Search

Charcot-Marie-Tooth disease (CMT) is a spectrum of clinically and genetically heterogeneous peripheral neuropathies. CMT can be classified into demyelinating, intermediate, or axonal neuropathy based on clinical, histopathological, and electrophysiological findings. Approximately 140 genes have been reported to be associated with CMT. Mutations in the myelin protein zero (MPZ), ganglioside-induced differentiation related protein 1 (GDAP1), and neurofilament light-chain polypeptide gene (NEFL) genes have been reported to cause all three types of CMT, which is noteworthy because most CMT-related genes cause a single type of neuropathy (either demyelinating or axonal). In contrast, it remains unclear why these genes cause several types of CMT. CMT is presently incurable; however, ongoing attempts to treat CMT with various drugs and dietary supplements have increased the importance of an exact genetic diagnosis for precision medicine. Therefore, it is important to identify the causative mutations and compare the associated clinical characteristics. Taken together, a comparison of causative mutations and clinical features of patients with MPZ, GDAP1, and NEFL mutations will be the first step in understanding how different types of CMT are caused, and will enable a molecular genetic diagnosis. In this review, we describe the clinical, electrophysiological, and genetic characteristics of MPZ-, GDAP1-, and NEFL-related CMT.

Osmotic demyelination syndrome (ODS) is an acute demyelinating disorder characterized by the loss of myelin in the center of the basis pons which is defined as central pontine myelinolysis (CPM) and demyelination process in locations outside the pons which is defined as extrapontine myelinolysis (EPM). ODS including CPM and EPM is mainly caused by the rapid correction of hyponatremia. However, there are several reports of ODS in medical condition such as malnutrition, alcoholism, liver transplantation, malignancy, sepsis, electrolyte imbalance including hypernatremia, hypokalemia, hypophosphatemia, and chronic illness. Rarely, ODS was reported in patients with hyperammonemia or hyperbilirubinemia without sodium fluctuations. The symptoms usually correspond to the lesion site and EPM precedes CPM. Because ODS may be irreversible, prevention is more important. Here, we report a case of ODS secondary to the hyperammonemia and hyperbilirubinemia, as it can have unfavorable prognosis.

Charcot-Marie-Tooth disease (CMT) and related diseases are a genetically and clinically heterogeneous group of peripheral neuropathies. Particularly, mutations in several aminoacyl-tRNA synthetase (ARS) genes have been reported to cause axonal CMT (CMT2) or distal hereditary motor neuropathy (dHMN). However, the common pathogenesis among CMT subtypes by different ARS gene defects is not well understood. This study was performed to investigate ARS gene mutations in a CMT cohort of 710 Korean families. Whole-exome sequencing was applied to 710 CMT patients who were negative for PMP22 duplication. We identified 12 disease-causing variants (from 13 families) in GARS1, AARS1, HARS1, WARS1, and YARS1 genes. Seven variants were determined to be novel. The frequency of overall ARS gene mutations was 1.22% among all independent patients diagnosed with CMT and 1.83% in patients negative for PMP22 duplication. WARS1 mutations have been reported to cause dHMN; however, in our patients with WARS1 variants, CMT was associated with sensory involvement. We analyzed genotype-phenotype correlations and expanded the phenotypic spectrum of patients with CMT possessing ARS gene variants. We also characterized clinical phenotypes according to ARS genes. This study will be useful for performing exact molecular and clinical diagnoses and providing reference data for other population studies.

Background: Pain is one of the most common chief complaints in neurological field. Authors try to inform the current situation of pain medicine in neurological practice and present an effective method for pain-related education during neurology residency and for practicing neurologists.Methods: A survey was conducted from November 16 to November 27, 2020 for members of the Korean Neurological Association, and the results were analyzed.Results: About two-thirds of neurologists replied that more than 25% of their patients were suffered from diverse pain including headache, spine pain or neuropathic pain. Despite many patients are visiting to neurologist for pain treatment, most neurologists are aware that they have not received sufficient practical pain education in the past and present. Therefore, they want more educational opportunities in pain medicine including interventional pain management and physical and pharmacologic therapies for more effective treatment.Conclusions: More follow-up studies on pain treatment and education should be conducted. It is also essential that the members of the society continue to interest and participate in the change of the pain education program.

