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Abstract The human epidermal growth factor receptor 2 (HER2)-positive breast cancer with overexpression of HER2 accounts for approximately 25% of breast cancers and is more aggressive than other types of breast cancer. Lapatinib has been widely used as a HER2-targeted therapy, however, a number of patients develop lapatinib resistance and still suffer from poor prognosis. Therefore, it is essential to identify novel therapeutic targets that could overcome lapatinib resistance. In this study, we carried out phosphoproteomic analysis of lapatinib sensitive and resistant cell lines (SKBR3 and SKBR3-LR) using stable isotope labeling with amino acids in cell culture (SILAC). We identified 3808 phosphopeptides from 1807 proteins and then analyzed signaling pathways, Gene Ontology, and protein-protein interaction networks. Finally, we identified PAK2 as a therapeutic target from the network analysis and validated that PAK2 knockdown and PAK inhibitor treatment resensitize the lapatinib resistant cells to lapatinib. This results suggest that PAK2 is a potent therapeutic target to overcome acquired lapatinib resistance in HER2-positive breast cancer cells. Highlights • Phosphoproteomic analysis identified PAK2 as a drug target for lapatinib resistance. • PAK2 knockdown restores lapatinib sensitivity of lapatinib-resistant SKBR-LR cells. • Cotreatment of lapatinib with PAK inhibitor restores the sensitivity to lapatinib. [ABSTRACT FROM AUTHOR]

Background: The renin-angiotensin system (RAS) is related to the regulation of cell proliferation, angiogenesis, and tumor progression. Patients and Methods: We retrospectively analyzed the effect of angiotensin I-converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor blockers (ARBs) in 63 patients with advanced gastric cancer (AGC) with platinum-based chemotherapy. All patients analyzed had received medications for hypertension at the diagnosis of AGC. Patients were divided into two groups: an ACEI/ARB group (n = 30) and a non-ACEI/ARB group (n = 33). Results: Patient characteristics were not different between patients with and without ACEI/ARB. The response rate for all patients was 25.4% and the disease control rate was 77.8%. The median progression-free survival (PFS) for first-line chemotherapy was 5.5 months (95% CI 3.71-7.29) in the ACEI/ARB group and 4.3 months (95% CI 2.39-6.21) in the non-ACEI/ARB group (p = 0.506). There was a significant difference in overall survival (OS) in the ACEI/ARB group compared to the non-ACEI/ARB group (median OS: 8.2 vs. 13.9, p = 0.0095). In multivariate analysis, the use of ACEI/ARB was a significant independent prognostic factor for OS (p = 0.039) but not for PFS. Conclusion: ACEI/ARB in combination with standard chemotherapy might improve survival in patients with AGC and hypertension. These results support further investigation into the anticancer effects of ACEL/ARB. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Aim: To analyze the chemotherapy regimens and outcomes of advanced gastric cancer (AGC) patients older than 70 years of age. Methods: Between May 2001 and October 2009, 1135 patients with metastatic or recurrent gastric cancer received palliative chemotherapy. Of these patients 56 (4.9%) were ≥70 years old and were analyzed retrospectively. Results: The median age at the time of first-line chemotherapy was 73 years (range, 70-85) and the median Charlson comorbidity index was 0 (0-5). In all 17 patients (30%) received surgery with curative or palliative intent; 43 (77%) were treated by doublet or triplet first-line chemotherapy regimens and 13 patients (23%) received single agent chemotherapy. Median progression-free survival for first-line chemotherapy was 3.97 months (95% CI 2.05-5.89) with an overall response rate of 26%. After the first-line chemotherapy, only 18 of 56 (32%) patients received second-line chemotherapy. The median overall survival (OS) was 12.4 months (95% CI 2.81-21.99). In multivariate analysis, receiving surgery and disease control for first-line chemotherapy were independent prognostic factors for increased OS for all 56 patients. Conclusion: Patients older ≥70 years with metastatic or recurrent gastric cancer might achieve clinical benefit from chemotherapy. Receiving surgery and response of over more stable disease for first-line chemotherapy were independent prognostic factors for increased OS. [ABSTRACT FROM AUTHOR]

Background: Varicella zoster virus (VZV) infection is a representative opportunistic infection in patients with hematological malignancies, with a high incidence of 30-50%. Many studies on the risk factors of VZV infection in this patient group have been conducted. However, few data have been reported exploring VZV infection during systemic chemotherapy in solid cancer patients. Patients and Methods: We retrospectively analyzed 92 patients diagnosed with VZV infection between April 2001 and July 2010 during systemic chemotherapy for solid tumors. All patients had received antiviral prophylaxis for VZV. Results: The median age at the time of diagnosis of VZV infection was 60.8 years (range 30.1-83.0) and the majority of patients (79.3%) did not have comorbidities. Eighty-one patients (88%) received chemotherapy for locally advanced or metastatic/recurrent disease and 11 (12.0%) had adjuvant chemotherapy after curative resection. Of 92 patients, 14 (15.2%) had non-small cell lung cancer and 10 (10.9%) breast cancer. All patients had a median of 2 metastatic lesions (range 0-4). At the time of diagnosis, 55 patients (59.8%) were receiving first-line chemotherapy and 15 (16.3%) more than third-line chemotherapy. The mean white blood cell, platelet and albumin level was 5,736/μl, 205.7 × 103 and 3.8 mg/dl, respectively. On analysis for disease evaluation at the time nearest to diagnosis of VZV infection, only 14 patients (15.2%) revealed tumor response to chemotherapy. After the diagnosis of VZV infection, all patients were treated with antiviral agents. None of the patients experienced failure of therapy for VZV. Conclusion: We reported VZV infection during systemic chemotherapy in solid cancer patients. Patients may have a relatively poor tumor response to chemotherapy at the time nearest to diagnosis of VZV infection. A prospective or matched controlled trial is needed to confirm this finding. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Array comparative genomic hybridization (aCGH) provides a method to quantitatively measure the changes of DNA copy number with an extremely high resolution and to map them directly onto the complete linear genome sequences. In this study, we used aCGH to compare genomic alterations in fresh-frozen lung cancer tissues of 21 adenocarcinomas (AdCCs) (11 early relapse and 10 nonrelapse) and identified genomic alterations that showed significant by different frequency between early relapse and nonrelapse AdCCs. Twelve clones were identified by the false discovery rate (FDR) test, and Kaplan-Meier analyses were selected as predictive markers. The significant gain clones were found in 11p (11p15.4, 11p15.1, and 11p13). When the cutoff value was 2, study of the association between candidate clones and relapse prediction revealed that early relapse and nonrelapse groups were most effectively separated. To further validate the gain of chromosome 11p region that was identified by array CGH, fluorescence in situ hybridization (FISH) was performed. To further confirm the results of aCGH, copy number changes of cancer-related candidate genes in AdCC patients were compared by real-time quantitative polymerase chain reaction. Array CGH and real-time quantitative polymerase chain reaction data were found to correspond to delineated DNA copy number changes. Genomic alterations of chromosome 11p region in AdCC patients were observed with aCGH, and a relapsable marker was identified in the nonrelapse group. This marker could be useful in stratifying patient groups according to likelihood of relapse for adjuvant treatment after surgical resection. [Copyright &y& Elsevier]

Summary: Insulin-like growth factor binding protein-3 (IGFBP-3) is a putative tumor suppressor and inhibits the mitogenic and antiapoptotic activity of insulin-like growth factor (IGF) by blocking the binding to its receptors or by IGF-independent manner. Epidemiological studies have suggested that serum level of IGFBP-3 is associated with lung cancer risk. The present study was conducted to evaluate the association between single nucleotide polymorphisms (SNPs) of the IGFBP-3 gene and susceptibility to lung cancer and the effect of the SNPs on the serum levels of IGFBP-3, total IGF-I and free IGF-I in a Korean population. After a preliminary study for polymorphism screening of the promoter region of the IGFBP-3 gene in randomly selected 41 lung cancer patients, two polymorphisms (−1590 C>A; −202 A>C) were identified with PCR-based restriction fragment length polymorphism (PCR-RFLP) and SNaPshot primer extension assay in 415 Korean lung cancer patients and 415 matched normal controls. Although the genotype and allele frequency distribution of each SNP did not differ significantly between cases and controls in the single-locus analysis, we found that the polymorphisms of −1590A and −202C were associated with increased risk for lung cancer in females (−1590 C>A; adjusted OR=2.11, 95% CI=1.08–4.12, −202 A>C; adjusted OR=1.96, 95% CI=1.02–3.75, respectively) and never-smokers (−1590 C>A; adjusted OR=2.06, 95% CI=1.12–3.78, −202 A>C; adjusted OR=1.99, 95% CI=1.10–3.62, respectively) in a dominant model after stratification for gender and smoking history. Haplotype analysis showed that carriers of A–C had significantly higher risk for lung cancer in females (dominant aOR=2.05, 95% CI=1.14–3.68) and in never-smokers (codominant aOR=1.71, 95% CI=1.11–2.64 and dominant aOR=1.99, 95% CI=1.17–3.40). Functional analysis in H1703 cell line using DNA fragments containing A–C haplotype of the promoter region showed significantly decreased transcriptional activity. Furthermore, there was a negative correlation between the number of polymorphic alleles in −1590/−202 loci and serum levels of IGFBP-3 in lung cancer patients, but it was not statistically significant in the test for linear trend. These results suggest that IGFBP-3 promoter polymorphisms of −1590 C>A and −202 A>C might be a genetic risk factor for lung cancer by means of decreased IGFBP-3 expression among females or never-smoking Koreans. [Copyright &y& Elsevier]

