Nationwide precision oncology pilot study: KOrean Precision Medicine Networking Group Study of MOlecular profiling-guided therapy based on genomic alterations in advanced solid tumors (KOSMOS) KCSG AL-20-05.

BACKGROUND: Next-generation sequencing (NGS) has become widely available but molecular profiling-guided therapy (MGT) had not been well established in the real world due to lack of available therapies and expertise to match treatment. Our study was designed to test the feasibility of a nationwide platform of NGS-guided MGT recommended by a central molecular tumor board (cMTB) for metastatic solid tumors. PATIENTS AND METHODS: Patients with advanced or metastatic solid tumors with available NGS results and without standard treatment were enrolled. The cMTB interpreted the patients' NGS reports and recommended the following: (i) investigational medicinal products (IMPs) approved in other indications; (ii) alternative treatments; (iii) clinical trials. The primary variables were the proportion of patients with actionable genomic alterations and those receiving MGT as per cMTB recommendations. Others included treatment duration (TD), overall response rate (ORR), disease control rate (DCR), and safety. RESULTS: From February 2021 to February 2022, 193 cases [99 (51.3%) men; median age 58 years (range 24-88 years); median line of previous treatment 3 (range 0-9)] from 29 sites were enrolled for 60 cMTB sessions. The median time from case submission to cMTB discussion was 7 days (range 2-20 days), and to IMP treatment initiation was 28 days (range 14-90 days). Actionable genetic alterations were found in 145 patients (75.1%). A total of 89 (46.1%) patients received actual dosing of IMPs, and 10 (5.2%) were enrolled in cMTB-recommended clinical trials, achieving an MGT rate of 51.3%. ORR and DCR of IMPs were 10.1% and 72.5%, respectively. The median TD was 3.5 months [95% confidence interval (CI) 2.8-5.5 months], and the 4-month TD rate was 44.9%. The median overall survival of patients who received IMPs was 6.9 months (95% CI 5.2-10.0 months). CONCLUSION: KOSMOS confirmed the feasibility of MGT recommended by the cMTB, achieving a high MGT match rate and promising effectiveness in heavily pretreated advanced cancer patients.

Safety and efficacy of trastuzumab biosimilar plus irinotecan or gemcitabine in patients with previously treated HER2 (ERBB2)-positive non-breast/non-gastric solid tumors: a phase II basket trial with circulating tumor DNA analysis.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) (ERBB2)-directed agents are standard treatments for patients with HER2-positive breast and gastric cancer. Herein, we report the results of an open-label, single-center, phase II basket trial to investigate the efficacy and safety of trastuzumab biosimilar (Samfenet®) plus treatment of physician's choice for patients with previously treated HER2-positive advanced solid tumors, along with biomarker analysis employing circulating tumor DNA (ctDNA) sequencing. METHODS: Patients with HER2-positive unresectable or metastatic non-breast, non-gastric solid tumors who failed at least one prior treatment were included in this study conducted at Asan Medical Center, Seoul, Korea. Patients received trastuzumab combined with irinotecan or gemcitabine at the treating physicians' discretion. The primary endpoint was the objective response rate as per RECIST version 1.1. Plasma samples were collected at baseline and at the time of disease progression for ctDNA analysis. RESULTS: Twenty-three patients were screened from 31 December 2019 to 17 September 2021, and 20 were enrolled in this study. Their median age was 64 years (30-84 years), and 13 patients (65.0%) were male. The most common primary tumor was hepatobiliary cancer (seven patients, 35.0%), followed by colorectal cancer (six patients, 30.0%). Among 18 patients with an available response evaluation, the objective response rate was 11.1% (95% confidence interval 3.1% to 32.8%). ERBB2 amplification was detected from ctDNA analysis of baseline plasma samples in 85% of patients (n = 17), and the ERBB2 copy number from ctDNA analysis showed a significant correlation with the results from tissue sequencing. Among 16 patients with post-progression ctDNA analysis, 7 (43.8%) developed new alterations. None of the patients discontinued the study due to adverse events. CONCLUSIONS: Trastuzumab plus irinotecan or gemcitabine was safe and feasible for patients with previously treated HER2-positive advanced solid tumors with modest efficacy outcomes, and ctDNA analysis was useful for detecting HER2 amplification.

