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1.
Nat Commun ; 12(1): 2385, 2021 04 22.
Artículo en Inglés | MEDLINE | ID: mdl-33888701

RESUMEN

Nanoparticle internalisation is crucial for the precise delivery of drug/genes to its intracellular targets. Conventional quantification strategies can provide the overall profiling of nanoparticle biodistribution, but fail to unambiguously differentiate the intracellularly bioavailable particles from those in tumour intravascular and extracellular microenvironment. Herein, we develop a binary ratiometric nanoreporter (BiRN) that can specifically convert subtle pH variations involved in the endocytic events into digitised signal output, enabling the accurately quantifying of cellular internalisation without introducing extracellular contributions. Using BiRN technology, we find only 10.7-28.2% of accumulated nanoparticles are internalised into intracellular compartments with high heterogeneity within and between different tumour types. We demonstrate the therapeutic responses of nanomedicines are successfully predicted based on intracellular nanoparticle exposure rather than the overall accumulation in tumour mass. This nonlinear optical nanotechnology offers a valuable imaging tool to evaluate the tumour targeting of new nanomedicines and stratify patients for personalised cancer therapy.


Asunto(s)
Antineoplásicos/administración & dosificación , Portadores de Fármacos/análisis , Imagen Molecular/métodos , Nanopartículas/análisis , Neoplasias/tratamiento farmacológico , Animales , Línea Celular Tumoral/trasplante , Modelos Animales de Enfermedad , Doxorrubicina/administración & dosificación , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/química , Femenino , Colorantes Fluorescentes/química , Humanos , Microscopía Intravital , Ratones , Sondas Moleculares/administración & dosificación , Sondas Moleculares/análisis , Sondas Moleculares/química , Nanopartículas/administración & dosificación , Nanopartículas/química , Neoplasias/diagnóstico por imagen , Neoplasias/patología , Imagen Óptica/métodos , Paclitaxel/administración & dosificación , Selección de Paciente , Reproducibilidad de los Resultados , Nanomedicina Teranóstica/métodos , Distribución Tisular , Microambiente Tumoral/efectos de los fármacos
2.
Cancer Treat Rev ; 96: 102180, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33812339

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive form of cancer with a dismal prognosis. The lack of symptoms in the early phase of the disease makes early diagnosis challenging, and about 80-85% of the patients are diagnosed only after the disease is locally advanced or metastatic. The current front-line treatment landscape in local stages comprises surgical resection and adjuvant chemotherapy. In Switzerland, although both FOLFIRINOX and gemcitabine plus nab-paclitaxel regimens are feasible and comparable in the first-line setting, FOLFIRINOX is preferred in the treatment of fit (Eastern Cooperative Oncology Group [ECOG] performance status [PS]: 0-1), young (<65 years old) patients with few comorbidities and normal liver function, while gemcitabine plus nab-paclitaxel is used to treat less fit (ECOG PS: 1-2) and more vulnerable patients. In the second-line setting of advanced PDAC, there is currently only one approved regimen, based on the phase III NAPOLI-1 trial. Furthermore, the use of liposomal-irinotecan in the second line is supported by real-world data. Beyond the standard of care, various alternative treatment modalities are being explored in clinical studies. Immunotherapy has demonstrated only limited benefits until now, and only in cases of high microsatellite instability (MSI-H). However, data on the benefit of poly (ADP-ribose) polymerase (PARP) inhibition as maintenance therapy in patients with germline BRCA-mutated tumors might signal of an advance in targeted therapy. Currently, there is a lack of molecular and genetic biomarkers for optimal stratification of patients and in guiding treatment decisions. Thus, identification of predictive and prognostic biomarkers and evaluating novel treatment strategies are equally relevant for improving the prognosis of metastatic pancreatic cancer patients.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Albúminas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/cirugía , Ensayos Clínicos Fase III como Asunto , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Fluorouracilo/administración & dosificación , Humanos , Irinotecán/administración & dosificación , Leucovorina/administración & dosificación , Liposomas/administración & dosificación , Metástasis de la Neoplasia , Oxaliplatino/administración & dosificación , Paclitaxel/administración & dosificación , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/cirugía , Ensayos Clínicos Controlados Aleatorios como Asunto
3.
J Surg Oncol ; 123(6): 1395-1404, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33831247

RESUMEN

The annual incidence of pancreatic cancer is nearly 50,000 patients. The 5-year overall survival is only 9%, and there remains a great need for better therapy. A subset of these patients presents with locally advanced disease. Multidisciplinary therapy has evolved to include some combination of systemic chemotherapy, locoregional radiation, and surgery in select patients with excellent biology. This review will address the thoughtful evidence-based and individualized approach to these patients.


