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Purpose: The relationship between ligament remnant quality and postoperative outcomes after arthroscopic lateral ankle ligament repair for chronic lateral ankle instability is controversial. This study aimed to determine whether the signal intensity of the anterior talofibular ligament on preoperative magnetic resonance imaging and ligament remnant quality identified on arthroscopy are associated with recurrent ankle instability after arthroscopic lateral ankle ligament repair., Methods: A total of 68 ankles from 67 patients with chronic lateral ankle instability who underwent arthroscopic lateral ankle ligament repair were retrospectively studied. The signal intensity of the anterior talofibular ligament was evaluated using T2-weighted magnetic resonance imaging. Arthroscopy was used to evaluate the thickness and mechanical resistance of the anterior talofibular ligament by hook palpation and to classify ankles into two groups: the present anterior talofibular ligament group with adequate mechanical resistance and the absent anterior talofibular ligament group with no mechanical resistance. The outcomes included recurrent ankle instability (respraining of the operated ankle after surgery) and Self-Administered Foot Evaluation Questionnaire scores., Results: Thirteen ankles were diagnosed with recurrent ankle instability. Patients with a high anterior talofibular ligament T2 signal intensity experienced more recurrent ankle instability than those with a low intensity. As determined via arthroscopy, the absent anterior talofibular ligament group had a higher rate of recurrent ankle instability than the present anterior talofibular ligament group. There were no significant differences in Self-Administered Foot Evaluation Questionnaire scores between patients with high and low anterior talofibular ligament T2 signal intensity, as well as between absent and present anterior talofibular ligament groups based on arthroscopy., Conclusion: Poor quality of the anterior talofibular ligament remnant could result in recurrent ankle instability after arthroscopic lateral ankle ligament repair. Therefore, when treating chronic lateral ankle instability, surgeons should consider ligament quality., Level of Evidence: IV., (© 2022. The Author(s) under exclusive licence to European Society of Sports Traumatology, Knee Surgery, Arthroscopy (ESSKA).)

In 1995, Yoshida et al. proposed first the concept of "autoimmune pancreatitis" (AIP). Since then, AIP has been accepted as a new pancreatic inflammatory disease and is now divided two subtypes. Type 1 AIP affected immunoglobulin G4 (IgG4) and implicates the pancreatic manifestation of IgG4-related disease, while type 2 is characterized by neutrophil infiltration and granulocytic epithelial lesions (GEL). Recent research has clarified the clinical and pathophysiological aspects of type 1 AIP, which is more than type 2 among the Japanese population. However, many details remain unclear about the pathogenesis and progression of this disease. In this review, we discuss the current knowledge and recent advances relating to type 1 AIP., (© 2022. The Author(s).)

Purpose: The purpose of this study was to evaluate perioperative and short-term clinical and radiographical results of a modern PS mobile-bearing cementless TKA system., Methods: A retrospective review of a consecutive series of TKAs was performed by a single surgeon using a cementless or cemented TKA of the same design (Attune, DePuy Synthes, Massachusetts, USA). The 2011 Knee Society Score, Forgotten Joint Score-12, Hip-Knee-Ankle angle, and the presence of radiolucent lines (RLLs) were reviewed 1-year postoperatively with 1:1 matching performed for age, gender, body mass index, and preoperative UCLA score. Fisher's exact test or independent Student's t-test were used for statistical analyses., Results: Forty-five cementless and 45 cemented TKAs were reviewed after 1:1 matching. The mean operative time was 8.8 min shorter (P < .01), and the mean amount of drainage was 40.0 ml greater (P = .04) in the cementless cohort. At 1-year postoperatively, there were no significant differences in both cohorts in 2011 Knee Scores and Forgotten Joint Scores-12, with no patients requiring revision surgery (NS). The incidence of RLLs was significantly higher in cementless TKAs (51%) than that in cemented TKAs (22%, P < .01). However, the mean width of RLLs in the cementless TKAs (0.2 mm) was significantly smaller (P < .01) than that in the cemented TKAs (0.8 mm) at 1-year postoperatively with no progression., Conclusion: A recently introduced cementless PS mobile-bearing TKA design demonstrated comparable postoperative and radiographical results to its cemented predecessor at 1-year follow-up., Level of Evidence: Retrospective cohort study, Level III., (© 2022. The Author(s) under exclusive licence to European Society of Sports Traumatology, Knee Surgery, Arthroscopy (ESSKA).)

Purpose: The purpose of this study was to investigate the impact of social isolation and loneliness on the overall survival and death at home in patients with lung cancer., Methods: This prospective cohort study was conducted in a Japanese tertiary hospital. The enrollment period was from April 2018 to March 2020. Patients with pathologically diagnosed advanced lung cancer were included in this study. The primary outcome was overall survival, whereas the secondary outcome was death at home. The exposures were social isolation and loneliness., Results: A total of 211 patients were enrolled and divided into two groups and further into quartiles according to their social isolation and loneliness level, respectively. The hazard ratios of social isolation were 1.65 (95% confidence interval; 1.12 to 2.44) and 1.87 (95% confidence interval; 1.15 to 3.03) in the univariate analysis, while 1.40 (95% confidence interval; 0.92 to 2.13) in the multivariate analysis with complete case and multiple imputation. The odds ratio of death at home with social isolation was 3.47 (95% confidence interval; 1.08 to 11.1) in the multivariate analysis with multiple imputation. Loneliness was not associated with overall survival or death at home., Conclusions: Our study suggests that social isolation may be related to overall survival and death at home among patients with advanced lung cancer. More attention should be given to such patients at the time of diagnosis., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The effect of romosozumab is affected by previous osteoporosis treatment. Here we showed that the duration of the previous treatment just before romosozumab affects the therapeutic effect of romosozumab. Using denosumab and oral bisphosphonates for more than 1 year attenuates the effect of romosozumab., Introduction: As an anti-sclerostin antibody, romosozumab suppresses bone resorption and stimulates bone formation. We investigated whether the effectiveness of 12 months of romosozumab treatment depended on the duration of previous treatment with teriparatide, denosumab, or oral bisphosphonates., Methods: In total, 259 osteoporosis patients received subcutaneous injections of romosozumab (210 mg) every 4 weeks during 2019 and 2020. This study was designed as a pre-post comparison. The end points were the percent changes of bone mineral density (BMD) after 12 months of romosozumab treatment. The patients were divided into seven groups depending on the type and duration of previous treatment before starting romosozumab as follows: non-previous treatment group, change from teriparatide used for 1 year or less/more than 1 year, change from denosumab used for 1 year or less/more than 1 year, and change from oral bisphosphonates used for 1 year or less/more than 1 year., Results: The effects of previous treatment with teriparatide on the effectiveness of 12-month romosozumab did not clearly depend on the duration of treatment (p > 0.05). In contrast, the effects of previous treatments with denosumab or oral bisphosphonates on the effectiveness of 12-month romosozumab depended on the previous treatment duration, which was reflected by the differences in percent change of the spine BMD (both p < 0.05), however, there were no significant differences in the percent change of the total hip BMD (both p > 0.05)., Conclusion: The duration of the previous treatment affected the effectiveness of romosozumab. Using denosumab and oral bisphosphonate for more than 1 year attenuated the effect of romosozumab., (© 2021. International Osteoporosis Foundation and National Osteoporosis Foundation.)

In response to the latest knowledge and the amendment of the Japanese diagnostic criteria for autoimmune pancreatitis (AIP) in 2018, the Japanese consensus guidelines for managing AIP in 2013 were required to be revised. Three committees [the professional committee for developing clinical questions (CQs) and statements by Japanese specialists; the expert panelist committee for rating statements by the modified Delphi method; and the evaluating committee of moderators] were organized. Twenty specialists in AIP extracted the specific clinical statements from a total of 5218 articles (1963-2019) from a search in PubMed and the Cochrane Library. The professional committee made 14, 9, 5, and 11 CQs and statements for the current concept and diagnosis, extra-pancreatic lesions, differential diagnosis, and treatment, respectively. The expert panelists regarded the statements as valid after a two-round modified Delphi approach with individually rating these clinical statements, in which a clinical statement receiving a median score greater than 7 on a 9-point scale from the panel was regarded as valid. After evaluation by the moderators, the amendment of the Japanese consensus guidelines for AIP has been proposed in 2020., (© 2022. The Author(s).)

