RESUMEN
Despite the availability of multiple treatment options, the prognosis for advanced gastric cancer (AGC) remains poor and more effective treatment options are needed. Ramucirumab is an established and recommended second-line treatment for AGC. In recently completed and ongoing clinical trials, ramucirumab has been investigated in combination with new therapeutics and in new clinical settings to address the unmet treatment needs of AGC. In this review, the findings of recent clinical trials are discussed. The aims of this review are to present the current picture of ramucirumab-containing regimens in AGC and offer practical guidance on the clinical position and target populations of ramucirumab-containing regimens in light of emerging therapeutic developments.
Asunto(s)
Neoplasias Gástricas , Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Humanos , Paclitaxel/uso terapéutico , Pronóstico , Neoplasias Gástricas/tratamiento farmacológico , RamucirumabRESUMEN
BACKGROUND: This study evaluated the safety and effectiveness of ramucirumab monotherapy and combination therapy for advanced gastric cancer in the real-world setting. METHODS: This single-arm, prospective, multicenter, non-interventional, observational, post-marketing study was conducted in Japan from August 2015 to March 2019. Patients with unresectable advanced or recurrent gastric cancer and newly prescribed ramucirumab were followed for up to 12 months after first treatment. Data on adverse events and survival were collected via Electronic Data Capture. RESULTS: Of 687 enrolled patients, 658 were eligible for analysis. Most patients received either ramucirumab monotherapy (123/658; 18.7%) or ramucirumab plus paclitaxel combination therapy (528/658; 80.2%). The majority of patients reported ≥ 1 adverse events in both the combination therapy (any grade, 479/528; 90.7%; ≥ Grade 3, 321/528; 60.8%) and monotherapy groups (any grade, 77/123; 62.6%; ≥ Grade 3, 42/123; 34.2%). The most common any grade adverse events were neutropenia (combination: 49.6%; monotherapy: 8.9%), fatigue (combination: 19.5%; monotherapy: 13.8%), and decreased appetite (combination: 18.2%; monotherapy: 10.6%). Grade 5 adverse events were reported in 4 patients, including metastases to meninges, pneumonia aspiration, death, and gastric perforation; of these, gastric perforation was deemed treatment-related. Median survival time was 5.7 months (95% confidence interval: 4.1-6.8 months) following monotherapy and 11.0 months (95% confidence interval: 9.8-12.2 months) following combination therapy. CONCLUSIONS: This analysis adds to the limited data available on ramucirumab use in a real-world setting, demonstrating similar safety and effectiveness for ramucirumab in treating advanced gastric cancer in routine clinical practice in Japan to that of global clinical trials.
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Sistemas de Registro de Reacción Adversa a Medicamentos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Paclitaxel/uso terapéutico , Estudios Prospectivos , Neoplasias Gástricas/mortalidad , Análisis de Supervivencia , Adulto Joven , RamucirumabRESUMEN
Patients with advanced or metastatic gastric cancer often suffer from malnutrition, which can have an impact on quality of life, increase the toxicity of chemotherapy and reduce overall survival. Options available to the clinician to manage a patient's nutritional status include screening and assessment of malnutrition at diagnosis, monitoring during the 'cancer journey', early detection of precachexia and the ongoing use of a multidisciplinary team (oncologists, other medical specialists and nutritionists). Because malnutrition is frequently overlooked and under treated in patients with advanced or metastatic gastric cancer, this narrative review focuses on the clinical meaning of nutritional status in gastric cancer and provides general guidance regarding nutritional care management for patients with advanced or metastatic gastric cancer.
Lay abstract Patients with gastric cancer that has spread to other parts of the body often suffer from malnutrition. This can impact patients' lives, increase side effects from cancer treatment and reduce life expectancy. This article provides guidance for healthcare providers on nutritional care for patients with gastric cancer. Key ways healthcare providers can contribute to nutritional care include: looking for malnutrition when a patient is diagnosed with gastric cancer; watching carefully for malnutrition during cancer treatment; keeping a lookout for early signs of extreme weight loss and muscle wasting; and involving a team of healthcare providers with a broad range of expertise in patients' nutritional care.
