Feasibility of comprehensive genomic profiling using endoscopic ultrasound-guided tissue acquisition with a 22-gauge Franseen needle.

Aim: Comprehensive genomic profiling (CGP) test for solid tumors is now increasingly utilized in clinical practice, especially in pancreatobiliary cancer, and specimens obtained by endoscopic ultrasound-guided tissue acquisition (EUS-TA) are often submitted for tissue-based CGP test. In this study, we evaluated the feasibility of EUS-TA using a 22-gauge Franseen needle for the CGP test. Methods: Consecutive patients with solid tumors who underwent EUS-TA using a 22-gauge Franseen needle, and whose tissue samples were pre-checked for suitability for CGP test, were included in this single-center, retrospective analysis. The success rates of appropriate sample collection for CGP evaluated by pathologists (1st quality control) and CGP test (2nd quality control) were evaluated. In addition, The EUS-TA slides were evaluated for the tissue area and tumor area content, using the image software. Results: A total of 50 cases, with 78% of pancreatic cancer, were included in the analysis. A median of 3 passes of EUS-TA were performed with an adverse event rate of 4%. The success rates for 1st and 2nd quality control for CGP tests were 86% and 76%, respectively. The image analyses suggested EUS-TA specimen did not always fulfill CGP test criteria, with 18% of tissue area ≥16 mm2 and 38% of tumor area content ≥20%, even in cases with successful CGP tests. The suction method yielded a significantly larger amount of DNA but without a significant difference in the multivariate analysis. Conclusions: The present study demonstrated the feasibility of EUS-TA using a 22-gauge Franseen needle for CGP test.

Skeletal muscle status and survival among patients with advanced biliary tract cancer.

BACKGROUND: Studies have demonstrated a prognostic role of sarcopenia (i.e., loss of skeletal muscle volume and functionality) in patients with various cancer types. In patients with biliary tract cancer, the quantity and quality of skeletal muscles and their serial changes have not been fully investigated in relation to survival outcomes. METHODS: We identified 386 patients with unresectable or recurrent biliary tract cancer and calculated skeletal muscle index (SMI) and skeletal muscle density (SMD) to estimate muscular quantity and quality, respectively, based on computed tomography images. Using the Cox regression model with adjustment for potential confounders, we calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for progression-free survival (PFS) and overall survival (OS) according to skeletal muscle status and its serial change. RESULTS: Compared to patients without sarcopenia, patients with sarcopenia were associated with shorter PFS (multivariable HR, 1.60; 95% CI, 1.15-2.22; P = 0.005), but not with OS (P = 0.027) at the adjusted α level of 0.013. SMD at baseline was associated with OS (multivariable HR comparing the extreme quartiles, 1.52; 95% CI, 1.07-2.14; Ptrend = 0.012), but not with PFS (Ptrend = 0.13). A reduction in SMI rather than that in SMD was associated with OS. Progressive disease was a risk factor for reductions in SMI and SMD. CONCLUSIONS: Skeletal muscle quantity and quality and their serial changes were associated with survival outcomes in patients with advanced biliary tract cancer. Our data highlight the importance of designing nutritional and physical interventions for improvements in skeletal muscle status.

Retrospective comparative study of new slim-delivery and conventional large-cell stents for stent-in-stent methods for hilar malignant biliary obstruction.

OBJECTIVES: Endoscopic management of unresectable hilar malignant biliary obstruction (HMBO) is technically challenging, and effectiveness of stent-in-stent using large-cell, metal stents was reported. A new, large-cell stent with a 6F tapered delivery system was recently developed. The aim of this study was to compare clinical outcomes of slim-delivery and conventional large-cell stents. METHODS: This was a multicenter retrospective comparative study of stent-in-stent methods using slim-delivery stents (Niti-S Large Cell SR Slim Delivery [LC slim-delivery]) and conventional stents (Niti-S large-cell D-type; LCD) for unresectable HMBO. RESULTS: Eighty-three patients with HMBO were included; 31 LC slim-delivery and 52 LCD. Overall technical and clinical success rates were 100% and 90% in LC slim-delivery group and 98% and 88% in LCD group. Use of the LC slim-delivery was associated with shorter stent placement time in the multiple regression analysis, with a stent placement time of 18 and 23 min in LC slim-delivery and LCD groups, respectively. The early adverse event (AE) rate of LC slim-delivery was 10%, with no cholangitis or cholecystitis as compared to 23% in the LCD group. Recurrent biliary obstruction (RBO) rates and time to RBO were comparable between the two groups: 35% and 44%, and 8.5 and 8.0 months in LC slim-delivery and LCD groups, respectively. The major cause of RBO was tumor ingrowth (82%) in the LC slim-delivery group and sludge (43%) and ingrowth (48%) in LCD group. CONCLUSION: Stent-in-stent methods using LC slim-delivery shortened stent placement time with low early AE rates and comparable time to RBO in patients with HMBO.

