RESUMO
Immune checkpoint blockade has provided a paradigm shift in cancer therapy, but the success of this approach is very variable; therefore, biomarkers predictive of clinical efficacy are urgently required. Here, we show that the frequency of PD-1+CD8+ T cells relative to that of PD-1+ regulatory T (Treg) cells in the tumor microenvironment can predict the clinical efficacy of programmed cell death protein 1 (PD-1) blockade therapies and is superior to other predictors, including PD ligand 1 (PD-L1) expression or tumor mutational burden. PD-1 expression by CD8+ T cells and Treg cells negatively impacts effector and immunosuppressive functions, respectively. PD-1 blockade induces both recovery of dysfunctional PD-1+CD8+ T cells and enhanced PD-1+ Treg cell-mediated immunosuppression. A profound reactivation of effector PD-1+CD8+ T cells rather than PD-1+ Treg cells by PD-1 blockade is necessary for tumor regression. These findings provide a promising predictive biomarker for PD-1 blockade therapies.
Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Inibidores de Checkpoint Imunológico/farmacologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Antígenos/química , Antígenos/imunologia , Biomarcadores Tumorais , Antígenos CD28/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunomodulação , Ativação Linfocitária/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Terapia de Alvo Molecular , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias/tratamento farmacológico , Neoplasias/etiologia , Neoplasias/metabolismo , Neoplasias/mortalidade , Peptídeos/química , Peptídeos/imunologia , Prognóstico , Receptor de Morte Celular Programada 1/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Linfócitos T Reguladores/efeitos dos fármacos , Resultado do Tratamento , Microambiente Tumoral/imunologiaRESUMO
BACKGROUND: Few studies have focused on the impact of single-organ pulmonary metastases on progression-free survival and overall survival in patients with metastatic colorectal cancer. Recognizing differences in prognosis and chemotherapeutic efficacy based on metastasized organs may help in optimizing treatment strategies. The exploratory study was conducted to evaluate the comparative clinical outcomes and prognoses of patients with metastatic colorectal cancer presenting with single-organ pulmonary metastases and treated with folinic acid, 5-fluorouracil, irinotecan, and vascular endothelial growth factor inhibitors as second-line chemotherapy. METHODS: This retrospective study included 289 patients with metastatic colorectal cancer treated with second-line folinic acid, 5-fluorouracil, irinotecan, and vascular endothelial growth factor inhibitors. The response rate, disease control rate, progression-free survival, and overall survival were assessed in the participants. RESULTS: Among the 289 patients enrolled, 26 (9.0%) had single-organ pulmonary metastasis with left-sided primary locations, lower levels of tumor markers at the initiation point of chemotherapy, a significantly higher disease control rate (96.2% vs. 76.7%, P = .02), and a longer progression-free survival (median 29.6 months vs. 6.1 months, P < .001) and overall survival (median 41.1 months vs. 18.7 months, P < .001) than patients with other forms of metastatic colorectal cancer. Multivariate analysis showed that single-organ pulmonary metastasis was an independent predictor of longer progression-free survival (hazard ratio 0.35, P = .00075) and overall survival (hazard ratio 0.2, P = .006). CONCLUSION: Single-organ pulmonary metastasis was a strong predictor of progression-free survival and overall survival in patients with metastatic colorectal cancer treated with folinic acid, 5-fluorouracil, irinotecan, and vascular endothelial growth factor inhibitors as second-line chemotherapy; this provides preliminary evidence for medical guidelines and clinical decision-making on novel therapeutic strategies for these patients.
Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Pulmonares , Neoplasias Retais , Humanos , Irinotecano/uso terapêutico , Neoplasias Colorretais/patologia , Fator A de Crescimento do Endotélio Vascular , Camptotecina , Prognóstico , Leucovorina , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Fluoruracila , Neoplasias do Colo/tratamento farmacológico , Neoplasias Retais/tratamento farmacológico , Neoplasias Pulmonares/etiologia , Metástase Neoplásica/tratamento farmacológicoRESUMO
PD-1 blockade is a cancer immunotherapy effective in various types of cancer. In a fraction of treated patients, however, it causes rapid cancer progression called hyperprogressive disease (HPD). With our observation of HPD in â¼10% of anti-PD-1 monoclonal antibody (mAb)-treated advanced gastric cancer (GC) patients, we explored how anti-PD-1 mAb caused HPD in these patients and how HPD could be treated and prevented. In the majority of GC patients, tumor-infiltrating FoxP3highCD45RA-CD4+ T cells [effector Treg (eTreg) cells], which were abundant and highly suppressive in tumors, expressed PD-1 at equivalent levels as tumor-infiltrating CD4+ or CD8+ effector/memory T cells and at much higher levels than circulating eTreg cells. Comparison of GC tissue samples before and after anti-PD-1 mAb therapy revealed that the treatment markedly increased tumor-infiltrating proliferative (Ki67+) eTreg cells in HPD patients, contrasting with their reduction in non-HPD patients. Functionally, circulating and tumor-infiltrating PD-1+ eTreg cells were highly activated, showing higher expression of CTLA-4 than PD-1- eTreg cells. PD-1 blockade significantly enhanced in vitro Treg cell suppressive activity. Similarly, in mice, genetic ablation or antibody-mediated blockade of PD-1 in Treg cells increased their proliferation and suppression of antitumor immune responses. Taken together, PD-1 blockade may facilitate the proliferation of highly suppressive PD-1+ eTreg cells in HPDs, resulting in inhibition of antitumor immunity. The presence of actively proliferating PD-1+ eTreg cells in tumors is therefore a reliable marker for HPD. Depletion of eTreg cells in tumor tissues would be effective in treating and preventing HPD in PD-1 blockade cancer immunotherapy.
Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Nivolumabe/efeitos adversos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Gástricas/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Idoso , Animais , Antígeno CTLA-4/metabolismo , Progressão da Doença , Humanos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Masculino , Camundongos , Neoplasias Gástricas/tratamento farmacológico , Linfócitos T Reguladores/metabolismoRESUMO
Six strains of Gram-stain-negative, obligately anaerobic, non-spore-forming, non-motile rods were isolated from human faeces. Based on phylogenetic characteristics, the six isolates were included in the family Ruminococcaceae, and divided into three groups. The six isolates showed 16S rRNA gene sequence similarity values lower than 96.2â% to the closely related species, Oscillibacter ruminantium GH1T, Oscillibacter valericigenes Sjm18-20T and Dysosmobacter welbiomis J115T. Coherently with the 16S rRNA gene sequence results, the in silico DNA-DNA hybridization and average nucleotide identity values clearly indicated that strains MM35T, MM50T and MM59T belong to different species from the closely related three species. Based on phenotypic features and phylogenetic positions, three novel species, Vescimonas coprocola gen. nov., sp. nov., Vescimonas fastidiosa gen. nov., sp. nov. and Pusillimonas faecalis gen. nov., sp. nov. are proposed. The type strain of V. coprocola is strain MM50T (=JCM 34012T=DSM 111893T). The type strain of V. fastidiosa is strain MM35T (=JCM 34016T=DSM 111899T). The type strain of P. faecalis is strain MM59T (=JCM 34011T=DSM 111669T). The DNA G+C contents estimated according to the whole genomes of strains MM35T, MM50T and MM59T were 56.4, 58.2 and 55.2 mol%, respectively.
Assuntos
Clostridiales/classificação , Fezes/microbiologia , Filogenia , Técnicas de Tipagem Bacteriana , Composição de Bases , Clostridiales/isolamento & purificação , DNA Bacteriano/genética , Humanos , Hibridização de Ácido Nucleico , RNA Ribossômico 16S/genética , Análise de Sequência de DNARESUMO
