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To date, there is controversy regarding unilateral versus bilateral stent placement in patients with malignant hilar biliary strictures (MHBSs). The aim of this study was to compare the clinical outcomes and complications of unilateral and bilateral (stent-in-stent method) stent placements for these patients.We conducted a multicenter retrospective analysis of patients with inoperable MHBS who underwent endoscopic self-expandable metal stent (SEMS) placement from January 2009 to December 2019. Two groups classified according to the stent procedure method were compared for demographic, procedural, and postprocedure factors. Survival analysis for patency loss and overall survival was also conducted.A total of 236 subjects were included. A superior technical success rate was found in the unilateral stent group (98.8% vs. 82.5%, P0.001), whereas the clinical success rate was higher in the bilateral group (85.7% vs. 70.5%, P = 0.028). There was no significant difference with respect to complications or patency loss, and the bilateral group had better overall survival (P0.01). In the Cox proportional hazard model, MHBSs from lymph node compression were associated with a higher risk of death (HR = 9.803, P = 0.003). In contrast, bilateral SEMS insertion showed reduced postprocedural mortality (HR = 0.316, P = 0.001).Y-type stent-in-stent bilateral SEMSs are technically difficult but demonstrated more favorable overall survival for palliative bile drainage of inoperable MHBS patients compared to unilateral insertions.

Background The rates of very elderly patients (≥85 years old) undergoing percutaneous coronary intervention (PCI) for acute coronary syndromes (ACS) are rapidly increasing. They are under-represented in clinical trials, and those who are included may not reflect the real-world population. We aim to review the clinical characteristics of very elderly patients undergoing PCI for ACS and identify factors associated with adverse outcomes. Method All very elderly patients undergoing PCI for ACS in the Auckland region between January 2014 to December 2016 were included. Baseline clinical and procedural details were obtained, and the primary endpoint was all-cause mortality measured up to a maximum of 4 years. Secondary endpoints include recurrent myocardial infarction, unplanned revascularisation, stroke and major bleeding. Results A total of 186 patients were included for analysis (mean age 87.6±2.8 years, 51.6% male). Indications for PCI were ST-elevation myocardial infarction (STEMI) in 74 (39.8%), non-ST elevation myocardial infarction (NSTEMI) in 97 (52.2%) and unstable angina in 15 patients (8.1%). Successful PCI was completed in 180 patients. At a maximal follow-up of 4 years (mean 23.4 mo), the rates of all-cause mortality and recurrent myocardial infarction were 22.0% and 14.0% respectively. The risk of mortality was increased by the presence of diabetes (44.8% vs 17.8%, HR=3.0, 95%CI: 1.6–5.9, p=0.001), STEMI (33.8% vs 13.5%, HR=3.1, 95%CI: 1.6–5.9, p=0.001), and reduced eGFR (every -10 mL/min/1.73m2, HR=1.7, 95%CI: 1.3–2.1, p Conclusion Very elderly patients who undergo PCI for ACS have acceptable survival outcomes. STEMI, diabetes and impaired renal function were predictive of mortality in this elderly cohort.

Background The purpose of the present study was to investigate the effectiveness of using the computed tomography (CT) capsular sign with lipohemarthrosis of the hip joint as a selective indicator for preoperative magnetic resonance imaging (MRI) of the hip or prophylactic fixation of the ipsilateral femoral neck for the prevention of unplanned surgery due to delayed diagnosis of occult ipsilateral femoral neck fractures in patients with high-energy femoral shaft fractures. Methods We evaluated the CT capsular sign with lipohemarthrosis in patients with a high-energy femoral shaft fracture without a preoperative diagnosis of an ipsilateral femoral neck fracture. The CT capsular sign with lipohemarthrosis was considered positive when the side-to-side difference in anterior capsular distension was >1 mm and lipohemarthrosis was seen on soft-tissue-window CT images. A positive CT capsular sign with lipohemarthrosis prompts preoperative hip MRI or prophylactic femoral neck fixation with a reconstruction nail. Results One hundred and fifty-six consecutive patients were included. Eight patients were preoperatively diagnosed with a displaced or hairline ipsilateral femoral neck fracture, whereas the remaining 148 patients showed no ipsilateral femoral neck fracture on radiographs and bone-window CT images. On soft-tissue-window CT images, 29 (19.6%) of the 148 patients had a positive CT capsular sign with lipohemarthrosis. We performed preoperative MRI for 3 patients; in the remaining 26 patients, prophylactic femoral neck fixation was performed with a reconstruction nail. We identified 5 occult ipsilateral femoral neck fractures among the 29 patients with a positive sign: 2 on preoperative MRI scans, 2 on immediate postoperative radiographs, and 1 on radiographs made 6 weeks postoperatively. In 119 patients with a negative sign, no occult ipsilateral femoral neck fracture was identified. All occult ipsilateral femoral neck fractures healed without further displacement of the femoral neck. Consequently, additional unplanned surgery for delayed diagnosis of occult ipsilateral femoral neck fracture was not required. Conclusions The use of the CT capsular sign with lipohemarthrosis as a selective indicator for preoperative hip MRI or prophylactic femoral neck fixation with a reconstruction nail in patients with high-energy femoral shaft fractures is effective for preventing unplanned surgery due to delayed diagnosis of occult ipsilateral femoral neck fractures. Level of evidence Diagnostic Level I. See Instructions for Authors for a complete description of levels of evidence.

Hypoxia regulates fibroblast function by changing intracellular signaling and secretion factors, that influence the states of nearby cells. In this work, we investigated how medium (CM) from human adult dermal fibroblasts (HDFs) cultured in normoxic and hypoxic conditions affected cervical cancer (HeLa) cells. The HeLa cells showed decreased cell viability, increased apoptosis, and cell cycle arrest in response to CM from hypoxic-cultured HDFs (H-CM) compared with CM from normoxic-cultured HDFs (N-CM). Among the proteins up-regulated (>2-fold) in H-CM compared with N-CM, lymphotoxin-beta receptor (LTBR) decreased the viability of HeLa cells. Among the intracellular proteins down-regulated (>2-fold) in HeLa cells treated with H-CM compared with N-CM, the most enriched biological process GO term and KEGG pathway were protein deubiquitination and hsa05166:HTLV-I infection, respectively. In the protein–protein interaction network of intracellular proteins with altered expression (>2-fold), 1 up-regulated (TNF) and 8 down-regulated (ESR1, MCL1, TBP, CD19, LCK, PCNA, CHEK1, and POLA1) hub proteins were defined. Among the down-regulated hub proteins, the most enriched biological process GO term and KEGG pathway were leading strand elongation and hsa05166:HTLV-I infection, respectively. This study reveals that H-CM had stronger anti-cancer effects on cervical cancer cells than N-CM and induced intracellular signaling patterns related to those enhanced anti-cancer effects.

Aim We scrutinised the computed tomography (CT) capsular sign, which refers to the anterior capsular distension of the hip, to determine whether we can use it as an additional clue for detecting occult ipsilateral femoral neck fracture (IFNF) before operation. Patients and Methods We retrospectively examined 79 patients who suffered high-energy femoral shaft fracture and were evaluated with preoperative CT for occult IFNF. The occult IFNF was defined as a fracture that was not diagnosed confirmatively during preoperative evaluation. Thirteen patients were included in the occult IFNF group and 66 were included in the femoral neck intact group. A side-to-side difference of more than 1 mm of capsular distension was considered a positive CT capsular sign. Results Among 13 patients in the occult IFNF group, 6 had a hairline fracture (bony window images) and 12 had a positive CT capsular sign (soft tissue window images) on preoperative CT scans. The presence of IFNF was more significantly associated with the CT capsular sign than with the hairline fracture (p = 0.031). Among the 66 patients in the femoral neck intact group, the CT capsular sign was false positive in 4. Conclusion The CT capsular sign can be used to detect the presence of occult IFNF in high-energy trauma patients with femoral shaft fractures. During the preoperative evaluation of IFNF, surgeons must pay extra attention to the presence of occult IFNF when the CT capsular sign is positive.

Background: Developing personalized strategies for cancer has shown good efficacies. Methods: We assessed the molecular targets programmed death ligand 1 (PD-L1), microsatellite instability (MSI), and PIK3CA. Seventy-four patients with liposarcomas who underwent curative resection were assessed for PD-L1 expression in the tumor and tumor-infiltrating lymphocytes (TILs), mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6) by immunohistochemistry, MSI using polymerase chain reaction, and PIK3CA mutation/amplification using pyrosequencing and fluorescence in situ hybridization. Results: Seventeen (23%) cases were TIL+ (≥1 + expression) and associated with longer 5-year overall survival than those with TIL– tumors (84.4 vs. 60.8%, p = 0.007). Six (35.3%) PD-L1+ tumors were detected only in TIL+ cases, with none detected in tumor cells. Two well-differentiated liposarcomas showed MSI, one low and one high with concurrent loss of MLH1, MSH6, and PMS2. PIK3CA mutation was detected in 7 (9.5%) [exon 9 (n = 4) and exon 20 (n = 3)] and only 1 Q546K mutation was a PD-L1+ tumor. PIK3CA copy number gain was detected in 18 (24.4%) and was associated with TIL+ tumors (p = 0.045). Conclusions: Our comprehensive immuno-molecular panel suggests that liposarcoma should be categorized based on the molecular genomic subtype for precision medicine.

