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Ogilvie syndrome (acute colonic pseudo-obstruction) is a rare, acquired, life-threatening disorder for which treatment plans vary from simple observation to surgical intervention. Ogilvie syndrome has been reported in patients after renal or liver transplant, but its occurrence after simultaneous pancreas-kidney transplant is rare. Herein, we present the case of a 45-year-old female recipient of a deceased donor simultaneous pancreas-kidney transplant who developed Ogilvie syndrome 10 days after a previous fecal ileus that had resolved at posttransplant week 3. She demonstrated Ogilvie syndrome with obstructive colitis features (severe abdominal pain and high-grade fever), which we immediately treated with colonic decompensation by placement of a transanal ileus tube. After several screening examinations and discontinuation of unnecessary medicines, we were not able to confirm the cause of Ogilvie syndrome in our patient. After 2 weeks, the patient remained unresponsive to the conservative treatment, and so hand-assisted laparoscopic subtotal colectomy was performed to remove the dilated colon. Her symptoms gradually resolved after surgery. Histologically, we confirmed submucosal fibrotic changes, especially at the distal end of the resected colon, without evidence of amyloidosis, and the number of Auerbach plexus ganglia had decreased. Nevertheless, we observed no degenerated appearance of ganglion cells in the Auerbach plexus or the Meissner plexus. After exclusion of several collagen diseases, including systemic sclerosis, we determined that idiopathic colonic fibrosis was the likely cause of Ogilvie syndrome in our patient. When surgery is indicated in transplant patients with Ogilvie syndrome with obstructive colitis features, colectomy should be considered.

Background Catheter ablation of atrial fibrillation (AFCA) is an effective treatment to develop left ventricular (LV) functional recovery. However, the degree of recovery differs between individuals due to the different extent of myocardial fibrosis and scarring. Purpose To examine whether pre-ablation LV wall thickness (WT) and its regional heterogeneity predict LV functional recovery after AFCA in patients with LV systolic dysfunction. Methods Of 3682 consecutive patients who underwent first-time AFCA between January 2012 and September 2020 in our institution, 174 (age, 63±10 years; male, 83%; ischemic cardiomyopathy, 14%) with a baseline LV ejection fraction (LVEF) of Results LVEF significantly improved from 30±7% to 57±17% (p7.4mm, SD of end-systolic WT Conclusion Myocardial WT and its regional heterogeneity as well as LV end-diastolic volume predicted functional recovery after AFCA in patients with reduced LVEF. Funding Acknowledgement Type of funding sources: None.

Background Although Lowe syndrome and Dent disease-2 are caused by Oculocerebrorenal syndrome of Lowe (OCRL) mutations, their clinical severities differ substantially and their molecular mechanisms remain unclear. Truncating mutations in OCRL exons 1–7 lead to Dent disease-2, whereas those in exons 8–24 lead to Lowe syndrome. Herein we identified the mechanism underlying the action of novel OCRL protein isoforms. Methods Messenger RNA samples extracted from cultured urine-derived cells from a healthy control and a Dent disease-2 patient were examined to detect the 5′ end of the OCRL isoform. For protein expression and functional analysis, vectors containing the full-length OCRL transcripts, the isoform transcripts and transcripts with truncating mutations detected in Lowe syndrome and Dent disease-2 patients were transfected into HeLa cells. Results We successfully cloned the novel isoform transcripts from OCRL exons 6–24, including the translation-initiation codons present in exon 8. In vitro protein-expression analysis detected proteins of two different sizes (105 and 80 kDa) translated from full-length OCRL, whereas only one protein (80 kDa) was found from the isoform and Dent disease-2 variants. No protein expression was observed for the Lowe syndrome variants. The isoform enzyme activity was equivalent to that of full-length OCRL; the Dent disease-2 variants retained >50% enzyme activity, whereas the Lowe syndrome variants retained Conclusions We elucidated the molecular mechanism underlying the two different phenotypes in OCRL-related diseases; the functional OCRL isoform translated starting at exon 8 was associated with this mechanism.

Background Immunocomplex capture fluorescence analysis has recently been applied as a method for detection of intragraft donor-specific anti–major histocompatibility complex (MHC) antibodies (DSA) in humans. Although intragraft DSA in humans is an intense topic of investigation, there is no report to assess intragraft DSA in murine organ transplantation. Methods A model of presensitized mouse cardiac transplantation by donor splenocytes was used. To capture mouse MHC, anti-MHC class I/II antibodies were immobilized on Luminex beads. The MHC/DSA complexes were captured by the Luminex beads followed by detection of phycoerythrin-conjugated antimouse IgG antibodies where DSA had already reacted with the allograft in vivo. Results Luminex beads were capable of detecting class I DSA in the cardiac allograft, though results for class II DSA were negative. Immunohistochemical investigation revealed that cardiac allografts had abundant MHC class I expression but only minor expression of MHC class II. Furthermore, MHC/class II DSA complexes were successfully detected in splenocytes and serum from a presensitized recipient. Conclusions These data suggested that graft immunocomplex capture fluorescence analysis can be also applied in murine cardiac transplantation. This novel application in mice would accelerate our comprehension of DSA through mechanistic studies.

This study aimed to investigate the effect of the particles releasing chitosan upon exposure to radiation on inhibition of metastasis. A 10 mL solution of water containing 0.2% weight/volume alginate, 0.1% hyaluronic acid, and 100-mg chitosan was sprayed into the vibrating solution through a stainless mesh filter (pore size: 0.8 [Formula: see text]m) using an ultrasound disintegrator, thereby generating chitosan particles. Further, [Formula: see text] particles floating in 0.1 mL normal saline were subcutaneously injected around the 4TI cells-derived tumor in the left hind legs of six-week-old male C3He/N mice. Six hours after injection, tumors were exposed to 10 Gy or 20 Gy of 100-keV soft X-ray radiation. The release of chitosan was expressed as the frequency of ruptured chitosan particles 12 h after radiation. The antimetastatic effect was confirmed by a reduction in the number of metastatic pulmonary nodules 21 days after completion of treatment. More than [Formula: see text]% of the chitosan particles released chitosan in response to radiation. The particles releasing chitosan had a prolonged antimetastatic effect when compared with the particles not releasing chitosan, thereby resulting in a significantly greater antimetastatic effect lasting for four weeks since the completion of treatment, in tumors treated with both 10 Gy and 20 Gy of radiation. Hence, particlizing chitosan could be useful in reducing metastasis in irradiated tumors.

Background Blood pressure (BP) variability has reportedly been a risk factor for various clinical events. To clarify the influence of BP visit‐to‐visit variability on adverse events in patients with nonvalvular atrial fibrillation, a post hoc analysis of the J‐RHYTHM Registry was performed. Methods and Results Of 7406 outpatients with nonvalvular atrial fibrillation from 158 institutions, 7226 (age, 69.7±9.9 years; men, 70.7%), in whom BP was measured 4 times or more (14.6±5.0 times) during the 2‐year follow‐up period or until occurrence of an event, constituted the study group. SD and coefficient of variation of BP values were calculated as BP variability. Thromboembolism, major hemorrhage, and all‐cause death occurred in 110 (1.5%), 121 (1.7%), and 168 (2.3%) patients, respectively. When patients were divided into quartiles of systolic BP‐SD (P =0.015 for thromboembolism; HR, 2.60, 95% CI, 1.36–4.97, P =0.004 for major hemorrhage; and HR, 1.85, 95% CI, 1.11–3.07, P =0.018 for all‐cause death) after adjusting for components of the CHA 2 DS 2 ‐VASc score, warfarin and antiplatelet use, atrial fibrillation type, BP measurement times, and others. These findings were consistent when BP‐coefficient of variation was used instead of BP‐SD. Conclusions Systolic BP visit‐to‐visit variability was significantly associated with all adverse events in patients with nonvalvular atrial fibrillation. Further studies are needed to clarify the causality between BP variability and adverse outcomes in patients with nonvalvular atrial fibrillation. Registration URL: https://www.umin.ac.jp/ctr/ ; Unique Identifier: UMIN000001569.

