Hidehisa Kitada

LIM only 4 is overexpressed in late stage pancreas cancer

BackgroundLIM-only 4 (LMO4), a member of the LIM-only (LMO) subfamily of LIM domain-containing transcription factors, was initially reported to have an oncogenic role in breast cancer. We hypothesized that LMO4 may be related to pancreatic carcinogenesis as it is in breast carcinogenesis. If so, this could result in a better understanding of tumorigenesis in pancreatic cancer.MethodsWe measured LMO4 mRNA levels in cultured cells, pancreatic bulk tissues and microdissected target cells (normal ductal cells; pancreatic intraepithelial neoplasia-1B [PanIN-1B] cells; PanIN-2 cells; invasive ductal carcinoma [IDC] cells; intraductal papillary-mucinous adenoma [IPMA] cells; IPM borderline [IPMB] cells; and invasive and non-invasive IPM carcinoma [IPMC]) by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR).Results9 of 14 pancreatic cancer cell lines expressed higher levels of LMO4 mRNA than did the human pancreatic ductal epithelial cell line (HPDE). In bulk tissue samples, expression of LMO4 was higher in pancreatic carcinoma than in intraductal papillary-mucinous neoplasm (IPMN) or non-neoplastic pancreas (p < 0.0001 for both). We carried out microdissection-based analyses. IDC cells expressed significantly higher levels of LMO4 than did normal ductal epithelia or PanIN-1B cells (p < 0.001 for both) or PanIN-2 cells (p = 0.014). IPMC cells expressed significantly higher levels of LMO4 than did normal ductal epithelia (p < 0.001), IPMA (p < 0.001) and IPMB cells (p = 0.003).ConclusionPancreatic carcinomas (both IDC and IPMC) expressed significantly higher levels of LMO4 mRNA than did normal ductal epithelia, PanIN-1B, PanIN-2, IPMA and IPMB. These results suggested that LMO4 is overexpressed at late stages in carcinogenesis of pancreatic cancer.

Revival of effective and safe high-dose mizoribine for the kidney transplantation*

Abstract:  We investigated whether high‐dose Mizoribine (MIZ: a water‐soluble anti‐metabolite), 4–6 mg/kg/d was as effective and safe as mycophenolate mofetil (MMF) for patients after kidney transplantation. Between January 2001 and December 2005, 36 recipients at a stable phase more than one month passed after transplantation underwent conversion from MMF to MIZ, two from Azathioprine to MIZ, and two cases on MIZ from the beginning. There were 24‐male and 16‐female patients whose average age was 43.3 yr old and average weight was 54.0 kg. The types of transplantations were living donor renal transplantation 25, cadaveric renal transplantation 11, and simultaneous pancreas–kidney transplantation four examples. Of these, 33 patients were on Tacrolimus‐based triple regimen and seven patients on Cyclosporine A base. The drugs used together with MIZ were basically the same as those before conversion. The reasons for conversion to MIZ were infection in 18 cases (45.0%), bone marrow suppression in nine cases (22.5%) and diarrhea in eight cases (20.0%), and post‐transplant lymphoproliferative disorder in one case (2.5%). We initiated 4–6 mg/kg/d of MIZ divided twice a day depending on the serum creatinine (sCr) value of each patient.

Effect of Milrinone on Ischemia-Reperfusion Injury in the Rat Kidney

BACKGROUND Milrinone (MIL), a phosphodiesterase (PDE) 3 inhibitor, exhibits cardiotonic and angioectatic effects. Various PDE inhibitors have been shown to suppress inflammatory cytokines. In this study, we evaluated the angioectatic and anti-inflammatory cytokine effects of MIL on renal function after warm ischemia in a rat ischemia-reperfusion (I-R) injury model. MATERIALS AND METHODS MIL or control solution was perfused from the left renal artery to the right kidney, and the left kidney was excised. The right renal artery, vein, and ureter were clamped and then released after 50 minutes to produce warm ischemia. We evaluated control (n = 7), MIL (n = 7), and sham operation (n = 7) groups for serum creatinine, blood urea nitrogen (BUN), blood flow, expression of tumor necrosis factor (TNF)-α mRNA, apoptosis index, and histological evidence of acute tubular necrosis. RESULTS Serum creatinine and BUN concentrations peaked at 24 hours after reperfusion. MIL treatment significantly reduced serum creatinine (control group 1.27 ± 0.45 mg/dL vs MIL group 0.77 ± 0.19 mg/dL, P < .05; sham 0.35 ± 0.2 mg/dL) and BUN (control 67.6 ± 13.6 mg/dL vs MIL 51.0 ± 8.8 mg/dL, P < .05; sham 23.0 ± 4.2 mg/dL) levels at 24 hours. Thereafter, serum creatinine and BUN concentrations in the MIL group remained significantly lower compared with the control group for 120 hours (P < .05). MIL group exhibited significantly higher tissue blood flow, less acute tubular necrosis, lower expression of TNF-α mRNA in renal tissue, and lower apoptotic index (P < .05). CONCLUSIONS MIL maintained renal tissue blood flow by its vasodilatory effect, suppressed expression of TNF-α mRNA by increasing intracellular cyclic adenosine monophosphate, and ultimately decreased tubular cell apoptosis, thus protecting renal function after warm I-R injury.

