Associations of PD-L1, PD-L2, and HLA class I expression with responses to immunotherapy in patients with advanced sarcoma: post hoc analysis of a phase 1/2 trial.

BACKGROUND: Although immunotherapy is thought to be a promising cancer treatment, most patients do not respond to immunotherapy. In this post hoc analysis of a phase 1/2 study, associations of programmed death ligand 1 (PD-L1), PD-L2, and HLA class I expressions with responses to dendritic cells (DCs)-based immunotherapy were investigated in patients with advanced sarcoma. METHODS: This study enrolled 35 patients with metastatic and/or recurrent sarcomas who underwent DC-based immunotherapy. The associations of PD-L1, PD-L2, and HLA class I expressions in tumor specimens, which were resected before immunotherapy, with immune responses (increases of IFN-γ and IL-12) and oncological outcomes were evaluated. RESULTS: Patients who were PD-L2 (+) showed lower increases of IFN-γ and IL-12 after DC-based immunotherapy than patients who were PD-L2 (-). The disease control (partial response or stable disease) rates of patients who were PD-L1 (+) and PD-L1 (-) were 0% and 22%, respectively. Disease control rates of patients who were PD-L2 (+) and PD-L2 (-) were 13% and 22%, respectively. Patients who were PD-L1 (+) tumors had significantly poorer overall survival compared with patients who were PD-L1 (-). No associations of HLA class I expression with the immune response or oncological outcomes were observed. CONCLUSIONS: This study suggests that PD-L1 and PD-L2 are promising biomarkers of DC-based immunotherapy, and that addition of immune checkpoint inhibitors to DC-based immunotherapy may improve the outcomes of DC-based immunotherapy.

Salvage living-donor liver transplantation for liver failure following definitive radiation therapy for recurrent hepatocellular carcinoma: a case report.

A 57-year-old man with a history of hepatitis B virus infection was referred to our hospital for living-donor liver transplantation (LDLT). Five years earlier, right lobectomy had been performed for solitary hepatocellular carcinoma (HCC) with bile duct tumor thrombus in segments 5 and 6 in the liver. Two years later, transarterial chemoembolization and radiofrequency ablation were performed for recurrent HCC. Two years after those local therapies, another recurrent HCC was treated with transhepatic arterial infusion chemotherapy with cisplatin and conventional radiation therapy (RT) with 60 Gy in 20 fractions, because the tumor was contiguous to the trunk of the portal vein. After the completion of RT, symptoms due to liver failure and severe infection caused by multiple liver abscesses developed despite the administration of antibiotics and percutaneous transhepatic cholangiodrainage. Therefore, LDLT was performed with the use of a right lobe graft donated by his wife. Vascular anastomosis was successfully performed with the use of normal procedures. The patient recovered uneventfully, and has since been doing well for 34 months, with no evidence of vascular complications. However, the degree of injury to the anastomotic vessels caused by definitive RT before LDLT remains unclear, whereas the safety and efficacy of some forms of RT as a bridge to deceased-donor LT have been reported. Salvage LDLT is effective for patients with liver failure after multidisciplinary treatment including radiation, while carefully taking radiation-induced vessel injury as a potential late complication into consideration, especially in LDLT cases.

Biocompatibility of cardiopulmonary bypass circuit with new polymer Senko E-Ternal Coating™.

OBJECTIVE: The aim of this study was to compare the biocompatibility of a new Senko E-Ternal coating (SEC) for cardiopulmonary bypass (CPB) circuits with the well-established poly-2-methoxyethyl acrylate (PMEA) coating. METHODS: Forty patients undergoing aortic valve replacement were randomly assigned to either an SEC-coated group (n = 20) or a PMEA-coated group (n = 20). Clinical data and the following markers were analyzed: platelet count, platelet factor (PF) 4, fibrinogen, fibrinogen degradation products (FDPs), antithrombin III (AT III), thrombin-antithrombin complex (TAT), plasminogen, complement hemolytic activity (CH50), complement 3 (C3) and interleukin-6 (IL-6). Blood samples were obtained at five time points in both groups. RESULTS: CPB time, aortic cross-clamp time and blood loss and transfusion were similar in both groups. There were no significant differences between the groups in terms of platelet count, PF4 and all coagulation and fibrinolytic parameters (FDP, AT III, TAT, and plasminogen) at any time points. Inflammatory markers (CH50, C3 and IL-6) were also similar in both groups at all time points. CONCLUSIONS: The SEC-coated circuit demonstrated equivalent biocompatibility to the PMEA-coated circuit. SEC-coated circuits are, therefore, favorably comparable to PMEA-coated circuits for clinical use in CPB.

