RESUMO
BACKGROUND: KEAP1 mutations have been associated with reduced survival in lung adenocarcinoma (LUAD) patients treated with immune checkpoint inhibitors (ICIs), particularly in the presence of STK11/KRAS alterations. We hypothesized that, beyond co-occurring genomic events, clonality prediction may help identify deleterious KEAP1 mutations and their counterparts with retained sensitivity to ICIs. PATIENTS AND METHODS: Beta-binomial modelling of sequencing read counts was used to infer KEAP1 clonal inactivation by combined somatic mutation and loss of heterozygosity (KEAP1 C-LOH) versus partial inactivation [KEAP1 clonal diploid-subclonal (KEAP1 CD-SC)] in the Memorial Sloan Kettering Cancer Center (MSK) MetTropism cohort (N = 2550). Clonality/LOH prediction was compared to a streamlined clinical classifier that relies on variant allele frequencies (VAFs) and tumor purity (TP) (VAF/TP ratio). The impact of this classification on survival outcomes was tested in two independent cohorts of LUAD patients treated with immunotherapy (MSK/Rome N = 237; DFCI N = 461). Immune-related features were studied by exploiting RNA-sequencing data (TCGA) and multiplexed immunofluorescence (DFCI mIF cohort). RESULTS: Clonality/LOH inference in the MSK MetTropism cohort overlapped with a clinical classification model defined by the VAF/TP ratio. In the ICI-treated MSK/Rome discovery cohort, predicted KEAP1 C-LOH mutations were associated with shorter progression-free survival (PFS) and overall survival (OS) compared to KEAP1 wild-type cases (PFS log-rank P = 0.001; OS log-rank P < 0.001). Similar results were obtained in the DFCI validation cohort (PFS log-rank P = 0.006; OS log-rank P = 0.014). In both cohorts, we did not observe any significant difference in survival outcomes when comparing KEAP1 CD-SC and wild-type tumors. Immune deconvolution and multiplexed immunofluorescence revealed that KEAP1 C-LOH and KEAP1 CD-SC differed for immune-related features. CONCLUSIONS: KEAP1 C-LOH mutations are associated with an immune-excluded phenotype and worse clinical outcomes among advanced LUAD patients treated with ICIs. By contrast, survival outcomes of patients whose tumors harbored KEAP1 CD-SC mutations were similar to those with KEAP1 wild-type LUADs.
Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/patologia , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Fator 2 Relacionado a NF-E2/genética , Mutação , Perda de Heterozigosidade , ImunoterapiaRESUMO
BACKGROUND: Oxaliplatin-based adjuvant chemotherapy is the standard treatment of high-risk colon cancer (CC). A shorter duration (3 months) can achieve a similar outcome [in terms of relapse-free survival (RFS)] to a longer duration. This study reports the overall survival (OS) analysis of the three or six colon adjuvant (TOSCA) phase III study. It assessed different adjuvant chemotherapy durations in patients with resected high-risk stage II and stage III CC. MATERIAL AND METHODS: TOSCA was an open-label, phase III, multicentre, non-inferiority trial conducted in 130 Italian centres. Patients were randomly assigned, in a 1 : 1 ratio, to receive 3 months of standard doses of FOLFOX/CAPOX, or 6 months of FOLFOX/CAPOX. Patients with histologically confirmed high-risk stage II and III CC were included, with RFS being the primary end point. OS was a secondary end point. RESULTS: From June 2007 to March 2013, 3759 patients were accrued. At a median follow-up of 7 years, the hazard ratio (HR) for RFS of the 3-month versus 6-month arms was 1.13; 95% confidence interval (CI) 0.99-1.29, P for non-inferiority = 0.380, P for superiority = 0.068, crossing the non-inferiority limit of 1.20. This result did not allow us to reject the null hypothesis of the inferiority of the 3-month arm. The HR for OS of the 3-month versus 6-month arms was 1.09 (95% CI 0.93-1.26, P for superiority = 0.288). At the last follow-up analysis, the absolute OS difference between arms was <1%. CONCLUSIONS: The present analysis of the TOSCA trial does not indicate any significant difference in OS between the treatment groups. The extra benefit provided by the longer treatment should be balanced against the extra toxicity of more prolonged therapy. The trial is registered with ClinicalTrials.gov, registration number: NCT0064660.