AIM Plasma cell-rich rejection (PCRR) has been considered a subtype of acute T-cell-mediated rejection (ATCR). However, PCRR is recognized as refractory rejection and different from ATCR in various ways. In order to elucidate the pathogenesis of PCRR, we analysed PCRR clinicopathologically and immunohistochemically by comparing it with ATCR. METHODS Twelve cases of PCRR (PCRRs) and 22 cases of usual ATCR (ATCRs) diagnosed at our hospital between January 2008 and March 2017 were included. Between PCRRs and ATCRs, we compared clinical data, Banff classification, graft outcome and the total sum number of T-bet- and GATA3-positive lymphocytes infiltrating in tubular epithelium using immunohistochemistry. RESULTS Plasma cell-rich rejections occurred later than ATCRs (median time after transplantation 1340.5 days vs. 52.5 days). Serum creatinine levels at discharge after treatment were significantly higher in PCRRs than in ATCRs (median 2.38 vs. 1.65 mg/dL). Cumulative rate of graft loss was significantly higher in PCRRs than in ATCRs (1-, 2- and 5-year: 26.7%, 51.1% and 51.1% vs. 0%, 0% and 17.5%). For profiles of Th1 and Th2, we found significantly lower ratio of T-bet/GATA3-positive lymphocytes in PCRRs compared with ATCRs. CONCLUSION This study suggests that PCRR is more refractory than ATCR and there are significant differences in populations of helper T-cell subsets between them. We consider helper T-cell subset analysis valuable for developing new treatment strategies for PCRR.

Digital ischemia is a serious problem in peripheral artery diseases (PAD) patients. Case 1: A 60-year-old woman with large arteriovenous fistula (AVF) complained of digital ischemia symptoms. The patient underwent dissection of AVF and distal bypass to the palmar arch with successful repair. Case 2: A 47-year-old female, diagnosed with renal failure, and scleroderma, complained of a digital gangrene. A bypass was performed from the left brachial artery to the superficial palmar arch. The digital gangrene showed a complete recovery within 2 months after surgery. Distal bypass to the palmar arch thus appears to be a useful procedure to re-establish digital circulation in PAD patients.

Microcapsules that release antigen-capturing nanoparticles (AC-NPs) with macrophage inflammatory protein-3 alpha (MIP-3[Formula: see text]) and anti-programmed death-1 (PD-1) antibody are developed, and these microcapsules have the ability to enhance immunoresponses through cross-priming of cluster of differentiation 8+ (CD8+) T cells by dendritic cells (DCs) in vivo in BALB/c mice. Lipid protamine hyaluronic acid nanoparticles containing AC-NPs generated via nanoprecipitation of 4 mg/mL of polylactic-co-glycolic acid (PLGA), 1,000 ng/mL of MIP-3[Formula: see text] and 400 [Formula: see text]g of anti-PD-1 were mixed with 1 mL of 4.0% alginate and 3.0% of hyaluronate and then sprayed with 0.5 mM of ferrous chloride. These capsules were injected subcutaneously around LM17 tumor in the left hind legs of BALB/c mice. The tumors were exposed to a radiation dose of 10 or 20 Gy from 100 keV soft X-ray radiation. PLGA AC-NPs and MIP-3[Formula: see text] were released in response to the radiation dose. PLGA AC-NPs captured tumor-derived protein antigens are released by exposure to radiation, and these antigens were transported to DCs that were recruited and activated by MIP-3[Formula: see text], intensifying the DC-associated cross-priming of CD8+ T cells. These treatments resulted in increased antitumor effect and reduced metastasis by abscopal effect. Our targeted immunotherapy may lead to better tumor therapy.

Purpose/Objective(s) We investigated the efficacy of a combination of radiotherapy with antigen-capturing nanoparticles (AC-NPs; 123 ± 45 nm) containing digitoxin and anti-PODXL siRNA encapsulated in nanocapsules (567 ± 38 nm) that release their contents upon radiation exposure. We performed two radiotherapy sessions. Treatment with AC-NPs achieved successful immuno-radiotherapeutic effects on the primary tumors. An abscopal effect was also observed in the metastatic tumors by dendritic cell (DC)-mediated T-cell priming with PD-L1 blockade. New metastasis reduction was achieved by the dissociation of circulating tumor cell (CTC)-clusters by digitoxin and by reducing the extravasation of the dissociated CTCs via siRNA-mediated silencing of PODXL. Materials/Methods For session 1; nanocapsules were generated by mixing iopamiron and 400 μg anti-PD-L1 antibody (Ab) with a 1.0 mL solution containing 4.0% alginate, 3.0% hyaluronate, and 1 µg/mL P-selectin. This mixture was sprayed into 0.5 mmol/l FeCl2 supplemented with 1 µg/mL anti-VEGFR-1/2 Ab. For session two, 400 nM digitoxin and 50 nM anti-PODXL siRNA were encapsulated in poly lactic-co-glycolic acid (PLGA) AC-NPs using the nanoprecipitation method. The particles were mixed with the above cocktail and sprayed into 0.5 mM/L FeCl2 with 1 µg/mL anti-P-selectin Ab. This yielded encapsulated PLGA AC-NPs containing digitoxin. In session 1; 1 × 1010 nanocapsules were intravenously injected in BALB/c mice exhibiting primary 4TI mammary carcinoma in the left hind leg and lung metastases. Tumor accumulation was monitored using CT imaging. Subsequently, 10/20 Gy 60Co γ-radiation was locally administered to the primary tumors. In session 2; 1 × 1010 nanocapsules were intravenously injected and allowed to interact with P-selectin for 9 h; 10/20 Gy 60Co γ-radiation was locally administered. Results In session 1, CT revealed the accumulation of anti-VEGFR-1/2 nanocapsules around the primary and metastatic tumors. The microcapsules released P-selectin and anti-PD-L1 Ab in response to the initial irradiation. After session 2, the nanocapsules amassed around the primary tumor via a P-selectin Ag-Ab reaction. PLGA AC-NPs captured tumor-derived protein antigens released by the second radiation dose and transported them to DCs. This intensified DC-associated cross-priming of CD8+ T-cells. Primed CD8+ T-cells attacked PD-L1 and suppressed primary and metastatic tumors. PLGA AC-NPs also released digitoxin and anti-PODXL siRNA. The released digitoxin dissociated CTC clusters into single CTCs, and extravasation was reduced by siRNA-mediated silencing of PODXL, which reduced new metastasis formation. These treatments significantly increased the antitumor effect (EF 1.5) and reduced metastasis by 87.2%. Conclusion CT-detectable microcapsules exhibited targeted AC-NP-mediated immunotherapeutic benefits. They caused abscopal effects and reduced new metastasis formation, which improved the diagnosis and treatment of the tumor.