Unstable fracture-dislocation of the ankle is a common lower-extremity injury. Treatment is challenging when the fracture-dislocation is open and cannot be treated with conventional open reduction and internal fixation (ORIF). Immediate ORIF may not be possible for severe, unstable ankle injuries, such as those with ischemic foot because of a poor blood supply caused by soft-tissue injury, or open fracture-dislocation of the ankle with a deltoid ligament rupture. We describe a staged treatment for unstable open fracture-dislocation of the ankle with a deltoid ligament rupture. The first stage involves temporary vertical transarticular pinning combined with external fixation. The second stage involves delayed definitive plating with autogenous bone graft for the bone defect of the distal fibula. This staged management is useful in select emergency cases of unstable open fracture-dislocations of the ankle combined with deltoid ligament rupture for which conventional ORIF cannot be performed.

Rationale: Emphysematous pancreatitis, a rare complication of acute necrotizing pancreatitis with a high mortality rate, is associated with gas-forming bacteria. When using the step-up approach for treating emphysematous pancreatitis, it is preferable to delay drainage interventions for 4 weeks. However, percutaneous drainage may be necessary, even in the early phase of acute pancreatitis, for a patient whose sepsis deteriorates despite optimal medical management. Percutaneous drainage can then be followed by endoscopic necrosectomy through the percutaneous tract. Patient concerns: A 52-year-old man was transferred to our hospital for treatment of sepsis and multiorgan failure associated with emphysematous pancreatitis. Diagnosis: An abdominal computed tomography scan had shown pancreatic and peripancreatic necrosis, along with extensive gas bubbles. Interventions: Despite optimal medical management, the patient's condition continued to deteriorate, and it became necessary to insert 2 percutaneous catheter drainages (PCDs), even though the patient was still in the early phase of pancreatitis. Each PCD was upsized and irrigated with sterile saline by an interventional radiologist twice a week. The infected necrosis around the tail of the pancreas was completely resolved after PCD. However, PCD through the transperitoneal route did not resolve necrosis around the pancreatic head. Following the PCDs, percutaneous pancreatic necrosectomy using an ultra-slim upper endoscope was performed, after which the patient recovered quickly and was discharged. Outcomes: Follow-up computed tomography was performed 12 weeks after the patient was discharged, and it showed complete resolution of the walled-off necrosis. The patient's condition improved without any fluid collection or complications. Lessons: PCD can be used in the early phase of emphysematous pancreatitis for patients who continue to deteriorate due to sepsis. This can easily be followed, if necessary, by percutaneous pancreatic necrosectomy using an ultra-slim endoscope.

Public interventions have shown to optimize the use of antibiotics in children with acute otitis media (AOM). In this study, we describe the AOM-related antibiotic use among children in South Korea using national cohort data. We retrieved the Health Insurance Review & Assessment Service data to construct a national cohort of children aged 0–6 years who had been diagnosed with AOM between 2012 and 2018. Of 25,212,264 children included, the antibiotic prescription has increased for amoxicillin/amoxicillin-clavulanate from 56.1% in 2012 to 61.8% in 2018. Prescription has decreased for cephalosporin (35.1% in 2012 to 31.8% in 2018) and macrolide (8.7% in 2012 to 6.4% in 2018). National cohort data have shown an increased trend in AOM-related aminopenicillin prescription and downward trend cephalosporin and macrolide use in South Korea. A multi-faceted approach is required to control the antimicrobial resistance at a population level., Graphical Abstract

Hemosuccus pancreaticus (HP) is a rare cause of gastrointestinal bleeding that sometimes leads to life-threatening conditions. However, the diagnosis of HP is often delayed due to its rarity and intermittent signs of bleeding, making it challenging to determine the source of bleeding in some patients.An 83-years-old man was transferred to our hospital for evaluation of the source of intermittent upper gastrointestinal bleeding involving melena and worsening anemia.HP was diagnosed via endoscopic retrograde cholangiopancreatography (ERCP) and sequential angiography using a multidisciplinary approach.Initial upper and lower gastrointestinal endoscopies did not reveal any source of bleeding. Emergency upper endoscopy performed when the patient had hematochezia and hypotension confirmed a spurt of bleeding from the major duodenal papilla. However, contrast-enhanced computed tomography and angiography could not identify the source of the bleeding from the major duodenal papilla. ERCP for inducing bleeding from the source and indicating the bleeding point was performed according to the decision of the multidisciplinary team. Immediately thereafter, sequential angiography was performed and HP, due to the rupture of a pseudoaneurysm of the splenic artery, was diagnosed. As a result, surgical resection of the pancreas could be avoided by accurately embolizing the bleeding focus of HP using a multidisciplinary team approach.The patient was discharged in a hemodynamically stable condition. There was no further gastrointestinal bleeding or procedure-related complication until 6 months after discharge.HP should be considered by endoscopists during the differential diagnosis of intermittent upper gastrointestinal bleeding in patients with a history of pancreatitis. A multidisciplinary team approach is an effective method to determine the source or location of bleeding, which may reduce mortality and morbidity by avoiding additional pancreatectomies.

The purpose of this study is to compare the acetabular teardrop (the structure located inferomedially in the acetabulum, just superior to the obturator foramen. The medial lip is the interior, and the lateral lip is the exterior of the acetabular wall) with the inferior acetabular rim as anatomical landmarks to measure the acetabular abduction angle (AAD) using coronal CT images from different levels. Our retrospective study included 120 pelvic CT scans from patients with non-orthopedic pathologies or stress fractures of the proximal femur. The patients included 60 females with a mean age of 48 years (range 40–66) and 60 males with a mean age of 46 years (range 38–65). Each AAD was measured using coronal plane CT slices from five levels: AAD (+ 10) (10 mm anterior to the femoral head center), AAD (+ 5) (5 mm anterior to the femoral head center), AAD (0) (through the femoral head center), AAD (− 5) (5 mm posterior to the femoral head center), and AAD (− 10) (10 mm posterior to the femoral head center). The measurements were then divided into two groups: teardrop-based AADs [AAD (+ 10), AAD (+ 5), and AAD (0)] and rim-based AADs [AAD (− 5) and AAD (− 10)]. There were no mean significant differences in AAD within the groups, whereas the difference between the groups was significant. The mean teardrop-based AAD was quite significantly different from the mean rim-based AAD due to the use of different anatomical landmarks. Teardrop-based AADs are lower than rim-based AADs, leading to measurement differences of more than 10°. AAD measurements considering the inferior acetabular rim can be more accurate than those considering the acetabular teardrop because the inferior rim represents the nearly hemispheric acetabulum better than does the teardrop. It is recommended to differentiate between the teardrop and the inferior acetabular rim when measuring AAD to avoid confusion regarding acetabular abduction.

Enhancing gait stability in people who use crutches is paramount for their health. With the significant difference in gait compared to users who do not require an assistive device, the use of standard gait analysis tools to measure movement for temporary crush users and physically disabled people proves to be more challenging. In this paper, a novel approach based on video analysis is proposed as non-contact low-cost solution to the more expensive alternative with the data collected from processed videos, two values are calculated: the Signal to Noise Ratio (SNR) of acceleration, and the Signal to Noise Ratio of the jerk (time derivative of acceleration), to assess the user’s stability while they walk with crutches. The adopted methodology has been tested on a total of 10 participants. Five are temporary users of assistive devices with one being a long-term user and the other four novice users, and five are disabled participants who use those assistive devices permanently. Preliminary results show differences between novice users, long-term users, and physically disabled users. The approach is promising and could improve the assessment of crutch user stability, allowing for the correction of gait for individuals while using an inexpensive non-contact setup and preventing unnecessary falls.

Using a microsimulation model, the impact of increased diagnosis and treatment of postmenopausal women with osteoporosis on anticipated reduction in fractures and associated costs in South Korea from 2020 to 2040 was projected.The economic burden of osteoporosis was US $5.1B in 2011 in South Korea. Osteoporosis is expected to strain resources in South Korea as the population most susceptible to osteoporotic fracture, females 50 years old, is projected to increase by 32% from 2020 to 2040.A microsimulation model was developed to project annual incidence and costs of osteoporotic fractures among postmenopausal women from 2020 to 2040. Fracture risk was estimated using the simplified Fracture Risk Assessment Tool (FRAX). The fracture estimates were based on annualized FRAX risk and impact of treatment. Korean National Health Insurance data informed treatment and case-finding rates in the reference case. Two scenarios were evaluated: 50% increases to (i) case finding (screening rate and subsequent treatment rate) and (ii) treatment rate among those at highest risk.Among individuals modeled in the reference case from 2020 to 2040, 41.2 M fractures at a cost of US $263.6B were projected. Increased treatment scenario prevented 4.4 M fractures and saved US $13.5B. Increased case-finding scenario prevented 4.0 M fractures and saved US $11.1B.Implementation of policies to enable increasing case finding or treatment may result in fewer fractures and substantial cost savings across the healthcare system. These results highlight the importance of early screening, diagnosis, and preventive treatment.