BACKGROUND: Pembrolizumab, an anti-PD-1 antibody, results in tumour response in around 15% of patients with advanced gastric cancer who have a PD-L1 combined positive score of at least 1. Lenvatinib, a multikinase inhibitor of VEGF receptors and other receptor tyrosine kinases, substantially decreased tumour-associated macrophages and increased infiltration of CD8 T cells, resulting in enhanced anti-tumour activity of PD-1 inhibitors in an in-vivo model. We aimed to assess the combination of lenvatinib plus pembrolizumab in patients with advanced gastric cancer in a phase 2 study. METHODS: This study was an open-label, single-arm, phase 2 trial undertaken at the National Cancer Center Hospital East (Chiba, Japan). Eligible patients were aged 20 years or older and had metastatic or recurrent adenocarcinoma of the stomach or gastro-oesophageal junction, an Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1), irrespective of the number of previous lines of treatment. Patients received 20 mg oral lenvatinib daily plus 200 mg intravenous pembrolizumab every 3 weeks until disease progression, development of intolerable toxicity, or withdrawal of consent. The primary endpoint was objective response rate according to RECIST, analysed in all patients who were eligible and received protocol treatment at least once. The safety analysis included all those who received protocol treatment at least once, regardless of eligibility. This study is registered at ClinicalTrials.gov, NCT03609359, and enrolment is complete. FINDINGS: Between Oct 15, 2018, and March 25, 2019, 29 patients were enrolled in the first-line or second-line settings. At data cutoff (March 20, 2020), the median follow-up was 12·6 months (IQR 10·5-14·3). 20 (69%, 95% CI 49-85) of 29 patients had an objective response. The most common grade 3 treatment-related adverse events were hypertension (in 11 [38%] patients), proteinuria (five [17%]), and platelet count decrease (two [7%]). No grade 4 treatment-related adverse events, serious treatment-related adverse events, or treatment-related deaths occurred. INTERPRETATION: Lenvatinib plus pembrolizumab showed promising anti-tumour activity with an acceptable safety profile in patients with advanced gastric cancer. On the basis of these results, a confirmatory trial will be planned in the future. FUNDING: Merck Sharp & Dohme.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Quinolinas/administração & dosagem , Quinolinas/efeitos adversosRESUMO
BACKGROUND: Although regorafenib or trifluridine/tipiracil (FTD/TPI) has been recognized as a later-line standard treatment in patients with metastatic colorectal cancer (mCRC), not all patients have beneficial outcomes. This study aimed to develop a prognostic scoring system for evaluating the overall survival (OS) benefit. METHODS: Patients included in the REGOTAS study, which comprised 489 patients (regorafenib group: 199; FTD/TPI group: 290 patients), were evaluated. OS was analyzed using multivariate Cox proportional model. The prognostic score was calculated using the worst four individual factors weighted by hazard ratio, and the total scores were categorized as low-, moderate-, and high-OS benefit. RESULTS: The worst four factors in the regorafenib group were AST > 40 IU/dL (point, + 3), CRP ≥ 1.0 mg/dL (+ 2), number of metastatic organ site ≥ 3 (+ 2), and duration from initiation of 1st-line chemotherapy < 18 months (+ 2), while they were AST (+ 2), CRP (+ 2), CA19-9 > 37.0 U/mL (+ 2), and ECOG PS ≥ 1 (+ 2) in the FTD/TPI group. These corresponded to a total prognostic score of > 5, 2-4, and 0 points in the regorafenib group and 8, 2-6, and 0 points in the FTD/TPI group. The median OS in the low, moderate, and high OS benefit group was 3.3 (95% CI 3.0-3.7), 8.1 (95% CI 6.4-9.7), and 12.6 months (95% CI 10.6-14.6) in the regorafenib group and 2.8 (95% CI 2.0-3.5), 7.5 (95% CI 6.6-8.3), and 15.4 months (95% CI 9.7-21.2) in the FTD/TPI group. CONCLUSION: These prognostic scores are useful for identifying patients with mCRC who will obtain survival benefits from these drugs.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Compostos de Fenilureia/uso terapêutico , Piridinas/uso terapêutico , Pirrolidinas/uso terapêutico , Trifluridina/uso terapêutico , Uracila/análogos & derivados , Idoso , Neoplasias Colorretais/patologia , Combinação de Medicamentos , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos , Timina , Resultado do Tratamento , Uracila/uso terapêuticoRESUMO
In Japan, the social (medical) health-care system is on the way to being developed to advance personalized medicine through the implementation of cancer genomic medicine, known as "cancer clinical sequencing," which uses a next-generation sequencer. However, no Japanese guidance for cancer genomic testing exists. Gene panel testing can be carried out to help determine patient treatment, confirm diagnosis, and evaluate prognostic predictions of patients with mainly solid cancers for whom no standard treatment is available. This guidance describes how to utilize gene panel testing according to the type of cancer: childhood cancer, rare cancer, carcinoma of unknown primary, and other cancers. The level of evidence classification for unified use in Japan is also detailed. This guidance establishes the basic principles of the quality control of specimens, requirements of medical institutions, informed consent, handling of data during the postanalysis stage, and treatment options based on the evidence level. In Japan, gene panel testing for cancer treatment and diagnosis is recommended to comply with this guidance. This is a collaborative work of the Japanese Society of Medical Oncology, Japan Society of Clinical Oncology, and the Japanese Cancer Association.
Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Neoplasias/genética , Guias de Prática Clínica como Assunto , Humanos , Consentimento Livre e Esclarecido , Neoplasias/diagnóstico , Neoplasias/terapia , Controle de QualidadeRESUMO
BACKGROUND: This study compared the efficacy of regorafenib and trifluridine/tipiracil (TFTD) in patients with metastatic colorectal cancer (mCRC) who are refractory to standard chemotherapy, because despite their clinical approval, it still remains unclear which of these two drugs should be used as initial treatment. MATERIALS AND METHODS: The clinical data of patients with mCRC who were treated with regorafenib or TFTD and those of drug-naive patients, between June 2014 and September 2015, were retrospectively collected from 24 institutions in Japan. Overall survival (OS) was evaluated using the Cox's proportional hazard models based on propensity score adjustment for baseline characteristics. RESULTS: A total of 550 patients (223 patients in the regorafenib group and 327 patients in the TFTD group) met all criteria. The median OS was 7.9 months (95% confidence interval [CI], 6.8-9.2) in the regorafenib group and 7.4 months (95% CI, 6.6-8.3) in the TFTD group. The propensity score adjusted analysis showed that OS was similar between the two groups (adjusted hazard ratio [HR], 0.96; 95% CI, 0.78-1.18). In the subgroup analysis, a significant interaction with age was observed. Regorafenib showed favorable survival in patients aged <65 years (HR, 1.29; 95% CI, 0.98-1.69), whereas TFTD was favored in patients aged ≥65 years (HR, 0.78; 95% CI, 0.59-1.03). CONCLUSION: No significant difference in OS between regorafenib and TFTD was observed in patients with mCRC. Although the choice of the drug by age might affect survival, a clearly predictive biomarker to distinguish the two drugs should be identified in further studies. IMPLICATIONS FOR PRACTICE: Previous studies of patients with metastatic colorectal cancer refractory to standard chemotherapy had demonstrated that both regorafenib and trifluridine/tipiracil could result in increased overall survival compared with placebo, but there are no head-to-head trials. This large, multicenter, observational study retrospectively compared the efficacy of regorafenib and trifluridine/tipiracil in 550 patients with metastatic colorectal cancer refractory to standard chemotherapy who had access to both drugs. Although no difference in overall survival was found between the two drugs in adjusted analysis using propensity score, regorafenib showed favorable survival in patients aged <65 years, whereas trifluridine/tipiracil was favored in patients aged ≥65 years in the subgroup analysis.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Terapia de Salvação , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/secundário , Neoplasias Colorretais/patologia , Combinação de Medicamentos , Feminino , Seguimentos , Humanos , Japão , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/administração & dosagem , Prognóstico , Pontuação de Propensão , Piridinas/administração & dosagem , Pirrolidinas , Estudos Retrospectivos , Taxa de Sobrevida , Timina , Trifluridina/administração & dosagem , Uracila/análogos & derivadosRESUMO
BACKGROUND: Ramucirumab has recently proved to be effective for advanced or recurrent gastric cancer (AGC). Ascites and peritoneal metastasis are among the most common complications of AGC. However, there are few data on the safety and efficacy of paclitaxel plus ramucirumab in patients with AGC with ascites. The purpose of this retrospective study was to evaluate the safety and efficacy of paclitaxel plus ramucirumab in patients with AGC with ascites. METHODS: We retrospectively evaluated the safety and efficacy of paclitaxel plus ramucirumab in patients with AGC with ascites in comparison with patients without ascites in a single institution from June 2015 to May 2016. The median progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method, and differences evaluated using the Log-lank test. The differences in baseline characteristics and response rates of each ascites group were calculated for homogeneity by chi-square tests and for trends by Fisher's exact test. RESULTS: Eighty-three patients were analyzed in this study. Ascites was detected in 40 patients, 26 patients (31%) had small to moderate ascites and 14 (17%) had massive ascites. The proportion of patients who started with a reduced dose of paclitaxel was higher for patients with massive ascites than others. The frequencies of any grade 3 or 4 hematological toxicity were 51% in patients without ascites, 77% in patients with small to moderate ascites, and 71% in patients with massive ascites. The frequencies of common ramucirumab-related adverse events were also not significantly different among ascites groups, however one patient had a tumor hemorrhage, and one patient had a gastrointestinal perforation. PFS and OS were shorter in patients with massive ascites than in patients with small or moderate ascites or patients without ascites. CONCLUSIONS: The use of paclitaxel and ramucirumab in patients with AGC with large amounts of ascites was tolerable with adequate dose modification. However, we should pay attention to the risks of ramucirumab-related toxicity in patients with bleeding tumors or intestinal stenosis.