In vitro antimicrobial activity of cold atmospheric microwave plasma against bacteria causing canine skin and ear infections.

BACKGROUND: Cold atmospheric plasma (CAP) is a new generation medical therapeutic option for bacterial infections. CAP causes physical cell wall rupture and DNA damage, therefore making it highly useful in the treatment of various conditions such as skin infections. HYPOTHESIS/OBJECTIVES: The antimicrobial activity of cold atmospheric microwave plasma (CAMP) against major strains in canine skin infections was tested and the difference in antimicrobial activity between the antibiotic-resistant and antibiotic-susceptible strains of Staphylococcus pseudintermedius was evaluated. METHODS AND MATERIALS: American Type Culture Collection (ATCC) strains (Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli) and clinical isolates identified as methicillin-resistant S. pseudintermedius (n = 27) and methicillin-susceptible S. pseudintermedius (n = 13) were exposed to CAMP for 10 s, 30 s and 60 s. Afterwards, the bacterial survival rate was confirmed. RESULTS: Gram-negative bacteria (P. aeruginosa and E. coli) were more susceptible than Gram-positive bacteria (S. aureus and S. pseudintermedius) for the same duration of CAMP exposure. Only the Gram-negative bacteria were completely killed after 60 s exposure. In S. pseudintermedius isolates, CAMP exposure had similar antibacterial effects regardless of antibiotic resistance. CONCLUSIONS AND CLINICAL IMPORTANCE: CAMP has sufficient antimicrobial activity against major bacterial strains that cause pyoderma and otitis externa in dogs, and may be an alternative therapeutic option for S. pseudintermedius skin infections, for which antibiotics often are ineffective because of antimicrobial resistance in clinical veterinary medicine.

Relationship between heavy metal exposure and type 2 diabetes: a large-scale retrospective cohort study using occupational health examinations.

OBJECTIVES: To investigate the associations between heavy metal exposure and serum ferritin levels, physical measurements and type 2 diabetes mellitus (DM). DESIGN: A retrospective cohort study. SETTING: Changwon, the location of this study, is a Korean representative industrial city. Data were obtained from medical check-ups between 2002 and 2018. PARTICIPANTS: A total of 34 814 male subjects were included. Of them, 1035 subjects with lead exposure, 200 subjects with cadmium exposure and the 33 579 remaining were assigned to cohort A, cohort B and the control cohort, respectively. Data including personal history of alcohol and smoking, age, height, weight, the follow-up duration, haemoglobin A1c (HbA1c), fasting blood sugar (FBS), ferritin levels, and lead and cadmium levels within 1 year after exposure were collected. PRIMARY OUTCOME MEASURE: In subjects without diabetes, changes in FBS and HbA1c were analysed through repeated tests at intervals of 1 year or longer after the occupational exposure to heavy metals. RESULTS: In Cohort A, DM was diagnosed in 33 subjects. There was a significant difference in lead concentrations between the subjects diagnosed with DM and those without DM during the follow-up period (3.94±2.92 mg/dL vs 2.81±2.03 mg/dL, p=0.002). Simple exposure to heavy metals (lead and cadmium) was not associated with DM in Cox regression models (lead exposure (HR) 1.01, 95% CI: 0.58 to 1.77, p 0.971; cadmium exposure HR 1.48, 95% CI: 0.61 to 3.55, p=0.385). Annual changes in FBS according to lead concentration at the beginning of exposure showed a positive correlation (r=0.072, p=0.032). CONCLUSION: Our findings demonstrated that simple occupational exposure to heavy metals lead and cadmium was not associated with the incidence of DM. However, lead concentrations at the beginning of the exposure might be an indicator of DM and glucose elevations.

One health approach to genetic relatedness in SCCmec between methicillin-resistant Staphylococcus isolates from companion dogs with pyoderma and their owners.