Rationale: Autosomal dominant type II (AD II) osteopetrosis is a rare inheritable metabolic bone disease characterized by hard but brittle bone and a narrow medullary canal. Intramedullary nailing (IMN) is a difficult but attractive option for the treatment of subtrochanteric fractures in patients with AD II osteopetrosis. Patient concerns and diagnosis: Two patients with AD II osteopetrosis sustained subtrochanteric fractures after a fall. Interventions: IMN was performed through the sequential use of instruments such as a 4.9-mm drill bit, small reamer, and larger reamer for over-reaming. Outcomes: In the first case, IMN left some gap at the fracture site. Dynamization was performed to treat the delayed union at 6 months postoperatively. The fracture healed at 10 months after the dynamization. In the second case, IMN was successful without a gap, and the fracture healed at 8 months. Lessons: Although IMN is difficult to perform owing to partial obliteration of the medullary canal in AD II osteopetrosis, it can be performed with sequential widening of the medullary canal using various instruments. In addition, the fracture gap should not be left uncorrected during IMN to attain fracture union.

Introduction Severe valgus-impacted femoral neck fractures are associated with femoral neck shortening (FNS). However, no study has focused on the effect of reduction for severe valgus impaction in terms of healing and restoration of the femoral neck length. This study aimed to compare FNS and treatment outcomes of in situ fixation and fixation after reduction for severe valgus-impacted femoral neck fractures in patients aged 65 years or younger. Methods This retrospective study included 55 patients who underwent internal fixation with three parallel screws for femoral neck fractures with valgus impaction >15° (AO/OTA classification 31-B1.1) between January 2006 and December 2018. Twenty-eight and 27 patients underwent in situ fixation (in situ group) and fixation after reduction (reduction group), respectively. In the reduction group, reduction using lateral traction with a Schanz pin was performed before internal fixation. Complications such as fixation failure, non-union, and avascular necrosis (AVN), caput-collum-diaphysis (CCD) angle, posterior tilt angle, amount of FNS, and Harris Hip Score (HHS) were compared between the groups. Results Bone union was achieved in all patients; AVN occurred in two patients in each group. No significant difference was seen in the preoperative characteristics between the groups. The CCD angle at 1 year postoperatively was significantly different between the groups, whereas the posterior tilt angle at 1 year postoperatively was not different. FNS at 1 year postoperatively was significantly lower in the reduction group than in the in situ group. FNS by >5 mm was significantly less frequent in the reduction group than in the in situ group (11% versus 75%). The mean HHS at 1 year and 2 years postoperatively was significantly higher in the reduction group than in the in situ group. FNS and HHS were negatively correlated; the mean HHS was significantly higher in patients with none/mild shortening ( Conclusion In patients aged 65 years or younger, internal fixation after reduction for severe valgus-impacted femoral neck fractures is safe and effective for achieving successful bone union and restoring the femoral neck length.

Background Despite many reports on the diagnostic yield of cytology from endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA), inter-slide differences are unknown. This prospective study aimed to compare diagnostic yield and cellular characteristics of bottom slides (BS) and top slides (TS) from EUS-FNA cytology performed without an on-site cytopathologist. Methods In patients with suspected pancreatic cancer on previous imaging explorations, a single endoscopist performed EUS-FNA and obtained 2 sets of cytology slide (8 BS and 8 TS), 1 cellblock slide, and 1 biopsy slide. Both slide sets were randomly assigned. A cytopathologist with more than 10 years of expertise in pancreatic cytopathology blindly inspected and compared two slide sets. Results In total, 73 specimens [42 head (57.5%), 16 body (21.9%), and 15 tail (20.5%)] were acquired for final analysis. Seventy-one cases were finally diagnosed with pancreatic cancer. The sensitivity and specificity of BS were 80.3% and 100.0%; and of TS 78.9% and 100.0%, respectively. In analyzing inter-slide difference, 66 cases (90.4%) showed consistent results between BS and TS. However, seven (9.6%) were positive only in one slide sets (4 BS and 3 TS). The proportions of specimens more than moderate and high cellularity were 75.3% and 60.3% in both slide sets (P> 0.99), and the proportion of artifact-free sets were 50.7%, and 52.1% for the BS and TS, respectively (P= 0.869). Conclusions Although BS and TS exhibited highly consistent diagnostic yields in cytologic smears from EUS-FNA, the proportion of inter-slide discordance is clinically considerable. Both slide sets need to be examined if there is no on-site cytopathologist.

PURPOSE Melanoma is a highly heterogeneous neoplasm, composed of subpopulations of tumor cells with distinct molecular and biological phenotypes and genotypes. In this study, to determine the genetic heterogeneity between primary and metastatic melanoma in Korean melanoma patients, we evaluated several well-known genetic alterations of melanoma. In addition, to elucidate the clinical relevance of each genetic alteration and heterogeneity between primary and metastatic lesions, clinical features and patient outcome were collected. Materials and Methods In addition to clinical data, BRAF, NRAS, GNAQ/11 mutation and KIT amplification data was acquired from an archived primary Korean melanoma cohort (KMC) of 188 patients. Among these patients, 43 patients were included for investigation of tumor heterogeneity between primary melanoma and its corresponding metastatic lesions. RESULTS Overall incidence of genetic aberrations of the primary melanomas in KMC was 17.6% of BRAF V600, 12.6% of NRAS mutation, and 28.6% of KIT amplification. GNAQ/11 mutation was seen in 66.6% of the uveal melanoma patients. Patients with BRAF mutation were associated with advanced stage and correlated to poor prognosis (p < 0.01). Among 43 patients, 55.8% showed heterogeneity between primary and metastatic lesion. The frequency of BRAF mutation and KIT amplification significantly increased in the metastatic lesions compared to primary melanomas.

Patient-reported outcomes (PROs) provide practical guides for treatment; however, studies that have evaluated PROs of women in Korea with postmenopausal osteoporosis (PMO) are lacking. This cross-sectional, multi-center (29 nationwide hospitals) study, performed from March 2013 to July 2014, aimed to assess PROs related to treatment satisfaction, medication adherence, and quality of life (QoL) in Korean PMO women using osteoporosis medication for prevention/treatment. Patient demographics, clinical characteristics, treatment patterns, PROs, and experience using medication were collected. The 14-item Treatment Satisfaction Questionnaire for Medication (TSQM) (score-range, 0-100; domains: effectiveness, side effects, convenience, global satisfaction), Osteoporosis-Specific Morisky Medication Adherence Scale (OS-MMAS) (score-range, 0-8), and EuroQol-5 dimensions questionnaire (index score range, - 0.22 to 1.0; EuroQol visual analog scale score range, 0-100) were used. To investigate factors associated with PROs, linear (treatment satisfaction/QoL) or logistic (medication adherence) regression analyses were conducted. A total of 1804 patients (age, 62 years) were investigated; 60.1% used bisphosphonate, with the majority (67.2%) using weekly medication, 27.8% used daily hormone replacement therapy, and 12.1% used daily selective estrogen receptor modulator. Several patients reported gastrointestinal (GI) events (31.6%) and dental visits due to problems (24.1%) while using medication. Factors associated with the highest OS-MMAS domain scores were convenience and global satisfaction. GI events were associated with non-adherence. TSQM scores for effectiveness, side effects, and GI risk factors were significantly associated with QoL. Our study elaborately assessed the factors associated with PROs of Korean PMO women. Based on our findings, appropriate treatment-related adjustments such as frequency/choice of medications and GI risk management may improve PROs.

