudinally showed a significant adverse prognostic role, thus suggesting the collection and use of such data for better clinical decision making. In the specific setting, we considered this is particularly important as the treatment effect seemed to be modified by both the baseline and longitudinal inflammation statuses. However, further research is needed to understand the possible factors underlying these results.
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Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Humanos , Bevacizumab/uso terapêutico , Biomarcadores , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Linfócitos/patologia , Neutrófilos/patologia , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Ensaios Clínicos Fase III como AssuntoRESUMO
The identification of predictive factors for treatment of pancreatic cancer (PC) is an unmet clinical need. In the present work, we analyzed blood-derived extracellular vesicles (EVs) from patients with advanced PC in order to find a molecular signature predictive of response to therapy. We analyzed samples from 21 patients with advanced PC, all receiving first-line treatment with gemcitabine + nab-paclitaxel. Isolated EVs have been analyzed, and the results of laboratory have been matched with clinical data in order to investigate possible predictive factors. EV concentration and size were similar between responder and non-responder patients. Analysis of 37 EV surface epitopes showed a decreased expression of SSEA4 and CD81 in responder patients. We detected more than 450 expressed miRNAs in EVs. A comparative survey between responder and non-responder patients showed that at least 44 miRNAs were differently expressed. Some of these miRNAs have already been observed in relation to the survival and gemcitabine sensitivity of tumor cells. In conclusion, we showed the ability of our approach to identify EV-derived biomarkers with predictive value for therapy response in PC. Our findings are worthy of further investigation, including the analysis of samples from patients treated with different schedules and in different settings.
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Background: Validated predictors of sensitivity or resistance to Bevacizumab (Bev) are not available, and Inflammatory Indexes (IIs) has been reported to be useful prognostic factors in various malignant solid tumours, including metastatic colorectal cancer (mCRC). Objectives: To explore the prognostic value of IIs in mCRC patients treated with first-line chemotherapy plus Bev. Design: One hundred and eighty-two patients diagnosed with mCRC and treated with first line chemotherapy plus Bev were considered for this prospective non-pharmacological study. Neutrophil, lymphocyte, platelet, aspartate transaminase (AST) and lactate dehydrogenase (LDH) tests were carried out at baseline and before each treatment cycle, according to clinical practice. Methods: Pre-treatment Systemic Immune-inflammation Index (SII), Colon Inflammatory Index (CII) and Aspartate aminotransferase-Lymphocyte Ratio Index (ALRI) were evaluated to assess a correlation with progression-free survival (PFS) and overall survival (OS). Results: In the overall population, PFS and OS were lower in patients with high SII (HR 1.64, p = 0.006 and HR 1.75, p = 0.004, respectively) and high ALRI (HR 2.13, p = 0.001 and HR 1.76, p = 0.02, respectively), but no difference was detected according to CII value. The multivariate analysis confirmed both SII and ALRI as independent prognostic factors for PFS (HR 1.64 and 2.82, respectively) and OS (HR 1.65 and 2.12, respectively). Conclusion: Our results demonstrate and confirm that IIs, and in particular SII and ALRI, are easy to measure prognostic markers for patient candidates to first line chemotherapy plus Bev for mCRC.
Inflammatory Indexes can predict the efficacy of bevacizumab in metastatic colorectal cancer Bevacizumab (Bev) is a humanized monoclonal antibody with antiangiogenic activity, used in combination with chemotherapy as a standard first line treatment for many metastatic colorectal cancer patients. Validated predictors of sensitivity or resistance to Bevacizumab are not available, although several studies have investigated this issue in recent years. In this study, we investigated whether some selected baseline inflammatory indexes levels, namely Systemic Immune-inflammation Index (SII) and Aspartate aminotransferase-Lymphocyte Ratio Index (ALRI) could predict the survival in patients with metastatic colorectal cancer treated with Bevacizumab plus chemotherapy. We enrolled 182 patients diagnosed with mCRC and treated with first line chemotherapy plus Bev. For each patient we tested blood neutrophils, lymphocytes, platelets, aspartate transaminase (AST) and lactate dehydrogenase (LDH) before each treatment cycle, according to clinical practice. We calculated the SII value as platelet count × neutrophil count/lymphocyte count, and ALRI as AST/lymphocyte count. We found that patients with high SII and high ALRI values had lower survival as compared to those with low values. These parameters represent reproducible, inexpensive and easy to measure biomarkers to be used in both clinical practice and clinical trials, for patient selection.
