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AIM: To compare the efficacy and safety of folinic acid, fluorouracil and irinotecan (FOLFIRI) plus bevacizumab or aflibercept in metastatic colorectal cancer (mCRC) patients pretreated with oxaliplatin-based chemotherapy. MATERIALS AND METHODS: We analysed the treatment outcomes of patients receiving FOLFIRI in combination with bevacizumab or aflibercept as second-line treatment for mCRC between October 2017 and March 2020. This analysis included 67 patients receiving FOLFIRI plus aflibercept and 83 receiving FOLFIRI plus bevacizumab. RESULTS: The overall response rate (ORR) was 13.6% (95% confidence interval 4.85-22.34) in the FOLFIRI-aflibercept group and 14.7% (95% confidence interval 6.68-22.71) in the FOLFIRI-bevacizumab group. This difference in ORR was not statistically significant. The median progression-free survival was 8.6 months in the FOLFIRI-bevacizumab group and 8.5 months in the FOLFIRI-aflibercept group (P = 0.752). Patients in the FOLFIRI-bevacizumab group showed a median overall survival of 12.4 months, whereas patients in the FOLFIRI-aflibercept group had a median overall survival of 13.7 months (P = 0.276). There were no significant differences in survival between the two treatment groups. The adverse events were also largely similar between the two groups. However, hypertension of grade 3 or more was more frequent in the FOLFIRI-aflibercept group. CONCLUSION: FOLFIRI plus bevacizumab and FOLFIRI plus aflibercept had similar anti-tumour activities and toxicity profiles when used as second-line therapy in mCRC patients. Based on these data, both aflibercept and bevacizumab are suitable anti-angiogenic agents when used in combination with FOLFIRI for mCRC.
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Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias del Recto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/efectos adversos , Camptotecina/efectos adversos , Neoplasias del Colon/tratamiento farmacológico , Fluorouracilo/efectos adversos , Humanos , Irinotecán , Leucovorina/efectos adversos , Metástasis de la Neoplasia , Receptores de Factores de Crecimiento Endotelial Vascular , Proteínas Recombinantes de Fusión , Neoplasias del Recto/tratamiento farmacológicoRESUMEN
BACKGROUND: There is no clear consensus on the recommended second-line treatment for patients with metastatic pancreatic cancer who have disease progression following gemcitabine-based therapy. We retrospectively evaluated the clinical outcomes of liposomal irinotecan (nal-IRI) plus fluorouracil/leucovorin (FL) and FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin) in patients who had failed on the first-line gemcitabine-based therapy. PATIENTS AND METHODS: From January 2015 to August 2019, 378 patients with MPC who had received nal-IRI/FL (n = 104) or FOLFIRINOX (n = 274) as second-line treatment across 11 institutions were included in this retrospective study. RESULTS: There were no significant differences in baseline characteristics between groups, except age and first-line regimens. With a median follow-up of 6 months, the median progression-free survival (PFS) was 3.7 months with nal-IRI/FL versus 4.6 months with FOLFIRINOX (P = 0.44). Median overall survival (OS) was 7.7 months with nal-IRI/FL versus 9.7 months with FOLFRINOX (P = 0.13). There was no significant difference in PFS and OS between the two regimens in the univariate and multivariate analyses. The subgroup analysis revealed that younger age (<70 years) was associated with better OS with FOLFIRINOX. In contrast, older age (≥70 years) was associated with better survival outcomes with nal-IRI/FL. Adverse events were manageable with both regimens; however, the incidence of grade 3 or higher neutropenia and peripheral neuropathy was higher in patients treated with FOLFIRINOX than with nal-IRI/FL. CONCLUSIONS: Second-line nal-IRI/FL and FOLFIRINOX showed similar effectiveness outcomes after progression following first-line gemcitabine-based therapy. Age could be the determining factor for choosing the appropriate second-line therapy.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Pancreáticas , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Fluorouracilo/efectos adversos , Humanos , Irinotecán/uso terapéutico , Leucovorina/efectos adversos , Oxaliplatino/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , República de Corea , Estudios RetrospectivosRESUMEN