Assuntos
Fluoruracila , Recidiva Local de Neoplasia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Capecitabina/uso terapêutico , Quimioterapia Adjuvante , Intervalo Livre de Doença , Fluoruracila/efeitos adversos , Humanos , Itália , Recidiva Local de Neoplasia/patologia , Estadiamento de NeoplasiasAssuntos
COVID-19 , Neoplasias , Humanos , Avaliação de Estado de Karnofsky , Cuidados Paliativos , SARS-CoV-2RESUMO
BACKGROUND: Immune checkpoint inhibitors (ICIs) have demonstrated significant overall survival (OS) benefit in lung adenocarcinoma (LUAD). Nevertheless, a remarkable interpatient heterogeneity characterizes immunotherapy efficacy, regardless of programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB). KEAP1 mutations are associated with shorter survival in LUAD patients receiving chemotherapy. We hypothesized that the pattern of KEAP1 co-mutations and mutual exclusivity may identify LUAD patients unresponsive to immunotherapy. PATIENTS AND METHODS: KEAP1 mutational co-occurrences and somatic interactions were studied in the whole MSKCC LUAD dataset. The impact of coexisting alterations on survival outcomes in ICI-treated LUAD patients was verified in the randomized phase II/III POPLAR/OAK trials (blood-based sequencing, bNGS cohort, N = 253). Three tissue-based sequencing studies (Rome, MSKCC and DFCI) were used for independent validation (tNGS cohort, N = 289). Immunogenomic features were analyzed using The Cancer Genome Atlas (TCGA) LUAD study. RESULTS: On the basis of KEAP1 mutational co-occurrences, we identified four genes potentially associated with reduced efficacy of immunotherapy (KEAP1, PBRM1, SMARCA4 and STK11). Independent of the nature of co-occurring alterations, tumors with coexisting mutations (CoMut) had inferior survival as compared with single-mutant (SM) and wild-type (WT) tumors (bNGS cohort: CoMut versus SM log-rank P = 0.048, CoMut versus WT log-rank P < 0.001; tNGS cohort: CoMut versus SM log-rank P = 0.037, CoMut versus WT log-rank P = 0.006). The CoMut subset harbored higher TMB than the WT disease and the adverse significance of coexisting alterations was maintained in LUAD with high TMB. Significant immunogenomic differences were observed between the CoMut and WT groups in terms of core immune signatures, T-cell receptor repertoire, T helper cell signatures and immunomodulatory genes. CONCLUSIONS: This study indicates that coexisting alterations in a limited set of genes characterize a subset of LUAD unresponsive to immunotherapy and with high TMB. An immune-cold microenvironment may account for the clinical course of the disease.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/terapia , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Humanos , Imunoterapia , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Mutação , Fator 2 Relacionado a NF-E2 , Ensaios Clínicos Controlados Aleatórios como Assunto , Microambiente TumoralAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/enzimologia , MAP Quinase Quinase Quinases/antagonistas & inibidores , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/enzimologia , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Carcinoma Ductal Pancreático/patologia , Processos de Crescimento Celular/efeitos dos fármacos , Sinergismo Farmacológico , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , MAP Quinase Quinase Quinases/metabolismo , Morfolinas/farmacologia , Neoplasias Pancreáticas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Piridonas/administração & dosagem , Piridonas/farmacologia , Pirimidinonas/administração & dosagem , Pirimidinonas/farmacologia , Triazinas/farmacologiaRESUMO