Second Covered and Uncovered Self-Expandable Metal Stents for Recurrent Gastric Outlet Obstruction: A Retrospective Comparative Study.

Background: Endoscopic self-expandable metal stent (SEMS) placement is a current mainstay for malignant gastric outlet obstruction (GOO), but symptomatic recurrence due to initial SEMS dysfunction commonly occurs. We aimed to compare the safety and effectiveness of second SEMS for recurrent GOO (RGOO). Methods: Between April 2006 and December 2022, a total of 95 cases with malignant RGOO undergoing second endoscopic SEMS placement were enrolled. Technical and clinical success rates, RGOO, time to RGOO (TRGOO), stent patency rate, adverse events (AE), and overall survival (OS) were retrospectively compared between covered and uncovered SEMS (cSEMS/uSEMS) groups. Risk factors for TRGOO were also explored. Results: Baseline characteristics were well balanced between cSEMS (n = 48) and uSEMS (n = 47) groups, except for the causes of the initial SEMS dysfunction. High technical and clinical success rates with a similar incidence of AE (15% vs. 17%, p = 0.78) and OS (median of 101 vs. 102 days, p = 0.68) were achieved in both groups. There were no statistical differences in cumulative incidence of RGOO (19% vs. 13%, p = 0.58), TRGOO (median, not reached in both groups, p = 0.57), and stent patency rates at 1, 2, and 3 months between the groups (60%, 47% and 26%, respectively vs. 70%, 55% and 38%, respectively). However, TRGOO tended to be longer in cSEMS in cases with RGOO due to tumor ingrowth (median, not reached vs. 111 days, p = 0.19). A Cox regression analysis demonstrated that chemotherapy after second SEMS placement was significantly associated with an improved TRGOO (the hazard ratio of 0.27 [95% confidence interval, 0.08-0.93], p = 0.03). Conclusions: Regardless of the type of SEMS, second SEMS placement was similarly safe and effective for RGOO. The type of second SEMS might be considered based on the cause of initial SEMS dysfunction.

Clinical trajectory of intraductal papillary mucinous neoplasms progressing to pancreatic carcinomas during long-term surveillance: a prospective series of 100 carcinoma cases.

BACKGROUND: Trajectories of serological and morphological signatures have not been documented in pancreatic carcinogenesis related to intraductal papillary mucinous neoplasms (IPMNs). METHODS: Using a prospective cohort of 3437 IPMN patients, we identified 100 IPMN patients who developed pancreatic carcinomas during long-term surveillance. We examined serial changes of blood markers (carbohydrate antigen 19-9 [CA19-9], hemoglobin A1c [HbA1c], and pancreatic enzymes) and morphological features (worrisome features and high-risk stigmata) during the prediagnostic period of pancreatic carcinomas, overall and by carcinoma types (IPMN-derived vs. concomitant pancreatic carcinomas). RESULTS: CA19-9 elevation was observed in 39 patients and was associated with a metastatic stage. Compared to IPMN-derived carcinomas, concomitant carcinomas were more likely to represent CA19-9 elevation (60% vs. 30%, respectively; P = 0.005). HbA1c levels elevated only in 3 patients. Pancreatic enzyme elevation was observed in 18 patients with no differences in frequencies between the carcinoma types. All patients with elevated levels of blood markers had positive findings on cross-sectional imaging. High-risk stigmata or worrisome features were observed in all patients but one with concomitant carcinoma. The most common types of worrisome features were the main pancreatic duct dilatation and CA19-9 elevation in IPMN-derived and concomitant carcinomas, respectively. Compared to IPMN-derived carcinomas, concomitant carcinomas were less likely to harbor high-risk stigmata (16% vs. 86%, respectively; P < 0.001). CONCLUSIONS: The usefulness of currently available blood biomarkers was limited in early detection of pancreatic carcinomas related to IPMNs. Morphological alterations were well correlated with long-term risk of IPMN-derived carcinomas, but not with that of concomitant carcinomas.

