The prognostic value of comprehensive geriatric assessment on the management of older patients with small cell lung cancer.

BACKGROUND/AIMS: The prognostic value of a comprehensive geriatric assessment (CGA) for the management of older small cell lung cancer (SCLC) patients remains to be established. METHODS: A retrospective cohort enrolled 21 SCLC patients over 65 years from March 2018 to 2019 at the Yonsei Cancer Center. The CGA included the following instruments: frailty, body mass index, sarcopenia (circumference of arm and calf, Timed Up and Go test, grip strength), comorbidity, polypharmacy, activities of daily living (ADL), Instrumental ADL, nutrition, depression, and cognitive function. The correlations of oncological and geriatric variables with overall survival (OS) were determined. The log-rank test with Cox model and Kaplan-Meier method were used for the analysis. RESULTS: The median age was 75 years (range, 67 to 85). All patients had the Eastern Cooperative Oncology Group performance status 0-2. The median survival was 9.93 months (range, 1.53 to 36.30). Among CGA parameters, ADL and nutritional status had significant differences in OS in univariate analysis. In multivariate analysis, only nutritional status was independently associated with survival (hazard ratio, 0.17; 95% confidence interval, 0.05 to 0.57). Median OS for low nutritional status was 5.63 months and the normal nutrition group was 15.5 months (p = 0.004). CONCLUSION: Pre-treatment nutritional status measured by CGA appears to be a predictor of OS in older SCLC patients. However, for further generalization of the implication of CGA in SCLC, a larger scale study with prospective design is strongly needed.

Low muscle mass, low muscle function, and sarcopenia in the urban and rural elderly.

Health outcomes of the elderly vary between rural and urban areas. Sarcopenia is diagnosed as loss of muscle strength or impaired physical performance, namely "low muscle function" and low muscle mass. Outcomes of low muscle mass and low muscle function are not equal. This study aimed to investigate the prevalence of low muscle mass, low muscle function, and sarcopenia in rural and urban populations and to determine whether regional differences were associated with each of these components. Participants aged ≥ 69 years (n = 2354) were recruited from three urban districts and one rural district in Korea. Low muscle mass was defined by appendicular lean mass using bioelectrical impedance analysis. Low muscle function was defined by handgrip strength and 5-chair stand test. Sarcopenia was defined as low muscle mass plus low muscle function. The prevalence of low muscle function (53.7% vs. 72.8%), and sarcopenia (16.3% vs. 24.4%) were higher in the rural elderly population. Rural residence was associated with low muscle function (OR 1.63; 95% CI 1.13-2.37, P = 0.009), but not with low muscle mass (OR 0.58; 95% CI 0.22-1.54, P = 0.271) or with sarcopenia (OR 1.13; 95% CI 0.63-2.00, P = 0.683). Interventions to detect and improve low muscle function in rural elderly population are needed.

Comparison of Major Clinical Outcomes between Accredited and Nonaccredited Hospitals for Inpatient Care of Acute Myocardial Infarction.

Hospital accreditation programs are used worldwide to improve the quality of care and improve patient safety. It is of great help in improving the structure of hospitals, but there are mixed research results on improving the clinical outcome of patients. The purpose of this study was to compare the levels of core clinical outcome indicators after receiving inpatient services from accredited and nonaccredited hospitals in patients with acute myocardial infarction (AMI). For all patients with AMI admitted to general hospitals in Korea from 2010 to 2017, their 30-day mortality and readmissions and length of stay were compared according to accreditation status. In addition, through a multivariate model that controls various patients' and hospitals' factors, the differences in those indicators were analyzed more accurately. The 30-day mortality of patients admitted to accredited hospitals was statistically significantly lower than that of patients admitted to nonaccredited hospitals. However, for 30-day readmission and length of stay, accreditation did not appear to yield more desirable results. This study shows that when evaluating the clinical impact of hospital accreditation programs, not only the mortality but also various clinical indicators need to be included, and a more comprehensive review is needed.

Clinical features and KRAS mutation in colorectal cancer with bone metastasis.