BACKGROUND: Six months of oxaliplatin-based adjuvant chemotherapy is standard of care for radically resected stage III colon cancer and an accepted option for high-risk stage II. A shorter duration of therapy, if equally efficacious, would be advantageous for patients and Health-Care Systems. PATIENTS AND METHODS: TOSCA ['Randomized trial investigating the role of FOLFOX-4 or XELOX (3 versus 6 months) regimen duration and bevacizumab as adjuvant therapy for patients with stage II/III colon cancer] is an open-label, phase III, multicenter, noninferiority trial randomizing patients with high-risk stage II or stage III radically resected colon cancer to receive 3 months (arm 3 m) versus 6 months (arm 6 m) of FOLFOX4/XELOX. Primary end-point was relapse-free survival. We present here safety and compliance data. RESULTS: From June 2007 to March 2013, 3759 patients were accrued from 130 Italian sites, 64% receiving FOLFOX4 and 36% XELOX in either arm. Treatment completion rate without any modification was 35% versus 12% and with delays or dose reduction 52% versus 44% in arm 3 and 6 m. Treatment was permanently discontinued in 8% (arm 3 m) and 33% (arm 6 m). In arm 6 m, 50% of patients discontinuing treatment did so after completing 80% of planned program. Grade 3+ toxicities were higher in arm 6 m than that in 3 m. Grade 2+ neuropathy was 31.2% versus 8.8% (P < 0.0001) while grade 3+ was 8.4 versus 1.3 (P < 0.0001), in arm 3 and 6 m. Seven deaths within 30 days from last treatment administration in arm 6 m and three deaths in arm 3 m were observed (0.3% versus 0.1%, P = 0.34). CONCLUSIONS: TOSCA is the first trial comparing 3 versus 6 months of adjuvant chemotherapy completing accrual within the international initiative of treatment duration evaluation (International Duration Evaluation of Adjuvant, IDEA). High compliance to treatment in control arm will allow a correct assessment of potential differences between the two treatment durations. CLINICALTRIALSGOV REGISTRATION NUMBER: NCT00646607.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias do Colo/tratamento farmacológico , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/administração & dosagem , Capecitabina , Quimioterapia Adjuvante/efeitos adversos , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Terapia Combinada , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Oxaliplatina , Oxaloacetatos , Cooperação do PacienteRESUMO
The etiology of testicular cancer is largely unexplained. Research has mainly focused on prenatal exposures, especially to sex hormones, while less attention has been paid to exposures that may act also postnatally. As baldness has been previously associated with testicular cancer risk we focused on baldness and body hairiness, which are both associated with androgen activity. We used data of the Postnatal Exposures and Male Health (EPSAM) study, a case-control study on testicular cancer conducted in the Province of Turin, Italy, involving cases diagnosed between 1997 and 2008. Information was collected using mailed questionnaires. Analyses included 255 cases and 459 controls. We calculated ORs and 95% CIs to estimate testicular cancer risk among those who developed baldness and among those with body hairiness. We found an inverse association between testicular cancer and baldness (OR: 0.67, 95% CI: 0.46-0.98) and body hairiness (OR: 0.78, 95% CI: 0.53-1.16), although the latter had wider CIs. The inverse association between baldness and testicular cancer is consistent with the results from previous studies. These results suggest that androgens activity may influence testicular cancer risk.