Staphylococcal cassette chromosome mec (SCCmec) confers methicillin resistance and shows ability for horizontal transfer. However, little is known about the potential transfer of SCCmec between different species of staphylococci in a clinical setting. In this study, we investigated the genetic relationship of SCCmec between staphylococci isolated from dogs affected with pyoderma and their owners. Clinical isolates were collected from pyoderma lesions of dogs and from the nasal cavity and finger of owners. Clonal lineages were characterized using multi-locus sequence typing. Genetic relatedness of SCCmec in the isolates from dogs and owners was first evaluated with dru and SCCmec typing, and whole-genome sequencing (WGS) was used to confirm the similarity of DNA sequences and the structural composition of SCCmec. A total of 100 Staphylococcus strains were isolated from 31 dog-owner pairs. One pair with isolates carrying the same SCCmec type V and dru type 11a was detected: 18D20-1 (S. pseudintermedius, dog), 18D20-2 (S. schleiferi, dog), and 18H20-F2 (S. epidermidis, dog owner). WGS revealed that these three isolates showed remarkable genetic similarity in SCCmec with respect to DNA sequences, dru type, structure composition of ccrC and the mec complex, and DR-1 in orfX, which is considered to be the insertion site of SCCmec. Entire identical nucleotide sequences of the whole SCCmec region in different Staphylococcus strains were absent between dogs and owners. However, the remarkable genetic similarity of SCCmec from staphylococci isolated from a dog and owner pair emphasizes that antimicrobial resistance surveillance adopted One Health concept should be continuously performed.

Choosing Wisely: The Korean Perspective and Launch of the 'Right Decision in Cancer Care' Initiative.

Government healthcare expenditure is rising in Korea, and the costs incurred by patients in Korea exceed those incurred by patients in other Organization for Economic Co-operation and Development countries. Despite the increasing health expenditure, patient demand for services is increasing as well, so it is now becoming recognized that cancer care needs to be balanced. The most important measure in cancer care optimization is to provide high-quality care while keeping costs sustainable. The Korean Cancer Association considers the current situation of cancer therapy in Korea the foremost issue, which has led to the implementation of the nationwide 'Right Decisions in Cancer Care' initiative. This initiative is based on the concepts of medical professionalism in that it should be led by physicians working in the field of oncology, that education should be offered to patients and clinicians, and that it should influence healthcare policy. In this article, we introduce the nationwide 'Right Decision in Cancer Care' initiative and highlight the five initial items on its agenda. The agenda is open to expansion and update as the medical environment evolves and additional clinical evidence becomes available.

First detection of multiresistance pRE25-like elements from Enterococcus spp. in Staphylococcus pseudintermedius isolated from canine pyoderma.

OBJECTIVES: Enterococcus pRE25 is a conjugative and mobilising multiresistance plasmid from Enterococcus faecalis RE25. pRE25-like enterococcal plasmid pWZ909 mediates the delivery of vancomycin resistance to methicillin-resistant Staphylococcus aureus via a Tn1546-like transposon. However, whether pRE25-like elements contribute to multidrug resistance in Staphylococcus spp. has not yet been investigated. Here we describe the first detection of multiresistance pRE25-like elements in the chromosomal DNA of multidrug-resistant Staphylococcus pseudintermedius (MDRSP). METHODS: A total of 46 MDRSP clinical strains were isolated from canine pyoderma in Korea. Their genetic characteristics were analysed by multilocus sequence typing (MLST) and PCR targeting pRE25-like elements. Whole-genome sequencing (WGS) was performed on four isolates. RESULTS: WGS detected that the chromosomal 22-kb pRE25-like elements contained five antimicrobial resistance genes [cat, erm(B), aphA-3, aadK and sat4], IS1252, IS256, and a toxin-antitoxin system within copies of IS1216. BLASTn alignment analysis revealed that 84% of the chromosomal 22-kb pRE25-like elements sequence is homologous (99.8% identity) to the enterococcal pRE25 plasmid sequence. PCR assay showed that 52.2% of MDRSP isolates were positive for pRE25-like elements and were presumed to contain pRE25-like elements (pRE25 group). The sequence types (STs) of the pRE25 group were diverse, with 18 STs identified, among which 12 STs were first reported in Korea. CONCLUSION: Enterococcal pRE25-like elements are suspected to be widespread in MDRSP isolated from companion dogs in Korea. Considering that companion dogs live in a closely shared environment with humans, continuous surveillance of pRE25-like elements is needed for other staphylococci commonly isolated from humans.

In vitro antibacterial activity of the manuka essential oil from Leptospermum scoparium combined with Tris-EDTA against Gram-negative bacterial isolates from dogs with otitis externa.