BACKGROUND To assess the association between HLA-B57.01 (Human leukocyte antigen) and clinical parameters of chronic periodontitis in people living with HIV (PLWHIV). METHODS All patients were recruited from the HIVCENTER at the University Hospital Frankfurt during April 2014 and July 2015. Periodontal examination included Periodontal Screening Index (PSI), Gingivalindex (GI), Bleeding on Probing Index (BOP), Periodontal Probing Depth (PD), Clinical Attachment Level (CAL) and DMF-T Score (decayed, missing, filled teeth). Associations among periodontitis, HLA-system and additional risk factors in PLWHIV were evaluated in multivariate analyses. RESULTS One hundred PLWHIV were enrolled. Forty-five patients were naive, meaning that these patients never took antiretroviral (ARV) drugs before, 55 patients treated with combined antiretroviral therapy (cART). Nineteen patients presented a positive HLA-B 57.01 status. PLWHIV who were carriers of HLA-B 57.01 had significantly lower PSI-scores (Grade 3 or higher; 0/19 [0%] versus 16/41 [39%] versus 17/40 [42%]; p =

BACKGROUND Intramedullary nailing is the treatment of choice for atypical femoral fractures. However, several problems, such as iatrogenic fracture and medial gap opening, can occur during intramedullary nailing when atypical femoral fractures are associated with excessive anterolateral bowing. To overcome these problems, we have developed a new grading system for anterolateral femoral bowing and a new technique for intramedullary nailing. The core of this new technique is matching the anterior curvature of the femoral nail with the anterolateral bowing of the femur when the nail passes the apex of the curvature, by rotating the nail externally. METHODS From January 2005 through March 2016, 24 female patients (30 cases) who underwent a surgical procedure for atypical femoral fracture with anterolateral bowing at 2 institutes were evaluated. The postoperative outcomes (anterolateral bowing grade, anterior and lateral bowing angles, medial gap and posterior gap of the fracture site, iatrogenic fracture, and time to initial medial callus formation and osseous union) were compared between the new technique (18 cases) and the conventional technique (12 cases). RESULTS With regard to the reliability of the new grading system, the interobserver and intraobserver reliability of the new grading system demonstrated an almost perfect agreement (kappainter = 0.893, kappaintra = 0.883). For patients with complete fractures, the differences between the preoperative and postoperative anterior and lateral bowing angles were significantly less (p = 0.013 for both) in the new technique group. The medial and posterior gaps at the fracture site were also significantly less in the new technique group (p = 0.013 for the medial gaps and p = 0.022 for the posterior gaps). Iatrogenic fracture occurred only in the conventional technique group, affecting 2 cases. The time to initial medial callus formation was significantly shorter (p = 0.033) in the new technique group compared with the conventional technique group. CONCLUSIONS Our new grading system for anterolateral femoral bowing is convenient and reliable. Furthermore, the new intramedullary nailing technique with the current intramedullary nail system is appropriate for the repair of atypical femoral fractures with excessive anterolateral bowing. LEVEL OF EVIDENCE Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Background FOLFIRINOX has increased efficacy but also toxicity. Despite various modified FOLFIRINOX regimens, how much reduction is acceptable remains unclear. This study aimed to find the optimal relative dose intensity (RDI, %) of FOLFIRINOX that preserves tumour responses in patients with advanced pancreatic cancer (PC). Methods We reviewed 201 patients with PC treated with first-line FOLFIRINOX during 2012–2015. We established a modified Hryniuk model ( http://www.rdicalc.com ) and defined cumulative RDI (cRDI, %). The optimal cRDI thresholds for response rate (RR) and disease control rate (DCR) were assessed using receiver operating characteristic (ROC) analysis. Relationships between cRDI and haematologic toxicities (neutropenia and febrile neutropenia [FN]) were also analysed according to use of granulocyte colony-stimulating factor (G-CSF). Results Among 156 eligible patients, 133 (48 locally advanced PC and 85 metastatic PC) completed initial treatment plan prior to the first radiological evaluation (median 58 days; 71.8% cRDI). For optimal cRDI thresholds, ROC curves showed a 71.2% cRDI for RR (83.3% sensitivity, 64.7% specificity, and 0.746 area under the curve [AUC]) and a 55.3% cRDI for DCR (93.6% sensitivity, 62.5% specificity and 0.805 AUC). Among 96 patients who did not receive prophylactic G-CSF, cRDI ≥80.1% was a significant predictor for frequent FN (73.7% sensitivity, 72.7% specificity and 0.793 AUC). There was no correlation between cRDI and haematologic toxicities in patients receiving prophylactic G-CSF. Conclusion To preserve optimal RR and DCR in advanced PC, cRDI values for FOLFIRINOX >70% and >55%, respectively, are recommended. If cRDI is >80%, primary G-CSF prophylaxis is needed.

Background and Aims Endoscopic ultrasound-guided gallbladder drainage (EUS-GBD) has been proposed as an alternative management strategy for acute cholecystitis caused by malignant cystic duct obstruction in patients for whom surgery is not an option. This study aimed to compare the results of EUS-GBD with those of percutaneous transhepatic gallbladder drainage (PTGBD) for palliative management of malignant cystic duct obstruction with acute cholecystitis or symptomatic gallbladder hydrops. Methods Between November 2013 and November 2015, 14 patients with acute cholecystitis or symptomatic gallbladder hydrops as a result of malignant cystic duct obstruction underwent EUS-GBD with covered metal stents. Nineteen patients with acute cholecystitis as a result of malignant cystic duct obstruction who received PTGBD served as a control group. Patients' medical records were reviewed retrospectively. Results The technical and clinical success rates of EUS-GBD were 85.7% (12/14) and 91.7% (11/12) and of PTGBD were 100% (19/19) and 86.4% (17/19), respectively. The groups had similar adverse event rates (28.5% and 21.1%, respectively). The average duration of stent patency in patients with EUS-GBD was 130.3 ± 35.3 days, and no patient required an additional procedure before death. In 6 of 17 patients (35.3%) with clinically successful PTGBD, the catheter was not removed until the end stage of life. Conclusions EUS-GBD is a feasible, safe, and effective modality for the treatment of malignant cystic duct obstruction in patients who are not indicated for surgery. It enables improved long-term quality of life in patients with advanced-stage cancer.

Background: Odanacatib, a cathepsin K inhibitor, reduces bone resorption while maintaining bone formation. Previous work has shown that odanacatib increases bone mineral density in postmenopausal women with low bone mass. We aimed to investigate the efficacy and safety of odanacatib to reduce fracture risk in postmenopausal women with osteoporosis. Methods: The Long-term Odanacatib Fracture Trial (LOFT) was a multicentre, randomised, double-blind, placebo-controlled, event-driven study at 388 outpatient clinics in 40 countries. Eligible participants were women aged at least 65 years who were postmenopausal for 5 years or more, with a femoral neck or total hip bone mineral density T-score between −2·5 and −4·0 if no previous radiographic vertebral fracture, or between −1·5 and −4·0 with a previous vertebral fracture. Women with a previous hip fracture, more than one vertebral fracture, or a T-score of less than −4·0 at the total hip or femoral neck were not eligible unless they were unable or unwilling to use approved osteoporosis treatment. Participants were randomly assigned (1:1) to either oral odanacatib (50 mg once per week) or matching placebo. Randomisation was done using an interactive voice recognition system after stratification for previous radiographic vertebral fracture, and treatment was masked to study participants, investigators and their staff, and sponsor personnel. If the study completed before 5 years of double-blind treatment, consenting participants could enrol in a double-blind extension study (LOFT Extension), continuing their original treatment assignment for up to 5 years from randomisation. Primary endpoints were incidence of vertebral fractures as assessed using radiographs collected at baseline, 6 and 12 months, yearly, and at final study visit in participants for whom evaluable radiograph images were available at baseline and at least one other timepoint, and hip and non-vertebral fractures adjudicated as being a result of osteoporosis as assessed by clinical history and radiograph. Safety was assessed in participants who received at least one dose of study drug. The adjudicated cardiovascular safety endpoints were a composite of cardiovascular death, myocardial infarction, or stroke, and new-onset atrial fibrillation or flutter. Individual cardiovascular endpoints and death were also assessed. LOFT and LOFT Extension are registered with ClinicalTrials.gov (number NCT00529373) and the European Clinical Trials Database (EudraCT number 2007-002693-66). Findings: Between Sept 14, 2007, and Nov 17, 2009, we randomly assigned 16 071 evaluable patients to treatment: 8043 to odanacatib and 8028 to placebo. After a median follow-up of 36·5 months (IQR 34·43–40·15) 4297 women assigned to odanacatib and 3960 assigned to placebo enrolled in LOFT Extension (total median follow-up 47·6 months, IQR 35·45–60·06). In LOFT, cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 3·7% (251/6770) versus 7·8% (542/6910), hazard ratio (HR) 0·46, 95% CI 0·40–0·53; hip fractures 0·8% (65/8043) versus 1·6% (125/8028), 0·53, 0·39–0·71; non-vertebral fractures 5·1% (412/8043) versus 6·7% (541/8028), 0·77, 0·68–0·87; all p

Objective: Delirium is an acute brain failure related to uncertain problems in neural connectivity, including aberrant functional interactions between remote cortical regions. This study aimed to elucidate the underlying neural mechanisms of delirium by clarifying the changes in resting-state functional connectivity induced by postoperative delirium using imaging data scanned before and after surgery. Method: Fifty-eight patients with a femoral neck fracture were preoperatively scanned using resting-state functional magnetic resonance imaging. Twenty-five patients developed postoperative delirium, and 14 of those had follow-up scans during delirium. Eighteen patients without delirium completed follow-up scans 5 or 6 days after surgery. We assessed group differences in voxel-based connectivity, in which the seeds were the posterior cingulate cortex, medial prefrontal cortex and 11 subcortical regions. Connections between the subcortical regions were also examined. Results: The results showed four major findings during delirium. Both the posterior cingulate cortex and medial prefrontal cortex were strongly connected to the dorsolateral prefrontal cortex. The posterior cingulate cortex had hyperconnectivity with the inferior parietal lobule, whereas the medial prefrontal cortex had hyperconnectivity with the frontopolar cortex and hypoconnectivity with the superior frontal gyrus. Connectivity of the striatum with the anterior cingulate cortex and insula was increased. Disconnections were found between the lower subcortical regions including the neurotransmitter origins and the striatum/thalamus in the upper level. Conclusions: Our findings suggest that cortical dysfunction during delirium is characterized by a diminution of the anticorrelation between the default mode network and task-positive regions, excessive internal connections in the posterior default mode network and a complex imbalance of internal connectivity in the anterior default mode network. These dysfunctions can be attributed to the loss of reciprocity between the default mode network and central executive network associated with defective function in the salience network, which might be closely linked to aberrant subcortical neurotransmission-related connectivity and striato-cortical connectivity.