The histological diagnosis of type 1 autoimmune pancreatitis (AIP) based on the findings obtained by an endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) is feasible, but the diagnostic consistency of this method has not been confirmed. We determined the interobserver agreement among 20 pathologists regarding the diagnosis of type 1 AIP, including the distinction from pancreatic ductal adenocarcinoma (PDAC) using large tissue samples obtained by EUS-FNB. After guidance for diagnosing AIP with biopsy tissues was provided, a round 2 was performed. The median sensitivity and specificity for diagnosing PDAC vs. non-neoplastic diseases were 95.2% and 100%, respectively. In groups of specialists (n = 7) and the generalists (n = 13), Fleiss' к-values increased from 0.886 to 0.958 and from 0.750 to 0.816 in round 2. The concordance was fair or moderate for obliterative phlebitis and storiform fibrosis but slight for ductal lesion of type 1 AIP. Discordant results were due to ambiguous findings and biopsy tissue limitations. Among the specialists, the ratio of cases with perfect agreement regarding the presence of storiform fibrosis increased in round 2, but agreement regarding obliterative phlebitis or ductal lesions was not improved. Although the histological definite diagnosis of type 1 AIP was achieved by most observers in > 60% of the cases, the confidence levels varied. Because some ambiguities exist, the histological diagnostic levels based on the diagnostic criteria of type 1 AIP should not be taken for granted. Guidance is effective for improving accurate PDAC diagnoses (notably by recognizing acinar-ductal metaplasia) and for evaluating storiform fibrosis., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The effectiveness of azathioprine (AZA) in preventing relapse and maintaining autoimmune pancreatitis (AIP) remission has been reported; however, most of these studies are case series with no randomized control trials available in the literature. Therefore, this study performed a systematic review and meta-analysis of the existing literature on this subject to determine the clinical efficacy of AZA as maintenance therapy for AIP patients. A systematic search was performed to identify studies on the clinical efficacy of AZA as maintenance therapy in AIP patients. The crude multiple relapse rate was estimated to assess the ability of AZA to control relapses in AIP. Pooled estimates were obtained using a random-effects model with the DerSimonian-Laird method. We identified AIP patients who did not respond to initial steroid treatment, experienced steroid weaning failure, or those who relapsed during remission as refractory cases. After reviewing the studies, ten articles fulfilled the inclusion criteria and were selected for meta-analysis. Of all 4504 patients, 3534 patients were treated with steroids, and 346 patients were treated with AZA for relapsed AIP. In this meta-analysis, 14/73 (19.2%) patients receiving AZA for refractory AIP relapsed. Meanwhile, 14/47 (29.8%) patients without AZA experienced relapse. The integrated odds ratio for relapse risk in patients receiving AZA was estimated to be 0.52 (p = 0.15). This systematic review and meta-analysis demonstrated the efficacy of AZA in preventing relapse of AIP, which supports the use of AZA as a maintenance treatment in patients with AIP who relapse upon withdrawal of steroid therapy., (© 2021. The Author(s).)

Romosozumab is an effective treatment for spine osteoporosis because it reduces the incidence of new fractures and significantly increases the percent change in the spine BMD at 12 months. The percent change in the spine BMD is higher in patients not previously treated with other anti-osteoporosis medications., Introduction: Romosozumab appeared as a new osteoporosis medication in Japan in 2019. It is an anti-sclerostin antibody, which increases bone formation and suppresses bone resorption. The aim of our study was to elucidate the clinical effects, safety, and predictors of the effects of one-year romosozumab treatment., Methods: This study was an observational study designed as a pre-post study in 262 patients. Romosozumab (210 mg) was administered subcutaneously once every 4 weeks during 12 months. We focused on incidence of new fractures, safety, bone mineral density (BMD) at the spine and total hip, and bone metabolism markers., Results: There were five cases of new fractures during one-year romosozumab treatment. There were no fatal adverse events. Percent changes from baseline in the spine and total hip BMD after 12 months of romosozumab treatment were 10.67% and 2.04%, respectively. Romosozumab had better effects in cases of severe osteoporosis with low spine BMD, high TRACP-5b, and high iP1NP at the start of romosozumab treatment. The percent change in the spine BMD at 12 months was significantly lower in the group transitioning from bisphosphonates than in the group not previously treated with other anti-osteoporosis medications., Conclusion: Romosozumab is an effective treatment for spine osteoporosis because it significantly increases the percent change in the spine BMD at 12 months. The percent change in the spine BMD is higher in patients not previously treated with other anti-osteoporosis medications., (© 2021. International Osteoporosis Foundation and National Osteoporosis Foundation.)

Our 6-month study showed the usefulness of romosozumab for preventing fractures and its safety. It was effective in patients with low baseline spine BMD, high TRACP-5b, and high iP1NP. Percent change from baseline of TRACP-5b and iP1NP after 1 month correlated with that from baseline of BMD after four to 6-month treatment., Introduction: Romosozumab appeared as a new osteoporosis medication in Japan in 2019. It is an anti-sclerostin antibody which increases bone formation and suppresses bone resorption. In this study, we analyzed the actual clinical effects, adverse effects, and the optimal way to evaluate the treatment., Methods: Romosozumab was administered as subcutaneous injection of 210 mg once every 4 weeks. We conducted pre-post study in 185 patients treated for 6 months. We focused on the incidence of new vertebral fractures, safety, bone mineral density (BMD) at the spine and total hip, and bone metabolism markers. We evaluated BMD before romosozumab treatment and after 4 to 6 months and performed the serum analysis before romosozumab treatment, after 1, 3, and 6 months., Results: There was no new fracture during treatment, and there was no fatal adverse event including cardiovascular disease. Since percent changes from baseline of the spine and total hip BMD were 6.34% and 1.53% after 4- to 6-month treatment, the treatment was effective for spine osteoporosis. Tartrate-resistant acid phosphatase 5b (TRACP-5b) and intact type I procollagen N-terminal propeptide (iP1NP) had significant changes during romosozumab treatment (p < 0.05). Percent change from baseline of TRACP-5b and iP1NP after 1 month correlated with percent change from baseline of BMD after 4 to 6 months of treatment., Conclusion: Romosozumab is effective in preventing fractures and useful for increasing the spine BMD. Also, romosozumab is relatively safe to use. It is especially effective in patients with low baseline spine BMD, high TRACP-5b, and high iP1NP.

Objectives: To provide updated clinico-epidemiological information on chronic pancreatitis (CP) in Japan., Methods: We conducted a two-stage nationwide epidemiological survey; the number of CP patients was estimated in the first-stage survey, and their clinical features were examined in the second-stage survey. We surveyed patients with CP who had visited hospitals in 2016 and were diagnosed according to the Japanese diagnostic criteria 2009 (DC2009). Furthermore, we validated the new Japanese diagnostic criteria (DC2019) in patients with early CP diagnosed according to DC2009., Results: The number of patients with definite/probable CP in 2016 was 56,520 (prevalence, 44.5 per 100,000 persons), and that of early CP was 4470 (prevalence, 3.5 per 100,000 persons). We obtained detailed clinical information of 2150 patients with definite/probable CP and 249 patients with early CP. Compared with the early CP cases, the definite/probable CP cases had higher proportions of male (4.8 vs. 1.3), alcohol-related etiology (72.0% vs. 45.8%), smoking history (69.6% vs. 41.0%), diabetes mellitus (42.3% vs. 19.3%), and past history of acute pancreatitis (AP) (50.4% vs. 22.1%). Among the patients with early CP diagnosed according to DC2009, 93 (37.3%) were diagnosed with early CP according to DC2019, but the diagnosis of the remaining 156 (62.7%) patients was downgraded. Alcohol-related etiology, smoking history, early disease onset, and past history of AP were associated with the maintenance of early CP diagnosis in DC2019., Conclusion: We clarified the current status of CP in Japan. Further validation studies are warranted to clarify the diagnostic utility of DC2019.

Background: IgG4-related disease (IgG4-RD) is a systemic inflammatory disease, which includes type 1 autoimmune pancreatitis (AIP). Interleukin-35 (IL-35) exhibits immunosuppressive effects in several autoimmune diseases. However, the expression of IL-35 had not been reported so far in type 1 AIP. We evaluated the association between IL-35 and several cytokines, which mediate the function of Tregs in type 1 AIP., Methods: Plasma was collected from patients with type 1 AIP, alcoholic chronic pancreatitis (ACP), and healthy controls (HC) and assayed for cytokine expression. Total mRNA separated from peripheral blood was isolated from naïve Tregs (nTregs) and effector Tregs (eTregs). EBI3 and IL-12p35 gene expressions were tested in these cells by quantitative PCR. In addition, expression of IL-35 subunits in the pancreatic tissues of patients with type 1 AIP and ACP was analyzed by immunohistochemistry., Results: IL-35 was significantly elevated in type 1 AIP (n = 32) plasma compared with ACP (n = 16) and HC (n = 22), but IL-27 was not. We also detected many cells expressing both EBI3 and IL-12p35 in type 1 AIP tissues. Moreover, in peripheral blood lymphocyte, the percentage of nTregs and eTregs of CD4 + T cells in patients with type 1 AIP (n = 14) compared with HC (n = 15) was significantly decreased and increased, respectively. There were no significant differences of gene expression in patients with type 1 AIP and HC., Conclusions: This study identified elevated expression of plasma IL-35 and tissue IL-35 subunits in patients with type 1 AIP. This might lead to inflammation suppression via activated eTregs. IL-35 might be associated with this anti-inflammatory role, especially against the Th2 response through several cytokines and the differentiation of Tregs in type 1 AIP.