Background The purpose of this study was to evaluate the effect and outcome of intraoperative fluid restriction in living liver donor hepatectomy, regarding changes in intraoperative CVP levels, blood loss, and postoperative renal function. Material/Methods The charts of 167 patients were reviewed and analyzed retrospectively. Intraoperative central venous pressure levels, blood loss, fluids infused, and urine output per hour, before and after the liver allograft procurement, were calculated. Perioperative renal functions were also analyzed. Results Fluid infused before and after liver allograft procurement was 3.21±1.5 and 9.0±3.9 mL/Kg/h and urine output was 1.5±0.7 and 1.8±1.4 mL/Kg/h, respectively. Intraoperative estimated blood loss was 91.3±78.9 mL. No patients required blood transfusion. Their preoperative and postoperative hemoglobin were 12.3±2.7 and 11.7±1.7 g/dL. CVP levels decreased gradually from 10.4±3.0 to a low of 8.1±1.9 mmHg at the time of transection of the liver parenchyma. Renal functions were not significantly affected based on the determination of BUN and creatinine levels. Conclusions The methods used to lower CVP are moderate and slow, with 2 main goals achieved: minimal blood loss (91.3±78.9 ml) and no blood transfusion. Furthermore, it did not have any negative effect on renal function.

BACKGROUND The outcome of living-donor liver transplantation (LDLT) is poor for recipients with severely deteriorated preoperative condition. This study therefore evaluated the proper graft selection according to the recipients' preoperative condition. MATERIAL AND METHODS We evaluated the clinical outcomes in 66 patients who underwent adult LDLT from October 2003 to June 2016 in our institution, excluding fulminant liver failure and ABO-incompatible cases. Preoperative risk factors included MELD score >20, preoperative hospitalization for over 2 weeks or intensive care unit admission and bacterial infection within 1 month before LDLT. Patients were classified into those with 0-1 risk factors (Group LR, n=44) and those with 2-3 risk factors (Group HR, n=22). RESULTS The overall survival (OS) rate after LDLT was significantly lower in Group HR than in Group LR (1-year: HR 83.9% vs. LR 93%, 3-year: HR 70.8% vs. LR 90.5%, 5-year: HR 62% vs. LR 87.6%; p=0.029). In Group LR, OS rates did not differ significantly by graft type or donor age. In Group HR, OS rates at 1 (93.8% vs. 66.7%), 3 (85.2% vs. 50%), and 5 (75.8% vs. 25%) years were significantly higher using right (n=16) vs. left (n=6) lobe grafts (p=0.046). CONCLUSIONS Proper graft selection is very important to improve the outcome of LDLT recipients in deteriorated preoperative condition. LDLT using right-lobe grafts may be recommended for high-risk severely deteriorated patients.

Advances in immunosuppressants enable organ transplantation for sensitized patients. However, influences of pre-formed donor-specific anti-human leukocyte antigen (HLA) antibodies (DSA) have not been fully understood in renal transplantation (RT). On the other hand, immunocomplex capture fluorescence analysis (ICFA) is a reliable method to detect donor-specific anti-HLA antibodies and HLA antigen complexes. Graft ICFA can detect DSA in an allograft (g-DSA).To elucidate the consequences of pre-formed DSA, 198 patients who underwent living-donor RT were enrolled for this study (observation period: 57.8 ± 34.9 months); 187 patients in the DSA- group (excluding ABO-incompatible cases) and 11 patients in the DSA+ group. Before RT, all DSA+ patients had undergone rituximab administration and plasmapheresis. For a graft ICFA, the biopsy specimen (1 × 10There were no significant differences in 5-year graft survival (87.9%/100% in the DSA-/DSA+ groups, respectively). In terms of antibody-mediated rejection (AMR), within 1 month after RT, pathologically determined AMR occurred 3.2% and 63.4% in the DSA- and DSA+ groups, respectively (P .0001). However, interestingly, more than half of them (57.1%) indicated only subclinical AMR, that is, no fluctuation of S-Cr. As representative of 2 cases of subclinical AMR, g-DSA deposition could be confirmed (1.15 ± 0.04) at 1 hour after reperfusion by graft ICFA. Furthermore, g-DSA shifted to 2.20 ± 0.98 at 3 weeks after transplantation, along with a decline in s-DSA mean of fluorescence intensity (1718-506.5).Although pathologically determined AMR occurred more frequently in pre-formed DSA+ recipients, it can be argued that a successful de-sensitization protocol inhibits further production of DSA and graft destruction.

Patient: Female, 28 Final Diagnosis: Ileus due to wandering spleen with a cyst Symptoms: Acute abdominal pain Medication: — Clinical Procedure: Tube decompression • laparotomy Specialty: Abdominal Surgery • Transplant Surgery Objective: Rare disease Background: Splenic cysts are rare. Most are due to previous trauma, infection, or infarction. They are generally handled by laparoscopic surgical removal if they are larger than 5 cm. However, very large cysts may require splenectomy. Another factor in the choice of therapy is the patient’s underlying condition. We present the case of a giant splenic cyst in a woman 1 year after a renal transplant. Case Report: A 28-year-old woman presented with acute abdominal pain and nausea. One year before, she had received an ABO-identical living donor renal transplantation from her father, and was maintained on oral tacrolimus and prednisolone. A CT scan with contrast showed enteric ileus and an abnormal position of the spleen, which was involved by a cyst measuring 12×12.5×9 cm. A nasogastric tube, and later a small bowel tube, were inserted to decompress the ileus. The patient underwent laparotomy 11 days after admission. We confirmed an internal hernia with volvulus due to migration of the spleen; however, there was no evidence of necrosis. The patient was treated with splenectomy and reduction of the hernia. There were no complications. Conclusions: This was a very unusual emergency following renal transplantation. Splenectomy has been performed in the past for immunosuppression in cases of donor ABO-incompatibility. We therefore considered that it would be more expedient to remove the spleen than to remove the cyst and perform splenopexy.

Background Arteriovenous fistula (AVF) trouble in a dialysis patient sometimes results in severe forearm ischemia. Case presentation We present the case of 27-year-old man with severe steal syndrome complained of AVF malfunction. There was a condition where an upstream artery of AVF is occluded and AVF is maintained by regurgitation from the palmar arch with ischemic digits. The patient underwent distal dual bypass: proximal to peripheral artery arterioarterial and arteriovenous bypasses and brachial arterioplasty. His skin perfusion pressure improved from 17 to 90 mmHg with enough quantity of blood: 250 ml/min for hemodialysis. Conclusions In severe steal syndrome cases, it is often observed that proximal artery is occluded and AVF inflow was supplied from palmar circulation and collateral vessels. Distal dual bypass is effective to re-establish digital circulation and repair AVF malfunction simultaneously in PAD patients.

