Drug-induced oral lichenoid reaction during nivolumab therapy.

Oral lichenoid reaction, an immune-related adverse event of immunotherapy, has been reported in very few patients receiving anti-programmed cell death receptor-1 (anti-PD-1) therapy. Here, we describe a case of severe stomatitis (grade ≥3 by the Common Terminology Criteria for Adverse Events, version 4.0) accompanied by pharyngolaryngitis that was observed in a patient receiving nivolumab therapy. The stomatitis was diagnosed as drug-induced lichenoid reaction. Nivolumab therapy was discontinued, and the patient was administered systemic prednisolone (1mg/kg). Most of the patient's mucosal changes in the oral cavity and pharyngolarynx resolved within approximately 3 weeks after starting the prednisolone. Clinicians should be aware that severe oral lichenoid reactions can occur in patients receiving anti-PD-1 therapy.

A phase I/II study of cancer peptide vaccine S-288310 in patients with advanced urothelial carcinoma of the bladder.

Background: S-288310, a cancer peptide vaccine composed of two HLA-A*24:02-restricted peptides derived from two oncoantigens, DEP domain-containing 1 (DEPDC1) and M-phase phosphoprotein 1 (MPHOSPH1), was investigated in urothelial carcinoma (UC) of the bladder. Patients and methods: Thirty eight HLA-A*24:02-positive patients with progressive UC were enrolled in this study. In the phase I part of the study, three patients each were treated with S-288310 at 1 mg or 2 mg/peptide subcutaneously once a week to evaluate safety and tolerability. In the phase II, 32 patients were randomized to receive either 1 mg or 2 mg to evaluate the difference in cytotoxic T lymphocytes (CTL) induction and safety. Results: S-288310 was safe and well tolerated in the phase I. Of 27 patients evaluable for immune responses in the phase II, there was no difference in CTL induction rate between the 1 mg (100%) and 2 mg (80.0%) groups. Of 32 patients receiving S-288310 in the phase II, the most frequent drug-related AE was the injection site reaction that was observed in 29 patients (90.6%), but none of the patients discontinued administration due to these reactions and no dose relationship in the frequency and severity was observed. The objective response rate of the 32 patients was 6.3% and the disease control rate was 56.3%. The median overall survival (OS) rates for patients vaccinated with S-288310 after one regimen of chemotherapy, 2 regimens, or 3 or more were 14.4, 9.1 and 3.7 months, respectively, and 32.2% of patients post first-line treatment were alive at 2 years. OS of patients who showed CTL induction to both peptides was longer than that of those with CTL induction to no or one peptide. Conclusion: S-288310 was well-tolerated and effectively induced peptide-specific CTLs, which were correlated with longer survival for patients with UC of the bladder. Trial registration ID: JapicCTI-090980.

Eµ/miR-125b transgenic mice develop lethal B-cell malignancies.

MicroRNA-125b-1 (miR-125b-1) is a target of a chromosomal translocation t(11;14)(q24;q32) recurrently found in human B-cell precursor acute lymphoblastic leukemia (BCP-ALL). This translocation results in overexpression of miR-125b controlled by immunoglobulin heavy chain gene (IGH) regulatory elements. In addition, we found that six out of twenty-one BCP-ALL patients without t(11;14)(q24;q32) showed overexpression of miR-125b. Interestingly, four out of nine patients with BCR/ABL-positive BCP-ALL and one patient with B-cell lymphoid crisis that had progressed from chronic myelogenous leukemia overexpressed miR-125b. To examine the role of the deregulated expression of miR-125b in the development of B-cell tumor in vivo, we generated transgenic mice mimicking the t(11;14)(q24;q32) (Eµ/miR-125b-TG mice). Eµ/miR-125b-TG mice overexpressed miR-125b driven by IGH enhancer and promoter and developed IgM-negative or IgM-positive lethal B-cell malignancies with clonal proliferation. B cells obtained from the Eµ/miR-125b-TG mice were resistant to apoptosis induced by serum starvation. We identified Trp53inp1, a pro-apoptotic gene induced by cell stress, as a novel target gene of miR-125b in hematopoietic cells in vitro and in vivo. Our results provide direct evidence that miR-125b has important roles in the tumorigenesis of precursor B cells.