Purpose: To assess the risk of injury to the neurovascular bundle on the interosseous membrane of the leg during drilling for distal screw insertion in open-wedge high tibial osteotomy (OWHTO), and to investigate the possible influence of the method of plate placement on the risk., Methods: This retrospective study involved, 55 patients (32 with a TomoFix plate, 23 with a TriS plate) who underwent postoperative CT scanning of the knee following OWHTO between 2009 and 2018. The angle and position of the locking plate, and the direction of screw insertion relative to the interosseous membrane were analysed., Results: All distal screws had a risk of neurovascular injury. In particular, 25 screws at the #4 hole (45%) had an extended insertion trajectory that intersected with the interosseous membrane. The angle of the proximal part of the TomoFix plate was a significant risk factor. In contrast, methods of TriS plate placement showed no statistically significant differences., Conclusions: Extended insertion trajectories of distal screws were likely to intersect with the interosseous membrane with the neurovascular bundle potentially on its surface; thus, drilling for bicortical fixation posed a risk of neurovascular injury. The risk increased as the TomoFix plate was placed more medially, suggesting that bicortical drilling must be performed with the utmost attention when the plate is placed at the medial position. Given the particularly high risk at the #3 and #4 screw holes, monocortical fixation of a few distal screws is recommended as long as good stability is ensured.

Background: To further clarify the clinico-epidemiological features of autoimmune pancreatitis (AIP) in Japan, we conducted the fourth nationwide epidemiological survey., Methods: This study consisted of two stage surveys; the number of AIP patients was estimated by the first survey and their clinical features were assessed by the second survey. We surveyed the AIP patients who had visited hospitals in 2016., Results: The estimated number of AIP patients in 2016 was 13,436, with an overall prevalence rate of 10.1 per 100,000 persons. The estimated number of newly diagnosed patients was 3984, with an annual incidence rate of 3.1 per 100,000 persons. Compared to the 2011 survey, both numbers more than doubled. We obtained detailed clinical information of 1474 AIP patients. The male-to-female sex ratio was 2.94, the mean age was 68.1, and mean age at diagnosis was 64.8. At diagnosis, 63% patients were symptomatic and nearly half of them presented jaundice. Pancreatic cysts were found in 9% of the patients and calcifications in 6%. Histopathological examination was performed in 64%, mainly by endoscopic ultrasonography-guided fine needle aspiration. Extra-pancreatic lesions were detected in 60% of the patients. Eighty-four % patients received the initial steroid therapy, and 85% received maintenance steroid therapy. Kaplan-Meier analysis revealed that the relapsed survival was 14% at 3 years, 25% at 5 years, 40% at 10 years, and 50% at 15 years. Mortality was favorable, but pancreatic cancer accounted for death in one quarter of fatal cases., Conclusion: We clarified the current status of AIP in Japan.

Background: Although there are numerous reports focusing on surgical indication for intraductal papillary mucinous neoplasm (IPMN), the recurrence patterns following surgery are less widely reported. To ascertain optimal treatment and postoperative surveillance for IPMN patients, we analyzed patterns and risk factors for recurrence after surgery for IPMN., Methods: This study is a retrospective, multi-institutional, observational study, including 1074 patients undergoing surgery for IPMN at 11 academic institutions. We analyzed the risk factors for recurrence after classifying postoperative recurrences into metachronous high-risk lesions (malignant progression of IPMN and/or metachronous pancreatic ductal adenocarcinoma) in the remnant pancreas and extra-pancreatic recurrence., Results: Of 1074 patients undergoing surgery for IPMN, 155 patients (14.4%) developed postoperative recurrence. We found that 34.3% of 70 high-risk lesions in the remnant pancreas occurred over 5 years after surgery, and survival of 36 patients undergoing second operation for high-risk lesions was better than that of 34 patients who did not (P = 0.04). We found four independent risk factors for metachronous high-risk lesions in remnant pancreas: symptoms [P = 0.005, hazard ratio (HR) 1.988], location of pancreatic body/tail (P < 0.001, HR 3.876), main duct size ≥ 10 mm (P = 0.021, HR 1.900), and high-grade dysplasia/invasive intraductal papillary mucinous carcinoma (IPMC) (P < 0.001, HR 3.204). Although six patients (0.7%) with low- or high-grade dysplasia IPMN developed extra-pancreatic recurrence, invasive IPMC was the strongest risk factor for extra-pancreatic recurrence (P < 0.001, HR 39.667)., Conclusion: We suggest that life-time continuous surveillance might be necessary for IPMN patients. Second surgery for metachronous high-risk lesions in remnant pancreas should be considered to improve survival.

Purpose: Magnetic resonance imaging with T1ρ mapping is used to quantify the amount of glycosaminoglycan in articular cartilage, which reflects early degenerative changes. The purposes of this study were to evaluate early degenerative changes in knees after anterior cruciate ligament (ACL) reconstruction by comparing T1ρ values before and 2 years after surgery and investigate whether surgical factors and clinical outcomes are related to differences in T1ρ values., Methods: Fifty patients who underwent unilateral primary ACL reconstruction were evaluated using T1ρ mapping before and 2 years after surgery. Three regions of interest (ROIs) were defined in the cartilage associated with the medial (M) and lateral (L) weight-bearing areas of the femoral condyle (FC) (anterior: MFC1 and LFC1, middle: MFC2 and LFC2, and posterior: MFC3 and LFC3). Two ROIs associated with the tibial plateau (T) were defined (anterior: MT1 and LT1, and posterior: MT2 and LT2). T1ρ values within the ROIs were measured before and 2 years after surgery and compared using the paired t test. Correlations between the difference in T1ρ values at these two time points and patient characteristics, presence of a cartilaginous lesion, graft type, and postoperative anteroposterior laxity were also evaluated using Pearson's and Spearman's correlation coefficients., Results: There was a significant increase in T1ρ before versus 2 years after surgery in the MT1, MT2, LFC1, and LT1 areas, and a significant decrease in the LFC3 and LT2 areas. There was a significant correlation between postoperative anterior-posterior laxity and a postoperative increase in T1ρ values in the MFC3 (r = 0.37, P = 0.013) and MT2 (r = 0.35, P = 0.021) areas. Increases in T1ρ values in the MFC2 area were negatively correlated with KOOS symptoms (ρ = - 0.349, P = 0.027) and quality of life (ρ = - 0.374, P = 0.017) subscale scores., Conclusion: Early degenerative changes in medial articular cartilage were observed with T1ρ mapping at 2 years after ACL reconstruction. Postoperative anterior-posterior laxity is correlated with an increase in T1ρ values in the posteromedial femur and tibia. An increase in T1ρ values in the central medial femoral condyle was associated with knee symptoms., Level of Evidence: III.

Background: Chronic pancreatitis (CP) is a fibro-inflammatory disease of the pancreas. Early diagnosis and intervention, before CP becomes established and irreversible, are essential to improve the long-term outcomes. The world's first diagnostic criteria for early CP were proposed in Japan in 2009, but their clinical utility remains elusive. This study aimed to clarify whether patients with early CP progress to definite CP., Methods: This is a multicenter, prospective study. Patients diagnosed as having early CP according to the Japanese diagnostic criteria were prospectively followed for 2 years. Clinical profiles including symptoms, drinking and smoking status, laboratory data, imaging findings and treatments were analyzed., Results: Among the 83 patients who completed the 2-year follow-up period, four (4.8%) patients progressed to definite CP. The diagnosis of 48 (57.8%) patients was unchanged, and that of 31 (37.3%) patients was downgraded. All the four progressive patients were male, alcohol-related, smokers (3 current and 1 ever), and continued drinking. Comparison of the clinical profiles between the progression group (n = 4) and non-progression group (n = 79) revealed that etiology (alcohol-related), smoking status and presence of acute pancreatitis episodes were associated with the progression to definite CP., Conclusions: The Japanese diagnostic criteria could identify some patients before the progression to definite CP, while the majority of the patients did not progress., Trial Registration Number: UMIN000015992.

