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BACKGROUND: Osimertinib is a recommended treatment for advanced non-small-cell lung cancer (NSCLC) with an epidermal growth factor receptor (EGFR) mutation and as adjuvant treatment for resected EGFR-mutated NSCLC. EGFR tyrosine kinase inhibitors have shown preliminary efficacy in unresectable stage III EGFR-mutated NSCLC. METHODS: In this phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with unresectable EGFR-mutated stage III NSCLC without progression during or after chemoradiotherapy to receive osimertinib or placebo until disease progression occurred (as assessed by blinded independent central review) or the regimen was discontinued. The primary end point was progression-free survival as assessed by blinded independent central review. RESULTS: A total of 216 patients who had undergone chemoradiotherapy were randomly assigned to receive osimertinib (143 patients) or placebo (73 patients). Osimertinib resulted in a significant progression-free survival benefit as compared with placebo: the median progression-free survival was 39.1 months with osimertinib versus 5.6 months with placebo, with a hazard ratio for disease progression or death of 0.16 (95% confidence interval [CI], 0.10 to 0.24; P<0.001). The percentage of patients who were alive and progression free at 12 months was 74% (95% CI, 65 to 80) with osimertinib and 22% (95% CI, 13 to 32) with placebo. Interim overall survival data (maturity, 20%) showed 36-month overall survival among 84% of patients with osimertinib (95% CI, 75 to 89) and 74% with placebo (95% CI, 57 to 85), with a hazard ratio for death of 0.81 (95% CI, 0.42 to 1.56; P = 0.53). The incidence of adverse events of grade 3 or higher was 35% in the osimertinib group and 12% in the placebo group; radiation pneumonitis (majority grade, 1 to 2) was reported in 48% and 38%, respectively. No new safety concerns emerged. CONCLUSIONS: Treatment with osimertinib resulted in significantly longer progression-free survival than placebo in patients with unresectable stage III EGFR-mutated NSCLC. (Funded by AstraZeneca; LAURA ClinicalTrials.gov number, NCT03521154.).
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Acrilamidas , Compuestos de Anilina , Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Receptores ErbB , Neoplasias Pulmonares , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Acrilamidas/uso terapéutico , Acrilamidas/efectos adversos , Compuestos de Anilina/uso terapéutico , Compuestos de Anilina/efectos adversos , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Quimioradioterapia/efectos adversos , Quimioradioterapia/métodos , Método Doble Ciego , Receptores ErbB/genética , Receptores ErbB/antagonistas & inhibidores , Indoles , Estimación de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Mutación , Estadificación de Neoplasias , Supervivencia sin Progresión , Pirimidinas , /uso terapéuticoRESUMEN
The direction and magnitude of immune responses are critically affected when dead cells are disposed of. Milk fat globule-epidermal growth factor-factor 8 (MFG-E8) promotes the engulfment of apoptotic normal and cancerous cells without inducing inflammation. We have previously reported that a certain proportion of the cancer cells express abundant MFG-E8, and that such expression is associated with the shorter survival of patients with esophageal cancer who had received chemotherapy before surgery. However, the influence of tumor-derived and systemically existing MFG-E8 on antitumor immune responses has not yet been fully investigated. Herein, we showed that CTL-dependent antitumor immune responses were observed in mice with no or decreased levels of systemic MFG-E8, and that such responses were enhanced further with the administration of anti-PD-1 antibody. In mice with decreased levels of systemic MFG-E8, the dominance of regulatory T cells in tumor-infiltrating lymphocytes was inverted to CD8+ T cell dominance. MFG-E8 expression by tumor cells appears to affect antitumor immune responses only when the level of systemic MFG-E8 is lower than the physiological status. We have also demonstrated in the clinical setting that lower levels of plasma MFG-E8, but not MFG-E8 expression in tumor cells, before the treatment was associated with objective responses to anti-PD-1 therapy in patients with non-small cell lung cancer. These results suggest that systemic MFG-E8 plays a critical role during the immunological initiation process of antigen-presenting cells to increase tumor-specific CTLs. Regulation of the systemic level of MFG-E8 might induce efficient antitumor immune responses and enhance the potency of anti-PD-1 therapy.