Background
Sarcopenia has been underscored as a significant predictor of poor prognosis in cancer patients undergoing immunotherapy with programmed death-1 (PD-1) inhibitors. We aimed to investigate ...the prognostic significance of computed tomography (CT)-determined sarcopenia in patients with microsatellite-stable (MSS) gastric cancer (GC) treated with PD-1 inhibitors.
Methods
We retrospectively assessed patients with MSS GC who had been treated with PD-1 inhibitors from March 2016 to June 2019. Pre-treatment sarcopenic status was determined by analyzing L3 skeletal muscle index with abdominal CT. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method, and the differences in survival probability according to sarcopenic status were compared using the log-rank test. Cox proportional hazards regression analyses were performed to identify predictors of PFS and OS.
Results
Of 149 patients with MSS GC (mean age, 57.0 ± 12.3 years; 93 men), 79 (53.0%) had sarcopenia. Patients with sarcopenia had significantly shorter PFS than patients without sarcopenia (median, 1.4 months vs. 2.6 months;
P
= 0.026). Sarcopenia was independently associated with shorter PFS (adjusted hazard ratio HR, 1.79; 95% confidence interval CI, 1.10−2.93;
P
= 0.020). Patients with sarcopenia had shorter OS than patients without sarcopenia (median, 3.6 months vs. 4.9 months;
P
= 0.052), but sarcopenia itself was not a significant prognostic factor for OS (adjusted HR, 1.01; 95% CI, 0.58−1.75;
P
= 0.974).
Conclusions
CT-determined sarcopenia is an independent prognostic factor for PFS in patients with MSS GC treated with PD-1 inhibitors.
A limited number of studies have characterized genomic properties of hepatocellular carcinoma (HCC) patients in response to anti-PD-1 immunotherapy.
Herein, we performed comprehensive molecular ...characterization of immediate (D-42 to D-1) pre-treatment tumor biopsy specimens from 60 patients with sorafenib-failed HCC in a single-arm prospective phase II trial of pembrolizumab. Objective response rate was the primary efficacy endpoint. We used whole-exome sequencing, RNA sequencing, and correlative analysis. In addition, we performed single-cell RNA sequencing using peripheral blood mononuclear cells.
The overall response rate of pembrolizumab in sorafenib-failed HCC patients was 10% (6/60 95% CI, 2.4-17.6). In a univariate analysis using clinicopathological features, female gender, PD-L1 positivity, and low neutrophil-to-lymphocyte ratio (NLR) were identified as contributing factors to pembrolizumab response. Somatic mutations in CTNNB1 and genomic amplifications in MET were found only in non-responders. Transcriptional profiles through RNA sequencing identified that pembrolizumab responders demonstrated T cell receptor (TCR) signaling activation with expressions of MHC genes, indicating increased levels of T cell cytotoxicity. In single-cell sequencing from 10 pre- and post-treatment peripheral blood mononuclear cells (PBMCs), patients who achieved a partial response or stable disease exhibited immunological shifts toward cytotoxic CD8+ T cells. Conversely, patients with progressive disease showed an increased number of both CD14+ and CD16+ monocytes and activation of neutrophil-associated pathways.
Taken together, HCC patients with infiltration of cytotoxic T cells, along with increased active circulating CD8+ T cells during pembrolizumab treatment and down-regulation of neutrophil-associated markers, significantly benefited from pembrolizumab treatment.
NCT#03163992 (first posted: May 23, 2017).
Triptolide induces apoptosis and DNA damage followed by inhibition of DNA repair associated gene expression. However, there is the limited data for biomarker to predict the benefit to triptolide in ...various cancers including pancreatic cancer.
We investigated the anti tumor efficacy of triptolide in various pancreatic cancer cell lines (Capan-1, Capan-2, SNU-213, SNU-410, HPAFII, and Hs766T) and patient derived cells (PDCs) from metastatic pancreatic cancer patients.