BACKGROUND: Adjuvant chemotherapy and chemoradiotherapy are some of the standards of care for gastric cancer (GC). The Adjuvant chemoRadioTherapy In Stomach Tumors (ARTIST) 2 trial compares two adjuvant chemotherapy regimens and chemoradiotherapy in patients with D2-resected, stage II or III, node-positive GC. PATIENTS AND METHODS: The ARTIST 2 compared, in a 1:1:1 ratio, three adjuvant regimens: oral S-1 (40-60 mg twice daily 4 weeks on/2 weeks off) for 1 year, S-1 (2 weeks on/1 week off) plus oxaliplatin 130 mg/m2 every 3 weeks (SOX) for 6 months, and SOX plus chemoradiotherapy 45 Gy (SOXRT). Randomization was stratified according to surgery type (total or subtotal gastrectomy), pathologic stage (II or III), and Lauren histologic classification (diffuse or intestinal/mixed). The primary endpoint was disease-free survival (DFS) at 3 years; a reduction of 33% in the hazard ratio (HR) for DFS with SOX or SOXRT, when compared with S-1, was considered clinically meaningful. The trial is registered at clinicaltrials.gov (NCT0176146). RESULTS: A total of 546 patients were recruited between February 2013 and January 2018 with 182, 181, and 183 patients in the S-1, SOX, and SOXRT arms, respectively. Median follow-up period was 47 months, with 178 DFS events observed. Estimated 3-year DFS rates were 64.8%, 74.3%, and 72.8% in the S-1, SOX, and SOXRT arms, respectively. HR for DFS in the control arm (S-1) was shorter than that in the SOX and SOXRT arms: S-1 versus SOX, 0.692 (P = 0.042) and S-1 versus SOXRT, 0.724 (P = 0.074). No difference in DFS was found between SOX and SOXRT (HR 0.971; P = 0.879). Adverse events were as anticipated in each arm, and were generally well-tolerated and manageable. CONCLUSIONS: In patients with curatively D2-resected, stage II/III, node-positive GC, adjuvant SOX or SOXRT was effective in prolonging DFS, when compared with S-1 monotherapy. The addition of radiotherapy to SOX did not significantly reduce the rate of recurrence after D2 gastrectomy.
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Neoplasias Gástricas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Capecitabina/uso terapéutico , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Fluorouracilo/uso terapéutico , Humanos , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Oxaliplatino/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patologíaRESUMEN
BACKGROUND: Patients with metastatic pancreatic cancer often have a detriment in health-related quality of life (HRQoL). In the randomized, double-blind, phase III POLO trial progression-free survival was significantly longer with maintenance olaparib, a poly(ADP-ribose) polymerase inhibitor, than placebo in patients with a germline BRCA1 and/or BRCA2 mutation (gBRCAm) and metastatic pancreatic cancer whose disease had not progressed during first-line platinum-based chemotherapy. The prespecified HRQoL evaluation is reported here. PATIENTS AND METHODS: Patients were randomized to receive maintenance olaparib (300 mg b.i.d.; tablets) or placebo. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item module at baseline, every 4 weeks until disease progression, at discontinuation, and 30 days after last dose. Scores ranged from 0 to 100; a ≥10-point change or difference between arms was considered clinically meaningful. Adjusted mean change from baseline was analysed using a mixed model for repeated measures. Time to sustained clinically meaningful deterioration (TSCMD) was analysed using a log-rank test. RESULTS: Of 154 randomized patients, 89 of 92 olaparib-arm and 58 of 62 placebo-arm patients were included in HRQoL analyses. The adjusted mean change in Global Health Status (GHS) score from baseline was <10 points in both arms and there was no significant between-group difference [-2.47; 95% confidence interval (CI) -7.27, 2.33; P = 0.31]. Analysis of physical functioning scores showed a significant between-group difference (-4.45 points; 95% CI -8.75, -0.16; P = 0.04). There was no difference in TSCMD for olaparib versus placebo for GHS [P = 0.25; hazard ratio (HR) 0.72; 95% CI 0.41, 1.27] or physical functioning (P = 0.32; HR 1.38; 95% CI 0.73, 2.63). CONCLUSIONS: HRQoL was preserved with maintenance olaparib treatment with no clinically meaningful difference compared with placebo. These results support the observed efficacy benefit of maintenance olaparib in patients with a gBRCAm and metastatic pancreatic cancer. CLINCALTRIALS.GOV NUMBER: NCT02184195.