A non-interventional cross-sectional re-contact study investigating the relationship between overactive bladder and frailty in older adults in Japan.

BACKGROUND: Increasing age is associated with frailty and a higher prevalence of overactive bladder (OAB). Given the rapidly increasing proportion of older adults in Japan, a better understanding of the relationship between frailty and OAB is needed to inform future healthcare planning. This study assessed the association between frailty and OAB in older adults in Japan and evaluated the impact on their health-related quality of life (HRQoL). METHODS: This was a cross-sectional re-contact study of respondents who previously completed the National Health and Wellness Survey 2018 in Japan. Participants were aged ≥65 years and Japanese speakers and readers. As part of a customized online survey, participants were screened for frailty using the Kihon Checklist (frail = scores ≥8 points) and OAB using the overactive bladder symptom score (OAB = total score ≥ 3 points and ≥ 2 points on question 3). The primary endpoint was the odds ratio of frailty in older adults with and without OAB assessed using a multivariable logistic regression model. Secondary endpoints were the prevalence rates of OAB and frailty. Exploratory endpoints assessed HRQoL using the Medical Outcomes Study 12-Item Short Form Survey Instrument version 2 (SF-12v2). RESULTS: Overall, 2953 participants were included: 150 (5.1%) were frail OAB, 416 (14.1%) non-frail OAB, 287 (9.7%) frail non-OAB, and 2100 (71.1%) non-frail non-OAB. There was a statistically significant correlation between frailty and OAB demonstrated by an adjusted odds ratio (95% CI) of 2.78 (2.18-3.54; p <  0.001). The prevalence (95% CI) of OAB was 34.3% (29.9-38.8) in frail and 16.5% (15.1-18.0) in non-frail older adults; the prevalence of frailty was 26.5% (22.9-30.1) and 12.0% (10.7-13.3) in older adults with and without OAB. HRQoL was assessed in 150 participants per group. The adjusted HRQoL analyses showed significantly lower scores in participants who were frail OAB vs. frail non-OAB for most of the SF-12v2 scores/sub-component scores. CONCLUSIONS: These data highlight the statistically significant positive correlation between frailty and OAB among older adults in Japan and may provide valuable information on the burden of OAB and frailty on older adults to healthcare professionals when considering future healthcare planning.

Usefulness of blood flow evaluation with indocyanine green fluorescence imaging during laparoscopic surgery for strangulated bowel obstruction: A cohort study.

INTRODUCTION: Intestinal blood flow evaluation during strangulated bowel obstruction is often based on the subjective assessment of the operator. Therefore, we aimed to comprehensively determine the presence or absence of intestinal blood flow based on normal light and indocyanine green (ICG) fluorescence imaging. Moreover, we ascertained whether the chosen surgical plan was appropriate, based on the patients' postoperative course and pathological findings. METHODS: All 14 patients diagnosed with strangulated bowel obstruction at our hospital who underwent laparoscopic surgery between July 2019 and January 2021 were enrolled. Surgical plans were chosen based on normal light imaging combined with near-infrared imaging after intravenous ICG injection. Intestinal resection was performed via a small laparotomy if resection was considered necessary. In the intestinal resection group, the presence of intestinal necrosis was examined based on the pathological findings of the resected specimens. In the intestinal preservation group, postoperative complications, such as delayed intestinal perforation and intestinal stricture, were examined. RESULTS: Intestinal resection was performed in 4 cases. The pathological findings of the resected specimens showed necrosis of the small intestine in all cases. No intra-abdominal complication occurred any of the cases, and the median postoperative hospital stay was 9.9 days. CONCLUSIONS: The selection of a surgical plan in conjunction with ICG fluorescence findings was valid in all 14 cases. ICG fluorescence imaging is useful in laparoscopic surgery for strangulated bowel obstruction and may be a novel method for evaluating intestinal blood flow during surgery.

Agent-based neutral competition in two-community networks.

