The Translational Landscape of the Human Heart.

Gene expression in human tissue has primarily been studied on the transcriptional level, largely neglecting translational regulation. Here, we analyze the translatomes of 80 human hearts to identify new translation events and quantify the effect of translational regulation. We show extensive translational control of cardiac gene expression, which is orchestrated in a process-specific manner. Translation downstream of predicted disease-causing protein-truncating variants appears to be frequent, suggesting inefficient translation termination. We identify hundreds of previously undetected microproteins, expressed from lncRNAs and circRNAs, for which we validate the protein products in vivo. The translation of microproteins is not restricted to the heart and prominent in the translatomes of human kidney and liver. We associate these microproteins with diverse cellular processes and compartments and find that many locate to the mitochondria. Importantly, dozens of microproteins are translated from lncRNAs with well-characterized noncoding functions, indicating previously unrecognized biology.

Novel susceptibility loci for steroid-associated osteonecrosis of the femoral head in systemic lupus erythematosus.

Osteonecrosis of the femoral head (ONFH) involves necrosis of bone and bone marrow of the femoral head caused by ischemia with unknown etiology. Previous genetic studies on ONFH failed to produce consistent results, presumably because ONFH has various causes with different genetic backgrounds and the underlying diseases confounded the associations. Steroid-associated ONFH (S-ONFH) accounts for one-half of all ONFH, and systemic lupus erythematosus (SLE) is a representative disease underlying S-ONFH. We performed a genome-wide association study (GWAS) to identify genetic risk factors for S-ONFH in patients with SLE. We conducted a two-staged GWAS on 636 SLE patients with S-ONFH and 95 588 non-SLE controls. Among the novel loci identified, we determined S-ONFH-specific loci by comparing allele frequencies between SLE patients without S-ONFH and non-SLE controls. We also used Korean datasets comprising 148 S-ONFH cases and 37 015 controls to assess overall significance. We evaluated the functional annotations of significant variants by in silico analyses. The Japanese GWAS identified 4 significant loci together with 12 known SLE susceptibility loci. The four significant variants showed comparable effect sizes on S-ONFH compared with SLE controls and non-SLE controls. Three of the four loci, MIR4293/MIR1265 [odds ratio (OR) = 1.99, P-value = 1.1 × 10-9)], TRIM49/NAALAD2 (OR = 1.65, P-value = 4.8 × 10-8) and MYO16 (OR = 3.91, P-value = 4.9 × 10-10), showed significant associations in the meta-analysis with Korean datasets. Bioinformatics analyses identified MIR4293, NAALAD2 and MYO16 as candidate causal genes. MIR4293 regulates a PPARG-related adipogenesis pathway relevant to S-ONFH. We identified three novel susceptibility loci for S-ONFH in SLE.

The association between surgical site infection and postoperative colorectal cancer recurrence and the effect of laparoscopic surgery on prognosis.

PURPOSE: Studies have shown that surgical site infection (SSI) incidence is lower in patients undergoing laparoscopic surgery. Therefore, we reported the SSI countermeasures adopted by our institution and aimed to evaluate the association between SSI occurrence and postoperative colorectal cancer recurrence and the usefulness of laparoscopic surgery for prognosis. METHODS: Among the patients with colorectal cancer who underwent radical surgery at our hospital between January 2015 and December 2017, 197 with stage I-III cancer without distant metastases were included. We retrospectively analyzed patients' electronic medical records and classified them into the non-SSI (without SSI, n = 159) and SSI (with SSI, n = 38) groups. We calculated and compared the 5-year relapse-free survival (RFS) and overall survival (OS) rates. Additionally, we assessed the relationship between prognosis in the non-SSI, incisional SSI, and organ/space SSI groups and the usefulness of laparoscopic surgery. RESULTS: The 5-year RFS and OS were 80.5% versus 63.2% (P = 0.024; hazard ratio [HR], 2.065; 95% confidence interval [CI], 1.099-3.883) and 88.7% versus 84.2% (P = 0.443; HR, 1.436; 95% CI, 0.570-3.617), respectively. The SSI group had a significantly worse 5-year RFS prognosis. Regarding the relationship with laparoscopic surgery, the SSI incidence was 45.0% (9/20 cases) and 16.4% (29/177 cases) with laparotomy and laparoscopic surgery, respectively, indicating a significantly reduced SSI occurrence with laparoscopic surgery (P = 0.005). CONCLUSION: Patients with SSI were at high risk for colorectal cancer recurrence, and laparoscopic surgery may be useful for reducing SSI.