The long-term outcome following the use of frozen autograft treated with liquid nitrogen in the management of bone and soft-tissue sarcomas.

In 1999, we developed a technique for biological reconstruction after excision of a bone tumour, which involved using autografts of the bone containing the tumour treated with liquid nitrogen. We have previously reported the use of this technique in 28 patients at a mean follow up of 27 months (10 to 54). In this study, we included 72 patients who underwent reconstruction using this technique. A total of 33 patients died and three were lost to follow-up, at a mean of 23 months (2 to 56) post-operatively, leaving 36 patients available for a assessment at a mean of 101 months 16 to 163) post-operatively. The methods of reconstruction included an osteo-articular graft in 16, an intercalary in 13 and, a composite graft with prosthesis in seven. Post-operative function was excellent in 26 patients (72.2%), good in seven (19.4%), and fair in three (8.3%) according to the functional evaluation system of Enneking. No recurrent tumour occurred within the grafts. The autografts survived in 29 patients (80.6%), and the rates of survival at five and ten years were 86.1% and 80.6 %, respectively. Seven of 16 osteo-articular grafts (44%) failed because of fracture or infection, but all the composite and intercalary grafts survived. The long-term outcomes of frozen autografting, particularly using composite and intercalary grafts, are satisfactory and thus represent a good method of treatment for patients with a sarcoma of bone or soft tissue.

Canine oocyte maturation in culture: significance of estrogen and EGF receptor gene expression in cumulus cells.

We examined the role of cumulus cells regarding in vitro maturation of canine oocytes, and investigated estrogen and epidermal growth factor (EGF) receptor gene expression and action on nuclear maturation. Canine cumulus-oocyte complexes (COC) were collected from anestrous and diestrous bitches; only COC with vitelline diameter >100 microm were used. In Experiment 1, expression of estrogen receptor (ER) alpha, ERbeta and EGF-receptor (EGF-R) were determined by reverse transcription-polymerase chain reaction (RT-PCR), using mRNA from the oocyte or cumulus cell. Transcripts for the ERbeta and EGF-R were detected in oocytes and cumulus cells, but no message was detected for ERalpha. In Experiment 2, intact COC and the denuded oocytes were cultured in TCM199 medium supplemented with various concentrations of estradiol-17beta (E(2); 0-10 microg/mL) or EGF (0-100 ng/mL) for 72 h; nuclear maturation was then evaluated. In oocytes cultured within intact COC, the rate of germinal vesicle breakdown (GVBD) was higher in the 1 microg/mL E(2) supplemented group (P<0.05), and the rate of metaphase I (MI) was higher in the 10 ng/mL EGF supplemented group, than in the non-supplemented group (P<0.05). However, supplementation of E(2) or EGF to denuded oocytes failed to promote nuclear maturation. In Experiment 3, intact COC were cultured in TCM199 supplemented with 1 microg/mL E(2), 10 ng/mL EGF, and 10% fetal bovine serum (FBS) for 72 h, and nuclear maturation was evaluated. There was no significant difference in the rate of metaphase II (MII) between the medium only, E(2)+EGF, and FBS supplement groups. When E(2) and EGF in combination with FBS were supplemented, the rate of MII was higher than in other groups (P<0.05). We inferred that cumulus cells were involved in mediating the stimulatory effects of E(2) and EGF on nuclear maturation of canine oocytes, and that E(2) and EGF in combination with FBS promoted the completion of oocyte meiotic maturation.

Re-implantation of tumour tissue treated by cryotreatment with liquid nitrogen induces anti-tumour activity against murine osteosarcoma.

We evaluated the possible induction of a systemic immune response to increase anti-tumour activity by the re-implantation of destructive tumour tissue treated by liquid nitrogen in a murine osteosarcoma (LM8) model. The tumours were randomised to treatment by excision alone or by cryotreatment after excision. Tissue from the tumour was frozen in liquid nitrogen, thawed in distilled water and then re-implanted in the same animal. In addition, some mice received an immunological response modifier of OK-432 after treatment. We measured the levels of interferon-gamma and interleukin-12 cytokines and the cytotoxicity activity of splenocytes against murine LM8 osteosarcoma cells. The number of lung and the size of abdominal metastases were also measured. Re-implantation of tumour tissue after cryotreatment activated immune responses and inhibited metastatic tumour growth. OK-432 synergistically enhanced the anti-tumour effect. Our results suggest that the treatment of malignant bone tumours by reconstruction using autografts containing tumours which have been treated by liquid nitrogen may be of clinical value.