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Desnutrición/dietoterapia , Apoyo Nutricional/métodos , Calidad de Vida , Neoplasias Gástricas/terapia , Humanos , Desnutrición/diagnóstico , Desnutrición/etiología , Desnutrición/psicología , Evaluación Nutricional , Neoplasias Gástricas/complicaciones , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/patologíaRESUMEN
Treatment options for patients with advanced gastric cancer (AGC) are limited. One approach to improving survival in patients with AGC is to optimize the available agents via sequential therapy. However, clinical trial reports of first-line chemotherapy indicate that elderly patients and patients with massive ascites are less likely to receive subsequent lines of therapy. In addition, clinical trials of second- and third-line chemotherapy generally exclude these two patient populations because they are likely to have poor performance status and additional issues that are difficult to manage. Good patient management is likely to be key to the successful use of sequential therapy in these two patient populations by minimizing adverse effects to allow patients to derive benefit from the additional treatment. This narrative review summarizes the available information on AGC treatment and patient management in elderly patients and patients with massive ascites. The available data suggest that elderly patients benefit from chemotherapy; however, monitoring toxicity is essential to avoid chemotherapy-related toxicities. Important aspects of patient management for elderly patients include symptom monitoring, nutritional support, and fall prevention. The available data for patients with massive ascites show limited success for a range of treatment approaches, including systemic chemotherapy. The management of ascites is also challenging, with no clear guidance on the preferred strategies. To address these gaps in knowledge, future clinical trials should incorporate more inclusive eligibility criteria to enroll populations of patients with AGC that are more reflective of the real-world population with respect to age, complications, and overall health status.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ascitis/terapia , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/terapia , Neoplasias Gástricas/tratamiento farmacológico , Anciano , Ascitis/etiología , Ascitis/patología , Manejo de la Enfermedad , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Humanos , Pronóstico , Neoplasias Gástricas/patologíaRESUMEN
We evaluated the incidence of proteinuria after receiving ramucirumab for the patients with advanced colorectal cancer using claim database. Among 1,706 evaluable patients, incidence proportion of proteinuria was 21.8% and incidence rate (/100 person-years)was 75.3. In patients with history of proteinuria or previous bevacizumab use, incidence rate was high and many patients tend to occur proteinuria in the early stage after initiating ramucirumab prescription. Appropriate management by periodical monitoring from the early stage after initiating ramucirumab prescription is important.
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Anticuerpos Monoclonales Humanizados/efectos adversos , Neoplasias Colorrectales , Proteinuria/epidemiología , Protocolos de Quimioterapia Combinada Antineoplásica , Estudios de Cohortes , Humanos , Incidencia , Japón , Proteinuria/inducido químicamente , RamucirumabRESUMEN
BACKGROUND: We evaluated the safety, tolerability, pharmacokinetics, and tumor response of ramucirumab in combination with one of three platinum/fluoropyrimidine regimens in Japanese patients with chemotherapy-naïve metastatic gastric/gastroesophageal junction cancer. METHODS: In this phase 1b study, patients received 8 mg/kg ramucirumab on days 1 and 8 every 3 weeks, following one of three regimens: capecitabine + cisplatin, XP; S-1 + cisplatin, SP; or S-1 + oxaliplatin, SOX. The primary objective was to assess safety and tolerability; the secondary objectives were to evaluate pharmacokinetics and tumor response. RESULTS: Six patients were treated in each cohort. All regimens were generally well tolerated, although 1 patient in SOX was associated with grade 3 enterocolitis, which was considered a dose-limiting toxicity. Common grade 3 or higher adverse events included neutropenia (1 in XP, 3 in SP, and 2 in SOX), decreased appetite (1 in SP), and hypertension (2 in XP). The mean trough ramucirumab concentrations were consistent across all cohorts, and those of most patients exceeded target levels, which were estimated from previous studies of the approved ramucirumab dose (8 mg/kg every 2 weeks). Among the 11 patients with measurable disease, overall response rate and disease control rate were 45.5% and 100.0%, respectively. Median progression-free survival (95% CI) was 7.6 months (6.0 to not estimable). CONCLUSION: Ramucirumab 8 mg/kg on days 1 and 8 every 3 weeks in combination with XP, SP, or SOX was generally well tolerated and demonstrated preliminary anti-tumor activity in chemotherapy-naïve Japanese metastatic gastric/gastroesophageal junction cancer patients.