Assuntos
Alopecia/complicações , Androgênios/fisiologia , Cabelo , Neoplasias Embrionárias de Células Germinativas/etiologia , Neoplasias Testiculares/etiologia , Adolescente , Adulto , Estudos de Casos e Controles , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: A combination of aprepitant, a 5-HT3 receptor antagonist (r.a.), and dexamethasone is recommended for the prophylaxis of cisplatin-induced nausea and vomiting in the acute phase, and aprepitant + dexamethasone (A + D) in the delayed phase. The aim of this study was to verify if A + D is superior to metoclopramide plus dexamethasone (M + D) in preventing delayed emesis in cancer patients receiving the same prophylaxis for acute emesis. PATIENTS AND METHODS: A randomized double-blind study comparing A + D versus M + D was completed in previously untreated cancer patients. Before chemotherapy, all patients were treated with intravenous palonosetron 0.25 mg and dexamethasone 12 mg, and oral aprepitant 125 mg. On day 2-4, patients randomly received oral dexamethasone 8 mg plus aprepitant 80 mg once daily (days 2-3) or metoclopramide 20 mg four times daily plus dexamethasone 8 mg bid. Primary endpoint was rate of complete response (no vomiting, no rescue treatment) in day 2-5 after chemotherapy. RESULTS: Due to difficulty in the accrual of patients, 303 of the 480 planned patients were enrolled, 284 were fully evaluable, 147 receiving A + D, 137 M + D. Day 1 results were similar in both arms. On day 2-5, complete response rate was not significantly different (80.3% with A + D versus 82.5% with M + D, P < 0.38, respectively), and all secondary endpoints were also similar (complete protection, total control, no vomiting, no nausea, and score of Functional Living Index-Emesis; P < 0.24). Adverse events incidence was not significantly different between the two treatments. CONCLUSIONS: In cancer patients submitted to cisplatin-based chemotherapy, receiving the same antiemetic prophylaxis for acute emesis, A + D is not superior to M + D in preventing delayed emesis, and both treatments present similar toxicity. CLINICALTRIALSGOV NUMBER: NCT00869310.
Assuntos
Antieméticos/administração & dosagem , Antineoplásicos/efeitos adversos , Cisplatino/efeitos adversos , Dexametasona/administração & dosagem , Metoclopramida/administração & dosagem , Morfolinas/administração & dosagem , Náusea/prevenção & controle , Vômito/prevenção & controle , Atividades Cotidianas , Administração Intravenosa , Administração Oral , Adolescente , Adulto , Idoso , Antieméticos/efeitos adversos , Aprepitanto , Dexametasona/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Combinação de Medicamentos , Feminino , Humanos , Isoquinolinas/administração & dosagem , Itália , Masculino , Pessoa de Meia-Idade , Morfolinas/efeitos adversos , Náusea/induzido quimicamente , Náusea/psicologia , Palonossetrom , Qualidade de Vida , Quinuclidinas/administração & dosagem , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Vômito/induzido quimicamente , Vômito/psicologia , Adulto JovemRESUMO
BACKGROUND: Osteonecrosis of the jaw (ONJ) is a chronic complication of bisphosphonate therapy, mainly when intravenous, in cancer patients with bone metastases and myeloma. Its pathophysiology is not yet fully elucidated; in particular, the molecular/cellular events triggering ONJ remain unclear. This complication could result from the effect of bisphosphonates released from bone into the soft-tissues, or from osteolysis induced by soft-tissues directly exposed to bisphosphonates. This research investigated the possibility that ONJ may be evocated by changes induced in osteoblast activity by factors released by soft-tissue cells exposed to zoledronic acid. METHODS: An 'in vitro' model was used, in which human osteoblast-like MG-63 cells were grown in medium conditioned by human keratinocytes NCTC 2544, exposed or not to zoledronic acid (5 or 50 µM); 5 µM zoledronic acid was also directly administered to MG-63 cells. RESULTS: In NCTC 2544 cells, zoledronic acid decreased proliferation via decreased hydroxy-3-methyl-glutaryl-CoA reductase, suggesting that a decrease in healing capability can occur in case of injury. An increased pro-inflammatory potential was also observed. Osteoblasts grown in medium conditioned in the presence of zoledronic acid showed decreased proliferation and osteogenic properties, and increased ability to induce osteoclast differentiation and inflammatory process. Zoledronic acid directly administered to MG-63 modulated only some parameters and in a lesser extent. CONCLUSIONS: The research evidenced, for the first time, the direct involvement of epithelial cells in zoledronic acid-triggered molecular mechanisms leading to osteonecrosis of the jaw, by modulating both osteoblast and osteoclast properties.
