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Background & aims: To elucidate the impact of synbiotics on bacterial translocation and subsequent bacteremia during neoadjuvant chemotherapy for esophageal cancer. Methods: Patients requiring neoadjuvant chemotherapy for esophageal cancer were randomized to receive synbiotics (synbiotics group) or no synbiotics (control group) during chemotherapy. Blood and fecal samples were taken before and after every chemotherapy cycle, and 1 day before surgery. Mesenteric lymph nodes (MLNs) were harvested at laparotomy (MLN-1) and after resection of the tumor (MLN-2). Bacteria in each sample were detected. Fecal microbiota and organic acid concentrations were also determined. The primary endpoint was the detection of bacteria in the blood samples, as well as the incidence of side effects during chemotherapy. The secondary endpoint was the detection rate of bacteria in the MLN samples collected during surgery. Results: The study recruited a total of 42 patients (22 in the control group, 20 in the synbiotics group). Bacteria were detected in 16 of 101 blood samples in the control group, whereas those were detected only 2 of 100 blood samples in the synbiotics group (p < 0.001) during neoadjuvant chemotherapy. Additionally, bacteria were detected in 12 of 34 MLN samples in the control group, whereas no bacteria were detected in 38 MLN samples in the synbiotics group (p < 0.001). Suppression of bacterial translocation was at least partly associated with an increased fecal acetic acid concentration as well as a lowered fecal pH by synbiotics. The incidence rate of grade 3 gastrointestinal toxicity during chemotherapy was lower in the synbiotics group compared to the control group (8/22 vs. 1/20, p = 0.022). Conclusions: Neoadjuvant chemotherapy for esophageal cancer may induce bacterial translocation and subsequent bacteremia, which can be prevented by synbiotics administration. Trial registration: The University Hospital Medical Information Network (http://www.umin.ac.jp; registration number ID 000007651).

Introduction: In 2018, the first Mobi-CⓇ total disk replacement (TDR) case was performed in Japan. In this study, we examined the preliminary clinical outcome of Mobi-CⓇ for degenerative cervical spine disease. Methods: We examined 24 consecutive patients who underwent 1-level TDR after 2018 and followed up for more than 6 months after surgery. The evaluation criteria included age, gender, diagnosis, follow-up period, surgical level, implant size, surgery time, intraoperative bleeding volume, complications, revision surgery, imaging findings, JOA score, and various questionnaires. Results: The mean age was 52.7 years, 13 males and 11 females. There were 15 cases of cervical disk herniation and 9 cases of cervical spondylosis. The mean follow-up period was 17.4 months. Surgical levels were C3/4 in 4 cases, C4/5 in 2 cases, C5/6 in 16 cases, and C6/7 in 2 cases. The mean operation time was 138.5 minutes, the amount of intraoperative bleeding was 32.1 ml, and there were no serious intraoperative complications. The range of motion of the affected level increased significantly, from 6.6 degrees preoperatively to 12.2 degrees at final follow-up. No patients required revision surgery at final follow-up, and there were no cases of heterotopic ossification or adjacent segment disease. One patient exhibited radiculopathy due to mild subsidence 1 year after surgery, and 1 had asymptomatic contact of device plates. Preoperative and final JOA scores improved from 11.7 to 15.8 points, and NRS improved from 4.3 to 1.3 points for neck pain and 4.3 to 1.7 points for arm pain. Preoperative and final NDI improved from 39.7% to 14.0%, and EQ-5D improved from 0.602 to 0.801. Conclusions: The short-term treatment outcomes of Mobi-CⓇ TDR were generally favorable. Spine surgeons should comply with guidelines when introducing this procedure and strive to adopt this new technology in Japan.

BACKGROUND Clinical tumor staging is essential information for making a therapeutic decision in cancer. This study aimed to identify the optimal tumor classification system for predicting resectability and survival probability in perihilar cholangiocarcinoma. METHODS Patients who were treated for perihilar cholangiocarcinoma between 2009 and 2018 were enrolled. Local tumor extension was staged radiologically according to a diameter-based classification system in addition to the AJCC, Blumgart, and Bismuth systems. Survival and resectability were compared between T subgroups, and the discriminability of the four systems was assessed with Harrell's concordance index (C-index). RESULTS Among 702 study patients, 559 (80.0%) underwent laparotomy, 489 (70.0%) of whom underwent resection. The resectability significantly decreased for more advanced tumors in all systems (P

The aim of this study was to verify the prognostic impact of the tumor exposure at the liver transection margin (LTM) in left-sided perihilar cholangiocarcinoma and the impact of middle hepatic vein (MHV) resection on this exposure.In perihilar cholangiocarcinoma, tumors are unexpectedly exposed at the LTM during left hemihepatectomy (LH).Patients who underwent LH for perihilar cholangiocarcinoma during 2002 to 2018 were retrospectively evaluated. LH was classified into conventional and extended types, which preserved and resected the MHVs, respectively. Positive LTM was defined as the involvement of invasive carcinoma at the liver transection plane and/or the adjacent Glissonean pedicle exposed. The clinicopathologic features and survival outcomes were compared between procedures.Among 236 patients, conventional and extended LHs were performed in 198 and 38 patients, respectively. The LTM was positive in 31 (13%) patients, with an incidence of 14% versus 8% (P = 0.432) and 24% versus 0% in advanced tumors (P = 0.011). Tumor size ≥18 mm (P = 0.041), portal vein invasion (P = 0.009), and conventional LH (P = 0.028) independently predicted positive LTM. In patients with negative LTM, the survival was comparable between the two groups: 60.4% versus 59.2% at 3 years (P = 0.206), which surpassed 17.7% for those with positive LTM in the conventional group (P0.001). Multivariable analysis demonstrated that LTM status was an independent prognostic factor (P = 0.009) along with ductal margin status (P = 0.030).The LTM status is an important prognostic factor in perihilar cholangiocarcinoma. Extended LH reduced the risk of tumor exposure at the LTM with a subsequent improvement in the survival, particularly in advanced tumors.

This study aimed to assess the safety risks associated with using nonsteroidal anti-inflammatory drugs (NSAIDs) in elderly patients (≥65 years) compared with younger patients (65 years) with osteoarthritis (OA) and/or chronic low back pain (CLBP).A retrospective analysis was conducted on anonymized claims data of patients prescribed NSAIDs for OA and/or CLBP from 2009 to 2018 using hospital-based administrative database-Medical Data Vision (MDV). The key outcome was the incidence of developing gastrointestinal (GI), renal, and acute myocardial infarction (AMI) that are well-known events associated with NSAID use.Of 288,715 patients included, 23.7%, 60.5%, and 15.8% had OA, CLBP, or both, respectively. Elderly patients used non-oral NSAIDs more frequently than oral NSAIDs (57.8% and 38.7%, respectively), whereas younger patients showed comparable use (50.7% and 52.8%, respectively). The incidence of events per 10,000 person-years (95% CI) was higher in the elderly than in younger patients: GI, 29.68(27.67-31.68) vs. 16.61(14.60-18.63); renal, 124.77(120.56-128.99) vs. 39.88(36.72-43.03); and AMI, 27.41(25.48-29.35) vs. 10.90(9.27-12.53), respectively. After adjusting for covariates, the increase in risk for these events was seen in patients70 years compared with younger patients (18-30 years) and was remarkable in patients80 years with 2-fold, 10-fold, and 7-fold higher risk for developing GI, renal, and AMI events, respectively.Risk for developing NSAID-associated events was higher in the elderly; particularly, renal and AMI events that remarkably increased in patients80 years. To reduce them, NSAIDs should be prescribed at the lowest effective dose for the shortest duration possible.

