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BACKGROUND: Theoretically, a rapid urease test (RUT) using a swab of the gastric wall (Swab-RUT) for Helicobacter pylori (H. pylori) is safe. However, the validity and utility of Swab-RUT remain unclear. Therefore, we assessed the validity and utility of Swab-RUT compared to RUT using mucosal forceps of the gastric wall (Forceps-RUT) and 13C-urea breath test (UBT). METHODS: This study was a multicenter prospective observational study. When the examinees were suspected of H. pylori infection during esophagogastroduodenoscopy, we performed Swab-RUT and Forceps-RUT continuously. When the examinees were not suspected of H. pylori infection, we performed Swab-RUT alone. We validated the status of H. pylori infection using UBT. RESULTS: Ninety-four examinees were enrolled from four institutions between May 2016 and December 2020 (median age [range], 56.5 [26-88] years). In this study, the sensitivity, specificity, and accuracy of Swab-RUT to UBT were 0.933 (95% confidence interval: 0.779-0.992), 0.922 (0.827-0.974), and 0.926 (0.853-0.970), respectively. The Kappa coefficient of Swab-RUT to UBT was 0.833, and that of Swab-RUT to forceps-RUT was 0.936. No complications were observed in this study. CONCLUSIONS: Swab-RUT is a valid examination for the status of H. pylori infection compared to the conventional Forceps-RUT.
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Pruebas Respiratorias , Infecciones por Helicobacter , Helicobacter pylori , Sensibilidad y Especificidad , Ureasa , Humanos , Pruebas Respiratorias/métodos , Pruebas Respiratorias/instrumentación , Infecciones por Helicobacter/diagnóstico , Infecciones por Helicobacter/microbiología , Persona de Mediana Edad , Estudios Prospectivos , Ureasa/análisis , Ureasa/metabolismo , Masculino , Femenino , Anciano , Helicobacter pylori/aislamiento & purificación , Helicobacter pylori/enzimología , Adulto , Anciano de 80 o más Años , Mucosa Gástrica/microbiología , Endoscopía del Sistema Digestivo , Reproducibilidad de los Resultados , Isótopos de Carbono , Instrumentos Quirúrgicos/microbiologíaRESUMEN
A 56-year-old man presented to our hospital for close examination of a mass in the portal vein. CT showed a homogeneously enhanced mass occupying the portal vein. No other lesions suggestive of a primary tumor were detected. Endoscopic ultrasound-guided fine-needle aspiration revealed that the tumor was pathologically acinar cell carcinoma (ACC) based on the positive staining for both BCL-10 and trypsin. He was diagnosed with an ectopic ACC developed in the portal vein. Because the tumor invaded secondary branches of the right intrahepatic portal vein and the superior mesenteric vein, it was considered surgically un-resectable. Therefore, chemotherapy with gemcitabine plus nab-paclitaxel (GEM + nab-PTX) was started. After 2 courses, CT showed progressive disease, so the regimen was switched to FOLFIRINOX. After starting treatment with FOLFIRINOX, the tumor shrank gradually. After 29 courses, CT scan eventually showed disappearance of the tumor and complete response was achieved. After 34 courses, the chemotherapy was discontinued. Since then, the patient has been recurrence-free for 5 years. Our English literature review yielded 6 cases, including this case, of un-resectable ACC in which complete response was achieved by chemotherapy. Our case suggest that platinum-based regimen might be an effective therapy for un-resectable ACC, including ectopic ACC.