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Adenocarcinoma/tratamiento farmacológico , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Adenocarcinoma/mortalidad , Anciano , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales Humanizados , Antineoplásicos Inmunológicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Capecitabina/administración & dosificación , Capecitabina/efectos adversos , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Supervivencia sin Enfermedad , Combinación de Medicamentos , Unión Esofagogástrica/patología , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Oxaliplatino , Ácido Oxónico/administración & dosificación , Ácido Oxónico/efectos adversos , Neoplasias Gástricas/mortalidad , Tegafur/administración & dosificación , Tegafur/efectos adversos , RamucirumabRESUMEN
BACKGROUND: In the AVAGAST study, fluoropyrimidine and cisplatin plus bevacizumab did not significantly improve overall survival (OS) versus fluoropyrimidine and cisplatin plus placebo in patients with advanced gastric cancer. Geographic differences in efficacy were observed in AVAGAST, but the study only included 12 Chinese patients. AVATAR, a study similar in design to AVAGAST, was a randomized, double-blind, phase III study conducted in Chinese patients with advanced gastric cancer. METHODS: Patients more than 18 years of age with gastric adenocarcinoma were randomized 1:1 to capecitabine-cisplatin plus either bevacizumab or placebo. The primary endpoint was OS; secondary endpoints included progression-free survival (PFS) and safety. RESULTS: In total, 202 patients were included (placebo n = 102; bevacizumab n = 100). Baseline characteristics were well balanced. The primary analysis result did not show a difference in OS for the bevacizumab arm compared to the placebo arm [hazard ratio, 1.11 (95% CI, 0.79-1.56); P = 0.5567]. Median PFS was also similar in both arms. Bevacizumab plus capecitabine-cisplatin was well tolerated. Grade 3-5 adverse events (AEs) occurred in 60% of bevacizumab-treated and 68% of placebo-treated patients, respectively. Grade 3-5 AEs of special interest with bevacizumab occurred in 8% of bevacizumab-treated patients and 15% of placebo-treated patients, mainly grade 3-5 hemorrhage (bevacizumab 4%, placebo 12%). CONCLUSIONS: Addition of bevacizumab to capecitabine-cisplatin in Chinese patients with advanced gastric cancer did not improve outcomes in AVATAR. There was no difference in OS between the two arms and PFS was similar in both arms. Safety findings were as previously experienced with bevacizumab, including AVAGAST; no new safety signals were reported.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Unión Esofagogástrica/patología , Neoplasias Gástricas/tratamiento farmacológico , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Pueblo Asiatico , Bevacizumab , Capecitabina , Cisplatino/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Supervivencia sin Enfermedad , Método Doble Ciego , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Resultado del TratamientoRESUMEN
BACKGROUND: Beer is a popular alcoholic malt beverage resulting from fermentation of the aqueous extract of malted barley with hops. The aroma of brewing barley impacts the flavor of beer indirectly, because some flavor compounds or their precursors in beer come from the barley. The objectives of this research were to study volatile profiles and to characterize odor-active compounds of brewing barley in order to determine the variability of the aroma composition among different brewing barley cultivars. RESULTS: Forty-one volatiles comprising aldehydes, ketones, alcohols, organic acids, aromatic compounds and furans were identified using solid phase microextraction combined with gas chromatography/mass spectrometry, among which aldehydes, alcohols and ketones were quantitatively in greatest abundance. Quantitative measurements performed by means of solvent extraction and calculation of odor activity values revealed that acetaldehyde, 2-methylpropanal, 3-methylbutanal, 2-methylbutanal, hexanal, heptanal, octanal, nonanal, 3-methyl-1-butanol, cyclopentanol, 2,3-butanedione, 2,3-pentanedione, 2-heptanone, acetic acid, ethyl acetate, 2-pentylfuran and benzeneacetaldehyde, whose concentrations exceeded their odor thresholds, could be considered as odor-active compounds of brewing barley. CONCLUSION: Principal component analysis was employed to evaluate the differences among cultivars. The results demonstrated that the volatile profile based on the concentrations of aroma compounds enabled good differentiation of most barley cultivars.
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Productos Agrícolas/química , Hordeum/química , Semillas/química , Compuestos Orgánicos Volátiles/análisis , Alcoholes/análisis , Aldehídos/análisis , Cerveza/análisis , Cerveza/microbiología , Fermentación , Cromatografía de Gases y Espectrometría de Masas , Cetonas/análisis , Análisis Multivariante , Odorantes , Análisis de Componente Principal , Reproducibilidad de los Resultados , Plantones/química , Umbral Sensorial , Microextracción en Fase Sólida , Especificidad de la EspecieRESUMEN
Hazelnut, one of the most popular tree nuts, is widely found in processed food and even very small amounts can trigger severe allergic reactions in susceptible people. Herein, we developed a sensitive and rapid method based on CRISPR and qPCR capable of detecting low-abundance hazelnut in processed food. The assay, known as CRISPR-based nucleic acid test method (Crinac) can detect 1 % of hazelnut in a mixture and allows the species to be identified in a complex processed sample. The detection process can be completed within 60 min. Contributed to amplification via PCR and CRISPR/Cas12a, enables end-fluorescence measurement for the quantification of hazelnut, thus reducing assay time and eliminating the need for costly real-time fluorescence PCR instruments. The assay based on CRISPR/Cas12 and PCR has potential as a sensitive and reliable analytical tool for the detection of food authenticity.