Background The management of acute or, in particular, chronic antibody-mediated rejection (AMR) resulting from donor-specific HLA antibodies (DSA) is a critical barrier to obtaining better long-term graft survival. To ascertain the efficacy of anti-AMR therapies, the transition of intra-graft DSA (g-DSA) was assessed. Methods Allograft biopsy specimens were analyzed by graft immunocomplex capture fluorescence analysis, as previously described. One hundred recipients who underwent graft biopsies between April 2016 and December 2017 were enrolled for this study. Fifteen recipients diagnosed with g-DSA positive (+) received anti-humoral treatments and underwent follow-up biopsies. g-DSA levels were assessed again by a follow-up biopsy at 6–12 months following the treatments. Results With anti-humoral treatments, 9 out of 15 recipients comprised a g-DSA negative (-) (3.59 ± 2.82-.58 ± .25): g-DSA6-12- group, while the remaining 6 recipients comprised a g-DSA +(20.6 ± 17.0-14.9 ± 14.1): g-DSA6-12+ group. The initial g-DSA scores were significantly higher in the g-DSA6-12+ group (P = .01). All samples were diagnosed as chronic AMR in the g-DSA+ groups, whereas there were 3 chronic AMR, 4 acute AMR, and 2 incomplete AMR samples in the g-DSA- group. Interestingly, the frequency of responsible DSA belonging to class II tended to be higher in the g-DSA6-12+ group (4/6) compared to the g-DSA6-12- group (2/9) (P = .14). Conclusion These results imply that chronic exposure to DSA causes significant and irreversible damage to the allograft. Timely and adequate anti-humoral intervention might reverse the early phase of AMR with complete clearance of g-DSA.

Background Everolimus (EVR) has been used widely for the purpose of reducing the dosage of calcineurin inhibitor (CNI), leading to decreasing CNI nephrotoxicity. In Japan, high-dose mizoribine (MZR) (6 mg/kg/day) has been increasingly used because of incidences of virus infection and gastrointestinal disorder in kidney transplant recipients. However, the efficacy and safety of EVR and MZR combination therapy is still uncertain. Methods A total of 29 living kidney transplant recipients from October 2012 to June 2014 were analyzed. Tacrolimus (TAC), MZR, basiliximab, and prednisolone were administered to all recipients. EVR was added to the regimen for 10 recipients from postoperative day 10 to 14; TAC trough levels were minimized simultaneously (EVR group). The remaining 19 recipients were defined as the control group. We evaluated the outcomes between the 2 groups. Results The mean TAC trough level was 5.17 ng/mL at 1 month after transplantation in the EVR group, and 7.89 ng/mL in the control group ( P = .007), respectively. The mean TAC trough level was 4.0 ng/mL at 18 months after transplantation in the EVR group, and 6.97 ng/mL in the control group ( P = .003) respectively. There were no differences in the rate of acute rejection and serum creatinine level. There was no significant difference in the incidence of histological nephrotoxicity between the 2 groups in the 1-year biopsy results. Conclusions We succeeded in reducing TAC trough level immediately after transplantation by adding EVR. Our study results suggest that this combination therapy is effective for kidney transplantation recipients.

Background Isolated superior mesenteric artery (SMA) dissection (SMAD) is considered a relatively rare disease. Especially, isolated SMAD following liver transplant has been rarely reported. Report of Cases Among 96 consecutive adult recipients who underwent liver transplant at our institution, 3 recipients (3.1%) demonstrated isolated noncommunicating SMAD, type IV according to Sakamoto's classification. Patient characteristics are the following: mean age, 53 years (range, 49–60 years); male to female ratio, 2:1, right lobe graft to left lobe graft ratio, 2:1; operating time, 760 minutes (range, 614–880 minutes); and blood loss, 6570 mL (range, 2435–13,329 mL). New onset of abdominal pain was noted in 33.3% (1/3). The diagnosis was made by the first follow-up computed tomography scan after liver transplant. The mean distance between the proximal end of SMAD and the root of SMA was 21.3 mm (range, 9–40 mm). There were no signs of ischemic changes in the small intestine in any of the 3 patients. Thus, conservative managements such as anticoagulation therapy were performed without other aggressive interventions. One patient died because of subarachnoid hemorrhage. In the other 2 patients, SMAD disappeared at 6 months following the diagnosis. Discussion The morbidity of isolated SMAD is around less than 0.1% at the autopsy. Compared with this result, we found significantly higher morbidity rate in liver transplant recipients. It is true that mechanical stress from retraction of the stomach to the caudal end including the root of SMA may play an important role in the onset of SMA dissection. Conclusion Isolated SMA dissection following living donor liver transplant is a rare but potentially life-threatening condition. It is required to ascertain whether emergency revascularization should be considered.

The rising demand for living renal donors has led to the recruitment of older donors. Findings vary, but these grafts appear to survive as long as grafts from standard criteria deceased and expanded criteria deceased donors. We investigated the effects of donor age ≥65 years and the presence or absence of donor antihypertensive therapy on patient condition 1 year after transplantation, and retrospectively examined 1-year (273 patients), 3-year (217 patients), and 5-year (140 patients) patient and graft survival.We divided 273 donor-recipient pairs into Group Y (donor age 65 years, n = 224) and Group O (donor age ≥65 years, n = 49). Group O was subdivided into donors receiving treatment for hypertension (subgroup O-1, n = 16) and those not receiving treatment for hypertension (subgroup O-2, n = 33). We compared results of 1 hour post-transplant biopsies and looked at a small number of 1 year post-transplant biopsies.Although a significantly larger percentage of recipients from younger donors were undergoing preemptive transplantation, and the incidence of arteriosclerosis was significantly higher in the Group O kidneys, there were no significant differences between the 2 groups in terms of patient or graft survival at 1, 3, or 5 years; serum creatinine levels; or number of episodes of acute rejection. The presence or absence of donor antihypertensive treatment had no effect.We found that donor age ≥65, with or without antihypertensive treatment, had no effect on graft or patient survival.

Aim Given the recent increase in the prevalence of diabetes mellitus, it is not uncommon for kidney transplantation donors to have diabetes. We perform kidney transplantation in our hospital if the diabetic donors are receiving oral hypoglycaemic agents, but not insulin, and their haemoglobin A1C (HbA1C) is below 6.5%. There are few reports about histological changes to diabetic nephropathy after transplantation of kidney grafts from donors with diabetes mellitus to non-diabetic recipients. Therefore, we studied the histological diabetic changes in grafts from diabetic donors at protocol biopsies (1 hour, 1 month, 1 year), and evaluated whether they improved under the recipient's good glycaemic control. Methods Three cases of kidney transplantation from donors with diabetes mellitus to non-diabetic recipients were selected. We used a pathological classification established by the Renal Pathology Society for evaluating histological improvements in diabetic nephropathy. Results The results revealed that early diabetic changes found at the 1-hour and 1-month protocol biopsies were reversed and improved at the 1-year biopsy. Conclusion We concluded that early diabetic changes in grafts from diabetic donors may improve if the graft recipient has good glycaemic control after kidney transplantation.

Improving the short-term outcome of kidney transplantation, the rejection induced by anti-donor specific antibody (DSA) has been the large complication. We analyzed 324 living-donor kidney transplant recipients (procedures performed between April 2003 and August 2014) to investigate the outcome of kidney transplant recipients with DSA. We divided them into four groups (anti-blood type antibody alone, group A [n = 73]; anti-human lymphocyte antigen [HLA] antibody alone, group B [n = 11]; both antibodies, group C [n = 8]; and no DSA, group D [n = 232]) and investigated the incidence of rejection and those histologic findings. Each case with DSA underwent some desensitization therapy before transplantation. There was no significant difference in graft survival (all cases: 100% at 1 year, group A: 97.6%, B: 95.9%, C: 100%, and at 5 years, group D: 96.1%). There were some significant differences in incidence of acute antibody-mediated rejection (AAMR) and chronic active antibody-mediated rejection (CAAMR) among four groups (group A: 4.1% and 2.7%, B: 18.2% and 9.1%, C: 12.5% and 12.5%, D: 0% and 0.9%, respectively). Each AAMR case was improved by ordinary desensitization therapy, but half of the CAAMR cases, diagnosed early after transplantation, had no effect of any therapy to result in graft failure. Our results suggested that even the case with DSA could be transplanted safely by some desensitization therapy. However, we should be cautious regarding recipients with DSA for the long term even if there is no histologic change early after transplantation because graft loss may occur due to CAAMR.

