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1.
BMJ Case Rep ; 14(2)2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33547122

RESUMO

We herein report a woman who was suffering from type 1 diabetes and hearing impairment and whose mother had mitochondrial disease. Abdominal ultrasound identified a hepatic tumour, and a further examination led to the diagnosis of rectal cancer with synchronous multiple liver metastases. A genetic test led to the diagnosis of mitochondrial disease with a mitochondrial gene 3243A>G mutation. After neoadjuvant chemotherapy, we performed hepatectomy and low anterior resection in one stage. Hepatic vascular exclusion was not performed in order to prevent damage to hepatocytes due to liver ischaemia, and Ringer's lactate solution was not used to prevent lactic acidosis. The postoperative course was uneventful. Only one other case involving hepatectomy being performed in a patient with mitochondrial disease has been reported. Considering the extreme rarity of such cases and the importance of perioperative management, we report this case here.


Assuntos
Hepatectomia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Doenças Mitocondriais/complicações , Neoplasias Retais/patologia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica , Camptotecina/análogos & derivados , Diabetes Mellitus Tipo 2/genética , Feminino , Fluoruracila , Humanos , Leucovorina , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/tratamento farmacológico , Doenças Mitocondriais/genética , Compostos Organoplatínicos , Linhagem , Neoplasias Retais/diagnóstico por imagem , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/cirurgia
2.
Bull Cancer ; 108(1): 67-79, 2021 Jan.
Artigo em Francês | MEDLINE | ID: mdl-33422340

RESUMO

Compared with other breast cancer subtypes, patients with metastatic triple-negative breast cancer (TNBC) are younger and have a worst overall survival with a median of 15 to 18 months. These tumors have long suffered from a purely negative definition, but the last few years have witnessed many breakthrough genomic and molecular findings, that could dramatically improve our understanding of the biological heterogeneity of TNBC. Moreover, based on these genomic analyses, new generation of clinical trials, using many innovative therapies directed against novel targets, had been conducted. Some TNBC have DNA damage response defects, particularly linked to germinal BRCA1/2 mutations. At the present time, two poly(ADP-ribose) polymerase (PARP) inhibitors have been approved for patients with germinal BRCA1/2 mutation. Breast cancers are not the more immunogenic solid tumors, but some of them have a high percentage of tumor infiltrating lymphocytes (TILs), express PD-L1 (about 40%) or have a high tumor mutational burden. These features of TNBC have given a strong rational to investigate the role of immune checkpoint inhibitors. One of them has been approved by FDA in association with a cytotoxic as a first line treatment. At last, targeting surface receptors outside genomic landscape with antibody drug conjugate (ADC) is a new strategy for metastatic TNBC. Sacituzumab-govitecan is the first ADC approved by FDA in advanced TNBC beyond two lines of treatment.


Assuntos
Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Neoplasias de Mama Triplo Negativas/terapia , Anticorpos Monoclonais Humanizados/uso terapêutico , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Distúrbios no Reparo do DNA/tratamento farmacológico , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , Imunoconjugados/uso terapêutico , Imunoterapia/métodos , Imunoterapia Adotiva/métodos , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/imunologia
3.
Anticancer Res ; 41(1): 533-541, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33419853

RESUMO

BACKGROUND/AIM: We compared the efficacy and safety of second-line FOLFIRI with bevacizumab (Bmab) or aflibercept (AFL) in patients with unresectable metastatic colorectal cancer (mCRC) to clarify selection criteria for anti-angiogenic agents. PATIENTS AND METHODS: The subjects were patients with mCRC who received second-line FOLFIRI in combination with Bmab or AFL. The primary endpoint was median overall survival (OS). Secondary endpoints were median time to treatment failure (TTF), overall response rate (ORR) and incidence of adverse events. RESULTS: Data from 26 patients in the Bmab group and 19 in the AFL group were analyzed. Median OS was slightly longer in the AFL group compared to the Bmab group, whereas median TTF was similar. ORR tended to be higher in the AFL group. The incidence of ≥grade 2 diarrhea and proteinuria was significantly higher in the AFL group than the Bmab group. CONCLUSION: In patients given combination treatment with FOLFIRI for second-line treatment of mCRC, AFL can increase response rates compared to Bmab, which may contribute to longer survival.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Neoplasias Colorretais/mortalidade , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Humanos , Estimativa de Kaplan-Meier , Leucovorina/efeitos adversos , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Retratamento , Resultado do Tratamento
4.
Nihon Yakurigaku Zasshi ; 156(1): 47-51, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-33390481