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Corylus , Proteínas de Plantas , Humanos , Proteínas de Plantas/análisis , Corylus/genética , Sistemas CRISPR-Cas , Análisis de los Alimentos/métodos , Técnicas de Amplificación de Ácido Nucleico/métodos , Reacción en Cadena en Tiempo Real de la Polimerasa/métodosRESUMEN
BACKGROUND: Oxaliplatin-containing adjuvant regimens (folinic acid, fluorouracil, and oxaliplatin/capecitabine and oxaliplatin [FOLFOX/CAPOX]) are used after curative resection of colorectal cancer (CRC). However, real-world evidence regarding treatment sequences and outcomes in patients with early recurrence CRC after adjuvant chemotherapy is limited. OBJECTIVE: We aimed to describe the patient characteristics, treatment sequence, and overall duration of second-line (2L) therapy in patients with early recurrence CRC who received adjuvant chemotherapy (FOLFOX/CAPOX) followed by folinic acid, fluorouracil, and irinotecan (FOLFIRI) + anti-angiogenesis drugs (AA) or FOLFIRI + anti-epidermal growth factor receptor (EGFR) antibodies. METHODS: This retrospective study analyzed Japanese administrative data from November 2014 to March 2023 of adult patients who underwent CRC resection surgery, started FOLFOX/CAPOX ≤3 months (mo) after surgery, and had early CRC recurrence. Early recurrence was defined as initiation of FOLFIRI+AA or FOLFIRI+anti-EGFR antibodies as 2L therapy, ≤12 mo of discontinuing adjuvant chemotherapy. Patient characteristics, treatment sequence, median time to treatment discontinuation (mTTD), i.e., duration between the start and end dates of 2L therapy (Kaplan-Meier method), and factors associated with 2L time to treatment discontinuation constituted the study outcomes (Cox regression model). Subgroup analyses were performed for timing of early CRC recurrence (≤6 mo and 6-12 mo) and tumor sidedness. RESULTS: Among the 832 selected patients (median age [minimum-maximum] 67 (24-86) years, 56.4% male), CAPOX (71.3%) was more commonly used than FOLFOX (28.7%) as adjuvant therapy. FOLFIRI+AA (72.5%) was used more commonly than FOLFIRI+anti-EGFR antibodies (27.5%) in 2L. AA and anti-EGFR antibodies groups had similar mTTD: 6.2 mo (95% confidence interval 5.8, 6.9) and 6.1 mo (95% confidence interval 5.2, 7.4). Age ≥70 years showed significant association with shorter 2L treatment duration (hazard ratio 1.2, 95% confidence interval 1.0, 1.4; p = 0.03). The AA cohort's mTTD was numerically shorter in the ≤6 mo recurrence subgroup compared with the 6-12 mo recurrence subgroup (6.1 mo vs 8.1 mo); the anti-EGFR antibodies cohort had similar mTTD (5.8 mo vs 6.2 mo). The AA and anti-EGFR antibodies cohorts also had similar mTTD in the left-sided CRC subgroup (6.5 mo vs 6.2 mo), but not in the right-sided subgroup (5.6 mo vs 3.9 mo). CONCLUSIONS: This is the first administrative data-based real-world evidence on treatment sequence and outcomes for patients with early recurrence CRC treated with FOLFIRI+AAs or FOLFIRI+ anti-EGFR antibodies after adjuvant FOLFOX/CAPOX therapy in Japan. Both regimens had similar TTD, but relapse timing and tumor sidedness may influence their efficacy.