BACKGROUND: The increasing prevalence of antimicrobial resistance among bacteria in dogs with otitis externa has led to a need for novel therapeutic agents. HYPOTHESIS/OBJECTIVE: To examine the antibacterial effects of manuka oil combined with ethylenediaminetetraacetic acid-tromethamine (Tris-EDTA) against Gram-negative bacteria isolates from dogs with otitis externa. METHODS AND MATERIALS: A total of 53 clinical isolates including Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae ssp. pneumoniae and Proteus mirabilis. Antimicrobial susceptibility was determined using disk diffusion; the minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of manuka essential oil, with or without Tris-EDTA, were investigated. RESULTS: A total of 44 isolates were resistant to at least one antibiotic and 19 strains were multidrug-resistant, with resistance to at least one agent in three or more antimicrobial classes. The MICs and MBCs of manuka oil alone were ≥1% (v/v) and ≥2% (v/v), respectively. There was no antimicrobial effect of Tris-EDTA (1.125:0.3 mg/mL) without manuka oil. However, the combination of manuka oil with Tris-EDTA significantly decreased the MICs (ranging from 0.06% to 0.5%, v/v; P < 0.001) and MBCs (ranging from 0.06% to 1%, v/v; P < 0.001). There also was no significant difference between multidrug-resistant and nonresistant bacterial isolates in terms of the antimicrobial activity of manuka oil with Tris-EDTA. CONCLUSIONS AND CLINICAL IMPORTANCE: The study findings suggest that manuka oil, especially when combined with Tris-EDTA, may be a promising alternative therapeutic option for Gram-negative otic pathogens. Clinical studies are needed to assess potential for in vivo ototoxic effects and efficacy.

Tumor Genomic Profiling Guides Patients with Metastatic Gastric Cancer to Targeted Treatment: The VIKTORY Umbrella Trial.

The VIKTORY (targeted agent eValuation In gastric cancer basket KORea) trial was designed to classify patients with metastatic gastric cancer based on clinical sequencing and focused on eight different biomarker groups (RAS aberration, TP53 mutation, PIK3CA mutation/amplification, MET amplification, MET overexpression, all negative, TSC2 deficient, or RICTOR amplification) to assign patients to one of the 10 associated clinical trials in second-line (2L) treatment. Capivasertib (AKT inhibitor), savolitinib (MET inhibitor), selumetinib (MEK inhibitor), adavosertib (WEE1 inhibitor), and vistusertib (TORC inhibitor) were tested with or without chemotherapy. Seven hundred seventy-two patients with gastric cancer were enrolled, and sequencing was successfully achieved in 715 patients (92.6%). When molecular screening was linked to seamless immediate access to parallel matched trials, 14.7% of patients received biomarker-assigned drug treatment. The biomarker-assigned treatment cohort had encouraging response rates and survival when compared with conventional 2L chemotherapy. Circulating tumor (ctDNA) analysis demonstrated good correlation between high MET copy number by ctDNA and response to savolitinib. SIGNIFICANCE: Prospective clinical sequencing revealed that baseline heterogeneity between tumor samples from different patients affected response to biomarker-selected therapies. VIKTORY is the first and largest platform study in gastric cancer and supports both the feasibility of tumor profiling and its clinical utility.This article is highlighted in the In This Issue feature, p. 1325.

Canine pyoderma gangrenosum with recurring skin lesions of unknown origin and splenic involvement.

BACKGROUND: Reports of canine pyoderma gangrenosum (PG) are uncommon in the veterinary literature. Rarer still are cases describing dogs with both skin lesions and internal organ involvement. OBJECTIVE: To describe a case of canine PG with skin and internal organ involvement. ANIMALS: A client-owned dog. METHODS AND MATERIALS: Complete blood count, serum chemistry, C-reactive protein and SNAP cPL tests, and abdominal ultrasonography and fine-needle aspiration of the spleen were performed. RESULTS: The dog was treated with oral prednisolone and ciclosporin. After three months of therapy, ultrasonography revealed normalization of the spleen and resolution of skin lesions. CONCLUSION AND CLINICAL IMPORTANCE: Dogs with skin lesions compatible with PG should be screened carefully for internal organ involvement. Ciclosporin may be a useful treatment for the immediate and long-term management of canine PG.