Lower incidence of inguinal hernia after radical prostatectomy using open gasless endoscopic single-site surgery.

Inguinal hernia is one of the long-term complications requiring surgical interventions after retropubic radical prostatectomy (RRP), and its incidence has been reported to range from 12 to 21%. The number of open gasless laparoendoscopic single-site surgery, especially minimum incision endoscopic radical prostatectomy (MIES-RRP) is increasing in Japan. The incidence of post-operative inguinal hernia was compared between conventional RRP and MIES-RRP. The medical records of 333 patients who underwent conventional RRP (n=214) or MIES-RRP (n=119) with pelvic lymphadenectomy at our hospital were retrospectively evaluated. There were no significant differences between the two groups in age, pre-operative PSA levels, or previous major abdominal surgery (cholecystectomy, gastrectomy and colectomy), appendectomy or inguinal hernia repair. MIES-RRP was carried out with a 5-8-cm lower abdominal midline incision. Inguinal hernia developed postoperatively in 41 (19%) of the 214 men undergoing conventional RRP during mean follow-up of 58 months (range: 7-60 months). In contrast, 7 (5.9%) of the 119 men receiving MIES-RRP, developed inguinal hernia during mean follow-up of 21 months (range: 13-31 months). The hernia-free survival was significantly higher after MIES-RRP than after conventional RRP (P=0.037). Our results suggest that MIES-RRP is less associated with post-operative inguinal hernia than conventional RRP.

Maximum tumor diameter: a simple independent predictor for biochemical recurrence after radical prostatectomy.

Previous studies have suggested that maximum tumor diameter (MTD) is a predictor of PSA recurrence or biochemical recurrence (BCR) in prostate cancer after radical prostatectomy (RP). The significance of MTD in BCR prediction was evaluated using RP specimens of 364 patients with a BCR of 18% (n=66) during a mean follow-up of 37.4 months (range: 10-109 months). MTD was defined as the largest diameter of the largest tumor, and its median MTD was 15 mm (range: 0.9-50 mm). MTD was significantly associated with pre-operative PSA levels, pathological T stage, Gleason's score and positive surgical margin. In a univariate analysis, pathological T stage, Gleason's score, positive surgical margin and MTD were associated significantly with the risk of BCR. Patients with >20 mm MTD had a significantly higher risk of BCR than did those with < or =20 mm MTD (P<0.001). Cox multivariate models indicated that pathological stage, Gleason's score, positive surgical margin and MTD were independent prognostic factors for BCR. MTD would be a useful tool for predicting BCR, as calculation of MTD is a simple and reliable measure.

Final report on low-dose estramustine phosphate (EMP) monotherapy and very low-dose EMP therapy combined with LH-RH agonist for previously untreated advanced prostate cancer.