This is a case report of a patient with soft palate muscle weakness that caused difficulties with phonation. A provisional palatal lift prosthesis (PLP) was developed, and the patient underwent simultaneous speech therapy. The elevation level of the palatal lift was subjectively assessed along with nasalance analysis and the Urimal Test of Articulation and Phonation results. The final PLP was applied to improve comfort and efficiency, and the patient continually underwent regular speech therapy. The patient showed satisfactory improvement in speech and pronunciation. PLP development combined with speech therapy can improve the accuracy of pronunciation in patients with palatal incompetence, thereby improving quality of life.

High-power terahertz radiation was observed to be emitted from a gas jet irradiated by 100-terawatt-class laser pulses in the laser-wakefield acceleration of electrons. The emitted terahertz radiation was characterized in terms of its spectrum, polarization, and energy dependence on the accompanying electron bunch energy and charge under various gas target conditions. With a nitrogen target, more than 4 mJ of energy was produced at

Duplication and deletion of the peripheral myelin protein 22 (PMP22) gene cause Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP), respectively, while point mutations or small insertions and deletions (indels) usually cause CMT type 1E (CMT1E) or HNPP. This study was performed to identify PMP22 mutations and to analyze the genotype–phenotype correlation in Korean CMT families. By the application of whole-exome sequencing (WES) and targeted gene panel sequencing (TS), we identified 14 pathogenic or likely pathogenic PMP22 mutations in 21 families out of 850 CMT families who were negative for 17p12 (PMP22) duplication. Most mutations were located in the well-conserved transmembrane domains. Of these, eight mutations were not reported in other populations. High frequencies of de novo mutations were observed, and the mutation sites of c.68C>G and c.215C>T were suggested as the mutational hotspots. Affected individuals showed an early onset-severe phenotype and late onset-mild phenotype, and more than 40% of the CMT1E patients showed hearing loss. Physical and electrophysiological symptoms of the CMT1E patients were more severely damaged than those of CMT1A while similar to CMT1B caused by MPZ mutations. Our results will be useful for the reference data of Korean CMT1E and the molecular diagnosis of CMT1 with or without hearing loss.

Objective To evaluate the effects of extracorporeal shockwave therapy (ESWT) on improving lymphedema, quality of life, and fibrous tissue in patients with stage 2 lymphedema.Methods Breast cancer-related lymphedema patients referred to the rehabilitation center were recruited. We enrolled stage 2 lymphedema patients who had firmness of the skin at their forearm, a circumference difference of more than 2 cm between each arm, or a volume difference between upper extremities greater than 200 mL, confirmed by lymphoscintigraphy. The patients were randomly divided into the ESWT group and the control group. ESWT was performed for 3 weeks (two sessions per week); both groups received complex decongestive physical therapy. All patients were evaluated at baseline and at 3 weeks after treatment. The measurements performed included visual analog scale score, volume, circumference, QuickDASH (Quick Disabilities of the Arm, Shoulder and Hand) score, bioelectrical impedance, and skin thickness.Results The patients in both groups (n=15 in each group) completed the 3-week therapy experiment. No significant differences were observed in demographic characteristics between groups. After the 3-week treatment period, improvement was noted in the circumference difference below the elbow, volume, ratio of extracellular water to total body water, and skin thickness in the ESWT group. A significant difference was found in all the above-mentioned areas except in circumference below the elbow in the ESWT group.Conclusion ESWT reduced edema and skin fibrosis without significant complications. Therefore, ESWT can be used together with complex decongestive physical therapy for treating lymphedema.

Charcot-Marie-Tooth disease type 1C (CMT1C) is a rare subtype associated with LITAF gene mutations. Until now, only a few studies have reported the clinical features of CMT1C.This study was performed to find CMT1C patients with mutation of LITAF in a Korean CMT cohort and to characterize their clinical features.In total, 1,143 unrelated Korean families with CMT were enrolled in a cohort. We performed whole exome sequencing to identify LITAF mutations, and examined clinical phenotypes including electrophysiological and MRI features for the identified CMT1C patients.We identified 10 CMT1C patients from three unrelated families with p.G112S mutation in LITAF. The frequency of CMT1C among CMT1 patients was 0.59%, which is similar to reports from Western populations. CMT1C patients showed milder symptoms than CMT1A patients. The mean CMT neuropathy score version 2 was 7.7, and the mean functional disability scale was 1.0. Electrophysiological findings showed a conduction block in 22% of affected individuals. Lower extremity MRIs showed that the superficial posterior and anterolateral compartments of the calf were predominantly affected.We found a conduction block in Korean CMT1C patients with p.G112S mutation and first described the characteristic MRI findings of the lower extremities in patients with LITAF mutation. These findings will be helpful for genotype-phenotype correlation and will widen understanding about the clinical spectrum of CMT1C.