Low prevalence of mupirocin resistance in Staphylococcus pseudintermedius isolates from canine pyoderma in Korea.

BACKGROUND: Mupirocin is a topical antibacterial drug used for the treatment of staphylococcal infections, including meticillin-resistant Staphylococcus pseudintermedius (MRSP). The recent emergence of resistance to mupirocin is a major concern in many countries. OBJECTIVES: This study investigated the prevalence and genotype of mupirocin-resistant S. pseudintermedius isolated from pet dogs with pyoderma. SAMPLES: A total of 110 clinical isolates of S. pseudintermedius were collected from dogs with pyoderma (n = 110) between July 2010 and September 2016. All animals were client-owned dogs. METHODS: Low- and high-level mupirocin resistance were evaluated with both the broth microdilution and disk diffusion tests. Mupirocin resistance in S. pseudintermedius isolates was confirmed by genetic analysis of the ileS-2 and naïve ileS genes. RESULTS: MRSP and meticillin-susceptible S. pseudintermedius were detected in 69 and 41 dogs, respectively. One MRSP strain was highly resistant to mupirocin and contained the high-level mupirocin resistance gene ileS-2. There were no low-level mupirocin-resistant isolates. CONCLUSION AND CLINICAL IMPORTANCE: Mupirocin is a useful topical antibacterial for MRSP, but a clinical MRSP isolate that had not previously been exposed to mupirocin exhibited the high-level mupirocin resistance in phenotype and genotype. Therefore, continuous monitoring for mupirocin resistance is important in small animal practice.

Chemotherapy versus Best Supportive Care in Advanced Biliary Tract Carcinoma: A Multi-institutional Propensity Score Matching Analysis.

PURPOSE: Although chemotherapy is recommended by various guidelines for advanced biliary tract cancer (BTC), the evidence supporting its use over best supportive care (BSC) is limited. The aim of this study was to investigate the survival benefit of chemotherapy over that of BSC in advanced BTC patients. MATERIALS AND METHODS: Advanced BTC patientswith a good performance status (Eastern CooperativeOncologyGroup [ECOG] 0-2) were eligible for the study. Data were retrospectively collected from four tertiary cancer centers and analyzed using propensity score matching (PSM). Of the 604 patients enrolled, 206 received BSC and 398 received chemotherapy. PSM analysis was performed using the following variables: age, ECOG status, carcinoembryonic antigen (CEA) level, white blood cell level, albumin level, total bilirubin level, and aspartate aminotransferase level. The sample size of each group was 164 patients after PSM. Median survival was compared between the two groups by using the Kaplan-Meier method, and prognostic factors were investigated using Cox proportional regression analysis. RESULTS: In post-PSM analysis, the respective median survival for the chemotherapy and BSC groups was dependent on the following prognostic factors: total population, 12.0 months vs. 7.5 months (p=0.001); locally advanced disease, 16.7 months vs. 13.4 months (p=0.490); cancer antigen 19-9 ≤ 100 IU/mL, 12.7 months vs. 10.6 months (p=0.330); and CEA ≤ 3.4 ng/mL, 17.1 months vs. 10.6 months (p=0.052). CONCLUSION: Chemotherapy improved overall survival of patients with advanced BTC who had a good performance status. However, this survival benefit was not observed in BTC patients with locally advanced disease or with lower tumor marker. Individualized approach is needed for initiation of palliative chemotherapy in advanced BTC.

Clonal distribution of methicillin-resistant Staphylococcus pseudintermedius isolates from skin infection of dogs in Korea.