Cannabis use frequency and pain interference among people with HIV.

Cannabis is often used by people with HIV (PWH) for pain, yet study results are inconsistent regarding whether and how it affects pain. This study examines whether greater cannabis use frequency is associated with lower pain interference and whether cannabis use modifies the association of pain severity and pain interference among 134 PWH with substance dependence or a lifetime history of injection drug use. Multi-variable linear regression models examined the association between past 30-day cannabis use frequency and pain interference. Additional models evaluated whether cannabis use modified the association between pain severity and pain interference. Cannabis use frequency was not significantly associated with pain interference. However, in a model with interaction between cannabis use frequency and pain severity, greater cannabis use frequency attenuated the strength of the association between pain severity and pain interference (p = 0.049). The adjusted mean difference (AMD) in pain interference was +1.13, + 0.81, and +0.05 points for each 1-point increase in pain severity for those with no cannabis use, 15 days of use, and daily use, respectively. These findings suggest that attenuating the impact of pain severity on pain-related functional impairment is a potential mechanism for a beneficial role of cannabis for PWH.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, staging and treatment of patients with metastatic breast cancer.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, staging and treatment of patients with metastatic breast cancer (MBC) was published in 2021. A special, hybrid guidelines meeting was convened by ESMO and the Korean Society of Medical Oncology (KSMO) in collaboration with nine other Asian national oncology societies in May 2022 in order to adapt the ESMO 2021 guidelines to take into account the differences associated with the treatment of MBC in Asia. These guidelines represent the consensus opinions reached by a panel of Asian experts in the treatment of patients with MBC representing the oncological societies of China (CSCO), India (ISMPO), Indonesia (ISHMO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO). The voting was based on the best available scientific evidence and was independent of drug access or practice restrictions in the different Asian countries. The latter were discussed when appropriate. The aim of these guidelines is to provide guidance for the harmonisation of the management of patients with MBC across the different regions of Asia, drawing from data provided by global and Asian trials whilst at the same time integrating the differences in genetics, demographics and scientific evidence, together with restricted access to certain therapeutic strategies.

Preoperative Chemoradiotherapy With Capecitabine With or Without Temozolomide in Patients With Locally Advanced Rectal Cancer: A Prospective, Randomised Phase II Study Stratified by O6-Methylguanine DNA Methyltransferase Status: KCSG-CO17-02.

AIMS: To evaluate the clinical efficacy of adding temozolomide (TMZ) to preoperative capecitabine (CAP)-based chemoradiotherapy in patients with locally advanced rectal cancer (LARC) and validate O6-methylguanine DNA methyltransferase (MGMT) methylation status as a predictive marker for TMZ combined regimens. MATERIALS AND METHODS: LARC patients with clinical stage II (cT3-4N0) or III (cTanyN+) disease were enrolled. They were stratified into unmethylated MGMT (uMGMT) and methylated MGMT (mMGMT) groups by methylation-specific polymerase chain reaction before randomisation and were then randomly assigned (1:1) to one of four treatment arms: uMGMT/CAP (arm A), uMGMT/TMZ + CAP (arm B), mMGMT/CAP (arm C) and mMGMT/TMZ + CAP (arm D). The primary end point was the pathological complete response (pCR) rate. RESULTS: Between November 2017 and July 2020, 64 patients were randomised. Slow accrual caused early study termination. After excluding four ineligible patients, 60 were included in the full analysis set. The pCR rate was 15.0% (9/60), 0%, 14.3%, 18.8% and 26.7% for the entire cohort, arms A, B, C and D, respectively (P = 0.0498 between arms A and D). The pCR rate was 9.7% in the CAP group (arms A + C), 20.7% in the TMZ + CAP group (arms B + D), 6.9% in the uMGMT group (arms A + B) and 22.6% in the mMGMT group (arms C + D). Grade 1-2 nausea or vomiting was significantly more frequent in the TMZ + CAP treatment groups (arms B + D) than in the CAP treatment groups (arms A + C, P < 0.001) with no difference in grade 3 adverse events. There were no grade 4 or 5 adverse events. CONCLUSION: The addition of TMZ to CAP-based chemoradiotherapy tended to improve pCR rates, particularly in those with mMGMT LARC. MGMT status may warrant further investigation as a predictive biomarker for chemotherapeutic agents and radiotherapy.