In vitro cell viability assay for triptolide in 6 PC cell lines, the IC
was 0.01 uM, 0.02 uM, 0.0096 uM for triptolide in Capan-1, Capan-2 and SNU-213. However, the growth of tumor cells was not significantly reduced by triptolide in Hs766T, SNU-410 and HPAFII. The distinct difference of gene expression was also observed between Capan-1, Capan-2 and SNU-213 and Hs766T, SNU-410 and HPAFII. In analysis of pathway using gene expression profiles, the integrin mediated RAS signaling pathway was associated with the sensitivity of the triptolide in PC cell lines. Immunoblot assay showed that Chk2 phosphorylation after triptolide was distinctively observed in SNU-213 sensitive to triptolide but, not in SNU-410 insensitive to triptolide. This finding in immunoblot assay was also reproduced in PDCs originated from pancreatic cancer patients.
Our findings might be helpful to completely capture the subset of patients who may benefit to tripolide (minnelide). More robust biomarkers such as KRAS mutation and Chk2 phosphorylation and careful clinical trial design using triptolide (minnelide) are warranted.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Tumor genetic heterogeneity may underlie poor clinical outcomes because diverse subclones could be comprised of metastatic and drug resistant cells. Targeted deep sequencing has been used widely as a ...diagnostic tool to identify actionable mutations in cancer patients. In this study, we evaluated the clinical utility of estimating tumor heterogeneity using targeted panel sequencing data. We investigated the prognostic impact of a tumor heterogeneity (TH) index on clinical outcomes, using mutational profiles from targeted deep sequencing data acquired from 1,352 patients across 8 cancer types. The TH index tended to be increased in high pathological stage disease in several cancer types, indicating clonal expansion of cancer cells as tumor progression proceeds. In colorectal cancer patients, TH index values also correlated significantly with clinical prognosis. Integration of the TH index with genomic and clinical features could improve the power of risk prediction for clinical outcomes. In conclusion, deep sequencing to determine the TH index could serve as a promising prognostic indicator in cancer patients.
Anemia is the most common and serious cancer-related complication. This study aimed to evaluate the efficacy of administration of ferric carboxymaltose without erythropoiesis-stimulating agents for ...treating anemia in cancer patients. Moreover, we identified the biomarkers of hemoglobin response to predict the need for iron therapy. We enrolled patients with solid cancers who were treated at a single institute (Samsung Medical Center, South Korea), from April 2015 to July 2017, in this prospective single-arm Phase II clinical trial. Patients received intravenous ferric carboxymaltose (1,000 mg) infusion on the first day (visit 1) of treatment. The primary end point was the number of hemoglobin responders, defined as patients with an increase in hemoglobin level greater than or equal to 1.0 g/dL from the baseline, a hemoglobin level greater than or equal to 11.0 g/dL, or both, within an 8-week observation period (week 3, 6, or 8). Secondary end points included changes in transferrin saturation and levels of soluble transferrin receptors, hepcidin, erythropoietin, interleukin-6, and C-reactive protein (CRP) at each visit. Of the 103 recruited patients, 92 were eligible for analysis. The mean patient age was 57.3 ± 12.5 years, and 54.3% of the patients were women. The most common diagnoses were breast cancer (n = 23, 25.1%), lung cancer (n = 21, 22.9%), gastrointestinal cancer (n = 20, 20.9%), and lymphoma (n = 16, 17.7%). A hemoglobin response was observed in 36 (39.1%), 53 (57.6%), and 61 (66.3%) patients in the third, fifth, and eighth weeks, respectively. The mean increase in hemoglobin levels from the baseline to the end of treatment was 1.77 ± 1.30 g/dL. Baseline values of hepcidin (p = 0.008), total iron binding capacity (p = 0.014), ferritin (p = 0.048), and CRP (p = 0.044) were significantly different between the responder and nonresponder groups. Multiple logistic regression analysis for baseline anemia-related biochemical variable significantly associated with the hemoglobin response showed that only baseline hepcidin level was a significant factor for hemoglobin response (odds ratio = 0.95, 95% confidence interval 0.90-1.0, p = 0.045). Hemoglobin responders had significantly lower hepcidin levels than nonresponders (mean ±standard deviation, 13.45 ±14.71 versus 35.22 ±40.470 ng/ml; p = 0.007). However, our analysis had some limitations such as the different patient characteristics in the studies that were included, institutional differences in the measurement of hepcidin level, and missing data on long-term safety. Therefore, our findings need further validation. Intravenous ferric carboxymaltose (1,000 mg) monotherapy increases hemoglobin levels without serious adverse events in patients with cancer. Hepcidin is a useful biomarker for predicting iron requirement in cancer patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Gastric cancer (GC) is one of the most common lethal cancer worldwide. In recent years, several new targeted therapeutic agents for the treatment of metastatic GC have been developed. These include ...drugs that block human epidermal growth factor receptor 2 (HER2) or epidermal growth factor receptor, ramucirumab monoclonal antibody that binds to a receptor for vascular endothelial growth factor, and other targeted agents such as sorafenib and apatinib, and immunotherapies. In this short review, we provide a summary of clinical and preclinical biomarkers (HER2, mesenchymal-epithelial transition MET, fibroblast growth factor receptor 2 FGFR2, ring finger protein 43 RNF43, microsatellite instability and mismatch repair, Epstein-Barr virus, programmed cell death ligand-1, and tumor infiltrating lymphocytes) for treatment strategies and will address the molecular classification of GC revisited with an aim to select the best-precision treatment strategies for GC patients.