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Carcinoma de Células Acinares , Neoplasias Pancreáticas , Masculino , Humanos , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Vena Porta/diagnóstico por imagen , Vena Porta/patología , Carcinoma de Células Acinares/diagnóstico por imagen , Carcinoma de Células Acinares/tratamiento farmacológico , Carcinoma de Células Acinares/patologíaRESUMEN
Next-generation sequencing (NGS)-based gene profiling can identify patients with pancreatic cancer with homologous recombinant repair gene pathogenic variants (HRRv). Several retrospective studies have reported a positive association between HRRv and the efficacy of platinum-based chemotherapy. However, this association remains to be validated in a prospective study. This multicenter, prospective, observational study included patients with histologically confirmed unresectable or recurrent pancreatic cancer who required systemic chemotherapy. Patients who were oxaliplatin-naïve patients were eligible. The HRRv status was measured using a College of American Pathologists-accredited NGS panel. One-year overall survival rate (1yr-OS%) was calculated after initiation of oxaliplatin-based chemotherapy and was set as the primary endpoint. Forty patients were enrolled between August 2018 and March 2020. The NGS success rate was 95% (38/40). HRRv was detected in 11 patients (27.5%). Oxaliplatin-based chemotherapy was administered to 9 of 11 patients with HRRv (81.8%) and 15 of 29 patients with non-HRRv (51.7%). The 1yr-OS% after initiation of oxaliplatin-based chemotherapy was 44.4% [95% confidence interval (CI) 13.7-71.9] and 57.1% (95% CI 28.4-78.0) in HRRv-positive and -negative cohorts, respectively. These data suggested that HRRv status alone could not be a potential predictive marker of oxaliplatin-based chemotherapy in patients with advanced pancreatic cancer. These results were in line with the results of a recent phase II study reporting the limited efficacy of poly(adenosine diphosphate-ribose) polymerase inhibitor in patients with pancreatic cancer who harbored HRRv other than BRCA. Future studies investigating patients with biallelic HRRv in the first-line setting are warranted.Trial registration UMIN000033655.
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Neoplasias Pancreáticas , Humanos , Oxaliplatino , Estudios Prospectivos , Estudios Retrospectivos , Neoplasias Pancreáticas/patología , Neoplasias PancreáticasRESUMEN
Endoscopic submucosal dissection (ESD) is a safe and minimally invasive method for the treatment of early gastric cancer (EGC). However, whether ESD for EGC is also safe and feasible in patients aged ≥85 years is unclear. The patients enrolled in this study were divided into three groups: age ≥85 years (44 patients, 49 lesions), age 65−84 years (624 patients, 687 lesions), and age ≤64 years (162 patients, 174 lesions). We evaluated the incidence of adverse events (AEs) and overall survival (OS) and disease-specific survival (DSS). We analyzed the factors that had a significant impact on the prognosis of patients aged ≥85 years. No significant differences were found in the incidence of AEs among the three groups (p = 0.612). The OS was significantly lower in patients aged ≥85 years (p < 0.001). Conversely, DSS was not significantly worse in patients aged ≥85 years (p = 0.100). The poor Geriatric Nutritional Risk Index correlated with poor prognosis in patients aged ≥85 years (p < 0.001). ESD is a safe and valid treatment for EGC in patients aged ≥85 years. However, the indications should be carefully decided because it is difficult to estimate the survival contribution of ESD for EGC in patients aged ≥85 years, especially in those with poor nutritional status.
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BACKGROUND: Somatic and germline variants are not distinguishable by circulating tumor DNA (ctDNA) testing without analyzing non-tumor samples. Although confirmatory germline testing is clinically relevant, the criteria for selecting presumed germline variants have not been established in ctDNA testing. In the present study, we aimed to evaluate the prevalence of pathogenic germline variants in clinical ctDNA testing through their variant allele fractions (VAFs). METHODS: A total of consecutive 106 patients with advanced solid tumors who underwent ctDNA testing (Guardant360®) between January 2018 and March 2020 were eligible for this study. To verify the origin of pathogenic variants reported in ctDNA testing, germline sequencing was performed using peripheral blood DNA samples archived in the Clinical Bioresource Center in Kyoto University Hospital (Kyoto, Japan) under clinical research settings. RESULTS: Among 223 pathogenic variants reported in ctDNA testing, the median VAF was 0.9% (0.02-81.8%), and 88 variants with ≥ 1% VAFs were analyzed in germline sequencing. Among 25 variants with ≥ 30% VAFs, seven were found in peripheral blood DNA (BRCA2: n = 6, JAK2: n = 1). In contrast, among the 63 variants with VAFs ranging from 1 to < 30%, only one variant was found in peripheral blood DNA (TP53: n = 1). Eventually, this variant with 15.6% VAF was defined to be an acquired variant, because its allelic distribution did not completely link to those of neighboring germline polymorphisms. CONCLUSION: Our current study demonstrated that VAFs values are helpful for selecting presumed germline variants in clinical ctDNA testing.