RESUMO

Antibody-drug conjugates (ADCs) combine the specific antibody and cytotoxic agent by a linker and represent a promising drug class with a wider therapeutic window than conventional chemotherapeutic agents by substantiating efficient and specific drug delivery to antigen-expressing tumor cells. However, there are rooms for improvement in terms of efficacy, safety, physicochemical property; therefore, the development of promising ADC drugs across multiple indications are eagerly awaited. In 2015, Daiichi Sankyo initiated the first-in-human study of HER2 ADC, trastuzumab deruxtecan (T-DXd, ENHERTU®) which possesses DNA topoisomerase I inhibitor, exatecan derivative and proprietary linker, in Japan. Based on the provocative results in phase 1 study, the global development program has been accelerated to show the high and durable efficacy in patients with HER2 positive breast cancer pretreated with trastuzumab emtansine. As a result, T-DXd was approved based on single arm phase 2 study in the US (Dec 2019) and Japan (March 2020) by leveraging the breakthrough designation and conditional early approval system, respectively, at the first time for the HER2 positive breast cancer. In addition, T-DXd was recently approved in gastric cancer through Sakigake designation in Japan based on a randomized phase 2 study. T-DXd is also being developed in the earlier lines or other indications where no anti-HER2 therapies were approved to date. Combination studies with other agents, such as immune checkpoint inhibitors are underway. In the near future, we hope that more patients worldwide can enjoy the therapeutic benefits of T-DXd through our continuous efforts to expand its indications.


Assuntos
Antineoplásicos , Neoplasias da Mama , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Camptotecina/análogos & derivados , Humanos , Imunoconjugados , Japão , Receptor ErbB-2/uso terapêutico , Trastuzumab/uso terapêutico
5.
Gan To Kagaku Ryoho ; 47(10): 1517-1520, 2020 Oct.
Artigo em Japonês | MEDLINE | ID: mdl-33130754

RESUMO

A 66-year-old male diagnosed with transverse colon cancer was admitted to our hospital. Computed tomography, colonoscopy, and esophagogastroduodenoscopy revealed locally advanced cancer with invasion of the gastric antrum. We staged the disease as cT4a, cN2, cM0, Stage ⅢB, with wild-type RAS expression. We performed an ileostomy prior to administering chemotherapy. The patient received 4 courses of modified FOLFOXIRI plus bevacizumab and 2 courses of FOLFIRI. The size of the tumor noticeably decreased after chemotherapy. The patient experienced grade 3 neutropenia, anorexia, and oral mucositis during chemotherapy. We performed a right hemicolectomy(D3), partial gastrectomy and ileum resection after administering neoadjuvant chemotherapy. The pathological stage of the disease was ypT2, ypN0, ypM0, ypStageⅠ, and the effect of the chemotherapy was Grade 1b. After the resection, he received mFOLFOX6 and CapeOX for 3 months as adjuvant chemotherapy. He remained cancer-free for 1 year and 3 months after the surgery. This result suggests that preoperative modified FOLFOXIRI plus bevacizumab chemotherapy is a useful regimen for the treatment of locally advanced colon cancer.


Assuntos
Colo Transverso , Neoplasias do Colo , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Camptotecina/análogos & derivados , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/cirurgia , Fluoruracila/uso terapêutico , Humanos , Leucovorina , Masculino , Terapia Neoadjuvante , Compostos Organoplatínicos , Antro Pilórico
6.
Anticancer Res ; 40(9): 5159-5170, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878804

RESUMO

BACKGROUND/AIM: The aim of this study was to elucidate the possibility of sensitizing colon cancer cells to the chemotherapeutic drug SN38 and investigate its mechanism of action after combined treatment with electroporation (EP). MATERIALS AND METHODS: Cells were treated with SN38, EP and their combination for 24/48 h. The cell viability, actin cytoskeleton integrity, mitochondrial superoxide, hydroperoxides, total glutathione, phosphatidyl serine expression, DNA damages and expression of membrane ABC transporters were analyzed using conventional analytical tests. RESULTS: The combination of EP and SN38 affected cell viability and cytoskeleton integrity. This effect was accompanied by: (i) high production of intracellular superoxide and hydroperoxides and depletion of glutathione; (ii) increased DNA damage and apoptotic/ferroptotic cell death; (iii) changes in the expression of membrane ABC transporters - up-regulation of SLCO1B1 and retention of SN38 in the cells. CONCLUSION: The anticancer effect of the combined treatment of SN38 and EP is related to changes in the redox-homeostasis of cancer cells, leading to cell death via apoptosis and/or ferroptosis. Thus, electroporation has a potential to increase the sensitivity of cancer cells to conventional anticancer therapy with SN38.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Oxirredução , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Dano ao DNA/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Imunofluorescência , Glutationa/metabolismo , Humanos , Modelos Biológicos , Espécies Reativas de Oxigênio/metabolismo
7.
Clin Nucl Med ; 45(9): 707-708, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32657876