Bacterial infection by methicillin-resistant Staphylococcus pseudintermedius (MRSP) is challenging in a small animal practice. Zoonotic transmission may occur. The aim of this study was to investigate the genotypic profiles of MRSP isolated from bacterial infections of canine skin in Korea and to compare their molecular lineages with dominant strains from other countries. Sixty MRSP isolates were obtained from the lesions of canine pyoderma and otitis externa. Their genetic diversity was assessed by multilocus sequence typing (MLST), staphylococcal protein A (spa) typing and direct-repeat unit (dru) typing. Staphylococcal cassette chromosome mec (SCCmec) elements were characterized by multiplex PCR. Thirty-nine different sequence types (STs) were detected. Among them, 21 STs were identified as internationally new sequence types. Fourteen dru types (dts) were detected, and the major types were dt11a and dt11y. spa typing characterised 21 isolates (35%, 21/60), including spa types t02 (n=8), t05 (n=5), t06 (n=6), and t15 (n=2). Two clonal complexes, CC568 and CC677, were revealed by MLST; this result differed from the dominant STs detected in MRSP isolates from Europe, North America, and other Asian countries. SCCmec type V was the major type (27/60. 45%), and 30 (50%) isolates were non-typeable by conventional classifying method. This is the first report about the clonal lineage of MRSP isolated from Korea. MRSP isolated from dogs in Korea displays independent lineage from other countries. Surveillance is needed to confirm cross-national disseminating patterns.

Efficacy and safety of controlled-release oxycodone/naloxone versus controlled-release oxycodone in Korean patients with cancer-related pain: a randomized controlled trial.

BACKGROUND: Controlled-release oxycodone/naloxone (OXN-CR) maintains the effect of opioid-induced analgesia through oxycodone while reducing the occurrence rate of opioid-induced constipation through naloxone. The present study was designed to assess the non-inferiority of OXN-CR to controlled-release oxycodone (OX-CR) for the control of cancer-related pain in Korean patients. METHODS: In this randomized, open-labeled, parallel-group, phase IV study, we enrolled patients aged 20 years or older with moderate to severe cancer-related pain [numeric rating scale (NRS) pain score ≥4] from seven Korean oncology/hematology centers. Patients in the intention-to-treat (ITT) population were randomized (1:1) to OXN-CR or OX-CR groups. OXN-CR was administered starting at 20 mg/10 mg per day and up-titrated to a maximum of 80 mg/40 mg per day for 4 weeks, and OX-CR was administered starting at 20 mg/day and up-titrated to a maximum of 80 mg/day for 4 weeks. The primary efficacy endpoint was the change in NRS pain score from baseline to week 4, with non-inferiority margin of -1.5. Secondary endpoints included analgesic rescue medication intake, patient-reported change in bowel habits, laxative intake, quality of life (QoL), and safety assessments. RESULTS: Of the ITT population comprising 128 patients, 7 with missing primary efficacy data and 4 who violated the eligibility criteria were excluded from the efficacy analysis. At week 4, the mean change in NRS pain scores was not significantly different between the OXN-CR group (n = 58) and the OX-CR group (n = 59) (-1.586 vs. -1.559, P = 0.948). The lower limit of the one-sided 95% confidence interval (-0.776 to 0.830) for the difference exceeded the non-inferiority margin (P < 0.001). The OXN-CR and OX-CR groups did not differ significantly in terms of analgesic rescue medication intake, change in bowel habits, laxative intake, QoL, and safety assessments. CONCLUSIONS: OXN-CR was non-inferior to OX-CR in terms of pain reduction after 4 weeks of treatment and had a similar safety profile. Studies in larger populations of Korean patients with cancer-related pain are needed to further investigate the effectiveness of OXN-CR for long-term pain control and constipation alleviation. Trial registration ClinicalTrials.gov NCT01313780, registered March 8, 2011.

Intravenous Oxycodone versus Intravenous Morphine in Cancer Pain: A Randomized, Open-Label, Parallel-Group, Active-Control Study.