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Inhibidores de la Angiogénesis , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Colorrectales , Fluorouracilo , Leucovorina , Recurrencia Local de Neoplasia , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de la Angiogénesis/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Quimioterapia Adyuvante/métodos , Neoplasias Colorrectales/tratamiento farmacológico , Pueblos del Este de Asia , Receptores ErbB , Fluorouracilo/uso terapéutico , Japón , Leucovorina/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Compuestos Organoplatinos/uso terapéutico , Estudios RetrospectivosRESUMEN
Aflatoxin B1 (AFB1), a hepatotoxic and carcinogenic food contaminant, is commonly found in agricultural food. Herein, Au NPs anchored ZIF-8-derived porous carbon-ZnO (Au NPs/PCZIF-8-ZnO) was firstly synthesized to act as the sensing substrate. Then, a ratiometric electrochemical (EC) and "off-on" photoelectrochemical (PEC) dual-mode paper-based aptasensor was presented for AFB1 detection based on a distance-modulation sensing strategy. The independent signal transduction mechanisms and output mode not only broaden the dynamic detection range but also provide a self-verification to assay results, improving the sensitivity and reliability. The wide detection ranges of 0.1 pg/mL-100 ng/mL (EC mode) and 0.02 pg/mL-100 ng/mL (PEC mode) were obtained using dual-mode aptasensor, with detection limits of 36.7 and 9.3 fg/mL, respectively. The fabricated aptasensor exhibited excellent selectivity, reproducibility and stability. Furthermore, it exhibited good practicability for AFB1 assays in real samples, demonstrating great potential applications for food safety evaluation.
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Aptámeros de Nucleótidos , Técnicas Biosensibles , Nanopartículas del Metal , Óxido de Zinc , Aflatoxina B1/análisis , Reproducibilidad de los Resultados , Técnicas Biosensibles/métodos , Técnicas Electroquímicas/métodos , Límite de Detección , OroRESUMEN
Due to the long-term and irrational use of antibiotics for the prevention and control of bacterial diseases in aquaculture, antibiotic resistance genes have become a new source of pollution in aquatic products. Factors such as the spread of drug-resistant strains and the horizontal transfer of drug-resistant genes have led to multi-drug resistance in fish-infecting bacteria, which seriously affects the quality and safety of aquatic products. In this study, 50 samples of horse mackerel and puffer fish sold in Dalian aquatic products market and seafood supermarket were collected, and the phenotypic characteristics of the bacteria carried by the fish for drugs such as sulfonamides, amide alcohols, quinolones, aminoglycosides and tetracyclines were tested and analyzed, and the resistance genes carried by fish samples were detected by SYBG qPCR. Our statistical analyses demonstrated that the drug resistance phenotypes and genotypes of bacteria carried by mariculture horse mackerel and puffer fish in the Dalian area of China were complex, and the multi-drug resistance rate reached 80%. Among the examined antibiotics, the resistance rates to cotrimoxazole, tetracycline, chloramphenicol, ciprofloxacin, norfloxacin, levofloxacin, kanamycin, and florfenicol exceeded 50%, whereas the resistance rates to gentamicin and tobramycin were 26 and 16%, respectively. The detection rate of the drug resistance genes tetA, sul1, sul2, qnrA, qnrS, and floR exceeded 70% and all samples carried more than three drug resistance genes. The correlation analysis of drug resistance genes and drug resistance phenotypes showed that the detection of the drug resistance genes sul1, sul2, floR, and qnrD was correlated with the detection of drug resistance phenotypes (p < 0.01). However, the correlation between the resistance genes cmlA, cfr, tetA, qnrA, qnrS, and aac(6')-Ib-cr and the corresponding resistance phenotype was not significant (p > 0.05). In general, our findings indicated that the multi-drug resistance of bacteria carried by marine horse mackerel and puffer fish in the Dalian area was serious. From the perspective of drug resistance rate and drug resistance gene detection rate, the aminoglycosides gentamicin and tobramycin are still considered effective in controlling bacterial infection in marine fish in the study area. Collectively, our findings provide a scientific basis for the management of drug use in mariculture, which can prevent the transmission of drug resistance through the food chain and minimize the associated human health risks.
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PURPOSE: Liver metastasis (LM) is reported in approximately 40% of patients with advanced/metastatic gastric/gastroesophageal junction adenocarcinoma (metastatic esophagogastric adenocarcinoma; mGEA) and is associated with a worse prognosis. This post-hoc analysis from the RAINBOW trial reported the efficacy, safety, and biomarker outcomes of ramucirumab and paclitaxel combination treatment (RAM+PAC) in patients with (LM+) and without (LM-) LM at baseline. MATERIALS AND METHODS: Patients (n=665) were randomly assigned on a 1:1 basis to receive either RAM+PAC (LM+: 150, LM-: 180) or placebo and paclitaxel (PL+PAC) (LM+: 138, LM-: 197). The overall survival (OS) and progression-free survival (PFS) were evaluated using stratified Kaplan-Meier and Cox regression models. The correlation of dichotomized biomarkers (VEGF-C, D; VEGFR-1,2) with efficacy in the LM+ versus LM- subgroups was analyzed using the Cox regression model with reported interaction P-values. RESULTS: The presence of LM was associated with earlier progression than those without LM, particularly in patients receiving PL+PAC (hazard ratio [HR], 1.68). RAM+PAC treatment improved OS and PFS irrespective of LM status but showed greater improvement in LM+ than that in LM- (OS HR, 0.71 [LM+] vs. 0.88 [LM-]; PFS HR, 0.47 [LM+] vs. 0.76 [LM-]). Treatment-emergent adverse events were similar between patients with and without LM. No predictive relationship was observed between biomarker levels (VEGF-C, D; VEGFR-1,2) and efficacy outcome (OS, PFS) (all interaction P-values >0.05). CONCLUSIONS: RAM provided a significant benefit, irrespective of LM status; however, its effect was numerically stronger in patients with LM. Therefore, RAM+PAC is a clinically meaningful therapeutic option for patients with mGEA and LM. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01170663.