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Esofágicas , Neoplasias Pulmonares , Animales , Humanos , Ratones , Antígenos de Superficie/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Esofágicas/tratamiento farmacológico , Inflamación/patología , Neoplasias Pulmonares/tratamiento farmacológico , Proteínas de la Leche/metabolismo , Linfocitos T Citotóxicos/metabolismoRESUMEN
Tepotinib is a highly selective MET tyrosine kinase inhibitor (TKI) that has demonstrated robust and durable clinical activity in patients with MET exon 14 (METex14) skipping non-small-cell lung cancer (NSCLC). In the Phase II VISION study, patients received oral tepotinib 500 mg once daily. The primary endpoint was an objective response by an independent review committee (IRC) according to RECIST v1.1 criteria. The secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Here we report the analysis of the efficacy and safety of tepotinib in all Japanese patients with advanced METex14 skipping NSCLC from VISION (n = 38) with >18 months' follow-up. The median age of the Japanese patients was 73 years (range 63-88), 39.5% of patients were ≥75 years old, 68.4% were male, 55.3% had a history of smoking, 76.3% had adenocarcinoma, and 10.5% of patients had known brain metastases at baseline. Overall, the objective response rate (ORR) was 60.5% (95% confidence interval (CI): 43.4, 76.0) with a median DOR of 18.5 months (95% CI: 8.3, not estimable). ORR in treatment-naïve patients (n = 18) was 77.8% (95% CI: 52.4, 93.6), and in patients aged ≥75 years (n = 15), ORR was 73.3% (95% CI: 44.9, 92.2). The most common treatment-related adverse event (AE) with any grade was blood creatinine increase (65.8%), which resolved following tepotinib discontinuation. Other common treatment-related AEs were peripheral edema (60.5%), hypoalbuminemia (34.2%), diarrhea (28.9%), and nausea (15.8%). In summary, tepotinib demonstrated robust and durable clinical activity irrespective of age or therapy line, with a manageable safety profile in Japanese patients with METex14 skipping NSCLC enrolled in VISION.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Piperidinas , Piridazinas , Pirimidinas , Humanos , Masculino , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Femenino , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Japón , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Exones/genética , Inhibidores de Proteínas Quinasas/efectos adversos , MutaciónRESUMEN
Hepatitis B virus (HBV) RNA and hepatitis B core-related antigen (HBcrAg) have been reported to reflect the transcriptional activity of covalently closed circular HBV DNA. We retrospectively investigated the proportions of quantifiable serum HBV RNA and immunoassay for total antigen including complex via pretreatment-hepatitis B core-related antigen (iTACT-HBcrAg) in chronic hepatitis B patients negative for hepatitis B e antigen (HBeAg) and/or with hepatitis B surface antigen (HBsAg) seroclearance. This study included 246 HBeAg-negative HBV-infected patients, who comprised 13 with liver cirrhosis (LC, the LC group), 118 chronic hepatitis (CH, the CH group), and 115 inactive carriers (IC, the IC group), and 44 patients with HBsAg seroclearance. iTACT-HBcrAg and HBV RNA levels were determined using stored serum samples. Higher proportions of the patients had quantifiable iTACT-HBcrAg than HBV RNA in all groups of HBeAg-negative patients (iTACT-HBcrAg: 84.6%, 90.7%, 35.7%, HBV RNA: 23.1%, 26.3%, 14.8%, for the LC, CH, IC groups). With HBsAg seroclearance (HBsAg <0.05 IU/mL), the proportions of quantifiable samples for HBV RNA were also lower than iTACT-HBcrAg (0% for HBV RNA). Thus, iTACT-HBcrAg was more often detectable than circulating HBV RNA in this study population. Further long-term prospective evaluation of iTACT-HBcrAg is desirable for its utilization in clinical practice.