Abstract: The present study was conducted to investigate the association between single nucleotide polymorphisms (SNPs) of the transforming growth factor-beta 1 (TGFB1) gene and susceptibility to lung cancer and the clinical effect of the SNPs on lung cancer progression in a Korean population. Two polymorphisms in the promoter region of the TGFB1 (T−1572C, C−509T), and one SNP in codon 10 (T+869C) were determined using a SNaPshot primer extension assay in 194 Korean lung cancer patients and 283 normal controls. The polymorphic allele frequencies of A−1572G, C−509T, and T+869C were similar among lung cancer patients (0.52, 0.47, and 0.47, respectively) and controls (0.54, 0.46, and 0.44, respectively). When the data was stratified for smoking history, patients who smoked heavily and had heterozygous C−509T and T+869C genotypes showed an increased lung cancer risk (odds ratio OR = 3.77, confidence interval 95% CI = 1.25–11.30, P = 0.017; OR = 3.61, 95% CI = 1.21–10.74, P = 0.021 for each), after adjustment for age and sex. When heterozygous and homozygous variants for each SNPs were analyzed together, patients who were smokers and had variant genotypes also showed increased risk compared to the reference group. Further analyses to test the effect of the SNPs on the clinical parameters did not reveal an association of each polymorphic allele to the tumor stage or response to treatment. In addition, DNA fragments containing polymorphic genotype of the promoter region (−509T) showed increased transcriptional activity in luciferase assays using non-small cell lung cancer cell lines. In conclusion, this study suggests that heavy smokers in this Korean population who have specific polymorphic variants, which have been associated with increased transcriptional activity of TGFB1, might be more vulnerable to lung cancer. [Copyright &y& Elsevier]

Background: Paclitaxel is commonly used as a second-line therapy for advanced gastric cancer (AGC). The decision to proceed with second-line chemotherapy and select an appropriate regimen is critical for vulnerable patients with AGC progressing after first-line chemotherapy. However, no predictive biomarkers exist to identify patients with AGC who would benefit from paclitaxel-based chemotherapy. Methods: This study included 288 patients with AGC receiving second-line paclitaxel-based chemotherapy between 2017 and 2022 as part of the K-MASTER project, a nationwide government-funded precision medicine initiative. The data included clinical (age [young-onset vs. others], sex, histology [intestinal vs. diffuse type], prior trastuzumab use, duration of first-line chemotherapy), and genomic factors (pathogenic or likely pathogenic variants). Data were randomly divided into training and validation sets (0.8:0.2). Four machine learning (ML) methods, namely random forest (RF), logistic regression (LR), artificial neural network (ANN), and ANN with genetic embedding (ANN with GE), were used to develop the prediction model and validated in the validation sets. Results: The median patient age was 64 years (range 25–91), and 65.6% of those were male. A total of 288 patients were divided into the training (n = 230) and validation (n = 58) sets. No significant differences existed in baseline characteristics between the training and validation sets. In the training set, the areas under the ROC curves (AUROC) for predicting better progression-free survival (PFS) with paclitaxel-based chemotherapy were 0.499, 0.679, 0.618, and 0.732 in the RF, LR, ANN, and ANN with GE models, respectively. The ANN with the GE model that achieved the highest AUROC recorded accuracy, sensitivity, specificity, and F1-score performance of 0.458, 0.912, 0.724, and 0.579, respectively. In the validation set, the ANN with GE model predicted that paclitaxel-sensitive patients had significantly longer PFS (median PFS 7.59 vs. 2.07 months, P = 0.020) and overall survival (OS) (median OS 14.70 vs. 7.50 months, P = 0.008). The LR model predicted that paclitaxel-sensitive patients showed a trend for longer PFS (median PFS 6.48 vs. 2.33 months, P = 0.078) and OS (median OS 12.20 vs. 8.61 months, P = 0.099). Conclusions: These ML models, integrated with clinical and genomic factors, offer the possibility to help identify patients with AGC who may benefit from paclitaxel chemotherapy. [ABSTRACT FROM AUTHOR]

We explored accumulated genomic alterations in patients with heavily treated HER2 + metastatic breast cancer enrolled in the KCSG BR18-14/KM10B trial. Targeted sequencing was performed with circulating tumor DNAs (ctDNAs) collected before the treatment of 92 patients. ctDNAs collected at the time of disease progression from seven patients who had a durable response for > 12 months were also analyzed. Sixty-five genes were identified as pathogenic alterations in 99 samples. The most frequently altered genes were TP53 (n = 48), PIKCA (n = 21) and ERBB3 (n = 19). TP53 and PIK3CA mutations were significantly related with shorter progression free survival (PFS), and patients with a higher ctDNA fraction showed a worse PFS. The frequency of homologous recombination deficiency (HRD)-related gene mutations was higher than that in matched tumor tissues, and these mutations tended to be associated with shorter PFS. New pathogenic variants were found at the end of treatment in all seven patients, including BRCA2, VHL, RAD50, RB1, BRIP1, ATM, FANCA, and PIK3CA mutations. In conclusion, TP53 and PIK3CA mutations, as well as a higher ctDNA fraction, were associated with worse PFS with trastuzumab and cytotoxic chemotherapy. The enrichment of HRD-related gene mutations and newly detected variants in ctDNA may be related to resistance to treatment. [ABSTRACT FROM AUTHOR]

Background: Although various coronavirus disease 2019 (COVID‐19) vaccines have been delivered to the public worldwide, data on cancer populations are limited. Vaccine hesitancy related to safety concerns is observed among cancer patients. We report the perception of COVID‐19 vaccines and their safety profile after vaccination among cancer patients. Materials and Methods: Between April and November 2021, a multicenter survey was conducted on 318 patients treated in any hemato‐oncology outpatient clinic among three hospitals under the Korea University Medical Center. The medical records of the patients were reviewed to obtain detailed clinical and hematological toxicity data. Results: A perception survey was conducted among 293 patients. Among them, 53.9% were concerned about developing vaccine‐related adverse events (VRAEs) and 23.5%, about negative effects on cancer treatment. During the study period, 255 and 186 patients participated in a safety survey after the first and second doses, respectively. After the first dose, 62% of patients reported VRAEs (2.4%, grade 3), whereas 48.9% reported VRAEs (2.7%, grade 3) after the second dose. For both doses, injection‐site pain and sore arm pain were the most common VRAEs, followed by myalgia, fatigue, and headache. No grade 4/5 VRAEs were observed, and there were no differences in complete blood count after vaccination. Multivariate analysis revealed female sex, active cancer treatment, and mRNA vaccines as independent risk factors for VRAE development in cancer patients. Conclusion: Despite high levels of concern, COVID‐19 vaccines were well tolerated by cancer patients, with a safety profile consistent with that of the general population. [ABSTRACT FROM AUTHOR]

Multi-color flow cytometry is the standard approach for immunophenotyping clinical samples. With the recent advances in cancer immunotherapy, myeloid-derived suppressor cells (MDSC), immature myeloid-lineage cells in cancer patient blood and the tumor microenvironment, are highlighted as an important immune cell population that correlates with prognosis and therapeutic efficacy. In contrast to their clear functions and existence, immunophenotyping of MDSC is not consistent among investigators due to surface antigens overlapping with many normal hematopoietic lineage cell populations. We performed a clinical study and analyzed more than 1000 breast cancer patients blood samples to quantitate MDSC during breast cancer progression. In this methodology manuscript, we described detailed procedures for study design, sample logistics and handling, staining and flow cytometric analysis. This protocol used a 7-color fluorochrome-conjugated antibody panel to analyze polymorphonuclear (PMN)- and monocytic (M)-MDSC subsets simultaneously. The interim analysis results of this study showed that both PMN and M-MDSC populations are increased in patients with bone metastasis compared with patients with visceral organ metastasis. In conclusion, this work provides a versatile, comprehensive, and practical protocol to measure MDSC in patient blood samples. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is the most commonly diagnosed malignancy among men in developed countries. The five-year survival rate for men diagnosed with early-stage PCa is approximately 100%, while it is less than 30% for castration-resistant PCa (CRPC). Currently, the detection of prostate-specific antigens as biomarkers for the prognosis of CRPC is criticized because of its low accuracy, high invasiveness, and high false-positive rate. Therefore, it is important to identify new biomarkers for prediction of CRPC progression. Extracellular vesicles (EVs) derived from tumors have been highlighted as potential markers for cancer diagnosis and prognosis. Specifically, urinary EVs directly reflect changes in the pathophysiological conditions of the urogenital system because it is exposed to prostatic secretions. Thus, detecting biomarkers in urinary EVs provides a promising approach for performing an accurate and non-invasive liquid biopsy for CPRC. In this study, we effectively isolated urinary EVs with low protein impurities using size-exclusion chromatography combined with ultrafiltration. After EV isolation and characterization, we evaluated the miRNAs in urinary EVs from healthy donors and patients with CRPC. The results indicated that miRNAs (miR-21-5p, miR-574-3p, and miR-6880-5p) could be used as potential biomarkers for the prognosis of CRPC. This analysis of urinary EVs contributes to the fast and convenient prognosis of diseases, including CRPC, in the clinical setting. [ABSTRACT FROM AUTHOR]