PURPOSE: In order to assess the efficacy and toxicity of oral estramustine phosphate (EMP) administration, low-dose EMP monotherapy (study 1) and very low-dose EMP therapy with luteinizing hormone-releasing hormone (LH-RH) agonist (study 2) were conducted in previously untreated prostate cancer and long-term outcomes were compared between the 2 study groups. MATERIALS AND METHODS: Studies 1 and 2 were independently performed beginning in June 1999 and November 2001, respectively. Study 1 was composed of 87 patients including 85 assessable patients. All 108 patients recruited for study 2 were assessable. Low-dose EMP monotherapy (2 capsules/day or 280 mg/day) was used in study 1 and very low-dose EMP (1 capsule/day or 140 mg/day) combined with LH-RH agonist was adopted in study 2. RESULTS: Overall prostate specific antigen (PSA) -response rates in studies 1 and 2 were 92.3% and 94.2%, respectively, and overall toxicity rates were 54.1% and 38.9%, respectively. EMP discontinuation due to side effects was encountered more often in study 1 (45.9%) than in study 2 (27.8%). Among the adverse side effects gastrointestinal toxicity was most prevalent in both studies. One patient died of acute pulmonary embolism in study 1, but no one died in study 2. There were 6 cancer deaths in the gastrointestinal tract in study 1 but only 2 cancer deaths in study 2. CONCLUSION: Our data indicate that the overall PSA response rate was comparable between both studies. However, rates in overall toxicity and drug discontinuation were higher in study 1 than in study 2. We consider that study 2 is more promising for the treatment of previously untreated advanced prostate cancer, although the rate of adverse side effects is still high as compared with other hormonal therapies. In order to overcome the high toxicity rate, especially the gastrointestinal toxicity, we recently elaborated a method employing tailor-made medicine using SNPs of 1A1 gene in cytochrome P-450 for decreasing the rate of gastrointestinal toxicity. Using this method of patient selection, study 3 has been successfully launched on September 2005 with high drug compliance. Better clinical results are being accumulated.

The use of recipient superficial femoral vein as a venous graft for portal vein reconstruction in right lobe living donor liver transplantation.

In living donor liver transplantation (LDLT), portal vein thrombosis (PVT) in the recipient is frequently regarded as a contraindication. To reconstruct the PV of a right-lobe liver graft (RLG) using an interposition or jump graft from the splenomesenteric junction, various vein grafts and technical modifications have been introduced. The internal jugular, external iliac, or great saphenous veins have been utilized in such reconstructive procedures. However, the superficial femoral vein (SFV) is preferable to the autologous vein grafts in terms of caliber, wall thickness, and length. We employed the recipient SFV to reconstruct PVT among 40 adult LDLT using RLG. Thirty-three were reconstructed by single end-to-end anastomosis with the right or left recipient PV. Three patients were transplanted with a RLG using 2 separated PVs reconstructed by double anastomoses with both the right and left PVs of the recipient. The remaining 4 patients required venous grafting for portal reconstruction. We used the recipient SFV as an interposition or jump graft from the splenomesenteric junction to the graft PV. There were 2 cases of anastomotic PV stenosis; 1 in portal reconstruction without a venous graft and the other with a SFV graft. Both were treated successfully by balloon angioplasty. The recipient SFV is an excellent size match for the PV reconstruction as a long interposition or jump conduit when the venous system from the deceased donor is not available. The indication for LDLT in patients with complete PVT should be carefully decided before transplantation in terms of portal reconstruction.

Microsurgical back wall support suture technique with double needle sutures on hepatic artery reconstruction in living donor liver transplantation.

OBJECTIVES: In living-donor-liver transplantation (LDLT), microsurgical reconstruction of the hepatic artery is an essential but challenging issue. Especially using a living donor graft, the hepatic artery is short, the intimal damage may be severe, and the usable vessel grafts are limited compared with cadaveric donors. Thus, sometimes it is difficult to use a conventional twist reconstruction technique in which one needs to turn over the hepatic artery. METHODS: To overcome these difficulties, we began to use a back wall support suture technique. From July 1991 to June 2007, we performed 110 LDLTs. In 87 cases, we used the conventional twist technique. In the most recent 23 cases, we used a back wall support suture technique. To put it briefly, we placed 2 sutures at the deepest, most difficult points in the artery for backside support. Each stitch was placed from the inner side of the arterial wall to the outer side with double needle sutures. The subsequent sutures were placed forward on either side adjacent to the previous suture. RESULTS: The total ratio of hepatic artery thrombosis (HAT) was 8.2% (9/110). In the conventional twist technique group, HAT occurred in 8 cases (9.2%). In the new technique group, it occurred in only 1 case that had an intimal dissection in the recipient artery (4.3%). Thus there was no HAT associated with the arterial anastomosis in the new technique group. CONCLUSION: Our technique allows for safe intimal adaptation without turning over the artery. In conclusion, this back wall support suture technique may contribute to more satisfactory results.