Despite the benefits from adjuvant chemotherapy or chemoradiotherapy, approximately one-third of stage II gastric cancer (GC) patients developed recurrences. The aim of this study was to develop and ...validate a prognostic algorithm for gastric cancer (GCPS) that can robustly identify high-risk group for recurrence among stage II patients. A multi-step gene expression profiling study was conducted. First, a microarray gene expression profiling of archived paraffin-embedded tumor blocks was used to identify candidate prognostic genes (N=432). Second, a focused gene expression assay including prognostic genes was used to develop a robust clinical assay (GCPS) in stage II patients from the same cohort (N=186). Third, a predefined cut off for the GCPS was validated using an independent stage II cohort (N=216). The GCPS was validated in another set with stage II GC who underwent surgery without adjuvant treatment (N=300). GCPS was developed by summing the product of Cox regression coefficients and normalized expression levels of 8 genes (LAMP5, CDC25B, CDK1, CLIP4, LTB4R2, MATN3, NOX4, TFDP1). A prospectively defined cut-point for GCPS classified 22.7% of validation cohort treated with chemoradiotherapy (N=216) as high-risk group with 5-year recurrence rate of 58.6% compared to 85.4% in the low risk group (hazard ratio for recurrence=3.16, p=0.00004). GCPS also identified high-risk group among stage II patients treated with surgery only (hazard ratio=1.77, p=0.0053).
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Several studies have suggested a cancer risk reduction in statin users although the evidence remains weak for stomach cancer. The purpose of this study was to use an exact-matching case-control ...design to examine the risk of gastric cancer associated with the use of statins in a cohort of patients with diabetes.
Cases were defined as patients with incident gastric cancer identified by International Classification of Diseases 16.0 ~ 16.9 recorded at Samsung Medical Center database during the period of 1999 to 2008, at least 6 months after the entry date of diabetes code. Each gastric cancer case patient was matched with one control patient from the diabetes patient registry in a 1:1 fashion, blinded to patient outcomes.
A total of 983 cases with gastric cancer and 983 controls without gastric cancer, matched by age and sex, were included in the analysis. The presence of prescription for any statin was inversely associated with gastric cancer risk in the unadjusted conditional logistic regression model (OR: 0.18; 95% CI: 0.14 - 0.24; P < .0001). Multivariate analysis using conditional logistic regression with Bonferroni's correction against aspirin indicated a significant reduction in the risk of gastric cancer in diabetes patients with statin prescriptions (OR: 0.21; 95% CI: 0.16 - 0.28; P < .0001). After adjustment for aspirin use, a longer duration of statin use was associated with reduced risk of gastric cancer, with statistical significance (P<.0001).