RESUMO

Triplet chemotherapy (FOLFOXIRI) + bevacizumab regimen is indicated as first-line treatment of BRAF-mutated metastatic colorectal cancer (mCRC). Nevertheless, its proven therapeutic efficacy in clinical trials was solely based on partial morphologic responses assessed by CT. To date, only 1 case of complete response assessed by FDG PET/CT was reported in literature in BRAF-mutated mCRC, but treated with doublet chemotherapy (FOLFIRI) + cetuximab regimen. We report a complete metabolic response assessed by FDG PET/CT, maintained over time (13 months) in a 60-year-old woman with BRAF-mutated mCRC treated by FOLFOXIRI-bevacizumab. This also confirms that FDG PET/CT is emerging as a useful approach for therapeutic assessment of targeted drugs in mCRC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Fluordesoxiglucose F18 , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Proteínas Proto-Oncogênicas B-raf/genética , Camptotecina/uso terapêutico , Cetuximab/uso terapêutico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Feminino , Fluoruracila/uso terapêutico , Humanos , Leucovorina/uso terapêutico , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Compostos Organoplatínicos/uso terapêutico , Resultado do Tratamento
8.
Bull Cancer ; 107(5S): S6-S16, 2020 Jun.
Artigo em Francês | MEDLINE | ID: mdl-32620209

RESUMO

Until 2014, no new therapeutic agent have been approved by authorities in more than 2 decades for bladder cancer. But the panel of treatments has expended in recent years with the emergence of at least 3 different therapeutic classes. First, the immune checkpoint inhibitors that have demonstrated an overall survival benefit in metastatic patients after failure of platinum based chemotherapy. They are therefore currently evaluated alone or in combination with chemotherapy in multiple studies at earlier stages (localized and meta-static). The second and third therapeutic classes are the targeted therapies (especially FGFR inhibitor) and the antibody-drug conjugates with promising results in early clinical trials. In this article, we review all the current and future studies conducted in urothelial carcinoma of the bladder.


Assuntos
Carcinoma de Células de Transição/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Carcinoma de Células de Transição/secundário , Humanos , Imunoconjugados/uso terapêutico , Imunoterapia , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Terapias em Estudo
13.
Oncology ; 98(9): 637-642, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32474564

RESUMO

BACKGROUND: FOLFIRI plus bevacizumab have been widely used as first-line treatment for metastatic colorectal cancer (mCRC). Pharmacokinetics and pharmacodynamics suggested a low dose of irinotecan given as a long-term infusion is expected to enhance antitumor activity. We conducted a randomized phase II study to compare oral S-1 with a 24-h infusion of irinotecan plus bevacizumab versus FOLFIRI plus bevacizumab. METHODS: The subjects comprised 120 chemotherapy-naïve patients with mCRC. The study group received a 24-h infusion of irinotecan at a dose of 125 mg/m2 on days 1 and 15, combined with oral S-1 80 mg/m2 on days 1-14 (24h-SIRI/B). The FOLFIRI/B group received irinotecan at a dose of 150 mg/m2, 5-fluorouracil given at a dose of 400 mg/m2 as a bolus injection and at a dose of 2,400 mg/m2 as a 46-h infusion, and 200 mg/m2 leucovorin on days 1 and 15. Bevacizumab was given at a dose of 5.0 mg/kg on days 1 and 15 in both groups. Treatment was repeated every 4 weeks. The primary endpoint was 1-year progression-free survival (PFS). Secondary endpoints were PFS, response rates (RR), overall survival (OS), and adverse events (AEs). RESULTS: From December 2013 through January 2018, 120 patients were randomly assigned, 61 patients to the 24h-SIRI/B and 59 patients to the FOLFIRI/B. The median follow-up period was 22.8 months. The 1-year PFS rate was 43.14% in the 24h-SIRI/B arm and 19.15% in the FOLFIRI/B arm (HR = 0.312 [95%CI 0.13-0.78], p = 0.01). The median PFS was 10.2 months (95%CI 8.8-14.3) and 10.0 months (95%CI 7.4-11.0), and the median OS was 29.7 months (95%CI 22.9-43.9) and 28.8 months (95%CI 18.4-ND), respectively (p = 0.3758, p = 0.8234). The overall RR was 86.3 and 61.7%, respectively (p = 0.0053). AEs were similar. CONCLUSIONS: Our results show that the 24h-SIRI/B regimen is an effective and reasonably well-tolerated regimen for the first-line treatment of mCRC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Administração Oral , Adulto , Idoso , Bevacizumab/administração & dosagem , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Esquema de Medicação , Combinação de Medicamentos , Feminino , Fluoruracila/administração & dosagem , Humanos , Infusões Intravenosas , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Ácido Oxônico/administração & dosagem , Intervalo Livre de Progressão , Taxa de Sobrevida , Tegafur/administração & dosagem , Adulto Jovem
14.
Medicine (Baltimore) ; 99(21): e20026, 2020 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-32481270