Asunto(s)
Carcinoma Ductal Pancreático/terapia , Neoplasias Pancreáticas/terapia , Albúminas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/cirugía , Quimioradioterapia , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Manejo de la Enfermedad , Medicina Basada en la Evidencia , Fluorouracilo/administración & dosificación , Humanos , Irinotecán/administración & dosificación , Leucovorina/administración & dosificación , Terapia Neoadyuvante , Oxaliplatino/administración & dosificación , Paclitaxel/administración & dosificación , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/cirugía , Medicina de Precisión
4.
J Surg Oncol ; 123(6): 1432-1440, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33831253
5.
Int J Nanomedicine ; 16: 2597-2613, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33833514

RESUMEN

Introduction: Limited by tumor vascular barriers, restricted intratumoural T cell infiltration and nanoparticles accumulation remain major bottlenecks for anticancer therapy. Platelets are now known to maintain tumor vascular integrity. Therefore, inhibition of tumor-associated platelets may be an effective method to increase T cell infiltration and drug accumulation at tumor sites. Herein, we designed an ultrasound-responsive nitric oxide (NO) release nanosystem, SNO-HSA-PTX, which can release NO in response to ultrasound (US) irradiation, thereby inhibiting platelet function and opening the tumor vascular barrier, promoting drug accumulation and T cell infiltration. Methods: We evaluated the ability of SNO-HSA-PTX to release NO in response to US irradiation. We also tested the effect of SNO-HSA-PTX on platelet function. Plenty of studies including cytotoxicity, pharmacokinetics study, biodistribution, blood perfusion, T cell infiltration, in vivo antitumor efficacy and safety assessment were conducted to investigate the antitumor effect of SNO-HSA-PTX. Results: SNO-HSA-PTX with US irradiation inhibited tumor-associated platelets activation and induced openings in the tumor vascular barriers, which promoted the accumulation of SNO-HSA-PTX nanoparticles to the tumor sites. Meanwhile, the damaged vascular barriers allowed oxygen-carrying hemoglobin to infiltrate tumor regions, alleviating hypoxia of the tumor microenvironment. In addition, the intratumoral T cell infiltration was augmented, together with chemotherapy and NO therapy, which greatly inhibited tumor growth. Discussion: Our research designed a simple strategy to open the vascular barrier by inhibiting the tumor-associated platelets, which provide new ideas for anti-tumor treatment.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Linfocitos Infiltrantes de Tumor/inmunología , Nanopartículas/administración & dosificación , Óxido Nítrico/metabolismo , Compuestos Nitrosos/química , Paclitaxel/farmacología , Albúmina Sérica Humana/química , Ondas Ultrasónicas , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/farmacocinética , Antineoplásicos Fitogénicos/farmacología , Apoptosis , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Nanopartículas/química , Paclitaxel/administración & dosificación , Paclitaxel/farmacocinética , Distribución Tisular , Células Tumorales Cultivadas , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto
6.
BMC Cancer ; 21(1): 426, 2021 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-33865364

RESUMEN

BACKGROUND: In the era of immunotherapy, it is still unclear which is the best first-line therapy for patients with oncogenic driver negative advanced non-squamous non-small cell lung cancer (NS-NSCLC) who cannot tolerate immunotherapy, or subsequent therapy for patients with oncogenic driver positive NS-NSCLC whose disease progressed on prior targeted therapy. To assess the optimal choice of first-line and maintenance treatment regimens, we performed a meta-analysis of prospective randomized controlled clinical trials (RCTs) of patients with NS-NSCLC on bevacizumab combined with chemotherapy. METHODS: All eligible RCTs comparing pemetrexed-platinum with or without bevacizumab (PP ± B) and paclitaxel-carboplatin with bevacizumab (PC + B) as a first-line therapy, or comparing bevacizumab plus pemetrexed (Pem + B) and bevacizumab alone (B) as a maintenance treatment for advanced NS-NSCLC, were included after systematically searching web databases and meeting abstracts. The main research endpoints were comparisons of overall survival (OS) and progression-free survival (PFS). The other endpoints were objective response rate (ORR), 1-year PFS rate (PFSR1y) and major grade 3/4 treatment-related adverse events. RESULTS: Data of 3139 patients from six RCTs were incorporated into analyses. Three RCTs were included in an analysis that compared PP ± B and PC + B as a first-line therapy for advanced NS-NSCLC. Patients treated with first-line PP ± B showed similar OS and ORR, but significantly improved PFS (hazard ratio [HR], 0.88) and PFSR1y (risk ratio [RR], 0.83), as compared to patients treated with PC + B (all P < 0.05). PP ± B resulted in higher rates of grade 3/4 anemia and thrombocytopenia, but lower rates of neutropenia, febrile neutropenia, and sensory neuropathy than PC + B (all P < 0.001). The other three RCTs were included in an analysis that compared Pem + B and B as a maintenance treatment. Compared with B, Pem + B maintenance treatment resulted in significant improvements in OS (HR, 0.88), PFS (HR, 0.64), and PFSR1y (RR, 0.70), but higher rates of anemia, thrombocytopenia, and neutropenia (all P < 0.001). CONCLUSION: Although the first-line PP + B regimen had longer PFS and PFSR1y than the PC + B regimen, no OS difference was observed. Addition of pemetrexed to bevacizumab as maintenance therapy significantly improved OS compared with bevacizumab maintenance alone, but led to more toxicity.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Femenino , Humanos , Quimioterapia de Inducción , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidad , Quimioterapia de Mantención , Masculino , Metástasis de la Neoplasia , Estadificación de Neoplasias , Paclitaxel/administración & dosificación , Pemetrexed/administración & dosificación , Sesgo de Publicación , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento
7.
Lancet Oncol ; 22(4): 439-449, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33705695