Endovascular treatment of postoperative hemorrhage after pancreatectomy: a retrospective study.

BACKGROUND: Ruptured aneurysm is a serious complication of distal pancreatectomy (DP) or pancreatoduodenectomy (PD) that can be life-threatening if not treated promptly. This study aimed to examine the efficacy of a Viabahn stent graft for stopping bleeding after pancreatectomy. METHODS: Between April 2016 and June 2022, we performed 245 pancreatectomies in our institution. Six patients experienced postoperative bleeding and underwent endovascular treatment. RESULTS: All six cases of bleeding occurred post-PD (3.7%). The bleeding was from gastroduodenal artery (GDA) pseudoaneurysms in three patients, and Viabahn stent grafts were inserted. All three patients did not show liver function abnormalities or hepatic blood flow disorders. One patient with a Viabahn stent graft experienced rebleeding, which required further management to obtain hemostasis. Of the six cases in which there was hemorrhage, one case of bleeding from the native hepatic artery could not be managed. CONCLUSIONS: Using the Viabahn stent graft is an effective treatment option for postoperative bleeding from GDA pseudoaneurysms following PD. In most cases, using this device resulted in successful hemostasis, without observed abnormalities in hepatic function or blood flow.

Sensitivity of endoscopic ultrasound-guided fine-needle aspiration cytology and biopsy for a diagnosis of pancreatic ductal adenocarcinoma: A comparative analysis.

The utility of endoscopic ultrasound fine-needle aspiration cytology (EUS-FNAC) or endoscopic ultrasound fine-needle aspiration biopsy (EUS-FNAB) for diagnosis of small and large pancreatic ductal adenocarcinomas (PDACs) remains in question. We addressed this by analyzing 97 definitively diagnosed cases of PDAC, for which both EUS-FNAC and EUS-FNAB had been performed. We subclassified the 97 solid masses into small (n = 35) or large (n = 62) according to the maximum tumor diameter (<24 mm or ≥24 mm) and compared the diagnostic sensitivity (truly positive rate) of EUS-FNAC and of EUS-FNAB for small and large masses. Diagnostic sensitivity of EUS-FNAC did not differ between large and small masses (79.0% vs. 60.0%; p = 0.0763). However, the diagnostic sensitivity of EUS-FNAB was significantly higher for large masses (85.5% vs. 62.9%; p = 0.0213). Accurate EUS-FNAC-based diagnosis appeared to depend on the degree of cytological atypia of cancer cells, which was not associated with quantity of cancer cells. The accuracy of EUS-FNAB-based diagnosis appeared to depend on cancer cell viability in large masses and cancer volume in small masses. Based on the advantages or disadvantages in each modality, both modalities play an important role in the qualitative diagnosis of PDAC as a complementary procedure.

Functional evaluations comparing Billroth I with a large remnant stomach and Roux en Y with a small remnant stomach following laparoscopic distal gastrectomy for gastric cancer: An investigation including laparoscopic total gastrectomy.