Extracorporeal shock wave therapy (ESWT) can reduce breast cancer-related lymphedema (BCRL). However, evidence of the long-term effectiveness of ESWT on BCRL is sparse. The aim of the study was to investigate whether ESWT has long-term effects on BCRL. We enrolled patients with stage 2 lymphedema. The 28 female patients were randomly divided into the ESWT group (n = 14) and the control group (n = 14). ESWT was applied thrice a week for a total of 3 weeks with an intensity of 0.056 to 0.068 mJ/mm2 and a frequency of 4 Hz. Complex decongestive therapy (CDT) was applied in both groups. The arm circumference, fluid volume, ratio of water content, and skin thickness were measured. Patients were evaluated at before treatment, 3 weeks after ESWT completion, and 3 months post-ESWT completion. The ESWT group, the circumference of the whole arm, volume, ratio of water content, QuickDASH score, and skin thickness showed statistically significant improvement at 3 weeks and 3 months post-treatment. When comparing the changes in measurement between the two groups at 3 weeks and 3 months post-treatment, ESWT group showed statistically significant improvement in circumference (cm) below the elbow, ratio of water content and skin thickness at 3 weeks and 3 months post treatment. Overall, ESWT improved lymphedema in patients with stage 2 BCRL, and the effects persisted for at least 3 months. Therefore, ESWT may be an additional treatment method for patients with lymphedema.

Charcot–Marie–Tooth disease (CMT) is the most common inherited peripheral neuropathy. Mutations in the GNB4 gene cause dominant intermediate CMT type F (CMTDIF). The aim of this study is to investigate phenotypic heterogeneities and characteristics of CMT patients with GNB4 mutations. We enrolled 1143 Korean CMT families and excluded 344 families with a PMP22 duplication. We further analyzed the 799 remaining families to find their GNB4 mutations using whole-exome sequencing (WES). We identified two mutations (p.Gly77Arg and p.Lys89Glu) in three families, among which a heterozygous p.Gly77Arg mutation was novel. In addition, a significant uncertain variant (p.Thr177Asn) was observed in one family. The frequency of the GNB4 mutation in the Korean population is 0.38% in PMP22 duplication-negative families. All three families showed de novo mutation. Electrophysiological findings regarding the p.Lys89Glu mutation showed that the motor nerve conduction velocity (MNCV) of the median nerve was markedly reduced, indicating demyelinating neuropathy, and sural nerve biopsy revealed severe loss of myelinated axons with onion bulb formation. Lower extremity Magnetic Resonance Imaging (MRI) demonstrated relatively more severe intramuscular fat infiltrations in demyelinating type (p.Lys89Glu mutation) patients compared to intermediate type (p.Gly77Arg mutation) patients. The anterolateral and superficial posterior compartment muscles of the distal calf were preferentially affected in demyelinating type patients. Therefore, it seems that the investigated GNB4 mutations do cause not only the known intermediate type but also demyelinating-type neuropathy. We first presented three Korean families with GNB4 mutations and found phenotypic heterogeneities of both intermediate and demyelinating neuropathy. We suggest that those findings are useful for the differential diagnosis of CMT patients with unknown GNB4 variants.

Background Charcot‐Marie‐Tooth disease (CMT) is the most common disorder of inherited peripheral neuropathies characterized by distal muscle weakness and sensory loss. CMT is usually classified into three types, demyelinating, axonal, and intermediate neuropathies. Mutations in myelin protein zero (MPZ) gene which encodes a transmembrane protein of the Schwann cells as a major component of peripheral myelin have been reported to cause various type of CMT. Methods This study screened MPZ mutations in Korean CMT patients (1,121 families) by whole exome sequencing and targeted sequencing. Results We identified 22 pathogenic or likely pathogenic MPZ mutations in 36 families as the underlying cause of the CMT1B, CMTDID, or CMT2I subtypes. Among them, five mutations were novel. The frequency of CMT patients with the MPZ mutations was similar or slightly lower compared to other ethnic groups. Conclusions We showed that the median onset ages and clinical phenotypes varied by subtypes: the most severe in the CMT1B group, and the mildest in the CMT2I group. This study also observed a clear correlation that earlier onsets cause more severe symptoms. We believe that this study will provide useful reference data for genetic and clinical information on CMT patients with MPZ mutations in Korea., Mutations in myelin protein zero (MPZ) gene which encodes a transmembrane protein of the Schwann cells have been reported to cause various type of CMT.We identified 22 pathogenic or likely pathogenic MPZ mutations in 36 families as the underlying cause of the CMT1B, CMTDID, or CMT2I subtypes.The mean onset ages and clinical phenotypes varied by subtypes: the most severe in the CMT1B group, and the mildest in the CMT2I group.