Purpose: Varus alignment is known as one of the major causes of medial compartment osteoarthritis (OA). Medial meniscus extrusion also plays a critical role in the in the development of OA. However, studies on the exact relationship between alignment parameters and medial meniscus extrusion are limited. Therefore, this study aimed to investigate this relationship in patients with knee OA., Methods: Based on a retrospective analysis of the outpatient magnetic resonance imaging (MRI) database, 190 knees were identified to be examined using weight-bearing, whole-leg radiographs and MRIs within 3 months from the first consultation. Subsequently, various parameters of lower leg alignment were measured, which affected the knee varus in radiographs. Finally, a statistical analysis was performed to assess the relationships between the OA grade, distance of medial meniscus extrusion (MME), and alignment parameters; hip-knee-ankle angle (HKAA), percentage of mechanical axis (% MA), medial proximal tibial angle (MPTA), and joint line convergence angle (JLCA). The subjects were divided according to the presence or absence of MME (Group A: MME distance below 3 mm, Group B: MME distance 3 mm and above) to assess the differences in each alignment parameter correlated with MME distance between the groups., Results: MME distance significantly increased with OA grade progression. HKAA, % MA, MPTA, and JLCA significantly correlated with medial meniscus extrusion distance (r = - 0.21, - 0.23, - 0.16, 0.3, respectively). Multiple regression analysis of each significant alignment combined with age, sex, and body mass index revealed that HKAA, % MA, MPTA, and JLCA were significant independent factors of MME distance (P = 0.008, 0.0026, 0.011, 0.0001, respectively). These significant findings were reinforced in group B. In contrast, the correlation between alignment parameters and medial meniscus extrusion distance was not significant in group A., Conclusion: Varus alignment factors are related to MME distance especially in extruded meniscus knees, as the OA grade progressed. Therefore, the coexistence of varus alignment and MME can be the risk factors for OA progression. As the low MPTA was an independent alignment factor for generating varus alignment, patients with osteoarthritis of the knee with both, low MPTA and MME could be the appropriate candidates for early intervention by high tibial osteotomy., Level of Evidence: III.

Purpose: To evaluate preoperative soft tissue balance for total knee arthroplasty (TKA), varus/valgus stress radiographs has been used in previous studies. While the joint line of femur and tibia is almost parallel in healthy and postoperative knees, osteoarthritis (OA) knees exhibit articular cartilage wear that causes the joint line tilting even in a non-stress condition. Therefore, the exact angle of the joint line might mislead to understand the joint laxity in OA knees. The purpose of this study was to evaluate soft tissue balance in varus OA knees using preoperative stress radiographs under three different constant loads, taking the articular cartilage wear into consideration., Methods: One hundred and eighteen varus-deformed OA knees in 102 patients were investigated before primary TKA. Preoperative knee radiographs were obtained in the anteroposterior view with no stress (defined as the neutral condition) and with varus and valgus stresses (5, 10, and 15 kg) in extension. Two different types of joint line angle (JLA), the absolute JLA (an exact angle of joint line) and the relative JLA (the absolute JLA minus the JLA in the neutral condition), were compared for the same load with the paired t test., Results: The absolute JLA was 7.9 ± 1.2°/- 1.5 ± 2.2° under varus/valgus 15 kg stress, 6.7 ± 2.4°/- 0.3 ± 2.1° under varus/valgus 10 kg stress, and 4.7 ± 2.4°/1.1 ± 2.2° under varus/valgus 5 kg stress. Significant differences in the numerical values of the absolute JLA were observed between varus and valgus stresses for each load. The neutral JLA was 3.2 ± 2.0°. The relative JLA was 4.8 ± 2.1°/- 4.7 ± 1.8° under varus/valgus 15 kg stress, 3.5 ± 2.0°/- 3.5 ± 1.8° under varus/valgus 10 kg stress, and 1.5 ± 1.9°/- 2.1 ± 1.8° under varus/valgus 5 kg stress. No significant differences in the numerical values of the relative JLA were observed between varus and valgus stresses for each load., Conclusions: Consideration of cartilage wear allowed knee laxity to be evaluated more precisely in this study than in previous reports. It was shown that medial soft tissue contracture did not always exist, even in varus OA knees. Regarding clinical relevance, surgeons should be aware that underestimating medial soft tissue laxity due to reliance on the absolute JLA might lead to excessive medial tissue release and result in postoperative instability and lower patient satisfaction., Level of Evidence: IV.

Heat-shock protein 90 (Hsp90) was recently identified as a silencing factor required for RNA interference (RNAi)-dependent heterochromatin assembly in the fission yeast Schizosaccharomyces pombe. As Hsp90 is known to contribute to the formation of small RNA-containing effector complexes, it would be expected that Hsp90 is also involved in the RNAi pathway in fission yeast. However, upon investigation, we found it very difficult to determine how Hsp90 modulates RNAi-dependent heterochromatin assembly in the cell. A lack of detectable small interfering RNAs in hsp90 mutant cells prevented us from examining the role of Hsp90 in the siRNA loading in the cell. In addition, deletion of genes encoding co-chaperones for Hsp90 appears not to affect RNAi-dependent pericentromeric silencing. One possible approach for elucidating the role of Hsp90 in RNAi-dependent heterochromatin assembly is the use of forward genetic screens to identify novel factors linking Hsp90 with other known RNAi factors. Here, we discuss the benefits of conducting further screenings and present some technical hints to help identify new factors.

Purpose: Neutral lower limb alignment does not necessarily produce a horizontal joint line after total knee arthroplasty (TKA). The orientation of the pre- and postoperative tibial mechanical axes (TMAs-G), tibial component, and joint line relative to the ground were evaluated., Methods: The study group included 46 knees, 23 posterior-stabilized (PS) and 23 bicruciate-stabilized (BCS) TKAs. Using whole-leg standing radiographs, the static orientation of the pre- and postoperative TMAs-G and the tibial component as well as the postoperative alignment were measured. Applying image-matching techniques, the dynamic coronal orientation of the tibial component and joint line over the stance phase of gait were analysed. The correlation between static and dynamic orientation of the tibial component and differences in the joint line between the PS and BCS TKAs were evaluated., Results: In standing, the postoperative TMA-G (0.8° ± 2.8°) and tibial component (1.5° ± 2.4°) were laterally tilted with a strong correlation. The preoperative lateral tilt of the TMA-G (7.9° ± 5.1°) was a significant predictor of the postoperative TMA-G. The lateral tilt of the tibial component increased to 5.1° ± 2.4° on dynamic analysis, and was moderately correlated to static orientation. The dynamic orientation of the joint line was smaller for the BCS (1.8° ± 2.4°) compared to the PS (5.5° ± 2.7°) TKA., Conclusion: Even with a mechanically well-aligned TKA, a lateral tilt of the tibial component was identified due to the lateral tilt of the postoperative TMA-G and the stance phase of gait. The BCS can better accommodate the residual lateral tilt of the joint line due to the 3° medial inclination of the joint surfaces of the implant. This study increases the awareness of surgeons regarding the possibility of the coronal joint line orientation to influence preoperative TMA-G and be accommodated by articular surface design, even in mechanically aligned TKA., Level of Evidence: IV.

Background: Dendritic cells (DCs), primary antigen-presenting cells, are now well known as an immunoregulator of many aspects of immune responses including inflammatory bowel diseases (IBDs) such as Crohn's disease and ulcerative colitis. We have reported that PIR-A/B high cDCs (conventional DCs) appeared in dextran sodium sulfate (DSS)-induced colitis and serve as a negative immunoregulator in an animal model of IBD. The immunoregulatory role of PIR-A/B + cDCs was confirmed in both an in vitro culture system and an in vivo transfer experiment. Here, we have investigated the differentiation process of PIR-A/B + cDCs in an in vitro inflammatory environment and examined their functions., Methods: cDCs were isolated from the large intestinal lamina propria from C57BL/6 mice and cultured in an inflammatory environment (IL-1, IL-6, TNFα, and LPS). The appearance of PIR-A/B + cDCs was determined after 24 h, and the in vitro-induced PIR-A/B + cDCs were functionally and genetically examined., Results: PIR-A/B + cDCs were detected after a 24-h culture only in the inflammatory environment, and the cells acted as a negative immunoregulator when examined in an allogenic mixed leukocyte reaction (MLR). The message level of IL-27 was highly upregulated in PIR-A/B + cDCs, while that of high mobility group box 1 protein (HMGB1) was downregulated in these cells. This was well in accordance with the fact that PIR-A/B + cDCs showed a suppressive function against activated T cells. We found that PIR-A/B + cDCs produced IL-27, as verified by an ELISA assay, and that the inhibitory effect by PIR-A/B + cDCs was, at least partially, due to IL-27. Furthermore, CD85d + cells, a human counterpart of mouse PIR-A/B + cDCs, were found in the lamina propria of the colon of the patients with ulcerative colitis, but not in the similar part of the non-inflammatory area of colon specimens from patients with colon cancer., Conclusions: PIR-A/B + cDCs induced in an in vitro inflammatory environment model showed a suppressive function against activated T cells by producing an inhibitory cytokine.