Effect of KRAS codon 12 or 13 mutations on survival with trifluridine/tipiracil in pretreated metastatic colorectal cancer: a meta-analysis.

BACKGROUND: KRAS gene mutations can predict prognosis and treatment response in patients with metastatic colorectal cancer (mCRC). METHODS: We undertook a meta-analysis of three randomized, placebo-controlled trials (RECOURSE, TERRA and J003) to investigate the impact of KRAS mutations in codons 12 or 13 on overall survival (OS) and progression-free survival in patients receiving trifluridine/tipiracil (FTD/TPI) for refractory mCRC. RESULTS: A total of 1375 patients were included, of whom 478 had a KRAS codon 12 mutation and 130 had a KRAS codon 13 mutation. In univariate analyses, the absence of a KRAS codon 12 mutation was found to significantly increase the OS benefit of FTD/TPI relative to placebo compared with the presence of the mutation {hazard ratio (HR), 0.62 [95% confidence interval (CI): 0.53-0.72] versus 0.86 (0.70-1.05), respectively; interaction P = 0.0206}. Multivariate analyses showed that taking confounding factors into account reduced the difference in treatment effect between the presence and the absence of KRAS codon 12 mutations, confirming that treatment benefit was maintained in patients with [HR, 0.73 (95% CI: 0.59-0.89)] and without [HR, 0.63 (95% CI: 0.54-0.74)] codon 12 mutations (interaction P = 0.2939). KRAS mutations in codon 13 did not reduce the OS benefit of FTD/TPI relative to placebo, and, furthermore, KRAS mutations at either codon 12 or codon 13 did not affect the progression-free survival benefit. CONCLUSIONS: Treatment with FTD/TPI produced a survival benefit, relative to placebo, regardless of KRAS codon 12 or 13 mutation status in patients with previously treated mCRC.

Seasonal variability of ocean circulation near the Dotson Ice Shelf, Antarctica.

Recent rapid thinning of West Antarctic ice shelves are believed to be caused by intrusions of warm deep water that induce basal melting and seaward meltwater export. This study uses data from three bottom-mounted mooring arrays to show seasonal variability and local forcing for the currents moving into and out of the Dotson ice shelf cavity. A southward flow of warm, salty water had maximum current velocities along the eastern channel slope, while northward outflows of freshened ice shelf meltwater spread at intermediate depth above the western slope. The inflow correlated with the local ocean surface stress curl. At the western slope, meltwater outflows followed the warm influx along the eastern slope with a ~2-3 month delay. Ocean circulation near Dotson Ice Shelf, affected by sea ice distribution and wind, appears to significantly control the inflow of warm water and subsequent ice shelf melting on seasonal time-scales.

Pan-Asian adaptation of the EHNS-ESMO-ESTRO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with squamous cell carcinoma of the head and neck.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of squamous cell carcinoma (SCC) of the oral cavity, larynx, oropharynx and hypopharynx was published in 2020. It was therefore decided by both the ESMO and the Korean Society of Medical Oncology (KSMO) to convene a special, virtual guidelines meeting in July 2021 to adapt the ESMO 2020 guidelines to consider the potential ethnic differences associated with the treatment of SCCs of the head and neck (SCCHN) in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with SCCHN (excluding nasopharyngeal carcinomas) representing the oncological societies of Korea (KSMO), China (CSCO), India (ISMPO), Japan (JSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of the current treatment practices and drug access restrictions in the different Asian countries. The latter was discussed when appropriate. This manuscript provides a series of expert recommendations (Clinical Practice Guidelines) which can be used to provide guidance to health care providers and clinicians for the optimisation of the diagnosis, treatment and management of patients with SCC of the oral cavity, larynx, oropharynx and hypopharynx across Asia.