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Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias Pancreáticas/tratamiento farmacológico , Ftalazinas/administración & dosificación , Piperazinas/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Adulto , Anciano , Método Doble Ciego , Femenino , Mutación de Línea Germinal/genética , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Ftalazinas/efectos adversos , Piperazinas/efectos adversos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Supervivencia sin Progresión , Calidad de VidaRESUMEN
BACKGROUND: Capecitabine plus oxaliplatin (XELOX) has shown modest activity and tolerable toxicity in a phase II trial for biliary tract cancers (BTCs). Meanwhile, gemcitabine plus oxaliplatin (GEMOX) has been the reference arm in recent phase II and III trials for BTCs. We aimed to investigate the efficacy of XELOX versus GEMOX as first-line therapy for advanced BCTs. PATIENTS AND METHODS: In this open-label, randomized, phase III, noninferiority trial, we randomly selected patients with metastatic BCTs to receive GEMOX (gemcitabine 1000 mg/m2 on days 1 and 8, and oxaliplatin 100 mg/m2 on day 1) or XELOX (capecitabine 1000 mg/m2, twice daily, on days 1-14 and oxaliplatin 130 mg/m2 on day 1) as first-line treatment, given every 3 weeks, totaling eight cycles. The primary end point was to prove the noninferiority of XELOX to GEMOX in terms of 6-month progression-free survival (PFS) rate. RESULTS: In total, 114 patients randomly received GEMOX and 108 randomly received XELOX. The median PFS was 5.3 months for the GEMOX group and 5.8 months for the XELOX group. The 6-month PFS rate was 44.5% for the GEMOX group and 46.7% for the XELOX group. The 95% confidence interval of the 6-month PFS rate difference between both groups was -12% to 16%, meeting the criteria for noninferiority of XELOX to GEMOX. There was no difference in objective response (P=0.171) and median overall survival (P=0.131) between both groups. The most common grade three to four adverse events were neutropenia and thrombocytopenia. No patient died of treatment-related causes. The XELOX group had significantly lower frequencies of hospital visits than the GEMOX group (P<0.001). CONCLUSION: XELOX showed significant noninferiority to GEMOX in terms of 6-month PFS rate. Thus, XELOX could be an alternative first-line treatment of BCTs. TRIAL REGISTRATION: This study was registered in ClinicalTrials.gov (number NCT01470443).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Sistema Biliar/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias del Sistema Biliar/patología , Capecitabina/administración & dosificación , Capecitabina/efectos adversos , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Femenino , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Oxaliplatino/administración & dosificación , Oxaliplatino/efectos adversos , Supervivencia sin Progresión , Tasa de Supervivencia , GemcitabinaRESUMEN
Background: To identify predictive markers for responders in lapatinib-treated patients and to demonstrate molecular changes during lapatinib treatment via cell-free genomics. Patients and methods: We prospectively evaluated the efficacy of combining lapatinib with capecitabine and oxaliplatin as first line neoadjuvant therapy in patients with previously untreated, HER2-overexpressing advanced gastric cancer. A parallel biomarker study was conducted by simultaneously performing immunohistochemistry and next-generation sequencing (NGS) with tumor and blood samples. Results: Complete response was confirmed in 7/32 patients (21.8%), 2 of whom received radical surgery with pathologic-confirmed complete response. Fifteen partial responses (46.8%) were observed, resulting in a 68.6% overall response rate. NGS of the 16 tumor specimens demonstrated that the most common co-occurring copy number alteration was CCNE1 amplification, which was present in 40% of HER2+ tumors. The relationship between CCNE1 amplification and lack of response to HER2-targeted therapy trended toward statistical significance (66.7% of non-responders versus 22.2% of responders harbored CCNE1 amplification; P = 0.08). Patients with high level ERBB2 amplification by NGS were more likely to respond to therapy, compared with patients with low level ERBB2 amplification (P = 0.02). Analysis of cfDNA showed that detectable ERBB2 copy number amplification in plasma was predictive to the response (100%, response rate) and changes in plasma-detected genomic alterations were associated with lapatinib sensitivity and/or resistance. The follow-up cfDNA genomics at disease progression demonstrated that there are emergences of other genomic aberrations such as MYC, EGFR, FGFR2 and MET amplifications. Conclusions: The present study showed that HER2+ GC patients respond differently according to concomitant genomic aberrations beyond ERBB2, high ERBB2 amplification by NGS or cfDNA can be a positive predictor for patient selection, and tumor genomic alterations change significantly during targeted agent therapy.
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Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Antineoplásicos/uso terapéutico , Lapatinib/uso terapéutico , Receptor ErbB-2/genética , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Adulto , Anciano , Anciano de 80 o más Años , Sistema Libre de Células , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Adulto JovenRESUMEN
OBJECTIVES: The aim was to evaluate the importance of clinical factors in the prediction of postoperative complications in patients with microvascular reconstruction for head and neck squamous cell cancer (HNSCC). DESIGN: A retrospective review of case notes was performed. SETTING: Patients treated at a single institute. PARTICIPANTS: This study included 259 patients with HNSCC treated with radical surgery and microvascular reconstruction between 1993 and 2014. MAIN OUTCOME MEASURES: We allocated the patients to three groups using a preoperative comorbidity score based on risk factors: group A (≥3 risk factors, n = 16), group B (2 risk factors, n = 49) and group C (0 or 1 risk factor, n = 194). RESULTS: Surgical mortality in this cohort was 1.9% (5 of 259 patients). The preoperative comorbidity score was associated with surgical mortality (P < .001). Pharyngocutaneous fistula (P = .001) and flap compromise (P = .023) were more frequent as preoperative comorbidity score increased. Preoperative comorbidity score (P < .001), advanced age (P = .007), advanced pathologic T stage (P = .028), advanced pathologic N stage (P = .005), preoperative (chemo) radiotherapy (P < .001), history of cardiovascular disease (P = .015) and pulmonary disease (P = .007), and diabetes (P < .001) had significant adverse effects on 5 year disease-specific survival (DSS) in a univariate analysis. The 5-DSS rates of groups A, B and C were 30%, 37% and 70%, respectively. Multivariate analysis showed that preoperative comorbidity score was significantly correlated with 5 year DSS (hazard ratio [HR], 3.56; 95% confidence interval [CI], 1.81-6.99; P < .001 for group A and HR, 1.91; 95% CI, 1.15-3.18; P = .013 for group B compared with group C). CONCLUSION: Patients with a high preoperative comorbidity score have an increased risk of surgical mortality and morbidity after microvascular reconstruction for HNSCC.