PURPOSE: This study compared the pros and cons of two post-distal gastrectomy (DG) reconstruction methods by comparing the patient quality of life and functional dynamics at one year postoperatively. METHODS: We compared functional outcomes between Billroth I following laparoscopic 1/2 DG (L-B1; n = 27) and Roux en Y following laparoscopic 4/5 DG (L-RY; n = 24), including laparoscopic total gastrectomy (L-TG; n = 25), at one year postoperatively. Clinical investigations were performed in each patient, and functional evaluations by the acetaminophen (AAP) absorption test and plasma gastrointestinal hormone measurements were performed in consenting patients in each group (L-B1: n = 10, L-RY: n = 10, L-TG: n = 5). RESULTS: Postoperative/preoperative body weight ratios were significantly higher in the L-B1 and L-RY groups, in descending order than the L-TG group, although the meal intake ratio was not significantly different between the L-B1 and L-RY groups. The incidence of remnant gastritis was significantly higher in the B1 than in the RY group. AAP levels, glucose and glucagon-like peptide 1 were significantly lower in the L-B1 than in the L-RY group. Active ghrelin levels (AGL) were similar between the L-B1 and L-RY groups. CONCLUSIONS: L-B1 maintains gradual intestinal absorption and physiological meal passage and prevents postoperative weight loss. L-RY results in maintenance of the postoperative meal intake via high AGL, equivalent to that in the L-B1 group.

Biological insights into systemic lupus erythematosus through an immune cell-specific transcriptome-wide association study.

OBJECTIVE: Genome-wide association studies (GWAS) have identified >100 risk loci for systemic lupus erythematosus (SLE), but the disease genes at most loci remain unclear, hampering translation of these genetic discoveries. We aimed to prioritise genes underlying the 110 SLE loci that were identified in the latest East Asian GWAS meta-analysis. METHODS: We built gene expression predictive models in blood B cells, CD4+ and CD8+ T cells, monocytes, natural killer cells and peripheral blood cells of 105 Japanese individuals. We performed a transcriptome-wide association study (TWAS) using data from the latest genome-wide association meta-analysis of 208 370 East Asians and searched for candidate genes using TWAS and three data-driven computational approaches. RESULTS: TWAS identified 171 genes for SLE (p<1.0×10-5); 114 (66.7%) showed significance only in a single cell type; 127 (74.3%) were in SLE GWAS loci. TWAS identified a strong association between CD83 and SLE (p<7.7×10-8). Meta-analysis of genetic associations in the existing 208 370 East Asian and additional 1498 cases and 3330 controls found a novel single-variant association at rs72836542 (OR=1.11, p=4.5×10-9) around CD83. For the 110 SLE loci, we identified 276 gene candidates, including 104 genes at recently-identified SLE novel loci. We demonstrated in vitro that putative causal variant rs61759532 exhibited an allele-specific regulatory effect on ACAP1, and that presence of the SLE risk allele decreased ACAP1 expression. CONCLUSIONS: Cell-level TWAS in six types of immune cells complemented SLE gene discovery and guided the identification of novel genetic associations. The gene findings shed biological insights into SLE genetic associations.

Meta-analysis of 208370 East Asians identifies 113 susceptibility loci for systemic lupus erythematosus.

OBJECTIVE: Systemic lupus erythematosus (SLE), an autoimmune disorder, has been associated with nearly 100 susceptibility loci. Nevertheless, these loci only partially explain SLE heritability and their putative causal variants are rarely prioritised, which make challenging to elucidate disease biology. To detect new SLE loci and causal variants, we performed the largest genome-wide meta-analysis for SLE in East Asian populations. METHODS: We newly genotyped 10 029 SLE cases and 180 167 controls and subsequently meta-analysed them jointly with 3348 SLE cases and 14 826 controls from published studies in East Asians. We further applied a Bayesian statistical approach to localise the putative causal variants for SLE associations. RESULTS: We identified 113 genetic regions including 46 novel loci at genome-wide significance (p<5×10-8). Conditional analysis detected 233 association signals within these loci, which suggest widespread allelic heterogeneity. We detected genome-wide associations at six new missense variants. Bayesian statistical fine-mapping analysis prioritised the putative causal variants to a small set of variants (95% credible set size ≤10) for 28 association signals. We identified 110 putative causal variants with posterior probabilities ≥0.1 for 57 SLE loci, among which we prioritised 10 most likely putative causal variants (posterior probability ≥0.8). Linkage disequilibrium score regression detected genetic correlations for SLE with albumin/globulin ratio (rg=-0.242) and non-albumin protein (rg=0.238). CONCLUSION: This study reiterates the power of large-scale genome-wide meta-analysis for novel genetic discovery. These findings shed light on genetic and biological understandings of SLE.