Bone metastasis is known as a poor prognostic factor in colorectal cancer (CRC), but its clinical manifestations and outcomes are uncertain. CRC with bone metastasis was searched from January 2006 to April 2016. Of 11,551 CRC patients, 321 (2.7%) patients had bone metastasis. Bone-only metastasis was found in only 8.7% of patients. Synchronous bone metastasis was present in 147 (45.8%) patients. In patients with metachronous bone metastasis, the median time from CRC diagnosis to bone metastasis (TTB) was 27.2 months. KRAS mutation status was a marginally significant factor affecting TTB (median TTB, KRAS wild-type or mutation: 29 or 25.8 months, respectively, P = 0.068). Skeletal-related events (SREs) were noted in 200 (62.3%) patients. Median overall survival (OS) from diagnosis of bone metastasis was 8.0 months. On multivariate analysis, multi-organ metastasis, peritoneal metastasis, neutrophil-to-lymphocyte ratio (NLR) ≥ 2.7, and alkaline phosphatase (ALP) ≥ 123 were independent factors for OS. Palliative chemotherapy prolonged survival in CRC patients with bone metastasis (HR 0.25, 95% CI 0.2-0.33). In conclusion, bone metastasis of CRC is rare, but it is related to SREs. Most patients have other organ metastasis and survival is 8.0 months. Attention should be paid to bone metastasis in CRC patients.

Association between Accreditation and In-Hospital Mortality in Patients with Major Cardiovascular Diseases in South Korean Hospitals: Pre-Post Accreditation Comparison.

The direct impact of hospital accreditation on patients' clinical outcomes is unclear. The purpose of this study was to evaluate whether mortality within 30 days of hospitalization for acute myocardial infarction (AMI), ischemic stroke (IS), and hemorrhagic stroke (HS) differed before and after hospital accreditation. This study targeted patients who had been hospitalized for the three diseases at the general hospitals newly accredited by the government in 2014. Thirty-day mortality rates of three years before and after accreditation were compared. Mortality within 30 days of hospitalization for the three diseases was lower after accreditation than before (7.34% vs. 6.15% for AMI; 4.64% vs. 3.80% for IS; and 18.52% vs. 15.81% for HS). In addition, hospitals that meet the criteria of the patient care process domain have a statistically lower mortality rate than hospitals that do not. In the newly accredited Korean general hospital, it was confirmed that in-hospital mortality rates of major cardiovascular diseases were lower than before the accreditation.

A Randomized Phase II Study of Perioperative Chemotherapy Plus Bevacizumab Versus Postoperative Chemotherapy Plus Bevacizumab in Patients With Upfront Resectable Hepatic Colorectal Metastases.

INTRODUCTION: Whether patients with resectable colorectal liver metastases (CRLM) gain a survival benefit from perioperative chemotherapy remains controversial. The benefit of including bevacizumab in chemotherapy also remains unclear. MATERIAL AND METHODS: Seventy-six patients with CRLM were randomly assigned to either 6 cycles of FOLFOX (folinic acid, 5-fluorouracil, and oxaliplatin)/FOLFIRI (folinic acid, 5-fluorouracil, and irinotecan) with bevacizumab before and after surgery or 12 cycles after surgery. Progression-free survival (PFS) was estimated using the Kaplan-Meier method and compared by the log-rank test. RESULTS: The median PFS of all patients was 37.4 months at 5.4 years follow-up, and the median overall survival (OS) was not reached. The PFS between the perioperative group and the postoperative group did not reveal a statistical difference (P = .280). The OS was significantly better in the perioperative group (hazard ratio [HR], 0.60; 95% confidence interval [CI],) 0.35-1.02; P = .049). In subgroup patients with carcinoembryonic antigens (CEA) ≥ 5 ng/mL or those with over 2 liver metastases, perioperative group had longer OS than postoperative group (CEA: HR, 0.49; 95% CI, 0.25-0.93; P = .030; number of liver metastases: HR, 0.55; 95% CI, 0.30-0.99; P = .049). The largest liver metastases size, disease-free interval, and sidedness did not affect PFS or OS. There was no difference between the 2 groups in postoperative complications with bevacizumab or adverse events during chemotherapy. CONCLUSIONS: In patients with resectable CRLMs, perioperative chemotherapy had no effect on PFS, but improved OS. Patients with high CEA levels or over 2 liver metastases may benefit from perioperative chemotherapy.

Patient-Derived Cells to Guide Targeted Therapy for Advanced Lung Adenocarcinoma.

Adequate preclinical model and model establishment procedure are required to accelerate translational research in lung cancer. We streamlined a protocol for establishing patient-derived cells (PDC) and identified effective targeted therapies and novel resistance mechanisms using PDCs. We generated 23 PDCs from 96 malignant effusions of 77 patients with advanced lung adenocarcinoma. Clinical and experimental factors were reviewed to identify determinants for PDC establishment. PDCs were characterized by driver mutations and in vitro sensitivity to targeted therapies. Seven PDCs were analyzed by whole-exome sequencing. PDCs were established at a success rate of 24.0%. Utilizing cytological diagnosis and tumor colony formation can improve the success rate upto 48.8%. In vitro response to a tyrosine kinase inhibitor (TKI) in PDC reflected patient treatment response and contributed to identifying effective therapies. Combination of dabrafenib and trametinib was potent against a rare BRAF K601E mutation. Afatinib was the most potent EGFR-TKI against uncommon EGFR mutations including L861Q, G719C/S768I, and D770_N771insG. Aurora kinase A (AURKA) was identified as a novel resistance mechanism to olmutinib, a mutant-selective, third-generation EGFR-TKI, and inhibition of AURKA overcame the resistance. We presented an efficient protocol for establishing PDCs. PDCs empowered precision medicine with promising translational values.