Ice front blocking of ocean heat transport to an Antarctic ice shelf.

Mass loss from the Antarctic Ice Sheet to the ocean has increased in recent decades, largely because the thinning of its floating ice shelves has allowed the outflow of grounded ice to accelerate1,2. Enhanced basal melting of the ice shelves is thought to be the ultimate driver of change2,3, motivating a recent focus on the processes that control ocean heat transport onto and across the seabed of the Antarctic continental shelf towards the ice4-6. However, the shoreward heat flux typically far exceeds that required to match observed melt rates2,7,8, suggesting that other critical controls exist. Here we show that the depth-independent (barotropic) component of the heat flow towards an ice shelf is blocked by the marked step shape of the ice front, and that only the depth-varying (baroclinic) component, which is typically much smaller, can enter the sub-ice cavity. Our results arise from direct observations of the Getz Ice Shelf system and laboratory experiments on a rotating platform. A similar blocking of the barotropic component may occur in other areas with comparable ice-bathymetry configurations, which may explain why changes in the density structure of the water column have been found to be a better indicator of basal melt rate variability than the heat transported onto the continental shelf9. Representing the step topography of the ice front accurately in models is thus important for simulating ocean heat fluxes and induced melt rates.

Neuropathic pain in ankylosing spondylitis: a meta-analysis.

AIM: The aim of this study was to compare demographic characteristics, disease activity, functional status, and quality of life between ankylosing spondylitis (AS) with neuropatic pain (NP) and AS without NP (Non-NP). METHODS: The MEDLINE via PubMed, Cochrane, Scopus, and Embase database, from the earliest available date of indexing through December 20, 2018, were searched for comparative studies evaluating NP in AS patients. Two authors performed the data extraction independently. Any discrepancies were resolved by consensus. RESULTS: Four comparative studies were identified. There was no statistically significant difference in terms of age, body mass index, symptom duration, and inflammatory markers, such as erythrocyte sedimentation rate and C­reactive protein between NP and Non-NP. The sex ratios (F/M) were approximately 1/1 in NP and 1/2 in Non-NP and the proportion of human leukocyte antigen (HLA) B27-positive patients in NP and Non-NP was 65.7% and 83.0%, respectively. NP patients had significantly higher visual analogue scale pain scores, higher Bath Ankylosing Spondylitis Disease Activity Index, higher Bath Ankylosing Spondylitis Functional Index, and lower SF-Item Short Form physical component scores compare to Non-NP patients. CONCLUSION: The current meta-analysis showed that NP patients had significantly higher pain severity, higher disease activity and lower quality of life than Non-NP patients. The sex ratio (F/M) and proportion of HLA-B27 positive patients were different between the two groups. Further well-designed studies are needed to substantiate our results.

Phase Ib study of atezolizumab combined with cobimetinib in patients with solid tumors.