Systemic sclerosis (SSc) is a chronic multisystem disorder characterized by fibrosis and autoimmunity. Interleukin (IL)-31 has been implicated in fibrosis and T helper (Th) 2 immune responses, both of which are characteristics of SSc. The exact role of IL-31 in SSc pathogenesis is unclear. Here we show the overexpression of IL-31 and IL-31 receptor A (IL-31RA) in dermal fibroblasts (DFs) from SSc patients. We elucidate the dual role of IL-31 in SSc, where IL-31 directly promotes collagen production in DFs and indirectly enhances Th2 immune responses by increasing pro-Th2 cytokine expression in DFs. Furthermore, blockade of IL-31 with anti-IL-31RA antibody significantly ameliorates fibrosis and Th2 polarization in a mouse model of SSc. Therefore, in addition to defining IL-31 as a mediator of fibrosis and Th2 immune responses in SSc, our study provides a rationale for targeting the IL-31/IL-31RA axis in the treatment of SSc., Systemic sclerosis (SSc) disease involves multisystem fibrosis and autoimmunity with limited treatment options. Here the authors demonstrate that IL-31 and IL-31RA are overexpressed in dermal fibroblasts from SSc patients and show that fibrosis and cytokine release can be reduced upon blocking of IL-31/IL-31RA.

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Forkhead box (FOX) proteins are family of transcriptional factors and regulate cell growth and differentiation as well as embryogenesis and longevity. Previous studies have demonstrated that several FOX members regulate growth or metastasis of breast carcinoma, but clinical significance of total FOX members remains unclear. We first examined associations between expression of 40 FOX genes and TNM status of 19 breast carcinoma using microarray data. Subsequently, we immunolocalized FOXI1 in 140 breast carcinomas and evaluated its clinicopathological significance. In the microarray analysis, we newly identified that gene expression of FOXI1 was most pronouncedly linked to metastasis of the breast carcinoma among the FOX members examined. However, clinicopathological significance of FOXI1 has not been examined in the breast carcinoma. FOXI1 immunoreactivity was positive in 44 out of 140 (31%) of breast carcinomas, and it was significantly associated with stage, lymph node metastasis and distant metastasis. The FOXI1 status was significantly associated with worse prognosis of the breast cancer patients, and it turned out to be an independent prognostic factor for both distant disease-free survival and breast cancer-specific survival. These findings suggest that FOXI1 plays important roles in the metastasis of breast carcinoma and immunohistochemical FOXI1 status is a potent prognostic factor.

OBJECTIVE To visualize the postoperative clinical course using the comprehensive complication index (CCI) and to propose an early alarming sign for subsequent serious outcomes in perihilar cholangiocarcinoma. BACKGROUND Surgery for this disease carries a high risk of morbidity and mortality. The developmental course of the overall morbidity burden and its clinical utility are unknown. METHODS Patients who underwent major hepatectomy for perihilar cholangiocarcinoma between 2010 and 2019 were reviewed retrospectively. All postoperative complications were evaluated according to the Clavien-Dindo classification (CDC), and the CCI was calculated on a daily basis until postoperative day 14 to construct an accumulating graph as a trajectory. Group-based trajectory modeling was conducted to categorize the trajectory into clinically distinct patterns and the predictive power of early CCI for a subsequent serious course was assessed. RESULTS A total of 4230 complications occurred in the 484 study patients (CDC grade I, n=27; II, n=132; IIIa, n=290; IIIb, n=4; IVa, n=21; IVb, n=1; and V, n=9). The trajectory was categorized into 3 patterns: mild (n=209), moderate (n=235), and severe (n=40) morbidity courses. The 90-day mortality rate significantly differed among the courses: 0%, 0.9%, and 17.5%, respectively (P

Aim The aim of this study was to evaluate the cost effectiveness of treatment strategies without opioid medications (non-opioid treatment strategy) versus strategies with opioid medications (opioid treatment strategy) among surgery-eligible patients with osteoarthritis (OA) of the knee or hip in Japan. Materials and Methods We built a Markov cohort model to evaluate outcomes for the treatment strategies in surgery-eligible patients aged ≥ 65 years with OA of the knee or hip in Japan. The opioid treatment strategy as an intervention includes a health state with opioid medication in the treatment pathway. On the other hand, for the non-opioid treatment strategy, there is no health state with opioid medication. A targeted literature review and database analysis were conducted to identify and define the values of the variables included in the model. The time horizon was set to 30 years, and a 2% discount was applied for cost and quality-adjusted life-years (QALYs). Sensitivity analysis and scenario analysis were performed in the model. The outcomes were QALYs and the incremental cost-effectiveness ratio (ICER). Results In the base-case analysis, the non-opioid treatment strategy was dominant over the opioid treatment strategy and associated with an incremental cost and QALYs of − 53,878 JPY (− 499 USD) and 0.03 QALYs, respectively, in patients with knee OA, and − 54,129 JPY (− 502 USD) and 0.02 QALYs, respectively, in patients with hip OA. One-way sensitivity analysis showed the ICER was most sensitive to the QALY for opioid monotherapy. Probabilistic sensitivity analyses showed a high degree of uncertainty associated with the results. Limitations Study limitations included assumptions related to transition probabilities of the health states, and a lack of Japanese-specific data for transition probabilities, incidence of adverse events and utility values. Conclusions This study suggests that the non-opioid treatment strategy is cost effective compared with the opioid treatment strategy in the management of surgery-eligible patients with OA of the knee or hip. However, this final conclusion may not be accurate as the methodology is heavily reliant on assumptions. Supplementary Information The online version contains supplementary material available at 10.1007/s41669-021-00292-5.

Angiosarcoma of the head and neck (ASHN) is one of the most aggressive malignancies of the skin, but the prognostic factors are not well known because of its rarity. Recently, high plasma fibrinogen levels were reported to predict poor prognosis in several malignancies. In the present retrospective study, we suggest that low plasma fibrinogen levels predict poor prognosis for ASHN.