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Carcinoma de Células Escamosas/cirugía , Colgajos Tisulares Libres , Neoplasias de Cabeza y Cuello/cirugía , Microcirugia/efectos adversos , Procedimientos de Cirugía Plástica/efectos adversos , Complicaciones Posoperatorias/epidemiología , Adulto , Anciano , Carcinoma de Células Escamosas/mortalidad , Femenino , Neoplasias de Cabeza y Cuello/mortalidad , Humanos , Masculino , Microcirugia/mortalidad , Persona de Mediana Edad , Procedimientos de Cirugía Plástica/mortalidad , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: This study aimed to identify the effect of lateral neck dissection on voice change in thyroidectomised patients. METHODS: Medical records from 264 patients who underwent thyroidectomy with (n = 65) or without (n = 199) lateral neck dissection were reviewed. Clinical and voice evaluation data were compared between the two groups. RESULTS: Patients who underwent surgery that included lateral neck dissection had lower fundamental frequencies and speaking fundamental frequencies. They also had a higher incidence of asymmetric mucosal wave and vocal fold oedema on videostroboscopy during the first month after surgery, with the incidence of vocal fold oedema remaining significantly higher at three months. Self-assessed voice quality scores were significantly higher in lateral neck dissection patients at both one and three months after surgery. CONCLUSION: In thyroidectomised patients, lateral neck dissection lowers the vocal pitch in the initial period after surgery and induces vocal fold oedema that persists for several months. Although most objective parameters improved within a month, subjective symptoms lasted for longer.
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Disección del Cuello/efectos adversos , Neoplasias de la Tiroides/cirugía , Tiroidectomía/métodos , Trastornos de la Voz/epidemiología , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Trastornos de la Voz/etiología , Calidad de la VozRESUMEN
BACKGROUND: The MAP2K1 K57T mutation is known to be a potential mechanism of primary and secondary resistance to EGFR inhibitors in metastatic colorectal cancer (CRC) and has also been reported to promote resistance to BRAF and MEK inhibitors. It is important to overcome therapeutic resistance to EGFR inhibitors to improve the treatment outcomes of metastatic CRC. METHODS: We established patient-derived tumor cells (PDCs) from metastatic lesions that newly appeared during treatment with a BRAF inhibitor (LGX-818) plus an EGFR inhibitor (cetuximab) in a patient with BRAF-mutant CRC. To investigate therapeutic options to overcome acquired resistance due to MAP2K1 mutation in BRAF-mutant CRC, we performed cell viability assays using the PDCs. RESULTS: We tested whether the PDCs were resistant to an EGFR inhibitor (cetuximab) and a BRAF inhibitor (sorafenib) as these cells were established at the time of resistance to the EGFR plus BRAF inhibitors. Moreover, the anti-tumor effect of AZD6244 (MEK inhibitor) was evaluated because PDCs harbored a MAP2K1 mutation at the time of resistance to the EGFR plus BRAF inhibitors. MTT proliferation assays showed that monotherapy with cetuximab, sorafenib, or AZD6244 did not suppress cell viability. We next tested viability of the PDCs to combination treatment with cetuximab plus AZD6244 and sorafenib plus AZD6244. Proliferation of PDCs was significantly inhibited by sorafenib and AZD6244, but not by cetuximab plus AZD6244. Investigation of the combined effect of sorafenib and AZD6244 using the calculated combination index (CI) showed synergistic effects of sorafenib and AZD6244 in combination therapy applied to PDCs with the MAP2K1 K57T mutation. CONCLUSION: Our results suggest that combination treatment with BRAF and MEK inhibitors might be a novel treatment strategy for MAP2K1 K57T-mutant CRC. This finding will be helpful to guide treatment of patients with CRC that is resistant to EGFR inhibitors.