MR findings of granulocytic sarcoma of the breasts.

We report a case of isolated extramedullary relapse of acute myeloid leukaemia (AML) that presented as granulocytic sarcoma of both breasts, with no other signs of relapse even in the bone marrow. The T2 weighted coronal images on MR showed both multiple ill-defined heterogeneous hyperintense masses relative to breast parenchyma; these masses were seen also with a visual washout enhancement. Pathohistological study showed infiltration by myeloblasts, which were relatively uniform in appearance, featuring round or oval nuclei and a small cytoplasm. After chemotherapy and radiotherapy, both breast masses disappeared on MR images. Although the MR findings of granulocytic sarcoma were indistinguishable from those of multicentric carcinoma and malignant lymphoma, the MR images were useful for evaluating and monitoring responses to the treatments, as well as for detecting non-palpable relapsed tumours.

Diminished cytokine signalling against bacterial components in mononuclear leucocytes from ulcerative colitis patients after leukocytapheresis.

Infiltration by circulating inflammatory cells is a prominent local inflammatory feature of ulcerative colitis (UC). Several trials have suggested that leukocytapheresis by filtration can benefit patients with active UC. We investigated how this therapy might modulate the inflammatory response. Patients with active UC who were beginning repeated filtration leukocytapheresis were studied. Mononuclear cell preparations were obtained from blood before and after the first treatment, and expression of cytokine signalling components and the cell-proliferative response were analysed in vitro. Leukocytapheresis reduced lipopolysaccharide-induced production of proinflammatory cytokines (interleukin-1, -6, -8 and tumour necrosis factor-alpha, P < 0.05 for all) and activation of intracellular signalling components (nuclear factor-kappaB, mitogen-activated protein kinases, and signal transducer and activator of transcription-3), as well as surface expression of toll-like receptor-4 (P < 0.05) in mononuclear cells. The therapy also reduced the cell-proliferative response by mononuclear cells stimulated with sonicated bacterial preparations from autologous intestine (P < 0.05). These results indicate that activated mononuclear cells in the peripheral blood of patients with active UC are removed by leukocytapheresis and replaced by cells with a lower activation status. This replacement may partly explain the therapeutic benefit.

Reconstruction using an autograft containing tumour treated by liquid nitrogen.

We describe a method of reconstruction using tumour-bearing autograft treated by liquid nitrogen in 28 patients. The operative technique consisted of en bloc excision of the tumour, removal of soft tissue, curettage of the tumour, drilling and preparation for internal fixation or prosthetic replacement before incubation for 20 minutes in liquid nitrogen, thawing at room temperature for 15 minutes, thawing in distilled water for ten minutes, and internal fixation with an intramedullary nail, plate or composite use of prosthetic replacement. Bone graft or cement was used to augment bone strength when necessary. The limb function was rated as excellent in 20 patients (71.4%), good in three (10.7%), fair in three (10.7%), and poor in two (7.1%). At the final follow-up six patients had died at a mean of 19.8 months after the operation, while 21 remained free from disease with a mean follow-up of 28.1 months (10 to 54). One patient is alive with disease. Bony union was seen at a mean of 6.7 months after the operation in 26 patients. Complications were encountered in seven patients, including three deep infections, two fractures, and two local recurrences. All were managed successfully. Our results suggest that this is a simple and effective method of biological reconstruction.

[Mitral regurgitation due to sole punched out lesion of the mitral anterior leaflet in infective endocarditis; report of a case].

Mitral regurgitation (MR) due to only punched out lesion is extremely rare in infective endocarditis. A 31-year-old male was admitted to our hospital due to unusual cause of MR. Echocardiography showed MR due to punched out lesion of the mitral anterior leaflet, which is extremely rare. A round shape punched out lesion (about 16 mm in size) was found intraoperatively in the anterior leaflet of the mitral valve. The surface around the punched out lesion was smooth, and the leaflet displayed good movability. Neither vegetation nor calcification was found. Punched out lesion was successfully closed with autologous pericardial patch and annuloplasty was performed.

[Selection of surgical strategy for abdominal aortic aneurysm coexisting with coronary artery disease; one-stage versus two-stage, and off-pump versus on-pump].