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Antígenos del Núcleo de la Hepatitis B , Antígenos de Superficie de la Hepatitis B , Antígenos e de la Hepatitis B , Virus de la Hepatitis B , Hepatitis B Crónica , ARN Viral , Humanos , Hepatitis B Crónica/virología , Hepatitis B Crónica/sangre , Masculino , Femenino , Antígenos de Superficie de la Hepatitis B/sangre , ARN Viral/sangre , Persona de Mediana Edad , Estudios Retrospectivos , Adulto , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/inmunología , Virus de la Hepatitis B/aislamiento & purificación , Antígenos del Núcleo de la Hepatitis B/sangre , Antígenos e de la Hepatitis B/sangre , Anciano , Inmunoensayo/métodosRESUMEN
BACKGROUND AND AIM: Serum interleukin-6 (IL-6) before the administration of atezolizumab plus bevacizumab (Atez + Bev) is a prognostic biomarker in patients with hepatocellular carcinoma (HCC) treated with Atez + Bev. We previously revealed that the neutrophil-to-lymphocyte ratio and serum chemokine levels during treatment with Atez + Bev were more useful as prognostic biomarkers. Therefore, we examined the predictive ability of serum IL-6 for the efficacy of Atez + Bev in patients with HCC. METHODS: We enrolled 94 patients with HCC who received treatment with Atez + Bev. Initial responses were assessed through dynamic computed tomography or magnetic resonance imaging. The levels of IL-6 in serum were measured before and at the initiation of the second course of Atez + Bev. Subsequently, the relationship of IL-6 levels with treatment efficacy was evaluated. RESULTS: IL-6 levels at the initiation of the second course tended to be higher in patients with progressive disease versus those with non-progressive disease in the initial evaluation (P = 0.054). Moreover, the cutoff value (7.4 pg/mL) was useful in stratifying patients by overall survival (i.e. low vs high: not reached vs 21.4 months, respectively, P = 0.001) and progression-free survival (low vs high: 11.9 vs 5.2 months, respectively, P = 0.004). This result was reproduced in patients with HCC who received Atez + Bev as first-line therapy. In the multivariate analyses, IL-6 levels at the initiation of the second course were independent predictive factors for progression-free and overall survival. CONCLUSIONS: Serum levels of IL-6 at the initiation of the second course of treatment may predict Atez + Bev efficacy and prognosis in HCC.
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In this study, we aimed to investigate the antimicrobial susceptibility of Staphylococcus saprophyticus in Japan. Additionally, we evaluated the effectiveness of different therapeutic agents and compared the differences in their outcomes in treating S. saprophyticus-induced acute cystitis, considering that cephem antibiotics are standard treatments for acute cystitis in Japan. This retrospective study was conducted at ten hospitals housing urology departments, where urologists were dispatched from the Department of Nephro-Urology, Nagoya City University Graduate School of Medicine. Initially, we prepared a list of S. saprophyticus cases detected between January 2012 and December 2021, using the bacteriological testing system of each hospital. Subsequently, we reviewed the electronic medical records of the listed cases to investigate the causative diseases, treatments, and outcomes in patients with acute cystitis. The number of S. saprophyticus samples collected in this study was 289 from urine specimens, including 157 from women with acute cystitis. All antimicrobial agents demonstrated good therapeutic efficacy in all patients, except in those who did not return for follow-up visits (30 %). Furthermore, only one case of inadequate therapeutic efficacy was observed in a patient treated with a third-generation cephalosporin. All the other patients were cured. These findings revealed that the susceptibility of S. saprophyticus to different antimicrobials did not differ considerably between the specimens from patients with acute cystitis and those from other patients, suggesting a similar trend of therapeutic efficacies of the tested antimicrobials against S. saprophyticus-induced acute cystitis.
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AIM: We retrospectively investigated patients with administration of nucleos(t)ide analogs (NAs) for prevention of or against hepatitis B virus (HBV) reactivation, and their clinical outcomes after cessation of the NA. METHODS: We enrolled 180 patients who were positive for HBsAg when they started immunosuppressive therapy or chemotherapy and an NA was administered to prevent HBV reactivation (HBV carrier group), and 82 patients with resolved HBV infection who started administration of an NA after HBV reactivation (de novo HBV group). Cessation of the NA depended on each physician's judgment without definite criteria. RESULTS: A total of 27 patients in the HBV carrier group and 22 in the de novo HBV group stopped NA therapy. In the HBV carrier group, 16 patients experienced virological relapse, which was defined as HBV DNA levels ≥20 IU/ml, and one with hematological disease had an alanine aminotransferase flare after cessation of NA. Of the 16 patients, the NA was reintroduced in three, whereas, the remaining 13 had low levels of HBV DNA and no alanine aminotransferase flare. In the de novo HBV group, virological relapse occurred in six patients, and one with hematological disease had an alanine aminotransferase flare after cessation of the NA. The NA was reintroduced in four of the six patients. CONCLUSIONS: We may be able to consider to cease NA therapy proactively in HBV carriers and resolved patients with non-hematological disease, if their primary diseases are under remission after completion of immunosuppressive therapy or chemotherapy. However, careful follow up is necessary after stopping NA therapy.