The aim of our study was to identify the risk factors for avascular necrosis of the femoral head (AVN) and fixation failure (FF) after screw osteosynthesis in patients with valgus angulated femoral neck fractures.We conducted a retrospective study of 308 patients (mean age, 72.5 years, range, 50-97 years), with a mean follow-up of 21.4 months (range, 12-64 months). The risk for failure in treatment (FIT) associated with patient- and fracture-related factors was evaluated by logistic regression analyses.FIT was identified in 32 cases (10.3%): 22 cases (7.1%) of AVN and 10 cases (3.2%) of FF. Initial valgus tilt15° (p=0.023), posterior tilt15° (p=0.012), and screw sliding distance (p=0.037) were significantly associated with FIT. FIT occurred in 7 patients (5.2%) with B1.2.1 fractures and 17 patients (48.6%) with B1.1.2 fractures (p0.001). The odds of FIT were 17-fold higher in patients with initial valgus and posterior tilts15° (B1.1.2) compared to patients with15° of tilt in both planes (B1.2.1).The severity of initial deformity predicts AVN and FF in patients with valgus angulated femoral neck fractures. Patients with an initial valgus and posterior tilt15° are reasonable candidates for primary arthroplasty due to high risk of FIT.

An entrapment of the femoral artery by cerclage wiring is a rare complication after spiral diaphyseal femoral fractures. We report the case of an 82-year-old female treated by an antegrade intramedullary nailing and multiple cable augmentation, which was then complicated by injury to the femoral artery that resulted in ipsilateral leg necrosis and amputation. The entrapment was caused by direct belting by the cable and resulted in a total obstruction of the femoral artery.

The treatment of a large segmental defect of over 6 cm in a long bone is a challenging procedure. Treatment options include cancellous bone graft (e.g., the Masquelet technique), vascularized fibular graft (VFG), and internal bone transport (IBT) with an external fixator. These methods may be performed with intramedullary (IM) nailing or plate fixation to enhance stability or to lessen the time of external fixation. Each method has its own advantages and limitations. This study aimed to describe the advantages of additional plate augmentation and autologous bone grafting after IM nail implantation. Three patients with large segmental femoral bone defects were treated with IM nail implantation; then, one- or two-stage autologous iliac bone grafting with additional plate augmentation was performed. All patients achieved bony union without metal failure. We describe a technique involving additional plate augmentation and autologous iliac bone grafting for treating large femoral defects after restoring the length of the femur using an IM nail implantation and an external fixator.

Structural compromise of the tumor suppressor gene, phosphatase and tensin homolog (PTEN), occurs in 10% of melanoma specimens, and loss of PTEN expression through DNA methylation of the PTEN promoter region has also been reported in a number of other malignancies. However, the role of PTEN promoter methylation in melanoma is not well understood. We thus sought to elucidate the prevalence of PTEN promoter methylation in melanoma specimens, its relationship to clinical features, and its impact on the outcome of patients with melanoma. PTEN promoter methylation data were acquired from an archived primary Korean melanoma cohort (KMC) of 158 patients and, for validation, 234 patients from The Cancer Genome Atlas melanoma (TCGA-MEL) cohort. Hierarchical clustering was performed to identify PTEN "high methylated" and "low methylated" samples. Subsequently, differences in clinical features and outcomes based on PTEN promoter methylation status were then analyzed using SPSS and R. In the KMC, all tumors were acquired from primary tumors and 65.7% (n = 105) were acral or mucosal by site, whereas in the TCGA-MEL cohort, 90.5% of the tumors were from regional lymph node and distant metastatic lesions. Overall, 17.7% and 45.7% of the specimens harbored BRAF mutations in the KMC and TCGA-MEL cohort, respectively. Neuroblastoma RAS viral oncogene homolog was mutated in 12.2% and 26.9% of the tumors in the KMC and TCGA-MEL cohort, respectively. In the KMC, 31 cases (19.6%) were included in the high methylated group versus 142 cases (60.7%) in the TCGA-MEL cohort (P0.001). Multivariate Cox-regression analysis revealed promoter methylation of PTEN to be an independent negative prognostic factor for survival in both the KMC (hazard ratio 3.76, 95% confidence interval = 1.24-11.12, P = 0.017) and TCGA-MEL cohort (HR 1.88, 95% confidence interval = 1.13-3.12, P = 0.015). Our results indicate that PTEN promoter methylation is an independent predictor for impaired survival in patients with melanoma.

// Joo Hoon Kim 1, * , Jae Seok Lee 2, * , Eo Jin Kim 2 , Kyu Hyun Park 3 , Ki Hyang Kim 4 , Seong Yoon Yi 5 , Han Seong Kim 6 , Yong Jin Cho 7 , Kyoo-Ho Shin 7 , Joong Bae Ahn 1 , Hyuk Hu 8 , Kyung Sik Kim 8 , Young Deuk Choi 9 , Sunghoon Kim 10 , Young Han Lee 11 , Jin-Suck Suh 11 , Sung Hoon Noh 8 , Sun Young Rha 1 , Hyo Song Kim 1 1 Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea 2 Department of Pathology, Dongguk University College of Medicine, Dongguk University Ilsan Hospital, Goyang, Korea 3 Cancer Metastasis Research Center, Song Dang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Korea 4 Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea 5 Department of Internal Medicine, Ilsan Paik Hospital, Inje University College of Medicine, Ilsan, Korea 6 Department of Pathology, Ilsan Paik Hospital, Inje University College of Medicine, Ilsan, Korea 7 Department of Orthopedic Surgery, Yonsei University College of Medicine, Seoul, Korea 8 Department of Surgery, Yonsei University College of Medicine, Seoul, Korea 9 Department of Urology, Yonsei University College of Medicine, Seoul, Korea 10 Department of Obstetrics and Gynecology, Yonsei University College of Medicine, Seoul, Korea 11 Department of Radiology, Yonsei University College of Medicine, Seoul, Korea * These authors have contributed equally to this work Correspondence to: Sun Young Rha, e-mail: rha7655@yuhs.ac Hyo Song Kim, e-mail: hyosong77@yuhs.ac Keywords: liposarcoma, PIK3CA, amplification, mutation Received: January 05, 2016 Accepted: March 02, 2016 Published: March 21, 2016 ABSTRACT Background: We investigated the epidemiologic characteristics and prognostic significance of PIK3CA mutations/amplifications in curative resected liposarcoma. Patients and methods: A total of 125 liposarcoma tissue samples were collected over a 12-year period. PIK3CA mutations and gene copy number amplifications were analyzed by pyrosequencing and fluorescence in situ hybridization (FISH). Results: Nine of the 105 liposarcomas (8.6%) had activating PIK3CA mutation. PIK3CA mutations were more frequent in myxoid/round cell and pleomorphic tumors compared with well-differentiated/dedifferentiated tumors (13.3% vs. 2.2%, P=0.043). In FISH PIK3CA analysis, copy number gain was detected in 14 of the 101 tumors (13.9%): 11 (10.9%) tumors had increased gene copy number (polysomy) and 3 (3.0%) exhibited gene amplification. In survival analysis, patients with PIK3CA copy number gain had a worse prognosis compared to patients without PIK3CA amplification (median disease-free survival [DFS] 22.2 vs. 107.6 months p=0.005). By multivariate analysis, PIK3CA copy number gain was an independent prognostic factor for worse DFS (P=0.027; hazard ratio, 2.400; 95% confidence interval 1.105 to 5.213). PIK3CA mutation was not associated with DFS and overall survival. Conclusions: We demonstrated PIK3CA mutation and amplification in liposarcoma. PIK3CA copy number gain was an independent poor prognostic factor for DFS. Further studies are needed to evaluate the potential diagnostic and therapeutic role of PIK3CA mutations and amplifications in liposarcoma.