To evaluate the serum cytokine profiles in patients with myelin oligodendrocyte glycoproteins antibody associated disease (MOGAD), compared to those in neuromyelitis optica spectrum disorder with aquaporin-4 immunoglobulin G (APQ4-IgG+ NMOSD), multiple sclerosis (MS), and other inflammatory demyelinating diseases (IDDs).The level of interleukin (IL)-1β, IL-5, IL-6, IL-10, IL-12p70, IL-17A, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ in sera from 21 patients with MOGAD, 32 APQ4-IgG+ NMOSD, 24 MS, and 16 other IDDs were assessed.In MOGAD patients, the levels of IL-1β and IL-12p70 were elevated compared to APQ4-IgG+ NMOSD. The level of IL-10 and the ratio of T helper (Th)-1/Th2-related cytokines were elevated in MOGAD patients compared to MS or other IDDs. In an intragroup analysis, the IL-1β was increased in acute stage of MOGAD, APQ4-IgG+ NMOSD, and also MS compared to their chronic stage counterpart. It was inversely correlated with time from acute attack to sampling in MOGAD (p 0.001) and AQP4-IgG+ NMOSD (p = 0.001), but not in MS. Moreover, the IL-1β was most markedly upregulated in MOGAD sera sampled within 1 week from acute attack compared to those sampled after (p = 0.002).The serum IL-1β can be elevated in the acute stage of patients with diverse IDDs including, MOGAD, APQ4-IgG+ NMOSD, and MS. This upregulation of serum IL-1β can be most markedly observed in the early acute stage of MOGAD patients. Further studies seem to be needed to determine the proper mechanism for the upregulation of serum IL-1β and also the role of IL-1β inhibition especially at the early acute stage of MOGAD.

Charcot‑Marie‑Tooth disease (CMT) is the most common inherited neurological disorder of the peripheral nervous system. The major subtype, CMT type 1A (CMT1A), accounts for ~40% of CMT cases and is characterized by distal muscle atrophy and gait disturbances. Short hairpin (sh) RNA sequences are potentially advantageous therapeutic tools for distal muscle atrophy‑induced gait disturbance. Therefore, the current study focused on the effects of an optimal shRNA injection using the myostatin (mstn) gene inhibition system. shLenti‑Mstn A demonstrated significant suppression of endogenous mstn gene expression (>40%) via RT‑qPCR following direct injection into the gastrocnemius and rectus femoris of the hind limb in C22 mice. The results also reported that shLenti‑Mstn A treatment increased muscle mass and size of the hind limbs compared with mock‑treated mice via measurement of the mass of injected muscles and magnetic resonance imaging study. Furthermore, electrophysiological measurement using a Nicolet Viking Quest device revealed significantly improved compound muscle action potential (CMAP) in shLenti‑Mstn A‑treated mice compared with the mock group (P

Objective To investigate the effects of hand training using low-frequency repetitive transcranial magnetic stimulation (rTMS) within the aftereffect period on hand function in patients with subacute stroke. Methods The subacute stroke patients with hand weaknesses were divided randomly into two groups. Patients in the intervention group underwent hand training within the aftereffect period, that is, immediately after receiving low-frequency rTMS treatment. Patients in the control group underwent hand training 2 hours after the low-frequency rTMS treatment. A manual function test (MFT) for ‘grasp and pinch’ and ‘hand activities’; a manual muscle test (MMT) for ‘grasp’, ‘release’, and ‘abductor pollicis brevis (APB)’; and the Modified Ashworth Scale for finger flexion were performed and measured before and immediately after combined therapy as well as 2 weeks after combined therapy. Results Thirty-two patients with hand weakness were enrolled in this study. The intervention group patients showed more improvements in grasp MMT and MMT APB tested immediately after combined therapy. However, the changes in all measurements were not significantly different between the two groups 2 weeks after the combined therapy. In both groups, hand functions improved significantly immediately after combined therapy and 2 weeks after combined therapy. Conclusion Hand training immediately after low-frequency rTMS showed more rapid improvement in the motor power of hands than hand training conducted 2 hours after low-frequency rTMS. Our results suggest that conducting hand training immediately after low-frequency rTMS could be an improved useful therapeutic option in subacute stroke patients.