Chronic allograft injury (CAI) is one of the most important factors for graft failure after renal transplantation. Protocol biopsy is the most valuable tool for revealing subclinical renal allograft failure. Transient elastography (TE) is a noninvasive technique that has shown utility for the assessment of hepatic and renal fibrosis. This study sought to evaluate whether TE was a viable and effective method for the assessment of renal allograft failure.Thirty-five patients underwent TE by Fibro Scan (Echosense, Paris, France). Biopsies were performed in 27 patients, allowing classification according to Banff chronic changes in the interstitium grade 0, grade 1 or grade 2.Measurement of parenchymal stiffness was successful in 31 of 35 patients (91%). Stiffness was significantly correlated with interstitial fibrosis (P.05) and inversely related with estimated glomerular filtration rate (eGFR; P.05). Stiffness values of patients with eGFR50 mL/min were lower than those of patients with eGFR50 mL/min (P.05). Patients classed as CAI Banff grade 0 had significantly less parenchymal stiffness than patients with Banff grade 1 or grade 2 CAI (P.05). Parenchymal stiffness measured by TE reflected interstitial fibrosis in renal allograft.Assessment of parenchymal renal allograft stiffness by TE was effective for identifying patients with CAI who may subsequently benefit from biopsy and modification of the immunosuppressive regimen. Assessment of parenchymal renal allograft stiffness can be effective for identifying patients with CAI. TE has the potential to reduce the number of renal allograft biopsies required for accurate assessment of CAI.

We aimed to image and treat the lung metastases of MM48 breast cancer cells in C3He/N mice by using microcapsules that release liposome-protamine-hyaluronic acid nanoparticles (LPH-NP) in response to two radiation sessions. In session one, computed tomography (CT)-detectable microcapsules containing P-selectin and 5% iopamiron were mixed with a 1 mL solution of 4% alginate, 3% hyaluronate, 1 mg ascorbate, and 1 μg/mL P-selectin. This was sprayed into 0.5 mmol/L FeCl2 containing 1 μg/mL VEGFR-1/2 antibodies (Abs). The mice were intravenously injected with microcapsules, which released the P-selectin, and then a CT study was performed to detect lung metastases. After the CT evaluation, the mice received 10 or 20 Gy (140 keV) of X-ray radiation to the lungs. In session two, carboplatin-LPH-NP was released into the tumor, which was treated with another dose of radiation. To do this, carboplatin LPH-NP was mixed with the cocktail used in session one and sprayed into 0.5 mmol/L FeCl2 containing 1 μg/mL anti-P-selectin Abs. Microcapsules (1 × 1010) were injected intravenously and then interacted with the P-selectin. The released carboplatin LPH-NP attacked lung metastases synergistically with radiation, which resulted in further reduction of the lung metastases.

Background Mizoribine (MZ) has been developed as an immunosuppressive agent in Japan, but it has a less-potent immunosuppressive effect up to 3 mg/kg/d. In the previous study, a Japanese multicenter study, we reported that high-dose MZ, at 6 mg/kg/d, with a calcineurin inhibitor was effective and safe in reducing the frequency of cytomegalovirus (CMV)-related events in ABO-incompatible (ABO-i) living-related kidney transplantation (LKT). In the present study, therefore, we investigated the effects of high-dose MZ with a CNI in ABO-i LKT recipients in a Japanese multicenter study. Methods A total of 37 patients were treated with high-dose MZ (6 mg/kg), a CNI (cyclosporine [CsA] or tacrolimus [Tac]), basiliximab (Bas), rituximab (Rit), and corticosteroids. CsA was started at a dose of 7 mg/kg to maintain blood levels [200 ng/mL (C0), 6000 ng-h/mL (AUC 0–9)]. Tac was started at a dose of 0.2 mg/kg to maintain blood levels [8–10 ng/mL (C0), 100 ng-h/mL (AUC 0–9)]. Bas (20 mg/body) was administrated on day 0 and day 4 after transplantation. Rit (100–200 mg/body) was administrated on day −14 and day −7 before transplantation. MZ was adjusted to maintain target C0 levels of 1.5 to 2.0 μg/mL. Results Patient and graft survival rates for 2 years were 100% in the CsA group (n = 22) and 93.3% in the Tac group (n = 15) (not significant, NS). Overall incidence of acute rejection for 2 years was 22.7% in the CsA group and 26.7% in the Tac group. Mean serum creatinine levels at 2 years were 1.29 ± 0.2 mg/dL in the CsA group and 1.21 ± 0.34 mg/dL in the Tac group (NS). The incidence of CMV disease was 0% in both groups, and positive rates of CMV antigenemia were 50.0% and 26.7% in the CsA and Tac groups, respectively (NS). Mean serum uric acid levels were 5.5 ± 1.3 mg/dL and 6.4 ± 1.2 mg/dL at 2 years (NS) in the CsA and Tac groups, respectively. Conclusions A high-dose MZ regimen including calcineurin inhibitor (CsA or Tac), Bas, Rit, and steroids was effective and safe in reducing the frequency of CMV-related events in ABO-i LKT.

Background Hepatitis C virus (HCV) infection is known to affect long-term patient and graft survivals after kidney transplantation (KT). Recently, combination therapy with the use of 2 oral direct-acting antivirals, daclatasvir (DCV) and asunaprevir (ASV) reportedly showed a high rate of HCV eradication. We report the safety and efficacy of DCV and ASV therapy in 2 KT patients. Methods The safety and viral responses were investigated in a prospective study of KT patients infected with HCV genotype 1. Two patients received 60 mg DCV once daily plus 100 mg ASV twice daily for 24 weeks. Results A 69-year-old woman and a 57-year-old man underwent DCV and ASV therapy for 24 weeks. In both cases, the HCV genotype was 1b. Case 1 had undergone KT twice and had received treatment with pegylated interferon and ribavirin. She received DCV and ASV therapy 12 years after the 2nd KT, and had undetectable virus after only 6 weeks of treatment and at 24 weeks after the end of treatment (SVR24). The post-transplantation immunosuppressive therapy at that time comprised tacrolimus, mycophenolate mofetil, and prednisolone. The other case, after failure of interferon treatment, received DCV and ASV therapy 27 years after his KT and achieved SVR24. His immunosuppressive regimen at that time was mizoribine and prednisolone. DCV and ASV therapy did not affect renal graft function or tacrolimus blood concentrations. Conclusions DCV and ASV therapy had high antiviral effect and a low rate of adverse events in KT patients.