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BACKGROUND: It is essential to collect a sufficient amount of tumor tissue for successful next-generation sequencing (NGS) analysis. In this study, we investigated the clinical risk factors for avoiding re-biopsy for NGS analysis (re-genome biopsy) in cases where a sufficient amount of tumor tissue could not be collected by bronchoscopy. METHODS: We investigated the association between clinical factors and the risk of re-genome biopsy in patients who underwent transbronchial biopsy (TBB) or endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and required re-genome biopsy in cases enrolled in LC-SCRUM Asia, a prospective nationwide genome screening project in Japan. We also examined whether the frequency of re-genome biopsy decreased between the first and second halves of the enrolment period. RESULTS: Of the 572 eligible patients, 236 underwent TBB, and 134 underwent EBUS-TBNA. Twenty-four TBBs required re-genome biopsy, and multivariate analysis showed that the risk of re-genome biopsy was significantly increased in lesions where the tumor lesion was centrally located. In these cases, EBUS-TBNA should be utilized even if the lesion is a pulmonary lesion. However, it should be noted that even with EBUS-TBNA, lung field lesions are at a higher risk of re-canalization than mediastinal lymph node lesions. It was also found that even when tumor cells were detected in rapid on-site evaluation, a sufficient amount of tumor tissue was not always collected. CONCLUSIONS: For centrally located pulmonary mass lesions, EBUS-TBNA, rather than TBB, can be used to obtain tumor tissues that can be analyzed by NGS.
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Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/patología , Estudios Retrospectivos , Estudios Prospectivos , Pulmón/patología , Broncoscopía , Biopsia por Aspiración con Aguja Fina Guiada por Ultrasonido Endoscópico , Sensibilidad y EspecificidadRESUMEN
It has been reported that the efficacy of EGFR-TKI is predicted, not by which exon of the EGFR gene is mutated, but by the structural change in the EGFR protein due to the mutation. Here, we present an EGFR-mutated lung cancer patient with a 13-year history of anticancer treatment, in which EGFR ex.19 deletion (E746_S752 > V) and G724S mutations were detected by liquid biopsy during 12th line afatinib treatment, and switching to dacomitinib showed improvement of cancerous meningitis. We choose dacomitinib as 14th line chemotherapy based on ex.19 deletion and G724S mutant EGFR structure and its penetration rate to cerebral fluid, which successfully prolonged her life by 6 months. The optimal EGFR-TKI may be selected by understanding the EGFR compound mutation profile by next generation sequencing and predicting the effect based on the structure. Dacomitinib may be effective choice in afatinib-refractory carcinomatous meningitis harboring G724S mutation. This is the first case report showing that a change to dacomitinib responded to afatinib refractory cancerous meningitis.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carcinomatosis Meníngea , Afatinib/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Receptores ErbB/genética , Receptores ErbB/metabolismo , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Carcinomatosis Meníngea/tratamiento farmacológico , Mutación , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/uso terapéutico , QuinazolinonasRESUMEN
BACKGROUND & AIMS: We recently analysed and reported the features of the micro biome under hepatitis C virus (HCV) infection, but the effect of HCV infection on bile acid (BA) metabolism in the gut-liver axis remains poorly understood. The aim of this study was to clarify the characteristics of the gut-liver axis in HCV-infected patients. METHODS: The faecal BAs composition and gut microbiota from 100 chronic hepatitis C (CHC) patients were compared with those from 23 healthy individuals. For transcriptional analysis of the liver, 22 mild CHC (fibrosis stages [F] 0-2) and 42 advanced CHC (F3-4) cases were compared with 12 healthy individuals. The findings were confirmed using chimeric mice with human hepatocytes infected with HCV HCR6. RESULTS: Chronic hepatitis C patients, even at earlier disease stages, showed BA profiles distinct from healthy individuals, in which faecal deoxycholic acid (DCA) was significantly reduced and lithocholic acid or ursodeoxycholic acid became dominant. The decrease in faecal DCA was correlated with reduction in commensal Clostridiales and increase in oral Lactobacillales. Impaired biosynthesis of cholic acid (CA) was observed as a reduction in the transcription level of cytochrome P450 8B1 (CYP8B1), a key enzyme in CA biosynthesis. The reductions in faecal DCA and liver CYP8B1 were also observed in HCV-infected chimeric mice. CONCLUSIONS: Chronic hepatitis C alters the intestinal BA profile, in association with the imbalance of BA biosynthesis, which differs from the pattern in NAFLD. These imbalances appear to drive disease progression through the gut-microbiome-liver axis.