Purpose: Perioperative blood transfusion in early stage cancer patients had a negative effect on the prognosis of patients, but the prognostic impact of transfusion in advanced cancer patients remains unclear. To minimize and guide rational transfusion, an institutional patient blood management (PBM) program was launched, and we evaluated the new program that has changed the practice and impacted on the prognosis of advanced cancer patients.Methods: We investigated the medical records of colorectal cancer patients who received chemotherapy from 2015 to 2020. The amount and frequency of transfusion, iron replacement and laboratory findings, and overall survival were compared before and after implementation of PBM.Results: The rate of transfusion in colorectal cancer patients was significantly decreased from 23.5/100 person-quarter in 2015 to 1.2/100 person-quarter in 2020, but iron supplementation therapy was frequently used, and the proportion of patients who received transfusion under hemoglobin 7 g/dL significantly increased from 15.9% in 2015 to 55.3% in 2020. Multivariate analysis revealed that transfusion was a significant risk factor affecting the overall survival of patients (HR 2.70, 95% CI: 1.93-3.78, p<0.001). Kaplan-Meier analysis revealed that overall survival was significantly longer in non-transfused patients than in transfused patients (11.0 versus 22.4 months; HR 0.69, 95% CI: 0.56-0.86, p<0.001).Conclusions: This study shows that minimized transfusion through an institutional PBM can positively affect the prognosis of patients who are receiving chemotherapy for advanced colorectal cancer. [ABSTRACT FROM AUTHOR]

Abstract: Aims: The role of salvage chemotherapy after first-line therapy in advanced pancreatic cancer has not yet been established. We intended to identify prognostic factors for long-term survival of advanced pancreatic adenocarcinoma patients with second-line chemotherapy and to devise a prognostic model of clinical parameters. Patients and methods: We analysed 90 patients who had received second-line chemotherapy after the failure of first-line therapy in recurrent or metastatic pancreatic adenocarcinoma between August 2003 and December 2008. Results: The median age at the time of second-line chemotherapy was 61.9 years (range 39.8–74.9) and the median Eastern Cooperative Oncology Group (ECOG) performance status was 1 (0–2). Median progression-free survival and overall survival for second-line chemotherapy were 2.1 and 4.5 months, respectively, with an overall response rate of 10%. In multivariate analysis, an ECOG performance status of 2 or more, non-responder for first-line chemotherapy and albumin level of <3.5mg/dl were independent prognostic factors for decreased overall survival for all 90 patients. Overall survival was estimated based on the number of adverse prognostic factors: zero or one (good prognostic group), two (intermediate group) or three (poor prognostic group). The median overall survival for good (n =50), intermediate (n =24) and poor (n =16) prognostic groups was 5.5, 3.3 and 2.1 months, respectively (P <0.001). Conclusion: Our result suggests that second-line chemotherapy may be beneficial for overall survival in patients with ECOG performance status 0–1, albumin level ≥3.5mg/dl and response to first-line chemotherapy. [Copyright &y& Elsevier]

Abstract: Although many studies have been performed on carbapenem-resistant Acinetobacter baumannii, only a few studies have addressed carbapenem resistance in Acinetobacter spp. other than A. baumannii (non-baumannii Acinetobacter). Amongst 287 Acinetobacter spp. isolates from patients with bacteraemia in a South Korean hospital collected between 2003 and 2010, 160 (55.7%) were non-baumannii Acinetobacter spp. Antimicrobial susceptibility testing was performed and the effect of efflux pump inhibitors was examined. Antimicrobial resistance genes were identified and pulsed-field gel electrophoresis (PFGE) analysis was performed. OprD expression was also evaluated by quantitative real-time polymerase chain reaction (qRT-PCR), and CarO disruption was investigated by PCR. Seventeen non-baumannii Acinetobacter isolates (10.6%) were resistant to imipenem or meropenem, comprising eight Acinetobacter pittii (or Acinetobacter genomospecies 3), four Acinetobacter nosocomialis (or Acinetobacter genomospecies 13TU), two Acinetobacter genomospecies ‘close to 13TU’, two Acinetobacter bereziniae (or Acinetobacter genomospecies 10) and one Acinetobacter genomospecies 16. bla IMP-1 genes were detected in seven and two carbapenem-resistant A. pittii and A. bereziniae isolates, respectively. PFGE showed that A. pittii isolates carrying bla IMP-1 belonged to the same clone. In addition, bla SIM-1 and bla PER-1 genes were simultaneously identified in two A. nosocomialis isolates. In four isolates (one each of A. pittii, A. nosocomialis, Acinetobacter genomospecies ‘close to 13TU’ and Acinetobacter genomospecies 16), efflux pumps were implicated in the increase in carbapenem minimum inhibitory concentrations. No decreased expression of OprD was identified in any carbapenem-resistant non-baumannii Acinetobacter isolates, and disruption of carO was also not detected. Clonal spread of carbapenem-resistant A. pittii carrying bla IMP-1, which contributes to a high resistance rate in this species, was identified. The bla IMP-1 and bla SIM-1 genes were first identified in A. bereziniae and A. nosocomialis, respectively. Since no carbapenem resistance mechanisms could be identified, further efforts to find the resistance mechanism should be made. [Copyright &y& Elsevier]

Background: Epidermal growth factor receptor (EGFR) mutations as prognostic marker in patients with non-small cell lung cancers remain controversial. In particular, there is only a limited amount of data on the subject in Asian patients with advanced lung adenocarcinomas. Patients and Methods: We analyzed 50 patients with advanced lung adenocarcinoma, who received best supportive care with and without cytotoxic chemotherapy, between March 2006 and December 2008. The patients had never been treated with EGFR tyrosine kinase inhibitors. Tumor tissues of all 50 patients were analyzed for the status of EGFR gene mutations. Results: The median age of patients was 64 years (range 32-84) at diagnosis, and the male/female ratio was 2.6/1.0. Thirty-two patients were current or ever smokers. EGFR gene mutations were detected in 11 patients (22%). Seven of them had in-frame deletion within exon 19, resulting in the loss of codon 746 through 750 (delE746-A750), 2 patients had L858R in exon 21, and 2 patients had point mutation at codon 709 in exon 18, resulting in the substitution of glycine either with glutamic acid or alanine. The status of EGFR mutations was not significantly associated with gender, smoking status, ages, metastatic sites and number of metastasized sites. Seventeen patients received best supportive care without cytotoxic chemotherapy and 33 patients received the standard platinum-based doublet chemotherapy. The median overall survival was 8.90 months (95% CI 4.01-13.79). There were no significant differences in overall survival (p = 0.282) according to the status of EGFR mutations. Conclusion: These results suggest that EGFR mutation is not a prognostic marker in Korean patients with advanced lung adenocarcinoma who had not been treated with EGFR tyrosine kinase inhibitors. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: High colistin resistance rates in Acinetobacter spp. were recently reported in Korean hospitals (J. Antimicrob. Chemother 2007;60:1163). In this study, we investigated if colistin-resistant Acinetobacter spp. isolates from Korean hospitals disseminated clonally or emerged independently. Multilocus sequence typing (MLST) analysis was performed for 58 colistin-resistant Acinetobacter spp. isolates: 8 isolates of the Acinetobacter baumannii subgroup A, 16 isolates of the A. baumannii subgroup B, and 34 isolates of the genomic species 13TU. A phylogenetic tree inferred from concatenated sequences of 7 MLST loci showed a clear distinction among the 3 Acinetobacter groups. In the MLST analysis, most colistin-resistant Acinetobacter spp. isolates showed different allele profiles at the 7 loci; that is, they belonged to different clones. Despite the clear distinction between the 3 Acinetobacter groups, interrelationships among the 3 groups were not consistent within the gene trees. In addition, some isolates showed clustering incongruent with their species or group identities in some gene trees. MLST analysis indicated that most colistin-resistant Acinetobacter spp. isolates from Korean hospitals arose independently. Considering the increasing use of colistin and the high recombination rate of Acinetobacter spp., independent but frequent emergence of colistin resistance in Acinetobacter spp. isolates is of great concern. [Copyright &y& Elsevier]

Cyclin-dependent kinase 5 (CDK5), a proline-directed serine/threonine kinase, which was originally known for its regulatory role in neuronal activities, has recently been suggested to play a role in extraneuronal activities. For example, a recent study detected overexpression of the CDK5 gene in non-small-cell lung cancer. Therefore, in order to explore the association of the CDK5 gene with lung cancer risk in a Korean population, the genotypes of the CDK5 promoter region were determined in 407 lung cancer patients and 402 normal participants. The result showed that the −904 G>A genotype affected susceptibility to lung cancer risk (odd ratios (OR)=1.53, 95% confidence interval (CI)=1.02–2.32). Furthermore, subsequent haplotype analysis of three single-nucleotide polymorphism (SNP) regions suggested that the A–G–C haplotype was associated with a higher overall risk of lung cancer (OR=1.59, 95% CI=1.16–2.18). These results suggest that CDK5 promoter polymorphisms contribute to the genetic susceptibility to lung cancer in the Korean population.Journal of Human Genetics (2009) 54, 298–303; doi:10.1038/jhg.2009.29; published online 3 April 2009 [ABSTRACT FROM AUTHOR]