Pancreatic tumor formed by infiltration of adult T-cell leukemia cells

SummaryConclusionWe have described a case of pancreatic tumor formed by adult T-cell leukemia (ATL) cell infiltration.BackgroundThe patient was diagnosed as chronic ATL hematologically with the findings of increased number of atypical lymphocytes, ATL cells in the peripheral blood, and positive human T-cell leukemia virus type I (HTLV-I) antibody in the serum. The pancreatic tumor was identified by ultrasonography and computed tomography as a diffusely swollen tumor from the body to the tail of the pancreas. Biopsy specimen confirmed the ATL cell infiltration into the pancreas immunohistochemically, and Southern blot analysis showed the integration of HTLV-I proviral DNA both in the pancreas and in the peripheral blood.ResultsThe pancreatic tumor diminished spontaneously without chemotherapy when ATL cells in the peripheral blood disappeared by spontaneous regression.

One-year follow-up of treatment with once-daily tacrolimus in de novo renal transplant

OBJECTIVES The once-daily prolonged-release formulation of tacrolimus (tacrolimus QD) is expected to demonstrate equivalent efficacy and safety to the twice-daily formulation (tacrolimus BID). We reviewed the 1-year outcomes of tacrolimus QD in de novo renal transplant. MATERIALS AND METHODS We reviewed 50 de novo renal transplant patients assigned in a nonrandomized fashion to either tacrolimus QD (n=23, historic control group) or tacrolimus BID (n=27). Other immunosuppressive drugs used in both groups included mycophenolate mofetil, basiliximab, and steroids. We evaluated trough levels, required dosages, renal function, rejection rates, and episodes of infection within 1 year after transplant. RESULTS Trough levels of both drugs varied during the perioperative periods, but subsequently stabilized in both groups. There was a tendency toward a slow elevation and a higher dosage requirement in the tacrolimus QD group, compared with the tacrolimus BID group in the early stages, though the required dosages decreased steadily. The rejection rate in the tacrolimus QD group was low, and only 1 patient experienced subclinical rejection. No severe infectious adverse events were observed. CONCLUSIONS Patients taking tacrolimus QD tended to have lower trough levels and require higher dosages than those taking tacrolimus BID during the early posttransplant period, though the differences decreased with increasing time after transplant. Tacrolimus QD can be administered with excellent efficacy and safety in de novo renal transplant recipients.

Availability of Pancreatic Allograft Biopsies Via a Laparotomy

OBJECTIVE The aim of this study was to evaluate the availability of a pancreatic allograft biopsy via a laparotpmy. PATIENTS AND METHODS From September 2004 to November 2007, 17 pancreas transplantations were performed: 15 simultaneous pancreas and kidney transplantations (SPK), 1 pancreas transplant alone (PTA), and one pancreas after kidney transplantation (PAK). Thirteen pancreatic allograft biopsies were obtained via an open laparotomy. This study evaluated the complications associated with this procedure, the rate of obtaining an adequate sample, and the relationship between biopsy-proven rejections and laboratory markers. In SPK cases we evaluated the synchronization between pancreas and kidney rejection. The pancreatic samples were diagnosed according to the Drachenberg classification. RESULTS No complications resulted from the procedure. The rate of obtaining adequate samples was 84.6%. Pancreas rejection correlated with elevation of the laboratory markers in 71.4%. Simultaneous pancreas and kidney rejection occurred in 62.5%, only kidney in 25%, and only pancreas in 12.5%. CONCLUSION A pancreas graft biopsy was absolutely imperative to improve the outcome in PTA, and even in SPK cases. A pancreatic allograft biopsy via a laparotomy was a safe, necessary and easy procedure to obtain an accurate diagnosis of rejection among pancreas transplantation patients.