Background: Several reports on immunoglobulin (Ig)G4-related disease (IgG4-RD) with gastrointestinal involvement (IgG4-related gastrointestinal disease; IgG4-GID) have been published, although this entity has not been fully established clinicopathologically. Thus, we carried out a multicenter survey., Methods: Patients with possible IgG4-GID who underwent resection were collected. Histologic slides were reevaluated, and eight cases with diffuse lymphoplasmacytic infiltration but without numerous neutrophils, granulations or epithelioid granulomas were further analyzed., Results: Overall, the IgG4 counts (87-345/high-power field) and IgG4/IgG-positive ratio were high (44-115%). The demographic findings included advanced age among the patients (55-80 years) and male preponderance (six cases). Six lesions (five gastric, one esophageal), consisting of lymphoplasmacytic infiltration with neural involvement in the muscularis propria and/or bottom-heavy plasmacytosis in the gastric mucosa, were histologically regarded as highly suggestive of IgG4-RD. Storiform fibrosis and obliterative phlebitis were found in two cases, and the former gave rise to a 7-cm-sized inflammatory pseudotumor (IPT) in one case. Ulceration and carcinoma co-existed in three and two lesions, respectively. All the patients had other organ involvement (OOI), and serum IgG4 levels were markedly elevated (four of five patients). The remaining two cases with gastric IPTs featuring reactive nodular fibrous pseudotumor or nodular lymphoid hyperplasia were regarded as possible cases of IgG4-RD because of the histologic findings and lack of OOI., Conclusions: IgG4-GID is found in the setting of IgG4-RD, often with ulceration or cancer. Characteristic histologic findings are observed in the muscularis propria and gastric mucosa. Cases with IPT may be heterogeneous, and there may be mimickers of IgG4-GID.

Purpose: The purpose of this study was to evaluate the relationship between posterior tibial slope and knee kinematics in bi-cruciate stabilized (BCS) total knee arthroplasty (TKA), which has not been previously reported., Methods: This computer simulation study evaluated Journey 2 BCS components (Smith & Nephew, Inc., Memphis, TN, USA) implanted in a female patient to simulate weight-bearing stair climbing. Knee kinematics, patellofemoral contact forces, and quadriceps forces during stair climbing (from 86° to 6° of flexion) were computed in the simulation. Six different posterior tibial slope angles (0°-10°) were simulated to evaluate the effect of posterior tibial slope on knee kinematics and forces., Results: At 65° of knee flexion, no anterior sliding of the tibial component occurred if the posterior tibial slope was less than 10°. Anterior contact between the anterior aspect of the tibial post- and the femoral component was observed if the posterior tibial slope was 6° or more. An increase of 10° in posterior tibial slope (relative to 0°) led to a 4.8% decrease in maximum patellofemoral contact force and a 1.2% decrease in maximum quadriceps force., Conclusion: BCS TKA has a wide acceptable range of posterior tibial slope for avoiding knee instability if the posterior tibial slope is less than 10°. Surgeons should prioritize avoiding adverse effects over trying to achieve positive effects such as decreasing patellofemoral contact force and quadriceps force by increasing posterior tibial slope. Our study helps surgeons determine the optimal posterior tibial slope during surgery with BCS TKA; posterior tibial slope should not exceed 10° in routine clinical practice.

In 1995, Yoshida and colleagues proposed the concept of "autoimmune pancreatitis" (AIP), which has recently been recognized as a new pancreatic inflammatory disease. Recent studies have suggested the existence of two subtypes of AIP: type 1, which involves immunoglobulin G4 (IgG4) and is the pancreatic manifestation of IgG4-related disease (IgG4-RD); and type 2, which is characterized by granulocytic epithelial lesions. Type 2 AIP is thought to be rare in Japan. Type 1 AIP is characterized by increased serum IgG4 concentrations, lymphoplasmacytic infiltrations, storiform fibrosis, and obliterative phlebitis. However, although type 1 AIP has become increasingly recognized, many clinical and basic issues remain to be solved. This review provides an overview of the recent clinical and basic knowledge of type 1 AIP.

In the original publication of this article, the Table 2 was published incorrectly.

Background: Pathophysiology of type 1 autoimmune pancreatitis (AIP) is still unclear. We previously reported that M2 macrophages might play an important role in type 1 AIP. Recently, it has been reported that basophils regulate differentiation to M2 macrophages. In this study, we investigated basophils from the pancreatic tissue and peripheral blood of individuals with type 1 AIP., Methods: By using immunohistochemistry, we investigated basophils in pancreatic tissue from 13 patients with type 1 AIP and examined expression of toll-like receptors (TLRs) by these cells. Additionally, we obtained peripheral blood samples from 27 healthy subjects, 40 patients with type 1 AIP, 8 patients with alcoholic chronic pancreatitis, 10 patients with bronchial asthma, and 10 patients with atopic dermatitis, and analyzed activation of basophils by stimulating them with ligands of TLR1-9. We also compared TLR expression in basophils from the tissue and blood samples., Results: Basophils were detected in pancreatic tissues from 10 of 13 patients with type 1 AIP. Flow cytometric analysis revealed that the ratios of basophils activated by TLR4 stimulation in type 1 AIP (9.875 ± 1.148%) and atopic dermatitis (11.768 ± 1.899%) were significantly higher than those in healthy subjects (5.051 ± 0.730%; P < 0.05). Levels of basophils activated by TLR2 stimulation were higher in seven type 1 AIP cases. Furthermore, stimulation of TLR2 and/or TLR4, which were expressed by basophils in pancreas, activated basophils in peripheral blood., Conclusions: Basophils activated via TLR signaling may play an important role in the pathophysiology of type 1 AIP.

Introduction: The primary aim of the current study was to examine the usefulness of our proposed olfactory scoring system in chronic rhinosinusitis (CRS) patients with olfactory disorders (n = 213) receiving endoscopic sinus surgery (ESS)., Materials and Methods: Analyzed patients were divided into two groups: an eosinophilic CRS (ECRS) group (n = 153); and a non-ECRS group (n = 60). The T&T recognition threshold test was used to evaluate olfaction at baseline and at 3 and 12 months after ESS. Patients with mean recognition threshold < 2.0 at 3 or 12 months or with a decrease of ≥ 1.0 as compared with baseline were defined as showing clinical improvement. We scored mucosal conditions as normal (0 points), edema (1 point), and polyp (2 points) at the canopy of olfactory cleft (OC), middle and superior turbinates, superior nasal meatus, and sphenoethmoidal recess during ESS. The total score of OCs (SOCs) was calculated (range 0-20 points). We compared SOCs between ECRS and non-ECRS groups. Factors related to olfactory improvement were also investigated using uni- and multivariate analyses., Results: SOCs in the ECRS and non-ECRS groups showed significant correlations with mean recognition thresholds at baseline and at 3 and 12 months. In the multivariate analysis for predicting improvement of mean recognition threshold, lower SOCs were significantly associated with olfactory improvement factors at 3 and 12 months postoperatively in the ECRS group., Conclusion: SOCs appears promising for estimating olfactory prognosis after ESS in CRS patients.

Background: The effect of maintenance steroid treatment (MST) in reducing the risk of relapse in patients with autoimmune pancreatitis (AIP) remains under debate. The aim of this study was to validate the effect of MST on AIP administered in accordance with the 2010 Japanese consensus guidelines., Methods: The clinical data of patients with (n = 510) from 22 high-volume centers in Japan were studied. The primary endpoints were the relapse rates (RRs) in patients administered MST versus those not administered MST. The secondary endpoints were the optimal dose and duration of MST in terms of steroid toxicity and the predictors of relapse., Results: The RRs were 10.0% within 1 year, 25.8% within 3 years and 35.1% within 5 years. The RR in the steroid therapy group reached a plateau at 42.7% at 7 years. In terms of the optimal dosage, the overall RR in the MST 5 mg/day group was 26.1%, which was significantly lower than that in the group which had discontinued steroid therapy (45.2%; p = 0.023) or was receiving MST at 2.5 mg/day (43.4%, p = 0.001). The RRs in the group receiving MST at ≥5 mg/day versus the patient group receiving MST at <5 mg/day were 10.6 vs. 10.3% within 1 year, 23.5 vs. 32.9% within 3 years and 32.2 vs. 41.3% within 5 years, respectively (log-rank, p = 0.028). The best cutoff value of the total steroid dose for serious steroid toxicity was 6405 mg, with a moderate accuracy of 0.717 determined using the area under the curve. Presence of diffuse pancreatic swelling [odds ratio OR) 1.745; p = 0.008) and MST at >5 mg/day were identified as predictors of relapse (OR 0.483; p = 0.001)., Conclusions: The RR could continue to increase for 7 years even under MST. Based on our analysis of the side effects of steroid therapy, MST at 5 mg/day for 2 (total 4625 mg) to 3 (total 6425 mg) years might be a rational and safe therapeutic strategy in terms of keeping the RR to <30% while avoiding potential steroid toxicity.