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BACKGROUND: KRAS mutations negatively affect outcome after treatment with cetuximab in metastatic colorectal cancer (mCRC) patients. As only 20% of KRAS wild type (WT) patients respond to cetuximab it is possible that other mutations, constitutively activating the EGFR pathway, are present in the non-responding KRAS WT patients. We retrospectively analyzed objective tumor response rate, (ORR) progression-free (PFS) and overall survival (OS) with respect to the mutational status of KRAS, BRAF, PIK3CA and PTEN expression in mCRC patients treated with a cetuximab-based regimen. METHODS: 67 mCRC patients were enrolled onto the study. DNA was extracted from paraffin-embedded sections derived from primary or metastatic lesions. Exon 2 of KRAS and exon 15 of BRAF were analyzed by direct sequencing, PIK3CA was evaluated by pyrosequencing and PTEN expression by immunohistochemistry. RESULTS: BRAF and PIK3CA mutations were independently associated with worse PFS (p = 0.006 and p = 0.028, respectively) and OS (p = 0.008 and p = 0.029, respectively). No differences in clinical outcome were found between patients who were positive or negative for PTEN expression. Conversely, patients negative for KRAS, BRAF and PIK3CA mutations were characterized by significantly better ORR, PFS and OS than patients with at least one of these mutations. CONCLUSIONS: BRAF and PIK3CA mutations would seem to be independent predictors of anti-EGFR therapy effectiveness and could be taken into consideration during treatment decision making.
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Anticorpos Monoclonais/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/secundário , Genes Neoplásicos/genética , Mutação/genética , Adulto , Idoso , Anticorpos Monoclonais Humanizados , Cetuximab , Neoplasias Colorretais/genética , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Resultado do TratamentoRESUMO
Background: After the REGATTA trial, patients with stage IV gastric cancer could only benefit from chemotherapy (CHT). However, some of these patients may respond extraordinarily to palliative chemotherapy, converting their disease to a radically operable stage. We present a single centre experience in treating peritoneal carcinomatosis from gastric cancer. Methods: All patients with stage IV gastric cancer with peritoneal metastases as a single metastatic site operated at a single centre between 2005 and 2020 were included. Cases were grouped according to the treatment received. Results: A total of 118 patients were considered, 46 were submitted to palliative gastrectomy (11 were considered M1 because of an unsuspected positive peritoneal cytology), and 20 were submitted to Hyperthermic Intraperitoneal Chemotherapy (HIPEC) because of a <6 Peritoneal Cancer Index (PCI). The median overall survival (OS) after surgery plus HIPEC was 46.7 (95% CI 15.8-64.0). Surgery (without HIPEC) after CHT presented a median OS 14.4 (8.2-26.8) and after upfront surgery 14.7 (10.9-21.1). Patients treated with upfront surgery and considered M1 only because of a positive cytology, had a median OS of 29.2 (25.2-29.2). The OS of patients treated with surgery plus HIPEC were 60.4 months (9.2-60.4) in completely regressed cancer after chemotherapy and 31.2 (15.8-64.0) in those partially regressed (p = 0.742). Conclusions: Conversion surgery for peritoneal carcinomatosis from gastric cancer was associated with long survival and it should always be taken into consideration in this group of patients.