Objective: To compare efficacy and safety of intravenous continuous infusion of oxycodone with morphine in patients with cancer pain. Methods: A 5-day, randomized, open-label, exploratory study at 6 sites in the Republic of Korea. Sixty-six adults aged ≥19 years with moderate-to-severe cancer pain (Numeric Rating Scale [NRS] ≥ 4) were enrolled. The study group received intravenous (IV) oxycodone, and the comparator group received IV morphine which were titrated depending on pain intensity. The efficacy endpoint is change in average NRS score from baseline to Day 5. Other assessments included worst, current, and average pain intensity; patient satisfaction; medication dose; and adverse events. Results: Both groups achieved >50% reduction in average pain intensity: from "moderate" at baseline (oxycodone versus morphine: 6.0 ± 1.8 versus 5.9 ± 1.4) to "mild" at Day 5 (2.5 ± 1.8 versus 2.8 ± 1.6). While this reduction was similar between groups (3.5 ± 2.2 versus 3.1 ± 1.8, P value = 0.562), oxycodone achieved faster pain relief (average pain: 3.0 ± 1.6 versus 3.9 ± 1.6, P value = 0.020) on Day 2 and significant NRS reductions for worst pain on Day 2 (P value = 0.045) and current pain on Day 2 (P value = 0.035) and Day 5 (P value = 0.020) compared to morphine. Patient satisfaction, adverse events, and adverse drug reactions were similar for both groups. Conclusions: For Asian patients with cancer pain, IV oxycodone is faster acting and showed similar analgesic efficacy and safety profiles as IV morphine. This trial is registered with Clinicaltrials.gov NCT02660229.

The role of adjuvant therapy after R0 resection for patients with intrahepatic and perihilar cholangiocarcinomas.

PURPOSE: There is still debated regarding the optimal treatment strategy for cholangiocarcinoma (CC) after curative resection. The aim of this study was to analyze the role of adjuvant therapy in R0-resected intrahepatic and perihilar CCs. METHODS: We retrospectively reviewed the patients who underwent R0 resection for intrahepatic and perihilar CCs between January 2001 and December 2013 at six tertiary medical centers; adjuvant therapy consisted of chemotherapy (CT), chemoradiotherapy (CRT), or radiotherapy (RT). The outcomes of our study were recurrence-free survival (RFS) and overall survival (OS). RESULTS: We included a total of 137 consecutive patients in the analysis; 58.4% of them had intrahepatic CCs, and 25.5% had lymph node (LN) involvement. Seventy-three patients (53.3%) had received adjuvant therapy (CT, CRT, RT: 48, 13, 12, respectively), and most patients who had received adjuvant therapy had stage III or IVA, T3 or 4 tumors, and positive LNs. Multivariable analysis identified positive LN [hazard ratio (HR) 3.47; P < 0.001] and high baseline CA 19-9 level (HR 1.82; P = 0.027) as predictors of decreased OS. The effects of adjuvant therapy varied according to the treatment modality; adjuvant CRT showed significantly longer RFS than surgery only (HR 0.44; P = 0.036), with a nonsignificant trend for better OS (HR 0.46; P = 0.115). CONCLUSIONS: Adjuvant CT and RT were not associated with a survival advantage in R0-resected intrahepatic and perihilar CCs. CRT appears to be appropriate treatment after complete resection.

Role of adjuvant therapy after R0 resection for patients with distal cholangiocarcinoma.

BACKGROUND: The optimal treatment strategy for cholangiocarcinoma (CC) after curative resection remains controversial. The aim of this study was to analyze the role of adjuvant therapy in R0-resected distal CC. METHODS: We retrospectively reviewed the medical records of patients who underwent R0 resection for distal CC at six cancer centers in Korea. Adjuvant therapy consisted of chemotherapy (CT), chemoradiotherapy (CRT), or radiotherapy (RT). The outcomes of the study were overall survival (OS) and recurrence-free survival (RFS). RESULTS: A total of 158 patients were included in the analysis; 47 patients (29.7 %) had lymph node involvement. Fifty-six patients (35.4 %) received adjuvant therapy (CT/CRT/RT: 27/20/9, respectively). Patients with advanced TNM stage (P < 0.001), T3/T4 disease (P = 0.009), positive lymph nodes (LN; P = 0.052), and elevated baseline carbohydrate antigen 19-9 (P = 0.071) were more likely to receive adjuvant therapy. The effect of adjuvant therapy varied according to treatment modality. A multivariable analysis showed a significant improvement in OS after CT [hazard ratio (HR) 0.21, 95 % confidence interval (CI) 0.08-0.53, P = 0.001] and CRT (HR 0.25, 95 % CI 0.08-0.83, P = 0.024). However, RT alone was associated with shorter OS (HR 2.38, P = 0.040), along with T3/T4 disease (HR 2.12, P = 0.012) and positive LN (HR 2.30, P = 0.008). RFS benefited from adjuvant treatment with CT (HR 0.34, P = 0.002) and CRT (HR 0.33, P = 0.004), but not with RT alone (HR 1.42, P = 0.361). In the subset analysis according to LN status, adjuvant therapy not including RT alone was associated with a significant OS and RFS advantage in both LN-negative and LN-positive patients. CONCLUSIONS: Our results show that patients receiving CT or CRT had significant improvements in OS and RFS. In addition, a benefit of adjuvant therapy (except RT alone) was observed even in LN-negative patients.