Molecular characterization of lung adenocarcinoma from Korean patients using next generation sequencing.

The treatment of Lung adenocarcinoma (LUAD) could benefit from the incorporation of precision medicine. This study was to identify cancer-related genetic alterations by next generation sequencing (NGS) in resected LUAD samples from Korean patients and to determine their associations with clinical features. A total of 201 tumors and their matched peripheral blood samples were analyzed using targeted sequencing via the Illumina HiSeq 2500 platform of 242 genes with a median depth of coverage greater than 500X. One hundred ninety-two tumors were amenable to data analysis. EGFR was the most frequently mutated gene, occurring in 106 (55%) patients, followed by TP53 (n = 67, 35%) and KRAS (n = 11, 6%). EGFR mutations were strongly increased in patients that were female and never-smokers. Smokers had a significantly higher tumor mutational burden (TMB) than never-smokers (average 4.84 non-synonymous mutations/megabase [mt/Mb] vs. 2.84 mt/Mb, p = 0.019). Somatic mutations of APC, CTNNB1, and AMER1 in the WNT signaling pathway were highly associated with shortened disease-free survival (DFS) compared to others (median DFS of 89 vs. 27 months, p = 0.018). Patients with low TMB, annotated as less than 2 mt/Mb, had longer DFS than those with high TMB (p = 0.041). A higher frequency of EGFR mutations and a lower of KRAS mutations were observed in Korean LUAD patients. Profiles of 242 genes mapped in this study were compared with whole exome sequencing genetic profiles generated in The Cancer Genome Atlas Lung Adenocarcinoma. NGS-based diagnostics can provide clinically relevant information such as mutations or TMB from readily available formalin-fixed paraffin-embedded tissue.

A phase Ib study of the combination of afatinib and ruxolitinib in EGFR mutant NSCLC with progression on EGFR-TKIs.

OBJECTIVES: We evaluated the safety and efficacy of the combination therapy of afatinib, an irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), and ruxolitinib, a JAK1/2 selective inhibitor, in patients with EGFR mutant NSCLC progressing on at least one kind of EGFR-TKI. MATERIALS AND METHODS: In this phase Ib open-label study, we used a 3 + 3 dose-escalation design. Patients with histologically diagnosed EGFR-mutant stage IV NSCLC and documented disease progression on EGFR-TKI therapies were enrolled. Afatinib only was administered on day 1 through day 8 (run-in period), then ruxolitinib was administered concurrently with afatinib until disease progression. The primary endpoints were to determine the dose-limiting toxicity (DLT) and a recommended phase II dose of the combination regimen. We also included a dose confirmation cohort for the highest dose, and an expansion cohort for T790 M mutation. RESULTS: As of October 2017, 30 patients participated in the study, of which 20 had T790 M mutations. Because no DLT was observed in nine patients at the highest dose level (50 mg afatinib once daily plus 25 mg ruxolitinib twice daily), nine patients with T790 M mutations were enrolled in a dose-expansion cohort. Frequent adverse events included diarrhea (G3 in 3 of 22 cases), anemia (G3 in 1 of 26 cases), paronychia (G1/2 in 14 cases), acneiform rash (G1 in 13 cases), and oral mucositis (G1/2 in 12 cases). Objective response rate was 23.3% (no complete response [CR] and 7 partial responses [PR]) and disease control rate was 93.3% (no CR, 7 PR and 21 stable diseases). The median progression-free survival was 4.9 months (95% CI, 2.4-7.5). CONCLUSION: The combination of afatinib and ruxolitinib was tolerated by patients, with modest clinical activity observed in NSCLC with acquired resistance to EGFR-TKIs (NCT02145637).

Significance of Metabolic Tumor Volume and Total Lesion Glycolysis Measured Using ¹8F-FDG PET/CT in Locally Advanced and Metastatic Gallbladder Carcinoma.