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Nanoliposomal irinotecan (nal-IRI) is a liposomal formulation of irinotecan with a longer half-life (t1/2 ), higher plasma total irinotecan (tIRI), and lower SN-38 maximum concentration (Cmax ) compared with nonliposomal irinotecan. Population pharmacokinetic (PK) analysis of nal-IRI was performed for tIRI and total SN-38 (tSN38) using patient samples from six studies. PK-safety association was evaluated for neutropenia and diarrhea in 353 patients. PK-efficacy association was evaluated from a phase III study in pancreatic cancer NAPOLI1. Efficacy was associated with longer duration of unencapsulated SN-38 (uSN38) above a threshold and higher Cavg of tIRI, tSN38, and uSN38. Neutropenia was associated with uSN38 Cmax and diarrhea with tIRI Cmax . Baseline predictive factors were race, body surface area, and bilirubin. Analysis identified PK factors associated with efficacy, safety, and predictive baseline factors. The results support the benefit of nal-IRI dose of 70 mg/m2 (free-base; equivalent to 80 mg/m2 salt base) Q2W over 100 mg/m2 Q3W.
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Camptotecina/análogos & derivados , Liposomas/efectos adversos , Liposomas/farmacocinética , Neoplasias/metabolismo , Adulto , Anciano , Camptotecina/efectos adversos , Camptotecina/sangre , Camptotecina/farmacocinética , Ensayos Clínicos como Asunto , Diarrea/inducido químicamente , Femenino , Humanos , Irinotecán , Liposomas/sangre , Masculino , Persona de Mediana Edad , Neoplasias/sangre , Neoplasias/tratamiento farmacológico , Neutropenia/inducido químicamenteRESUMEN
Background: Targeting oncogenic genomic aberrations is an established therapeutic strategy in multiple tumor types. Molecular classification has uncovered a number of novel targets, and rapamycin-insensitive companion of mTOR (RICTOR) amplification has been identified in lung cancer. Further investigation assessing the therapeutic potential of RICTOR amplification as a novel target across advanced cancers is needed. Patients and methods: Tumor samples from 640 patients with metastatic solid tumors, primarily gastrointestinal and lung cancers were prospectively subjected to a next-generation sequencing (NGS) assay to identify molecular targets. Samples with NGS-detected RICTOR amplification were confirmed with FISH. A RICTOR-amplified patient-derived cell (PDC) line was generated and used to investigate the effectiveness of selective AKT, mTORC1, and mTORC1/2 inhibition. Results: NGS identified 13 (2%) of 640 patients with RICTOR-amplified tumors (6 gastric, 3 NSCLC, 1 SCLC, 1 CRC, 1 sarcoma, 1 MUO). Of the 13 patients, seven patients had RICTOR protein overexpression by IHC. The prevalence of RICTOR amplification in gastric cancer by NGS was 3.8% (6/160). FISH testing confirmed amplification (RICTOR/control >2) in 5/13 (38%) of samples, including four gastric cancers and one lung cancer. Treatment of a RICTOR amplified PDC with a selective AKT (AZD5363), selective mTORC1 (everolimus), dual mTORC1/2 (AZD2014), and the multi-target kinase inhibitor pazopanib demonstrated preferential sensitivity to the mTORC1/2 inhibitor (AZD2014). Knockdown of RICTOR reversed PDC sensitivity to AZD2014, validating the importance of RICTOR amplification to the PDC line. Conclusions: RICTOR amplification is a rare but therapeutically relevant genomic alteration across solid tumors. Our results support further pre-clinical and clinical investigation with AZD2014 in RICTOR amplified gastric cancer and highlights the importance of genomic profiling.
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Neoplasias Pulmonares/tratamiento farmacológico , Morfolinas/administración & dosificación , Proteína Asociada al mTOR Insensible a la Rapamicina/genética , Neoplasias Gástricas/tratamiento farmacológico , Adulto , Anciano , Benzamidas , Línea Celular Tumoral , Everolimus/administración & dosificación , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Diana Mecanicista del Complejo 2 de la Rapamicina/genética , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirimidinas , Proteína Asociada al mTOR Insensible a la Rapamicina/biosíntesis , Transducción de Señal/efectos de los fármacos , Sirolimus/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Serina-Treonina Quinasas TOR/genéticaRESUMEN