Summary Background Systemic sclerosis is a connective tissue disease characterised by multiorgan fibrosis with an autoimmune background and poor prognosis. Although a few drugs have shown some efficacy in treating the disease, there remains a great unmet medical need. We aimed to investigate the efficacy and safety of rituximab in patients with systemic sclerosis. Methods We did a double-blind, investigator-initiated, randomised, placebo-controlled trial at four hospitals in Japan. Patients aged 20–79 years, who fulfilled the 2013 American College of Rheumatology and European League Against Rheumatism classification criteria for systemic sclerosis, with a modified Rodnan Skin Score (mRSS) of 10 or greater, and an expected survival of at least 6 months were randomly assigned (1:1) to receive intravenous rituximab (375 mg/m2) or placebo once per week for 4 weeks. Patients and investigators were masked to treatment allocation. The primary endpoint was the absolute change in mRSS 24 weeks after initiation of study treatment, measured in all patients who received at least one dose of study treatment and had one endpoint assessment. This study is registered with ClinicalTrials.gov, NCT04274257, and UMIN-CTR, UMIN000030139. Findings Between Nov 28, 2017, and Nov 6, 2018, 80 individuals were screened and 56 (70%) were enrolled and randomly assigned; 51 (91%) were women and five (9%) were men. 27 (96%) of 28 patients in the rituximab group and 22 (79%) of 28 patients in the placebo group received at least one dose of their allocated treatment and completed 24 weeks of follow-up. The absolute change in mRSS 24 weeks after initiation of study treatment was lower in the rituximab group than in the placebo group (−6·30 in the rituximab group vs 2·14 in the placebo group; difference −8·44 [95% CI −11·00 to −5·88]; p Interpretation Rituximab appears to be an effective and safe treatment for systemic sclerosis. Although this study has some limitations, this is the first clinical trial to show efficacy of rituximab with skin sclerosis as the primary endpoint. Funding Japan Agency for Medical Research and Development (AMED), Zenyaku Kogyo. Translation For the Japanese translation of the abstract see Supplementary Materials section.

BACKGROUND The efficacy of adjuvant chemotherapy for biliary cancers remains controversial because of conflicting results from previous phase 3 studies that used different key drugs and enrolled patients with heterogeneous tumor sites and disease stages. Fluoropyrimidine seems more beneficial than gemcitabine (GEM) combination regimens in the adjuvant setting; however, data comparing the survival benefit between GEM- and fluoropyrimidine-based regimens are lacking. METHODS Patients who underwent resection for node-positive perihilar cholangiocarcinoma were included. The patients who underwent adjuvant chemotherapy were divided into the S-1 and GEM groups according to the regimen. The recurrence-free survival (RFS) and the overall survival (OS) were compared between the groups and adjusted with propensity scores generated from 14 potentially confounding clinicopathological factors. RESULTS In total, 186 patients (Surgery alone, n = 71; S-1, n = 60; GEM, n = 55) were included. The S-1 and GEM completion rates were 75% and 65%, respectively. Among the patients who underwent adjuvant therapy, the RFS was longer in the S-1 group patients than the GEM group patients (median, 24.4 months vs 14.9 months; P = .044) whereas the OS was not significantly different between the groups (median, 48.5 months vs 35.0 months; P = .324). After propensity score adjustment, the differences in RFS and OS between the groups were more evident (HR: 2.696, 95% CI: 1.739-4.180 P

Background: Nutritional status and tumor markers are important prognostic indicators for surgical decisions in pancreatic carcinoma. This study aimed to stratify the probability of surviving pancreatic carcinoma based on systematically chosen nonanatomic biomarkers. Methods: We included 187 consecutive patients that underwent surgical resections for pancreatic carcinoma. We performed multivariable analyses to evaluate prognostic indicators, including 4 blood-test indexes: the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, prognostic nutritional index, and the modified Glasgow prognostic score; and 4 body-composition indexes: the normalized total psoas muscle area, the normalized total elector spine muscle area, the psoas muscle computed tomography value, and the elector spine muscle computed tomography value. Results: Poor survival was associated with 2 independent risk factors: neutrophil-to-lymphocyte ratio ≥3.0 (hazard ratio, 1.54) and prognostic nutritional index

Cancer progresses due to changes in the dynamic interactions of multidimensional factors associated with gene mutations. Cancer research has actively adopted computational methods, including data-driven and mathematical model-driven approaches, to identify causative factors and regulatory rules that can explain the complexity and diversity of cancers. A data-driven, statistics-based approach revealed correlations between gene alterations and clinical outcomes in many types of cancers. A model-driven mathematical approach has elucidated the dynamic features of cancer networks and identified the mechanisms of drug efficacy and resistance. More recently, machine learning methods have emerged that can be used for mining omics data and classifying patient. However, as the strengths and weaknesses of each method becoming apparent, new analytical tools are emerging to combine and improve the methodologies and maximize their predictive power for classifying cancer subtypes and prognosis. Here, we introduce recent advances in cancer systems biology aimed at personalized medicine, with focus on the receptor tyrosine kinase signaling network.

Introduction The oncological benefit of neoadjuvant chemotherapy (NAC) alone for locally advanced rectal cancer (LARC) remains controversial. The aim of this study was to clarify the clinical risk factors for poor prognosis before and after NAC for decision making regarding additional treatment in patients with LARC. Materials and methods We examined a total of 96 patients with MRI-defined poor-risk locally advanced mid-low rectal cancer treated by NAC alone between 2006 and 2018. Survival outcomes and clinical risk factors for poor prognosis before and after NAC were analyzed. Results In the median follow-up duration after surgery of 60 months (3–120), the rates of 5-year overall survival (OS), relapse-free survival (RFS), and local recurrence (LR) were 83.6%, 78.4%, and 8.2%, respectively. In the multivariate analyses, patients with cT4 disease had a significantly higher risk of poor OS (HR; 6.10, 95% CI; 1.32–28.15, P = 0.021) than those with cT3 disease. After NAC, ycN+ was significantly associated with a higher risk of poor OS (HR; 5.92, 95% CI; 1.27–27.62, P = 0.024) and RFS (HR; 2.55, 95% CI; 1.01–6.48, P = 0.048) than ycN-. In addition, patients with CEA after NAC (post-CEA) ≥ 5 ng/ml had a significantly higher risk LR (HR; 5.63, 95% CI; 1.06–29.93, P = 0.043). Conclusion NAC alone had an insufficient survival effect on patients with cT4 disease, ycN+, or an elevated post-CEA level. In contrast, NAC alone is a potential treatment for other patients with LARC.

The carcinoembryonic antigen (CEA) “value” itself is often useless in patients with a normal CEA level at initial presentation and those with tumor-irrelevant elevated CEA. Although the unified marker using CEA has been desirable for recurrent tumor staging as well as for primary tumor staging, little is known concerning its relationship with the survival of patients with recurrent colorectal cancer in particular. This retrospective historical study included patients who experienced disease relapse after curative surgery for stage I–III colorectal cancer between 2006 and 2018. A total of 129 patients with recurrent disease after curative surgery for colorectal cancer were included. We focused on the CEA “ratio” (CEA-R: the ratio of the CEA level at the time of recurrence to that measured 3 months before recurrence) and aimed to evaluate the correlation between CEA-R and survival in recurrent colorectal cancer. Patients with a high CEA-R (≥ 2) exhibited significantly worse 2 year survival than those with a low CEA-R (

Cutaneous arteritis (CA) is necrotizing vasculitis invading the small- to medium-sized arteries of the skin. The majority of patients can be favorably managed by low- to medium-dose systemic corticosteroids (prednisolone

Spinal cord herniation (SCH) is a rare condition associated with tethering of the spinal cord at the ventral dural defect. Idiopathic dorsal spinal cord herniation (IDSCH) is an extremely rare clinical entity. Here, we report the first case of IDSCH perforating the lamina in a patient with a history of ossification of the ligamentum flavum and diffuse idiopathic skeletal hyperostosis. Untethering of the spinal cord was performed by removing the surrounded ossified dura. Although urological symptoms and impaired proprioception remained, progressive neurological deterioration was prevented. Because this disease condition is extremely rare, it should be differentiated from ventral SCH.