Introduction There is no obvious criterion about kidney transplantation for patients with pretransplant malignancy. Minimum tumor-free waiting periods differ according to type of cancer, staging, site of occurrence, response to therapy, and risk of cancer recurrence. We report a case of living donor kidney transplantation (LDKT) in a patient after brachytherapy for prostate cancer. Case Report The patient was a 65-year-old man with chronic kidney disease due to chronic glomerular nephritis. He received hemodialysis 3 times a week. His prostate-specific antigen level (PSA) was high (6.57 ng/mL), and he was diagnosed with prostate cancer (T1cN0M0, Gleason Score 3 + 4 = 7, 3/10) by needle biopsy in urology. He was treated with maximum androgen blockade (MAB) therapy and brachytherapy in May 2014. He underwent LDKT from a spousal donor at our department in December 2015, because urologists concluded that the prostate cancer was completely cured. Immunosuppression consisted of induction with basiliximab and maintenance with tacrolimus, mizoribine, and steroids. The postoperative course was uneventful. He discharged at postoperative day 29 with a serum creatinine level of 1.30 mg/dL. Three months after LDKT, his PSA level was 0.477 ng/mL, and there was no evidence of prostate cancer recurrence. Conclusion This is the first case of LDKT for patients with prostate cancer after brachytherapy in combination with MAB. There is no recurrence of prostate cancer so far; however, careful follow-up including PSA is necessary and important.

Immunocomplex capture fluorescence analysis (ICFA) is an attractive method to detect donor-specific anti-HLA antibodies (DSA) and HLA antigen complexes. Currently, antibody-mediated rejection (AMR) due to DSA is usually diagnosed by C4d deposition and serological DSA detection. Conversely, there is a discrepancy between these findings frequently. Thereupon, our graft ICFA technique may contribute to establish the diagnosis of AMR.Graft samples were obtained by a percutaneous needle biopsy. Then, the specimen was dissolved in PBS by the lysis buffer. Subsequently, HLA antigens were captured by anti-HLA beads. Then, DSA-HLA complexes were detected by PE-conjugated anti-human IgG antibodies, where DSA had already reacted with the allograft in vivo, analyzed by a Luminex system.A ratio (sample MFI/blank beads MFI) was calculated: ≥ 1.0 was determined as positive. We found that DSA-HLA complexes in the graft were successfully detected from only slight positive 1.03 to 79.27 in a chronic active AMR patient by graft ICFA. Next, positive graft ICFA had predicted the early phase of AMR (MFI ratio: 1.38) even in patients with no serum DSA. Finally, appropriate therapies for AMR deleted DSA deposition (MFI ratio from 0.3 to 0.7) from allografts.This novel application would detect early phase or incomplete pathological cases of AMR, which could lead to a correct diagnosis and initiation of appropriate therapies. Moreover, graft ICFA might address a variety of long-standing questions in terms of DSA.AMR: Antibody-mediated rejection; DSA: Donor-specific antibodies; ICFA: Immunocomplex capture fluorescence analysis.

In this study, two types of microcapsules were designed: (1) computed tomography (CT)-detectable anti-αvβ3 (E[c(RGDfK)]2) microcapsules, containing P-selectin and P-selectin glycoprotein ligand-1 (PSGL-1), for the observation of metastases through αvβ3-antigen–antibody accumulation; and (2) metastasis-targeting microcapsules that upon irradiation release anticancer drugs with high affinity for P-selectin. These microcapsules were tested on C3He/N mice with MM48 tumors undergoing two radiotherapy sessions. The injected anti-αvβ3 microcapsules accumulated in the vascular endothelium of metastatic tissues and could be detected by CT. These microcapsules released P-selectin in response to the first irradiation, which was also induced in the endothelium of vessels in the case of metastasis. The microcapsules used for radiosensitizing metastases were injected 6 h after the first radiotherapy session. Their accumulation reached a maximum at 3 h after injection. After the second radiotherapy session, the microcapsules released carboplatin, which reduced the number of metastases; however, this reduction was not significant.

In this paper, we used microcapsules releasing liposome-protamine-hyaluronic acid nanoparticles (LPH-NP) with/without carboplatin in response to radiation to image and treat MM48 breast cancer in C3He/N mice in two radiation sessions. The micro-particle-induced X-ray emission (PIXE) camera and quantitative PIXE were used to image and measure the release of nanoparticles from the microcapsules. In session one, iopamiron and computed tomography (CT)-detectable microcapsules containing P-selectin and LPH-NP were mixed with a solution of alginate, hyaluronate, ascorbate, and P-selectin. This solution was sprayed into an FeCl2 solution containing VEGFR-1/2 antibodies (Abs). The microcapsules obtained were injected intravenously into mice, and after 9 h, the mice were exposed to 10 or 20 Gy (140 keV) of X-ray radiation. Anti-VEGFR-1/VEGFR-2 microcapsules accumulated around tumors and released P-selectin and the iopamiron-labeled LPH-NP in response to the first radiation. The iopamiron-containing nanoparticles were detected by CT, allowing detection of MM48 tumors by CT. In the second session, the microcapsules released LPH-NH that delivered carboplatin into the tumor cells. This treatment had a significant antitumor effect [Formula: see text]. The micro-PIXE camera and quantitative PIXE successfully imaged and measured the release of contents from microcapsules. Our results indicate that targeted nanoparticles allow for accurate detection and treatment of tumors.

We have been developing microcapsules that release anticancer drugs in response to radiation with an aim of targeted delivery and increasing the efficacy of anticancer drugs by a combination of these drugs with radiation. The aim of this study was to micronize microcapsules by adding carbonated water to the core material of microcapsules, which releases the anticancer drugs in response to radiation. The core material of microcapsules was prepared by mixing 0.1 g of hyaluronic acid and 0.2 g of alginate into 5 mL of carbonated water. The mixture was sprayed onto a 0.3 mmoL/L solution of calcium chloride (CaCl2) and ferrous chloride (FeCl2) using an ultrasound disintegrator. The vibration of the ultrasound disintegrator generated microbubbles in the carbonated water, which micronized the microcapsules. Intravenous injection of the micronized microcapsules to tumor-bearing mice showed that the micronized microcapsules passed more efficiently through the capillaries of lungs or kidneys, which resulted in increased delivery of microcapsules to the tumors and increased the anticancer effect.

The aim of this study was to determine whether oxygen-releasing microcapsules could be used to sensitize cancer cells to kill by radiation. The microcapsules were generated by spraying a mixture of 0.1% alginate and hyaluronic acid into a 0.3 mmol/l solution of CaCl2 and FeCl2. These were then subcutaneously injected around a MM48 tumor (a cell line derived from human breast cancer) in the left hind legs of C3H/HeN mice, and tumors were dosed with 60Co γ-ray radiation. We showed that the oxygen released from the microcapsules enhanced the anti-tumor effect of radiation treatment via the generation of oxygen radicals.