Competition between alternative states is an essential process in social and biological networks. Neutral competition can be represented by an unbiased random drift process in which the states of vertices (e.g., opinions, genotypes, or species) in a network are updated by repeatedly selecting two connected vertices. One of these vertices copies the state of the selected neighbor. Such updates are repeated until all vertices are in the same "consensus" state. There is no unique rule for selecting the vertex pair to be updated. Real-world processes comprise three limiting factors that can influence the selected edge and the direction of spread: (1) the rate at which a vertex sends a state to its neighbors, (2) the rate at which a state is received by a neighbor, and (3) the rate at which a state can be exchanged through a connecting edge. We investigate how these three limitations influence neutral competition in networks with two communities generated by a stochastic block model. By using Monte Carlo simulations, we show how the community structure and update rule determine the states' success probabilities and the time until a consensus is reached. We present a heterogeneous mean-field theory that agrees well with the Monte Carlo simulations. The effectiveness of the heterogeneous mean-field theory implies that quantitative predictions about the consensus are possible even if empirical data (e.g., from ecological fieldwork or observations of social interactions) do not allow a complete reconstruction of all edges in the network.

Ureteral navigation using a fluorescent ureteral catheter during laparoscopic colorectal surgery.

BACKGROUND: Ureteral injury is the most common urological complication of pelvic surgery, with a reported incidence during colon resection of 0.3-1.5%. Ureteral stenting is commonly performed preoperatively to prevent ureteral injury. Because tactile sensation is not reliable during laparoscopic surgery, the effect of the ureteral stent is considered limited. Recently, fluorescence imaging has been used in laparoscopic surgery. The Near-Infrared Ray Catheter (NIRC™) fluorescent ureteral catheter (NIRFUC) is a new catheter with built-in NIR fluorescent resin. This pilot study was performed to evaluate the utility of fluorescence ureteral navigation using the NIRFUC during laparoscopic colorectal surgery. METHODS: We evaluated the intraoperative utility of the NIRFUC and the short-term outcomes in 20 patients treated with colorectal surgery at Kawaguchi Municipal Medical Center between February and July 2020. In all, 18 patients with malignant tumors and 2 patients with benign disease, i.e., a sigmoid colovesical fistula, were included. Ten patients developed preoperative intestinal obstruction. One patient experienced preoperative perforation. Nine patients developed preoperative peritumoral abscesses. Laparoscopic surgery was performed with the VISERA ELITE2 system. RESULTS: In all cases, the ureters were very clearly identified as fluorescent without the need for dissection. In all cases, only a moment was required to identify the ureter by fluorescence observation. In all cases, R0 resection was performed. The mean surgical duration was 334 min (161-1014), the mean blood loss was 10 ml (1-500), and the mean postoperative hospital stay was 11 days (8-47). There were no cases of ureteral injury. CONCLUSION: The NIRFUC was very clearly identified as fluorescent in a moment during surgery without dissection around the ureter. Fluorescence ureteral navigation using the NIRFUC may make colorectal surgery easier and facilitate completion of complex minimally invasive surgery, especially during surgery in patients with invasion of the surrounding tissue or a history of pelvic surgery or radiation.

Intestinal blood flow evaluation using the indocyanine green fluorescence imaging method in a case of incarcerated obturator hernia: A case report.

In surgery for incarcerated hernia, intestinal blood flow is an important factor in intraoperative decision-making given that irreversible ischemia can result in intestinal necrosis. Here, we report a case of incarcerated obturator hernia in which the bowel was successfully preserved by evaluating intestinal blood flow with the indocyanine green fluorescence imaging method. A woman in her 80s was diagnosed with incarcerated right obturator hernia, and a laparoscopic operation was performed. The small bowel tissue that had been incarcerated exhibited dark red discoloration. Fluorescence examination of the bowel wall indicated that the ischemic changes were reversible, and accordingly, the bowel was not resected. The postoperative course was uneventful. The indocyanine green fluorescence imaging method is a useful new source of evidence that will improve intraoperative decision-making regarding bowel ischemia.

Cardiovascular safety of mirabegron add-on therapy to tamsulosin for the treatment of overactive bladder in men with lower urinary tract symptoms: A post hoc analysis from the MATCH study.