RESUMO

RATIONALE: Cutaneous metastases from colorectal cancer are extremely rare and generally appear several years after diagnosis or resection of the primary colorectal tumor. Although cutaneous metastasis is unusual, it often indicates a poor prognosis. PATIENT CONCERNS: We treated a 62-year-old woman with multiple cutaneous metastatic nodules on the chest, back, and armpit 7 months after resection of ascending colon cancer. DIAGNOSES: The patient was diagnosed with cutaneous metastasis of ascending colon cancer with BRAF V600E mutation. INTERVENTIONS: After 6 cycles of fluorouracil, leucovorin, oxaliplatin, cetuximab, and emurafenib, most of the metastatic lesions had begun to shrink, and no new metastases were observed. Serum tests showed that the levels of several tumor markers were decreased. OUTCOMES: The patient responded well to treatment and survived for 6.5 months after presentation with skin metastasis. LESSONS: Cutaneous metastasis of colorectal cancer with BRAF V600E mutation is a rare but important phenomenon that should not be ignored. Cutaneous metastasis of colorectal cancer frequently indicates advanced disease and poor prognosis. The SWOG 1406 program is one of the treatment options, but this needs further exploration.


Assuntos
Adenocarcinoma/patologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/secundário , Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Evolução Fatal , Feminino , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas B-raf , Neoplasias Cutâneas/tratamento farmacológico
15.
J Cancer Res Clin Oncol ; 146(9): 2399-2410, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32358699

RESUMO

PURPOSE: Some metastatic colorectal cancer (mCRC) patients receive conversion surgery (CS), including metastasectomy after palliative chemotherapy. Although targeted agents significantly improved the outcomes, the clinical outcome of CS in the targeted agent era has not yet been thoroughly investigated. METHODS: We analyzed the clinical data of 96 mCRC patients who initially had unresectable liver- and/or lung-limited metastases and underwent first-line cetuximab or bevacizumab plus FOLFIRI between January 2013 and June 2017. RESULTS: Liver-limited metastasis was seen in 44 patients (45.8%), lung-limited metastases in 21 patients (21.9%), and both liver and lung metastases in 31 patients (32.3%). Among them, 37 patients (38.5%) received cetuximab, and 59 patients (61.5%) received bevacizumab plus FOLFIRI. Overall response rate was 63.9% and 40.7%, respectively (p = 0.035). After median 8.7 (range 2.5-27.3) months, CS was performed in 11 patients (29.7%) in cetuximab group and 15 patients (25.4%) in bevacizumab group (p = 0.646). Median overall survival has not been reached in R0-resected patients (n = 23), during the median follow-up period of 22.5 (range 9.8-54.5) months. Median disease-free survival was 7.1 (95% CI 2.5-11.7) months: 11.0 (95% CI 3.1-19.0) months in cetuximab group and 3.2 (95% CI 0.0-7.8) months in bevacizumab group (p = 0.422). There was no progression after 18.5 months and disease-free survival reached a plateau at 19.9%. CONCLUSIONS: A substantial proportion of patients could receive CS after cetuximab or bevacizumab plus FOLFIRI chemotherapy. R0-resected patients had excellent overall survival, although 80.1% of them eventually experienced recurrence. Some patients could achieve durable disease-free state.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Bevacizumab/administração & dosagem , Camptotecina/uso terapêutico , Cetuximab/administração & dosagem , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Feminino , Fluoruracila/uso terapêutico , Humanos , Leucovorina/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/patologia , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Estudos Retrospectivos
16.
N Engl J Med ; 382(25): 2419-2430, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32469182