BACKGROUND: The purpose of this randomised phase III trial was to evaluate whether the addition of simvastatin, a synthetic 3-hydroxy-3methyglutaryl coenzyme A reductase inhibitor, to XELIRI/FOLFIRI chemotherapy regimens confers a clinical benefit to patients with previously treated metastatic colorectal cancer. METHODS: We undertook a double-blind, placebo-controlled phase III trial of 269 patients previously treated for metastatic colorectal cancer and enrolled in 5 centres in South Korea. Patients were randomly assigned (1:1) to one of the following groups: FOLFIRI/XELIRI plus simvastatin (40 mg) or FOLFIRI/XELIRI plus placebo. The FOLFIRI regimen consisted of irinotecan at 180 mg m(-2) as a 90-min infusion, leucovorin at 200 mg m(-2) as a 2-h infusion, and a bolus injection of 5-FU 400 mg m(-2) followed by a 46-h continuous infusion of 5-FU at 2400 mg m(-2). The XELIRI regimen consisted of irinotecan at 250 mg m(-2) as a 90-min infusion with capecitabine 1000 mg m(-2) twice daily for 14 days. The primary end point was progression-free survival (PFS). Secondary end points included response rate, duration of response, overall survival (OS), time to progression, and toxicity. RESULTS: Between April 2010 and July 2013, 269 patients were enrolled and assigned to treatment groups (134 simvastatin, 135 placebo). The median PFS was 5.9 months (95% CI, 4.5-7.3) in the XELIRI/FOLFIRI plus simvastatin group and 7.0 months (95% CI, 5.4-8.6) in the XELIRI/FOLFIRI plus placebo group (P=0.937). No significant difference was observed between the two groups with respect to OS (median, 15.9 months (simvastatin) vs 19.9 months (placebo), P=0.826). Grade⩾3 nausea and anorexia were noted slightly more often in patients in the simvastatin arm compared with with the placebo arm (4.5% vs 0.7%, 3.0% vs 0%, respectively). CONCLUSIONS: The addition of 40 mg simvastatin to the XELIRI/FOLFIRI regimens did not improve PFS in patients with previously treated metastatic colorectal cancer nor did it increase toxicity.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Simvastatina/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Capecitabina/administración & dosificación , Capecitabina/uso terapéutico , Método Doble Ciego , Esquema de Medicación , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/uso terapéutico , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Irinotecán , Leucovorina/administración & dosificación , Leucovorina/uso terapéutico , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , República de Corea , Simvastatina/efectos adversos , Simvastatina/uso terapéutico , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Recent advances have raised hope that transplantation of adherent somatic cells could provide dramatic new therapies for various diseases. However, current methods for transplanting adherent somatic cells are not efficient enough for therapeutic applications. Here, we report the development of a novel method to generate quasi-natural cell blocks for high-efficiency transplantation of adherent somatic cells. The blocks were created by providing a unique environment in which cultured cells generated their own extracellular matrix. Initially, stromal cells isolated from mice were expanded in vitro in liquid cell culture medium followed by transferring the cells into a hydrogel shell. After incubation for 1 day with mechanical agitation, the encapsulated cell mass was perforated with a thin needle and then incubated for an additional 6 days to form a quasi-natural cell block. Allograft transplantation of the cell block into C57BL/6 mice resulted in perfect adaptation of the allograft and complete integration into the tissue of the recipient. This method could be widely applied for repairing damaged cells or tissues, stem cell transplantation, ex vivo gene therapy, or plastic surgery.
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Adolescente , Adulto , Humanos , Persona de Mediana Edad , Adulto Joven , Infección Hospitalaria/epidemiología , Enterocolitis Seudomembranosa/epidemiología , Sistemas de Registros Médicos Computarizados , Vigilancia de Guardia , Algoritmos , Automatización/métodos , Centers for Disease Control and Prevention, U.S. , Clostridioides difficile/aislamiento & purificación , Infección Hospitalaria/microbiología , Registros Electrónicos de Salud , Enterocolitis Seudomembranosa/diagnóstico , Heces/microbiología , Instituciones de Salud , Sensibilidad y Especificidad , Estados Unidos/epidemiologíaRESUMEN
Recent advances have raised hope that transplantation of adherent somatic cells could provide dramatic new therapies for various diseases. However, current methods for transplanting adherent somatic cells are not efficient enough for therapeutic applications. Here, we report the development of a novel method to generate quasi-natural cell blocks for high-efficiency transplantation of adherent somatic cells. The blocks were created by providing a unique environment in which cultured cells generated their own extracellular matrix. Initially, stromal cells isolated from mice were expanded in vitro in liquid cell culture medium followed by transferring the cells into a hydrogel shell. After incubation for 1 day with mechanical agitation, the encapsulated cell mass was perforated with a thin needle and then incubated for an additional 6 days to form a quasi-natural cell block. Allograft transplantation of the cell block into C57BL/6 mice resulted in perfect adaptation of the allograft and complete integration into the tissue of the recipient. This method could be widely applied for repairing damaged cells or tissues, stem cell transplantation, ex vivo gene therapy, or plastic surgery.