OBJECTIVES: To investigate the cardiovascular safety of mirabegron add-on treatment to tamsulosin in male patients with residual overactive bladder symptoms. METHODS: This was a post hoc analysis of MATCH, the first double-blind, placebo-controlled study comparing mirabegron and placebo as add-on therapy to tamsulosin for treatment of overactive bladder in men with lower urinary tract symptoms. The analysis focused on treatment-emergent adverse events relating to the cardiovascular system or blood pressure, and changes in vital signs during 12 weeks of follow-up. RESULTS: Cardiovascular-related treatment-emergent adverse events were reported by 6/566 patients, although only one serious treatment-emergent adverse event was related to treatment (unstable angina in the tamsulosin + placebo group). Hypertension (two patients) and increased blood pressure (one patient) were reported in the tamsulosin + placebo group, but there were no blood pressure-related treatment-emergent adverse events among tamsulosin + mirabegron patients. There were no clinically meaningful changes from baseline in blood pressure, and changes in pulse rate were small (+1.2 bpm in the tamsulosin + mirabegron group). Increased pulse rate was more frequent with tamsulosin + mirabegron than with tamsulosin + placebo in older patients, although within the normal range. CONCLUSIONS: Cardiovascular-related adverse events were uncommon in both treatment groups. Mirabegron is a well-tolerated add-on therapy to tamsulosin in Japanese and Korean males with residual overactive bladder symptoms.

Usefulness of Preoperative Endoscopic Fluorescent Clip Marking in Laparoscopic Gastrointestinal Surgery.

BACKGROUND/AIM: Precise tumor localization during gastrointestinal surgery improves curability and function preservation. We investigated the efficacy of preoperative endoscopic fluorescent clip marking using a Zeoclip FS with built-in near-infrared fluorescent resins in delineating gastrointestinal cancer for surgery. PATIENTS AND METHODS: We evaluated the intraoperative visibility of the Zeoclip FS using a VISERA ELITE 2 and the short-term outcomes of 37 cancer patients (colorectal, n=23; gastric, n=14) who underwent preoperative fluorescent clip marking. RESULTS: The study included 23 male and 14 female subjects with a mean age of 73 years (range=39-87 years). Thirty-three patients (89.1%) exhibited clear fluorescent clip marking and easily determined transection lines. Fluorescence was not observed in 1 sigmoid colon cancer patient (2.7%), who required a colonic stent for preoperative obstruction. Three patients (8.1%) required additional procedures for fluorescence visualization. CONCLUSION: Endoscopic fluorescent clip marking can delineate tumors well for determining the extent of resection.

Laparoscopic fluorescence navigation for left-sided colon and rectal cancer: Blood flow evaluation, vessel and ureteral navigation, clip marking and trans-anal tube insertion.

BACKGROUND: Recently, the indocyanine green (ICG) fluorescence navigation method has attracted much attention as a means of intraoperative navigation, especially during laparoscopic surgery. The newly developed near-infrared (NIR) fluorescent resin also emits NIR fluorescence, as does ICG. Presently, new devices made with this resin are being developed. The purpose of this study was to present our fluorescence navigation techniques for left-sided colon and rectal cancer. METHOD: Fifty-nine patients with left-sided colon and rectal cancer underwent laparoscopic surgery with fluorescence navigation between July 2019 and April 2020. The surgeries included 54 intestinal blood flow (IBF) evaluations using ICG, 16 preoperative fluorescence clip marking (FCM) procedures, 7 fluorescence ureteral navigation procedures, 4 fluorescence vessel navigation (FVN) procedures during lateral lymph node dissection, and 3 fluorescence-guided trans-anal tube insertion procedures. Laparoscopic surgery and fluorescence observation were performed using a VISERA ELITE 2. In FCM, the Zeoclip FS device was used. In ureteral navigation and trans-anal tube insertion, the Near-Infrared Ray Catheter (NIRC™) fluorescent ureteral catheter (NIRFUC) was used. RESULTS: No complications related to the fluorescence navigation techniques, including those involving ICG, the Zeoclip FS and the NIRFUC, occurred. In 5 cases, the surgical plan was changed according to the IBF evaluation with ICG, and no anastomotic leakage occurred in those cases. These fluorescence navigation techniques provide previously unavailable visual information regarding the IBF, vessel and ureter routes and accurate endoscopic clip and drainage tube locations in the intestinal tract. CONCLUSIONS: Technology to visualize blood flow dynamics and structures using fluorescence can be considered innovative, especially when applied in laparoscopic surgery, which relies on vision. The popularity of fluorescence navigation has also appeared to increase the safety of colorectal surgery. CLINICAL TRIAL REGISTRATION: Examination of fluorescence navigation for laparoscopic colorectal cancer surgery. Research Ethics Committee of the Kawaguchi Municipal Medical Center (Saitama, Japan) approval number: 2020-3. https://kawaguchi-mmc.org/wp-content/uploads/clinicalresearch-r02.pdf.