A strong inverse association was found between the risk of gastric adenocarcinoma and statin use in diabetic patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Background Capecitabine plus oxaliplatin (CapeOX) is one of the reference doublet cytotoxic chemotherapy treatments for patients with metastatic colorectal cancer. We aimed to compare the ...efficacy and safety of CapeOX with that of S-1 plus oxaliplatin (SOX), a promising alternative treatment for patients with metastatic colorectal cancer. Methods In this open-label, multicentre, randomised phase 3 trial, we randomly assigned patients (1:1) from 11 institutions in South Korea to receive either CapeOX (capecitabine 1000 mg/m2 twice daily on days 1–14 and oxaliplatin 130 mg/m2 on day 1) or SOX (S-1 40 mg/m2 twice daily on days 1–14 and oxaliplatin 130 mg/m2 on day 1). Treatment was repeated every 3 weeks and continued for as many as nine cycles of oxaliplatin-containing chemotherapy, except in instances of disease progression, unacceptable toxicity, or a patient's refusal. Maintenance chemotherapy with S-1 or capecitabine was allowed after discontinuation of oxaliplatin. Randomisation was done with a computer-generated sequence (stratified by primary sites, previous adjuvant or neoadjuvant treatment, and the presence of measurable lesions). The primary endpoint was to show non-inferiority of SOX relative to CapeOX in terms of progression-free survival (PFS). The primary analysis was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00677443. Findings Between May 14, 2008, and Sept 23, 2009, we randomly assigned 168 patients to receive SOX and 172 to receive CapeOX. Median PFS was 8·5 months (95% CI 7·6–9·3) in the SOX group and 6·7 months (6·2–7·1) in the CapeOX group (hazard ratio, 0·79 95% CI 0·60–1·04; pnon-inferiority <0·0001, plog-rank =0·09). The upper limit of the CI was below the predefined margin of 1·43, showing the non-inferiority of SOX to CapeOX. We recorded a higher incidence of grade 3–4 neutropenia (49 29% vs 24 15%), thrombocytopenia (37 22% vs 11 7%), and diarrhoea (16 10% vs seven 4%) in the SOX group than in the CapeOX group. The frequency of any grade of hand-foot syndrome was greater in the CapeOX group than it was in the SOX group (51 31% vs 23 14%). Interpretation The SOX regimen could be an alternative first-line doublet chemotherapy strategy for patients with metastatic colorectal cancer. Further investigation is needed to explore its potential when used together with other targeted agents or as adjuvant chemotherapy. Funding Korea Healthcare Technology Research and Development Project, Ministry of Health and Welfare, South Korea.
Guidelines for management of non-small cell lung cancer (NSCLC) strongly recommend EGFR mutation testing. These recommendations are particularly relevant in Asians that have higher EGFR mutation ...prevalence. This study aims to explore current testing practices, logistics of testing, types of EGFR mutation, and prevalence of EGFR mutations in patients with advanced NSCLC in a large comprehensive cancer center in Korea.
Our retrospective cohort included 1,503 NSCLC patients aged ≥18 years, with stage IIIB/IV disease, who attended the Samsung Medical Center in Seoul, Korea, from January 2007 through July 2010. Trained oncology nurses reviewed and abstracted data from electronic medical records.
This cohort had a mean age (SD) of 59.6 (11.1) years, 62.7% were males, and 52.9% never-smokers. The most common NSCLC histological types were adenocarcinoma (70.5%) and squamous cell carcinoma (18.0%). Overall, 39.5% of patients were tested for EGFR mutations. The proportion of patients undergoing EGFR testing during January 2007 through July 2008, August 2008 through September 2009, and October 2009 through July 2010 were 23.3%, 38.3%, and 63.5%, respectively (P<0.001). The median time elapsed between cancer diagnoses and receiving EGFR testing results was 21 days. EGFR testing was most frequently ordered by oncologists (57.7%), pulmonologists (31.9%), and thoracic surgeons (6.6%). EGFR testing was more commonly requested for women, younger patients, stage IV disease, non-smokers, and adenocarcinoma histology. Of 586 cases successfully tested for EGFR mutations, 209 (35.7%) were positive, including 118 cases with exon 19 deletions and 62 with L858R mutations. EGFR mutation positive patients were more likely to be female, never-smokers, never-drinkers and to have adenocarcinoma.
In a large cancer center in Korea, the proportion of EGFR testing increased from 2007 through 2010. The high frequency of EGFR mutation positive cases warrants the need for generalized testing in Asian NSCLC patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