Summary Background The Harmonising Outcome Measures for Eczema (HOME) initiative has established a core outcome set of domains for atopic eczema (AE) clinical trials. Previous consensus meetings have agreed on preferred instruments for clinician‐reported signs (Eczema Area and Severity Index, EASI) and patient‐reported symptoms (Patient‐Oriented Eczema Measure, POEM). This paper reports consensus decisions from the HOME VII meeting. Objectives To complete the core outcome set for AE by agreeing on core outcome instruments for the domains of quality of life (QoL), long‐term control and itch intensity. Methods A face‐to‐face consensus meeting was held in Tokyo, Japan (8–10 April 2019) including 75 participants (49 healthcare professionals/methodologists, 14 patients, 12 industry representatives) from 16 countries. Consensus decisions were made by presentations of evidence, followed by whole and small group discussions and anonymous voting using predefined consensus rules. Results It was agreed by consensus that QoL should be measured using the Dermatology Life Quality Index (DLQI) for adults, the Children’s Dermatology Life Quality Index (CDLQI) for children and the Infant’s Dermatology Quality of Life Index (IDQoL) for infants. For long‐term control, the Recap of Atopic Eczema (RECAP) instrument or the Atopic Dermatitis Control Test (ADCT) should be used. Consensus was not reached over the frequency of data collection for long‐term control. The peak itch numerical rating scale (NRS)‐11 past 24 h was recommended as an additional instrument for the symptom domain in trials of older children and adults. Agreement was reached that all core outcome instruments should be captured at baseline and at the time of primary outcome assessment as a minimum. Conclusions For now, the core outcome set for clinical trials in AE is complete. The specified domains and instruments should be used in all new clinical trials and systematic reviews of eczema treatments., What is already known about this topic? Core outcomes sets improve the design and reporting of clinical trials, reduce selective outcome reporting bias and facilitate meta‐analysis of results in systematic reviews.The HOME core outcome set for eczema recommends the inclusion of four core domains in all atopic eczema trials: clinician‐reported signs, patient‐reported symptoms, health‐related quality of life (HrQoL) and long‐term control.Clinician‐reported signs should be captured using the Eczema Area and Severity Index (EASI) and patient‐reported symptoms using the Patient‐Oriented Eczema Measure (POEM). What does this study add? The HOME core outcome set is now complete and recommended core outcome instruments have been agreed on for all four domains.Core outcome instruments for HrQoL: Dermatology Life Quality Index (DLQI) for adults, Children’s Dermatology Life Quality Index (CDLQI) for children and Infant’s Dermatology Quality of Life Index (IDQoL) for infants.Core outcome instruments for long‐term control: either the Recap of Atopic Eczema (RECAP) or the Atopic Dermatitis Control Test (ADCT).In addition, itch intensity should be measured using the peak NRS‐11 past 24 h for trials including older children and adults. What are the clinical implications of this work? If all future trials of eczema treatments include the HOME core outcome instruments, then trial results will be more readily incorporated into meta‐analyses in systematic reviews and clinical care will be informed by the best available evidence. Linked Comment: D.F. Murrell and C.F. Paul. Br J Dermatol 2021; 185:13–14.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have long-term benefits but are limited by side effects. We assessed the health and economic burden of renal events associated with NSAID use in patients with osteoarthritis (OA) and/or chronic low back pain (CLBP). This retrospective, large-scale, medical claims database study of Japanese patients receiving NSAIDs for OA and/or CLBP between 2009 and 2018 assessed the incidence of renal events and effect of treatment duration, mode of administration, and usage consistency of NSAIDs. Of 180,371 patients, NSAIDs were prescribed as first-line analgesics in 89.3%. Incidence per 10,000 person-years (95% confidence interval [CI]) for renal events was 23.46 (21.84–25.08) and for progression of chronic kidney disease (CKD) was 267.12 (189.93–344.32). Longer treatment duration (> 1 to ≤ 3 years, risk ratio [RR] 1.32, 95% CI 1.12–1.54; P = 0.0007; > 3 to ≤ 5 years, RR: 1.38, 95% CI 1.04–1.84; P = 0.0254 vs.

The risk factors for skeletal-related events (SREs) among non-small cell lung cancer (NSCLC) patients during treatment with bone-modifying agents (BMAs) are not yet well-understood. The medical records of 238 consecutive NSCLC patients treated with BMAs, including zoledronic acid and denosumab, at the Chiba University Hospital from 2012 to 2016 were reviewed in the present study. SREs were defined as either pathologic fractures, spinal cord compression, the need for bone irradiation or surgery, or hypercalcemia. The risk factors for earlier occurrence of the first SRE from the time of the first bone metastasis diagnosis after the initiation of BMA treatment were identified. Of the 238 included patients, 92% (n = 220) had a performance status (PS) of 0–2 at diagnosis of bone metastasis. Forty-eight (20%) patients developed at least one SRE. The most common first SRE was the need for bone irradiation surgery (n = 27, 56%). Significant risk factors included poor PS (hazard ratio [HR]: 4.36; p = .024), male sex (HR: 2.17; p = .022), and the use of zoledronic acid (HR: 1.91; p = .032). The overall survival (OS) from the first bone metastasis diagnosis was 394 days (95% confidence interval [CI]: 331–465). The OS of patients with PS 3 and 4 at the diagnosis of bone metastasis (median: 36 days; 95% CI: 13–50) was significantly (p < 0.0001) shorter than that of patients with PS 0–2 (median: 411 days; 95% CI: 354–558) (HR: 4.53; 95% CI: 2.62–7.35). Careful observation is needed for patients with the identified risk factors, which include poor PS and male sex, despite the BMA treatment.