RESUMEN

BACKGROUND: The benefits of secondary cytoreduction for platinum-sensitive relapsed ovarian cancer are still widely debated. We aimed to assess the efficacy of secondary cytoreduction plus chemotherapy versus chemotherapy alone in this patient population. METHODS: This multicentre, open-label, randomised, controlled, phase 3 trial (SOC-1), was done in four primarily academic centres in China (two in Shanghai, one in Hangzhou, and one in Guangzhou). Eligible patients were women aged 18 years and older with platinum-sensitive relapsed epithelial ovarian cancer with a platinum-free interval of at least 6 months after the end of first-line platinum-based chemotherapy and were predicted to have potentially resectable disease according to the international model (iMODEL) score and PET-CT imaging. iMODEL score was calculated using six variables: International Federation of Gynecology and Obstetrics stage, residual disease after primary surgery, platinum-free interval, Eastern Cooperative Oncology Group performance status, serum level of cancer antigen 125 at recurrence, and presence of ascites at recurrence. An iMODEL score of 4·7 or lower predicted a potentially complete resection. As per a protocol amendment, patients with an iMODEL score of more than 4·7 could only be included if the serum level of cancer antigen 125 was more than 105 U/mL, but the principal investigators assessed the disease to be resectable by PET-CT. Eligible participants were randomly assigned (1:1) via a permuted block design (block size of six) and stratified by study centre, iMODEL score, residual disease at primary surgery, and enrolment in the Shanghai Gynecologic Oncology Group SUNNY trial, to undergo secondary cytoreductive surgery followed by intravenous chemotherapy (six 3-weekly cycles of intravenous paclitaxel [175 mg/m2] or docetaxel [75 mg/m2] combined with intravenous carboplatin [area under the curve of 5 mg/mL per min]; surgery group) or intravenous chemotherapy alone (no surgery group). Primary endpoints were progression-free survival and overall survival, analysed in all participants randomly assigned to treatment, regardless of treatment received (intention-to-treat [ITT] population). Here, we report the final analysis of progression-free survival and the prespecified interim analysis of overall survival. Safety was assessed in all participants who received their assigned treatment and had available adverse event data. This study is registered with ClinicalTrials.gov, NCT01611766, and is ongoing but closed to accrual. FINDINGS: Between July 19, 2012, and June 3, 2019, 357 patients were recruited and randomly assigned to the surgery group (182) or the no surgery group (175; ITT population). Median follow-up was 36·0 months (IQR 18·1-58·3). In the no surgery group, 11 (6%) of 175 participants had secondary cytoreduction during second-line therapy while 48 (37%) of 130 participants who had disease progression crossed-over and had surgery at a subsequent recurrence. Median progression-free survival was 17·4 months (95% CI 15·0-19·8) in the surgery group and 11·9 months (10·0-13·8) in the no surgery group (hazard ratio [HR] 0·58; 95% CI 0·45-0·74; p<0·0001). At the interim overall survival analysis, median overall survival was 58·1 months (95% CI not estimable to not estimable) in the surgery group and 53·9 months (42·2-65·5) in the no surgery group (HR 0·82, 95% CI 0·57-1·19). In the safety population, nine (5%) of 172 patients in the surgery group had grade 3-4 surgical morbidity at 30 days, and no patients in either group had died at 60 days after receiving assigned treatment. The most common grade 3-4 adverse events during chemotherapy were neutropenia (29 [17%] of 166 patients in the surgery group vs 19 [12%] of 156 patients in the no surgery group), leucopenia (14 [8%] vs eight [5%]), and anaemia (ten [6%] vs nine [6%]). Four serious adverse events occurred, all in the surgery group. No treatment-related deaths occurred in either group. INTERPRETATION: Secondary cytoreduction followed by chemotherapy was associated with significantly longer progression-free survival than was chemotherapy alone in patients with platinum-sensitive relapsed ovarian cancer, and patients should be counselled about the option of secondary cytoreduction in specialised centres. Long-term survival outcomes will be assessed using mature data on overall survival. FUNDING: Zhongshan Development Program. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Procedimientos Quirúrgicos de Citorreducción , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/cirugía , Adulto , Anciano , Bevacizumab/administración & dosificación , Carboplatino/administración & dosificación , Femenino , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Neoplasias Ováricas/patología , Paclitaxel/administración & dosificación , Supervivencia sin Progresión
8.
Clin Drug Investig ; 41(4): 381-389, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33674955

RESUMEN

BACKGROUND AND OBJECTIVES: Atezolizumab is an anti-programmed death ligand 1 (PD-L1) antibody that shows good safety and efficacy for patients with PD-L1-positive triple-negative breast cancer (TNBC). The cost of atezolizumab therapy is expensive, and its economic burden is an important problem. In this study, we evaluated the cost effectiveness of atezolizumab plus nab-paclitaxel therapy (AnP) compared with nab-paclitaxel monotherapy (nP) for PD-L1-positive TNBC under Japanese medical conditions and environments using a Markov model. METHODS: The medical information was collected from data published by the IMpassion130 trial. A Markov model was established to simulate the number of patients in each disease state after AnP or nP therapy during each time period. As indices for cost effectiveness, total cost, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICER) were calculated. Probabilistic sensitivity analysis (PSA) was used to assess the uncertainty of the model using 10,000 Monte Carlo simulations with difference parameters. RESULTS: The QALYs for AnP treatment were longer than for nP treatment (1.12 vs 0.82 QALYs), but the total cost of AnP treatment was more expensive than that of nP treatment (¥11,070,143 vs ¥2,056,164). The ICER values comparing AnP treatment with nP treatment were ¥30,208,143/QALY. The ICER/QALY was more expensive than the willingness-to-pay (WTP) of ¥15,000,000 per QALY. To achieve a 50% cost-effective probability with a WTP threshold, the price of the atezolizumab should be reduced by 55.1%. CONCLUSIONS: AnP was not cost effective compared to nP for PD-L1-positive inoperable TNBC under the Japanese condition.