BACKGROUND: In patients having a combination of severe coronary artery disease (CAD) and expanding abdominal aortic aneurysm (AAA), one-stage operation of simultaneous coronary artery bypass grafting (CABG) and AAA repair has been recommended. METHODS AND RESULTS: Of 96 patients (94 men, average 65 year) with AAA and CAD, 21 patients underwent one-stage operation of simultaneous CABG and AAA repair (Group A-1: off-pump CABG in 10 and on-pump in 11), and 75 underwent two-stage operation of CABG followed by AAA with an interval of less than 6 months in 23 patients (Group A-2) and more than 6 months in 52 patients (Group B). Baseline characteristics were similar between the one-stage and two-stage groups, and off-pump and on-pump subgroups, except the proportion of single vessel disease. Mean number of distal anastomoses was significantly lower in the off-pump subgroup than in the on-pump subgroup (p = 0.011) and the two-stage group (p = 0.0057). There was 1 hospital death among on-pump patients but none among off-pump patients. Mortality rate was 4.8% in the one-stage group. Two patients (8.7 &) in the two-stage group, who had AAA was 7.0 cm and 7.5 cm diameter, died of AAA rupture prior to repair. The 10-year all death free rates were 44% in Group A (A-1 and A-2), and 86% in Group B (p = 0.0004). CONCLUSIONS: Our data suggest that one-stage operation with off-pump CABG is an attractive option in selected patients with a large AAA (> 7 cm).

[Off-pump versus standard on-pump reoperative coronary artery bypass grafting].

BACKGROUND: Using standard on-pump procedures, repeat coronary artery bypass grafting (re-CABGs) are associated with a higher morbidity and mortality than first-time CABGs. This retrospective study assessed the clinical outcomes of off-pump re-CABG versus on-pump re-CABG. METHODS: From 1983, 2nd CABG and 3rd CABGs were performed in 162 patients at our institute. The early and late results of 142 patients who received standard on-pump re-CABGs and 20 patients who received off-pump re-CABGs were evaluated. The 2 groups were similar in age, sex, preoperative ejection fraction (EF) and number of coronary lesions. However, mean number of distal anastomoses per patient was significantly higher in on-pump (2.0 +/- 0.8) than in off-pump re-CABG (1.4 +/- 0.6) [p = 0.0009]. RESULTS: Hospital mortality tended to be higher in the on-pump group (5.6%) than in the off-pump group (0%) [p = 0.6]. Morbidity in term of total postoperative complications tended to be higher for on-pump (14.1%) than in off-pump (0%) [p = 0.14]. The 5-year survival rate tended to be higher in the off-pump group (100%) than in the on-pump group (80.8 +/- 3.5%) [p = 0.096]. CONCLUSIONS: In selected patients, off-pump re-CABG can be a reliable and safe option. The mid-term survival and event-free survival rates achievable with the off-pump option are encouraging.

[Surgical repair of left ventricular aneurysm; long-term results].

OBJECTIVE: The aim of this study was to evaluate the late results of left ventricular (LV) aneurysm repair. METHODS: From July 1968 to 1999, 86 consecutive patients (74 male, 12 female, mean age 56.0 +/- 9.3) underwent LV aneurysm repair at our institute. The surgical methods were as follows; linear repair in 71 patients, endoaneurysmorrhaphy in 5, endoventricular circular plasty in 4, Jatene method in 1 and plication of aneurysm in 5. Thirty-nine patients underwent concomitant myocardial revascularization. Major arrhythmias occurred in 38 patients. The results were retrospectively reviewed and follow-up was achieved in 95.3%. RESULTS: There were 6 operative deaths and 4 hospital deaths. Actuarial survival rate including the 10 deaths was 72.7% at 5 years and 46.3% at 10 years. In patients with coronary artery bypass grafting (CABG), survival rate was 82.2% at 5 years and 56.3% at 10 years, and was significantly higher than that in those without revascularization (p = 0.01). In patients without arrhythmias, survival rate was 79.2% at 5 years and 55.0% at 10 years, and was significantly higher than that in patients with arrhythmias. CONCLUSIONS: The patients were not homologous and the techniques were not the same; however, in spite of these study limitations, patients who underwent revascularization, and were without major arrhythmias preoperatively, had better long-term survival.

[Total arch replacement for right aortic arch with Kommerell diverticulum and aberrant left subclavian artery].