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A novel rutin-α-L-rhamnosidase hydrolyzing α-L-rhamnoside of rutin, naringin, and hesperidin was purified and characterized from Aspergillus niger DLFCC-90, and the gene encoding this enzyme, which is highly homologous to the α-amylase gene, was cloned and expressed in Pichia pastoris GS115. The novel enzyme was classified in glycoside-hydrolase (GH) family 13.
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Aspergillus niger/enzimología , Flavanonas/metabolismo , Glicósido Hidrolasas/genética , Glicósido Hidrolasas/metabolismo , Hesperidina/metabolismo , Rutina/metabolismo , Secuencia de Aminoácidos , Aspergillus niger/genética , Aspergillus niger/metabolismo , Clonación Molecular , ADN de Hongos/química , ADN de Hongos/genética , Expresión Génica , Glicósido Hidrolasas/aislamiento & purificación , Datos de Secuencia Molecular , Pichia/genética , Análisis de Secuencia de ADN , Homología de Secuencia de AminoácidoRESUMEN
INTRODUCTION: Clinical trials have proven the efficacy and safety of new therapies for advanced gastric cancer (AGC), but how those therapies are used in the real world is poorly described. Real-world treatment patterns of antitumor therapies and factors associated with overall therapy duration in patients with AGC in Japan were investigated. METHODS: This retrospective cohort study used a Japanese administrative claims database (June 2014 to September 2019). Patients with AGC who started the guideline-recommended first-line combination regimens with platinum and fluoropyrimidine agents between June 2015 and July 2019 were included. Cox regression analysis was performed to identify factors associated with overall therapy duration (first line to last administration of guideline-listed agent). RESULTS: Of the 10,581 patients included, the most common first-line combination regimen without trastuzumab was S-1 plus oxaliplatin (4327/9069 patients; 47.7%) and with trastuzumab was capecitabine plus cisplatin (608/1512 patients; 40.2%). Most common second- and third-line regimens were ramucirumab plus taxane (3650/5358 patients; 68.1%) and nivolumab (1229/2390 patients; 51.4%), respectively. Factors positively associated with longer overall therapy duration were: oral fluoropyrimidine in first line (hazard ratio [95% confidence interval]: 0.63 [0.57-0.69]); trastuzumab in any line (0.73 [0.68-0.78]); treatment at a designated cancer hospital (0.89 [0.84-0.94]); dietary consultation within 1 month before/after start of first line (0.92 [0.86-0.98]); and treatment at a surgical department (0.94 [0.89-0.99]). Negatively associated factors were: edema (1.21 [1.07-1.37]); physical therapy (1.21 [1.12-1.31]); nutritional intervention (1.21 [1.14-1.28]) within 1 month before/after start of first line; thrombosis (1.13 [1.04-1.23]); renal disease (1.11 [1.02-1.21]); age (1.07 [1.02-1.13]); and peritoneal metastasis/ascites (1.06 [1.01-1.13]). CONCLUSIONS: In real-world treatment practice for AGC in Japan, therapy choice after the recommended first-line chemotherapy was consistent with guidelines. Factors associated with overall therapy duration were identified, which may assist in optimizing treatment sequence.