RESUMO

BACKGROUND: Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate consisting of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. The drug may have efficacy in patients with HER2-positive advanced gastric cancer. METHODS: In an open-label, randomized, phase 2 trial, we evaluated trastuzumab deruxtecan as compared with chemotherapy in patients with HER2-positive advanced gastric cancer. Patients with centrally confirmed HER2-positive gastric or gastroesophageal junction adenocarcinoma that had progressed while they were receiving at least two previous therapies, including trastuzumab, were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan (6.4 mg per kilogram of body weight every 3 weeks) or physician's choice of chemotherapy. The primary end point was the objective response, according to independent central review. Secondary end points included overall survival, response duration, progression-free survival, confirmed response (response persisting ≥4 weeks), and safety. RESULTS: Of 187 treated patients, 125 received trastuzumab deruxtecan and 62 chemotherapy (55 received irinotecan and 7 paclitaxel). An objective response was reported in 51% of the patients in the trastuzumab deruxtecan group, as compared with 14% of those in the physician's choice group (P<0.001). Overall survival was longer with trastuzumab deruxtecan than with chemotherapy (median, 12.5 vs. 8.4 months; hazard ratio for death, 0.59; 95% confidence interval, 0.39 to 0.88; P = 0.01, which crossed the prespecified O'Brien-Fleming boundary [0.0202 on the basis of number of deaths]). The most common adverse events of grade 3 or higher were a decreased neutrophil count (in 51% of the trastuzumab deruxtecan group and 24% of the physician's choice group), anemia (38% and 23%, respectively), and decreased white-cell count (21% and 11%). A total of 12 patients had trastuzumab deruxtecan-related interstitial lung disease or pneumonitis (grade 1 or 2 in 9 patients and grade 3 or 4 in 3), as adjudicated by an independent committee. One drug-related death (due to pneumonia) was noted in the trastuzumab deruxtecan group; no drug-related deaths occurred in the physician's choice group. CONCLUSIONS: Therapy with trastuzumab deruxtecan led to significant improvements in response and overall survival, as compared with standard therapies, among patients with HER2-positive gastric cancer. Myelosuppression and interstitial lung disease were the notable toxic effects. (Funded by Daiichi Sankyo; DESTINY-Gastric01 ClinicalTrials.gov number, NCT03329690.).


Assuntos
Adenocarcinoma/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Camptotecina/análogos & derivados , Imunoconjugados/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/efeitos adversos , Medula Óssea/efeitos dos fármacos , Camptotecina/efeitos adversos , Camptotecina/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Feminino , Humanos , Imunoconjugados/efeitos adversos , Irinotecano/uso terapêutico , Doenças Pulmonares Intersticiais/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Paclitaxel/uso terapêutico , Receptor ErbB-2/análise , Análise de Sobrevida , Trastuzumab
17.
Eur J Med Chem ; 200: 112365, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32460113

RESUMO

Nanomedicines have shown success in cancer therapy in recent years because of their excellent solubility in aqueous solution and drug accumulation through controlled release in tumor tissues, but the preparation of most nanomedicines still requires ionic materials, surfactants or the amphiphilic structure to maintain nanoparticle stability and function. In this study, we developed a couple of novel dually hydrophobic prodrugs (DHPs) by combining two hydrophobic compounds through different linkers and elaborated their self-assembly mechanisms by virtue of computational simulation. Importantly, without using any excipients, FL-2 NPs exhibited significantly prolonged retention in blood circulation and displayed a remarkable anti-tumor effect at very low concentration in vivo. Both DHPs consisted of camptothecin structural analogue(FL118) and a marine natural product (ES-285). Comparative experiments proved that these compounds could quickly form nanoparticles by way of simple preparation and remained relatively stable for long periods in PBS. FL-2 NPs linked with a disulphide bond could rapidly release bioactive FL118 after being triggered by endogenous reductive stimulus to exert anti-cancer effects. Overall, this study provides a new strategy for design of therapeutic nanomedicines consisting of dually hydrophobic molecules for cancer therapy.