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Células Madre Adultas/trasplante , Adhesión Celular , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/citología , Tejido Adiposo/citología , Animales , Materiales Biocompatibles , Colágeno , Combinación de Medicamentos , Eficiencia , Femenino , Laminina , Masculino , Ratones Endogámicos C57BL , Cultivo Primario de Células/métodos , Proteoglicanos , Andamios del Tejido , Trasplante Homólogo/métodosRESUMEN
OBJECTIVES: The purpose of this study was to determine whether preoperative (18) F-FDG PET/CT is useful in assessing contralateral lymph node metastasis in the neck. DESIGN: A retrospective review of medical records was performed. SETTING: Patients treated at a single institute. PARTICIPANTS: One hundred and fifty-seven patients whose pathology results were positive for unilateral node metastasis (N1-3) involvement and underwent preoperative (18) F-FDG PET/CT for head and neck squamous cell carcinoma (HNSCC) were reviewed. MAIN OUTCOME MEASURES: Prognostic factors and nodal SUVmax were studied to identify the risk of contralateral disease. RESULTS: Thirty-six (22.9%) patients had contralateral cervical lymph node metastases. The (18) F-FDG PET/CT had a sensitivity of 80% and a specificity of 96% in identifying the contralateral cervical lymph node metastases on a level-by-level basis. The median SUVmax values of the ipsilateral and contralateral lymph nodes were 3.99 ± 3.36 (range, 0-20.4) and 2.94 ± 2.04 (range, 0-8.7), respectively (P = 0.001). There was a significant difference in the median SUVmax of contralateral nodes between the benign and malignant cervical lymph nodes (2.31 ± 0.62 versus 3.28 ± 2.43, P = 0.014). The cut-off value of contralateral median SUVmax in the context of contralateral cervical metastasis was 2.5 with the sensitivity of 75% and the specificity of 94%. A median contralateral lymph node SUVmax ≥ 2.5 was associated with 5-year disease-specific survival (P = 0.038). CONCLUSION: (18) F-FDG PET/CT median SUVmax cut-off values of contralateral lymph nodes ≥2.5 were associated with contralateral cervical lymph node metastases and 5-year disease-specific survival in HNSCC patients with unilateral metastases.
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Carcinoma de Células Escamosas/patología , Fluorodesoxiglucosa F18 , Neoplasias de Cabeza y Cuello/patología , Metástasis Linfática/patología , Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos X , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/diagnóstico por imagen , Carcinoma de Células Escamosas/mortalidad , Femenino , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Neoplasias de Cabeza y Cuello/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Cuello/diagnóstico por imagen , Estadificación de Neoplasias , Periodo Preoperatorio , Pronóstico , Estudios RetrospectivosRESUMEN
AIM: The study aimed to determine the adequacy of the distal margin in patients having preoperative chemoradiotherapy (CRT) followed by restorative surgery for rectal cancer. METHOD: A total of 368 patients with locally advanced rectal cancer treated for cure at our institution between July 1999 and March 2009 were included in the study. All underwent preoperative CRT and sphincter-sparing surgery. The distal margin and other factors were examined for their effect on recurrence and survival. The median duration of follow-up was 48 months. RESULTS: The length of distal margin ranged from 0 to 9.0 cm (median 1.5 cm). The pelvic control and disease-free survival rates at 5 years for patients with a margin of ≤ 3 mm were no different from those in whom it was > 3 mm (P = 0.6 and 0.8). The 5-year pelvic control rates between the ≤ 3 mm and > 3 mm groups were 66.7 and 86.2% in patients with a ypT3-4 tumour (P = 0.049) and 70.0 and 89.1% in patients who showed no response to CRT (P = 0.039). CONCLUSION: The results suggest that a distal margin of < 3 mm in the surgical specimen after preoperative CRT is associated with a lower rate of pelvic tumour control at 5 years in patients with Stage ypT3-4 tumours or in those who do not respond to CRT.
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Neoplasias del Recto/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Canal Anal , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioradioterapia , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Tratamientos Conservadores del Órgano/métodos , Dosificación Radioterapéutica , Neoplasias del Recto/mortalidad , Neoplasias del Recto/patología , Neoplasias del Recto/terapia , Resultado del TratamientoAsunto(s)
Cobamidas/uso terapéutico , Dermatitis Atópica/tratamiento farmacológico , Prurito/tratamiento farmacológico , Vitaminas/uso terapéutico , Administración Cutánea , Niño , Preescolar , Cobamidas/administración & dosificación , Dermatitis Atópica/complicaciones , Femenino , Geles , Humanos , Concentración de Iones de Hidrógeno , Masculino , Satisfacción del Paciente , Prurito/etiología , Índice de Severidad de la Enfermedad , Piel/química , Temperatura Cutánea , Vitaminas/administración & dosificación , Pérdida Insensible de AguaRESUMEN
BACKGROUND: Treatment options for patients with metastatic gastroenteropancreatic neuroendocrine tumours (GEP NETs) are still limited. We investigated the antitumour activity and safety profile of pazopanib--a multitarget drug with anti-angiogenic activity in patients with metastatic GEP NETs. METHODS: This was a nonrandomised, open-labeled, single-center phase II study. Pazopanib was orally administered at a dose of 800 mg daily continuously with a 28-day cycle. The primary end point was an objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST). The secondary end points were progression-free survival (PFS), overall survival (OS) and safety. An independent review of objective response was planned. The trial is registered with ClinicalTrials.gov, NCT number 01099540. Correlative biomarker analyses were performed. RESULTS: Between April 2010 and February 2012, a total of 37 patients were enrolled. Thirty-two percent of the enrolled patients had pancreatic primary and 22% of the patients had colorectal primary NETs. This phase II study demonstrated an objective response rate of 18.9% (7 of the 37, 95% CI 8.0-35.2) and a disease control rate (CR+confirmed PR+stable disease) of 75.7% (28 of the 37, 95% CI, 58.8-88.2) in metastatic GEP NETs. The independent review demonstrated a higher overall response rate of 24.3% (95% CI, 11.8-41.2%) with nine confirmed PRs. CONCLUSION: Pazopanib showed a comparable efficacy to other targeted agents not only in pancreatic NETs but also in NETs originating from gastrointestinal (GI) tract.