Protocol biopsy findings in living donor kidney transplant patients treated with once-daily or twice-daily tacrolimus formulation

BACKGROUND Once-daily extended-release tacrolimus (Tac-QD) has been shown to have equivalent efficacy and safety to the twice-daily formulation (Tac-BID) in kidney transplant patients. However, detailed comparison of allograft pathology found on a protocol biopsy (PB) in Tac-QD- versus Tac-BID-based regimens has not been described. METHODS We retrospectively investigated 119 de novo living donor kidney transplant patients treated with Tac-QD (n = 90) or Tac-BID (n = 29) and their 3- and 12-month PB results. Other immunosuppressive drugs administered included basiliximab, mycophenolate mofetil, and methylprednisolone. We evaluated daily doses and trough levels of Tac and serum creatinine levels, and compared pathologic findings. RESULTS Daily doses were higher in the Tac-QD group, but trough levels and serum creatinine levels were comparable. On 3- and 12-month PB, the frequency of subclinical rejection was similar between the groups, whereas interstitial fibrosis and tubular atrophy (IF/TA) were less common in the Tac-QD group at 12 months (42.2% vs 20.6%, P = .04). Univariate and multivariate logistic regression analyses revealed that allograft rejection (borderline changes or higher) was associated with IF/TA (odds ratio 4.09, 95% confidence interval 1.76-10.10, P = .001). The Tac-QD-based regimen showed a trend toward the absence of IF/TA but it did not reach statistical significance. Tubular vacuolization and arteriolar hyaline changes were also comparable in the two groups. CONCLUSIONS We found a trend toward milder IF/TA, but no significant differences in kidney allograft pathology in patients who were administered Tac-QD- versus Tac-BID-based regimens at 12 months. The effects of Tac-QD on chronic allograft injury must be studied by longer observation.

Temporal serum creatinine increase and exacerbation of tubulointerstitial inflammation during the first two months in resolving polyomavirus BK nephropathy

Polyomavirus BK nephropathy (BKVN) is an important complication in kidney transplantation. After immunosuppressive agents are reduced, some patients experience a temporal increase in serum creatinine (sCr) before viral clearance. The histological characteristics of re‐biopsies were therefore investigated to evaluate the time course of remission.

Early Disappearance of Urinary Decoy Cells in Successfully Treated Polyomavirus BK Nephropathy

BACKGROUND Polyomavirus BK nephropathy (BKVN) is an important infectious complication in kidney transplant patients. Regular screening using polymerase chain reaction for BK virus DNA in plasma and urinary cytology is effective for early diagnosis of BKVN. However, methods of follow-up and therapeutic targets are not well described. METHODS Ten patients with BKVN who received biweekly urinary cytology and repeat biopsies after diagnosis were retrospectively studied. Histological remission of BKVN was determined when biopsy revealed negative SV40 large T-antigen (TAg) staining. Results of urinary cytology and repeat biopsy findings were compared. RESULTS Urinary decoy cells disappeared in 8 of 10 patients 55 ± 25 (range 13-79) days after index biopsies. In those cases, allograft function was preserved and the final serum creatinine level was 2.14 ± 1.19 (0.80-4.55) mg/dL after 962 ± 393 (325-1563) days of follow-up. Two cases with persistent urinary decoy cells shedding lost their graft 195 and 362 days later. Amongst 29 repeat biopsies, there were 13 TAg-positive and 16 negative biopsies. In 12 of 13 TAg-positive biopsies (92%), urinary decoy cells were still positive, whereas at the same time in 15 TAg-negative biopsies, decoy cells had already disappeared (94%). CONCLUSIONS Cytology testing is advantageous because of its cost effectiveness. Clearance of decoy cells from urine was closely related to histological remission of BKVN, and may possibly be a therapeutic target in BKVN.

Subclinical nephrosclerosis is linked to left ventricular hypertrophy independent of classical atherogenic factors

Recently, cardio–renal interactions have been considered to be important and it has been demonstrated that mild renal dysfunction is associated with left ventricular hypertrophy (LVH). However, the correlation between LVH and subclinical renal damage is unclear. We investigated this association by assessing pretransplant biopsies from living kidney donors with normal renal function. We retrospectively categorized 238 living kidney donors into tertiles according to the percentage of global glomerulosclerosis (%GGS) observed in pretransplant biopsies (low, 0–3.45% (n=80); moderate, 3.46–11.76% (n=78); high, ⩾11.77% (n=80)) to analyze trends in their left ventricular mass index (LVMI) measured by echocardiography and baseline factors. LVH was defined as LVMI >110 g m−2 in female and >125 g m−2 in male subjects. We used a logistic regression model to evaluate any correlations between %GGS and LVH. LVMI increased significantly with increasing tertiles of %GGS, as did the prevalence of left ventricular remodeling and LVH. According to multivariate logistic regression analysis, subjects with high %GGS tertiles had a sevenfold greater risk of LVH than did those with low tertiles, even after adjusting for age, sex, systolic blood pressure, history of diabetes mellitus, total serum cholesterol and glomerular filtration rate (GFR) measured by a radioisotopic technique. There is an association between GGS and LVH in subjects with normal renal function. This association is significant after adjustment for age, sex, blood pressure, GFR and other atherogenic factors.