BACKGROUND: Preclinical evidence suggests that MEK inhibition promotes accumulation and survival of intratumoral tumor-specific T cells and can synergize with immune checkpoint inhibition. We investigated the safety and clinical activity of combining a MEK inhibitor, cobimetinib, and a programmed cell death 1 ligand 1 (PD-L1) inhibitor, atezolizumab, in patients with solid tumors. PATIENTS AND METHODS: This phase I/Ib study treated PD-L1/PD-1-naive patients with solid tumors in a dose-escalation stage and then in multiple, indication-specific dose-expansion cohorts. In most patients, cobimetinib was dosed once daily orally for 21 days on, 7 days off. Atezolizumab was dosed at 800 mg intravenously every 2 weeks. The primary objectives were safety and tolerability. Secondary end points included objective response rate, progression-free survival, and overall survival. RESULTS: Between 27 December 2013 and 9 May 2016, 152 patients were enrolled. As of 4 September 2017, 150 patients received ≥1 dose of atezolizumab, including 14 in the dose-escalation cohorts and 136 in the dose-expansion cohorts. Patients had metastatic colorectal cancer (mCRC; n = 84), melanoma (n = 22), non-small-cell lung cancer (NSCLC; n = 28), and other solid tumors (n = 16). The most common all-grade treatment-related adverse events (AEs) were diarrhea (67%), rash (48%), and fatigue (40%), similar to those with single-agent cobimetinib and atezolizumab. One (<1%) treatment-related grade 5 AE occurred (sepsis). Forty-five (30%) and 23 patients (15%) had AEs that led to discontinuation of cobimetinib and atezolizumab, respectively. Confirmed responses were observed in 7 of 84 patients (8%) with mCRC (6 responders were microsatellite low/stable, 1 was microsatellite instable), 9 of 22 patients (41%) with melanoma, and 5 of 28 patients (18%) with NSCLC. Clinical activity was independent of KRAS/BRAF status across diseases. CONCLUSIONS: Atezolizumab plus cobimetinib had manageable safety and clinical activity irrespective of KRAS/BRAF status. Although potential synergistic activity was seen in mCRC, this was not confirmed in a subsequent phase III study. CLINICALTRIALS.GOV IDENTIFIER: NCT01988896 (the investigators in the NCT01988896 study are listed in the supplementary Appendix, available at Annals of Oncology online).

Biomarker analysis beyond angiogenesis: RAS/RAF mutation status, tumour sidedness, and second-line ramucirumab efficacy in patients with metastatic colorectal carcinoma from RAISE-a global phase III study.

Background: : Second-line treatment with ramucirumab+FOLFIRI improved overall survival (OS) versus placebo+FOLFIRI for patients with metastatic colorectal carcinoma (CRC) [hazard ratio (HR)=0.84, 95% CI 0.73-0.98, P = 0.022]. Post hoc analyses of RAISE patient data examined the association of RAS/RAF mutation status and the anatomical location of the primary CRC tumour (left versus right) with efficacy parameters. Patients and methods: Patient tumour tissue was classified as BRAF mutant, KRAS/NRAS (RAS) mutant, or RAS/BRAF wild-type. Left-CRC was defined as the splenic flexure, descending and sigmoid colon, and rectum; right-CRC included transverse, ascending colon, and cecum. Results: RAS/RAF mutation status was available for 85% of patients (912/1072) and primary tumour location was known for 94.4% of patients (1012/1072). A favourable and comparable ramucirumab treatment effect was observed for patients with RAS mutations (OS HR = 0.86, 95% CI 0.71-1.04) and patients with RAS/BRAF wild-type tumours (OS HR = 0.86, 95% CI 0.64-1.14). Among the 41 patients with BRAF-mutated tumours, the ramucirumab benefit was more notable (OS HR = 0.54, 95% CI 0.25-1.13), although, as with the other genetic sub-group analyses, differences were not statistically significant. Progression-free survival (PFS) data followed the same trend. Treatment-by-mutation status interaction tests (OS P = 0.523, PFS P = 0.655) indicated that the ramucirumab benefit was not statistically different among the mutation sub-groups, although the small sample size of the BRAF group limited the analysis. Addition of ramucirumab to FOLFIRI improved left-CRC median OS by 2.5 month over placebo (HR = 0.81, 95% CI 0.68-0.97); median OS for ramucirumab-treated patients with right-CRC was 1.1 month over placebo (HR = 0.97, 95% CI 0.75-1.26). The treatment-by-sub-group interaction was not statistically significant for tumour sidedness (P = 0.276). Conclusions: In the RAISE study, the addition of ramucirumab to FOLFIRI improved patient outcomes, regardless of RAS/RAF mutation status, and tumour sidedness. Ramucirumab treatment provided a numerically substantial benefit in BRAF-mutated tumours, although the P-values were not statistically significant. ClinicalTrials.gov number: NCT01183780.

Alitretinoin can be a good treatment option for idiopathic recalcitrant trachyonychia in adults: an open-label study.