This study evaluated the telomere length changes (ΔTL) of peripheral blood mononuclear cells before and after repetitive standard-dose nonmyeloablative chemotherapy and the association of ΔTL with treatment response and myelosuppression severity. TL was measured with Southern blot analysis in 32 solid-cancer patients without bone marrow metastasis. The mean TL before chemotherapy (t0 TL) and after the 2nd (t1 TL), 4th (t2 TL) and 6th cycle (t3 TL) was 8.49, 8.33, 8.08 and 8.10 kb, respectively. TL became significantly decreased after 4 (p = 0.005) and 6 (p = 0.026) cycles of chemotherapy. The mean value of ΔTL before and after completion of chemotherapy (t0 TL – t3 TL) was 0.46 kb. ΔTL has a significant correlation with good treatment response (r = 0.448, p = 0.005) and the frequency of severe neutropenia (r = 0.417, p < 0.05). Consequently, TL of peripheral blood mononuclear cells was decreased by the repetitive nonmyeloablative standard-dose chemotherapy in solid-cancer patients without bone marrow metastasis, and ΔTL was associated with good treatment response and neutropenia severity. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Most epidemiologic data are related to the prevalence of anemia, and there is little information regarding the incidence or etiology of newly diagnosed anemia in older people. The purpose of this study was to define the incidence and characteristics of anemia in the elderly population of Korea. Three hundred thirty-two independent, community-living, elderly persons aged 60 years and older were enrolled, and laboratory tests including iron profiles were performed. The mean age was 72±4.8 years and the mean hemoglobin was 13.4±1.1g/dl. During the follow-up period of 3 years, 24 subjects (3 males and 21 females) were newly diagnosed with anemia, which led to a 3-year incidence of 7.2% (24/332). Among the 24 subjects with new-onset anemia, iron deficiency anemia (IDA) was diagnosed in 5 subjects, while anemia of chronic disease (ACD) was detected in 8 subjects. Underlying illnesses were diabetes mellitus, osteoarthritis, renal insufficiency, hypothyroidism and malignancy. In those subjects with new-onset anemia, the serum iron, ferritin, transferrin saturation and albumin were lower than in the normal group. In conclusion, the 3-year incidence of anemia among Korean elderly people was determined to be 7.2%, and ACD was the most commonly defined cause of anemia. [Copyright &y& Elsevier]

Metastatic breast cancer refractory to anthracycline and taxanes often shows rapid progression. The development of effective and tolerable combination regimens for these patients is needed. This phase II trial investigated the efficacy of pemetrexed plus vinorelbine in patients with metastatic breast cancer. This randomized, open-label, phase II trial was conducted in 17 centers in Korea. Patients with advanced breast cancer who had previously been treated with anthracyclines and taxanes were randomly assigned in a 1:1 ratio to receive either vinorelbine or pemetrexed plus vinorelbine. Randomization was stratified by prior capecitabine treatment and hormone receptor status. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included the objective response rate, overall survival, safety, and quality of life. Between March 2017 and August 2019, a total of 125 patients were enrolled. After a median follow-up duration of 14.1 months, 118 progression events and 88 death events had occurred. Sixty-two patients were assigned to the pemetrexed plus vinorelbine arm, and 63 were assigned to the vinorelbine arm. Pemetrexed plus vinorelbine significantly prolonged PFS compared to vinorelbine (5.7 vs. 1.5 months, p < 0.001). The combination arm had higher disease control rate (76.8% vs. 45.9%, p = 0.001) and a tendency toward longer overall survival (16.8 vs. 10.5 months, p = 0.102). Anemia was more frequent in the pemetrexed plus vinorelbine arm per cycle compared with vinorelbine (7.9% vs. 1.9%, p < 0.001), but there was no difference in the incidence of grade 3–4 neutropenia per cycle between the pemetrexed plus vinorelbine arm and the vinorelbine single arm (14.7% vs. 19.5%, p = 0.066). This phase II study showed that pemetrexed plus vinorelbine led to a longer PFS than vinorelbine. Adverse events of pemetrexed plus vinorelbine were generally manageable. • This phase II trial revealed the efficacy and safety of pemetrexed plus vinorelbine. • Pemetrexed plus vinorelbine prolonged progression free survival. • Pemetrexed plus vinorelbine was associated with higher disease control rate. • Pemetrexed plus vinorelbine had a tendency of longer overall survival. • Toxicity of pemetrexed plus vinorelbine was generally manageable. [ABSTRACT FROM AUTHOR]

We evaluated the efficacy and safety of nivolumab and eribulin combination therapy for metastatic breast cancer (BC) in Asian populations. In this parallel phase II study, adult patients with histologically confirmed recurrent/metastatic hormone receptor-positive/HER2-negative (HR+HER2-) or triple-negative BC (TNBC) were prospectively enroled from 10 academic hospitals in Korea (ClinicalTrials.gov Identifier: NCT04061863). They received nivolumab (360 mg) on day 1 plus eribulin (1.4 mg/m2) on days 1 and 8 every 3 weeks until disease progression or intolerable toxicity. The primary endpoint was the investigator-assessed 6-month progression-free survival (PFS) rate in each subtype. Secondary endpoints included investigator-assessed objective response rate (ORR) as per Response Evaluation Criteria in Advanced Solid Tumors version 1.1, disease control rate, overall survival, and treatment toxicity. The association between PD-L1 expression and efficacy was investigated. Forty-five patients with HR+HER2- BC and 45 with TNBC were enroled. Their median age was 51 (range, 31–71) years, and 74 (82.2%) received one or two prior treatments before enrolment. Six-month PFS was 47.2% and 25.1% in the HR+HER2- and TNBC cohorts, respectively. Median PFS was 5.6 (95% confidence interval [CI]: 5.3–7.4) and 3.0 (95% CI: 2.1–5.2) months in the HR+HER2- and TNBC groups, respectively. ORRs were 53.3% (complete response [CR]: 0, partial response [PR]: 24) and 28.9% (CR: 1, PR: 12). Patients with PD-L1+ tumours (PD-L1 expression ≥1%) and PD-L1- tumours (ORR 50% versus 53.8% in HR+HER2-, 30.8% versus 29.0% in TNBC) had similar ORRs. Neutropenia was the most common grade 3/4 adverse event; the most common immune-related adverse events (AEs) were grades 1/2 hypothyroidism and pruritus. Five patients discontinued therapy because of immune-related AEs. Nivolumab plus eribulin showed promising efficacy and tolerable safety in previously treated HER2- metastatic BC. NCT04061863 • First study of nivolumab plus eribulin in advanced breast cancer. • Progression-free survival rate at 6 months was 47.2% in the HR+HER2- breast cancer. • Progression-free survival rate at 6 months was 25.1% in the TNBC. • 6 of 90 patients had continued treatment up to 24 months. • Predictive value of PD-L1 expression was low. [ABSTRACT FROM AUTHOR]

Even though Korea was known to have the highest number of coronavirus disease-2019 (COVID-19) infection in the early phase of the pandemic, Korea was able to successfully flatten the curve in a short period of time without extreme measures. We compared the status of cancer management before and after COVID-19 and analysed how cancer care continuity was maintained in Korea. We investigated the medical records on the number of cancer diagnosis, cancer surgery, radiation therapy and scheduled chemotherapy conducted in Korea University Anam Hospital from January 1 to April 30, 2019 and from the same period in 2020. We also collected the data of metastatic cancer patients who were hospitalised due to respiratory disease. Of all diagnoses, 1694 cancer diagnoses were made in the study period of 2019, and 1445 diagnoses in 2020 (decreased by 14.7%); the cancer surgery performed 830 and 800 cases; the set-up for radiation therapy decreased from 185 to 140 cases; the number of systemic chemotherapies for metastatic cancer patients treated in department of medical oncology increased from 2555 to 2878 cases. Among hospitalised patients, emergency centre visit, intensive care unit admission, discharge after recovery and death reveal no drastic changes. Routine cancer care for patients with metastatic cancer has been maintained without significant difference before and after the COVID-19 pandemic. The Korean government's innovative countermeasures in the early phase of outbreak made it possible for cancer care practitioners to provide cancer patients with regular care under the standard infection control protocol. • Routine cancer care has been maintained before and after the coronavirus disease-2019 pandemic. • The Korean government's innovative countermeasures were important. • Information provided will help you understand public health in pandemic times. [ABSTRACT FROM AUTHOR]

Identification of tumor antigens that induce cytotoxic T lymphocytes (CTLs) is crucial for cancer-vaccine development. Despite their predictive ability, current algorithmic approaches and human leukocyte antigen (HLA)-peptidomic analysis allow limited selectivity. Here, we optimized a method to rapidly screen and identify highly immunogenic epitopes that trigger CTL responses. We used a combined application of this method involving immune-specific signature analysis and HLA-associated peptidomics using samples from six patients with triple-negative breast cancer (TNBC) in order to select immunogenic HLA epitopes for in vitro testing. Additionally, we applied high-throughput imaging at the single-cell level in order to confirm the immunoreactivity of the selected peptides. The results indicated that this method enabled identification of promising CTL peptides capable of inducing antitumor immunity. This platform combining high-resolution computational analysis, HLA-peptidomics, and high-throughput immunogenicity testing allowed rapid and robust identification of highly immunogenic epitopes and represents a powerful technique for cancer-vaccine development. [ABSTRACT FROM AUTHOR]