Assuntos
Camptotecina/análogos & derivados , Interações Hidrofóbicas e Hidrofílicas , Nanomedicina/métodos , Nanopartículas/química , Neoplasias/terapia , Pró-Fármacos/química , Animais , Benzodioxóis , Cromonas , Dissulfetos , Estabilidade de Medicamentos , Humanos , Indolizinas , Lipídeos
18.
J Cancer Res Clin Oncol ; 146(10): 2681-2691, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32449003

RESUMO

PURPOSE: In mCRC, disease dynamics may play a critical role in the understanding of long-term outcome. We evaluated depth of response (DpR), time to DpR, and post-DpR survival as relevant endpoints. METHODS: We analyzed DpR by central review of computer tomography images (change from baseline to smallest tumor diameter), early tumor shrinkage (≥ 20% reduction in tumor diameter at first reassessment), time to DpR (study randomization to DpR-image), post-DpR progression-free survival (pPFS = DpR-image to tumor progression or death), and post-DpR overall survival (pOS = DpR-image to death) with special focus on BRAF status in 66 patients and primary tumor site in 86 patients treated within the VOLFI-trial, respectively. RESULTS: BRAF wild-type (BRAF-WT) compared to BRAF mutant (BRAF-MT) patients had greater DpR (- 57.6% vs. - 40.8%, p = 0.013) with a comparable time to DpR [4.0 (95% CI 3.1-4.4) vs. 3.9 (95% CI 2.5-5.5) months; p = 0.8852]. pPFS was 6.5 (95% CI 4.9-8.0) versus 2.6 (95% CI 1.2-4.0) months in favor of BRAF-WT patients (HR 0.24 (95% CI 0.11-0.53); p < 0.001). This transferred into a significant difference in pOS [33.6 (95% CI 26.0-41.3) vs. 5.4 (95% CI 5.0-5.9) months; HR 0.27 (95% CI 0.13-0.55); p < 0.001]. Similar observations were made for patients stratified for primary tumor site. CONCLUSIONS: BRAF-MT patients derive a less profound treatment response compared to BRAF-WT patients. The difference in outcome according to BRAF status is evident after achievement of DpR with BRAF-MT patients hardly deriving any further disease control beyond DpR. Our observations hint towards an aggressive tumor evolution in BRAF-MT tumors, which may already be molecularly detectable at the time of DpR.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Progressão da Doença , Feminino , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Compostos Organoplatínicos/administração & dosagem , Panitumumabe/administração & dosagem , Resultado do Tratamento , Proteínas ras/genética
19.
Gan To Kagaku Ryoho ; 47(3): 453-455, 2020 Mar.
Artigo em Japonês | MEDLINE | ID: mdl-32381914

RESUMO

A 69-year-old man with dyschezia was diagnosed with locally advanced colorectal cancer invading the urinary bladder and pelvis. We performed ileostomy to avoid passage disturbance because curative resection was difficult. The patient received 2 courses of modified FOLFOXIRI plus bevacizumab. The size of the primary tumor and lymph nodes decreased after chemotherapy. High anterior resection with D3 lymph node dissection was performed. Histopathological analysis revealed that the tumor stage was pT3, N0, M0, StageⅡ. The patient has been receiving adjuvant chemotherapy with oral UFT/UZEL for 6months. No recurrence has been observed for the past 4 months.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Retais , Idoso , Bevacizumab , Camptotecina/análogos & derivados , Fluoruracila , Humanos , Leucovorina , Masculino , Recidiva Local de Neoplasia , Compostos Organoplatínicos , Neoplasias Retais/tratamento farmacológico
20.
Gan To Kagaku Ryoho ; 47(2): 298-300, 2020 Feb.
Artigo em Japonês | MEDLINE | ID: mdl-32381968

RESUMO

A 71-year-old woman with advanced ascending colon cancer was admitted to our hospital. Abdominal computed tomography( CT)revealed locally advanced sigmoid colon cancer with suspected invasion of the liver and duodenum. The clinical stage of the disease was cT4bN3M1a, cStage Ⅳa, with wild-type RAS and UGT1A1 expression. An ileostomy was performed because of bowel obstruction. The patient received 6 courses of FOLFOXIRI plus bevacizumab(Bev). The only adverse event was Grade 3 neutropenia. Laparoscopic right hemicolectomy with lymph node dissection was performed. The pathological diagnosis was the absence of viable, Grade 3 carcinoma cells. This result suggested that preoperative FOLFOXIRI plus Bev chemotherapy is useful for the treatment of locally advanced colon cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Colo Ascendente , Neoplasias do Colo , Idoso , Bevacizumab , Camptotecina/análogos & derivados , Neoplasias do Colo/tratamento farmacológico , Duodeno , Feminino , Fluoruracila , Humanos , Leucovorina , Fígado , Compostos Organoplatínicos
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