Background To clarify the influence of hypertension and blood pressure ( BP ) control on thromboembolism and major hemorrhage in patients with nonvalvular atrial fibrillation, a post hoc analysis of the J‐ RHYTHM Registry was performed. Methods and Results A consecutive series of outpatients with atrial fibrillation was enrolled from 158 institutions. Of 7937 patients, 7406 with nonvalvular atrial fibrillation (70.8% men, 69.8±10.0 years) were followed for 2 years or until an event occurred. Hypertension was defined as a systolic BP ≥140 mm Hg, a diastolic BP ≥90 mm Hg, a history of hypertension, and/or antihypertensive drug use. Hypertension was an independent risk factor for major hemorrhage (hazard ratio 1.52, 95% CI 1.05–2.21, P =0.027) but not for thromboembolism (hazard ratio 1.05, 95% CI 0.73–1.52, P =0.787). When patients were divided into quartiles according to their systolic BP at the time closest to the event or at the end of follow‐up (Q1, CI 1.75–4.74, P CI 1.02–2.53, P =0.041) after adjustment for components of CHA 2 DS 2 ‐ VAS c score, warfarin use, and antiplatelet use. A systolic BP of ≥136 mm Hg was an independent risk factor for thromboembolism and major hemorrhage. Conclusions BP control appears to be more important than a history of hypertension and baseline BP values at preventing thromboembolism and major hemorrhage in patients with nonvalvular atrial fibrillation. Clinical Trial Registration URL : http://www.umin.ac.jp/ctr . Unique identifier: UMIN 000001569.

Background Among living donor liver transplant (LDLT) recipients, the number of elderly individuals has been increasing because of longer survival due to the improvement of treatment for hepatic diseases such as hepatitis C (HCV). Here we report the outcomes of living donor recipients over the age of 60 years. Materials and Methods In 76 adult LDLT patients at our institution before September 2015, there were 21 recipients over 60 years old. We divided all of the recipients into 2 groups (“elderly” recipient group >60 years of age [n = 21], and a “nonelderly” recipient group Results The graft survival rates in the elderly group were 89.9% at 1 year, 89.9% at 3 years, 83.0% at 5 years, and 83.0% at 10 years. The graft survival rates in the nonelderly group was 91.1% at 1 year, 85.2% at 3 years, 82.8% at 5 years, and 82.9% at 10 year. There was no significant difference between the 2 age groups. In the elderly group, 3 patients died (2 patients had HCV recurrence and 1 patient had fungal infection in the brain, leading to a fatal subarachnoid hemorrhage). In the nonelderly group, 4 of 10 patients died of graft failure due to the graft size being too small. Conclusion Elderly patients, at the end stage of liver failure, are likely very frail and may have latent infections. Careful examination for latent infections before LDLT should be carefully performed in regard to indications for LDLT, which might reach satisfactory outcomes as in nonelderly LDLT recipients. Even if elderly patients are approved for transplantation, very careful management is needed.

Microencapsulated anti-RLIP76 was tested in vivo using C 3 He / J mice to determine the increasing of antitumor effects by chemotherapeutic agent efflux inhibition during chemoradiotherapy. Microcapsules were produced by spraying a mixture of 3.0% hyaluronic acid, 2.0% alginate, 3.0% H 2 O 2, and 0.3 mmol carboplatin onto a mixture of 0.3 mol FeCl 2 and 0.15 mol CaCl 2. Microcapsules were subcutaneously injected into MM46 tumors previously inoculated into the left hind legs of C 3 He / J mice. Subsequent radiotherapy consisted of tumor irradiation with 10 Gy or 20 Gy 60 Co . The antitumor effects of microcapsules were tested by measuring tumor size and monitoring tumor growth. Three types of adverse effects were considered: fuzzy hair, loss of body weight, and mortality. Carboplatin levels were monitored using particle-induced X-ray emission (PIXE) and a micro-PIXE camera. Anti-RLIP76 inhibited the efflux of carboplatin from tumor tissue, which led to an increase in the concentration of carboplatin. Higher carboplatin concentration significantly increased the combined antitumor effect of radiation and chemotherapy. A significant decrease in adverse effects was also observed with microencapsulated anti-RLIP76.

Background Due to the shortage of deceased donor kidneys, we have expanded the indications for living-donor kidney transplantation (LKT) including ABO-incompatible (ABO-i) donors in Japan. In this study, the utility of protocol biopsies was discussed in ABO-i LKT. Methods Protocol biopsies have been performed on kidney graft 1 hour, 3 weeks, and 1 year after LKT in our institution. The relationship between biopsies and clinical courses was considered retrospectively in 38 cases of ABO-i LKT. The immunosuppressive regimen consisted of anti-CD20 antibody, mycophenolate mofetil, prednisolone, calcineurin inhibitor (cyclosporine or tacrolimus), and anti-CD25 antibody. Anti-ABO blood type antibody removal by plasmapheresis was performed before LKT up to 32 times. The post-transplantation regimen consisted of mycophenolate mofetil or mizoribine as an antimetabolite. Results Episode biopsies have been performed in 6 cases within 3 weeks post-transplantation. Each pathological diagnosis was as follows: antibody-mediated rejection (AMR; 5 cases) and calcineurin inhibitor (CNI) nephrotoxicity (1 case). Subclinical chronic active AMR was found at 1 year post-transplantation follow-up biopsies in 4 of the 6 cases. Episode biopsies have been done in the other 6 cases from 1 month to 1 year post-transplantation. Each pathological diagnosis was as follows: acute T-cell–mediated rejection (TMR; 1 case), vesicoureteral reflux (VUR; 3 cases), CNI nephrotoxicity (2 cases), and VUR + CNI nephrotoxicity (1 case). AMR was also not found at 1 year post-transplantation follow-up biopsies in them. In all cases episode biopsies were performed based on pathological diagnosis and had no graft dysfunction after that. Conclusions Pathological study revealed that acute AMR was found early (ie, within 3 weeks) following transplantation. Although appropriate treatment made AMR go into remission once, chronic active AMR was often found at 1-year follow-up biopsies.

In Japan, diabetic nephropathy accounted for 16,225 (43.7%) of the 38,473 patients who began hemodialysis in 2010 and the number increases year by year. In 1991, we started a kidney transplantation program for patients with diabetic nephropathy in our institution, and the ratio of patients who underwent kidney transplantation for diabetic nephropathy traces the course of increase. Among the 516 patients who underwent primary kidney transplantation in our institution from January 1991 to February 2013, we divided them into 2 groups. One group was the diabetes mellitus (DM) group, which included patients with primary disease of diabetic nephropathy, and the other group was the non-DM group. The DM group included 50 patients, and in our institution the ratio traces the course to increase. There was no significant difference for the 1-year and 5-year patient survival rates and graft survival rates between the DM group and the non-DM group. Moreover, the rate of acute rejection in the 2 groups was not significantly different. Furthermore, when we investigated the causes of death in the 2 groups, there was no significant difference with the mortality of cases due to heart vascular disease in the DM group and the non-DM group. Also, no case in which the graft lost function due to recurrence of diabetic nephropathy was observed. Although the early outcome of kidney transplantation for diabetic nephropathy in our institution did not have inferiority in comparison with kidney transplantation for the other primary disease, we think that careful diabetic control after kidney transplantation is required for long-term outcome.