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ADN Tumoral Circulante , Neoplasias , Biomarcadores de Tumor , ADN Tumoral Circulante/genética , Células Germinativas , Humanos , Mutación , Neoplasias/genética , PrevalenciaRESUMEN
BACKGROUND: Tumor heterogeneity has been known to cause inter-assay discordance among next-generation sequencing (NGS) results. However, whether preclinical factors such as sample type, sample quality and analytical features of gene panel can affect the concordance between two different assays remains largely unexplored. METHODS: Replicate sets of DNA samples extracted from formalin-fixed paraffin-embedded tissues (FFPE) (n = 20) and fresh frozen (FF) tissues (n = 10) were herein analyzed using a tumor-only (TO) and paired tumor-normal (TN) gene panel in laboratories certified by the Clinical Laboratory Improvement Amendment. Reported variants from the TO and TN panels were then compared. Furthermore, additional FFPE samples were sequentially sliced from the same FFPE block and submitted to another TN panel assay. RESULTS: Substantial discordance (71.8%) was observed between the results of the two panels despite using identical DNA samples, with the discordance rate being significantly higher for FFPE samples (p < 0.05). Among the 99 variants reported only in the TO panel, 32.3% were consistent with germline variants, which were excluded in the TN panel, while 30.3% had an allele frequency of less than 5%, some of which were highly likely to be artificial calls. The comparison of two independent TN panel assay results from the same FFPE block also showed substantial discordance rate (55.3%). CONCLUSIONS: In the context of clinical settings, our comparative analysis revealed that inter-NGS assay discordance commonly occurred due to sample types and the different analytical features of each panel.
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Formaldehído , Neoplasias , ADN , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Neoplasias/genética , Neoplasias/patología , Adhesión en Parafina , Fijación del TejidoRESUMEN
BACKGROUND AND AIM: Colonic diverticular bleeding is a common cause of acute lower gastrointestinal bleeding. Endoscopic hemostasis is generally selected as the first-line treatment; however, a considerable number of patients experience early rebleeding after endoscopic treatment. We investigated the risk factors for early rebleeding after endoscopic treatment. METHODS: We retrospectively evaluated the data of 142 consecutive patients who underwent endoscopic treatment (endoscopic clipping or endoscopic band ligation) for colonic diverticular bleeding with stigmata of recent hemorrhage between April 2012 and April 2020. Multivariate logistic regression analysis was conducted to evaluate the statistical relationship between patient characteristics and the incidence of early rebleeding occurring within 30 days after endoscopic treatment. RESULTS: Of 142 patients, early rebleeding was detected in 34 (23.9%) patients. According to univariate analysis, platelet count of <10 × 104/µL, bleeding from the left-sided colon, and endoscopic clipping usage were associated with early rebleeding (P < 0.05). The subsequent multivariate logistic regression analysis identified bleeding from the left-sided colon (odds ratio [OR], 4.16; 95% confidence interval [CI], 1.73-10.0; P = 0.001) and endoscopic clipping usage (OR, 2.92; 95% CI, 1.21-7.00; P = 0.017) as the independent risk factors for early rebleeding. CONCLUSIONS: Bleeding from the left-sided colon and endoscopic clipping usage were the risk factors for early rebleeding after endoscopic treatment. Using endoscopic band ligation was associated with a decreased risk for early rebleeding compared with the use of endoscopic clipping, indicating that endoscopic band ligation was a preferable endoscopic modality to prevent early recurrent bleeding.