Sarcopenia and inflammation are independent predictors of survival in male patients newly diagnosed with small cell lung cancer.

PURPOSE: Sarcopenia is suggested to be associated with cancer-related inflammation. We assessed the clinical outcome of small cell lung cancer (SCLC) patients according to sarcopenia and the neutrophil-to-lymphocyte ratio (NLR). METHODS: A total of 117 male SCLC patients treated with first-line chemo- or chemoradiotherapy were assessed based on a retrospective chart review. The mass of the pectoralis muscle was measured by computed tomography and normalized to height. Patients with the lowest quartile of muscle mass were considered to have sarcopenia. Patients were classified into four groups according to their sarcopenia and NLR statuses: sarcopenia/high NLR, sarcopenia/low NLR, non-sarcopenia/high NLR, and non-sarcopenia/low NLR. RESULTS: Sarcopenic patients had lower progression-free survival (PFS) than did non-sarcopenic patients (median 6.0 vs. 7.5 months, p = 0.009), but the difference in overall survival (OS) was not statistically significant (median 10.5 vs. 13.5 months, p = 0.052). However, the OS of sarcopenic patients with high NLR was significantly lower than that in all other groups (median 3.2 vs. 16.0 vs. 12.5 vs. 13.7 months, respectively, p < 0.001), as was PFS (median 3.2 vs. 7.7 vs. 7.6 vs. 7.1 months, respectively, p < 0.001). On multivariate analysis, sarcopenia with high NLR was an independent prognostic factor for shorter PFS and OS. Early discontinuation of treatment (20.0 vs. 10.3 %) and treatment-related mortality (50.0 vs. 8.4 %) occurred more frequently in these patients than in the other groups (p < 0.001). CONCLUSIONS: In SCLC, sarcopenic male patients with high NLR have a poor prognosis and do not tolerate standard treatment. Intensive supportive care is needed in these patients.

Prognostic significance of the absolute monocyte counts in lung cancer patients with venous thromboembolism.

We investigated the clinical significance of the absolute monocyte count (AMC) as a predictor of the response to anticoagulation and survival in lung cancer patients with venous thromboembolism (VTE). We retrospectively reviewed 1707 patients with pathologically proven lung cancer who visited the hospital between July 2008 and May 2014. Among them, the clinical data of patients newly diagnosed with VTE and treated with anticoagulation were compared between the low and high AMC groups according to the median value of AMC (640/µL) at the time of VTE diagnosis. The incidence of VTE was 7.9 % during the study period. Most of the patients had non-small-cell lung cancer (82.1 %), stage IV (64.2 %), and pulmonary thromboembolism (76.1 %) and were incidentally diagnosed with VTE (76.9 %). The patients' characteristics and laboratory values were not significantly different between the low and high AMC groups. Among patients available for evaluation of the response to anticoagulation, the high AMC group was significantly more refractory to anticoagulation than the low AMC group (no response to anticoagulation, 21.7 vs. 6.8 %, respectively; p = 0.044). Additionally, the high AMC group showed worse overall survival (OS) than the low AMC group (median, 9.6 vs. 5.9 months; p = 0.038). On multivariate analysis, high AMC, low albumin, and advanced stage were independent poor prognostic factors for OS. High AMC is associated with refractoriness to anticoagulation and poor prognosis in lung cancer patients with VTE.

Natural history of metastatic biliary tract cancer (BTC) patients with good performance status (PS) who were treated with only best supportive care (BSC).