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Neoplasias Gástricas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Capecitabina/uso terapéutico , Humanos , Japón , Estudios Retrospectivos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patologíaRESUMEN
Food authenticity is a critical issue associated with the economy, religion, and food safety. Herein, we report a label-free and colorimetric nucleic acid assay for detecting DNA barcodes, enabling the determination of food authenticity with the naked eye. This method, termed the CRISPR-based colorimetric DNA barcoding (Cricba) assay, utilizes CRISPR/Cas12a (CRISPR = clustered regularly interspaced short palindromic repeats; Cas = CRISPR associated protein) to specifically recognize the polymerase chain reaction (PCR) products for further trans-cleavaging the peroxidase-mimicking G-quadruplex DNAzyme. Based on this principle, the presence of the cytochrome oxidase subunit I gene could be directly observed with the naked eye via the color change of 3,3',5,5'-tetramethylbenzidine sulfate (TMB). The whole detection process, including PCR amplification and TMB colorimetric analysis, can be completed within 90 min. The proposed assay can detect pufferfish concentrations diluted to 0.1% (w/w) in a raw pufferfish mixture, making it one of the most sensitive methods for food authenticity. The robustness of the assay was verified by testing four common species of pufferfish, including Lagocephalus inermis, Lagocephalus spadiceus, Takifugu bimaculatus, and Takifugu alboplumbeus. The assay is advantageous in easy signal readout, high sensitivity, and general applicability and thus could be a competitive candidate for food authenticity.
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Colorimetría , ADN Catalítico , Animales , Colorimetría/métodos , Código de Barras del ADN Taxonómico , ADN , TakifuguRESUMEN
The objectives were to describe treatment sequences for advanced colorectal cancer (CRC), use of second-line FOLFIRI (leucovorin, 5-fluorouracil, irinotecan) plus antiangiogenic drug (bevacizumab, ramucirumab, aflibercept beta) therapy, and the factors associated with the duration of antitumor drug treatment from second-line antiangiogenic therapy in Japan. This retrospective observational study was conducted using a Japanese hospital-based administrative database. Patients were enrolled if they started adjuvant therapy (and presumably experienced early recurrence) or first-line treatment for advanced CRC between May 2016 and July 2019, and were analysed until September 2019. Factors associated with overall treatment duration from second-line treatment with FOLFIRI plus antiangiogenic drugs were explored with multivariate Cox regression analysis. The most common first-line treatments were FOLFOX (leucovorin, 5-fluorouracil, oxaliplatin) or CAPOX (capecitabine, oxaliplatin) with bevacizumab (presumed RAS-mutant CRC) and FOLFOX with panitumumab (presumed RAS-wild type CRC). The most common second-line treatments were FOLFIRI-based. Many patients did not transition to subsequent lines of therapy. For second-line treatment, antiangiogenic drugs were prescribed more often for patients with presumed RAS-mutant CRC, right-sided CRC, and independent activities of daily living (ADL). The median duration of second-line FOLFIRI plus antiangiogenic drug treatment was 4.5 months; 66.2% of patients transitioned to third-line therapy. Low body mass index and not fully independent ADL were significantly associated with shorter overall duration of antitumor drug treatment from second-line therapy. Left-sided CRC, presumed RAS-wild type CRC, previous use of oral fluoropyrimidines and use of proteinuria qualitative tests, antihypertensives, or anticholinergics during second-line therapy were significantly associated with longer treatment. Treatment of advanced CRC in Japan is consistent with both international and Japanese guidelines, but transition rates to subsequent therapies need improvement. In addition to antitumor drug treatment, better ADL, higher body mass index, management of hypertension, and proteinuria tests were associated with continuation of sequential therapy that included antiangiogenic drugs.
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Inhibidores de la Angiogénesis/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Camptotecina/análogos & derivados , Neoplasias Colorrectales/tratamiento farmacológico , Adulto , Camptotecina/uso terapéutico , Estudios de Cohortes , Bases de Datos Factuales , Femenino , Fluorouracilo/uso terapéutico , Humanos , Japón , Leucovorina/uso terapéutico , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
This phase 1, multi-center, nonrandomized, open-label, dose-escalation study consisted of Part A wherein merestinib 80 or 120 mg (40-mg tablets) was administered orally QD during a 28-day cycle to patients diagnosed with solid tumors and Part B wherein merestinib 80 mg (40-mg tablets) was administered orally QD, and cisplatin 25 mg/m2 + gemcitabine 1000 mg/m2 administered IV on Day 1 and Day 8 of a 21-day cycle (for a maximum of eight cycles) to patients diagnosed with biliary tract carcinoma (BTC). Nineteen patients were screened and 18 patients were (Part A, n = 10; Part B, n = 8) enrolled in the trial and received treatment. All patients in Parts A and B were from Japan and were within an age range of 43-73 years, with an ECOG PS of 0.1. No dose-limiting toxicity or deaths were experienced in the study. Dose-limiting toxicity equivalent toxicity of Grade 4 platelet count decreased (n = 1) and was observed in Part B. In Part A, treatment-related Grade ≥3 TEAEs were reported in one patient (PT: ALT increased and AST increased), while in Part B, five patients reported treatment-related Grade ≥3 TEAEs with four of the five patients reporting an event of neutrophil count decreased. No complete response was reported in either Part. One patient in Part B reported partial response while four patients in each part reported stable disease. Merestinib monotherapy was concluded to be tolerable in Japanese patients, and its combination with cisplatin and gemcitabine is a tolerable regimen for Japanese patients with BTC. Trial registration: NCT03027284 (ClinicalTrials.gov) registered on 23 January 2017.