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Comprehensive genomic profiling (CGP) testing by next-generation sequencing has been introduced into clinical practice as part of precision cancer medicine to select effective targeted therapies. However, whether CGP testing at the time of first-line chemotherapy could be clinically useful is not clear. We conducted this single-center, prospective, observational study to investigate the feasibility of CGP testing for chemotherapy-naïve patients with stage III/IV gastrointestinal cancer, rare cancer, and cancer of unknown primary, using the FoundationOne® companion diagnostic (F1CDx) assay. The primary outcome was the detection rate of at least one actionable/druggable cancer genomic alteration. Actionable/druggable cancer genomic alterations were determined by the F1CDx report. An institutional molecular tumor board determined the molecular-based recommended therapies. A total of 197 patients were enrolled from October 2018 to June 2019. CGP success rate was 76.6% (151 of 197 patients), and median turnaround time was 19 days (range: 10-329 days). Actionable and druggable cancer genomic alterations were reported in 145 (73.6%) and 124 (62.9%) patients, respectively. The highest detection rate of druggable genomic alterations in gastrointestinal cancers was 80% in colorectal cancer (48 of 60 patients). Molecular-based recommended therapies were determined in 46 patients (23.4%). CGP testing would be a useful tool for the identification of a potentially effective first-line chemotherapy.
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Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Terapia Molecular Dirigida/métodos , Neoplasias/genética , Medicina de Precisión/métodos , Análisis de Secuencia de ADN/métodos , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Femenino , Perfilación de la Expresión Génica/métodos , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Adulto JovenAsunto(s)
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Carcinoma de Células Escamosas/diagnóstico por imagen , Neoplasias Esofágicas/diagnóstico por imagen , Carcinoma de Células Escamosas de Esófago/diagnóstico , Humanos , Metástasis LinfáticaRESUMEN
BACKGROUND: Cancer of unknown primary (CUP) is usually treated with nonselective and empirical chemotherapy; however, its prognosis is generally poor, with a median survival of less than a year. Thus, clinicians eagerly await the development of more effective treatment strategies. In recent years, advances in next-generation sequencing (NGS) have made it possible to analyze comprehensively the genome of individual cancers. NGS has identified many genomic alterations, some of which are potential molecular targets of specific agents. We report a case of CUP that was successfully treated with targeted therapy directed by the genomic data obtained from an NGS-based multiplex assay. CASE PRESENTATION: A 52-year-old Asian woman with right hip joint pain underwent fluorodeoxyglucose-positron emission tomography/computed tomography, which showed multiple metastatic tumors in her right hip joint, thyroid gland, lung, and vertebrae. Brain magnetic resonance imaging showed multiple cerebral metastases. Additional tests, including pathology examination and conventional epidermal growth factor receptor (EGFR) gene mutation analysis (single-strand conformation polymorphism assay), could not identify the primary origin of the tumors, so the patient was diagnosed with CUP. After empirical chemotherapy for CUP, an NGS-based multiplex assay performed using a resected specimen of thyroid tumor detected the EGFR mutation c.2573 T > G p.Leu858Arg (L858R). Her treatment was changed to erlotinib, an EGFR tyrosine-kinase inhibiter, which dramatically shrank the tumors and decreased her serum carcinoembryonic antigen level. She achieved long-term disease control and survived for 2 years and 9 months from the first diagnosis. CONCLUSION: This case might support the strategy that NGS-based multiplex assays could identify actionable molecular targets for individual patients with CUP.
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Receptores ErbB/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Neoplasias Primarias Desconocidas/tratamiento farmacológico , Femenino , Humanos , Persona de Mediana Edad , MutaciónRESUMEN
In tumor-only next-generation sequencing (NGS), identified variants have the potential to be secondary findings (SFs), but they require verification through additional germline testing. In the present study, 194 patients with advanced cancer who underwent tumor-only NGS between April 2015 and March 2018 were enrolled, and the incidences of possible and true SFs were evaluated. Among them, 120 patients (61.9%) harbored at least one possible SF. TP53 was the most frequent gene in which 97 variants were found in 91 patients (49.5%). Nine patients provided informed consent to undergo additional germline testing, and a total of 14 variants (BRCA1, n = 1; BRCA2, n = 2; PTEN, n = 2; RB1, n = 1; SMAD4, n = 1; STK11, n = 1; TP53, n = 6) were analyzed. Three variants (BRCA1, n = 1; BRCA2, n = 2) were confirmed to be SFs, whereas TP53 variants were confirmed to be somatic variants. To confirm the low prevalence of SFs in TP53, we analyzed 24 patients with TP53 variants who underwent a paired tumor-normal NGS assay. As expected, all TP53 variants were confirmed to be somatic variants. A total of 30 patients were tested for germline variants in TP53, but none of them resulted in true SFs, suggesting the low prevalence of SFs in this gene. Therefore, the significance of additional germline testing for TP53 variants appears to be relatively low in daily clinical practice using a tumor-only NGS assay, unless patients have any relevant medical or family history.