Gemcitabine–oxaliplatin (GEMOX) demonstrated mild toxicity and promising effectiveness in patients with advanced urothelial cell cancer (UCC). We investigated the activity and safety of first-line GEMOX compared with gemcitabine–carboplatin (GCb) in cisplatin-ineligible patients with advanced UCC. Treatment-naive, cisplatin-ineligible patients with advanced UCC were randomly assigned to GEMOX (gemcitabine 1000 mg/m2, oxaliplatin 100 mg/m2 on day 1 [D1] every 2 weeks) or GCb (1000 mg/m2 of gemcitabine on D1 and D8 and carboplatin area under the curve of 4.5 mg/mL/min on D1 every 3 weeks). We evaluated the objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Between January 2011 and March 2017, 80 patients were enrolled; 39 and 40 patients were allocated to GCb and GEMOX arms, respectively. The ORR was 48.7% in the GCb arm and 55.0% in the GEMOX arm. The median follow-up duration was 37.8 months; the median PFS and OS in the GCb and GEMOX arms were 5.5 months (95% confidence interval [CI], 4.8–6.2) vs. 4.4 months (95% CI, 2.7–6.1) and 9.1 months (95% CI, 5.2–13.0) vs. 11.0 months (95% CI, 6.9–15.0), respectively. ≥ Leucopenia, neutropenia and fatigue of ≥ grade III were significantly more common in the GCb arm (26% vs. 3%, P = 0.003; 33% vs. 10%, P = 0.014; 15% vs. 3%, P = 0.012), whereas any-grade neuropathy was more common in the GEMOX arm (8% vs. 60%). GEMOX showed similar efficacy with GCb and a favourable haematologic toxicity profile. GEMOX may be an additional chemotherapy option for patients with UCC ineligible for cisplatin-containing chemotherapy (NCT01487915). • Gemcitabine/carboplatin and gemcitabine/oxaliplatin had similar efficacy. • The toxicity profile differed between the two regimens. • Haematological toxicities and fatigue were more common in the gemcitabine/carboplatin arm. • Peripheral sensory neuropathy was more common in the gemcitabine/oxaliplatin arm. [ABSTRACT FROM AUTHOR]

Background: The continuum of anti-HER2 agents is a standard treatment of HER2 + metastatic breast cancer (MBC). This study evaluated the efficacy of lapatinib plus vinorelbine in patients progressed on both trastuzumab and lapatinib treatments.Methods: A total of 149 patients were randomly assigned to lapatinib with vinorelbine (LV) (n = 75; lapatinib, 1000 mg daily; vinorelbine 20 mg/m2 D1, D8 q3w) or vinorelbine (V) (n = 74; 30 mg/m2 D1, D8 q3w). The primary endpoint was progression-free survival (PFS) rate at 18 weeks.Results: The median number of previous anti-HER2 therapies was 2 (range 2-5). There was no significant difference in PFS rate at 18 weeks between LV and V arms (45.9% vs 38.9%, p = 0.40). ORR was 19.7% in LV arm, and 16.9% in V arm (p = 0.88). PFS and OS did not differ between two arms (LV vs V; median PFS, 16 vs 12 weeks, HR = 0.86, 95% CI 0.61-1.22; median OS, 15.0 vs 18.9 months, HR = 1.07, 95% CI 0.72-1.58). Toxicity profiles were similar in both arms and all were manageable.Conclusions: Lapatinib plus vinorelbine treatment was tolerable; however, it failed to demonstrate the clinical benefits over vinorelbine alone in patients with HER2 + MBC after progression on both trastuzumab and lapatinib.Clinical Trial Registration: ClinicalTrials.gov number NCT01730677. [ABSTRACT FROM AUTHOR]

• Cell-free DNA quantifications were associated with metabolic tumor volume and total lesion glycolysis. • The cell-free DNA and metabolic tumor burden were independently correlated with survival. • The patients with high amount of cell-free DNA correlated to poor survivals with low metabolic tumor burden. This study unravels the significance of cell-free DNA (cfDNA) quantification as a promising measure of the biological behavior/aggressiveness of tumors. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) measured by positron emission tomography/computed tomography scan enable a precise assessment of metabolic tumor burden. However, their clinical implications in identifying patients who need more aggressive treatment in advanced non-small cell lung cancer (NSCLC) are not fully understood. In the current prospective trial, we analyzed 101 newly diagnosed advanced NSCLC (stage III-IV) patients with measurable baseline MTV, TLG, and cfDNA quantification. The best cut-offs for cfDNA levels, MTV, and TLG to predict progression-free survival and overall survival were determined using X-tile analysis. There were significant positive correlations between cfDNA and MTV (r = 0.488, p < 0.001) and between cfDNA and TLG (r = 0.554, p < 0.001). High-cfDNA levels and high-MTV/TLG negatively correlated with overall survival (OS) (all p < 0.001). Patients with high-MTV showed similar median OS irrespective of their cfDNA levels (low-cfDNA vs. high-cfDNA=9.2 vs 6.6 months; p > 0.05). However, patients with low-MTV and low-cfDNA levels showed longer OS than those with low-MTV and high-cfDNA levels (low-cfDNA vs. high-cfDNA=49.3 vs 11.5 months; p < 0.001). The patient group with low-TLG also showed similar trends. The cfDNA level was an independent prognostic factor for OS by Cox-proportional hazard analysis. Although the patients with high metabolic tumor burden had a poor prognosis, regardless of the biological behavior/aggressiveness of the tumor, patients with low metabolic tumor burden and high cfDNA levels showed a poor prognosis. Taken together, this study indicates a stronger prognostic value of baseline cfDNA levels in identifying patients with advanced NSCLC and personalizing their treatment strategies for better survival. [ABSTRACT FROM AUTHOR]

Long-term complications are becoming more important as the survival rate of breast cancer improves. Treatment-related myeloid neoplasm is an important long-term complication in breast cancer survivors as it has a poor prognosis. We evaluated the incidence and risk factors for the development of treatment-related acute myeloid leukaemia (AML)/myelodysplastic syndrome (MDS) in patients treated with early breast cancer. We accessed the national Korean database to identify 153,565 patients diagnosed with breast cancer between January 2007 and October 2016 who underwent surgery for breast cancer. We estimated the cumulative incidence of AML/MDS and analysed the risk factors for developing AML/MDS. Of 153,575 patients, 79,321 received anthracycline-based adjuvant therapy, 14,317 received adjuvant therapy without anthracyclines and 46,657 did not receive adjuvant chemotherapy. Overall, 120 developed AML (105 in the anthracycline group, 9 in the non-anthracycline group and 6 in the control group), and 128 developed MDS (96, 9 and 23 in each group). The 10-year cumulative incidence of AML/MDS was the highest in the anthracycline group (0.221% and 0.199%), followed by the non-anthracycline group (0.122% and 0.163%) and the control group (0.024% and 0.089%). The risk of developing AML/MDS was significantly higher in patients treated with anthracyclines (hazard ratio [HR] 9.531; p < 0.0001 for AML and HR 2.559; p < 0.0001 for MDS) compared to patients in the control group. This study found that anthracycline-based adjuvant therapy significantly increased the risk of AML/MDS in Korean breast cancer patients, with the risk persisting for at least 10 years. While the cumulative incidence was low, the long-term risks of AML/MDS should be taken into account considering the poor outcomes associated with these neoplasms. • Therapy-related myeloid neoplasms are increasing as survival rates for breast cancer improve. • Anthracyclines increased the risk of AML/MDS in breast cancer patients. • Chemotherapy without anthracycline also increased the risk of AML. • Despite the low incidence, therapy-related AML/MDS should be kept in mind. [ABSTRACT FROM AUTHOR]

Background: This study was performed to investigate the disease burden of seasonal influenza in adults ≥20 years of age in Korea, based on surveillance data from the Hospital-based Influenza Morbidity & Mortality Surveillance (HIMM) network. Materials and methods: The HIMM network is composed of two surveillance systems: emergency room-based and inpatients-based surveillance. A total of ten university hospitals all over the country are included in the surveillance network. The adult catchment population of the HIMM network was calculated by using the data of each hospital and the database of the Health Insurance Review and Assessment Service (HIRA) of Korea. The incidence rates of laboratory-confirmed medically-attended influenza, laboratory-confirmed influenza-related admission and laboratory-confirmed influenza-related death were calculated based on the catchment population. The socioeconomic burden of influenza was estimated using the human capital approach. Results: During the 2013–2014 influenza season, the calculated adult catchment population of the HIMM network was 1,380,000. The incidence of medically-attended laboratory-confirmed influenza infection was 242.8 per 100,000 adults. The incidence of laboratory-confirmed influenza-related admission was 57.9 per 100,000 adults. The incidence of laboratory-confirmed influenza-related death was 3.1 per 100,000 adults. The total socioeconomic cost of 2013–2014 seasonal influenza in Korean adult population was estimated as 125 million USD (1 USD = 1,100 KRW). Conclusion: The disease burden of 2013–2014 seasonal influenza in Korean adult population is very high and indicates that more active prevention and control policies will be needed to decrease the burden. Additional researches will be needed to assess the burden of seasonal influenza in the Korean child population. [ABSTRACT FROM AUTHOR]