Purpose: The RET proto-oncogene encodes a receptor tyrosine kinase that is activated by gene fusion in 1%–2% of non–small cell lung cancers (NSCLC) and rarely in other cancer types. Selpercatinib is a highly selective RET kinase inhibitor that has recently been approved by the FDA in lung and thyroid cancers with activating RET gene fusions and mutations. Molecular mechanisms of acquired resistance to selpercatinib are poorly understood. Patients and Methods: We studied patients treated on the first-in-human clinical trial of selpercatinib (NCT03157129) who were found to have MET amplification associated with resistance to selpercatinib. We validated MET activation as a targetable mediator of resistance to RET-directed therapy, and combined selpercatinib with the MET/ALK/ROS1 inhibitor crizotinib in a series of single patient protocols (SPP). Results: MET amplification was identified in posttreatment biopsies in 4 patients with RET fusion–positive NSCLC treated with selpercatinib. In at least one case, MET amplification was clearly evident prior to therapy with selpercatinib. We demonstrate that increased MET expression in RET fusion–positive tumor cells causes resistance to selpercatinib, and this can be overcome by combining selpercatinib with crizotinib. Using SPPs, selpercatinib with crizotinib were given together generating anecdotal evidence of clinical activity and tolerability, with one response lasting 10 months. Conclusions: Through the use of SPPs, we were able to offer combination therapy targeting MET-amplified resistance identified on the first-in-human study of selpercatinib. These data suggest that MET dependence is a recurring and potentially targetable mechanism of resistance to selective RET inhibition in advanced NSCLC.

OBJECTIVENonunion after posterior lumbar interbody fusion (PLIF) is associated with poor long-term outcomes in terms of health-related quality of life. Biomechanical factors in the fusion segment may influence spinal fusion rates. There are no reports on the relationship between intervertebral union and the absorption of autografts or vertebral endplates. Therefore, the purpose of this retrospective study was to evaluate the risk factors of nonunion after PLIF and identify preventive measures.METHODSThe authors analyzed 138 patients who underwent 1-level PLIF between 2016 and 2018 (75 males, 63 females; mean age 67 years; minimum follow-up period 12 months). Lumbar CT images obtained soon after the surgery and at 6 and 12 months of follow-up were examined for the mean total occupancy rate of the autograft, presence of a translucent zone between the autograft and endplate (more than 50% of vertebral diameter), cage subsidence, and screw loosening. Complete intervertebral union was defined as the presence of both upper and lower complete fusion in the center cage regions on coronal and sagittal CT slices at 12 months postoperatively. Patients were classified into either union or nonunion groups.RESULTSComplete union after PLIF was observed in 62 patients (45%), while nonunion was observed in 76 patients (55%). The mean total occupancy rate of the autograft immediately after the surgery was higher in the union group than in the nonunion group (59% vs 53%; p = 0.046). At 12 months postoperatively, the total occupancy rate of the autograft had decreased by 5.4% in the union group and by 11.9% in the nonunion group (p = 0.020). A translucent zone between the autograft and endplate immediately after the surgery was observed in 14 and 38 patients (23% and 50%) in the union and nonunion groups, respectively (p = 0.001). The nonunion group had a significantly higher proportion of cases with cage subsidence and screw loosening at 12 months postoperatively in comparison to the union group (p = 0.010 and p = 0.009, respectively).CONCLUSIONSA lower occupancy rate of the autograft and the presence of a translucent zone between the autograft and endplate immediately after the surgery were associated with nonunion at 12 months after PLIF. It may be important to achieve sufficient contact between the autograft and endplate intraoperatively for osseous union enhancement and to avoid excessive absorption of the autograft. The achievement of complete intervertebral union may decrease the incidence of cage subsidence or screw loosening.

We aimed to investigate the hypothesis that preoperative thickness of the abdominal cavity influenced on the gastrojejunostomy position and the incidence of delayed gastric emptying (DGE) after pancreatoduodenectomy.Between January 2009 and December 2018, consecutive patients who underwent subtotal stomach-preserving pancreatoduodenectomy were retrospectively reviewed. Thickness of the abdominal cavity at the level of the celiac axis (TACC) and umbilicus (TACU) were measured using computed tomography before surgery. The ventral deviation of the gastrojejunostomy was evaluated as the sagittal fundus anastomotic angle (SFAA) using sagittal computed tomography images taken after surgery.A total of 281 patients were included. Of these, clinically relevant DGE (CR-DGE) was observed in 47 patients. TACC was significantly correlated with SFAA (R = 0.53, P 0.001). Both TACC and SFAA were significantly greater in patients with CR-DGE compared to those without CR-DGE. In contrast, TACU was not associated with SFAA and the incidence of CR-DGE. Multivariate analysis revealed that TACC110 mm (odds ratio, 3.07; p = 0.002) and pancreatic fistula (odds ratio, 2.71; p = 0.013) were identified as independent risk factors for CR-DGE.Thickness of the upper abdominal cavity had a significant influence on gastrojejunal anatomic position and the development of CR-DGE after pancreatoduodenectomy.

The potential benefit of heart rate reduction (HRR), independent of β-blockade, on right ventricular (RV) function in pulmonary hypertension (PH) remains undecided. We studied HRR effects on RV fib...

Purpose Part 1 of this two-part, open-label, Phase 1 study (NCT03233139) assessed the safety, tolerability, pharmacokinetics, immunogenicity, and clinical activity of cemiplimab in Japanese patients with advanced malignancies. Methods Patients received cemiplimab 250 mg (n = 6) or 350 mg (n = 7) every 3 weeks intravenously for up to 108 weeks in Part 1. Tumor responses were assessed by investigators every 9 weeks using the Response Evaluation Criteria in Solid Tumors version 1.1. Results Of 13 patients enrolled, median age was 62 years (range 33–75) and eight patients were female. Median duration of cemiplimab exposure was 13.1 weeks (range 3.0‒113.6). At the time of data cut-off, 11 patients (84.6%) had discontinued treatment (majority due to disease progression: n = 8, 61.5%). The most common treatment-emergent adverse events (TEAEs) of any grade were contact dermatitis, rash, and viral upper respiratory tract infection (each n = 3, 23.1%). Five grade ≥ 3 TEAEs were reported in four patients: autoimmune colitis, dehydration, hyponatremia, hypophosphatemia, and muscular weakness. No dose-limiting toxicities were reported and no TEAEs led to death. Cemiplimab concentrations in serum were consistent with previously reported pharmacokinetic characteristics of cemiplimab. No anti-drug antibodies were detected in serum. Objective response rate [ORR; complete response + partial response (PR)] was 30.8% (four PR) and disease control rate [ORR + stable disease (SD)] was 46.2% (6/13; two SD). Conclusion Cemiplimab exhibited antitumor activity in Japanese patients with advanced malignancies. The safety profile was comparable to those previously reported for cemiplimab and other PD-1 inhibitors. Trial registration NCT03233139 at ClinicalTrials.gov. Graphic abstract

The indications for neoadjuvant chemotherapy (NAC) in resectable colorectal liver metastases (CRLMs) remain unclear. Tumor burden score (TBS) is a prognostic tool based on tumor size and number of tumors. However, its utility in the NAC setting for initially resectable CRLM has never been investigated. TBS is a distance from the origin on a Cartesian plane to the coordinates (x, y) = (tumor size in centimeter, number of tumors). TBS

