Anterior mediastinal solid tumours in adults: characterisation using dynamic contrast-enhanced MRI, diffusion-weighted MRI, and FDG-PET/CT.

AIM: To find significant parameters to characterise anterior mediastinal solid tumours in adults using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), diffusion-weighted MRI (DWI), and combined 2-[(18)F]-fluoro-2-deoxy-d-glucose positron-emission tomography/computed tomography (FDG-PET/CT). MATERIALS AND METHODS: Forty-eight histologically confirmed anterior mediastinal solid tumours in 48 patients (24 men, 24 women; age range 21-83 years, mean 50.7 years) were examined. The parameters analysed were maximal diameter, presence of capsule/septa on T2-weighted images, time-signal intensity curves (TICs), apparent diffusion coefficient (ADC), and maximum standardised uptake value (SUVmax). Also examined was whether any differences between histological types could be seen in these parameters. In a validation study, 42 anterior mediastinal solid tumours in 42 patients were examined consecutively. RESULTS: The washout pattern on TIC was seen only in thymic epithelial tumours (20/32). SUVmax of lymphoma (mean, 17.9), malignant germ cell tumours (14.2), and thymic carcinomas (15.6) were significantly higher than that of thymomas (6.1). The mean maximal diameter of thymic epithelial tumours was significantly smaller than that of lymphomas (p<0.01) and malignant germ cell tumours (p<0.05). The validation study also yielded high accuracy (38/42, 91%) in differentiation among the anterior mediastinal solid tumours. CONCLUSION: The SUVmax, TIC pattern on DCE-MRI, and maximal diameter might be useful to differentiate anterior mediastinal solid tumours in adults.

Risk factors for persistent positive anticardiolipin antibodies in women with recurrent pregnancy loss.

Antiphospholipid syndrome (APS) is an established cause of recurrent pregnancy loss (RPL). It is necessary to detect persistently positive antiphospholipid antibodies to diagnose APS. This study aimed to explore risk factors for persistent anticardiolipin (aCL) positivity. Women with a history of RPL or with a history of one or more intrauterine fetal deaths after 10 weeks underwent examinations to determine the causes of RPL, including antiphospholipid antibodies. If aCL-IgG or aCL-IgM antibodies were positive, retests were performed at least 12 weeks apart. Risk factors for persistent aCL antibody positivity were retrospectively investigated. The number and percentage of cases above the 99th percentile were 74/2399 (3.1%) for aCL-IgG, and 81/2399 (3.5%) for aCL-IgM. Of the initially tested cases, 2.3% (56/2399) for aCL-IgG and 2.0% (46/2289) for aCL-IgM were ultimately positive above the 99th percentile in retests. Retest values after 12 weeks were significantly lower than the initial values for both IgG and IgM immunoglobulin classes. Initial aCL antibody titers were significantly higher in the persistent-positive group than in the transient-positive group for both IgG and IgM immunoglobulin classes. The cut-off values for predicting persistent positivity of aCL-IgG antibodies and aCL-IgM antibodies were 15 U/mL (99.1 percentile) and 11 U/mL (99.2 percentile), respectively. The only risk factor for persistently positive aCL antibodies is a high antibody titer during the initial test. When the aCL antibody titer in the initial test exceeds the cut-off value, therapeutic strategies can be defined in subsequent pregnancies without waiting for 12 weeks.

Malignant seminoma with multiple visceral metastases in a guinea fowl (Numida meleagris) kept in a zoo.

A case of seminoma found in an adult guinea fowl (Numida meleagris) that has been exhibited in a zoo is reported. The right testis was extremely enlarged and replaced by round and polyhedral pleomorphic neoplastic cells showing nest, sheet, and diffuse growth patterns. The neoplastic cells had acidophilic cytoplasm and hyperchromatic and eccentrically placed nuclei. Metastatic lesions composed of diffuse growth of neoplastic cells similar to those of the primary tumor were seen in the liver, lungs, kidneys, and heart, and neoplastic emboli were often detected within blood vessels of these organs, indicating hematogenous metastasis. This is the first report of malignant seminoma with multiple metastases in the visceral organs in the guinea fowl.

Diagnosis and treatment of obscure gastrointestinal bleeding using combined capsule endoscopy and double balloon endoscopy: 1-year follow-up study.