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Inhibidores de la Angiogénesis/uso terapéutico , Neoplasias Intestinales/tratamiento farmacológico , Tumores Neuroendocrinos/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Pirimidinas/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Sulfonamidas/uso terapéutico , Administración Oral , Adulto , Anciano , Inhibidores de la Angiogénesis/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Indazoles , Neoplasias Intestinales/patología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/patología , Pirimidinas/efectos adversos , Neoplasias Gástricas/patología , Sulfonamidas/efectos adversos , Tasa de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
The purpose of this study was to evaluate the use of (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) to identify extracapsular spread (ECS) with histologic correlations in oral squamous cell carcinoma (OSCC). The medical records of 80 patients who underwent of FDG PET/CT for OSCC before surgery were reviewed. ECS was present in 60% (24/40) dissected necks and in 55% (39/71) of dissected cervical levels. A significant difference was found between the maximum standardized uptake (SUVmax) values of cervical lymph nodes with ECS and without ECS (3.33±1.91 vs. 1.12±1.24, p<0.001). When receiver operating characteristic (ROC) curve analysis and SUVmax values were used to detect ECS, the area under the ROC curve was 0.864±0.045 (p<0.001). At an optimal SUVmax cut-off value of 2.25 the sensitivity and specificity were 85% and 88%, respectively. The presence of ECS and a SUVmax>2.25 had a significant adverse effect on 5-year disease specific survival. A SUV(max)>2.25 was found to be associated with a greater risk of cervical lymph node metastasis in OSCC.
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Carcinoma de Células Escamosas/patología , Neoplasias de la Boca/patología , Invasividad Neoplásica/patología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/diagnóstico por imagen , Carcinoma de Células Escamosas/cirugía , Supervivencia sin Enfermedad , Femenino , Fluorodesoxiglucosa F18 , Humanos , Ganglios Linfáticos/patología , Metástasis Linfática/diagnóstico por imagen , Metástasis Linfática/patología , Masculino , Persona de Mediana Edad , Suelo de la Boca/diagnóstico por imagen , Suelo de la Boca/patología , Suelo de la Boca/cirugía , Neoplasias de la Boca/diagnóstico por imagen , Neoplasias de la Boca/cirugía , Cuello , Invasividad Neoplásica/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Modelos de Riesgos Proporcionales , Curva ROC , Radioterapia Adyuvante , Estudios Retrospectivos , Estadísticas no Paramétricas , Tomografía Computarizada por Rayos X/métodos , Neoplasias de la Lengua/diagnóstico por imagen , Neoplasias de la Lengua/patología , Neoplasias de la Lengua/cirugía , Adulto JovenRESUMEN
BACKGROUND: Docetaxel is widely used as a chemotherapeutic agent for gastric cancer treatment. A combined regimen with sunitinib demonstrated a synergistic antitumour effect in a preclinical model. The aim of this study was to evaluate the efficacy and safety of this combination in patients with unresectable or metastatic advanced gastric cancer following failure of treatment with a fluoropyrimidine and platinum combination. METHODS: This open-label, phase II, randomised trial enrolled patients with unresectable or metastatic gastric cancer. Patients were assigned to either a docetaxel monotherapy arm (D only arm: 60 mg m(-2), every 3 weeks) or a combination arm (DS arm: docetaxel+sunitinib 37.5 mg every day). The primary end point of the study was time to progression and the secondary end points were overall response rate, disease control rate, overall survival, and toxicity profile. A pharmacokinetic study was also performed. RESULTS: A total of 107 patients were entered into the study. The TTP was not significantly prolonged in the DS arm when compared with the D only arm (DS vs D only arm: 3.9 months (95% confidence interval (CI) 2.9-4.9) vs 2.6 months (95% CI 1.8-3.5) (P=0.206). The hazard ratio for TTP was 0.77 (95% CI 0.52-1.16). However, the objective response rate was significantly higher in the DS arm (41.1% vs 14.3%, P=0.002). Patients in the DS arm experienced stomatitis, diarrhoea, and hand-foot syndrome more frequently. CONCLUSION: The addition of sunitinib to docetaxel did not significantly prolong TTP, although it significantly increased response.