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Paclitaxel/administração & dosagem , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Ascite/patologia , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Paclitaxel/efeitos adversos , Estudos Retrospectivos , Neoplasias Gástricas/patologia , RamucirumabRESUMO
BACKGROUND: Although patients with advanced gastric cancer (AGC) have a poor prognosis when conventional therapies fail, they are often candidates for phase I trials. However, there is no detailed report on clinical outcomes of patients with AGC treated in phase I trials. METHODS: We retrospectively reviewed the medical records of 66 consecutive patients with AGC enrolled in phase I trials between March 2008 and July 2014 at our institution in Japan. RESULTS: Median age was 66 years (range, 28-78 years) and median number of previous lines of conventional chemotherapy was 3 (range, 1-6). Five (8.6 %) and seven (12 %) patients showed objective response and stable disease >3 months, respectively. Although the time to treatment failure (TTF) of the best phase I treatment was shorter than that of the last line of conventional chemotherapy (median 1.5 vs. 2.3 months; P = 0.002), TTF of the best phase I treatment was longer than that of the last line of treatment in 21 patients (32 %). Severe adverse events and grade 3 or higher toxicities were reported in eight (12 %) and 13 patients (20 %), respectively. No treatment-related death was observed. Median survival time from the start of phase I treatment was 7.5 months, and four deaths (6 %) within 30 days after last administration were observed. CONCLUSION: Phase I trials of patients with AGC was acceptably feasible with some efficacy signal. Our results suggest that phase I trials might be one treatment option for patients with AGC when conventional therapies fail.
Assuntos
Ensaios Clínicos Fase I como Assunto , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Biópsia , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estômago/patologia , Resultado do TratamentoRESUMO
BACKGROUND: The mutation in KRAS exon 2 is a validated biomarker of resistance to anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer (mCRC). Several reports have confirmed associations of other RAS mutations with resistance to anti-EGFR therapy. However, the impact of BRAF and PIK3CA mutations on the efficacy of anti-EGFR therapy remains controversial. Little is known about the frequencies and clinicopathological features of these mutations, as well as the therapeutic effects of anti-EGFR therapy in mCRC patients with these mutations, especially in the Asian population. METHODS: In this retrospective observational study, frequencies and clinicopathological features of KRAS, NRAS, BRAF and PIK3CA mutations were evaluated in patients with mCRC. Among patients treated with anti-EGFR therapy, objective response, progression-free survival (PFS), and overall survival (OS) were evaluated according to gene status. RESULTS: Among 264 patients, mutations in KRAS exon 2, KRAS exons 3 or 4, NRAS, BRAF and PIK3CA were detected in 34.1%, 3.8%, 4.2%, 5.4% and 6.4%, respectively. Thus, a total of 12.1% of patients without KRAS exon 2 mutations had other RAS mutations. Primary rectal tumors tended to be more frequently observed in RAS mutant tumors. BRAF mutations were more frequently observed with right-sided colon, poorly differentiated or mucinous adenocarcinoma, and peritoneal metastasis. Among the 66 patients with KRAS exon 2 wild-type tumors treated with anti-EGFR agents, PFS (5.8 vs. 2.2 months) and OS (17.7 vs. 5.2 months) were significantly better in patients with all wild-type tumors (n = 56) than in those with any of the mutations (n = 10). The response rate also tended to be better with all wild-type tumors (26.8 vs. 0%). CONCLUSION: Other RAS and BRAF mutations were observed in KRAS exon 2 wild-type tumors, which were associated with some clinicopathological features and resistance to anti-EGFR therapy in our patient cohort.