Asunto(s)
Albúminas/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Paclitaxel/administración & dosificación , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/economía , Antígeno B7-H1/metabolismo , Análisis Costo-Beneficio , Femenino , Humanos , Japón , Años de Vida Ajustados por Calidad de Vida
9.
Lancet Oncol ; 22(2): 267-276, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33539744

RESUMEN

BACKGROUND: Bevacizumab is approved in combination with chemotherapy for the treatment of ovarian cancer, either in first-line therapy or for patients with recurrent disease not previously treated with the same drug. We aimed to test the value of continuing bevacizumab beyond progression after first-line treatment with the same drug. METHODS: In our open-label, randomised, phase 3 trial done at 82 sites in four countries, we enrolled women (aged ≥18 years) who had previously received first-line platinum-based therapy including bevacizumab, and had recurrent (≥6 months since last platinum dose), International Federation of Gynaecology and Obstetrics stage IIIB-IV ovarian cancer with an Eastern Cooperative Oncology Group performance status 0-2. Patients were randomly assigned (1:1) to receive a carboplatin-based doublet intravenously (carboplatin area under the concentration curve [AUC] 5 on day 1 plus paclitaxel 175 mg/m2 on day 1, every 21 days; carboplatin AUC 4 on day 1 plus gemcitabine 1000 mg/m2 on days 1 and 8, every 21 days; or carboplatin AUC 5 on day 1 plus pegylated liposomal doxorubicin 30 mg/m2 on day 1, every 28 days), or a carboplatin-based doublet plus bevacizumab (10 mg/kg intravenous every 14 days combined with pegylated liposomal doxorubicin-carboplatin, or 15 mg/kg every 21 days combined with gemcitabine-carboplatin or paclitaxel-carboplatin). Evaluable disease according to RECIST 1.1 guidelines was required before randomisation. Randomisation was done through the trial website with a minimisation procedure, stratified by centre, time of recurrence, performance status, and type of second-line chemotherapy. The primary endpoint was investigator-assessed progression-free survival, analysed on an intention-to-treat basis. Safety was assessed in all participants who received at least one dose. This trial is registered with ClinicalTrials.gov, NCT01802749 and EudraCT 2012-004362-17. FINDINGS: Between Dec 6, 2013, and Nov 11, 2016, 406 patients were recruited (203 [50%] assigned to the bevacizumab group and 203 [50%] to the standard chemotherapy group). 130 patients (64%) in the bevacizumab group and 131 (65%) in the standard chemotherapy group had progressed after receiving a last dose of platinum more than 12 months before, and 146 patients (72%) in the bevacizumab group and 147 (72%) in the standard chemotherapy group had progressed after completion of first-line bevacizumab maintenance. 161 participants (79%) progressed in the standard chemotherapy group, as did 143 (70%) in the bevacizumab group. Median progression-free survival was 8·8 months (95% CI 8·4-9·3) in the standard chemotherapy group and 11·8 months (10·8-12·9) in the bevacizumab group (hazard ratio 0·51, 95% CI 0·41-0·65; log-rank p<0·0001). Most common grade 3-4 adverse events were hypertension (20 [10%] in the standard chemotherapy group vs 58 (29%) in the bevacizumab group), neutrophil count decrease (81 [41%] vs 80 [40%]), and platelet count decrease (43 [22%] vs 61 [30%]). 68 patients (33%) died in the standard chemotherapy group and 79 (39%) died in the bevacizumab group; two deaths (1%) in the standard chemotherapy group and one death (<1%) in the bevacizumab group were deemed to be treatment-related. INTERPRETATION: Continuing bevacizumab beyond progression combined with chemotherapy in patients with platinum-sensitive recurrent ovarian cancer improves progression-free survival compared with standard chemotherapy alone and might be considered in clinical practice. FUNDING: Hoffmann-La Roche and Associazione Italiana per la Ricerca sul Cancro.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bevacizumab/administración & dosificación , Carboplatino/administración & dosificación , Neoplasias Ováricas/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/efectos adversos , Carboplatino/efectos adversos , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Doxorrubicina/análogos & derivados , Resistencia a Antineoplásicos , Femenino , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Neoplasias Ováricas/patología , Paclitaxel/administración & dosificación , Polietilenglicoles/administración & dosificación
10.
Medicine (Baltimore) ; 100(7): e24795, 2021 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-33607838