Respiratory Disorder at the End of Surgery for Peritonitis Due to Colorectal Perforation Is a Critical Predictor of Postoperative Sepsis.

BACKGROUND/AIM: The aim of this study was to identify a critical predictor of postoperative sepsis in patients with peritonitis due to colorectal perforation. PATIENTS AND METHODS: Between 2009 and 2014, fifty-three patients who underwent emergency surgery for peritonitis due to colorectal perforation in our hospital were examined retrospectively to identify the critical predictor of postoperative sepsis. Between 2016 and 2017, twelve patients with peritonitis due to colorectal perforation were enrolled in a prospective study to validate the critical predictor obtained by the previous retrospective study. RESULTS: Mechanical ventilation for more than two days after surgery seemed to be a critical predictor of postoperative sepsis. In the prospective study, six patients who were withdrawn from mechanical ventilation within one day after surgery did not develop sepsis. CONCLUSION: Respiratory disorders at the end of surgery for peritonitis due to colorectal perforation seem to be a critical predictor of postoperative sepsis.

Usefulness of Fecoflowgram for Assessment of Defecation after Intersphincteric Resection.

AIM: We have developed an imaging functional assessment of defecation after partial intersphincteric resection (ISR) by fecoflowgram obtained by defecography. PATIENTS AND METHODS: Between January 2012 and December 2014, 6 patients with temporary ileostomy who underwent partial ISR for lower rectal cancer at our hospital were enrolled in this study. Defecography was performed 2 weeks after closure of the ileostomy. The defecation of all patients was evaluated by defecography and a fecoflowgram calculated from defecography. During the same period, the control group was comprised of 2 male and 2 female healthy volunteers. RESULTS: The descent of the perineum and linearization of the anorectal angle was observed relative to normal defecation in the healthy volunteers. All barium was discharged by a single abdominal pressure within 5 s in the controls. In patients after partial ISR, all barium could not be discharged by a single abdominal pressure. The time course of pressure distribution after ISR was lower than that of healthy volunteers, which could not be evaluated by defecography. Defecation time in patients following ISR was longer than that of healthy volunteers. CONCLUSION: Fecoflowgrams calculated from defecography seem to be useful for functional assessment of defecation after rectal resection.

Usefulness of TAS-102 as Third-line Chemotherapy for Metastatic Colorectal Cancer.

BACKGROUND/AIM: The feasibility and oncological outcomes of treatment with TAS-102, that is recommended as third-line chemotherapy for patients with metastatic colorectal cancer (mCRC), remain unknown. PATIENTS AND METHODS: Between 2013 and 2015, seven patients (five males, two females) with mCRC who were administered TAS-102 as third-line chemotherapy at our Institution were retrospectively studied. During the same period, seven patients with mCRC with Kirsten rat sarcoma viral oncogene homolog (KRAS) wild-type primary lesions who were administered irinotecan with panitumumab comprised the control group. RESULTS: The duration of third-line chemotherapy in the TAS-102 group was 217.0 (range=136-337) days compared to 226.9 (range=122-335) days in the control group, with no significant difference in the duration of administration between the two groups. No significant difference in overall survival was identified between the two groups No serious adverse effects were encountered in either group. CONCLUSION: TAS-102 may be suitable as third-line chemotherapy for patients with mCRC.

Safety and effectiveness of tacrolimus add-on therapy for rheumatoid arthritis patients without an adequate response to biological disease-modifying anti-rheumatic drugs (DMARDs): Post-marketing surveillance in Japan.

OBJECTIVES: Post-marketing surveillance (PMS) was conducted to assess the safety and effectiveness of tacrolimus (TAC) add-on therapy for patients with rheumatoid arthritis (RA) and an inadequate response to biological disease-modifying anti-rheumatic drugs (DMARDs). METHODS: Patients with RA from 180 medical sites across Japan were registered centrally with an electronic investigation system. The observational period was 24 weeks from the first day of TAC administration concomitantly with biological DMARDs. RESULTS: Safety and effectiveness populations included 624 and 566 patients, respectively. Patients were predominantly female (81.1%), with a mean age of 61.9 years. Overall, 125 adverse drug reactions (ADRs) occurred in 94 patients (15.1%), and 15 serious ADRs occurred in 11 patients (1.8%). These incidences were lower compared with previously reported incidences after TAC treatment in PMS, and all of the observed ADRs were already known. A statistically significant improvement was observed in the primary effectiveness variable of Simplified Disease Activity Index after TAC treatment; 62.7% of patients achieved remission or low disease activity at week 24. CONCLUSIONS: TAC is well tolerated and effective when used as an add-on to biological DMARDs in Japanese patients with RA who do not achieve an adequate response to biological DMARDs in a real-world clinical setting.