Purpose: The purpose of this study was to assess the differences in proximal tibial deformity between closing wedge (CW) and opening wedge (OW) high tibial osteotomy (HTO) and their effects on the difficulty of total knee arthroplasty (TKA) conversion., Methods: Surgical simulations of CW-HTO and OW-HTO were performed on the same 3D computer-aided design knee models reconstructed from computed tomographic datasets of patients (median age 77 years; range 55-87 years; 40 knees) with medial osteoarthritis or osteonecrosis, and proximal tibial deformities were analysed. Subsequent TKA conversion was simulated in both CW and OW models, and the interference between the tibial implant and endosteal cortex was assessed., Results: The difference in the metaphyseal-diaphyseal angle in the CW-HTO and OW-HTO groups was 0.3° ± 0.2° (p < 0.001). The mechanical axis in the CW-HTO group was shifted laterally by 1.8 ± 1.1 mm relative to that in the OW-HTO group (p < 0.001) on the resection surface in TKA. Finally, the TKA tibial implant was substantially closer to the endosteal cortex in the CW-HTO group (mean 5.6 ± 1.6 mm) than to that in the OW-HTO group (mean 7.3 ± 1.6 mm) (p < 0.001)., Conclusion: The difference in the post-operative angular deformities of the proximal tibia between CW-HTO and OW-HTO was considered to be clinically irrelevant. The risk of interference between TKA tibial implant and endosteal bone was greater after CW-HTO than after OW-HTO. For clinical relevance, the difference between the two techniques has little influence on subsequent TKA difficulty regarding the proximal tibial deformity, although preoperative planning is obligatory, particularly after CW-HTO, to prevent interference with the tibial implant., Level of Evidence: II.

Purpose: To investigate the optimal starting points for drilling on the lateral femoral condyle for better coverage of the anatomical footprint of the anterior cruciate ligament (ACL) using the outside-in (OI) technique in a single-bundle ACL reconstruction., Methods: Femoral tunnel drilling was simulated on three-dimensional bone models from 40 subjects by connecting the centre of the ACL footprint with various points on the lateral femoral surface. The percentage of the femoral footprint covered by apertures of the virtual tunnel sockets with 9 mm diameter was calculated for each tunnel., Results: The mean percentages of the femoral footprint covered by the apertures of the virtual tunnel sockets were significantly higher when drilled at 2 and 3 cm from the lateral epicondyle on a 45° line and a 60° line anterior from the proximal-distal axis than the other points. However, articular cartilage damage was occurred in nine subjects at 3 cm on a 60° line and eight subjects at 3 cm on a 45° line. Posterior wall blowout occurred in five subjects at 3 cm on a 45° line. Thus, OI drilling at 3 cm from the epicondyle has a risk of these complications., Conclusion: During the OI drilling of the femoral tunnel, connecting the centre of the anatomical footprint of the ACL and the entry drilling point at 2 cm from the lateral epicondyle on between the 45° line and the 60° line anterior from the proximal-distal axis provides an oval-shaped socket aperture that covers and restores the native ACL footprint as nearly as possible., Level of Evidence: III.

Purpose: Laparoscopic and open surgical skills differ distinctly from one another. Our institute provides laparoscopic surgical skills training for currently active surgeons throughout Japan. This study was performed to evaluate the effectiveness of our 2-day standardized laparoscopic surgical skills training program over its 10-year history., Methods: We analyzed the data on trainee characteristics, outcomes of skills assessments at the beginning and end of the program, and self-assessment after 6 months using a questionnaire survey., Results: From January 2004 to December 2013, 914 surgeons completed the 2-day training program. Peaks in postgraduate years of experience occurred at years 2, 8, and 17. Suturing and knot tying times were significantly shorter at the end than beginning of the program (p < 0.001). However, the numbers of misplaced and loose sutures, maximum misplacement distance, and number of injuries to the rubber sheet were significantly higher at the end of the program (p < 0.001). A questionnaire at 6 months post-training revealed significant improvements in the overall skills and forceps manipulation (p < 0.0001) and a significantly shorter mean operation time for laparoscopic cholecystectomy (p < 0.001)., Conclusion: Our 2-day training program for active Japanese surgeons is thus considered to be effective; however, continued voluntary training is important and further outcomes assessments are needed.

Chronic pancreatitis is considered to be an irreversible progressive chronic inflammatory disease. The etiology and pathology of chronic pancreatitis are complex; therefore, it is important to correctly understand the stage and pathology and provide appropriate treatment accordingly. The newly revised Clinical Practice Guidelines of Chronic Pancreatitis 2015 consist of four chapters, i.e., diagnosis, staging, treatment, and prognosis, and includes a total of 65 clinical questions. These guidelines have aimed at providing certain directions and clinically practical contents for the management of chronic pancreatitis, preferentially adopting clinically useful articles. These revised guidelines also refer to early chronic pancreatitis based on the Criteria for the Diagnosis of Chronic Pancreatitis 2009. They include such items as health insurance coverage of high-titer lipase preparations and extracorporeal shock wave lithotripsy, new antidiabetic drugs, and the definition of and treatment approach to pancreatic pseudocyst. The accuracy of these guidelines has been improved by examining and adopting new evidence obtained after the publication of the first edition.

Purpose: The first purpose of this study was to compare the reproducibility of two-dimensional (2D) and three-dimensional (3D) measurements for preoperative planning of the femoral side in total knee arthroplasty (TKA). The second purpose was to evaluate the factors affecting the differences between the 2D and 3D measurements., Methods: Two-dimensional and 3D measurements for preoperative planning of the femoral side in TKA were evaluated in 75 varus knees with osteoarthritis. The femoral valgus angle, defined as the angle between the mechanical and anatomical axes of the femur, and the clinical rotation angle and surgical rotation angle, defined by the angles between the posterior condylar line and the clinical or surgical transepicondylar axes, respectively, were analysed using 2D (radiographs and axial CT slices) and 3D (3D bone models reconstructed from CT images) measurements., Results: For all variables, 3D measurements were more reliable and reproducible than 2D measurements. The medians and ranges of the clinical rotation angle and surgical rotation angle were 6.6° (-1.7° to 12.1°) and 2.3° (-2.5° to 8.6°) in 2D, and 7.1° (2.7° to 11.4°) and 3.0° (-2.0° to 7.5°) in 3D. Varus/valgus alteration of the CT scanning direction relative to the mechanical axis affected the difference in clinical rotation angles between 2D and 3D measurements., Conclusion: Significantly, smaller values of the clinical rotation angle and surgical rotation angle were obtained by 2D compared to 3D measurements, which could result in internal rotation of the femoral component even if the surgeon performs the bone cutting precisely. Regarding clinical relevance, first, this study confirmed the reliability of 3D measurements. Second, it underscored the risk of internal rotation of the femoral component when using 2D measurement, even with precise bone cutting technique. These results will help surgeons avoid malpositioning of the femoral component if 2D measurements are used for preoperative planning in TKA., Level of Evidence: Prospective comparative study, Level Ш.

Purpose: Prediction of the risk of osteoarthritis in asymptomatic active patients with an isolated injury of the posterior cruciate ligament (PCL) is difficult. T1ρ magnetic resonance imaging (MRI) enables the quantification of the proteoglycan content in the articular cartilage. The purpose of this study was to evaluate subclinical cartilage degeneration in asymptomatic young athletes with chronic PCL deficiency using T1ρ MRI., Methods: Six athletes with chronic PCL deficiency (median age 17, range 14-36 years) and six subjects without any history of knee injury (median age 31.5, range 24-33 years) were recruited. Regions of interest were placed on the articular cartilage of the tibia and the distal and posterior areas of the femoral condyle, and T1ρ values were calculated., Results: On stress radiographs, the mean side-to-side difference in posterior laxity was 9.8 mm. The T1ρ values at the posterior area of the lateral femoral condyle and the superficial layer of the distal area of the medial and lateral femoral condyle of the patients were significantly increased compared with those of the normal controls (p < 0.05). At the tibial plateau, the T1ρ values in both the medial and lateral compartments were significantly higher in patients compared with those in the normal controls (p < 0.05)., Conclusion: T1ρ MRI detected unexpected cartilage degeneration in the well-functioning PCL-deficient knees of young athletes. One should be alert to the possibility of subclinical cartilage degeneration even in asymptomatic patients who show no degenerative changes on plain radiographs or conventional MRI., Level of Evidence: IV.