BACKGROUND: Trachyonychia can be refractory to conventional treatments including topical, intralesional or systemic corticosteroids, as well as cyclosporine and retinoids. Therefore, new treatment options are needed for recalcitrant trachyonychia. OBJECTIVE: To evaluate the efficacy and safety of oral alitretinoin for idiopathic recalcitrant trachyonychia. METHODS: A total of 21 adult patients with 210 nails affected by idiopathic recalcitrant trachyonychia were evaluated in this open-label prospective study. All patients took 30 mg of alitretinoin daily for at least 3 months. Clinical outcomes were assessed using the Physician Global Assessment (PGA) scale proposed by Park et al. (degree of roughness: 0, clear; 1, mild; 2, moderate; 3, marked; 4, severe) at baseline and 1, 3 and 6 months after treatment. RESULTS: After 1, 3 and 6 months of treatment, 74.3% (123/210), 98.1% (206/210) and 99.2% (119/120) of nails showed clinical improvement, respectively; 0% (0/210), 22.9% (48/210) and 69.2% (83/120) were completely free from nail abnormalities. The mean PGA score at baseline was 3.4, decreasing significantly to 2.7, 1.3 and 0.7 at 1, 3 and 6 months following treatment, respectively. LIMITATIONS: A small number of participants and lack of a control group were limitations. CONCLUSIONS: For the first time, this study evaluated the efficacy and safety of oral alitretinoin for idiopathic recalcitrant trachyonychia in adults. The results suggest that oral alitretinoin can be a good treatment option for adult patients with recalcitrant trachyonychia.

Effect of goal-directed haemodynamic therapy in free flap reconstruction for head and neck cancer.

BACKGROUND: In free flap reconstruction for head and neck cancer, achieving a haemodynamic target using excessive fluid infusion is associated with decreased flap survival rates and extended hospital stays. We hypothesized that goal-directed haemodynamic therapy would improve flap survival rates and shorten hospitalization periods. METHODS: Patients scheduled for free flap reconstruction were randomly assigned to a goal-directed haemodynamic therapy group (n = 31) or a conventional haemodynamic therapy control group (n = 31). The control group received extra bolus fluid and ephedrine or norepinephrine to maintain a mean arterial pressure ≥ 65 mmHg. The goal-directed haemodynamic therapy group received a colloid solution as the extra bolus fluid to maintain a stroke volume variation < 12%; dobutamine, ephedrine, or norepinephrine was administered to maintain a cardiac index ≥ 2.5 l/min/m2 and mean arterial pressure ≥ 65 mmHg. Enhanced recovery after surgery protocols were not used except for fluid therapy. An otolaryngologist blinded to group assignments assessed flap outcomes and classified them as 'survival,' 'at risk' or 'failure.' RESULTS: The hospitalization period was not significantly different between the groups. The goal-directed haemodynamic therapy group had significantly shorter intensive care unit stays and a higher flap survival rate. The crystalloid volume was significantly lower in goal-directed haemodynamic therapy group. Reoperation rates, post-operative complications, and laboratory data including inflammatory markers were similar between the groups. CONCLUSION: Compared to conventional haemodynamic therapy, goal-directed haemodynamic therapy does not reduce hospitalization periods; it may, however, reduce the length of intensive care unit stays and increase flap survival rates. Further studies including multi-centre trials with larger sample sizes are warranted.

Pharmacokinetic profiles of the active metamizole metabolites after four different routes of administration in healthy dogs.

Metamizole (MT), an analgesic and antipyretic drug, is rapidly hydrolyzed to the active primary metabolite 4-methylaminoantipyrine (MAA) and relatively active secondary metabolite 4-aminoantipyrine (AA). The aim of this study was to assess the pharmacokinetic profiles of MAA and AA after dose of 25 mg/kg MT by intravenous (i.v.), intramuscular (i.m.), oral (p.o.), and rectal (RC) routes in dogs. Six dogs were randomly allocated to an open, single-dose, four-treatment, four-phase, unpaired, crossover study design. Blood was collected at predetermined times within 24 hr, and plasma was analyzed by a validated HPLC-UV method. Plasma concentrations of MAA and AA after i.v., i.m., p.o., and RC administrations of MT were detectable from 5 (i.v. and i.m.) or 30 (p.o. and RC) min to 24 hr in all dogs. The highest concentrations of MAA were found in the i.v., then i.m., p.o., and RC groups. Plasma concentrations of AA were similar for i.v., i.m., and RC, and the concentrations were approximately double those in the PO groups. The AUCEV/IV ratio for MAA was 0.75 ± 0.11, 0.59 ± 0.08, and 0.32 ± 0.05, for i.m., p.o., and RC, respectively. The AUCEV/IV ratio for AA was 1.21 ± 0.33, 2.17 ± 0.62, and 1.08 ± 0.19, for i.m., p.o., and RC, respectively. Although further studies are needed, rectal administration seems to be the least suitable route of administration for MT in the dog.