Presence of purpura is related to active inflammation in association with IL-5 in eosinophilic granulomatosis with polyangiitis.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a relatively rare necrotizing vasculitis that causes asthma, nasal involvement, peripheral nerve disturbance, renal disorder, and cutaneous lesions like purpura and is characterized by eosinophil infiltration into the damaged tissue. Purpura is the most common cutaneous lesion, but it remains unknown whether this skin lesion is associated with disease activity of EGPA and laboratory data including interleukin (IL)-5, a target cytokine of this disease. We conducted a search of our hospital electronic records for cases of EGPA from the last 10 years. Symptoms related to EGPA (fever, asthma, nasal and cutaneous manifestations, neuropathy), the Birmingham Vasculitis Activity Score (BVAS), and laboratory parameters, such as eosinophil count, urinalysis, antineutrophil cytoplasmic antibody (ANCA), CRP, IgE and IL-5, before and during treatment were compared among the eligible cases. A total of 28 EGPA patients (21 females and 7 males) were selected. Almost all developed peripheral neuropathy. Fever occurred in 25%, nasal symptoms in 38.1% and purpura in 44%. Glomerulonephritis developed in 7.7%. One patient had cardiac involvement (3.6%). The laboratory data showed a marked increase in peripheral eosinophil count, CRP, serum IgE and serum IL-5. ANCA was positive in 15.4%. In the univariate analysis, presence of purpura was associated with increased CRP and IL-5, and high BVAS score. Multivariate analysis revealed a robust relationship between purpura and CRP. Our findings showed that presence of purpura was associated with increased CRP and IL-5, and high disease activity in EGPA.

Preventive procedure for stenosis after esophagojejunostomy using a circular stapler and transorally inserted anvil (OrVil™) following laparoscopic proximal gastrectomy and total gastrectomy involving reduction of anastomotic tension.

BACKGROUND: Recently, due to increasing reports of stenosis after esophagojejunostomy created using circular staplers and a transorally inserted anvil (OrVil™) following laparoscopic proximal gastrectomy (LPG) and total gastrectomy (LTG), linear staplers are being used instead. We investigated our preventive procedure for esophagojejunostomy stenosis following use of circular staplers. METHODS: Since the anastomotic stenosis is considered to be mainly caused by tension in the esophageal and jejunal stumps at the anastomotic site, we have been performing procedures to relieve this tension, by cutting off the rubber band and pushing the shaft of the circular stapler toward the esophageal side, since July 2015. We retrospectively compared the incidence of anastomotic stenosis in cases of LPG and LTG performed before July 2015 (early phase, 30 cases) versus those performed after this period (later phase, 22 cases). RESULTS: Comparison of the incidence of anastomotic stenosis according to the type of surgery, LPG or LTG, and between the two time periods versus all cases, indicated a significantly lower incidence in the later phase than in the early phase (4.5 vs. 26.7%, p < 0.05), especially for LPG (0 vs. 38.5%, p < 0.05). CONCLUSIONS: It is possible to use a circular stapler during laparoscopic esophagojejunostomy, as with open surgery, if steps to reduce tension on the anastomotic site are undertaken. These procedures will contribute to the spread of safe and simple laparoscopic anastomotic techniques.

Short-term outcomes of OTSC for anastomotic leakage after laparoscopic colorectal surgery.