Tissue distribution of cynomolgus adeno-associated viruses AAV10, AAV11, and AAVcy.7 in naturally infected monkeys.

Adeno-associated virus (AAV) is used in gene-therapy studies, but its tissue distribution is unknown in natural infection. We examined cynomolgus AAVs (previously isolated AAV10 and AAV11 and novel AAVcy.7) for their tissue distribution in 14 cynomolgi by type-specific PCR. We found AAV10, AAV11, and AAVcy.7 in 6, 10, and 14 monkeys, respectively, and two or three types in 11 monkeys, showing that these AAVs are widespread in the monkeys. We detected AAV at a higher level mainly in the lymphatic tissues and ileum, which suggests that AAV may invade the host through Peyer's patches in the ileum and infect immune cells.

[Epicardial atrial pacing using an active fixation bipolar endocardial lead in children].

Good performance was observed over 10 years after implantation of bipolar epicardial atrial pacing using an active fixation bipolar endocardial lead in 3 pediatric patients with congenital heart block. The bipolar endocardial lead which was supposed to be fixed transvenously was implanted on the atrial surface by first screwing the lead's helix into the myocardium. The catheter was then laid down on the atrial surface, and both electrodes were wrapped by the atrial tissue. The good performance of this pacing lead seemed to depend on stable positioning of the electrode. This lead is superior to the commercially available, and steroid eluting epicardial bipolar pacing lead, on the point of its small size in head and body, and could be applied to dual chamber pacing in smaller children.

Invasive growth of hepatic angiomyolipoma; a hitherto unreported ominous histological feature.

AIMS: Although histological features of hepatic angiomyolipoma (AML) are highly variable, true malignant change is extremely rare. The aim was to review the histological features of invasive growth and clinical outcomes in 39 cases of hepatic AML. METHODS AND RESULTS: An invasive growth pattern into surrounding hepatic parenchyma, portal triads and/or around hepatic veins was found in 24 of 39 tumours (62%). One variant showed tumour cells replacing hepatocytes within the liver cell cords. The other consisted of portal or perivascular invasive growth along blood vessels. In the former pattern, small isolated tumour cell clusters were occasionally found in the vicinity of the main mass, showing a sprouting pattern. Although these histological features suggest malignancy, distant metastases were not found in any of the cases within a mean follow-up period of 6.8 years. CONCLUSIONS: A previously unrecognized histological feature of an invasive growth pattern, which suggests malignancy and might promote an erroneous diagnosis, was frequently found in hepatic AMLs. However, among about 180 reported hepatic AMLs, including the present cases, only one hepatic AML with distant metastasis has been reported to date and nearly all hepatic AMLs behave in a benign fashion. Therefore, pathologists should not overdiagnose malignancy based solely on the histological invasive growth patterns described in this paper.

[New method for localization of the small ground-glass opacity lesion in resected lung].

A small lesion showing ground-glass opacity (GGO) by preoperative computed tomography (CT) is sometimes difficult to detect after lobectomy when it locates in the central part of the lobe. In order to facilitate to identify the lesion for marking pathological specimen, we developed a new method using CT. After surgery, the resected pulmonary lobe was expanded with airflow through the bronchial stump and the target lesion was examined with CT. The laser beam of the CT on the surface of the lung is used as a guiding line for cutting. Through the application of this method for 2 clinical cases, it was found to be possible to exactly identify the GGO lesion from the surface of the resected lung enabling to visualize a fresh surface of the lesion like a CT image with minimal destruction of the structure.

[Concomitant off-pump coronary artery bypass and left lower lobectomy for lung cancer with pneumoconiosis].