Background/Aims: For the suspected choledocholithiasis, the American Society for Gastrointestinal Endoscopy has proposed guidelines to assign risk based on clinical predictors. The study aimed to assess the usefulness of clinical predictors of choledocholithiasis set forth by the guidelines in patients with intermediate risk of choledocholithiasis. Methods: In 2014, 109 patients with intermediate risk of choledocholithiasis underwent endoscopic ultrasound. Their medical records were retrospectively reviewed. The gold standard for choledocholithiasis was endoscopic retrograde cholangiopancreatography or clinical follow-up. Results: Based on endoscopic ultrasound findings, choledocholithiasis was suspected in 18 patients, and it was removed in 17 patients. Choledocholithiasis was absent in the remaining 91 who did not show any signs from endoscopic ultrasound. Among the 2 strong (common bile duct (CBD) diameter >6 mm and bilirubin 1.8-4 mg/dl) and 3 moderate (abnormal liver biochemical test other than bilirubin, age >55 years and gallstone pancreatitis) clinical predictors, 28.8% of patients with one of the strong predictors had choledocholithiasis; however, only 3.5% of patients with any one of the moderate predictors had choledocholithiasis. As a result, only strong clinical predictors showed predictability: increased bilirubin level (OR 3.23; 90% CI 0.85-12.28) and dilated CBD diameter (OR 5.83; 90% CI 1.93-17.57). Conclusion: Only strong clinical predictors of choledocholithiasis showed predictability for patients with intermediate risk of choledocholithiasis.

Peritoneal carcinomatosis accompanied by malignant ascites is a major cause of death of advanced gastric cancer (GC). To comprehensively characterize the underlying genomic events involved in GC peritoneal carcinomatosis, we analyzed whole-exome sequences of normal gastric tissues, primary tumors, and malignant ascites from eight GC patients. We identified a unique mutational signature biased toward C-to-A substitutions in malignant ascites. In contrast, the patients who received treatment of adjuvant chemotherapy showed a high rate of C-to-T substitutions along with hypermutation in malignant ascites. Comparative analysis revealed several candidate mutations for GC peritoneal carcinomatosis: recurrent mutations in COL4A6, INTS2, and PTPN13; mutations in druggable genes including TEP1, PRKCD, BRAF, ERBB4, PIK3CA, HDAC9, FYN, FASN, BIRC2, FLT3, ROCK1, CD22, and PIK3C2B; and mutations in metastasis-associated genes including TNFSF12, L1CAM, DIAPH3, ROCK1, TGFBR1, MYO9B, NR4A1, and RHOA. Notably, gene ontology analysis revealed the significant enrichment of mutations in the Rho-ROCK signaling pathway-associated biological processes in malignant ascites. At least four of the eight patients acquired somatic mutations in the Rho-ROCK pathway components, suggesting the possible relevance of this pathway to GC peritoneal carcinomatosis. These results provide a genome-wide molecular understanding of GC peritoneal carcinomatosis and its clinical implications, thereby facilitating the development of effective therapeutics.

A possible mechanism of disrupted circadian rhythms in delirium was identified using resting-state functional connectivity. Thirty-four delirious patients and 38 non-delirious controls were scanned for resting-state functional MRI. Seed-based connectivity of the suprachiasmatic nucleus was compared between the groups. In delirious patients functional connectivity from the circadian clock was increased to the dorsal anterior cingulate cortex and decreased to the posterior cingulate cortex, parahippocampal gyrus, cerebellum, and thalamus. A dysregulation of the default mode network and mental coordination processing areas by the circadian clock may be the underlying pathophysiology of sleep-wake cycle disturbance and symptom fluctuation in delirium.

Implant breakage is a serious complication after cephalomedullary nailing for unstable intertrochanteric fracture. Failure usually occurs at the lag screw hole in the nail body. On the other hand, lag screw failure is extremely rare and occurs around the nail-lag screw junction. We experienced rare mechanical failure of the Intertan nail, which showed breakage at the lag screw hole and failure of the integrated compression screw underneath the main lag screw.

Casein kinase (CK) 2 activation has been implicated in the proliferation of various tumor types and resistance to chemotherapy. We investigated the mechanistic basis for the association between CK2 activation and paclitaxel resistance in a gastric cancer (GC). CK2 expression was evaluated in 59 advanced GC patients treated with paclitaxel as the second-line therapy. The efficacy of a CK2 inhibitor, CX-4945, and paclitaxel was evaluated in GC cell lines and a xenograft model. Patients with high CK2 expression (29/59, 39%) showed lower disease control rates (47.7% vs. 72.3%, p = 0.017) and shorter progression-free survival (2.8 vs. 4.8 months, p = 0.009) than patients with low CK2 expression. CK2 protein expression was associated with sensitivity to paclitaxel in 49 GC cell lines. Combination therapy with CX-4945 and paclitaxel exerted synergistic antiproliferative effects and inhibited the downregulation of phosphatidylinositol 3-kinase/AKT signaling in SNU-1 cells. In the SNU-1 xenograft model, the combination treatment was significantly superior to either single agent, suppressing tumor growth without notable toxicities. These results demonstrated that CK2 activation was related to paclitaxel resistance and that CX-4945 in combination with paclitaxel could be used as a potential treatment for paclitaxel resistance in GC.

OBJECTIVES To determine the effect of interfragmentary appositional (gap-closing) screw fixation in minimally invasive plate osteosynthesis (MIPO) for distal tibial fractures on the clinical and radiologic results. DESIGN Prospective nonrandomized study. SETTING Level I trauma center. PATIENTS Sixty patients who were diagnosed as distal metadiaphyseal oblique or spiral tibial fracture without displaced articular fragment. INTERVENTION Thirty patients (group A) of the 60 patients were treated with MIPO without appositional screw fixation, and the other 30 (group B) were treated with the screw. MAIN OUTCOME MEASUREMENTS Radiologic union, clinical union, clinical functional score [American Orthopaedic Foot and Ankle Society (AOFAS) score], and complications. RESULTS The time for initial callus formation and radiologic union was significantly longer in group A than those in group B (76.8 vs. 58.0 days, P = 0.044; 409 vs. 258.7 days, P = 0.002, respectively). The rate of clinical union during 1 year was significantly higher in group B than in group A (P = 0.0063). Four nonunion patients in group A achieved bone union after placement of an additional bone graft. None of the patients in group B diagnosed with delayed union or nonunion (P < 0.001). None of the patients of both groups had malreduction, skin problems, or infection. Overall, the AOFAS score did not significantly differ between groups A and B (85.4 vs. 87.0, P = 0.43). CONCLUSIONS The use of additional interfragmentary appositional screw fixation in distal tibia MIPO for the fixation of oblique or spiral fracture promoted callus formation and union rate compared with MIPO without appositional screw fixation. LEVEL OF EVIDENCE Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

PURPOSE The purpose of this study is to investigate the prognostic significance of SOX2 gene amplification and expression in patients with American Joint Committee on Cancer stage III lung squamous cell carcinoma (SCC) who underwent surgery followed by adjuvant radiotherapy. MATERIALS AND METHODS Pathological specimens were obtained from 33 patients with stage III lung SCC treated with surgery followed by adjuvant radiotherapy between 1996 and 2008. SOX2 gene amplification and protein expression were analyzed using fluorescent in situ hybridization and immunohistochemistry, respectively. Patients were divided into two groups according to their SOX2 gene amplification and protein expression status. Kaplan-Meier estimates and a Cox proportional hazards model were used to identify the prognostic factors affecting patient survival. RESULTS The median follow-up period for surviving patients was 58 months (range, 5 to 102 months). SOX2 gene amplification was observed in 22 patients and protein overexpression in 26 patients. SOX2 overexpression showed significant association with SOX2 gene amplification (p=0.002). In multivariate analysis, SOX2 overexpression was a significant prognostic factor for overall survival (OS) (hazard ratios [HR], 0.1; 95% confidence interval [CI], 0.002 to 0.5; p=0.005) and disease-free survival (DFS) (HR, 0.15; 95% CI, 0.04 to 0.65; p=0.01). Age (HR, 0.33; 95% CI, 0.11 to 0.98; p=0.046) and total radiation dose (HR, 0.13; 95% CI, 0.02 to 0.7; p=0.02) were the independent prognostic factors for OS and DFS. Patients with SOX2 amplification did not show a longer OS (p=0.95) and DFS (p=0.48). CONCLUSION Our data suggested that SOX2 overexpression could be used as a positive prognostic factor in patients with stage III lung SCC receiving adjuvant radiotherapy.