Assuntos
Neoplasias Colorretais/genética , GTP Fosfo-Hidrolases/genética , Proteínas de Membrana/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Classe I de Fosfatidilinositol 3-Quinases , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Proteínas Proto-Oncogênicas p21(ras) , Estudos Retrospectivos , Transdução de Sinais , Resultado do TratamentoRESUMO
Of late, there has been rapid development of chemotherapeutic agents for treating metastatic colorectal cancers. However, the so-called "druglag" is a long-standingproblem; it refers to the drugapproval delays in Japan that occur after drugs have been developed and approved in Europe and the USA. Clinical trials for the drugTAS -102 were stopped in the USA, but the drugwas evaluated in phase I and II clinical trials in Japan. The Phase II trial for TAS-102 in Japan provided positive results, and it received approval in Japan first, ahead of the world. Data from the global phase III RECOURSE trial were presented in the ESMO-GI 2014, where the efficacy of TAS-102 was proved again. Herein, we present data about the efficacy and side effects of TAS-102 from each clinical trial.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Trifluridina/uso terapêutico , Uracila/análogos & derivados , Antineoplásicos/efeitos adversos , Ensaios Clínicos como Assunto/efeitos adversos , Combinação de Medicamentos , Humanos , Pirrolidinas , Timina , Uracila/uso terapêuticoRESUMO
The freezing-thawing (F/T) method for fusing giant unilamellar vesicles (GUVs) can provide substrates, enzymes and membrane material simultaneously and repetitively, and is useful for constructing a recursive model of an artificial cell. However, enzymatic efficiency after F/T is reduced due to rupture of the GUVs and leakage of the inner solution during F/T. Previously, liposomes composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and a negatively charged lipid, such as 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (POPG), showed lower rupture and leakage rates during F/T. In this study, we investigated the effect of POPG on the supply of components required for T7 RNA polymerase reactions via F/T by flow cytometry analysis. We found that the addition of POPG to liposome preparations reduced the efficiency of RNA synthesis. In addition, DNA was concentrated during F/T and RNA synthesis occurred after F/T in liposomes composed of POPC and POPG. Our results provide new insights for more efficient supply of substrates and enzymes by the F/T method, thereby increasing the utility of the F/T method for the construction of recursive bioreactors.
Assuntos
Bicamadas Lipídicas , Lipossomos , Congelamento , RNARESUMO
PURPOSE: To investigate circulating tumor DNA (ctDNA) RAS mutant (MT) incidence before salvage-line treatment and the clinicopathological features and molecular biological factors associated with the efficacy of anti-epithelial growth factor receptor (EGFR) monoclonal antibody (mAb) rechallenge for tissue RAS/BRAF wild type (WT) metastatic colorectal cancer (mCRC). METHODS: This multi-institutional retrospective observational study included 74 patients with mCRC with tissue RAS/BRAF WT refractory to first-line chemotherapy containing anti-EGFR mAb. ctDNA RAS status was assessed using the OncoBEAM™ RAS CRC Kit. We explored the clinicopathological features associated with ctDNA RAS status and the factors related to anti-EGFR mAb rechallenge efficacy in multivariate Cox proportional hazard regression. RESULTS: The incidence of RAS MT in ctDNA was 40.5% (30/74), which was associated with primary tumor resection (P = 0.016), liver metastasis (P < 0.001), and high tumor marker levels (P < 0.001). Among the 39 patients treated with anti-EGFR mAb rechallenge, those with ctDNA RAS WT showed significantly longer progression-free survival (PFS) than those with ctDNA RAS MT (median 4.1 vs. 2.7 months, hazard ratio [HR] = 0.39, P = 0.045). Patients who responded to first-line anti-EGFR mAb showed significantly longer PFS (HR = 0.21, P = 0.0026) and overall survival (OS) (HR = 0.23, P = 0.026) than those with stable disease. CONCLUSIONS: The incidence of ctDNA RAS MT mCRC was 40.5%, which was associated with liver metastases and high tumor volumes. Anti-EGFR mAb rechallenge may be effective for patients with mCRC who responded to first-line chemotherapy containing anti-EGFR mAb. No patients with RAS MT in ctDNA responded to anti-EGFR mAb rechallenge.