Assuntos
Conservadores da Densidade Óssea/farmacologia , Difosfonatos/farmacologia , Imidazóis/farmacologia , Queratinócitos/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos , Comunicação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Técnicas de Cocultura , Células Epiteliais/efeitos dos fármacos , Humanos , Hidroximetilglutaril-CoA Redutases/metabolismo , Ácido ZoledrônicoRESUMO
BACKGROUND: MEK is activated in â¼40% colorectal cancer (CRC) and 20-30% non-small cell lung cancer (NSCLC). Selumetinib is a selective inhibitor of MEK1/2, which is currently in clinical development. METHODS: We evaluated the effects of selumetinib in vitro and in vivo in CRC and NSCLC cell lines to identify cancer cell characteristics correlating with sensitivity to MEK inhibition. RESULTS: Five NSCLC and six CRC cell lines were treated with selumetinib and classified according to the median inhibitory concentration (IC(50)) values as sensitive (≤1 µM) or resistant (>1 µM). In selumetinib-sensitive cancer cell lines, selumetinib treatment induced G1 cell-cycle arrest and apoptosis and suppression of tumour growth as xenografts in immunodeficient mice. Evaluation of intracellular effector proteins and analysis of gene mutations showed no correlation with selumetinib sensitivity. Microarray gene expression profiles revealed that the activation of cAMP-dependent protein kinase A (PKA) was associated with MEK inhibitor resistance. Combined targeting of both MEK and PKA resulted in cancer cell growth inhibition of MEK inhibitor-resistant cancer cell lines in vitro and in vivo. CONCLUSION: This study provides molecular insights to explain resistance to an MEK inhibitor in human cancer cell lines.
Assuntos
Benzimidazóis/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Neoplasias Pulmonares/tratamento farmacológico , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos , Ativação Enzimática/efeitos dos fármacos , Perfilação da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia , Mutação , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Osteonecrosis of the jaw (ONJ) is associated with bisphosphonate (BP) therapy and invasive dental care. An Interdisciplinary Care Group (ICG) was created to evaluate dental risk factors and the efficacy of a preventive restorative dental care in the reduction of ONJ risk. PATIENTS AND METHODS: This prospective single-center study included patients with bone metastases from solid tumors. Patients who received at least one BP infusion between October 2005 and 31 August 2009 underwent one or more ICG evaluation and regular dental examinations. We also retrospectively evaluated patients with bone metastases from solid tumors who did not undergo dental preventive measures. RESULTS: Of 269 patients, 211 had received at least one infusion of BP therapy: 62% were BP naive and 38% had previous BP exposure. Of these 211 patients followed for 47 months, 6 patients developed ONJ (2.8%). Of 200 patients included in the retrospective analysis, 11 patients developed ONJ (5.5%). CONCLUSIONS: In comparison with published ONJ rates and those extrapolated from the retrospective analysis, the observed ONJ rate in the prospective group was lower, suggesting that implementation of a preventive dental program may reduce the risk of ONJ in metastatic patients treated with i.v. BP therapy.
Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/prevenção & controle , Conservadores da Densidade Óssea/efeitos adversos , Assistência Odontológica/métodos , Difosfonatos/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
The papillary thyroid microcarcinoma (PTMC) is a subtype of the papillary thyroid carcinoma (PTC) 1 cm or less in diameter, bilateral and multifocal in a percentage of 15-20%. We describe our experience on the surgical treatment of 217 patient treated between 2005 and 2008. Our therapeutic algorithm for PTMC includes always total thyroidectomy with surgical exploration of the median cervical compartment and recurrent laryngeal nerve lymph node dissection, reserving the median lymph node dissection only to the cases with pathological lymph nodes and the lateral compartment lymphectomy to the cases that show suspect nodes with or without positive cytology. We usually perform total thyroidectomy rather than partial one, in relation to the high rate of multifocality of papillary microcarcinoma, to reduce rate of recurrencies and to better utilize I131 with diagnostic and curative aims. Complete central compartment dissection is mandatory when pathological nodes are present at surgical exploration. It prevents nodal recurrencies and decrease number of re-operations, that have a greater number of complications or morbidity, including hypoparathyroidism and inferior laryngeal nerve lesions. The rate of nodal metastases is not affected by the site of primitive tumor, but the tumor size does. The rate of nodal metastases varies from 55.7% for tumors 5 mm or less in diameter, to 73.7% for tumors sized from 5 to 10 mm, and is affected from the capsular infiltration, the presence of multiple foci, and the histological type, i.e. sclerosing type. All patients presenting papillary microcarcinoma with invasion of the capsule and extension to the perithyroid tissues, sclerosing histological type, multifocal and/or metastatic to the regional nodes, were treated with radiometabolic therapy and suppressing l-tiroxin administration, according to the guidelines of the Multidisciplinary Group for the Thyroid Cancer of our Institution.