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Proteína BRCA1/genética , Proteína BRCA2/genética , Biomarcadores de Tumor/genética , Variación Genética/genética , Proteína p53 Supresora de Tumor/genética , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia de ADNRESUMEN
BACKGROUND: Tumor mutational burden (TMB) measured via next-generation sequencing (NGS)-based gene panel is a promising biomarker for response to immune checkpoint inhibitors (ICIs) in solid tumors. However, little is known about the preanalytical factors that can affect the TMB score. MATERIALS AND METHODS: Data of 199 patients with solid tumors who underwent multiplex NGS gene panel (OncoPrime), which was commercially provided by a Clinical Laboratory Improvement Amendments-licensed laboratory and covered 0.78 megabase (Mb) of capture size relevant to the TMB calculation, were reviewed. Associations between the TMB score and preanalytical factors, including sample DNA quality, sample type, sampling site, and storage period, were analyzed. Clinical outcomes of patients with a high TMB score (≥10 mutations per megabase) who received anti-programmed cell death protein 1 antibodies (n = 22) were also analyzed. RESULTS: Low DNA library concentration (<5 nM), formalin-fixed paraffin-embedded tissue (FFPE), and the prolonged sample storage period (range, 0.9-58.1 months) correlated with a higher TMB score. After excluding low DNA library samples from the analysis, FFPE samples, but not the sample storage period, exhibited a marked correlation with a high TMB score. Of 22 patients with a high TMB score, we observed the partial response in 2 patients (9.1%). CONCLUSION: Our results indicate that the TMB score estimated via NGS-based gene panel could be affected by the DNA library concentration and sample type. These factors could potentially increase the false-positive and/or artifactual variant calls. As each gene panel has its own pipeline for variant calling, it is unknown whether these factors have a significant effect in other platforms. IMPLICATIONS FOR PRACTICE: A high tumor mutational burden score, as estimated via next-generation sequencing-based gene panel testing, should be carefully interpreted as it could be affected by the DNA library concentration and sample type.
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Biomarcadores de Tumor/metabolismo , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Carga Tumoral/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Humanos , Persona de Mediana Edad , Adulto JovenRESUMEN
AIM: Recent advances in next-generation sequencing (NGS) technologies allow for evaluation of genetic alterations in various cancer-related genes in daily clinical practice. Archival formalin-fixed paraffin-embedded (FFPE) tumor tissue is often used for NGS-based clinical sequencing assays; however, the success rate of NGS assays using archival FFPE tumor tissue is reported to be lower than that using fresh tumor tissue. We aimed to evaluate the feasibility and safety of ultrasound (US)-guided liver tumor biopsy for NGS-based multiplex gene assays. METHODS: We compared the success rate of NGS assays between archival FFPE tumor tissues and US-guided liver tumor biopsy tissues, and summarized the treatment progress of the patients. RESULTS: Next-generation sequencing assays using US-guided liver biopsy samples were successful in all patients (22/22), whereas the success rate with archival FFPE tumor tissue was 84.8% (151/178, P < 0.05). At least one potentially actionable genetic alteration was identified from the US-guided liver biopsy samples in 20 of 22 patients. Among the 18 patients with actionable genetic alterations targetable with drugs approved by the US Food and Drug Administration, eight initiated mutation-driven targeted therapies. Of these eight patients, four achieved partial response or stable disease for at least 4 months, and three were not assessable for response due to short exposure. There were no biopsy-related complications requiring additional treatment. CONCLUSION: Our findings suggest that US-guided liver tumor biopsy is a useful and safe method for obtaining high-quality samples for NGS-based clinical sequencing. In cases with metastatic liver tumors, US-guided biopsy should be considered to provide accurate and optimal sequencing results for patients.