Objective: This retrospective study was undertaken to assess the incidence of and risk factors for febrile neutropenia (FN) during adjuvant chemotherapy for early-stage breast cancer (ESBC). Methods: A multicenter survey of three tertiary hospitals was conducted, with data extracted from the records of ESBC patients treated with adjuvant chemotherapy containing AC (doxorubicin, 60 mg/m² and cyclophos-phamide, 600 mg/m² every 21 days). Assessments included clinical characteristics, chemotherapy dose modifications, and incidence of FN. Results: A total of 610 patients were included for analysis. The incidence of grade 4 neutropenia and FN was 44.6 and 8.5%, respectively. Reduced relative dose intensity (RDI) less than 85% occurred in 11.0% of patients, and there were treatment delays in 12.6% of patients. Multivariate analysis identified several independent predictors for FN, including the presence of grade 4 neutropenia and pretreatment calculated estimated glomerular filtration rate less than 60 ml/min. Conclusion: Patients with ESBC are at substantial risk for FN and reduced RDI when treated with adjuvant AC chemotherapy. Predictive models based on risk factors identified in this study should enable the selective application of supportive measures in an effort to deliver the full dose of chemotherapy. [ABSTRACT FROM AUTHOR]

The urinary exosomal miRNAs are recently emerging prostate cancer (PC)-associated biomarkers for the early-stage diagnosis and prognosis due to their non-invasiveness, inherent stability and the representation of the status of the originated cells. However, developing a urinary exosomal miRNA detection method with high accuracy is challenging because of the low abundance and high sequence homology of miRNAs. Herein, we present a quantitative and label-free miRNA sensing platform using surface-enhanced Raman scattering (SERS) based on three-dimensional (3D) hierarchical plasmonic nano-architecture to detect urinary exosomal miRNAs. This hierarchical nanostructure is constructed by self-assembly between target-complementary DNA probes-conjugated gold nanoparticles and head-flocked gold nanopillars in the presence of the target miRNAs, creating numerous 3D plasmonic hot-spots inducing exceedingly high amplification of SERS signals. This 3D SERS biosensor achieved ∼10 aM detection limits for the target miRNAs (miR-10a and miR-21), which is over 1000-fold more sensitive than previously reported miRNA sensors without the requirement of any labelling or pre-treatment steps. Finally, the clinical validation using urinary samples revealed that our 3D SERS sensor discriminates PC patients from healthy control with high diagnostic accuracy (0.93) based on the differential expression level of urinary exosomal miRNAs. These outputs demonstrate that our SERS sensor based on 3D hierarchical nano-architecture can offer facile, accurate and rapid methods to measure miRNA expression and is helpful for the diagnosis of various diseases. [Display omitted] • The introduction of SAP-AuNP on the head-flocked nanopillar structure induces the formation of 3D plasmonic hot-spots. • As remarkably enhancing the Raman signal from target miRNAs, the 3D SERS sensor enabled label-free detection of miRNAs. • 3D hierarchical nanoarchitecture-based SERS sensors could discriminate PC patients with high diagnostic accuracy. [ABSTRACT FROM AUTHOR]

Background: The efficacy of second-line chemotherapy (CT2) after the failure of first-line chemotherapy (CT1) for advanced biliary tract cancer (BTC) has not been established. We investigated the favorable prognostic factors for CT2 to determine which patients could be expected to benefit from CT2. Methods: From a total of 168 patients who were treated with chemotherapy at our institution between January 2003 and December 2012, we retrospectively reviewed 50 patients who received CT2. Patients were treated with various chemotherapeutic combinations as CT1 and CT2. Results: The median overall survival (OS) of patients who received and CT2 was 10.2 and 5.5 months, respectively. Good performance status (PS), a serum albumin level >3.5 g/dl and metastasis to only 1 organ were independent prognostic factors that affected the OS of the patients who received CT2. Patients who had only 1 metastastic organ, a good PS and a serum albumin level >3.5 g/dl at the beginning of CT2 demonstrated prolonged survival compared to patients who did not exhibit these 3 factors (9.5 vs. 4.3 months, p < 0.005). Conclusions: CT2 should be considered for patients with advanced BTC, especially for those who have only 1 metastatic organ and remain in generally good medical condition after the failure of CT1. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Single nucleotide polymorphism (SNP) are frequently observed during anti-cancer therapy and their detection is critical for the prognosis and therapeutic monitoring of cancers. However, the detection of SNP is challenging due to the poor selectivity and limit of detection of the existing clinical evaluation methods because of the extreme similarities between the wild-type oligonucleotides and those with SNP. Therefore, in this study, we developed an innovative method to detect SNP with high sensitivity and selectivity. In the proposed method, LNA-modified primers and hairpin-shaped primers interact synergistically to promote target selectivity and sensitive amplification in real-time polymerase chain reaction (PCR). This method was able to detect the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) point mutation E545K from cell-free DNA with 0.1% selectivity and 10 aM (0.12 fg) limit of detection. The present method was further successfully applied to the clinical samples of a colorectal cancer patient and the results were validated using digital droplet PCR. The present method of utilizing LNA-modified hairpin primers was found to be a highly sensitive, simple, and robust diagnostic tool to detect the PIK3CA E545K point mutation, which can also be used to detect various single nucleotide polymorphism in the patients with cancer. • Single point mutation was detected with high selectivity (0.1%) in the target DNA at a very low concentration of 10 aM. • Easy and cost-effective PCR assay with hairpin-shaped LNA primers and TMAC buffer. • Successful application to clinical samples with validation of digital droplet PCR. [ABSTRACT FROM AUTHOR]

Direct sequencing remains the most widely used method for the detection of epidermal growth factor receptor (EGFR) mutations in lung cancer; however, its relatively low sensitivity limits its clinical use. The objective of this study was to investigate the sensitivity of detecting an epidermal growth factor receptor (EGFR) mutation from peptide nucleic acid-locked nucleic acid polymerase chain reaction (PNA-LNA PCR) clamp and Ion Torrent Personal Genome Machine (PGM) techniques compared to that by direct sequencing. Furthermore, the predictive efficacy of EGFR mutations detected by PNA-LNA PCR clamp was evaluated. EGFR mutational status was assessed by direct sequencing, PNA-LNA PCR clamp, and Ion Torrent PGM in 57 patients with non-small cell lung cancer (NSCLC). We evaluated the predictive efficacy of PNA-LNA PCR clamp on the EGFR-TKI treatment in 36 patients with advanced NSCLC retrospectively. Compared to direct sequencing (16/57, 28.1%), PNA-LNA PCR clamp (27/57, 47.4%) and Ion Torrent PGM (26/57, 45.6%) detected more EGFR mutations. EGFR mutant patients had significantly longer progressive free survival (14.31 vs. 21.61 months, P = 0.003) than that of EGFR wild patients when tested with PNA-LNA PCR clamp. However, no difference in response rate to EGFR TKIs (75.0% vs. 82.4%, P = 0.195) or overall survival (34.39 vs. 44.10 months, P = 0.422) was observed between the EGFR mutations by direct sequencing or PNA-LNA PCR clamp. Our results demonstrate firstly that patients with EGFR mutations were detected more frequently by PNA-LNA PCR clamp and Ion Torrent PGM than those by direct sequencing. EGFR mutations detected by PNA-LNA PCR clamp may be as a predicative factor for EGFR TKI response in patients with NSCLC. [ABSTRACT FROM AUTHOR]

Background. It has long been recognized that some human breast cancers are hormone dependent. Preeclampsia is a syndrome of pregnancy defined by the onset of hypertension and proteinuria and characterized by dysfunction of the maternal endothelium. Many hormonal changes occur with preeclampsia, and we hypothesize that these changes may influence the risk of maternal breast cancer. We also analyzed the relation between pregnancy-induced hypertension (PIH) and maternal risk of breast cancer. Methods. Among 13 relevant publications about preeclampsia and six relevant publications about PIH, some studies find preeclampsia associated with a lower risk of breast cancer, but others did not. Therefore, these results are inconclusive. We conducted meta-analysis to evaluate more precisely the relationship between preeclampsia, PIH and maternal risk of breast cancer. Results. The pooled estimate of the hazard ratio (HR) associated with preeclampsia was 0.86 (95% CI 0.73-1.01), and that associated with PIH was 0.83 (0.66-1.06), both based on the random effects model. Conclusion. Some suggestive but not entirely consistent nor conclusive evidence was found on the association between the history of preeclampsia or PIH with the subsequent risk of breast cancer. [ABSTRACT FROM AUTHOR]