Assuntos
Carcinoma/cirurgia , Neoplasias da Glândula Tireoide/cirurgia , Adulto , Idoso , Carcinoma Papilar , Humanos , Pessoa de Meia-Idade , Câncer Papilífero da Tireoide , Tireoidectomia , Adulto JovemRESUMO
AIMS: Several randomised trials have tested adjuvant regimens using concomitant high-dose cisplatin and radiotherapy to improve outcome in high-risk locally advanced squamous cell head and neck cancer (HNSCC), showing a substantial increase in locoregional control and disease-free survival, despite a higher and eventually detrimental toxicity profile. The aim of the present phase II single-stage prospective study was to investigate whether a weekly cisplatin-based chemoradiotherapy regimen might be able to improve patients' compliance compared with standard-dose cisplatin with similar outcome results. MATERIALS AND METHODS: Between January 2004 and November 2008, 54 patients with high-risk locally advanced HNSCC were enrolled on to this phase II trial. Patient characteristics were: median age 59.7 years, Eastern Cooperative Oncology Group performance status 1 in 72% of patients and stage IV disease in 82%, extracapsular nodal spread in 67% and positive/close surgical margins in 37%. Patients received cisplatin (30 mg/m(2)) once a week for 7-8 weeks concurrent with external beam radiotherapy delivered with a median dose of 66.6 Gy (1.8 Gy each day; five fractions/week) on the primary site and 50 Gy (2 Gy each day) for the lower neck. RESULTS: Major acute toxicity of the combined treatment, defined as grade 3-4 mucositis, was observed in 35.2% of patients. No fatal complications occurred, with 81.5% of patients completing the planned regimen. Late reactions were mild (total 16% with a grade 3 dysphagia rate of 12%). The locoregional control rate was 82%; 5 year overall and disease-free survival were 63 and 62%, respectively. CONCLUSIONS: Concomitant adjuvant chemoradiotherapy with weekly cisplatin seems to be a feasible and well-tolerated therapeutic approach in 'unfit' patients. Clinical results seem to be at least comparable with those previously reported. However, to draw any definitive conclusion, large confirmatory phase III randomised trials are demanded.
Assuntos
Antineoplásicos/administração & dosagem , Cisplatino/administração & dosagem , Cooperação do Paciente/estatística & dados numéricos , Adulto , Idoso , Carcinoma/tratamento farmacológico , Carcinoma/radioterapia , Carcinoma de Células Escamosas , Quimioterapia Adjuvante , Esquema de Medicação , Estudos de Viabilidade , Feminino , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias de Células Escamosas/tratamento farmacológico , Neoplasias de Células Escamosas/radioterapia , Estudos Prospectivos , Radioterapia Adjuvante , Medição de Risco , Carcinoma de Células Escamosas de Cabeça e Pescoço , Resultado do Tratamento , Adulto JovemRESUMO
Crohn's disease is a chronic intestinal inflammation which can involve all the gastrointestinal tract, but it prefers the terminal ileum and ascendant colon. It is often associated with autoimmunity systemic findings (oral ulcer, arthritis). Behçet's disease is a systemic vasculitis of the small vessels. Its intestinal involvement causes bleeding diarrhoea until possible perforation. It's not easy clinically to distinguish between Behçet's colitis and Crohn's disease. We describe a case report in which the problem of differential diagnosis is still open after two years from the first findings.