Background: Two types of autoimmune pancreatitis (AIP) have been reported, lymphoplasmacytic sclerosing pancreatitis and idiopathic duct-centric chronic pancreatitis (IDCP), which are now recognized as type 1 and type 2 AIP, respectively. Since the clinical features of type 2 AIP have not been fully elucidated and this condition is frequently accompanied by inflammatory bowel disease (IBD), we performed a nationwide survey of patients with AIP complicated with IBD to precisely characterize this disease entity., Methods: We collected 138 cases of pancreatitis with complicating IBD from affiliated institutes specializing in AIP or IBD, and comparative study between the IDCP groups and type 1 AIP was performed., Results: Histological examination revealed 15 AIP cases to be IDCP of institutional diagnosis, among which 11 cases were upgraded to IDCP of central diagnosis by an expert pathologist. The IDCP group exhibited younger onset age, no gender bias, frequent abdominal pain, and normal IgG4 value, similar to those of type 2 AIP reported previously. We also witnessed a lower prevalence of jaundice in type 2 AIP than in type 1 AIP that corresponded to imaging findings of less frequent pancreatic head swelling and scarce bile duct stenosis., Conclusions: A characteristic feature of type 2 AIP compared with type 1 AIP is a low frequency of obstructive jaundice that is related to rare lower bile duct stricture due to lower prevalence of pancreatic head swelling. Contrary to type 1 AIP, lower bile duct stricture in this condition has no apparent relation to sclerosing cholangitis.

Purpose: The aim of the present study was to clarify whether varus-valgus laxities under static stress in extension, femoral condylar lift-off during walking, and patient-reported outcomes after total knee arthroplasty (TKA) were correlated with each other., Methods: Ninety-four knees, which had undergone posterior-stabilized TKA, were analysed. The varus-valgus laxity during knee extension was measured using a stress radiograph. New Knee Society Score (KSS) questionnaires were mailed to all patients. Correlations between the values of stress radiographs and KSS were analysed. Additionally, continuous radiological images were taken of 15 patients while each walked on a treadmill to determine condylar lift-off from the tibial tray using a 3D-to-2D image-to-model registration technique. Correlations between the amount of lift-off and either the stress radiograph or the KSS were also analyzed., Results: The mean angle measured was 5.9 ± 2.7° with varus stress and 5.0 ± 1.6° with valgus stress. The difference between them was 0.9 ± 2.8°. Varus-valgus laxities, or the differences between them, did not show any statistically significant correlation with either component of the KSS (p > 0.05). The average amount of femoral condylar lift-off during walking was 1.4 ± 0.8 mm (medial side) and 1.3 ± 0.6 mm (lateral side). The amount of lift-off did not correlate with either varus-valgus laxities or the KSS (p > 0.05)., Conclusions: No correlations were found among varus-valgus laxities under static stress in extension, femoral condylar lift-off during walking, or patient-reported outcomes after well-aligned TKA. This study suggests that small variations in coronal laxities do not influence lift-off during walking and the patient-reported outcomes., Level of Evidence: IV.

Background: High serum immunoglobulin G4 (IgG4) levels and IgG4-positive plasma cell infiltration are characteristic of type 1 autoimmune pancreatitis (AIP). It is unclear whether innate immunity is a cause of type 1 AIP; the possible involvement of microbial infection has been suggested in its pathogenesis. To clarify the pathogenesis of type 1 AIP, we investigated Toll-like receptors (TLRs) in type 1 AIP patients., Methods: We studied nine cases of type 1 AIP with ten cases of alcoholic chronic pancreatitis (ACP) and three of the samples from non-tumorous lesion of neuroendocrine tumor (NET) as control subjects. We counted the number of TLR1-11-positive cells immunohistochemically stained with anti-TLR1-11 antibodies. To identify TLR-positive cells in pancreata from type 1 AIP patients, we used a double-immunofluorescence method and counted the numbers of identifiable CD68-, CD163-, CD123-, and CD20-positive cells., Results: In type 1 AIP, TLR7 (8.815 ± 1.755), TLR8 (3.852 ± 1.489), and TLR10 (3.852 ± 0.921) were highly expressed. Only the ratio of TLR7 per monocyte was significantly higher in type 1 AIP (0.053 ± 0.012) than in ACP (0.007 ± 0.004; p < 0.01) and non-tumorous lesion of NET (0.000 ± 0.000; p < 0.01). In type 1 AIP, the CD163 to TLR7 ratio (0.789 ± 0.031) was significantly higher both than that of CD123 to TLR7 ratio (0.034 ± 0.006; p < 0.001) and CD20 to TLR7 ratio (0.029 ± 0.010; p < 0.001)., Conclusions: TLR7 might be key pattern-recognition receptors involved in the development of type 1 AIP.

Purpose: To evaluate the influences of knee flexion angle and portal position on the location of femoral tunnel outlet in anterior cruciate ligament (ACL) reconstruction with the anteromedial (AM) portal technique., Methods: We recruited 6 volunteers with 12 normal knees. Each knee was flexed 120° or 135° and scanned with an open MRI. A 3D knee model was created. Virtual femoral tunnels were created on the footprint of the AM bundle and the posterolateral (PL) bundle of the ACL from three arthroscopic portals: the standard AM portal, the far medial and low portal, and the far medial and high (FMH) portal. The location of the femoral tunnel outlet was evaluated by comparing to the dissected cadaveric knee., Results: Both increased flexion angle and lowering the drilling portal have a similar influence on the femoral tunnel outlet by moving them anterior and distally. Medialization of the portal moves them posteriorly and distally. PL tunnels created on the 120° knee model are more likely to be located under the lateral head of the gastrocnemius especially when they are drilled through the AM or FMH portals., Conclusion: If the femoral tunnel outlet is located under the soft tissue such as gastrocnemius attachment, suspension fixation devices may lapse into fixation failure by sitting on the soft tissue rather than the cortex bone surface. It is more desirable to drill in 135° knee flexion rather than 120°, and through a lower portal, to avoid creating the femoral tunnel outlet under soft tissues.

Purpose: We aimed to clarify whether the coronal alignment after medial unicompartmental knee arthroplasty (UKA) is predictable using preoperative full-length valgus stress radiography., Methods: Thirty-seven consecutive patients with a mean age of 71.5 ± 7.0 years awaiting medial UKA were recruited. Full-length weight-bearing radiographs of the lower limbs were obtained pre- and postoperatively. Preoperative full-length valgus stress radiography in the supine position was also performed, and the transition of the hip-knee-ankle angle (HKAA) and the weight-bearing ratio were assessed. The tibia first cut technique was used, and the distal femur was cut parallel to the cutting surface of the proximal tibia during surgery., Results: The mean postoperative HKAA was 2.0° ± 2.1° varus, and the mean weight-bearing ratio was 43.1 ± 7.7 %; each of these parameters demonstrated significantly strong correlations with the values on the preoperative valgus stress radiographs (p < 0.01), while the correlation between the postoperative alignment and the preoperative standing alignment without stress was moderate (p < 0.01). The postoperative alignment was slightly undercorrected compared to that observed on the valgus stress radiographs (p < 0.05), and no knees exhibited evident overcorrection compared to that on the valgus stress radiographs., Conclusion: Preoperative valgus stress radiography is useful for evaluating the correctability of varus deformities and predicting the postoperative coronal alignment. For clinical relevance, performing preoperative valgus stress radiography would help to more precisely select patients and, when combined with the tibia first cut technique, aid in achieving the expected knee alignment and avoid severe undercorrection or overcorrection., Level of Evidence: Diagnostic study, Level II.

Purpose: In total knee arthroplasty (TKA), a high soft-tissue tension in extension at the time of operation would cause a post-operative flexion contracture. However, how tight the extension gap should be during surgery to avoid a post-operative flexion contracture remains unclear. The hypothesis is that some laxity in the intraoperative extension gap is necessary to avoid the post-operative flexion contracture., Methods: A posterior-stabilized TKA was performed for 75 osteoarthritic knees with a varus deformity. The intraoperative extension gap was measured using a tensor device that provides the gap length and the angle between the femoral component and the tibial cut surface. The medial component gap was defined as the gap calculated by subtracting the selected thickness of the tibial component, including the polyethylene liner, from the extension gap at the medial side. Then, the patients were divided into three groups according to the medial component gap, and post-operative extension angle measured 1 year after the surgery was compared between each groups., Results: One year post-operatively, a flexion contracture of more than 5° was found in 0/34 patients when the medial component gap was more than 1 mm, in 2/26 (8%) patients when the gap was between 0 and 1 mm, and in 3/15 (20%) patients when the gap was <0 mm. Three factors were associated significantly with the post-operative extension angle: age, preoperative extension angle, and medial component gap., Conclusion: The intraoperative extension gap is related to the post-operative extension angle. Surgeons should leave more than 1-mm laxity after the implantation to avoid the post-operative flexion contracture. As a clinical relevance, this study clarified the optimal extension gap to avoid the post-operative flexion contracture., Level of Evidence: Prospective comparative study, Level II.