The guidelines for osteoarthritis (OA) treatment recommend different therapies including pharmacotherapy, and several analgesic options are available for pain management. In Japan, research on hip and knee OA treatment trends is scarce and OA-related healthcare costs are unknown. Therefore, this study aimed to examine the treatment and healthcare cost trends among Japanese patients with hip or knee OA. This was a cross-sectional study held between 2013 and 2019, using a medical claims database. The demographic and treatment characteristics of hip or knee OA patients for each year were descriptively analyzed and the medians for healthcare utilization and all-cause healthcare costs were calculated. The yearly mean age of 59,218 hip OA and 270,722 knee OA patients ranged from 66.3 to 68.6 years and 71.1 to 73.1 years, respectively. The prevalence of comorbidities was higher in knee OA than hip OA. In both groups, > 70% of patients were female, and the most common treatment was pain-related medication. In hip OA, topical and systemic nonsteroidal anti-inflammatory drugs (NSAIDs) were mostly used throughout the study period (34.1–41.4% and 32.0–40.3%, respectively). Similarly, in knee OA, topical and systemic NSAIDs were used in 58.3–63.3% and 36.5–46.0% patients, respectively. Increase in the use of acetaminophens (10.9% in hip OA and 10.2% in the knee OA) and weak opioids (3.7%, and 3.4%, respectively) from 2013 to 2019 were observed. Most patients were treated as outpatients in both groups. The median all-cause healthcare costs were approximately 35,000 JPY for hip OA and 74,000 JPY for knee OA. Although a considerable change in total healthcare cost was not observed in our study, the contents of medical treatment and cost breakdown were greatly altered due to the treatment and cost for OA itself, and the treatment and cost for comorbidities. Similar studies to investigate such a trend may help predict necessary resources and social needs. Thus, further investigation utilizing other databases is needed.

Although bile duct resection (BDR) in addition to pancreaticoduodenectomy (PD) is considered a surgical approach in patients with middle-third cholangiocarcinoma (MCC), available prognostic information after BDR remains very limited. The aim of this study was to reappraise BDR from the viewpoint of surgical oncology. Patients who underwent BDR or PD for MCC between 2001 and 2010 at 32 Japanese hospitals were included. Clinicopathological factors were retrospectively compared according to surgical procedure to identify a subset cohort who benefited most from BDR. During the study, 92 patients underwent BDR (n = 38) or PD (n = 54). BDR was characterized by a shorter operation time, less blood loss, less frequent complications, and lower mortality, than PD. The incidence of positive surgical margins was 26.3% versus 5.6% (P = 0.007). The survival rate after BDR was significantly worse than that after PD: 38.8% versus 54.8% at 5 years (P = 0.035), and BDR was independently associated with deteriorated survival [hazard ratio (HR), 1.76; P = 0.023] by multivariable analysis. In the BDR group, tumor length

In “anatomic” right hepatic trisectionectomy for advanced perihilar cholangiocarcinoma, the left hepatic duct is divided at the left side of the umbilical portion (UP) of the left portal vein (LPV). For this reason, the left hepatic duct is completely detached from the UP after all division of the portal branches arising cranially from the UP. However, little is known about these thin portal branches. Using 3D imaging processing software, we examined the portal branches arising cranially from the UP of the LPV in 100 patients who underwent multidetector row computed tomography (MDCT). Special attention was paid to the portal branch running to the left lateral sector, designated as the left cranio-lateral branch. The left cranio-lateral portal branch number was 0 in 57 patients, 1 in 32 patients, and 2 in 11 patients. Thus, 54 left cranio-lateral branches were identified, arising from near the cul-de-sac of the UP, from near the elbow of the LPV, or from the UP trunk. The median volume of the territory supplied by the left cranio-lateral portal branch was 21 mL (range, 5–47 mL), and the median ratio to the left lateral sector was 11.8% (range, 1.7–25.0%). Approximately 40% of patients had the left cranio-lateral portal branches arising cranially from the UP and running to the left lateral sector. When planning anatomic right hepatic trisectionectomy, the presence or absence of this branch should be checked by using 3D imaging with MDCT.

Perineural invasion (PN) is often found in perihilar cholangiocarcinoma. New procedure was developed to assess PN around the right hepatic artery (RHA) using dual-energy computed tomography (DECT). Thirty patients with perihilar cholangiocarcinoma who underwent DECT before biliary drainage were retrospectively reviewed. Mask images, i.e., the periarterial layer (PAL) around the RHA and superior mesenteric artery (SMA), were made from late arterial phase DECT. The mean CT number of the PAL was measured. Twenty patients with PN around the RHA were classified into the PN (+) group. The remaining 10 patients without PN and other 26 patients with other diseases that are never accompanied with PN were classified into the PN (−) group. The PAL ratio (the CT number of the PAL around the RHA relative to that around the SMA) was calculated. Both the mean CT number of the PAL around the RHA and the PAL ratio were significantly higher in the PN (+) group than in the PN (−) group. According to an ROC analysis, the predictive ability of the PAL ratio was superior. Using the cutoff value of the PAL ratio 1.009, a diagnosis of PN around the RHA was made with approximately 75% accuracy. Assessment with CT number of the PAL reconstructed from DECT images is an easy and objective method to diagnose PN.

To date, five randomized controlled trials have assessed the clinical benefit of perioperative steroid administration in hepatectomy; however, all of these studies involved a substantial number of ‘minor’ hepatectomies. The benefit of steroid administration for patients undergoing ‘complex’ hepatectomy, such as major hepatectomy with extrahepatic bile duct resection, is still unclear. This study aimed to evaluate the clinical benefit of perioperative steroid administration for complex major hepatectomy. Patients with suspected hilar malignancy scheduled to undergo major hepatectomy with extrahepatic bile duct resection were randomized into either the control or steroid groups. The steroid group received hydrocortisone 500 mg immediately before hepatic pedicle clamping, followed by hydrocortisone 300 mg on postoperative day (POD) 1, 200 mg on POD 2, and 100 mg on POD 3. The control group received only physiologic saline. The primary endpoint was the incidence of postoperative liver failure. A total of 94 patients were randomized to either the control (n = 46) or steroid (n = 48) groups. The two groups had similar baseline characteristics; however, there were no significant differences between the groups in the incidence of grade B/C postoperative liver failure (control group, n = 8, 17%; steroid group, n = 4, 8%; p = 0.188) and other complications. Serum bilirubin levels on PODs 2 and 3 were significantly lower in the steroid group than those in the control group; however, these median values were within normal limits in both groups. Perioperative steroid administration did not reduce the risk of postoperative complications, including liver failure following major hepatectomy with extrahepatic bile duct resection.

Hilar cholangiocarcinoma is a highly intractable malignancy. One of the reasons for its intractability is that most patients with the disease are diagnosed with an advanced stage of the disease at their initial presentation. Surgical resection is the standard therapy for hilar cholangiocarcinoma, providing a chance for a cure, and an aggressive surgical approach substantially increases the number of resectable tumors that are initially regarded as unresectable tumors. The success and standardization of the aggressive approach is warranted by meticulous preoperative management that prevents fatal postoperative complications. Extended resection procedures, including hepatic trisectionectomy for Bismuth type IV tumors, hepatopancreaticoduodenectomy for tumors with extensive longitudinal tumor spreading, and combined vascular resection with reconstruction for tumors with the involvement of hepatic vascular structures, have been challenged to expand the surgical indication. Due to acceptable surgical/survival outcomes, the three extended procedures are currently regarded as extended but standard options in specialized hepatobiliary centers. Although it remains a controversial multidisciplinary approach, the combination of these extended procedures with an adjuvant/neoadjuvant treatment is a promising approach for further improving the resectability of tumors and the survival of patients.