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Microbioma Gastrointestinal , Hepatitis C Crónica , Animales , Ácidos y Sales Biliares/metabolismo , Hepacivirus , Hepatitis C Crónica/metabolismo , Humanos , Hígado/metabolismo , RatonesRESUMEN
AIMS: To prevent hepatitis B virus (HBV) reactivation-related hepatitis, we examined the clinical usefulness of a highly sensitive HB core-related antigen (iTACT-HBcrAg) assay in patients with resolved HBV infection after nucleos(t)ide analog (NA) treatment for HBV reactivation. METHODS: We retrospectively analyzed 27 patients with resolved HBV infection who experienced HBV reactivation (defined as HBV DNA levels of 1.3 log IU/ml or more), and who received systemic chemotherapies for hematological malignancies between 2008 and 2020. iTACT-HBcrAg, HBsAg-HQ, and antibodies against hepatitis B surface antigen (anti-HBs) were measured using samples stored after HBV reactivation. The lower limit of quantification for iTACT-HBcrAg was 2.0 log U/ml. RESULTS: HBV reactivation was diagnosed at a median HBV DNA level of 1.8 log IU/ml, and then all patients received NA treatment. No patient had HBV-related hepatitis with a median maximum HBV DNA level of 2.0 log IU/ml. The positivities of iTACT-HBcrAg and HBsAg-HQ were 96% and 52% after HBV reactivation, respectively. Of 25 patients with detectable iTACT-HBcrAg at the initiation of NA treatment, 17 (68%) achieved iTACT-HBcrAg loss. Median durations from NA treatment to HBV DNA loss and iTACT-HBcrAg loss or the last follow-up were 35 and 175 days, respectively. Recurrence of HBV reactivation after NA cessation was not observed in seven of eight patients who achieved iTACT-HBcrAg loss or seropositive for anti-HBs during follow-up, except for one without anti-HBs after allogeneic transplantation. CONCLUSIONS: iTACT-HBcrAg could be a potential surrogate marker for diagnosing early-stage HBV reactivation as well as safe cessation of NA treatment in patients with resolved HBV infection after HBV reactivation.
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BACKGROUND & AIMS: A fully automated, novel high-sensitivity hepatitis B core-related antigen assay (iTACT-HBcrAg) has been developed. We demonstrate the clinical utility of iTACT-HBcrAg for monitoring chronic hepatitis B (CHB) and for the early detection of HBV reactivation. METHODS: After fundamental assessments, the clinical performance of iTACT-HBcrAg was compared with other HBV markers. i) Serial sera, available from 161 HBeAg-negative patients with CHB and persistently undetectable HBV DNA, were measured by iTACT-HBcrAg and a conventional HBcrAg assay (G-HBcrAg). ii) Serial sera from 13 HBV-reactivated patients were measured by iTACT-HBcrAg and an ultra-high-sensitivity HBsAg immune complex transfer-chemiluminescent enzyme immunoassay (lower limit of detection; 0.0005 IU/ml, ICT-CLEIA) to compare HBV DNA detection. iii) To elucidate the various HBcrAg components detected by iTACT-HBcrAg, OptiPrep density gradient centrifugation analysis was performed on sera obtained before and after HBV reactivation. RESULTS: The analytical performance of iTACT-HBcrAg was satisfactory. The sensitivity of iTACT-HBcrAg (2.1 Log U/ml) was approximately 10-fold greater than that of G-HBcrAg (2.8 Log U/ml). i) HBcrAg was detectable in the sera of 97.5% (157/161) of patients with CHB by iTACT-HBcrAg, of whom 75.2% (121/161) had ≥2.8 Log U/ml HBcrAg and 22.4% (36/161) had 2.1-2.8 Log U/ml HBcrAg, which was undetectable by G-HBcrAg. ii) 9 and 2 of 13 HBV-reactivated patients were HBcrAg-positive by iTACT-HBcrAg before and at HBV DNA positivity, respectively; 7 and 4 were HBcrAg-positive by iTACT-HBcrAg before and at HBsAg-positivity by ICT-CLEIA, respectively. iii) The HBcrAg detected by iTACT-HBcrAg before HBV reactivation was contained in empty particles (22 KDa precore protein). CONCLUSIONS: iTACT-HBcrAg could be used to better monitor responses to anti-HBV treatments in HBeAg-negative patients and for the early detection of HBV reactivation. LAY SUMMARY: A fully automated, novel high-sensitivity hepatitis B core-related antigen assay (iTACT-HBcrAg) has been developed. iTACT-HBcrAg can be used to monitor HBeAg-negative patients with chronic hepatitis B, as well as for the early detection of HBV reactivation. iTACT-HBcrAg could be used as a general marker of disease progression and treatment response.