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Antineoplásicos/uso terapéutico , Indazoles/uso terapéutico , Neoplasias/tratamiento farmacológico , Niacinamida/análogos & derivados , Adulto , Anciano , Antineoplásicos/farmacología , Femenino , Humanos , Indazoles/farmacología , Japón , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Neoplasias/mortalidad , Niacinamida/farmacología , Niacinamida/uso terapéuticoRESUMEN
PURPOSE: We investigated the impact of infusion duration (30 and 60 min) on the pharmacokinetic profile of ramucirumab using a population pharmacokinetic (PopPK) modeling approach. We also assessed the relationship between infusion rate and incidence of immediate infusion-related reactions (IRRs; occurring on the day of administration) using ramucirumab phase II/III study data. METHODS: The impact of different infusion durations (30 vs. 60 min) on the time-course of ramucirumab concentration profiles were evaluated using a PopPK model, established using ramucirumab pharmacokinetic data from 2522 patients. Logistic regression was used to evaluate the association between ramucirumab infusion rate and incidence of immediate IRRs in clinical trials. RESULTS: Ramucirumab time-course concentration profiles were equivalent following a 30- or 60-min infusion. In the pooled clinical study dataset, 254 of 3216 (7.9%) patients receiving ramucirumab experienced at least one immediate IRR (any grade). When grouped according to infusion rate quartile, the incidence of immediate IRRs (any grade or grade ≥ 3) was similar across quartiles; findings were confirmed in sensitivity analyses. The risk of immediate IRRs was not found to be associated with infusion rate based on multivariate logistic analysis. CONCLUSION: Shortening the infusion duration of ramucirumab from 60 to 30 min has no impact on ramucirumab exposure. Analysis of trial data found no relationship between an increased risk of immediate IRRs and a faster infusion rate. Such a change in infusion duration is unlikely to affect the clinical efficacy or overall safety profile of ramucirumab.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Antineoplásicos/administración & dosificación , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacocinética , Femenino , Humanos , Infusiones Intravenosas , Modelos Logísticos , Masculino , Persona de Mediana Edad , Modelos Biológicos , Factores de Tiempo , RamucirumabRESUMEN
BACKGROUND AND OBJECTIVE: Gastric cancer has been associated with notable geographic heterogeneity in previous multi-regional studies. In particular, patients from Japan have better outcomes compared with patients from other regions. Here, we assess patient-focused outcomes for the subgroup of Japanese patients in the global RAINBOW study. METHODS: Quality of life (QoL) was assessed using the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 (QLQ-C30) at baseline and 6-week intervals. Investigators assessed performance status before each 4-week cycle. Time-to-deterioration in each QLQ-C30 scale was defined as randomization to first worsening of ≥ 10 points (on a 100-point scale). Time-to-deterioration in performance status was defined as first worsening to ≥ 2. Hazard ratios were estimated using Cox proportional hazards models. RESULTS: The Japan subgroup contained 140 patients (ramucirumab plus paclitaxel, n = 68; placebo plus paclitaxel, n = 72); baseline QoL data were available for all patients. At baseline, QLQ-C30 scores were similar between study arms. Of the 15 QLQ-C30 scales, nine had a hazard ratio < 1, indicating similar or numerically longer time-to-deterioration in QoL for ramucirumab plus paclitaxel; all 95% confidence intervals included 1. Best mean change from baseline numerically favored ramucirumab plus paclitaxel in most QoL scales. The hazard ratios for time-to-deterioration of performance status to ≥ 2 were 0.64 in the Japan subgroup and 0.88 in the non-Asian subgroup. The Japan subgroup had better QoL at baseline compared with the non-Asian subgroup. CONCLUSIONS: Treatment with ramucirumab plus paclitaxel maintained QoL and performance status over time compared with placebo plus paclitaxel in the Japan subgroup of the RAINBOW trial. These data suggest that the heterogeneity in gastric cancer between geographic regions includes multiple measures of QoL. TRIAL REGISTRATION NUMBER: NCT01170663 (first submitted 21 July, 2010).