RESUMEN

RATIONALE: Ramucirumab, a human Ig 1 monoclonal antibody against vascular endothelial growth factor receptor-2, in combination with paclitaxel is a second-line chemotherapy for patients with metastatic gastric cancer. Several reports have suggested that dose adjustments of cetuximab, an anti- epidermal growth factor receptor antibody, are not required in patients with renal impairment. However, the combination chemotherapy of ramucirumab and cytotoxic drug for hemodialysis (HD) patients has not been reported. PATIENT CONCERNS: A 65-year-old man on HD was diagnosed with gastric cancer and underwent a subtotal gastrectomy with D2 lymphadenectomy. Abdominal computed tomography (CT) was examined after completion of 8 cycles of adjuvant chemotherapy with capecitabine combination oxaliplatin. DIAGNOSIS: The patient was diagnosed with advanced gastric cancer at stage IIIb (pT3N2M0) 11 months ago. Unfortunately, 9 months after the start of adjuvant chemotherapy, multiple liver metastases from gastric cancer were found by abdominal CT. INTERVENTIONS: He began receiving weekly paclitaxel(80 mg/m2) and every 15-day ramucirumab (8 mg/kg). HD was performed next day after administration of chemotherapy and repeated 3 times a week. OUTCOMES: He was treated with ramucirumab without dose adjustment. The metastatic liver mass had a partial response, after 2 and 4 cycles of chemotherapy and had a stable disease up to 12 cycles of chemotherapy. No obvious adverse effect was observed during treatment. However, after 14 cycles chemotherapy, follow-up abdominal CT revealed progression disease of multiple liver metastasis and lymph nodes invasion. LESSONS: The paclitaxel chemotherapy with ramucirumab is effective and safe in HD patients with metastatic gastric cancer. As seen in patients with normal kidney function, ramucirumab can be safely administered without a dose reduction.


Asunto(s)
Adenocarcinoma/secundario , Anticuerpos Monoclonales Humanizados/administración & dosificación , Antineoplásicos Fitogénicos/administración & dosificación , Neoplasias Hepáticas/secundario , Paclitaxel/administración & dosificación , Neoplasias Gástricas/tratamiento farmacológico , Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/patología , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Humanos , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/terapia , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/patología , Masculino , Diálisis Renal , Neoplasias Gástricas/complicaciones , Tomografía Computarizada por Rayos X
11.
BMC Cancer ; 21(1): 118, 2021 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-33541289

RESUMEN

BACKGROUND: To compare the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) and solvent-based taxanes (sb-taxanes) as neoadjuvant therapy in the treatment of breast cancer. METHODS: We systematically searched the PubMed, Embase, and Cochrane Central Register databases. Randomized controlled trials (RCTs) and cohort studies, published in English, about the comparison between nab-paclitaxel and sb-taxanes as neoadjuvant therapy in patients with breast cancer were searched up to September 2019. RESULTS: The primary outcome was the proportion of patients with pathological complete response (pCR, defined as ypT0 ypN0 or ypT0/is ypN0). Other main outcomes included long-term survival and adverse events (AEs). Seven studies (five RCTs and two cohorts) and 2949 patients were included. Neoadjuvant nab-paclitaxel improved pCR compared with sb-taxanes (ypT0 ypN0: OR = 1.52, 95%CI: 1.27-1.83, P < 0.001; ypT0/is ypN0: OR = 1.40, 95%CI: 1.17-1.68, P < 0.001). The benefits of nab-paclitaxel on pCR were persistent in HER2-negative, hormone receptor (HR)-positive breast cancer (OR = 1.53, 95%CI: 1.07-2.19, P = 0.020), triple-negative breast cancer (weekly/every 2 weeks regimen; OR = 2.95, 95%CI: 1.54-5.67, P < 0.001), and tumors with Ki-67 > 20% (OR = 1.63, 95%CI: 1.26-2.12, P < 0.001). Patients treated with nab-paclitaxel had better event-free survival (EFS; HR = 0.69, 95%CI: 0.57-0.85, P < 0.001) than with sb-taxanes. There were no differences in most of grade > 3 AEs between nab-paclitaxel and sb-taxanes (all P > 0.05), besides of any grade hypersensitivity (OR = 0.29, 95%CI: 0.11-0.72, P = 0.008), any grade (OR = 2.10, 95%CI: 1.37-3.23, P = 0.001) and grade > 3 (OR = 4.01, 95%CI: 2.51-6.41, P < 0.001) neuropathy. CONCLUSION: Nab-paclitaxel is effective for the treatment of non-metastatic breast cancer in the neoadjuvant setting. Nab-paclitaxel could improve pCR rate and EFS compared with sb-taxanes and with reasonable toxicities.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Solventes/química , Albúminas/administración & dosificación , Neoplasias de la Mama/patología , Femenino , Humanos , Paclitaxel/administración & dosificación , Pronóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Taxoides/administración & dosificación
12.
Am J Clin Oncol ; 44(4): 158-161, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33625121

RESUMEN

OBJECTIVE: The objective of this study was to review real-world patterns of chemotherapy utilization among patients with metastatic gastric/lower esophageal adenocarcinoma with particular focus on the use of ramucirumab plus paclitaxel in previously treated patients. METHODS: This is a retrospective, registry-based study using datasets from Alberta Cancer Registry and other provincial databases in Alberta, Canada. Multivariable logistic regression analysis was used to identify factors associated with palliative chemotherapy use. Among patients who received >1 line of chemotherapy, Kaplan-Meier survival estimates were used to compare outcomes according to ramucirumab plus paclitaxel use. Multivariable Cox regression analysis was then used to identify factors associated with overall survival (OS) in this cohort. RESULTS: A total of 1590 patients were included (including 1070 gastric patients and 520 lower esophageal patients). The following factors were associated with use of palliative chemotherapy: younger age (odds ratio with increasing age: 0.95; 95% confidence interval [CI]: 0.94-0.95), and lower Charlson Comorbidity Index (odds ratio with increasing index: 0.82; 95% CI: 0.74-0.91). Within the subcohort of patients who received >1 line of chemotherapy, use of ramucirumab/paclitaxel was associated with better OS (P=0.033). Multivariable Cox regression analysis suggested that the following factors are associated with better OS: use of ramucirumab/paclitaxel (hazard ratio [HR]: 1.56; 95% CI: 1.07-2.29) and living within urban zones including Calgary or Edmonton zones (vs. Northern zone) (HR for Calgary zone vs. Northern zone: 0.44; 95% CI: 0.23-0.85; HR for Edmonton zone vs. Northern zone: 0.41; 95% CI: 0.22-0.77). CONCLUSIONS: Use of paclitaxel/ramucirumab combination beyond first-line treatment is associated with improved OS among patients with metastatic gastric/lower esophageal adenocarcinoma in this real-world study. Further work is needed to reduce disparity in our health care system between individuals living in rural versus urban areas.