INTRODUCTION: There are several reports on the use of the over-the-scope clip (OTSC) for gastrointestinal bleeding/fistula and endoscopic iatrogenic perforation. However, there are almost no reports on OTSC use for anastomotic leakage (AL) after colorectal cancer surgery. The purpose of this study was to evaluate the outcome of AL closure using the OTSC. MATERIAL AND METHODS: Five patients who had undergone AL after laparoscopic surgery for colorectal cancer from April 2017 to April 2019 were evaluated. RESULTS: The average distance from the anal verge of the anastomosis site was 12 (5-18) cm. The average diameter of the dehiscent part was 10.9 (9.3-14.4) mm. The average number of OTSC days after the occurrence of AL was 11 (5-22). On the contrast examination immediately after OTSC, all cases were completely closed, but in the later contrast examination, only one case remained completely closed. The average incompletely closed diameter was 3.6 (2.9-5.1) mm, and the diameter of the dehiscent part was reduced in all cases. Only one patient ultimately underwent colostomy; the rest were cured with OTSC alone. CONCLUSION: AL site closure using the OTSC after colorectal cancer surgery is a useful minimally invasive treatment when combined with appropriate drain management.

A case of high-grade pancreatic intraepithelial neoplasia concomitant with type 1 autoimmune pancreatitis: The process underlying both conditions.

We report a case of high-grade pancreatic intraepithelial neoplasia (PanIN) concomitant with lymphoplasmacytic sclerosing pancreatitis. The patient was an 82-year-old man in whom narrowing of the main pancreatic duct was detected incidentally by abdominal ultrasonography. Magnetic resonance cholangiopancreatography further revealed abrupt narrowing plus distal dilatation of the duct, from the pancreatic body to the tail. Distal pancreatectomy was performed under a preoperative diagnosis of intraductal papillary-mucinous neoplasm. Macroscopic examination of the surgical specimen showed an ill-demarcated, white-gray area and prominent pancreatic atrophy, while histological analysis detected small (<5 mm in diameter) cystic dilatations of the main pancreatic duct and some branch ducts plus pancreatic atrophy with fibrosis and fatty replacement of acinar cells. We also detected variously sized papillary projections, fused glands, and scattered focal papillary proliferation of columnar ductal epithelium comprising cells with elongated, mildly hyperchromatic nuclei, consistent with high-grade PanIN. In addition, we observed marked lymphoplasmacytic infiltration, periductal storiform fibrosis, and obliterative phlebitis. Immunohistochemical staining revealed abundant immunogloblin G4-positive plasma cells, indicative of type 1 autoimmune pancreatitis (AIP). The coexistence of high-grade PanIN and marked lymphoplasmacytic infiltration, typical of AIP, point to a close association between the former, as a carcinogenic process, and the latter, as an immune response.

Functional evaluations comparing the double-tract method and the jejunal interposition method following laparoscopic proximal gastrectomy for gastric cancer: an investigation including laparoscopic total gastrectomy.

PURPOSE: Functional outcomes were prospectively compared between two types of reconstruction [double tract (L-DT; n = 15) and jejunal interposition (L-JIP; n = 15)] following laparoscopic half-proximal gastrectomy (LPG), including laparoscopic total gastrectomy (L-TG; n = 30) as a control group, at 1 year after surgery. METHODS: Clinical investigations were performed in each patient, and functional evaluations, involving the swallowing of an alimentary liquid containing acetaminophen (AAP), followed by measurements of the concentrations of AAP and hormones in the sitting (n = 5) and in the supine positions (n = 5), were carried out in each group. RESULTS: The post-/preoperative body weight ratios were significantly higher in the L-DT and L-JIP groups than in the L-TG group. The AAP levels were significantly lower in the LPG group than in the LTG group. The AAP, insulin, and gastrin levels in the L-JIP group were markedly increased in the sitting position compared with the supine position, while those in the L-DT and L-TG groups were stable in both positions. CONCLUSIONS: L-JIP and L-DT are procedures that maintain gradual intestinal absorption and help improve the quality of life. Intestinal absorption and hormonal secretion were relatively unaffected by the posture of the meal intake after L-DT, so L-DT might be the procedure providing the most stable results.

Low psoas muscle index is a poor prognostic factor for lower gastrointestinal perforation: a single-center retrospective cohort study.