Assuntos
Neoplasias Colorretais , Receptores ErbB , Proteínas Proto-Oncogênicas B-raf , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/genética , Masculino , Feminino , Proteínas Proto-Oncogênicas B-raf/genética , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Adulto , Idoso de 80 Anos ou mais , Mutação , DNA Tumoral Circulante/genética , Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos Imunológicos/administração & dosagemRESUMO
BACKGROUND: Immune checkpoint inhibitor (ICI) combinations represent an emerging treatment strategies in cancer. However, their efficacy in microsatellite stable (MSS) or mismatch repair-proficient (pMMR) colorectal cancer (CRC) is variable. Here, a multiomic characterization was performed to identify predictive biomarkers associated with patient response to ICI combinations in MSS/pMMR CRC for the further development of ICI combinations. METHODS: Whole-exome sequencing, RNA sequencing, and multiplex fluorescence immunohistochemistry of tumors from patients with MSS/pMMR CRC, who received regorafenib plus nivolumab (REGONIVO) or TAS-116 plus nivolumab (TASNIVO) in clinical trials were conducted. Twenty-two and 23 patients without prior ICI from the REGONIVO and TASNIVO trials were included in this study. A biomarker analysis was performed using samples from each of these studies. RESULTS: The epithelial-mesenchymal transition pathway and genes related to cancer-associated fibroblasts were upregulated in the REGONIVO responder group, and the G2M checkpoint pathway was upregulated in the TASNIVO responder group. The MYC pathway was upregulated in the REGONIVO non-responder group. Consensus molecular subtype 4 was significantly associated with response (p=0.035) and longer progression-free survival (p=0.006) in the REGONIVO trial. CD8+ T cells, regulatory T cells, and M2 macrophages density was significantly higher in the REGONIVO trial responders than in non-responders. Mutations in the POLE gene and patient response were significantly associated in the TASNIVO trial; however, the frequencies of other mutations or tumor mutational burden were not significantly different between responders and non-responders in either trial. CONCLUSIONS: We identified molecular features associated with the response to the REGONIVO and TASNIVO, particularly those related to tumor microenvironmental factors. These findings are likely to contribute to the development of biomarkers to predict treatment efficacy for MSS/pMMR CRC and future immunotherapy combinations for treatment.
Assuntos
Neoplasias Colorretais , Nivolumabe , Humanos , Nivolumabe/farmacologia , Nivolumabe/uso terapêutico , Linfócitos T CD8-Positivos , Multiômica , Imunoterapia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , BiomarcadoresRESUMO
A 81 year-old male patient visited our hospital on February, 2011 because he found the subcutaneous tumor on his back. The dermatologist performed skin biopsy and found that large atypical cells diffusely proliferated in the sub-epidermal and subcutaneous tissue. Two month later, we diagnosed him as blastic plasmacytoid dendritic cell tumor, as the blastic cells in the lymph node were CD4+, CD56+, CD3-, CD5-, CD20-, CD138-, MPO-, granzyme B-, TCL1+. None of the gene rearrangements of T-cell receptor and immunoglobulin was negative in the lymph node. The tumor was relapsed after 3 courses of COP therapy and the patient failed to respond to the salvage therapies such as CEPP and FMD therapy. As this tumor is rare and there are no standard regimens, we reviewed the past case series and discussed about the pathogenesis, clinical course and treatment options of this tumor in this article.
Assuntos
Células Dendríticas/patologia , Neoplasias Cutâneas/patologia , Idoso de 80 Anos ou mais , Biópsia , Evolução Fatal , Humanos , Masculino , Invasividade NeoplásicaRESUMO
Renal impairment may be associated with an increased risk of hematologic events (AEs) in patients undergoing treatment with trifluridine/tipiracil (FTD/TPI). This study aimed to investigate the specific types of AEs linked to renal impairment in patients with metastatic colorectal cancer (mCRC) receiving FTD/TPI, using real-world data. Among the patients included in the REGOTAS study (a retrospective study of FTD/TPI versus regorafenib), those treated with FTD/TPI were evaluated. Creatinine clearance values of < 30, 30-60, 60-90, and > 90 mL/min were defined as severe, moderate, mild renal impairment, and normal renal function, respectively. Renal impairment was analyzed as a risk factor for grade 3 or higher AEs using a logistic regression model. Overall survival (OS) and progression-free survival (PFS) based on renal impairment were evaluated. A total of 309 patients were included in the analysis, with 124, 130, and 55 patients divided into the normal, mild, and moderate-to-severe groups, respectively. The risk of grade 3 or higher neutropenia was significantly higher in the moderate-to-severe group (odds ratio 3.47; 95% confidence interval 1.45-8.30; P = 0.005), but there was no significant increase in the risk of non-hematologic AEs in any of the groups. The OS and PFS of patients in the mild and moderate-to-severe groups were comparable to those in the normal group. Patients with mCRC and moderate/severe renal impairment receiving FTD/TPI therapy may develop severe neutropenia; however, FTD/TPI remains a viable treatment option due to its clinical benefit.
Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Demência Frontotemporal , Neutropenia , Neoplasias Retais , Humanos , Uracila/uso terapêutico , Estudos Retrospectivos , Trifluridina/efeitos adversos , Demência Frontotemporal/tratamento farmacológico , Neoplasias Colorretais/patologia , Timina/uso terapêutico , Pirrolidinas/efeitos adversos , Neoplasias do Colo/tratamento farmacológico , Neoplasias Retais/tratamento farmacológico , Combinação de Medicamentos , Fatores de Risco , Neutropenia/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
The PI3K-Akt-mTOR (PAM) pathway is implicated in tumor progression in many tumor types, including metastatic gastric cancer (GC). The initial promise of PAM inhibitors has been unrealized in the clinic, presumably due, in part, to the up-regulation of Akt signaling that occurs when the pathway is inhibited. Here we present that DIACC3010 (formerly M2698), an inhibitor of two nodes in the PAM pathway, p70S6K and Akt 1/3, blocks the pathway in in vitro and in vivo preclinical models of GC while providing a mechanism that inhibits signaling from subsequent Akt up-regulation. Utilizing GC cell lines and xenograft models, we identified potential markers of DIACC3010-sensitivity in Her2-negative tumors, i.e., PIK3CA mutations, low basal pERK, and a group of differentially expressed genes (DEGs). The combination of DIACC3010 and trastuzumab was evaluated in Her2-positive cell lines and models. Potential biomarkers for the synergistic efficacy of the combination of DIACC3010 + trastuzumab also included DEGs as well as a lack of up-regulation of pERK. Of 27 GC patient-derived xenograft (PDX) models tested in BALB/c nu/nu mice, 59% were sensitive to DIACC3010 + trastuzumab. Of the 21 HER2-negative PDX models, DIACC3010 significantly inhibited the growth of 38%. Altogether, these results provide a path forward to validate the potential biomarkers of DIACC3010 sensitivity in GC and support clinical evaluation of DIACC3010 monotherapy and combination with trastuzumab in patients with HER2- negative and positive advanced GCs, respectively.
Assuntos
Neoplasias Gástricas , Animais , Camundongos , Humanos , Neoplasias Gástricas/tratamento farmacológico , Proteínas Quinases S6 Ribossômicas 70-kDa , Proteínas Proto-Oncogênicas c-akt , Fosfatidilinositol 3-Quinases , Inibidores de Proteínas Quinases , Inibidores da Angiogênese , Modelos Animais de DoençasRESUMO
PURPOSE: Determination of optimal treatment strategies for HER2-positive advanced gastric cancer (AGC) in randomized trials is necessary despite difficulties in direct comparison between trastuzumab deruxtecan (T-DXd) and nivolumab as third or later-line treatments. MATERIALS AND METHODS: This single-institution, retrospective study aimed to describe the real-world efficacy and safety of T-DXd and nivolumab as ≥ third line treatments for HER2-positive AGC between March 2016 and May 2022. Overall, 58 patients (median age, 64 years; 69% male) were eligible for the study (T-DXd group, n=20; nivolumab group, n=38). RESULTS: Most patients exhibited a HER2 3+ status (72%) and presented metastatic disease at diagnosis (66%). The response rates of 41 patients with measurable lesions in the T-DXd and nivolumab groups were 50% and 15%, respectively. The T-DXd and nivolumab groups had a median progression-free survival of 4.8 months (95% confidence interval [CI], 3.3, 7.0) and 2.3 months (95% CI, 1.5, 3.5), median overall survival (OS) of 10.8 months (95% CI, 6.9, 23.8) and 11.7 months (95% CI, 7.6, 17.1), and grade 3 or greater adverse event rates of 50% and 2%, respectively. Overall, 64% patients received subsequent treatment. Among 23 patients who received both regimens, the T-DXd-nivolumab and nivolumab-T-DXd groups had a median OS of 14.0 months (95% CI, 5.0, not reached) and 19.3 months (95% CI, 9.5, 25.1), respectively. CONCLUSIONS: T-DXd and nivolumab showed distinct efficacy and toxicity profiles as ≥ third line treatments for HER2-positive AGC. Considering the distinct features of each regimen, they may help clinicians personalize optimal treatment approaches for these patients.