Assuntos
Síndrome de Behçet/diagnóstico , Doença de Crohn/diagnóstico , Adulto , Síndrome de Behçet/complicações , Colite/diagnóstico , Doença de Crohn/complicações , Diagnóstico Diferencial , Feminino , Humanos , Úlceras Orais/etiologiaRESUMO
Mammalian target of rapamycin (mTOR) is a key protein kinase controlling signal transduction from various growth factors and upstream proteins to the level of mRNA translation and ribosome biogenesis, with pivotal regulatory effects on cell cycle progression, cellular proliferation and growth, autophagy and angiogenesis. The mTOR pathway, and its upstream regulators in the PI3K/PTEN/AKT cascade, are altered in a variety of experimental and human malignancies.This has led to the prediction that mTOR inhibitors may be used as anticancer agents. With the recent approval of two mTOR-targeted drugs (temsirolimus and everolimus) for the treatment of renal cell carcinoma and mantle cell lymphoma, this paradigm has been effectively translated into the clinical setting. In this review, we discuss mTOR biology and regulation, the mode of action of mTOR inhibitors as anti-cancer agents, and current clinical evidence supporting the use of rapamycin-like mTOR inhibitors in cancer treatment.
Assuntos
Antineoplásicos/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Proteínas Serina-Treonina Quinases/efeitos dos fármacos , Antineoplásicos/farmacologia , Humanos , Serina-Treonina Quinases TORRESUMO
The neuroendocrine carcinoma of the breast is a very rare tumor. In this paper we describe our experience in 10 cases of neuroendocrine carcinoma of the breast, and an integrated diagnostic-therapeutic proposal for this tumor. Since no positive association has been shown between neuroendocrine differentiation and tumor size, staging, grading, survival and therefore prognosis, we consider that surgical therapy for neuroendocrine tumors of the breast should be the same as that performed in common invasive histotypes. Due to the presence of specific cellular receptors in neuroendocrine tumors of the breast, somatostatin has been claimed as a useful tool both for diagnostic (Octreoscan) and therapy (for metastatic disease). As for therapy, synthetic analogs show advantages versus native somatostatin, because of a longer half-life, and data from literature report encouraging results obtained by using radiolabelled somatostatin analogs. One of these is 90 Y-Dotatoc; we have already used it in patients with neuroendocrine tumors of the lung. Our algorithm for neuroendocrine tumors of the breast includes diagnostic scintigraphy with Octreoscan and receptor-mediated radiolabelled therapy with 90 Y-Dotatoc in patients with confirmed scintigraphic expression of somatostatin receptors in tumoral tissue.
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/terapia , Carcinoma Neuroendócrino/terapia , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Biomarcadores Tumorais/análise , Biópsia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/metabolismo , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/metabolismo , Feminino , Humanos , Mastectomia/métodos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Octreotida/análogos & derivados , Cintilografia , Receptores de Somatostatina/análise , Estudos Retrospectivos , Resultado do Tratamento , Radioisótopos de ÍtrioRESUMO
BACKGROUND: A phase II study was carried out to investigate an induction regimen with cisplatin, paclitaxel followed by radiotherapy concurrent with weekly cisplatin for locally advanced squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: Stage III-IV disease patients were eligible. Two cisplatin (100 mg/m2) and paclitaxel (175 mg/m2) courses were administered every 21 days followed by standard fractionated external beam radiotherapy (approximately 70 Gy), concomitant to weekly cisplatin (30 mg/m2). RESULTS: Thirty-five patients were enrolled: over 70% had unresectable disease with bulky lesions. Grade 3-4 neutropenia developed in 14% and G3 mucositis in 23%. Locoregional control was achieved in 51%. Median time to progression and overall survival were 10,7 and 17 months respectively; 2- and 3-year survival rates were 30% and 25% respectively. CONCLUSION: Our induction two-drug regimen followed by chemoradiotherapy with concurrent weekly cisplatin was well tolerated with low acute toxicity and good locoregional control and survival rate.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Escamosas/patologia , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Terapia Combinada , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Indução de Remissão , Resultado do TratamentoRESUMO