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Recent innovations in next-generation sequencing (NGS) technologies have enabled comprehensive genomic profiling of human cancers in the clinical setting. The ability to profile has launched a worldwide trend known as precision medicine, and the fusion of genomic profiling and pharmacogenomics is paving the way for precision medicine for cancer. The profiling is coupled with information about chemical therapies available to patients with specific genotypes. As a result, the chemogenomic space in play is not only the standard chemical and genome space but also the mutational genome and chemical space. In this chapter, we introduce clinical genomic profiling using an NGS-based multiplex gene assay (OncoPrime™) at Kyoto University Hospital.
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Biomarcadores de Tumor/genética , Biología Computacional/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Farmacogenética , Análisis Mutacional de ADN , Humanos , Terapia Molecular Dirigida , Mutación , Selección de Paciente , Medicina de PrecisiónRESUMEN
OBJECTIVES: We aimed to examine the association between homologous recombination repair (HRR)-related gene mutations and efficacy of oxaliplatin-based chemotherapy in patients with pancreatic ductal adenocarcinoma (PDAC). RESULTS: Non-synonymous mutations in HRR-related genes were found in 13 patients and only one patient had a family history of pancreatic cancer. Eight patients with HRR-related gene mutations (group A) and nine without HRR-related gene mutations (group B) received oxaliplatin-based chemotherapy. Median progression-free survival after initiation of oxaliplatin-based chemotherapy was significantly longer in group A than in group B (20.8 months vs 1.7 months, p = 0.049). Interestingly, two patients with inactivating HRR-related gene mutations who received FOLFIRINOX as first-line treatment showed exceptional responses with respect to progression-free survival for > 24 months. MATERIALS AND METHODS: Complete coding exons of 12 HRR-related genes (ATM, ATR, BAP1, BRCA1, BRCA2, BLM, CHEK1, CHEK2, FANCA, MRE11A, PALB2, and RAD51) were sequenced using a Clinical Laboratory Improvement Amendment-certified multiplex next-generation sequencing assay. Thirty consecutive PDAC patients who underwent this assay between April 2015 and July 2017 were included. CONCLUSIONS: Our results suggest that inactivating HRR-related gene mutations are predictive of response to oxaliplatin-based chemotherapy in patients with PDAC.
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Advances in next-generation sequencing (NGS) technologies have enabled physicians to test for genomic alterations in multiple cancer-related genes at once in daily clinical practice. In April 2015, we introduced clinical sequencing using an NGS-based multiplex gene assay (OncoPrime) certified by the Clinical Laboratory Improvement Amendment. This assay covers the entire coding regions of 215 genes and the rearrangement of 17 frequently rearranged genes with clinical relevance in human cancers. The principal indications for the assay were cancers of unknown primary site, rare tumors, and any solid tumors that were refractory to standard chemotherapy. A total of 85 patients underwent testing with multiplex gene assay between April 2015 and July 2016. The most common solid tumor types tested were pancreatic (n = 19; 22.4%), followed by biliary tract (n = 14; 16.5%), and tumors of unknown primary site (n = 13; 15.3%). Samples from 80 patients (94.1%) were successfully sequenced. The median turnaround time was 40 days (range, 18-70 days). Potentially actionable mutations were identified in 69 of 80 patients (86.3%) and were most commonly found in TP53 (46.3%), KRAS (23.8%), APC (18.8%), STK11 (7.5%), and ATR (7.5%). Nine patients (13.0%) received a subsequent therapy based on the NGS assay results. Implementation of clinical sequencing using an NGS-based multiplex gene assay was feasible in the clinical setting and identified potentially actionable mutations in more than 80% of patients. Current challenges are to incorporate this genomic information into better therapeutic decision making.