Surgical strategy for patients for lung cancer with coronary disease remains controversial. We performed concomitant off-pump coronary artery bypass grafting (off-pump CABG: OPCAB) and left lower lobectomy with ND 2a lymph nodes dissection for lung cancer with pneumoconiosis. After CABG, due to fixed adhesion of peribronchial lymph node, left lower lobectomy was hard to carry out. Postoperative management was done with much difficulty for massive sputum and pneumonia caused by chronic inflammatory lung disease. As a result, postoperative course has been uneventful for 2 years after operation. In the concomitant OPCAB and lung resection with chronic inflammatory lung disease, whether the synchronous or 2 periods operation was appropriate was still unknown. We think that careful pre- and intraoperative assessment for this disease is important.

New strategy for ABO-incompatible living donor liver transplantation with anti-CD20 antibody (rituximab) and plasma exchange.

It is more difficult to control humoral rejection in living donor liver transplantations (LDLT) across the ABO blood group barrier than in matched or compatible combinations. We achieved excellent results in ABO-incompatible transplantation with novel immunosuppressive regimens and plasma exchange (PE). Among 82 LDLT were 10 cases of ABO-incompatible recipients, including three who were administered rituximab for rescue or prophylactic therapy. Pretransplantation PE was performed as necessary to maintain hemagglutinin titers below 1:16 and posttransplantation PE was performed when there were signs of hyperacute rejection associated with high titers. Induction immunosuppression consisted of FK506, steroid, mycophenolate mofetil (MMF), and rituximab. The first patient was administered rituximab with deoxyspergualin (DSG), steroid pulse therapy, and PE on postoperative day (POD) 7, because of biopsy-proven humoral acute rejection. The titers and LFTs improved drastically. The second and third patients were administered rituximab just after the operation with other routine immunosuppressants for prophylaxis of hyperacute rejection. The second patient showed a slight deterioration in LFTs with an elevated titer, which normalized after steroid pulse therapy and PE. The third patient had no episodes of rejection. At present, that is 27, 17, and 6 months after the operations respectively, the 3 transplant recipients are in stable condition.

Experience with recipient's superficial femoral vein as conduit for middle hepatic vein reconstruction in a right-lobe living donor liver transplant procedure.

Middle hepatic vein reconstruction during the right-lobe living donor liver transplant procedure has been recognized to be a significant factor. We initially reconstructed only a single middle hepatic vein orifice draining into segment 8. In cases where the right-lobe liver graft has several major middle hepatic vein tributaries, including veins draining segment 5 that are remote from the right hepatic vein orifice, a long and thick interposition conduit is necessary for reconstruction. Among 11 consecutive adult patients who received a right-lobe liver graft without a middle hepatic vein at our institution, 8 underwent reconstruction of all major middle hepatic vein tributaries using a vein graft from the recipient's superficial femoral vein. The remaining 3 patients had no major middle hepatic vein tributaries. Posttransplant-computed tomography imagings showed increased liver mass with a patent superficial femoral vein graft in 8 patients. In the absence of a venous system from a deceased donor, a recipient superficial femoral vein offers an excellent size match to maintain the venous outflow of middle hepatic vein tributaries. Reconstruction with recipient superficial femoral vein plays an important role in maximizing liver function and minimizing morbidity in the early posttransplant period.

Cloning and characterization of a p53-related protein kinase expressed in interleukin-2-activated cytotoxic T-cells, epithelial tumor cell lines, and the testes.

A human protein kinase, p53-related protein kinase (PRPK), was cloned from an interleukin-2-activated cytotoxic T-cell subtraction library. PRPK appears to be a homologue of a growth-related yeast serine/threonine protein kinase, YGR262c. However, a complementation assay using YGR262c-disrupted yeast indicated that PRPK is not functionally identical to the yeast enzyme. PRPK expression was observed in interleukin-2-activated cytotoxic T-cells, some human epithelial tumor cell lines, and the testes. The intrinsic transcriptional activity of p53 was up-regulated by a transient transfection of PRPK to COS-7 cells. PRPK was shown to bind to p53 and to phosphorylate p53 at Ser-15. These results indicate that PRPK may play an important role in the cell cycle and cell apoptosis through phosphorylation of p53.