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Anticuerpos contra la Hepatitis B/análisis , Hepatitis B Crónica/sangre , Infección Latente/sangre , Resultado del Tratamiento , Adulto , Biomarcadores/análisis , Biomarcadores/sangre , Progresión de la Enfermedad , Femenino , Anticuerpos contra la Hepatitis B/sangre , Hepatitis B Crónica/diagnóstico , Humanos , Japón , Infección Latente/diagnóstico , Masculino , Persona de Mediana EdadRESUMEN
Exon 18 mutations account for only 3.6% of EGFR mutations, and tumors with exon 18 mutations are often unresponsive to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). We present a novel case of a lung adenocarcinoma with an exon 18 mutation resulting in a glycine to serine substitution at position 719 of the EGFR protein. The patient received osimertinib, a third generation EGFR-TKI, as the first-line treatment, but the disease progressed during treatment. Analysis of circulating free DNAs via next generation sequencing revealed TP53 mutations and EGFR and MET amplifications, as well as the exon 18 mutation. On the basis of these results, we administered afatinib, a second-generation TKI, and bevacizumab, a vascular endothelial growth factor inhibitor, as the second-line treatment. The patient's symptoms improved, and this treatment was continued for 12 months. This report suggests that afatinib plus bevacizumab can effectively treat osimertinib-refractory lung tumors with an exon 18 mutation.
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Adenocarcinoma del Pulmón/tratamiento farmacológico , Afatinib/uso terapéutico , Bevacizumab/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Acrilamidas/farmacología , Adenocarcinoma del Pulmón/genética , Adulto , Compuestos de Anilina/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos , Receptores ErbB/genética , Exones , Humanos , Neoplasias Pulmonares/genética , Masculino , MutaciónRESUMEN
Hepatitis B virus (HBV) reactivation under systemic chemotherapy or immunosuppressive therapy is a serious complication among HBV-resolved patients. Some medications, such as more than 2 weeks of corticosteroid therapy, can influence HBV reactivation; therefore, screening tests that measure hepatitis B surface antigen (HBsAg), hepatitis B core antibody, and hepatitis B surface antibody before therapy are required. Additionally, because HBV reactivation has been reported in patients positive for HBsAg treated with immune checkpoint inhibitors (ICIs), the prophylactic administration of nucleos(t)ide analogues prior to administering ICIs is recommended for HBsAg-positive patients. Under these circumstances, highly sensitive novel biomarkers are expected to be used for the early diagnosis of HBV reactivation. A fully automated high-sensitivity HBsAg assay (detection limit: 5 mIU/ml) by Lumipulse HBsAg-HQ, with 10-fold higher sensitivity than that of conventional assays, is currently used. Furthermore, ultra-sensitive HBsAg assays using a semi-automated immune complex transfer chemiluminescence enzyme immunoassay (ICT-CLEIA; detection limit: 0.5 mIU/ml) have been developed. Recently, a fully automated, novel high-sensitivity hepatitis B core-related antigen assay (iTACT-HBcrAg; cut-off value: 2.1 Log U/mL) has been developed and reported. The utility of ICT-CLEIA and iTACT-HBcrAg for the diagnosis of HBV reactivation appears comparable to the use of HBV DNA. In this review, we provide the latest information related to medications that influence HBV reactivation and recently developed novel biomarkers that predict and monitor HBV reactivation.
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BACKGROUND: The aim of this study was to evaluate the efficacy and safety of nab-paclitaxel plus cisplatin in chemotherapy-naïve patients with advanced non-small-cell lung cancer (NSCLC). METHODS: Chemotherapy-naïve patients with advanced NSCLC were eligible. In the phase I dose-escalation cohort (3 + 3 design), patients received nab-paclitaxel (80 or 100 mg/m2 given intravenously on days 1, 8 and 15) plus cisplatin (60 or 75 mg/m2 given intravenously on day 1) every 4 weeks. The maximum tolerated dose was not reached. Nab-paclitaxel (100 mg/m2 given intravenously on days 1, 8 and 15) plus cisplatin (75 mg/m2 given intravenously on day 1) every 4 weeks was selected for the phase II cohort. The primary endpoint was the objective response rate (ORR). RESULTS: Twenty-three patients (phase I, n = 6; phase II, n = 17) were enrolled, and 22 patients were eligible. The median age was 67.5 years (range 37-75), 90.9% were males, 45.5% had adenocarcinoma and 81.8% had stage IV disease. The ORR was 59.1% (90% confidence interval (CI); 41.8-74.4), and the disease control rate was 86.4% (95% CI; 66.7-95.3). The median progression-free survival was 5.1 months (95% CI; 4.0-6.7), and the median overall survival was 24.2 months (95% CI; 8.4 months to not estimable). The common grade ≥ 3 adverse events were neutropenia (31.8%), leukopenia (27.3%), lung infection (18.2%) and hyponatremia (18.2%). There was one instance of grade 2 interstitial pneumonia and no treatment-related death. CONCLUSIONS: Nab-paclitaxel plus cisplatin was well tolerated and associated with encouraging response outcomes in chemotherapy-naïve patients with advanced NSCLC. Further investigation is warranted. TRIAL REGISTRATION: UMIN Clinical Trials Registry: UMIN000011776; Date of registration: 17 September 2013; Date of enrolment of the first participant to the trial: 23 January 2014.