Purpose: Controversy still exists whether coronal malalignment would influence the long-term survival of total knee arthroplasty (TKA). The hypothesis was that an improved design of the articular surface of modern TKA would prevent the increase in contact stresses and thus decrease the wear even when the implant was placed in a varus position. Two different designs of TKA were compared biomechanically and clinically., Methods: The patients whose prosthesis was initially placed in a varus alignment by the postoperative long-leg radiographs were selected. Seventeen knees using the NexGen LPS and 16 knees using the MG I were examined. Changes in postoperative alignment and the thickness of the polyethylene insert in a follow-up period of approximately 7 years were evaluated. Additionally, an in vitro biomechanical testing was conducted to measure the contact stresses and the contact area at the tibiofemoral joint of the NexGen LPS and the MG I components mounted on a servohydraulic testing device., Results: Although the long-leg alignment did not change in NexGen LPS, the varus alignment significantly progressed in MG I. The thickness of polyethylene insert in MG I decreased a significantly greater amount compared with that in NexGen LPS. Biomechanical test showed that the NexGen LPS had a larger contact area and lower mean and peak contact stresses than the MG I significantly., Conclusion: These results suggest that comprehensive factors of modern prosthesis including improved implant designs could improve the durability of polyethylene insert and decrease implant failures due to component malalignment.

Background: Dendritic cells (DCs) may play an important role in forms of inflammatory bowel disease (IBD), such as Crohn's disease and ulcerative colitis. DCs are generally recognized as initiators of acquired immunity and also serve as regulators of both innate and acquired immunity. We used the animal model of colitis induced by dextran sodium sulfate (DSS), and examined whether DCs prepared from the colon show immunoregulatory roles in the termination of DSS-induced colitis., Methods: C57BL/6 mice exposed to DSS for 5 days developed acute colitis. DCs were isolated from the large intestinal lamina propria, and then analyzed for phenotypical, functional, and genetic data., Results: Only PIR-A/B(low) conventional DCs (cDCs) were detected in the steady state. However, after the treatment of DSS, PIR-A/B(high) cDCs appeared and gradually increased from day 5 to day 7, at which time the DSS-induced colitis was terminated. Then, allogeneic mixed leukocyte reaction (MLR) was performed. The stimulatory activity of PIR-A/B(high) cDCs obtained on day 7 was very low, and the addition of PIR-A/B(high) cDCs suppressed the T cell proliferation in MLR, indicating the immunoregulatory role of PIR-A/B(high) cDCs. The immunoregulatory role of PIR-A/B(high) cDCs was confirmed by the in vivo transfer experiment, showing their therapeutic effect on DSS-induced colitis. The message level of TGFβi was significantly higher in PIR-A/B(high) cDCs, while that of IFN-γ was highly upregulated in PIR-A/B(low) cDCs, being well in accordance with the fact that PIR-A/B(high) cDCs showed a suppressive function against activated T cells., Conclusion: PIR-A/B(high) cDCs showed a suppressive function against activated T cells by producing inhibitory cytokines.

Background: Although attention has been focused for over 20 years on the possible increased risk for hematologic malignancies (HM) in patients with inflammatory bowel diseases (IBD) receiving immune-modulators or anti-TNF-alpha antibodies, the association is still controversial. To understand the actual conditions of HM in the Japanese patients with IBD, the research committee for IBD supported by the Ministry of Health, Welfare and Labor of Japan (IBD-MHWL) conducted a multi-center retrospective study., Methods: Questionnaires for the development of HM in IBD patients were sent to the 70 facilities participating with IBD-MHWL in the first survey, followed by the second survey using a more detailed questionnaire, sent to the 27 members with HM patients., Results: Out of a total of 36,939 IBD patients in 70 facilities, 28 cases of HM related with IBD [12 of 10,500 UC patients (0.11 %), 16 of 6,310 CD patients (0.25 %)] were analyzed. The numbers of UC patients who developed HM were 2 (0.15 %) from the group receiving and 10 (0.13 %) from the group non-receiving thiopurine, without significant differences. The numbers of CD patients who developed HM were 4 (0.39 %) from the group receiving and 12 (0.21 %) from the group non-receiving thiopurine, without significant differences. The odds ratios of developing HM by thiopurine were 1.37 (95 % CI 0.30-6.24) in UC patients and 1.86 (95 % CI 0.60-5.78) in CD patients., Conclusions: Our results suggested that thiopurine therapy may not be a risk factor for HM in Japanese patients with IBD. Further accumulation of cases and prospective studies are necessary to conclude this important issue.

Purpose: In vivo fluoroscopic analyses have revealed the kinematics after total knee arthroplasty (TKA), including femoral condylar lift-off. This study asked whether differences in static varus-valgus laxity or coronal limb alignment after TKA affect lift-off under weight-bearing conditions. It was hypothesised that there is a correlation between coronal laxity or alignment and lift-off during walking., Methods: The current study analysed nineteen subjects undergoing cruciate-retaining TKA performed by the measured resection technique. The varus-valgus laxity at knee extension was measured using a 150 N stress radiograph. The mechanical axis was measured using a full-standing radiograph. Continuous radiological images were taken while the subject walked on a treadmill, and the images during single-leg stance were analysed to determine the lift-off using a 3D-to-2D image-to-model registration technique., Results: The average angle in varus/valgus stress was 6.8 ± 1.8°/6.6 ± 2.1°. No statistically significant differences were observed between the varus and valgus laxity. The average amount of lift-off was 0.7 ± 0.4 mm. The static varus-valgus laxity (n. s.) or the differences in the laxities (n. s.) on the stress radiograph did not influence lift-off. The weight-bearing ratio was achieved within the middle third of the knee in 90 % of subjects. Two outliers with valgus alignment (68 ± 1 %) demonstrated no significant difference in lift-off in comparison with the majority of the subjects (46 ± 9 %)., Conclusion: The static coronal laxity and alignment did not influence the lift-off under dynamic weight-bearing conditions after well-balanced and aligned cruciate-retaining TKA. Measured resection technique can produce sufficient coronal stability and alignment without significant lift-off during walking.

The standard treatment for autoimmune pancreatitis (AIP) is steroid therapy, although some patients improve spontaneously. Indications for steroid therapy in AIP patients are symptoms such as obstructive jaundice, abdominal pain, back pain, and the presence of symptomatic extrapancreatic lesions. Prior to steroid therapy, obstructive jaundice should be managed by biliary drainage, and blood glucose levels should be controlled in patients with diabetes mellitus. The recommended initial oral prednisolone dose for induction of remission is 0.6 mg/kg/day, which is administered for 2-4 weeks. The dose is then tapered by 5 mg every 1-2 weeks, based on changes in clinical manifestations, biochemical blood tests (such as liver enzymes and IgG or IgG4 levels), and repeated imaging findings (US, CT, MRCP, ERCP, etc.). The dose is tapered to a maintenance dose (2.5-5 mg/day) over a period of 2-3 months. Cessation of steroid therapy should be based on the disease activity in each case. Termination of maintenance therapy should be planned within 3 years in cases with radiological and serological improvement. Re-administration or dose-up of steroid is effective for treating AIP relapse. Application of immunomodulatory drugs is considered for AIP patients who prove resistant to steroid therapy. The prognosis of AIP appears to be good over the short-term with steroid therapy. The long-term outcome is less clear, as there are many unknown factors, such as relapse, pancreatic exocrine or endocrine dysfunction, and associated malignancy.

Perturbation of transforming growth factor (TGF)-β signaling in hepatocytes persistently infected with hepatitis viruses promotes both fibrogenesis and carcinogenesis (fibro-carcinogenesis). Insights into hepatocytic fibro-carcinogenesis have emerged from recent detailed analyses of context-dependent and cell type-specific TGF-β signaling processes directed by multiple phosphorylated forms (phospho-isoforms) of Smad mediators. In the course of hepatitis virus-related chronic liver diseases, chronic inflammation, ongoing viral infection, and host genetic/epigenetic alterations additively shift hepatocytic Smad phospho-isoform signaling from tumor suppression to fibro-carcinogenesis, accelerating liver fibrosis and increasing risk of hepatocellular carcinoma (HCC). After successful antiviral therapy, patients with chronic hepatitis can experience less risk of HCC occurrence by reversing Smad phospho-isoform signaling from fibro-carcinogenesis to tumor suppression. However, patients with cirrhosis can still develop HCC owing to sustained, intense fibro-carcinogenic signaling. Recent progress in understanding Smad phospho-isoform signaling should permit use of Smad phosphorylation as a tool predicting the likelihood of liver disease progression, and as a biomarker for assessing the effectiveness of interventions aimed at reducing fibrosis and cancer risk.