Asunto(s)
Adenocarcinoma/secundario , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Gástricas/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Cuidados Paliativos , Estudios Retrospectivos
13.
Int J Nanomedicine ; 16: 789-802, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33568906

RESUMEN

Purpose: The aims of this study were to test the feasibility, targeting specificity and anticancer therapeutic efficacy of CendR motif tLyP-1 functionalized at the N-terminal of ferritin for paclitaxel (PTX) delivery. Methods: A tumor homing and penetrating peptide tLyP-1 was fused to the N-terminal of human H chain ferritin (HFtn) to generate a dual-targeting nanoparticle delivery system. PTX molecules were encapsulated into the HFtn nanocage using the disassembly/assembly method by adjusting pHs. Cellular uptake was examined by confocal laser scanning microscopy (CLSM) and flow cytometry. The MTT assay was used to test the cytotoxicity of various PTX-loaded NPs against MDA-MB-231 and SMMC-7721 tumor cells. The wound healing and cell migration assays were conducted to assess the inhibitory effect on cell motility and metastasis. The inhibition effect on the SMMC-7721 tumor spheroids was studied and penetration ability was evaluated by CLSM. The antitumor efficacy of PTX-loaded NPs was assessed in MDA-MB-231 breast cancer xenografted in female BALB/c nude mice. Results: Compared with HFtn-PTX, in vitro studies demonstrated that the tLyP-1-HFtn-PTX displayed enhanced intracellular delivery and better cytotoxicity and anti-invasion ability against both SMMC-7721 and MDA-MB-231 cells. The better penetrability and growth inhibitory effect on SMMC-7721 tumor spheroids were also testified. In vivo distribution and imaging demonstrated that the tLyP-1-HFtn-PTX NPs were selectively accumulated and penetrated at the tumor regions. Verified by the breast cancer cells model in BABL/c nude mice, tLyP-1-HFtn-PTX displayed higher in vivo therapeutic efficacy with lower systemic toxicity. Conclusion: Ferritin decorated with tumor-homing penetration peptide tLyP-1 at the N terminal could deliver PTX specifically inside the cell via receptor-mediated endocytosis with better efficacy. The peptide tLyP-1 which is supposed to work only at the C terminus showed enhanced tumor tissue penetration and antitumor efficacy, demonstrating that it also worked at the N-terminal of HFtn.


Asunto(s)
Apoferritinas/química , Sistemas de Liberación de Medicamentos , Paclitaxel/administración & dosificación , Péptidos Cíclicos/química , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Liberación de Fármacos , Endocitosis/efectos de los fármacos , Femenino , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Nanopartículas/química , Nanopartículas/ultraestructura , Paclitaxel/farmacología , Esferoides Celulares/efectos de los fármacos , Esferoides Celulares/patología , Cicatrización de Heridas/efectos de los fármacos
15.
Anticancer Res ; 41(2): 1063-1068, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33517316

RESUMEN

BACKGROUND/AIM: We evaluated the impact of the relative dose intensity (RDI) of neoadjuvant chemotherapy (NAC) on the survival of patients with breast cancer (BC). PATIENTS AND METHODS: This randomized phase II trial included 188 patients with human epidermal growth factor receptor 2 (HER2)-negative BC treated with anthracycline followed by paclitaxel as NAC. We grouped patients using a relative dose intensity (RDI) threshold of 85% and evaluated clinicopathological features and clinical outcomes. RESULTS: The 5-year overall survival rate was 91.2% and 76.3%, when RDI ≥85% and <85%, respectively (p=0.015). Age, tumor, and node status, and the RDI were significantly different on univariate analysis, but not on multivariate analysis. An exploratory subgroup analysis revealed that a low RDI was associated with low overall survival of patients with obesity, T1/2 disease, and lymph node metastases. CONCLUSION: Maintaining the RDI of NAC is crucial for achieving the survival benefit in selected patients with HER2-negative BC.