Cutaneous squamous cell carcinomas and keratoacanthomas commonly occur in patients treated with BRAF inhibitors. We investigated the effect of the BRAF inhibitor vemurafenib on normal immortalized human HaCaT keratinocytes to explore the mechanism of hyperproliferative cutaneous neoplasia associated with the use of BRAF inhibitors. Vemurafenib induced an increase in viable cell number in BRAF wild-type cell lines (SK-MEL-2 and HaCaT) but not in BRAF mutant cell lines (SK-MEL-24 and G361). In HaCaT keratinocytes, a low concentration (2 μmol/L) of vemurafenib increased cell proliferation and activated mitogen-activated protein kinase kinase/extracellular signal-regulated kinase in a CRAF-dependent manner. Invasiveness of HaCaT cells in a Matrigel assay significantly increased upon cultivation of cells with 2 μmol/L vemurafenib for 24 h. Gelatin zymography, reverse transcription polymerase chain reaction and western blot results revealed that 2 μmol/L vemurafenib treatment increased matrix metalloproteinase (MMP)-2 and MMP-9 expressions and activities in HaCaT cells. These results offer additional insight into the complex mechanism of paradoxical mitogen-activated protein kinase signaling involved in hyperproliferative cutaneous neoplasias that arise after BRAF inhibition and suggest a possible role for MMP in tumor progression and invasion.

Background RAS gene activation and its association with human papillomavirus (HPV) infection have been extensively studied in various cancers. However, the correlation between RAS mutations and HPV in keratoacanthoma (KA) has not yet been investigated. Methods Detection of HPV DNA was performed by nested polymerase chain reaction in 28 KA specimens. Molecular analysis was also performed to identify oncogenic mutations (HRAS, KRAS, NRAS). Statistical analyses were performed using the Fisher's exact tests. Results HPV DNA was detected in eight (28.6%) of the 28 samples, and RAS mutations were detected in eight (28.6%). Six samples had an HRAS mutation, and two showed the NRAS mutation. The presence of an RAS mutation was significantly correlated with a history of chronic sun damage (P = 0.005). However, no significant correlation was observed between HPV infection and RAS mutation. Conclusions Our findings suggest that mutational activation of the RAS gene is a common event in KA. However, RAS oncogene activation and HPV infection seem to represent two independent factors in the development of KA.

Sinonasal mucosal melanoma (SMM) is an aggressive and rare type of melanoma. Although the classic RAS-RAF-MEK pathway is thought to be the main pathway involved in melanoma pathogenesis, genetic alterations in the phosphatidylinositol 3-kinase-AKT pathway, including PTEN-regulated signaling, are also thought to contribute. So far, data regarding altered PTEN expression and epigenetic mechanism of PTEN silencing in development of SMM is extremely limited. Herein we report on a case of SMM with liver and bone metastases with an epigenetic alteration of PTEN. Results of mutation analysis for BRAF, NRAS, HRAS, KRAS, PIK3CA, c-Kit, and PTEN were negative; however, methylation of PTEN CpG islands was observed. Our case not only supports PTEN as a major tumor suppressor involved in melanoma tumorigenesis, but also a potential epigenetic mechanism of PTEN silencing in development of SMM.

Elderly adults are more likely to develop delirium after major surgery, but there is limited knowledge of the vulnerability for postoperative delirium. In this study, we aimed to identify neural predisposing factors for postoperative delirium and develop a prediction model for estimating an individual’s probability of postoperative delirium. Among 57 elderly participants with femoral neck fracture, 25 patients developed postoperative delirium and 32 patients did not. We preoperatively obtained data for clinical assessments, anatomical MRI, and resting-state functional MRI. Then we evaluated gray matter (GM) density, fractional anisotropy, and the amplitude of low-frequency fluctuation (ALFF), and conducted a group-level inference. The prediction models were developed to estimate an individual’s probability using logistic regression. The group-level analysis revealed that neuroticism score, ALFF in the dorsolateral prefrontal cortex, and GM density in the caudate/suprachiasmatic nucleus were predisposing factors. The prediction model with these factors showed a correct classification rate of 86% using a leave-one-out cross-validation. The predicted probability computed from the logistic model was significantly correlated with delirium severity. These results suggest that the three components are the most important predisposing factors for postoperative delirium, and our prediction model may reflect the core pathophysiology in estimating the probability of postoperative delirium.

Background: To investigate the role of the phosphoinositide 3-kinase (PI3K) pathway activation in human epidermal growth factor receptor 2 (HER2)-targeted therapy. Methods: We evaluated the predictive roles of PI3K, catalytic alpha (PIK3CA), and phosphatase and tensin homolog (PTEN) in HER2-based therapy (either trastuzumab or lapatinib). PTEN expression and PIK3CA mutation were analyzed using immunohistochemistry and pyrosequencing. Results: Forty-eight patients received trastuzumab (n = 39) or lapatinib (n = 9) combination chemotherapy. PTEN loss was found in 47.9% (n = 23), but no PIK3CA mutations were identified. Twenty-six (54.1%) patients responded to HER2-based therapy, without a significant difference between patients with PTEN loss and those without (52.2 vs. 56.0%). Among the patients with responsive disease, time to best response did not differ by PTEN status, but the duration of response was significantly shorter for patients with PTEN loss (median 4.2 vs. 6.1 months, p = 0.04). In addition, patients with PTEN loss had a significantly shorter progression-free survival time (median 4.9 vs. 7.3 months, p = 0.047). Conclusions: PTEN deficiency is an important predictive marker for early resistance to HER2 inhibitor treatment in gastric cancer patients. This finding may be useful for the development of drug combinations and identification of patients who need a modified treatment strategy. © 2014 S. Karger AG, Basel

PURPOSE To evaluate the kinetics of serum testosterone (T) recovery following short-term androgen deprivation therapy (ADT), as the understanding thereof is essential for the proper management of prostate cancer (PCa), especially intermittent ADT. MATERIALS AND METHODS This prospective analysis included male sex offenders who voluntarily received leuprolide acetate in order to alleviate sexual aberrance. Thirty-three and 25 patients who received 3 and 6 months of ADT were assigned to Group A and Group B, respectively. Serum T levels were obtained every week during the on-cycle period, then monthly during the off-cycle period for at least 12 months. RESULTS The kinetics of serum T during the on-cycle period were similar in both groups. After flare reaction at week 2, a nadir of 0.45±0.29 ng/mL was achieved. In Group A, an abrupt rebound-upsurge was observed during the first 2 month off-cycle period, which surpassed the baseline level and reached a plateau level of 8.74±2.11 ng/mL during the flare (p

Despite the fact that dermal fibroblasts are a practical model for research related to cell physiology and cell therapy, an in vitro culture system excluding serum, which complicates standardization and specificity and induces variability and unwanted effects, does not exist. We tried to establish a CDCS that supports effective proliferation of aHDFs. KDMEM supplemented with 5% (v/v) KSR, 12 ng/ml bFGF, 5 ng/ml EGF and 1 μg/ml hydrocortisone supported sufficient proliferation of aHDFs for 1 week. However, aHDF proliferation was decreased greatly after subculture. This problem could be overcome by culturing aHDFs in CDCM in culture plates coated with 10 μg/ml FN. Long-term culture of aHDFs was achieved using CDCM and FN-coated culture plates for 7 weeks. The optimized CDCS increased the proliferation of aHDFs significantly, without any increase in the senescence rate or alteration in morphology of aHDFs, despite long-term culture. In conclusion, we established a CDCS that improved proliferation of aHDFs while inhibiting cellular senescence. The CDCS will contribute to advances in various future research related to clinical skin regeneration.

Introduction Though augmentation plating (AP) with decortication and bone grafting (BG) reportedly has excellent outcomes for femoral shaft nonunions, there are no established indications of AP with decortication and BG. The purpose of this study was to evaluate the results of AP with decortication and autogenous BG for femoral shaft nonunions, focussing on the indications of AP with decortication and BG. Methods Thirty-nine patients treated with AP combined with decortication and BG for femoral shaft nonunions after femoral nail failure between November 1996 and October 2010 were retrospectively reviewed. Indications of AP with decortication and BG at the time of surgery and outcomes (bony union) were evaluated. Results The mean follow-up duration was 24.8 months (range 12–81 months). Thirty-eight (97%) of 39 femoral shaft nonunions achieved bony union. One incompliant patient showed screw breakage, which was healed uneventfully with subsequent cast application. The mean time to union was 6.1 months (range 3–16 months). Primary indications at the time of surgery were nonisthmal femoral nonunions in 17 patients, isthmal nonunions in 10 patients (cortical bone defect in five and widened canal in five), failed exchange nail in seven patients, nonunions with malrotation in two patients and difficult removal in three patients. Conclusions AP with decortication and autogenous BG is a good option for nonisthmal femoral shaft nonunions, such as supra-isthmal and infra-isthmal nonunions. In addition, this option is useful for selected cases of isthmal femoral shaft nonunions in which failure of exchange nailing is expected due to lack of a tight fit between the new larger nail and femoral cortices.