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Second-line treatments are standard care for advanced hepatocellular carcinoma (HCC) patients with preserved liver function who are intolerant of or progress on first-line therapy. However, determinants of treatment benefit and post-treatment survival (PTS) remain unknown. HCC patients previously treated with sorafenib and enrolled in second-line clinical trials were pooled according to the investigational treatment received and the subsequent regulatory approval: approved targeted agents and immune checkpoint inhibitors (AT) or other agents (OT) not subsequently approved. Univariate and multivariate analyses using Cox proportional hazards models established relationships among treatments received, clinical variables, and overall survival (OS) or PTS. For 174 patients (80 AT; 94 OT) analyzed, baseline factors for longer OS in multivariate analysis were second-line AT, absence of both portal vein thrombosis and extrahepatic spread (EHS). Treatment with AT (versus OT) was associated with significantly longer OS among patients with EHS (pinteraction = 0.005) and patients with low neutrophil-to-lymphocyte ratio (NLR; pinteraction = 0.032). Median PTS was 4.0 months (95% CI 2.8−5.3). At second-line treatment discontinuation, alpha-fetoprotein (AFP) levels <400 ng/dl, albumin-bilirubin (ALBI) grade 1, and enrolment onto subsequent trials independently predicted longer PTS. Treatment with AT, PVT, and EHS were prognostic factors for OS, while AFP, ALBI grade and enrolment onto a third-line trial were prognostic for PTS. Presence of EHS and low NLR were predictors of greater OS benefit from AT.
RESUMO
Spontaneous pneumothorax (PNX) is an infrequent manifestation of primary lung cancer, soft tissue sarcoma and metastasis. There are no easily accessible data in the literature regarding the correlation between PNX and antibiotics, whereas cases of PNX following chemotherapy have been observed. Only 1-10% of treatment-related adverse events are estimated to be reported to the Food and Drug Administration. The present study described a case of PNX of the left lung in a 70-year-old treatment-naive patient with retroperitoneal liposarcoma. The PNX developed after 8 days of treatment with levofloxacin and after 6 days of piperacillin/tazobactam treatment for a suspicious inflammatory area in the right lung detected by an FDG-PET scan before the patient started chemotherapy. A chest CT scan confirmed the presence of metastasis in the right lung, but neither FDG-PET/CT nor CT showed metastatic disease in the left lung. A total of 14 days after the end of the third cycle of doxorubicin (2 months after the initial diagnosis of PNX), the patient manifested a massive PNX of the right lung. In conclusion, these findings indicated that spontaneous PNX could be linked to the use of some antibiotics.
RESUMO
BACKGROUND AND AIMS: Biliary tract cancers are rare malignancies with a poor prognosis and scarce therapeutic strategies. The significance of BRCAness in this setting is already unknown. METHOD: Tissue specimens of BTC patients treated with platinum-based chemotherapy have been analyzed through the FOUNDATIONPne assay. RESULTS: 72/150 (48%) BRCAness mutated and 78/150 (52.0%) wild type (WT) patients were included. The most commonly mutated genes in the BRCAness mutated group were: ARID1A (N = 32, 44%), CDKN2A (N = 23, 32%), KRAS/NRAS (N = 16, 22%), CDKN2B (N = 13, 18%), BRCA2 (N = 13, 18%), PBRM1 (N = 12, 17%), ATM (N = 11, 15%), FGFR2 (N = 10, 14%), TP53 (N = 8, 11%), IRS2 (N = 7, 10%), CREBBP (N = 7, 10%) (table 3, figure 1). At the univariate analysis BRCAness mutation was associated with longer median Progression Free Survival (mPFS) (HR 0.68; 95% CI 0.49-0.95; p = 0.0254); it was not associated with longer mOS but a trend toward a benefit in survival was found (HR 0.77; 95% CI 0.50-1.19; p = 0.2388). Patients with BRCAness mutation showed a higher percentage of disease control rate (77.8 vs 67.9; p = 0.04) compared to patients WT. Multivariate analysis confirmed BRCAness mutation (HR 0.66; 95% CI: 0.45-0.98; p = 0.0422) as independent favorable prognostic factors for PFS and a positive trend was found for OS (HR 0.84; 95% CI: 0.53-1.33; p = 0.3652). CONCLUSION: BRCAness BTC patients showed a better PFS compared BRCAnessWT patients after exposure to platinum-based chemotherapy. Moreover, the OS curves' trend showed in our analysis suggests that BRCAness mutated patients could benefit from a maintenance therapy with PARPi.