BACKGROUND: Although chemotherapy is widely recommended for patients with metastatic biliary tract cancer, the natural course of these patients, especially those with good performance status who are indicated for chemotherapy, is not known. METHODS: We retrospectively reviewed patients with metastatic or locally advanced biliary cancer who were diagnosed at six cancer centers. Patients were eligible if they had good performance (ECOG 0-2) and no history of any treatment for cancer. The primary objective was to evaluate the survival time of patients with advanced biliary cancer with good performance who were untreated. RESULTS: Of the 1677 patients, 204 met the inclusion criteria. The median age and overall survival were 72.0 years and 7.1 months. Overall survival (months) by location was 4.7 for intrahepatic, 9.7 for extrahepatic, 4.4 for gallbladder and 11.2 for ampulla of vater cancer. In subgroup analysis, overall survival of locally advanced biliary cancer was 13.8 months and that of patients with normal carcinoembryonic antigen/carbohydrate antigen 19-9 was 10.6 months. In multivariate analysis, variables that were associated with poor prognosis were metastatic biliary cancer [hazard ratio 2.19 (P = 0.001)], high baseline carcinoembryonic antigen level (defined as >4.0 ng/ml) [hazard ratio 1.51 (P = 0.024)] and high baseline carbohydrate antigen 19-9 level (defined as >100 U/ml) [hazard ratio 1.93 (P = 0.001)]. CONCLUSIONS: Advanced biliary tract cancer with good performance status showed modest survival without any treatment. Furthermore, subgroup analysis showed that patients with normal carbohydrate antigen 19-9 or carcinoembryonic antigen level or locally advanced status had favorable survival. Further studies comparing the outcome of chemotherapy with that of best supportive care in patients with unresectable biliary tract cancer are warranted.

Prognostic significance of the lymphocyte-to-monocyte ratio in patients with small cell lung cancer.

We investigated the role of the lymphocyte-to-monocyte ratio (LMR) at diagnosis in patients with small cell lung cancer (SCLC) treated with standard chemotherapy. We retrospectively reviewed all SCLC patients who received frontline platinum-based chemotherapy or chemoradiotherapy. The cut-off LMR value at diagnosis was 4.19 according to time-dependent receiver-operating characteristic analysis. A total of 188 patients were divided into two groups according to the LMR at diagnosis (low vs. high LMR). Of the 171 patients evaluated for treatment response, 14 (12.4%) in the low LMR group and 1 (1.7%) in the high LMR group were non-responders (p = 0.025). In the whole patient cohort, progression-free survival and overall survival were significantly shorter in the low LMR group (low vs. high: median 6.4 vs. 7.1 months, p = 0.001; median 10.6 vs. 13.1 months, p = 0.003, respectively). On multivariate analysis, a low LMR at diagnosis was an independent unfavourable prognostic factor for predicting survival. The LMR at diagnosis could be helpful for predicting prognosis in SCLC.

Clinical significance of the neutrophil-lymphocyte ratio in venous thromboembolism patients with lung cancer.

BACKGROUND: The neutrophil-lymphocyte ratio (NLR) has been identified as a potentially useful marker for predicting clinical outcome in patients with cardiovascular disease, diabetes, and various malignancies. The aim of this study was to determine whether NLR at the time of venous thromboembolism (VTE) diagnosis is a prognostic factor for the response to anticoagulation and survival in lung cancer patients treated with anticoagulation for VTE. PATIENTS AND METHODS: We retrospectively analyzed the clinical characteristics, laboratory parameters, and NLR in 114 lung cancer patients newly diagnosed with VTE, among 991 patients pathologically confirmed for lung cancer between July 2008 and August 2013. RESULTS: High NLR was significantly associated with high hematocrit (p=0.028), high C-reactive protein (p=0.002), and low albumin (p=0.001). Compared with the low NLR group, stage IV non-small cell lung cancer (NSCLC) at the time of VTE diagnosis (55.6 vs. 74.6%, p=0.055), central nervous system metastasis (5.8 vs. 25.8%, p=0.004), and cancer progression (14.3 vs. 38.8%, p=0.008) at the time of VTE diagnosis were also significant in the high NLR group. Moreover, the poor response to anticoagulation was statistically correlated with patients with NSCLC (p=0.037), high NLR (p=0.004), and low albumin (p=0.029). CONCLUSIONS: The results demonstrate that the NLR at the time of VTE diagnosis could be a useful biomarker for predicting the response and prognosis following anticoagulation in patients with lung cancer and VTE.