Aim: Granulysin (cytolytic molecules of cytotoxic T lymphocytes and natural killer cells) is synthesized as cytosolic 9-kDa and secretary 15-kDa isoforms. We evaluated the prognostic significance of the pretreatment serum level of 15-kDa granulysin in patients with diffuse large B cell lymphoma (DLBCL). Patients and Methods: A retrospective analysis was conducted on 88 DLBCL patients treated homogeneously with standard chemotherapy. The granulysin level was quantified in pretreatment samples. Results: The granulysin level in DLBCL patients was significantly lower than that in healthy controls (522 ± 496 vs. 1,945 ± 1,696 pg/ml; p < 0.0001), and the level in patients who experienced recurrence within 3 years was significantly lower than that of patients without recurrence (305 ± 337 vs. 720 ± 607 pg/ml; p = 0.001). Patients with granulysin levels higher than the median level showed significantly longer progression-free and overall survival according to univariate analysis (p = 0.031 and p = 0.014, respectively). In multivariate analysis, the granulysin level was an independently significant prognostic factor of overall survival (p = 0.018; hazard ratio, 0.521; 95% confidence interval, 0.188-0.841). Conclusions: Pretreatment serum level of 15-kDa granulysin may be a valuable prognostic marker in DLBCL patients treated with standard chemotherapy. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: We analyzed the prognostic factors from 259 cases of febrile neutropenia occurring in 137 patients with hematologic disease. Based on multivariate analysis, significant prognostic factors are recovery of neutropenia, respiratory infection, baseline serum albumin, baseline bicarbonate, baseline CRP, and CRP on the fifth day after antibiotic treatment. From these variables, we derived a predictive model for the prognosis of febrile neutropenia using baseline serum albumin, bicarbonate, and CRP, which could be easily checked before chemotherapy. Further studies in prospective setting are needed for the validation of this model. [Copyright &y& Elsevier]

Abstract: Published studies on the association between the progesterone receptor gene +331 G/A polymorphism and breast cancer risk are inconclusive, and meta-analysis is required to verify the association. Six studies, including a total of 6,849 cases and 6,589 controls, were subjected to meta-analysis. When all eligible subjects were pooled for meta-analysis, the AG + AA variant genotype was not associated with a significantly elevated breast cancer risk [odds ratio (OR) = 1.11; 95% confidence interval (95%CI) = 0.99–1.24; P = 0.071]. However, subgroup analysis revealed that the AG + AA variant genotype was associated with an increased risk of breast cancer in American (OR = 1.32; 95%CI = 1.10–1.58; P = 0.003), but not in European or Australian. We could carefully suggest that the progesterone receptor promoter +331 G/A variant polymorphism might increase breast cancer risk, and this effect appeared to be more prominent in Americans than in Europeans and Australians. [Copyright &y& Elsevier]

Abstract: We investigated the characteristics of 48 carbapenem-resistant Acinetobacter baumannii isolates collected from 5 tertiary care hospitals in Korea by multilocus sequencing typing, pulsed-field gel electrophoresis, and polymerase chain reaction amplification of the antimicrobial resistance determinants. We identified 2 distinct main clones of carbapenem-resistant A. baumannii isolates, which showed different antimicrobial resistance profiles and are also differentiated by the kinds of oxacillinase (OXA) carbapenemases and Acinetobacter-derived cephalosporinase (ADC) β-lactamases. One main clone, ST22:A, had 27 carbapenem-resistant isolates (56.3%), showed high polymyxin B and colistin resistances (33.3% and 37.0%, respectively), and contained both bla OXA-51–like and bla OXA-23–like genes and the bla ADC-29 or bla ADC-30 gene. In contrast, the other main clone, ST28:B, included 15 isolates (31.3%), showed complete susceptibilities to polymyxin B and colistin, and contained only the bla OXA-51–like gene and bla ADC-31 or bla ADC-32 genes. The distribution of these main carbapenem-resistant A. baumannii clones did not relate to locality, indicating that they are widespread in Korean hospitals. In addition, we found new types of PER β-lactamases, PER-6. [Copyright &y& Elsevier]

Summary: The RASSF1 gene, a putative tumor suppressor gene located on human chromosome 3p21, has attracted a great deal of attention because of frequent allelic loss and gene silencing via promoter hypermethylation in a variety of human malignancies. To evaluate the role of RASSF1A gene in lung cancer risk, genotypes of the RASSF1A promoter region (−710 C>T and −392T>C) were determined in 410 lung cancer patients and 410 normal subjects. Furthermore, to examine potential effects of the common haplotypes (C–C, T–T and C–T haplotypes) on RASSF1A transcription, luciferase reporter assays were performed in H2009 and H358 non-small cell lung cancer (NSCLC) cell lines. We found that ht2 C–T haplotype was associated with susceptibility to the risk of lung cancer in dominant (odds ratio (OR): 0.69; 95% CI: 0.46–0.99) model. In particular, we found that C–T haplotype showed a decreased risk of lung cancer in males (codominant OR: 0.59; 95% CI: 0.38–0.93 and dominant OR: 0.58; 95% CI: 0.35–0.96) and in smokers (codominant OR: 0.58; 95% CI: 0.36–0.93 and dominant OR: 0.56; 95% CI: 0.33–0.96). Interestingly, C–T haplotype induced transcriptional activity by 50–60% compared with other haplotypes in NSCLC cell lines. These results suggest that RASSF1A promoter polymorphisms affect RASSF1A expression, further contributing to the genetic susceptibility to lung cancer. [Copyright &y& Elsevier]

The important prognostic factors were evaluated for T-cell non-Hodgkin lymphoma (NHL) patients in a prospective study using the CEOP-B protocol [a modified cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP)-like regimen that uses epirubicin instead of doxorubicin with the addition of bleomycin]. Fifty-two patients were enrolled in the study. The overall response rate was 63·5%. The median progression-free survival (PFS) and median overall survival (OS) was 18·0 and 39·5 months respectively. The most common toxicity was neutropenia. The factors related to poor outcome were a high International Prognostic Index (IPI) and a high ‘B’ score (bone marrow involvement, B symptoms, bulky disease). We developed a new prognostic model, namely the Prognostic Group for T cell NHL (PGT) that included four groups: PGT1 (low IPI/low B score), PGT2 (low IPI/high B score), PGT3 (high IPI/Low B score) and PGT4 (high IPI/Low B score). OS and PFS (not reached, 48 months) in the PGT1 group were significantly longer than those (11·5 and 4·8 months) in PGT2. The same result was observed in the PGT3 and PGT4 groups. The CEOP-B regimen was moderately active and tolerable for T-cell NHL patients, and the PGT system might be useful for the prediction of long-term survival of T-cell NHL patients. [ABSTRACT FROM AUTHOR]

Advanced breast cancer frequently metastasizes to the skeleton causing major mobility issues and hazards to quality of life. To manage osteolytic bone metastasis, bone-modifying agents and chemotherapy are recommended as the standard of care. Here, we investigated serologic biomarkers that might be associated with prognosis in breast cancer patients treated with zoledronic acid (ZA) and taxane-based chemotherapy. We collected serum samples from breast cancer patients with bone metastasis who received taxane plus ZA as palliative treatment. Fourteen biomarkers of angiogenesis, immunogenicity, and apoptosis were assessed, and the correlation between serum cytokine levels and patient's prognosis was statistically analyzed. Sixty-six patients were enrolled, and samples from 40 patients were analyzed after laboratory quality control. Patients with low baseline PDGF-AA, high IFN-γ, low MCP-2, low TGF-β1, and low TNF-α were significantly associated with longer progression-free survival (PFS). Decreasing VEGF and TNF-α and increasing FGF-2 and PDGF-AA in the early treatment phase indicated longer PFS. In univariate and multivariate analyses, low TGF-β1 and TNF-α and high IFN-γ at baseline were associated with a significantly low hazard ratio for disease progression. Further, we designed a risk score with TGF-β1, TNF-α, and IFN-γ levels, which could prognosticate patients for PFS. In conclusion, serum cytokine level, such as TGF-β1, TNF-α, and IFN-γ, could be a potential prognostic biomarker for breast cancer patients with bone metastasis treated with ZA and taxane-based chemotherapy. [ABSTRACT FROM AUTHOR]

• Our nanoplasmonic biosensor has been developed to detect hot-spot mutant p53 protein utilizing the binding of the GADD45 promoter and protein. • Kinetic parameters of DNA-protein interactions were characterized to estimate equilibrium dissociation and relative transcriptional activities of wild-type and mutated p53 proteins. • Application of the kinetic parameters on the sensor for real-time kinetic analysis allowed highly accurate distinction of mutant protein with improved analytical performance. • Our nanoplasmonic biosensor is confirmed to have a satisfactory sensing performance for the application in clinical assay by comparing it with conventional analytical methods. Hot-spot mutant p53 proteins are highly associated with cancer malignancy and chemotherapy resistance of various cancers. Precise detection of the hot-spot mutant protein is therefore important in predicting therapeutic effects in cancer. However, conventional analytical methods such as liquid chromatography couple with tandem mass spectrometry (LC–MS/MS) and immunohistochemistry (IHC) have limited sensitivity as well as accuracy and require labor-intensive pretreatment steps. Here, an efficient individual nanorod-based plasmonic biosensor has been developed to detect hot-spot mutant p53 protein with the growth arrest and DNA damage 45 (GADD45) promoter. DNA-protein interactions of wild-type/mutant p53 proteins are kinetically analyzed on the biosensor surface through real-time monitoring of the localized surface plasmon resonance shift, and their dissociation constants and relative transcriptional activities are estimated. Hot-spot mutant proteins exhibited 14.29-fold higher in the dissociation constants and 19.91-fold lower in the relative transcriptional activities as compared to the wild-type proteins. These distinct kinetic values of hot-spot mutants allowed precise detection of hot-spot mutant protein and identification of mutated site of the protein using very small volume of clinical samples. We also demonstrated the clinical validation of the sensor by evaluating its performance in human breast tumor surgical specimens. The sensor's ability to identify the mutant protein with high specificity and extremely low detection limit (11.47 fM) in comparison with the LC–MS/MS and IHC. The results confirmed that our sensor could be characterized as an efficient biosensor for application in clinical assays in terms of analytical performance. [ABSTRACT FROM AUTHOR]