Asunto(s)
Antraciclinas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Paclitaxel/administración & dosificación , Receptor ErbB-2/metabolismo , Adulto , Anciano , Antraciclinas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Esquema de Medicación , Cálculo de Dosificación de Drogas , Femenino , Humanos , Persona de Mediana Edad , Terapia Neoadyuvante , Paclitaxel/uso terapéutico , Análisis de Supervivencia , Resultado del Tratamiento
16.
Lancet Oncol ; 22(1): 118-131, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33387490

RESUMEN

BACKGROUND: Standard chemotherapy remains inadequate in metastatic pancreatic adenocarcinoma. Combining an agonistic CD40 monoclonal antibody with chemotherapy induces T-cell-dependent tumour regression in mice and improves survival. In this study, we aimed to evaluate the safety of combining APX005M (sotigalimab) with gemcitabine plus nab-paclitaxel, with and without nivolumab, in patients with pancreatic adenocarcinoma to establish the recommended phase 2 dose. METHODS: This non-randomised, open-label, multicentre, four-cohort, phase 1b study was done at seven academic hospitals in the USA. Eligible patients were adults aged 18 years and older with untreated metastatic pancreatic adenocarcinoma, Eastern Cooperative Oncology Group performance status score of 0-1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. All patients were treated with 1000 mg/m2 intravenous gemcitabine and 125 mg/m2 intravenous nab-paclitaxel. Patients received 0·1 mg/kg intravenous APX005M in cohorts B1 and C1 and 0·3 mg/kg in cohorts B2 and C2. In cohorts C1 and C2, patients also received 240 mg intravenous nivolumab. Primary endpoints comprised incidence of adverse events in all patients who received at least one dose of any study drug, incidence of dose-limiting toxicities (DLTs) in all patients who had a DLT or received at least two doses of gemcitabine plus nab-paclitaxel and one dose of APX005M during cycle 1, and establishing the recommended phase 2 dose of intravenous APX005M. Objective response rate in the DLT-evaluable population was a key secondary endpoint. This trial (PRINCE, PICI0002) is registered with ClinicalTrials.gov, NCT03214250 and is ongoing. FINDINGS: Between Aug 22, 2017, and July 10, 2018, of 42 patients screened, 30 patients were enrolled and received at least one dose of any study drug; 24 were DLT-evaluable with median follow-up 17·8 months (IQR 16·0-19·4; cohort B1 22·0 months [21·4-22·7], cohort B2 18·2 months [17·0-18·9], cohort C1 17·9 months [14·3-19·7], cohort C2 15·9 months [12·7-16·1]). Two DLTs, both febrile neutropenia, were observed, occurring in one patient each for cohorts B2 (grade 3) and C1 (grade 4). The most common grade 3-4 treatment-related adverse events were lymphocyte count decreased (20 [67%]; five in B1, seven in B2, four in C1, four in C2), anaemia (11 [37%]; two in B1, four in B2, four in C1, one in C2), and neutrophil count decreased (nine [30%]; three in B1, three in B2, one in C1, two in C2). 14 (47%) of 30 patients (four each in B1, B2, C1; two in C2) had a treatment-related serious adverse event. The most common serious adverse event was pyrexia (six [20%] of 30; one in B2, three in C1, two in C2). There were two chemotherapy-related deaths due to adverse events: one sepsis in B1 and one septic shock in C1. The recommended phase 2 dose of APX005M was 0·3 mg/kg. Responses were observed in 14 (58%) of 24 DLT-evaluable patients (four each in B1, C1, C2; two in B2). INTERPRETATION: APX005M and gemcitabine plus nab-paclitaxel, with or without nivolumab, is tolerable in metastatic pancreatic adenocarcinoma and shows clinical activity. If confirmed in later phase trials, this treatment regimen could replace chemotherapy-only standard of care in this population. FUNDING: Parker Institute for Cancer Immunotherapy, Cancer Research Institute, and Bristol Myers Squibb.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Albúminas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígenos CD40/antagonistas & inhibidores , Desoxicitidina/análogos & derivados , Nivolumab/administración & dosificación , Paclitaxel/administración & dosificación , Neoplasias Pancreáticas/tratamiento farmacológico , Adenocarcinoma/inmunología , Adenocarcinoma/secundario , Anciano , Albúminas/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Antígenos CD40/inmunología , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nivolumab/efectos adversos , Paclitaxel/efectos adversos , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Factores de Tiempo , Resultado del Tratamiento , Estados Unidos
17.
AAPS PharmSciTech ; 22(2): 56, 2021 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-33486601

RESUMEN

Compared with single micelle, the new PTX-HS15/T80 mixed micelle system (PTX-HS15/T80 MMs) had achieved better results in solubilization, stability, and sensitization before. Therefore, we intend to further verify the potential advantages of the mixed micelle delivery system through in vitro cytotoxicity test and animal test to understand the anticancer effect and in vivo pharmaceutical behavior of the system. In vitro cytotoxicity test showed that the new PTX-HS15/T80 MMs had a stronger ability to inhibit the proliferation of cancer cells. The results of in vivo pharmacokinetics showed that the micelle had shorter half-life, higher clearance rate, and lower blood concentration and had good blood clearance characteristics. The results of in vivo tissue distribution showed that, compared with the single micelle Taxol®, the new PTX-HS15/T80 MMs had good distribution characteristics in the lung (AUC (lung 0-4 H) increased about 26%) and low concentration in the heart (AUC (Heart 0-4 H) decreased about 10%). Paclitaxel was mainly metabolized through the liver and kidney. The above results suggested that the new PTX-HS15/T80 MMs may have a certain therapeutic potential against lung cancer and reduce the toxic and side effects. In general, the mixed micelle delivery system was not only simple and cheap to prepare but also had certain advantages in vitro and in vivo, indicating that the combination of surfactants provides a good choice for solving the problem of insoluble drug delivery.