Several studies have demonstrated increased pericardial effusion during anti‐PD‐1 immunotherapy, and treatment in patients who have developed pericardial tamponade is controversial. In this study, we describe a 63‐year‐old woman with stage IVA lung adenocarcinoma given pembrolizumab as a first‐line therapy. After four cycles of pembrolizumab treatment, the patient suddenly developed a pericardial tamponade. Although pericardial effusion was increased, her tumor lesions were reduced. After an emergency pericardiocentesis, she continued the pembrolizumab therapy without recurrent pericardial effusions for three months until the primary tumor and lymph node metastasis progressed. Nine months after the pericardiocentesis, the patient died of progressive lung cancer, but pericardial effusion did not recur throughout the treatment course. This case study suggests that pembrolizumab therapy can be continued with a strict follow‐up in some patients with pembrolizumab‐induced pericardial tamponade. Key points • Significant findings of the study Our patient developed pericardial tamponade during pembrolizumab treatment but continued pembrolizumab treatment after emergency pericardiocentesis without recurrent pericardial effusions. • What this study adds Pembrolizumab treatments may be resumed with a strict follow‐up in some patients with treatment‐related pericardial tamponade.

Study design Retrospective multicenter cohort study. Objective We evaluated a new upper instrumented vertebra (UIV) selection method that used the modified Shinshu line (MSL) to establish the selected UIV as the MSL vertebra (MSLV). Summary of background data No reports have addressed optimal UIV selection according to the lower instrumented vertebra (LIV) for good trunk balance in Lenke 1A curves. Methods Forty-five consecutive patients (44 female, 14.4 ± 2.4 yrs) receiving posterior spinal fusion (PSF) for a Lenke 1A adolescent idiopathic scoliosis (AIS) curve were analyzed. We defined the novel MSL as the line between the center of the spinous process of C7 and that of the spinous process of the LIV. The vertebral body with which the MSL first contacted proximally was defined as the MSLV. The groups in which the UIV was at, proximal to, or distal to the MSLV were defined as the matched group (M-group; 15 cases [15 female], 14.7 ± 2.1 yrs), proximal group (P-group; 20 cases, [19 female], 15.0 ± 2.2 yrs), and distal group (D-group; 10 case [10 female], 14.8 ± 2.5 yrs), respectively. We measured Cobb angle, main thoracic (MT) curve correction rate, and C7 plumb line absolute value (C7PL) at pre- and 2 years postoperatively for comparisons using Dunnett test, with the M-group as the control. Results In the M-group, P-group, and D-group, the Cobb angle correction rate between pre- and postoperative time points were 65.3 ± 1.3%, 62.4 ± 1.6%, and 52.8 ± 6.8%, respectively, and comparable apart from a smaller correction tendency in the D-group versus the M-group (P = 0.08). At 2 years postoperatively, C7PL was 0.5 ± 0.4, 1.0 ± 0.6, and 1.3 ± 0.9 cm, respectively, and significantly smaller for the M-group (both P Conclusion Better trunk balance were obtained without reducing correction rate by setting the novel MSLV as the UIV in PSF for Lenke type 1A curves. Level of evidence 3.

Introduction Novel rearranged in transfection (RET)-specific tyrosine kinase inhibitors (TKIs) such as selpercatinib (LOXO-292) have shown unprecedented efficacy in tumors positive for RET fusions or mutations, notably RET fusion-positive NSCLC and RET-mutated medullary thyroid cancer (MTC). However, the mechanisms of resistance to these agents have not yet been described. Methods Analysis was performed of circulating tumor DNA and tissue in patients with RET fusion-positive NSCLC and RET-mutation positive MTC who developed disease progression after an initial response to selpercatinib. Acquired resistance was modeled preclinically using a CCDC6-RET fusion-positive NSCLC patient-derived xenograft. The inhibitory activity of anti-RET multikinase inhibitors and selective RET TKIs was evaluated in enzyme and cell-based assays. Results After a dramatic initial response to selpercatinib in a patient with KIF5B-RET NSCLC, analysis of circulating tumor DNA revealed emergence of RET G810R, G810S, and G810C mutations in the RET solvent front before the emergence of clinical resistance. Postmortem biopsy studies reported intratumor and intertumor heterogeneity with distinct disease subclones containing G810S, G810R, and G810C mutations in multiple disease sites indicative of convergent evolution on the G810 residue resulting in a common mechanism of resistance. Acquired mutations in RET G810 were identified in tumor tissue from a second patient with CCDC6-RET fusion-positive NSCLC and in plasma from patients with additional RET fusion-positive NSCLC and RET-mutant MTC progressing on an ongoing phase 1 and 2 trial of selpercatinib. Preclinical studies reported the presence of RET G810R mutations in a CCDC6-RET patient-derived xenograft (from a patient with NSCLC) model of acquired resistance to selpercatinib. Structural modeling predicted that these mutations sterically hinder the binding of selpercatinib, and in vitro assays confirmed loss of activity for both anti-RET multikinase inhibitors and selective RET TKIs. Conclusions RET G810 solvent front mutations represent the first described recurrent mechanism of resistance to selective RET inhibition with selpercatinib. Development of potent inhibitor of these mutations and maintaining activity against RET gatekeeper mutations could be an effective strategy to target resistance to selective RET inhibitors.

The global alignment and proportion (GAP) score was recently developed to consider proportional analysis of spinopelvic alignment and has been indicated for setting surgical goals to decrease the prevalence of mechanical complications. The goal of this study was to clarify the limitations and problems with spinal corrective surgery with minimally invasive lateral lumbar interbody fusion (LLIF) without osteotomy using GAP score, and to establish a preoperative radiographical evaluation to understand the necessity for three-column osteotomy. We included data from 57 consecutive patients treated with spinal corrective surgery with LLIF and without Schwab grade 3–6 osteotomy for ASD. To evaluate flexibility of the pelvis and lumbar spine, we examined full-length lateral radiographs with patients standing and prone. Correlations between pre- and postoperative radiographic parameters and GAP score were determined. Most patients achieved a sufficiently ideal lumbar lordosis (87.7%), but ideal sacral slope (SS) was achieved in only 50.8% of patients. Preoperative prone SS showed a significant positive correlation with postoperative SS and a significant negative correlation with GAP score. Patients whose preoperative prone SS was larger than pelvic incidence × 0.59–7.5 tended to achieve proportioned spinopelvic alignment by using LLIF. The cause of poor outcome of GAP score for ASD corrective surgery with LLIF without osteotomy is a postoperative small SS. Preoperative prone SS is useful for predicting postoperative SS. When preoperative SS in prone patients is relatively small to ideal as calculated using PI, osteotomy or other correctors should be considered to achieve satisfactory spinopelvic parameters. III. These slides can be retrieved under Electronic Supplementary Material.