PURPOSE: This study aimed to determine the prognostic value of new quantitative parameters of ¹8F-fluorodeoxyglucose positron emission tomography/computed tomography (¹8F-FDG PET/CT), including metabolic tumor volume (MTV), in patients with locally advanced and metastatic gallbladder cancer (GBC). MATERIALS AND METHODS: In total, 83 patients initially diagnosed with locally advanced and metastatic GBC and who underwent ¹8F-FDG PET/CT at the time of initial diagnosis were retrospectively reviewed. The metabolic volume-based PET parameters of primary tumors and metastatic lesions were measured, including maximum and average standardized uptake values (SUV), MTV, and total lesion glycolysis. An overall survival (OS) analysis was performed using the Kaplan-Meier method with PET and clinical parameters. A Cox proportional hazards regression analysis was performed to determine independent prognostic factors. RESULTS: In univariate analysis, pathologic differentiation (p<0.001), performance status (PS; p=0.003), C-reactive protein (CRP) level (p=0.009), and PET-related SUVmt max (the highest SUV among the metastatic lesions) (p=0.040) and MTVtotal (the sum of the MTVs of both the primary and metastatic lesions) (p=0.031), were significant for OS. In multivariate analysis, MTVtotal (hazard ratio: 2.07; 95% confidence interval: 1.23-3.48; p=0.006) remained significant for the prediction of OS, as did differentiation (p=0.001), PS (p=0.001), and CRP (p=0.039). CONCLUSION: In locally advanced and metastatic GBC, volume-based PET/CT parameters of the total tumor burden of malignancy, such as MTVtotal, were found to be useful for the identification of patients with poor prognosis.

Marked Loss of Muscle, Visceral Fat, or Subcutaneous Fat After Gastrectomy Predicts Poor Survival in Advanced Gastric Cancer: Single-Center Study from the CLASSIC Trial.

BACKGROUND: There is increasing interest in the influence of body composition on oncological outcomes. We evaluated the role of skeletal muscle and fat among patients with gastric cancer (GC) who underwent gastrectomy with or without adjuvant chemotherapy, as well as those changes' associations with survival outcomes. METHODS: The present study evaluated 136 patients with GC who were enrolled in the CLASSIC Trial at Yonsei Cancer Center. Baseline body compositions including skeletal muscle area, Hounsfield units (HU), visceral fat area, and subcutaneous fat area were measured by preoperative computed tomography (CT). CT before and after the gastrectomy were used to determine the 6-month relative changes in body composition parameters. Continuous variables were dichotomized according to the best cutoff values by Contal and O'Quigley method. RESULTS: Seventy-three patients (53.7%) underwent surgery alone, and 63 patients (46.3%) underwent surgery followed by adjuvant chemotherapy. The baseline body composition parameters were not associated with disease-free survival (DFS) or overall survival (OS). Except for the HU, the marked loss of muscle, visceral fat, or subcutaneous fat significantly predicted shorter DFS and OS. Patients with a marked loss in at least one significant body composition parameter had significantly shorter DFS (hazard ratio 2.9, 95% confidence interval 1.7-4.8, P < 0.001) and OS (hazard ratio 2.9, 95% confidence interval 1.7-5.0, P < 0.001). CONCLUSIONS: Marked loss in body composition parameters significantly predicted shorter DFS and OS among patients with GC who underwent gastrectomy. Postoperative nutrition and active healthcare interventions could improve the prognosis of these GC patients.

Prognostic Factors and Scoring Model for Survival in Metastatic Biliary Tract Cancer.

PURPOSE: Metastatic biliary tract cancer (mBTC) has a dismal prognosis. In this study, an independent dataset of patients with mBTC was used to implement and validate a routine clinico-laboratory parameter-based scoring model for risk group identification. MATERIALS AND METHODS: From September 2006 to February 2015, 482 patients with mBTC were assigned randomly (ratio, 7:3) into investigational (n=340) and validation datasets (n=142). The continuous variables were dichotomized using a normal range or the best cutoff values determined using the Contal and O'Quigley statistical methods. Following a Cox's proportional hazard model, the scoring model was derived by summing the rounded chi-square scores for the factors identified by multivariate analysis. RESULTS: The performance status (Eastern Cooperative Oncology Group 3-4), hypoalbuminemia (< 3.4 mg/dL), carcinoembryonic antigen (≥ 9 ng/mL), neutrophil-to-lymphocyte ratio (≥ 3.0), and carbohydrate antigen 19-9 (≥ 120 U/mL) were identified as independent prognosticators (Harrell's C index, 0.682; integrated area under the curve, 0.653). Survival was clearly correlated with the risk groups (low, intermediate, and high, 14.0, 7.3, and 2.3 months, respectively; p < 0.001). The prognosis was also discriminative in the validation data set (median survival, 16.7, 7.5, and 1.9 months, respectively; p < 0.001). Chemotherapy did not offer any survival benefits for high-risk patients. CONCLUSION: These proposed prognostic criteria for mBTC can facilitate accurate patient risk stratification and treatment-related decision-making.