Simple Summary: Lapatinib is a tyrosine kinase inhibitor widely used as a treatment for a Human Epidermal growth factor Receptor 2 (HER2) (+) breast cancer patients. However, when resistance is acquired through continued exposure, and it is associated with a poor prognosis for patients. In this study, we identified HSP90 as a common node for acquired resistance to lapatinib in two lapatinib resistant cell lines using proteomic analysis. Notably, in vitro and in vivo studies demonstrated synergy effect between lapatinib and an HSP90 inhibitor were observed in the estrogen receptor (+) HER2 (+) breast cancer cell only. These results could be a potential strategy for future clinical trials for HSP90 inhibitors in treatment—refractory HER2 (+) metastatic cancer patients Lapatinib, a Human Epidermal growth factor Receptor 2 (HER2)-targeting therapy in HER2-overexpressing breast cancer, has been widely used clinically, but the prognosis is still poor because most patients acquire resistance. Therefore, we investigated mechanisms related to lapatinib resistance to evaluate new therapeutic targets that may overcome resistance. Lapatinib-resistant cell lines were established using SKBR3 and BT474 cells. We evaluated cell viability and cell signal changes, gene expression and protein changes. In the xenograft mouse model, anti-tumor effects were evaluated using drugs. Analysis of the protein interaction network in two resistant cell lines with different lapatinib resistance mechanisms showed that HSP90 protein was commonly increased. When Heat Shock Protein 90 (HSP90) inhibitors were administered alone to both resistant cell lines, cell proliferation and protein expression were effectively inhibited. However, inhibition of cell proliferation and protein expression with a combination of lapatinib and HSP90 inhibitors showed a more synergistic effect in the LR-BT474 cell line than the LR-SKBR3 cell line, and the same result was exhibited with the xenograft model. These results suggest that HSP90 inhibitors in patients with lapatinib-resistant Estrogen Receptor (ER) (+) HER2 (+) breast cancer are promising therapeutics for future clinical trials. [ABSTRACT FROM AUTHOR]

Mutations in the EGFR gene downstream signaling pathways may cause receptor-independent pathway activation, making tumors unresponsive to EGFR inhibitors. However, the clinical significance of RAS, PIK3CA or PTEN mutations in NSCLC is unclear. In this study, patients who were initially diagnosed with NSCLC or experienced recurrence after surgical resection were enrolled, and blood samples was collected. Ultra-deep sequencing analysis of cfDNA using Ion AmpliSeq Cancer Hotspot Panel v2 with Proton platforms was conducted. RAS/PIK3CA/PTEN mutations were frequently detected in cfDNA in stage IV NSCLC (58.1%), and a high proportion of the patients (47.8%) with mutations had bone metastases at diagnosis. The frequency of RAS/PIK3CA/PTEN mutations in patients with activating EGFR mutation was 61.7%. The median PFS for EGFR-TKIs was 15.1 months in patients without RAS/PIK3CA/PTEN mutations, and 19.9 months in patients with mutations (p = 0.549). For patients with activating EGFR mutations, the overall survival was longer in patients without RAS/PIK3CA/PTEN mutations (53.8 months vs. 27.4 months). For the multivariate analysis, RAS/PIK3CA/PTEN mutations were independent predictors of poor prognosis in patients with activating EGFR mutations. In conclusion, RAS, PIK3CA and PTEN mutations do not hamper EGFR-TKI treatment outcome; however, they predict a poor OS when activating EGFR mutations coexist. [ABSTRACT FROM AUTHOR]

Encoded hydrogel microparticles synthesized via flow lithography have drawn attention for multiplex biomarker detection due to their high multiplex capability and solution-like hybridization kinetics. However, the current methods for preparing particles cannot achieve a flexible, rapid probe-set modification, which is necessary for the production of various combinations of target panels in clinical diagnosis. In order to accomplish the unmet needs, streptavidin was incorporated into the encoded hydrogel microparticles to take advantage of the rapid streptavidin–biotin interactions that can be used in probe-set modification. However, the existing methods suffer from low efficiency of streptavidin conjugation, cause undesirable deformation of particles, and impair the assay capability. Here, we present a simple and powerful method to conjugate streptavidin to the encoded hydrogel microparticles for better assay performance and rapid probe-set modification. Streptavidin was directly conjugated to the encoded hydrogel microparticles using the aza-Michael addition click reaction, which can proceed in mild, aqueous condition without catalysts. A highly flexible and sensitive assay was developed to quantify DNA and proteins using streptavidin-conjugated encoded hydrogel microparticles. We also validated the potential applications of our particles conducting multiplex detection of cancer-related miRNAs. [ABSTRACT FROM AUTHOR]

Background: "End of life" is a difficult topic of conversation in East Asian cultures, even among patients and doctors who share a good rapport. In 2016, the Hospice, Palliative Care, and Life-Sustaining Treatment Decision-Making Act, which took the form of "Physician Orders for Life-Sustaining Treatment," was introduced in South Korea. This study was conducted to investigate the completion rate of Physician Orders for Life-Sustaining Treatment in patients with advanced cancer on the active recommendation of physicians, as well as patients' general attitudes toward end-of-life care. Methods: We conducted a preliminary, cross-sectional descriptive survey on patients with advanced cancer. A total of 101 patients with advanced solid cancer agreed to participate in the study. The primary endpoint was the rate of completion of Physician Orders for Life-Sustaining Treatment based on a doctor's suggestion. Written interviews were conducted to understand the perceptions and factors influencing patients' decisions. Results: Of the 101 patients, 72 (71.3%) agreed to prepare Physician Orders for Life-Sustaining Treatment. Patients who had an educational level of high school or higher were more likely to agree to complete Physician Orders for Life-Sustaining Treatment documentation as compared to the lower educational status group. More than half of the respondents who completed Physician Orders for Life-Sustaining Treatment documentation reported that they had more than a fair understanding of "life-sustaining care" or "Physician Orders for Life-Sustaining Treatment." Participants' reasons for Physician Orders for Life-Sustaining Treatment completion were diverse. Conclusions: We found that highly educated patients, who understood the concept behind the policy well, tended to accept Physician Orders for Life-Sustaining Treatment without hesitation. Better education, information shared through the media, and conversations with health care providers might improve understanding of Physician Orders for Life-Sustaining Treatment in patients with cancer. [ABSTRACT FROM AUTHOR]

Aberrant activation of fibroblast growth factor receptor (FGFR) signalling contributes to progression and metastasis of many types of cancers including breast cancer. Accordingly, FGFR targeted tyrosine kinase inhibitors (TKIs) are currently under development. However, the efficacy of FGFR TKIs in the bone microenvironment where breast cancer cells most frequently metastasize and also where FGFR is biologically active, has not been clearly investigated. We investigated the FGFR-mediated interactions among cancer and the bone microenvironment stromal cells (osteoblasts and osteoclasts), and also the effects of FGFR inhibition in bone metastasis. We showed that addition of culture supernatant from the MDA-MB-134-VI FGFR-amplified breast cancer cells-activated FGFR siganalling in osteoblasts, including increased expression of RANKL, M-CSF, and osteoprotegerin (OPG). Further in vitro analyses showed that AZD4547, an FGFR TKI currently in clinical trials for breast cancer, decreased RANKL and M-CSF, and subsequently RANKL and M-CSF-dependent osteoclastogenesis of murine bone marrow monocytes. Moreover, AZD4547 suppressed osteoclastogenesis and tumor-induced osteolysis in an orthotopic breast cancer bone metastasis mouse model using FGFR non-amplified MDA-MB-231 cells. Collectively, our results support that FGFR inhibitors inhibit the bone microenvironment stromal cells including osteoblasts and osteoclasts, and effectively suppress both tumor and stromal compartments of bone metastasis. [ABSTRACT FROM AUTHOR]

The authors describe an isothermal and ultrasensitive colorimetric DNA assay that consists of two amplification stages using enzymes and a catalytic hairpin assembly (CHA). The first step consists in the selective amplification of DNA using Klenow fragment and nicking enzyme. The second step consists in the amplification of the optical signal by using a catalytic hairpin assembly. After two amplification steps, the DNA reaction induces the aggregation of the red gold nanoparticles to give a blue color shift. The degree of aggregation can be quantified by measurement of the ratio of the UV-vis absorbances of the solutions at 620 and 524 nm which are the wavelengths of the aggregated gold nanoparticles and bare gold nanoparticles. The detection limit is as low as 3.1 fM. Due to the use of a specific enzyme, only the desired DNAs will be detected. The method can be applied to the determination of DNA of various lengths. Despite the presence of large amounts of wildtype DNA, it can readily detect a target DNA. Conceivably, the technique has a large potential because of its high sensitivity and selectivity.Schematic presentation of DNA detection using gold nanoparticles (AuNP), enzymes and catalytic hairpin assembly (CHA). Effective DNA detection is achieved through the aggregation of AuNPs which is caused by DNA amplification using enzymes and signal amplification using CHA. [ABSTRACT FROM AUTHOR]