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Adulto , Anciano , Albúminas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/etiología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Cisplatino/administración & dosificación , Femenino , Humanos , Quimioterapia de Inducción , Estimación de Kaplan-Meier , Neoplasias Pulmonares/etiología , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Mutación , Estadificación de Neoplasias , Paclitaxel/administración & dosificación , Pronóstico , Resultado del TratamientoRESUMEN
AIM: Although some relationships between gut microbiota and liver diseases have been reported, it remains uncertain whether changes in gut microbiota owing to differences in race, food and living environment have similar effects. Response to ursodeoxycholic acid (UDCA) may predict the long-term prognosis of patients with primary biliary cholangitis (PBC); however, little is known about the significance of the gut microbiome in patients with PBC. We elucidated the relationships among clinical profiles, biochemical response to UDCA and gut microbiome composition in patients with PBC. METHODS: Fecal samples from 76 patients with PBC treated at our hospital were collected; patients whose UDCA intake period was <1 year were excluded. The microbiome structures of patients were determined using 16S ribosomal RNA gene sequencing and were statistically compared with those of healthy subjects. The structures of patients in the UDCA responder (n = 43) and non-responder (n = 30) groups were compared according to the Nara criteria (reduction rate of gamma-glutamyl transpeptidase, ≥69%, after 1 year). RESULTS: Compared with healthy subjects, bacterial diversity was lower in patients with PBC, with a decreased abundance of the order Clostridiales and increased abundance of Lactobacillales. The UDCA non-responder group had a significantly lower population of the genus Faecalibacterium, known as butyrate-producing beneficial bacteria (P < 0.05), although no significant differences in gender, body mass index, medicated drugs or other serological data were indicated between these two groups. CONCLUSIONS: Gut dysbiosis with loss of beneficial Clostridiales commensals was observed in patients with PBC. Decrease in Faecalibacterium abundance might predict the long-term prognosis of patients with PBC.
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Aim: We aimed to improve the success rate of NGS (next-generation sequencing) analysis through improved strategies of lung cancer sampling. Materials & methods: The improvement strategies are as follows. Surgically resected specimens were preferentially submitted in cooperation with pathologists and surgeons. In bronchoscopic samples, the size of the sample collection device and the number of samples collected was increased. Results: The strategies increased the success rate of NGS analysis of DNA from 69.3 to 91.1%, and that of RNA from 64.6 to 90.0%. Discussion: The introduction of strategies aimed at improving the success of NGS analysis resulted in an improvement in the success rate and brought us closer to the delivery of effective precision medicine in cancer therapy.
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Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Neoplasias Pulmonares/genética , Adulto , Anciano , Anciano de 80 o más Años , ADN/análisis , Femenino , Humanos , Masculino , Persona de Mediana Edad , Medicina de Precisión , Estudios ProspectivosRESUMEN
The hepatitis B virus (HBV) cannot be removed completely from infected hepatocytes, owing to the presence of intrahepatic covalently closed circular DNA (cccDNA). As chronic hepatitis B (CHB) can progress to cirrhosis and hepatocellular carcinoma (HCC), predicting HCC development in high-risk patients with high viral replicative activity or advanced fibrosis is important. Novel serological biomarkers reflect intrahepatic viral replicative activity or the progression of liver fibrosis, indicating non-invasive alternatives to liver biopsy: (1) Hepatitis B core-related antigen (HBcrAg) correlates with serum HBV DNA and intrahepatic cccDNA. In CHB patients, a decrease in HBcrAg is associated with favorable outcomes. HBcrAg can predict HCC occurrence or recurrence. (2) Measurement of the Mac-2 binding protein glycosylation isomer (M2BPGi) has been introduced for the evaluation of liver fibrosis. An increase in M2BPGi in CHB patients is related to the progression of liver fibrosis and high potential (risk) of HCC development. Here, we describe the clinical applications of HBcrAg and M2BPGi in CHB patients. Additionally, because new potential therapeutic agents that eliminate intrahepatic cccDNA are being developed, monitoring of HBcrAg or M2BPGi might be suitable for evaluating therapeutic effects and the clinical outcomes. In conclusion, these would be appropriate surrogate markers for predicting disease progression.