BACKGROUND: Various body composition indices have been reported as prognostic factors for different cancers. However, whether body composition affects prognosis after lower gastrointestinal tract perforation requiring emergency surgery and multidisciplinary treatment has not been clarified. This study examined whether body composition evaluations that can be measured easily and quickly from computed tomography (CT) are useful for predicting prognosis. METHODS: Subjects comprised 64 patients diagnosed with perforation at final diagnosis after emergency surgery for a preoperative diagnosis of lower gastrointestinal tract perforation and penetration. They were divided into a survival group and a non-survival (in-hospital mortality) group and compared. Body composition indices (psoas muscle index (PMI); psoas muscle attenuation (PMA); subcutaneous adipose tissue index (SATI); visceral adipose tissue index (VATI); visceral-to-subcutaneous fat area ratio (VSR)) were measured from preoperative CT. Cross-sectional psoas muscle area at the level of the 3rd lumbar vertebra was quantified. Optimal cut-off values were calculated using receiver operating characteristic curve analysis. Poor prognostic factors were investigated from multivariate logistic regression analyses that included patient factors, perioperative factors, intraoperative factors, and body composition indices as explanatory variables. RESULTS: The cause of perforation was malignant disease in 12 cases (18.7%), and benign disease in 52 cases (81.2%). The most common cause was diverticulum of the large intestine. Emergency surgery for the 64 patients led to survival in 52 patients and death in 12 patients. On multivariate logistic regression analysis, independent predictors of poor prognosis were Sequential Organ Failure Assessment score (odds ratio 1.908; 95% confidence interval (CI) 1.235-3.681; P = 0.0020) and PMI (odds ratio 13.478; 95%CI 1.342-332.690; P = 0.0252). The cut-off PMI was 4.75 cm2/m2 for males and 2.89 cm2/m2 for females. Among survivors, duration of hospitalization was significantly longer in the low PMI group (29 days) than in the high PMI group (22 days, p = 0.0257). CONCLUSIONS: PMI is easily determined from CT and allows rapid evaluation of prognosis following lower gastrointestinal perforation.

A reliability study using computer-based analysis of finger joint space narrowing in rheumatoid arthritis patients.

The joint space difference index (JSDI) is a newly developed radiographic index which can quantitatively assess joint space narrowing progression of rheumatoid arthritis (RA) patients by using an image subtraction method on a computer. The aim of this study was to investigate the reliability of this method by non-experts utilizing RA image evaluation. Four non-experts assessed JSDI for radiographic images of 510 metacarpophalangeal joints from 51 RA patients twice with an interval of more than 2 weeks. Two rheumatologists and one radiologist as well as the four non-experts examined the joints by using the Sharp-van der Heijde Scoring (SHS) method. The radiologist and four non-experts repeated the scoring with an interval of more than 2 weeks. We calculated intra-/inter-observer reliability using the intra-class correlation coefficients (ICC) for JSDI and SHS scoring, respectively. The intra-/inter-observer reliabilities for the computer-based method were almost perfect (inter-observer ICC, 0.966-0.983; intra-observer ICC, 0.954-0.996). Contrary to this, intra-/inter-observer reliability for SHS by experts was moderate to almost perfect (inter-observer ICC, 0.556-0.849; intra-observer ICC, 0.589-0.839). The results suggest that our computer-based method has high reliability to detect finger joint space narrowing progression in RA patients.

Biologic-free remission of established rheumatoid arthritis after discontinuation of abatacept: a prospective, multicentre, observational study in Japan.