Lung cancer is a widespread disease and its incidence is growing. Since therapies have increased the life expectancy of lung cancer patients, the development of bone osteolytic metastases is becoming a common cause of morbidity. Osteolysis is caused by an increased osteoclast activity and may be reduced by inhibiting their formation and activity. We studied 60 male patients affected by NSCLC, divided in early and advanced stage disease. Patients' blood and urinary samples were collected at tumor diagnosis and at follow-up. PBMCs were cultured to investigate the spontaneous osteoclastogenesis. IL-7 was dosed in serum and its quantitative gene expression was evaluated on tumor and healthy tissues by RQ-PCR. Both at diagnosis and follow-up, osteolytic bone patients showed high spontaneous osteoclastogenesis level compared to non-bone metastatic and healthy controls. The presence of spontaneous osteoclastogenesis correlated with urinary crosslinks increase. Serum IL-7 levels were higher in bone metastatic patients than in patients without bone lesions and healthy controls. The serum IL-7 increase correlated with the osteoclastogenesis and, at least in part, depended on an increased IL-7 production by tumor cells. At follow-up, patients with increased osteoclastogenesis and serum IL-7 levels, were subjected to standard clinical analysis, which showed early secondary bone lesions. The in vitro assay for spontaneous osteoclastogenesis and serum IL-7 dosage could be useful for diagnostic purposes and it might be able to monitor cancer patients with a high risk to develop osteolytic metastases at follow-up, especially after a curative treatment.
Assuntos
Neoplasias Ósseas/secundário , Carcinoma Pulmonar de Células não Pequenas/secundário , Neoplasias Pulmonares/patologia , Osteoclastos/citologia , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/mortalidade , Reabsorção Óssea , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Expressão Gênica , Humanos , Interleucina-17/sangue , Interleucina-17/genética , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Relapsed or refractory adult acute lymphoblastic leukemias (ALL) have poor prognosis. The strategy for treating these patients is through reinduction chemotherapy followed by allogeneic stem cell transplantation, provided that the toxicity of the salvage regimen is acceptable. Twenty three patients with relapsed/refractory adult ALL were treated with fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-IDA). Five patients had primary refractory disease, and 18 were in first relapse. Nine (39.1%) patients achieved complete remission (CR) following salvage therapy, whereas 13 (56.5%) patients were refractory, and one patient died in aplasia due to infection. In patients achieving remission, the median time to reach absolute neutrophil count (ANC) more than 0.5x10(9)/l and 1x10(9)/l was 20 (range 16-25) and 24 (range 20-28) days from the start of chemotherapy, respectively. Platelet levels of more than 20x10(9)/l and 100x10(9)/l were achieved in a median time of 23 (range 19-25) and 33 (range 28-39) days, respectively. Fever more than 38.5 degrees C was observed in 18 of 23 patients (78.2%), 13 had fever of unknown origin, and 5 had documented infections. Nonhematological side effects, consisting mainly of mucositis (18/23 or 78.2%) and transient liver toxicity increase (10/23 or 43.4%), were generally tolerated. All nine patients who achieved CR received a second course with FLAG-IDA, and seven patients underwent allogeneic stem cell transplantation (four from a matched donor, one from a mismatched donor, and two from an unrelated donor), while two did not reach that stage due to early relapse from CR. The median overall survival (OS) for all 23 patients was 4.5 (range 1-38) months; for the nine responders, the disease-free survival (DFS) and the OS were 6 (range 3-38) and 9 (7-38) months, respectively; the seven patients who received allogeneic stem cell transplantation had a DFS of 10 (range 7-38) months. In our experience, FLAG-IDA is a well-tolerated regimen in relapsed/refractory ALL patients; the toxicity is acceptable, enabling patients who have achieved CR to receive allogeneic transplantation.