Leukocyte-depleted blood cardioplegia reduces cardiac troponin T release in patients undergoing coronary artery bypass grafting.

OBJECTIVE: Activated neutrophils have been implicated in reperfusion injury of the myocardium. Leukocyte depletion at reperfusion may contribute to better myocardial protection during cardiac surgery. We tested the efficacy of leukocyte-depleted blood cardioplegia in reducing myocardial injury during coronary artery bypass grafting. METHODS: Subjects were 27 patients undergoing elective coronary artery bypass grafting divided into controls (perfused with nonfiltered blood cardioplegia, n = 12) and those undergoing leukocyte-depleted blood cardioplegia (n = 15). Oxygenated blood mixed with a potassium crystalloid cardioplegic solution was delivered through the aortic root at every 30 minutes during cardiac arrest and terminal warm blood was administered before aortic declamping in both groups. In leukocyte depletion, blood was filtered prior to the mixture with crystalloid solution in the cardioplegic reservoir. RESULTS: Patient profiles did not differ significantly between groups, nor did systemic leukocyte count during or after surgery despite more than 81% removal of leukocytes in cardioplegic delivery. No consistent differences between groups in creatine kinase or creatine kinase-MB were seen up to 18 hours after surgery. Peak troponin T levels were significantly lower in the leukocyte-depleted blood cardioplegia group (0.52 +/- 0.13 ng/ml), however, than in controls (3.85 +/- 0.85 ng/ml). CONCLUSION: We concluded that leukocyte-depleted blood cardioplegia reduces the release of cardiac troponin T in patients undergoing elective coronary artery bypass grafting and may produce better myocardial protection in patients with impaired cardiac function or a damaged myocardium.

CT-Guided acetic acid injection therapy for aldosterone-producing adrenocortical adenoma: a preliminary report of three cases.

We reported the preliminary outcomes of CT-guided percutaneous injection therapy for aldosterone-producing adrenocortical adenoma (APA). Five sessions of injection therapy, 4 percutaneous acetic acid injections (PAI) and 1 percutaneous ethanol injection (PEI) were performed in 3 patients with APA. A small amount of acetic acid or ethanol solution was injected via a needle placed precisely inside the tumor. The procedure was frequently monitored by repetitive CT scanning. The follow-up period ranged from 5 to 27 months. After the treatment, hypertension was normalized or controlled by a low dose of conventional anti-hypertensive drug. In 2 of 3 cases the plasma aldosterone levels were normalized. Although temporary symptoms of alcoholic intoxication were observed in the single session of PEI, the 4 sessions of PAI were associated with no adverse symptoms or complications. Although this study covers only short-term results in 3 patients, CT-guided PAI appears to be a safe and effective treatment and may be a promising alternative as a simple and far less invasive therapy for APA.

Extended septoplasty for subaortic stenosis developed 19 years after double-outlet right ventricle repair.

A 27-year-old woman developed subaortic stenosis 19 years after double-outlet right ventricle repair. Subaortic stenosis was caused by a narrow ring of fibromuscular ridge associated with a bulge of the underlying septal muscle. The aortic valve was bicuspid and stenotic. We conducted extended septoplasty, replacing the aortic valve. Postoperative cineangiogram showed an adequate left ventricular outflow pathway. Double-outlet right ventricle repair may thus be followed by subaortic stenosis as long as 19 years after initial surgery. This lesion was assumed due to acquired disease secondary to flow disturbances in the left ventricular outflow, so reconstructing an adequate outflow pathway is effective and appears to help avoid recurring stenosis.