Pharmacokinetic profiles of the two major active metabolites of metamizole (dipyrone) in cats following three different routes of administration.

This study was performed to determine pharmacokinetic profiles of the two active metabolites of the analgesic drug metamizole (dipyrone, MET), 4-methylaminoantipyrine (MAA), and 4-aminoantipyrine (AA), after intravenous (i.v., intramuscular (i.m.), and oral (p.o.) administration in cats. Six healthy mixed-breed cats were administered MET (25 mg/kg) by i.v., i.m., or p.o. routes in a crossover design. Adverse clinical signs, namely salivation and vomiting, were detected in all groups (i.v. 67%, i.m. 34%, and p.o. 15%). The mean maximal plasma concentration of MAA for i.v., i.m., and p.o. administrations was 148.63 ± 106.64, 18.74 ± 4.97, and 20.59 ± 15.29 µg/ml, respectively, with about 7 hr of half-life in all routes. Among the administration routes, the area under the plasma concentration curve (AUC) value was the lowest after i.m. administration and the AUCEV/i.v . ratio was higher in p.o. than the i.m. administration without statistical significance. The plasma concentration of AA was detectable up to 24 hr, and the mean plasma concentrations were smaller than MAA. The present results suggest that MET is converted into the active metabolites in cats as in humans. Further pharmacodynamics and safety studies should be performed before any clinical use.

Pan-Asian adapted ESMO consensus guidelines for the management of patients with metastatic colorectal cancer: a JSMO-ESMO initiative endorsed by CSCO, KACO, MOS, SSO and TOS.

The most recent version of the European Society for Medical Oncology (ESMO) consensus guidelines for the treatment of patients with metastatic colorectal cancer (mCRC) was published in 2016, identifying both a more strategic approach to the administration of the available systemic therapy choices, and a greater emphasis on the use of ablative techniques, including surgery. At the 2016 ESMO Asia Meeting, in December 2016, it was decided by both ESMO and the Japanese Society of Medical Oncology (JSMO) to convene a special guidelines meeting, endorsed by both ESMO and JSMO, immediately after the JSMO 2017 Annual Meeting. The aim was to adapt the ESMO consensus guidelines to take into account the ethnic differences relating to the toxicity as well as other aspects of certain systemic treatments in patients of Asian ethnicity. These guidelines represent the consensus opinions reached by experts in the treatment of patients with mCRC identified by the Presidents of the oncological societies of Japan (JSMO), China (Chinese Society of Clinical Oncology), Korea (Korean Association for Clinical Oncology), Malaysia (Malaysian Oncological Society), Singapore (Singapore Society of Oncology) and Taiwan (Taiwan Oncology Society). The voting was based on scientific evidence and was independent of both the current treatment practices and the drug availability and reimbursement situations in the individual participating Asian countries.

The importance of dermoscopy for the diagnosis of acquired bilateral telangiectatic macules: the angioid streak pattern reveals underlying chronic liver disease.