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Análisis Mutacional de ADN/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Neoplasias/genética , Medicina de Precisión/métodos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Comprehensive genomic profiling using next-generation sequencing technologies provides insights into understanding the genomic architecture of human cancer. This new understanding of the cancer genome allows us to identify many more genomic alterations occurring within tumors than before, some of which could be potential therapeutic targets through molecular targeted agents. Currently, a large number of molecular targeted agents are being developed, and consequently, cancer treatment is rapidly shifting from empiric therapy employing cytotoxic anticancer drugs to genotype-directed therapy using molecular targeted agents. In current daily clinical practice, hotspot-based single-gene assays that detect RAS mutations in colorectal cancer or EGFR mutations in non-small cell lung cancer are widely used to identify variants. However, it is becoming evident that more comprehensive genomic analysis is crucial in identifying the patient population that may benefit from molecular targeted therapy and the accelerated development of novel drugs for early clinical trials. For these purposes, an increasing number of gene panel-based targeted sequencing is commercially available in clinical practice from sequencing companies. Despite several challenges in implementing this approach, comprehensive genomic profiling and identification of actionable mutations is likely to become one of the standard options in the management of cancer in the near future. The use of clinical sequencing has the potential to usher a new era in precision medicine for cancer diagnosis and treatment. In this review, we discuss the application of comprehensive genomic profiling using next-generation sequencing technologies in clinical oncology and address the current challenges for its implementation.
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Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Biomarcadores de Tumor/sangre , Ligamiento Genético , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Terapia Molecular Dirigida , Neoplasias/genética , Neoplasias/patología , Medicina de PrecisiónRESUMEN
BACKGROUND: In the GEST study of unresectable pancreatic cancer, S-1 demonstrated non-inferiority compared to gemcitabine, but gemcitabine plus S-1 (GS) did not show superiority over gemcitabine for overall survival (OS). We performed subgroup analysis of these data focused on the efficacy and safety of these regimens as a first-line treatment for elderly patients. METHODS: Elderly patients (≥ 70 years, n = 261) treated for unresectable pancreatic cancer (GS: n = 90, S-1: n = 85 and gemcitabine: n = 86) were analysed. RESULTS: No significant differences between the GS, S-1, or gemcitabine groups in OS (median: 10.2, 8.0 and 8.5 months, respectively) or objective response rates (27.6%, 25.3% and 14.3%, respectively) were noted. Grade ≥ III adverse haematological events were observed more frequently in GS-treated than in S-1- or gemcitabine-treated elderly patients (p < 0.001 and p = 0.016, respectively). Four of 8 patients aged ≥ 80 years experienced serious adverse events. CONCLUSIONS: S-1 and gemcitabine are both efficacious options for treatment of elderly patients with unresectable pancreatic cancer. Conversely, first-line treatment of elderly patients with GS should only be used after careful consideration.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Desoxicitidina/análogos & derivados , Ácido Oxónico/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Tegafur/uso terapéutico , Factores de Edad , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Desoxicitidina/efectos adversos , Desoxicitidina/uso terapéutico , Supervivencia sin Enfermedad , Combinación de Medicamentos , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Ácido Oxónico/efectos adversos , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Modelos de Riesgos Proporcionales , Factores de Riesgo , Tegafur/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , GemcitabinaRESUMEN
BACKGROUND: We aimed to construct a prognostic model to predict survival in patients with advanced pancreatic cancer (APC) receiving palliative chemotherapy using readily available pretreatment factors. METHODS: The model was constructed using data from 306 consecutive patients with APC who received palliative chemotherapy between January 2006 and March 2013. The predictive accuracy of the model was assessed using a concordance index (c-index) and calibration curves. RESULTS: Among the 12 potential prognostic factors investigated, multivariate analysis identified the following six independent negative prognostic factors-performance status (PS), the presence of distant metastatic disease, the status of initially unresectable disease, carcinoembryonic antigen (CEA) level, carbohydrate antigen 19-9 (CA19-9) level, and neutrophil-lymphocyte ratio (NLR). A prognostic index (PI) based on the coefficients of these factors was constructed as follows-PI = 2 (if PS 2-3) + 1 (if distant metastatic disease) + 1 (if initially unresectable disease) + 1 (if CEA level ≥5.0 ng/ml) + 1 (if CA 19-9 level ≥1,000 U/ml) + 2 (if NLR ≥5). The patients were classified into three prognostic groups-favorable (PI 0-1, n = 73), intermediate (PI 2-3, n = 145), and poor (PI 4-8, n = 88). The median overall survival times for each prognostic group were 16.5, 12.3, and 6.2 months, respectively (P < 0.001). Bootstrapping verified the good fitness of this model for predicting 1-year survival, and the c-index was 0.658. CONCLUSIONS: This simple prognostic model could help clinicians to estimate survival in patients with APC who receive palliative chemotherapy.