OBJECTIVE: The aim of this study was to determine whether biologic-free remission of RA is possible with discontinuation of abatacept. METHODS: Japanese RA patients in 28-joint DAS with CRP (DAS28-CRP) remission (<2.3) after >2 years of abatacept treatment in a phase II study and its long-term extension entered this 52 week, multicentre, non-blinded, prospective, observational study. At enrolment, the patients were offered the option to continue abatacept or not. The primary endpoint was the proportion of patients who remained biologic-free at 52 weeks after discontinuation. Clinical, functional and structural outcomes were compared between those who continued and those who discontinued abatacept. RESULTS: Of 51 patients enrolled, 34 discontinued and 17 continued abatacept treatment. After 52 weeks, 22 of the 34 patients (64.7%) remained biologic-free. Compared with the continuation group, the discontinuation group had a similar remission rate (41.2% vs 64.7%, P = 0.144) although they had a significantly higher mean DAS28-CRP score at week 52 (2.9 vs 2.0, P = 0.012). The two groups were also similar with regard to mean HAQ Disability Index (HAQ-DI) score (0.6 for both, P = 0.920), mean change in total Sharp score (ΔTSS; 0.80 vs 0.32, P = 0.374) and proportion of patients in radiographic remission (ΔTSS ≤ 0.5) at the endpoint (64.3% vs 70.6%, P = 0.752). Those attaining DAS28-CRP < 2.3 or < 2.7 without abatacept at the endpoint had significantly lower HAQ-DI score and/or CRP at enrolment. Non-serious adverse events occurred in three patients who continued or resumed abatacept. CONCLUSION: Biologic-free remission of RA is possible in some patients after attaining clinical remission with abatacept. Lower baseline HAQ-DI or CRP may predict maintenance of remission or low disease activity after discontinuation of abatacept. TRIAL REGISTRATION: UMIN Clinical Trials Registry, http://www.umin.ac.jp/ctr/ (UMIN000004137).

Everyday clinical practice in IgG4-related dacryoadenitis and/or sialadenitis: results from the SMART database.

Abstract Objective. Immunoglobulin (Ig)G4-related disease (IgG4-RD) is a new disease entity that has only been identified this century. Clinical information is thus lacking. We established the Sapporo Medical University and Related Institutes Database for Investigation and Best Treatments of IgG4-related Disease (SMART) to clarify the clinical features of IgG4-RD and provide useful information for clinicians. Methods. Participants comprised 122 patients with IgG4-related dacryoadenitis and/or sialadenitis (IgG4-DS), representing lacrimal and/or salivary lesions of IgG4-RD, followed-up in December 2013. We analyzed the sex ratio, mean age at onset, organ dysfunction, history or complications of malignancy, treatments, rate of clinical remission, and relapse. Results. The sex ratio was roughly equal. Mean age at diagnosis was 59.0 years. Positron emission tomography revealed that the ratio of other organ involvements was 61.4%. Complications of malignancy were observed in 7.4% of cases. Glucocorticoid was used to treat 92.1% of cases, and the mean maintenance dose of prednisolone was 4.8 mg/day. Rituximab was added in three cases, and showed good steroid-sparing effect. The clinical remission rate was 73.8%, and the annual relapse rate was 11.5%. Half of the cases experienced relapses within 7 years of initial treatment. Conclusion. We analyzed the clinical features and treatments of IgG4-DS using SMART, providing useful information for everyday clinical practice.

Adalimumab, a human anti-TNF monoclonal antibody, outcome study for the prevention of joint damage in Japanese patients with early rheumatoid arthritis: the HOPEFUL 1 study.

OBJECTIVES: To evaluate the efficacy and safety of adalimumab+methotrexate (MTX) in Japanese patients with early rheumatoid arthritis (RA) who had not previously received MTX or biologics. METHODS: This randomised, double-blind, placebo-controlled, multicentre study evaluated adalimumab 40 mg every other week+MTX 6-8 mg every week versus MTX 6-8 mg every week alone for 26 weeks in patients with RA (≤2-year duration). The primary endpoint was inhibition of radiographic progression (change (Δ) from baseline in modified total Sharp score (mTSS)) at week 26. RESULTS: A total of 171 patients received adalimumab+MTX (mean dose, 6.2±0.8 mg/week) and 163 patients received MTX alone (mean dose, 6.6±0.6 mg/week, p<0.001). The mean RA duration was 0.3 years and 315 (94.3%) had high disease activity (DAS28>5.1). Adalimumab+MTX significantly inhibited radiographic progression at week 26 versus MTX alone (ΔmTSS, 1.5±6.1 vs 2.4±3.2, respectively; p<0.001). Significantly more patients in the adalimumab+MTX group (62.0%) did not show radiographic progression (ΔmTSS≤0.5) versus the MTX alone group (35.4%; p<0.001). Patients treated with adalimumab+MTX were significantly more likely to achieve American College of Rheumatology responses and achieve clinical remission, using various definitions, at 26 weeks versus MTX alone. Combination therapy was well tolerated, and no new safety signals were observed. CONCLUSIONS: Adalimumab in combination with low-dose MTX was well tolerated and efficacious in suppressing radiographic progression and improving clinical outcomes in Japanese patients with early RA and high disease activity.