Asunto(s)
Antineoplásicos Fitogénicos/administración & dosificación , Sistemas de Liberación de Medicamentos , Micelas , Paclitaxel/administración & dosificación , Polietilenglicoles/química , Polisorbatos/química , Ácidos Esteáricos/química , Animales , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos/métodos , Femenino , Masculino , Paclitaxel/farmacocinética , Paclitaxel/farmacología , Ratas , Ratas Sprague-Dawley , Distribución Tisular
18.
ACS Appl Mater Interfaces ; 13(2): 2988-2996, 2021 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-33403846

RESUMEN

Hollow graphene oxide microcapsules (GOMs) have been widely used in energy, electronics, catalysis, sensing, tissue engineering, and drug loading due to their unique properties. However, it is still a great challenge to prepare GOMs with high quality and in large quantity using a simple method. In this work, we obtained single-component GOMs using the liquid nitrogen cavitation effect, which directed the self-assembly of graphene oxide (GO) debris at the gas-liquid interface. This method avoids the introduction of additional components and removal of templates. The morphology of GOM with wrinkles on its surface was characterized by transmission electron microscopy and scanning electron microscopy. The abundant polar groups of GO microcapsules enabled them to easily disperse in water. Based on this, GOMs have good potential for loading hydrophobic drugs. Subsequently, we used GOMs as carriers to deliver a hydrophobic drug paclitaxel (PTX), which exhibited a good loading capacity. Moreover, PTX loaded GOMs showed excellent cytotoxicity to A549 and MDA-MB-231 cells. The GOMs also showed a pH-dependent drug release performance. Therefore, GOMs can be regarded as potential carriers for biomedical applications.


Asunto(s)
Antineoplásicos Fitogénicos/administración & dosificación , Portadores de Fármacos/química , Grafito/química , Paclitaxel/administración & dosificación , Células A549 , Antineoplásicos Fitogénicos/farmacocinética , Cápsulas/química , Línea Celular Tumoral , Liberación de Fármacos , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Paclitaxel/farmacocinética , Agua/química
19.
Expert Opin Drug Metab Toxicol ; 17(2): 227-239, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33401943

RESUMEN

Introduction: Peripheral neuropathy (PN) is an adverse effect of several classes of chemotherapy including the taxanes. Predictive PN biomarkers could inform individualized taxane treatment to reduce PN and enhance therapeutic outcomes. Pharmacogenetics studies of taxane-induced PN have focused on genes involved in pharmacokinetics, including enzymes and transporters. Contradictory findings from these studies prevent translation of genetic biomarkers into clinical practice. Areas covered: This review discusses the progress toward identifying pharmacogenetic predictors of PN by assessing the evidence for two independent associations; the effect of pharmacogenetics on taxane pharmacokinetics and the evidence that taxane pharmacokinetics affects PN. Assessing these direct relationships allows the reader to understand the progress toward individualized taxane treatment and future research opportunities. Expert opinion: Paclitaxel pharmacokinetics is a major determinant of PN. Additional clinical trials are needed to confirm the clinical benefit of individualized dosing to achieve target paclitaxel exposure. Genetics does not meaningfully contribute to paclitaxel pharmacokinetics and may not be useful to inform dosing. However, genetics may contribute to PN sensitivity and could be useful for estimating patients' optimal paclitaxel exposure. For docetaxel, genetics has not been demonstrated to have a meaningful effect on pharmacokinetics and there is no evidence that pharmacokinetics determines PN.


Asunto(s)
Docetaxel/efectos adversos , Paclitaxel/efectos adversos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Biomarcadores/análisis , Docetaxel/administración & dosificación , Docetaxel/farmacocinética , Relación Dosis-Respuesta a Droga , Humanos , Paclitaxel/administración & dosificación , Paclitaxel/farmacocinética , Enfermedades del Sistema Nervioso Periférico/genética , Farmacogenética , Medicina de Precisión
20.
Int J Mol Sci ; 22(3)2021 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-33498454

RESUMEN

Selectively targeted drug delivery systems are preferable chemotherapeutic platforms, as they specifically deliver the drug cargo into tumor cells, while minimizing untoward toxic effects. However, these delivery systems suffer from insufficient encapsulation efficiency (EE), encapsulation capacity (EC), and premature drug release. Herein, we coencapsulated paclitaxel (PTX) and Jasmine oil (JO) within PEG-PCL nanoparticles (NPs), with an average diameter < 50 nm, selectively targeted to non-small cell lung cancer (NSCLC) cells, via S15-aptamer (APT) decoration. JO was selected as an "adhesive" oily core to enhance PTX entrapment, as JO and PTX share similar hydrophobicity and terpenoid structure. JO markedly enhanced EE of PTX from 23% to 87.8% and EC from 35 ± 6 to 74 ± 8 µg PTX/mg PEG-PCL. JO also markedly increased the residual amount of PTX after 69 h, from 18.3% to 65%. Moreover, PTX cytotoxicity against human NSCLC A549 cells was significantly enhanced due to the co-encapsulation with JO; the IC50 value for PTX encapsulated within JO-containing APT-NPs was 20-fold lower than that for APT-NPs lacking JO. Remarkably, JO-containing APT-NPs displayed a 6-fold more potent cell-killing, relatively to the free-drug. Collectively, these findings reveal a marked synergistic contribution of JO to the cytotoxic activity of APT-NP-based systems, for targeted PTX delivery against NSCLC, which may be readily applied to various hydrophobic chemotherapeutics.


Asunto(s)
Antineoplásicos/administración & dosificación , Nanopartículas/química , Paclitaxel/administración & dosificación , Aceites Vegetales/química , Células A549 , Humanos , Polietilenglicoles/química
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