BACKGROUND: Acquired bilateral telangiectatic macules (ABTM) are a newly recognized disease entity, which manifest as multiple telangiectatic pigmented macules confined mostly to the upper arms. OBJECTIVES: To evaluate clinical and dermoscopic features in a group of 50 patients with ABTM and to determine the diagnostic usefulness of dermoscopy in ABTM. METHODS: Patients were selected from two tertiary teaching hospitals in Korea [Pusan National University Hospitals (Busan and Yangsan)]. Fifty patients (41 males and 9 females; mean age 48.1 years; range 26-78 years) with ABTM were included in the study. The dermoscopic findings were graded using a 4-point scale: none (0), mild (1), moderate (2) and severe (3). In addition, the results of 23 patients with and 27 patients without chronic liver disease (CLD) were compared to determine whether the presence of CLD affects dermoscopic findings. RESULTS: Three distinct dermoscopic patterns were observed; brown pigmentations, telangiectasia (linear-irregular vessels) and an angioid streak pattern. Brown pigmentation in the group without CLD had higher severity score than those in CLD group (mean score: 2.00 vs. 1.48, P = 0.033). However, mean telangiectasia severity score was higher in the CLD group (2.14 vs. 1.39, P < 0.001). The angioid streak pattern was more severe and more common in patients with CLD than in those without [1.37 vs. 0.35 (P < 0.001) and 63.0% vs. 26.1%, respectively]. CONCLUSIONS: Detailed observations with dermoscopy can provide first clues of the presence of ABTM and underlying chronic liver disease.

Pharmacokinetics of tapentadol in laying hens and its residues in eggs after multiple oral dose administration.

1. The aim of the study was to evaluate the pharmacokinetics (PKs) of tapentadol (TAP), a novel opioid analgesic, in laying hens after intravenous (IV) and oral (PO) administration and to quantify the concentrations of TAP residues in eggs. 2. Twenty healthy laying hens were divided into three groups: A (n = 6), B (n = 6) and C (n = 8). The study was conducted in two phases. Groups A and B received TAP by IV and PO routes at the dose of 1 and 5 mg/kg, respectively. 3. No visible adverse effects were observed after administration of the drug. TAP plasma concentrations were detectable up to 4 h following administration. Following IV administration, TAP plasma concentrations were only higher than the minimal effective concentration (148 ng/ml) reported for humans for 1 h. After single PO administration, plasma concentrations of TAP would not conform to software algorithms and the PK parameters were not calculated. TAP concentration following multiple PO doses at 5 mg/kg for 5 d was found to be higher and more persistent (12 h vs. 7 h) in yolk compared with albumen. 4. This is the first PK study on the novel atypical opioid TAP in laying hens. Further studies are required to investigate the analgesic efficacy and actual effective plasma concentration of TAP in this species.

Spontaneous recovery of non-operated traumatic brachial plexus injury.

PURPOSE: We investigated the spontaneous recovery of non-operated traumatic brachial plexus injury (BPI). METHODS: A total of 25 cases of non-operated traumatic BPI were analysed by retrospective review of medical records; in all cases, consecutive electrodiagnostic studies (ES) were conducted from 1 to 4 months and 18 to 24 months post-trauma. Injury severity was assessed using a modified version of Dumitru and Wilbourn's scale (DWS) based on ES. Spontaneous recovery of brachial plexus components per subject was analysed using Wilcoxon's signed-rank test. A two-tailed Fisher's exact or Pearson's Chi-square test was used to examine the associations between initial injury severity (DWS grade 2 vs. 3, complete vs. incomplete), accompanying injury type (open vs. closed), main lesion location (supraclavicular vs. infraclavicular lesion), and spontaneous recovery. RESULTS: The most common cause of BPI was traffic accident (TA) (15 cases, 60%), and the most common type of TA-induced BPI was a motorcycle TA (5 cases), accounting for 20% of all injuries. The second most common type of injury was an occupational injury (6 cases, 24%). Thirty-eight (69%) of 55 injured brachial components in 25 cases had DWS grade 3 and 17 brachial components (31%) had grade 2. The DWS grade of brachial plexus components per subject significantly differed between the first and follow-up ES (p = 0.000). However, initial injury severity, accompanying injury type, and main lesion location were not statistically associated with spontaneous recovery (p > 0.05). CONCLUSIONS: Spontaneous recovery may be possible even in severe traumatic BPI. Multiple factors should be considered when predicting the clinical course of traumatic BPI.