Nodal metastasis is a leading attributable factor of poor survival in biliary tract cancer (BTC), and adjuvant chemotherapy targeting this high-risk feature has not been attempted to date. This study aimed to test the efficacy of adjuvant S − 1 for patients with node-positive BTC. This single-arm multicenter phase 2 trial enrolled patients who underwent resection for histologically proven node-positive BTC. In this trial, S − 1 was administered at a dose of 80–120 mg/day on 14 days of a tri-weekly cycle for 6 months. The primary end point of the trial was 3-year overall survival (OS), in which the result would be promising if the 90% confidence interval (CI) surpassed a threshold of 30% (alpha error, 0.1; beta error, 0.2). The secondary end points were relapse-free survival (RFS), feasibility, and toxicity. The trial included 50 patients with perihilar (n = 23) or distal (n = 20) cholangiocarcinoma, or gallbladder cancer (n = 7). The median numbers of positive lymph nodes and examined lymph nodes were respectively 2 and 15. The 3-year OS and RFS were respectively 50% (90% CI, 40.9–59.1%) and 32.0% (95% CI, 19.1–44.9%), with median survival times of 34.6 months (95% CI, 19.3–49.8 months) and 18.4 months (95% CI, 11.9–24.9 months). Although hematologic toxicity often occurred, grades 3 and 4 toxicity were rare. The completion rate of the test therapy was 64%, and the median relative dose intensity was 87.5% (interquartile range, 50–100%). Adjuvant chemotherapy with S − 1 may be promising for patients with node-positive BTC.

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody (Ab) is myositis-specific autoantibody associated with rapidly progressive interstitial lung disease (ILD) and poor prognosis. In this retrospective observational study, we aimed to verify the efficacy and safety of introducing combined immunosuppressive therapy for anti-MDA5 Ab-positive dermatomyositis (DM) from their early stage. We recruited all Japanese patients diagnosed with DM in our clinic between January 2011 and October 2018, who had anti-MDA5 Ab, anti-aminoacyl transfer RNA synthetase Ab or anti-transcriptional intermediary factor 1-γ Ab. Combined immunosuppressive therapy was defined as combination of systemic corticosteroids, i.v. cyclophosphamide and tacrolimus. The difference of clinical features among the three groups was analyzed by multiple comparison analysis. The longitudinal change of the measurements from baseline was examined by Wilcoxon signed-rank test. Association between therapeutic regimens and adverse events was examined by logistic regression analysis. As a result, combined immunosuppressive therapy was most frequently used in the anti-MDA5 Ab-positive group, which significantly improved their forced vital capacity of the lung. Interval time since initial visit until starting treatment was the shortest in the anti-MDA5 Ab-positive group. There was no significant difference in the incidence of death and recurrence among the three groups. Cytomegalovirus reactivation was most common in the anti-MDA5 Ab-positive group, associated with combined immunosuppressive therapy. Collectively, early introduction of combined immunosuppressive therapy was effective for DM patients with anti-MDA5 Ab. At the same time, clinicians should be aware of the risk of cytomegalovirus reactivation during the treatment.

Study design Multicenter, prospective randomized study. Objective Evaluate the impact of weekly teriparatide (WT) and bone contact (BC) status of grafted bone in patients recovering from multilevel lumbar interbody fusion (M-LIF). Summary of background data WT has been reported to significantly improve bone fusion following posterior or transforaminal interbody fusion in osteoporosis patients. Methods Patients older than 50 years and osteoporotic were recruited. We defined the fusion of two or more consecutive intervertebral levels as M-LIF. All patients were instrumented with pedicle, iliac, or S-2 alar iliac screws after transplanting cages and autogenous bone between vertebral bodies. After surgical indication for M-LIF, the subjects were randomly allocated to receive either subcutaneous WT from 1 week to 6 months postoperatively (WT arm, N = 50) or a bisphosphonate (BP; BP arm, N = 54). Blinded radiological evaluations were performed using computed tomography (CT). Evaluation of bone fusion was performed at the intervertebral disc located at the bottom of the fixed range. The degree of bone fusion was calculated as a score from 2 to 6 points, with 2 defined as complete fusion. Bone fusion rate was also compared at 6 months postoperatively based on BC status of the grafted bone on CT immediately after surgery. Results Mean bone fusion score at 6 months postoperatively was 3.9 points in the WT group and 4.2 points in the BP group. The bone fusion rate at 6 months postoperatively tended to be higher in the WT group (46.8% vs. 32.7% in the BP group). The 6-month postoperative fusion rate of immediately postoperative of BC+ patients was significantly higher than that of BC- patients (47.4% vs. 9.5%). Conclusion In M-LIF, there were no significant differences in bone fusion score between WT- and BP-treated patients. In contrast, BC status immediately postoperatively had a major impact on 6-month bone fusion. Level of evidence 1.

Study design Prospective study. Objectives Preoperative and postoperative dysphagia was evaluated by an otolaryngology doctor and a speech-language-hearing therapist using the eating assessment tool (EAT-10) and Hyodo-Komagane scores. The objective was to achieve a more precise evaluation of the incidence and risk factors of early and persistent dysphagia after anterior cervical discectomy and fusion (ACDF). Summary of background data Although numerous reports have explored the risk factors for dysphagia after ACDF, these factors remain controversial. The main reason for this situation is that the methods for evaluating dysphagia are not adequate or uniform. Materials and methods This study involved a retrospective 47 consecutive patients who had undergone ACDF and been followed up for at least 1 year. Sagittal alignment of the cervical spine was evaluated by a preoperative x-ray. Univariate and multivariate logistic regression analyses were performed to determine risk factors for transient or persistent dysphagia. Results The study showed that 34% of patients developed dysphagia in the early postoperative period and that 25.5% of patients still had persistent dysphagia 1 year postoperatively. 8.5% of patients had already developed dysphagia preoperatively, with a significant positive correlation observed between preoperative and postoperative dysphagia.Aging and smoking were significant risk factors for transient dysphagia. A preoperative cervical kyphotic angle at the C3/C4, C4/C5 disk-level and change in the kyphotic angle at C4/C5 during surgery were significant risk factors of persistent dysphagia 1 year after surgery. Conclusions This is the first study to show dysphagia after anterior cervical spine surgery using the EAT-10 score and Hyodo-Komagane score with endoscopic evaluation. Aging and smoking were significant risk factors for transient dysphagia, while preoperative local kyphosis angles of C3-C4 and C4-C5 and change in the kyphotic angle at C4/C5 during surgery may be a key alignment of risk factors for postoperative persistent dysphagia. Level of evidence Level: III.

The title compound, 2-ethylhexyl-4-methoxycinnamate (2EH4MC), is known as a typical ingredient of sunscreen cosmetics that effectively converts the absorbed UV-B light to thermal energy. This energy conversion process includes the nonradiative decay (NRD)