A 57-year-old man suspected of having angina pectoris underwent coronary angiography and comprehensive examination, which revealed a right-side aortic arch accompanying Kommerell diverticulum and a aberrant left subclavian artery. Esophagography indicated that the esophagus was compressed on its right posterior side and the computed tomography (CT) revealed that the posterior side of the tracheal was compressed, however, the patient experienced no difficulty in breathing, hoarseness of voice or dysphasia. The size of the aortic diverticulum was less than 5 cm and the patient showed no symptom, however, if it was left untreated, there was a risk of rupture in the future. Also the esophagus and tracheal may develop complications due to prolonged compression. Therefore, we decided that the case required surgical operation. Total arch replacement was performed through mediastinotomy and right posterolateral in the 4th intercostal. The postoperative condition was good, and the patient was discharged without any complications.

Intrapancreatic accessory spleen: evaluation by CT arteriography.

BACKGROUND: Intrapancreatic accessory spleens are frequently confused with primary pancreatic tumors, and differentiation from neoplastic lesions is important to avoid an unnecessary laparotomy. We present three cases of intrapancreatic accessory spleen evaluated by computed tomographic arteriography (CTA) and discuss the characteristic findings. METHODS: CTA was performed, followed by digital subtraction angiography, with an injection of contrast material through a 4-F catheter placed in the celiac artery. Single-level dynamic CTA was also performed in two patients with a 30-s continuous scan in one breath-hold. RESULTS: CTA clearly demonstrated early inhomogeneous enhancement of the lesion, similar to the splenic parenchyma. On single-level dynamic CTA, inhomogeneous enhancement of the lesion in the early phase was diminished in the late phase. Multiplanar reformatted images obtained in two cases showed the deep cleft between the lesion and the pancreas, which suggested that the lesion was originally extrapancreatic. CONCLUSIONS: These two findings on CTA, inhomogeneous enhancement of the lesion and the deep cleft between the lesion and the pancreas, may help to confirm the diagnosis of an intrapancreatic accessory spleen.

[Early and mid-term results of all arterial graft coronary artery bypass grafting using bilateral internal thoracic and radial arterial conduits].

From March 1996 to May 2000, 41 patients [age 39-78 (mean 63.5 +/- 8.8) years, 90.2% male] underwent all arterial multiple coronary artery bypass grafting (CABG) using bilateral internal thoracic (BiITA) and radial (RA) arterial conduits. The reason for using RA was that the right gastroepiploic artery (RGEA) was small or occluded on preoperative angiography, a history of upper abdominal surgery or disease, or the right coronary arterial lesion was proximal and mild. The BiITA were used as in situ grafts and the proximal anastomosis of RA was to the ascending aorta in all cases. All patients underwent conventional elective CABG with median sternotomy using cardiopulmonary bypass. The mean number of anastomoses was 3.3 +/- 0.5 branches and complete revascularization rate was 80.5%. Postoperative follow-up averaged 20 months and the longest was 50 months. There was no early death, and overall graft patency 2-3 weeks after surgery was 96.2% (LITA 94.0%, RITA 97.6%, RA 97.6%). Four-year actuarial survival rate was 96.4 +/- 3.5% (1 patient: 9 months, no cardiac death), and cardiac event-free rate after surgery was 89.7 +/- 4.9% [4 patients: percutaneous transluminal coronary angioplasty (PTCA)]. However, once patients were discharged from hospital, cardiac event-free rate was 100%. These excellent results suggest that all arterial graft CABG was satisfactory, and RA can be used as a third suitable arterial bypass conduit, if RGEA cannot be used or is unsuitable for use.

Study on social responses (encouraging public awareness) to sudden infant death syndrome: evaluation of SIDS prevention campaigns.

The sudden infant death syndrome (SIDS) prevention campaign promulgated by the SIDS Family Associations was initiated and directed to medical professionals in 1996 and to mothers in 1997. In mid-1998, the Ministry of Health and Welfare began to support this campaign. In parallel with these moves and with cooperation from the study group of the Ministry of Health and Welfare and the SIDS Family Associations of Japan, a Japanese segment of the International Child Care Practices Survey (ICCPS) was conducted in two phases--from 1996 to 1997 and from 1998 to 1999--to observe the trends in risk factors for SIDS that may exist in the child rearing environment in Japan. Consequently, after the SIDS prevention campaign, the risk factors for SIDS, such as the practice of placing infants in a prone posture, smoking, and formula feeding, were reduced. Correspondingly, it was shown that the incidence of SIDS in Japan and in Kanagawa Prefecture where the survey was carried out considerably decreased (0.42-0.24 per 1000 live births). These data indicate that this prevention campaign has been effective.