Recovery of clinical but not radiographic outcomes by the delayed addition of adalimumab to methotrexate-treated Japanese patients with early rheumatoid arthritis: 52-week results of the HOPEFUL-1 trial.

OBJECTIVE: The aim of this study was to compare efficacy outcomes of initial treatment with adalimumab + MTX vs adalimumab addition following 26 weeks of MTX monotherapy in Japanese early RA patients naive to MTX with high disease activity. METHODS: Patients completing the 26-week, randomized, placebo-controlled trial of adalimumab + MTX were eligible to receive 26 weeks of open-label adalimumab + MTX. Patients were assessed for mean change from baseline in the 28-joint DAS with ESR (DAS28-ESR) and modified total Sharp score (mTSS), and for the proportions of patients achieving clinical, functional or radiographic remission. RESULTS: Of 333 patients assessed, 278 (137 from the initial adalimumab + MTX and 141 from the initial placebo + MTX groups) completed the 52-week study. Significant differences in clinical and functional parameters observed during the 26-week blinded period were not apparent following the addition of open-label adalimumab to MTX. Open-label adalimumab + MTX slowed radiographic progression through week 52 in both groups, but patients who received adalimumab + MTX throughout the study exhibited less radiographic progression than those who received placebo + MTX during the first 26 weeks (mean ΔmTSS at week 52 = 2.56 vs 3.30, P < 0.001). CONCLUSION: Delayed addition of adalimumab in Japanese MTX-naive early RA patients did not impact clinical and functional outcomes at week 52 compared with the earlier addition of adalimumab. However, the accrual of significant structural damage during blinded placebo + MTX therapy contributed to the persistence of differences between the treatment strategies, suggesting that Japanese patients at risk for aggressive disease should benefit from the early inclusion of adalimumab + MTX combination therapy. Trial registration. ClinicalTrials.gov (http://clinicaltrials.gov/), NCT00870467.

Intraoperative Video Analysis of Pancreatic Stump and Stapler Closure-Induced Pancreatic Fistula in Laparoscopic Distal Pancreatectomy: A Retrospective Study.

Objectives Pancreatic stump closure in laparoscopic distal pancreatectomy (Lap-DP) is commonly performed using an automatic stapler. Herein, the magnification effect of laparoscopy was used to observe the pancreatic stump and retrospectively investigate factors that may cause postoperative pancreatic fistula. Methods This is a single-center retrospective study. We selected 62 cases of Lap-DP performed between March 2016 and May 2022. We retrospectively analyzed 54 cases where pancreatic transection sites could be observed using an intraoperative video. Pancreatic transection was performed using the Powered ECHELON FLEX®+ GST® System (Ethicon, Somerville, USA). For quantitative studies, we investigated the factors that cause pancreatic fistula and other factors causing pancreatic fistula. Results Pancreatic parenchymal hemorrhage and injury occurred in 22.2% and 29.6% of cases, respectively. International Study Group of Pancreatic Surgery grade B/C pancreatic fistula was observed in 12 cases (22.2%). Univariate analysis of pancreatic (n = 12) and nonpancreatic (n = 42) fistula groups showed no significant differences in pancreatic thickness. The pancreatic fistula group had a significantly high incidence of the hard pancreas (p = .009), pancreatic parenchymal bleeding (p = .002), and pancreatic parenchymal damage (p < .001). Multivariate analysis revealed that pancreatic parenchymal damage was an independent cause of pancreatic fistula (hazard ratio, 81.4 (8.5-772.3), p < .001). Conclusion Pancreatic parenchymal damage due to compression during pancreatic stump closure using an automatic stapler in Lap-DP may cause pancreatic fistula.