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Antígenos de Neoplasias/sangre , Biomarcadores de Tumor/sangre , Carcinoma Hepatocelular/virología , Antígenos del Núcleo de la Hepatitis B/sangre , Hepatitis B Crónica/metabolismo , Neoplasias Hepáticas/virología , Biomarcadores/sangre , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/metabolismo , ADN Circular/metabolismo , Progresión de la Enfermedad , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/inmunología , Hepatitis B Crónica/inmunología , Humanos , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/metabolismo , Regulación hacia ArribaRESUMEN
Background: Little is known about the effect of hepatitis C virus (HCV) infection on gut microbiota and the relationship between alteration of gut microbiota and chronic hepatitis C (CHC) progression. We performed a comparative study of gut microbiota composition between CHC patients and healthy individuals. Methods: Fecal samples from 166 CHC patients were compared with those from 23 healthy individuals; the gut microbiota community was analyzed using 16S ribosomal RNA gene sequencing. CHC patients were diagnosed with persistently normal serum alanine aminotransferase without evidence of liver cirrhosis (LC) (PNALT, n = 18), chronic hepatitis (CH, n = 84), LC (n = 40), and hepatocellular carcinoma in LC (n = 24). Results: Compared with healthy individuals, bacterial diversity was lower in persons with HCV infection, with a decrease in the order Clostridiales and an increase in Streptococcus and Lactobacillus. Microbiota dysbiosis already appeared in the PNALT stage with the transient increase in Bacteroides and Enterobacteriaceae. Predicted metagenomics of microbial communities showed an increase in the urease gene mainly encoded by viridans streptococci during CHC progression, consistent with a significantly higher fecal pH in CH and LC patients than in healthy individuals or those in the PNALT stage. Conclusions: HCV infection is associated with gut dysbiosis, even in patients with mild liver disease. Additionally, overgrowth of viridans streptococci can account for hyperammonemia in CH and LC. Further studies would help to propose a novel treatment strategy because the gut microbiome can be therapeutically altered, potentially reducing the complications of chronic liver disease.
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Bacterias/aislamiento & purificación , Disbiosis/virología , Heces/microbiología , Microbioma Gastrointestinal , Hepatitis C Crónica/complicaciones , Anciano , Anciano de 80 o más Años , Alanina Transaminasa/sangre , Bacterias/clasificación , Estudios de Casos y Controles , ADN Bacteriano/genética , Progresión de la Enfermedad , Femenino , Hepacivirus/aislamiento & purificación , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Metagenómica , Persona de Mediana Edad , ARN Ribosómico 16S/genéticaRESUMEN
BACKGROUND: Preclinical studies suggested that the addition of bevacizumab could overcome acquired resistance (AR) to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). The aim of this study was to evaluate the clinical efficacy and safety of a combination of afatinib and bevacizumab after AR. METHODS: Patients with EGFR-mutant non-small cell lung cancer after AR were enrolled during any line of therapy. Afatinib was prescribed at 30 mg, and 15 mg/kg bevacizumab was administered every 3 weeks until progression. RESULTS: Between October 2014 and May 2017, 32 eligible patients were evaluated. The mutation subtypes were Del-19 (20 [63%]), L858R (11 [34%]), and L861Q (1 [3%]). T790M was detected in 14 patients (44%). The median number of prior regimens was 4 (range, 1-10). Six patients obtained a partial response, and 23 had stable disease; this resulted in an objective response rate (ORR) of 18.8% (95% confidence interval [CI], 7.2%-36.4%) and a disease control rate of 90.7% (95% CI, 75.0%-98.0%). The median progression-free survival (PFS) was 6.3 months (95% CI, 3.9-8.7 months). The ORRs and median PFS times of T790M+ and T790M- patients were 14.3% and 22.2%, respectively, and 6.3 and 7.1 months, respectively; those of Del-19 and L858R patients were 20.0% and 11.1%, respectively, and 6.3 and 5.1 months, respectively. Grade 3 or higher adverse events (incidence ≥ 10%) included paronychia (25%), hypertension (41%), and proteinuria (19%). There were no treatment-related deaths, interstitial lung disease, or bevacizumab-associated severe bleeding. CONCLUSIONS: Afatinib plus bevacizumab demonstrated clinical efficacy and safety after AR to EGFR TKIs and could be a therapeutic salvage option for T790M- populations.