The radiation-induced releasing of the liquid-core of the microcapsules was improved using H 2 O 2, which produced O 2 generation of H 2 O 2 after irradiation. Further, we tested whether these microcapsules enhanced the antitumor effects and decreased the adverse effects in vivo in C3He / J mice. The capsules were produced by spraying a mixture of 3.0% hyaluronic acid, 2.0% alginate, 3.0% H 2 O 2, and 0.3 mmol of carboplatin on a mixture of 0.3 mol FeCl 2 and 0.15 mol CaCl 2. The microcapsules were subcutaneously injected into MM46 tumors that had been inoculated in the left hind legs of C3He / J mice. The radiotherapy comprised tumor irradiation with 10 Gy or 20 Gy 60 Co . The antitumor effect of the microcapsules was tested by measuring tumor size and monitoring tumor growth. Three types of adverse effects were considered: fuzzy hair, loss of body weight, and death. The size of the capsule size was 23 ± 2.4 µ m ɸ and that of the liquid core, 20.2 ± 2.2 µ m ɸ. The injected microcapsules localized drugs around the tumor. The production of O 2 by radiation increased the release of carboplatin from the microcapsules. The antitumor effects of radiation, carboplatin, and released oxygen were synergistic. Localization of the carboplatin decreased its adverse effects. However, the H 2 O 2 caused ulceration of the skin in the treated area. The use of our microcapsules enhanced the antitumor effects and decreased the adverse effects of carboplatin. However, the skin-ulceration caused by H 2 O 2 must be considered before these microcapsules can be used clinically.

Purpose Radiation-sensitive microcapsules composed of alginate and hyaluronic acid are being developed. We report the development of improved microcapsules that were prepared using calcium- and yttrium-induced polymerization. We previously reported on the combined antitumor effect of carboplatin-containing microcapsules and radiotherapy. Methods and Materials We mixed a 0.1% (wt/vol) solution of hyaluronic acid with a 0.2% alginate solution. Carboplatin (l mg) and indocyanine green (12.5 μg) were added to this mixture, and the resultant material was used for capsule preparation. The capsules were prepared by spraying the material into a mixture containing a 4.34% CaCl 2 solution supplemented with 0–0.01% yttrium. These capsules were irradiated with single doses of 0.5, 1.0, 1.5, or 2 Gy 60 Co γ-rays. Immediately after irradiation, the frequency of microcapsule decomposition was determined using a microparticle-induced X-ray emission camera. The amount of core content released was estimated by particle-induced X-ray emission and colorimetric analysis with 0.25% indocyanine green. The antitumor effect of the combined therapy was determined by monitoring its effects on the diameter of an inoculated Meth A fibrosarcoma. Results Microcapsules that had been polymerized using a 4.34% CaCl 2 solution supplemented with 5.0 × 10 −3 % (10 −3 % meant or 10% −3 ) yttrium exhibited the maximal decomposition, and the optimal release of core content occurred after 2-Gy irradiation. The microcapsules exhibited a synergistic antitumor effect combined with 2-Gy irradiation and were associated with reduced adverse effects. Conclusion The results of our study have shown that our liquid core microcapsules can be used in radiotherapy for targeted delivery of chemotherapeutic agents.

Rapid and sensitive micromethods for the study of alcohol dehydrogenase and adehyde dehydrogenase isozymes in skin extracts, cultured fibroblasts and other organs are presented. Possibilities for the application of these techniques to the study of interindividual variations in response to alcohol are discussed. While fibroblasts cultured from a skin biopsy from one Japanese individual revealed a heterodimer (ADH2 2-1) of alcohol dehydrogenase, skin extract from another Japanese showed a homodimer (ADH2 2-2). Up to four isozyme sets for aldehyde dehydrogenase (ALDH) were detected in various human organs and at least three sets were found in skin and fibroblasts extracts. Our preliminary data on liver, stomach, and skin indicate that ALDH is polymorphic and several loci are concerned in the determination of these isozyme sets.

We report two medical applications of particle-induced X-ray emission (PIXE) as described below (1) Observation of biological events: The kinetics of trace elements during the initiation of radiation-induced apoptosis (RIA) was observed using a micro-PIXE and PIXE. RIA is a process in which irradiated cells commit suicide; it results in the removal of severely damaged and harmful cells. During RIA, cytochrome c is released from the mitochondria and reaches the nucleus, where it activates a Ca- or Mg-dependent endonuclease. We examined this phenomenon by using a micro-PIXE and PIXE. A high concentration of Fe was detected in the stroma of cells in the early apoptotic phase. We also observed accumulation of large amounts of Ca and Mg in the nucleus.(2) Development of liquid-core microcapsules for novel cancer chemoradiotherapy: Currently, we are developing liquid-core (containing an anticancer drug) microcapsules that release their core content upon irradiation. These microcapsules will localize the anticancer drug within the irradiated field. The outer shell of these microcapsules is prepared from alginate and hyaluronic acid and polymerized by Fe, while the anticancer drug Paraplatin®(carboplatin) containing Pt is the liquid core. The micro-PIXE revealed that these microcapsules released their core content after irradiation, and the amount of carboplatin released was measured by PIXE. More than 83.1% ± 8.3% of the microcapsules were ruptured, and the amount of carboplatin released was more than 81.2% ± 2.3%. Thus, the combination of radiotherapy and chemotherapy showed improved antitumor effects and a decrease in adverse effects because of drug localization.

Purpose The effect of alginate-hyaluronate microcapsules that release carboplatin in response to radiation was improved by adding ascorbic acid (AA). Materials and Methods Four measures of the effectiveness of the microcapsules were evaluated: 1) release of carboplatin in response to radiation in vitro and in vivo; 2) detectability of their accumulation by computed tomography (CT) in vivo; 3) enhancement of antitumor effects in vivo; and 4) reduction of adverse effects in vivo. Results There were significant increases in the rupture of microcapsules by adding AA in vitro. Subcutaneously injected microcapsules around the tumor could be detected by using CT and the alteration of CT-values correlated with the accumulation of the microcapsules. Those microcapsules released carboplatin and resulted in synergistic antitumor effect with concomitant radiation. With the encapsulation of carboplatin, chemotherapeutic effects were still observed two weeks after treatment. However, addition of AA did not result in increased antitumor effect in vivo. A reduction in adverse effects was observed with the encapsulation of carboplatin, through localization of carboplatin around the tumor. Conclusion Addition of AA to the materials of microcapsules did not result in increasing antitumor effect. However encapsulation of carboplatin will be useful as a clinical cancer-therapy option.

Background The introduction of rituximab has led to a growing tendency to perform ABO-incompatible living-donor kidney transplantation (LDKT) without splenectomy. However, the optimal dosage of rituximab is undefined. Method Fifty-five LDKT recipients who had neither a history of hepatitis B infection nor positive crossmatch were enrolled between October 2005 and June 2014. Recipients were divided into three groups by year of transplantation: 2005 to 2008; 2009 to 2011; and 2012 to 2014. Percentages of CD20-positive B lymphocytes and blood-group antibody titers were monitored before renal transplantation. An initial rituximab dosage of 100 mg/body (for titers below 64) or 200 mg/body (for titers above 128) was administered 2 weeks before transplantation. If the percentage of peripheral B lymphocytes remained greater than 0.5%, additional rituximab (100 mg or 200 mg) was administered. Patient demographics, patient survival, graft survival, and complication rates were compared. Results Nine patients received rituximab 100 mg/body (low-dose rituximab [LDR] group). Overall survival and graft survival rates did not differ significantly between the LDR group and other cases. The incidences of myelosuppression and viral infection were lower in the LDR group than the other cases. Conclusion A low dose of rituximab (100 mg/body) is adequate in ABO-incompatible LDKT, especially in cases with low blood-type antibody titer against ABO-antigens. Rituximab dosage reduction has been successful in our hospital without serious complications. Moreover, as over-dosage of rituximab may cause myelosuppression, it is reasonable to believe that LDR is a suitable option to safely perform ABO-incompatible LDKT without splenectomy.