Objective To demonstrate the usefulness of early videofluoroscopic swallowing study (VFSS) and to investigate change patterns in dietary methods in stroke patients with dysphagia. Methods The VFSS was performed within 7 days of stroke onset in neurologically stable patients. The patients were divided into three groups according to type of brain lesion: cortical lesion (CL), subcortical lesion (SCL), and brainstem/cerebellar lesion (BCL). Based on the VFSS results, this study investigated change patterns in feeding method and discrepancies in the aspiration risk predicted by the Water Swallowing Test (WST) and the VFSS. Complications, such as aspiration pneumonia, were also evaluated. Results A total of 163 patients met the inclusion criteria and the VFSS was performed within 7 days of stroke. Patients considered at risk for aspiration (Penetration-Aspiration Scale [PAS] scores of 6 to 8) were found in all three groups using the VFSS (47.5% of the CL group, 59.3% of the SCL group, and 47.9% of the BCL group). After early VFSS, 79.7% of the patients were assessed to require restricted feeding methods. A 19.0% discrepancy was found between the WST and VFSS results. At 3-week follow-up after the VFSS, aspiration pneumonia was observed in 12 patients (7.4%) with restricted feeding methods. Conclusion Early VFSS during the acute period can facilitate determination of the most appropriate feeding method, and support effective dysphagia management for stroke patients.

Background and ObjectiveTo investigate the clinical relevance of CSF myelin oligodendrocyte glycoprotein-immunoglobulin G (MOG-IgG) testing in a large multicenter cohort.MethodsIn this multicenter cohort study, paired serum-CSF samples from 474 patients with suspected inflammatory demyelinating disease (IDD) from 11 referral hospitals were included. After serum screening, patients were grouped into seropositive myelin oligodendrocyte glycoprotein antibody associated disease (MOGAD, 31), aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4-IgG + NMOSD, 60), other IDDs (217), multiple sclerosis (MS, 45), and non-IDDs (121). We then screened CSF for MOG-IgG and compared the clinical and serologic characteristics of patients uniquely positive for MOG-IgG in the CSF to seropositive patients with MOGAD.ResultsNineteen patients with seropositive MOGAD (61.3%), 9 with other IDDs (CSF MOG + IDD, 4.1%), 4 with MS (8.9%), but none with AQP4-IgG + NMOSD nor with non-IDDs tested positive in the CSF for MOG-IgG. The clinical, pathologic, and prognostic features of patients uniquely positive for CSF MOG-IgG, with a non-MS phenotype, were comparable with those of seropositive MOGAD. Intrathecal MOG-IgG synthesis, observed from the onset of disease, was shown in 12 patients: 4 of 28 who were seropositive and 8 who were uniquely CSF positive, all of whom had involvement of either brain or spinal cord. Both CSF MOG-IgG titer and corrected CSF/serum MOG-IgG index, but not serum MOG-IgG titer, were associated with disability, CSF pleocytosis, and level of CSF proteins.DiscussionCSF MOG-IgG is found in IDD other than MS and also in MS. In IDD other than MS, the CSF MOG-IgG positivity can support the diagnosis of MOGAD. The synthesis of MOG-IgG in the CNS of patients with MOGAD can be detected from the onset of the disease and is associated with the severity of the disease.Classification of EvidenceThis study provides Class II evidence that the presence of CSF MOG-IgG can improve the diagnosis of MOGAD in the absence of an MS phenotype, and intrathecal synthesis of MOG-IgG was associated with increased disability.