[Hypocalcemia Induced by Denosumab in Patients with Renal Insufficiency].

Denosumab is a monoclonal antibody that can be administrated subcutaneously. Although it is not recommended to adjust the dosages for patients with impaired renal function, hypocalcemia has been reported in patients with renal impairment; therefore, it should be administered cautiously. We retrospectively investigated the serum concentrations of calcium after denosumab administration. The results indicated that after continuous administration to patients with a Ccr<40mL/min, serum calcium levels decreased. Grade 2 or above hypocalcemia was detected in 75% of the patients studied. From these results, it is recommended that serum concentrations of calcium be closely monitored in continuous administration of denosu- mab to patients with renal impairment.

Evaluation of the Safety and Effectiveness of Add-On Tacrolimus in Patients with Rheumatoid Arthritis Who Failed to Show an Adequate Response to Biological DMARDs: The Interim Results of a Specific Drug Use-Results Survey of Tacrolimus.

BACKGROUND: Tacrolimus (TAC) is an immunosuppressive macrolide that blocks T-cell activation by specifically inhibiting calcineurin. TAC was approved in Japan for the treatment of rheumatoid arthritis (RA) in 2005. However, the safety and effectiveness of TAC adding on to biological disease-modifying anti-rheumatic drugs (DMARDs) in the real clinical setting may not be clear enough. OBJECTIVES: We report here the interim results of post marketing surveillance (PMS) of TAC adding on to biological DMARDs in RA patients who failed to show an adequate response to biological DMARDs. METHODS: Patients who had an inadequate response to biological DMARDs were enrolled. An inadequate response to biological DMARDs was defined as that all of the following conditions were met: a Simplified Disease Activity Index (SDAI) score of >3.3 when TAC was started; both the tender joint count and swollen joint count were the same or increased compared with those at 4-8 weeks prior to TAC; and biological DMARDs were used for at least 8 weeks prior to TAC. This study was conducted in compliance with the ministerial ordinance on "Good Post-Marketing Study Practice" (GPSP). RESULTS: The safety data collection and evaluation for 172 patients and effectiveness data collection and evaluation for 165 patients were reported. The mean age was 61.9 years. Adverse drug reactions occurred in 18 patients. The mean SDAI decreased from 20.1 at baseline to 11.7 at week 24. CONCLUSIONS: TAC is well tolerated and effective when added on to biological DMARDs in RA patients who failed to achieve an adequate response to biological DMARDs.

Post-marketing surveillance of the safety and effectiveness of tacrolimus in 3,267 Japanese patients with rheumatoid arthritis.

OBJECTIVES: A post-marketing surveillance (PMS) program was implemented to assess the safety and effectiveness of tacrolimus (TAC) in Japanese rheumatoid arthritis (RA) patients and to identify risk factors related to adverse drug reactions (ADRs). METHODS: Patients were registered centrally and monitored for all adverse events (AEs) for 24 weeks. Effectiveness was evaluated using the Disease Activity Score 28-CRP (DAS28-CRP). RESULTS: Data from 3,172 patients (mean age 62.2 years) were evaluated in the safety analysis. Of the safety population, 78.5 %were female and 25.9 % were in Steinbrocker's functional class 3 or 4. TAC was prescribed as monotherapy in 52.5 % and the most common concomitant disease modifying antirheumatic drug (DMARD) was methotrexate, used in 28.9 % of the patients. The incidence of AEs, serious AEs (SAEs), ADRs and serious ADRs were 41.2, 6.4, 36.0, and 4.9 %, respectively. The most frequent serious ADR category was infections and infestations. Age ≥ 65 years, concurrent renal dysfunction, and concurrent diabetes mellitus were identified as significant risk factors for ADR. Based on EULAR response criteria, 65.4 % of the patients showed moderate or good response. CONCLUSIONS: The results demonstrate that TAC is well tolerated by Japanese patients with active RA, including those receiving concomitant methotrexate, in the real world.