Although innate immunity plays important roles in xenograft rejection, there have been few studies on the role of toll-like receptors (TLRs) in xenotransplantation. Furthermore, most studies focused on the recipient's TLRs. Therefore, we investigated whether TLRs in porcine islets can contribute to islet xenograft rejection. Adult porcine islets were isolated and stimulated by polyinosinic/polycytidylic acid (poly I:C) or lipopolysaccharide (LPS). Both poly I:C and LPS stimulation in porcine islets induced expression of chemokines (RANTES, MCP-1, IP-10, and IL-8), cytokines (IL-6 and type I interferons), and adhesion molecules (VCAM-1 and ICAM-1). Porcine islet supernatants stimulated by TLR agonists induced chemotaxis of human leukocytes. They also induced procoagulant activation (tissue factor and fgl-2). However, TLR stimulation did not influence insulin secretion. When porcine MyD88 was knocked down using shRNA lentivirus, TLR-mediated induction of proinflammatory mediators and procoagulants was attenuated. When LPS was injected to MyD88 or TLR4 knockout mice after porcine islet transplantation, LPS stimulation on donor islets interfered with islet xenograft tolerance induction by anti-CD154 antibodies. Inflammatory cell infiltration and expression of proinflammatory chemokines and cytokines in islet xenografts also increased. In conclusion, TLR activation in porcine islets induced both a proinflammatory and procoagulant response and thereby contributed to xenograft rejection.

PURPOSE To access the predictive value of the European Randomized Screening of Prostate Cancer Risk Calculator (ERSPC-RC) and the Prostate Cancer Prevention Trial Risk Calculator (PCPT-RC) in the Korean population. MATERIALS AND METHODS We retrospectively analyzed the data of 517 men who underwent transrectal ultrasound guided prostate biopsy between January 2008 and November 2010. Simple and multiple logistic regression analysis were performed to compare the result of prostate biopsy. Area under the receiver operating characteristics curves (AUC-ROC) and calibration plots were prepared for further analysis to compare the risk calculators and other clinical variables. RESULTS Prostate cancer was diagnosed in 125 (24.1%) men. For prostate cancer prediction, the area under curve (AUC) of the ERSPC-RC was 77.4%. This result was significantly greater than the AUCs of the PCPT-RC and the prostate-specific antigen (PSA) (64.5% and 64.1%, respectively, p

There have been various studies showing increased iron levels in parkinsonian disorders. The purpose of this study was to demonstrate topographical differences of brain iron deposition between progressive supranuclear palsy (PSP) and the parkinsonian variant of multiple system atrophy (MSA-p) with SWI images.A total of 11 patients with PSP, 12 with MSA-p, 15 with Parkinson's disease (PD), and 20 age-matched healthy controls underwent SWI of the brain. Mean phase shift values of the red nucleus (RN), substantia nigra (SN), head of the caudate nucleus (CN), globus pallidus (GP), putamen (PUT), and thalamus (TH) were calculated and compared between groups. A voxel-based analysis of the processed SWI was performed to determine topographical differences of iron-related hypointense signals in PUT, GP, and TH.Patients with PSP and MSA-p had significantly higher levels of iron deposition than control and PD groups. Comparing patients with PSP and MSA-p, differences were found in iron concentrations of the RN, SN, GP, and TH, which were higher in the PSP group. However, iron levels in the PUT were higher in the MSA group (p0.05). The area under curve (AUC) indicated that the PUT was the most valuable nucleus in differentiating MSA-p from PSP and PD according to phase shift values (AUC=0.836). Meanwhile the GP (AUC=0.869) and TH (AUC=0.884) were the two most valuable nuclei in differentiating PSP from MSA-p and PD. Voxel-based analysis showed subregional differences in iron-related hypointense signals in the PUT, GP, and TH between MSA-p and PSP groups. Patients with MSA-p had significant increases of iron-related hypointense signals in the posterolateral PUT and adjacent lateral aspect of the GP, whereas the PSP group had increased hypodense signals in the anterior and medial aspects of the GP and TH.Our data demonstrate that pathological iron accumulations are more prevalent and severe in PSP compared to MSA-p. The distribution of high-iron-content regions in this study reflects pathoanatomically relevant sites. This finding allows for the use of MRI-based brain iron mapping as a technique to indirectly identify pathological changes.

We tested the clinical utility of combined profiling of Ion Torrent PGM based next-generation sequencing (NGS) and immunohistochemistry (IHC) for assignment to molecularly targeted therapies. A consecutive cohort of 93 patients with advanced/metastatic GC who underwent palliative chemotherapy between March and December 2015 were prospectively enrolled. Formalin fixed paraffin embedded tumor biopsy specimens were subjected to a 10 GC panels [Epstein Barr virus encoding RNA in-situ hybridization, IHC for mismatch repair proteins (MMR; MLH1, PMS2, MSH2, and MSH6), receptor tyrosine kinases (HER2, EGFR, and MET), PTEN, and p53 protein], and a commercial targeted NGS panel of 52 genes (Oncomine Focus Assay). Treatment was based on availability of targeted agents at the time of molecular diagnosis. Among the 81 cases with available tumor samples, complete NGS and IHC profiles were successfully achieved in 66 cases (81.5%); only IHC results were available for 15 cases. Eight cases received matched therapy based on sequencing results; ERBB2 amplification, trastuzumab (n = 4); PIK3CA mutation, Akt inhibitor (n = 2); and FGFR2 amplification, FGFR2b inhibitor (n = 2). Eleven cases received matched therapy based on IHC; ERBB2 positivity, trastuzumab (n = 5); PTEN loss (n = 2), PI3Kβ inhibitor; MMR deficiency (n = 2), PD-1 inhibitor; and EGFR positivity (n = 2), pan-ERBB inhibitor. A total of 19 (23.5%) and 62 (76.5%) cases were treated with matched and non-matched therapy, respectively. Matched therapy had significantly higher overall response rate than non-matched therapy (55.6% vs 13.1%, P = 0.001). NGS and IHC markers provide complementary utility in identifying patients who may benefit from targeted therapies.

Background Although various physical risk factors for delirium have been identified, the effect of psychological aspects is currently unknown. This study aimed to examine psychological risk factors for postoperative delirium and to identify hidden subgroups of delirium in clinical and psychological feature space. Methods Among 200 patients with hip fracture, 78 elderly patients were prospectively evaluated for clinical and psychological assessments before surgery. As delirium was assessed from the next day to the 7th day after surgery, postoperative delirium was found in 40 patients, but not in 38 patients. Univariate and multivariate logistic regression analyses were used to explore risk factors for postoperative delirium. Phenotypic subgroups of delirium were assessed using Topological Data Analysis, in which the significant risk factors were used for evaluating filter and distance metrics. Results Mini-Mental State Examination, neuroticism, conscientiousness, and regional anesthesia were identified as a predictive risk factor for postoperative delirium. The filter metric showed significant negative correlations with nutrition-related factors such as total protein and albumin. When filter metric and Euclidean distances were entered, delirious patients were bifurcated as a function of personality traits and anesthesia method in the patient-patient network. Conclusions A personality trait of neuroticism and conscientiousness may predispose elderly patients to postoperative delirium and this influence may be amplified by regional anesthesia. This study verifies the contribution of psychological risk factors to delirium and provides new insight for complex etiologies of delirium by mapping various clinical variables in the topological space. Electronic supplementary material The online version of this article (doi:10.1186/s12888-016-1079-z) contains supplementary material, which is available to authorized users.

Background The adjunctive role of magnetic resonance imaging of the liver before pancreatic ductal adenocarcinoma has been unclear. We evaluated whether the combination of hepatic magnetic resonance imaging with multidetector computed tomography using a pancreatic protocol (pCT) could help surgeons select appropriate candidates and decrease the risk of early recurrence. Methods We retrospectively enrolled 167 patients in whom complete resection was achieved without grossly visible residual tumor; 102 patients underwent pCT alone (CT group) and 65 underwent both hepatic magnetic resonance imaging and pCT (magnetic resonance imaging group). Results By adding hepatic magnetic resonance imaging during preoperative evaluation, hepatic metastases were newly discovered in 3 of 58 patients (5%) without hepatic lesions on pCT and 17 of 53 patients (32%) with indeterminate hepatic lesions on pCT. Patients with borderline resectability, a tumor size >3 cm, or preoperative carbohydrate antigen 19-9 level >1,000 U/mL had a greater rate of hepatic metastasis on subsequent hepatic magnetic resonance imaging. Among 167 patients in whom R0/R1 resection was achieved, the median overall survival was 18.2 vs 24.7 months (P = .020) and the disease-free survival was 8.5 vs 10.0 months (P = .016) in the CT and magnetic resonance imaging groups, respectively (median follow-up, 18.3 months). Recurrence developed in 82 (80%) and 43 (66%) patients in the CT and magnetic resonance imaging groups, respectively. The cumulative hepatic recurrence rate was greater in the CT group than in the magnetic resonance imaging group (P Conclusion Preoperative hepatic magnetic resonance imaging should be considered in patients with potentially resectable pancreatic ductal adenocarcinoma, especially those with high tumor burden.