The use of a whole-body vibration (WBV) therapy has recently been applied and investigated as a rehabilitation method for subacute stroke patients.To evaluate the effects of a WBV therapy on recovery of balance in subacute stroke patients who were unable to gain sitting balance.The conventional rehabilitation group (CG) received conventional physical therapy, including sitting balance training by a physical therapist, for 30 min a one session, for twice a day for five days a week for two weeks. The whole-body vibration group (VG) received one session of conventional physical therapy, and received WBV therapy instead of conventional physical therapy for 30 min a day for five days a week for two weeks.There were 15 patients in the CG and 15 patients in the VG who completed the two-week therapy. After the two-week therapy, both groups showed functional improvement. Patients in the VG improved functional ambulation categories, Berg balance scale, trunk impairment scale scores. But, no statistically significant correlations between the therapeutic methods and outcomes were observed in either group.Our results suggest that WBV therapy led to improvement of the recovery in balance recovery for subacute stroke patients. Because the WBV therapy was as effective as conventional physical therapy, we can consider a WBV therapy as a clinical method to improve the sitting balance of subacute stoke patients.

Despite the importance of water sorption isotherms for a fundamental understanding of protein-water interactions, the microscopic origin of hysteresis between the adsorption and desorption branches is not well understood. Using our recently developed simulation technique, we compute the water sorption isotherms of two proteins, lysozyme and Trp-cage, a miniprotein. We explicitly compare protein-water interactions in adsorption and desorption processes, by analyzing local hydration in terms of hydrogen bonding, water density, and solvent-accessible surface area. We find that significant differences in hydration behavior between adsorption and desorption manifest themselves at the individual amino acid level, in particular around polar or charged residues. We confirm this observation by demonstrating that Trp-cage's hysteresis can be significantly reduced by mutating charged residues to alanine, a neutral and nonpolar amino acid.

// Won Il Jang 1, * , Mi-Sook Kim 1, 2 , Shin Hee Kang 2, * , Ae Jung Jo 2 , Yun Jung Kim 2 , Ha Jin Tchoe 2 , Chan Mi Park 2 , Hyo Jeong Kim 2 , Jin A Choi 2 , Hyung Jin Choi 3 , Eun-Kyung Paik 1 , Young Seok Seo 1 , Hyung Jun Yoo 1 , Jin-Kyu Kang 1 , Chul Ju Han 4 , Yeon Ju Kim 4 , Sang Beom Kim 5 , Min Jung Ko 2 1 Department of Radiation Oncology, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea 2 Division for Healthcare Technology Assessment Research, National Evidence-based Healthcare Collaborating Agency, Seoul 04554, Republic of Korea 3 Department of Anatomy, Seoul National University College of Medicine, Seoul 03080, Republic of Korea 4 Department of Internal Medicine, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea 5 Department of Surgery, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea * These authors contributed equally to this work and share co-first author Correspondence to: Mi-Sook Kim, email: mskim@kirams.re.kr Min Jung Ko, email: minjungko@neca.re.kr Keywords: pancreatic cancer, resection, diabetes, metformin, nationwide database Received: October 04, 2016 Accepted: November 24, 2016 Published: January 05, 2017 ABSTRACT Background: Preclinical studies support an antitumor effect of metformin. However, clinical studies have conflicting results and metformin’s effect remains controversial. The aim of this study was to evaluate metformin’s effect on clinical outcomes in diabetic patients with pancreatic cancer treated with curative resection. Results: A total of 764 patients underwent curative resection, met none of the exclusion criteria, and were prescribed oral hypoglycemic agents. The cancer-specific survival (5-year, 31.9% vs. 22.2%, p < 0.001) was significantly higher in the 530 metformin users than in the 234 diabetic metformin non-users. After multivariable adjustments, metformin users had significantly lower cancer-specific mortality as compared with metformin non-users (hazard ratio, 0.727; 95% confidence interval, 0.611–0.868). Cubic spline regression analysis demonstrated significantly decreased cancer-specific mortality with increasing dose of metformin ( p = 0.0047). Materials and Methods: Data were provided from the Korea Central Cancer Registry and the National Health Insurance Service in the Republic of Korea. The study cohort consisted of 28,862 patients newly diagnosed with pancreatic cancer between 2005 and 2011. Metformin exposure was determined from prescription information from 6 months before the first diagnosis of pancreatic cancer to last follow-up. The main outcome was cancer-specific survival. Conclusions: This large study indicates that metformin might decrease cancer-specific mortality rates in localized resectable pancreatic cancer patients with pre-existing diabetes, independently of other factors, with a dose-response relationship.