BACKGROUND AND STUDY AIMS: Several studies have shown the value of capsule endoscopy and double balloon endoscopy (DBE) in small-intestinal bleeding. The purpose of this study was to evaluate the impact of capsule endoscopy results on subsequent DBE examination, and the 1-year clinical outcome of this combined approach in patients with obscure gastrointestinal bleeding (OGIB). PATIENTS AND METHODS: A total of 45 consecutive patients with OGIB underwent capsule endoscopy. Patients with positive capsule endoscopy results underwent DBE for biopsy or therapy, and those with negative results underwent further assessment for possible diagnostic misses on capsule endoscopy. Tumors, ulcerations, and vascular lesions were considered as sources of bleeding. Diagnoses of OGIB lesions and clinical outcome were assessed 1 year after these examinations. RESULTS: Responsible lesions were found in 22 patients (49 %): 19 lesions in 18/45 patients (40 %) undergoing capsule endoscopy, and 18/36 patients (50 %) undergoing subsequent DBE. In all, 10 tumors, nine vascular lesions, and four ulcerations were found. In two patients, vascular lesions were only later diagnosed by conventional methods (4 %). Capsule endoscopy results guided our choice of the proper DBE model for successful therapeutic intervention in five patients. Re-bleeding rates were low during 1-year follow-up of the entire group (mean follow-up, 18.8 months): 5 % in cases with positive diagnoses on capsule endoscopy and/or DBE, and 12 % in negative cases. CONCLUSIONS: A combined approach using capsule endoscopy followed by DBE proves valuable in the diagnosis and treatment of patients with OGIB, leaves a low rate of undiagnosed bleeding sources, and has a good long-term outcome.

The role of histone modifications in epigenetic transitions during normal and perturbed development.

Epigenetic mechanisms control eukaryotic development beyond DNA-stored information. DNA methylation, histone modifications and variants, nucleosome remodeling and noncoding RNAs all contribute to the dynamic make-up of chromatin under distinct developmental options. In particular, the great diversity of covalent histone tail modifications has been proposed to be ideally suited for imparting epigenetic information. While most of the histone tail modifications represent transient marks at transcriptionally permissive chromatin, some modifications appear more robust at silent chromatin regions, where they index repressive epigenetic states with functions also outside transcriptional regulation. Under-representation of repressive histone marks could be indicative of epigenetic plasticity in stem, young and tumor cells, while committed and senescent (old) cells often display increased levels of these more stable modifications. Here, we discuss profiles of normal and aberrant histone lysine methylation patterns, as they occur during the transition of an embryonic to a differentiated cell or in controlled self-renewal vs pro-neoplastic or metastatic conditions. Elucidating these histone modification patterns promises to have important implications for novel advances in stem cell research, nuclear reprogramming and cancer, and may offer novel targets for the combat of tumor cells, potentially leading to new diagnostic and therapeutic avenues in human biology and disease.

Establishment of an enzyme immunoassay system for gliostatin/platelet-derived endothelial cell growth factor (PD-ECGF).

A two-site enzyme immunoassay for gliostatin (GLS)/platelet-derived endothelial cell growth factor (PD-ECGF) has been developed. The detection limit of gliostatin/PD-ECGF was 30 pg/well, and the optimal assay range was 0.1 to ng/well. This assay system enabled us to confirm the immunochemical identity of both factors and to detect immunoreactive gliostatin/PD-ECGF (IR-GLS/PD-ECGF) in human biological body fluids. The age-related analysis from newborn to 69 years revealed that the serum IR-GLS/PD-ECGF level was high in infants younger than 1 year old (1.8 ng/ml) and in the 20-year-old age group (1.8 ng/ml), and highest in the umbilical cord blood (2.1 ng/ml). Curiously high concentrations were detected in saliva with a significant sex difference (11.3 ng/ml for males and 48.7 ng/ml for females), and in synovial fluids (3.7 ng/ml). A number of human tumor cells, gastric cancer cells, MKN-74, neuroblastoma cells, GOTO, as well as epidermoid carcinoma cells, A431, were found to produce a significant amount of IR-GLS/PD-ECGF (0.2 to 21.8 ng/mg protein), and some of them secreted the IR-GLS/PD-ECGF in the conditioned medium (approximately 0.5 ng/ml). The enzyme immunoassay system is sufficiently sensitive for the basic and clinical study of gliostatin/PD-ECGF in human body fluids, tissues and organs.

Low-dose CT screening using hybrid iterative reconstruction: confidence ratings of diagnoses of simulated lesions other than lung cancer.

OBJECTIVE: To evaluate the confidence ratings of diagnoses of simulated lesions other than lung cancer on low-dose screening CT with hybrid iterative reconstruction (IR). METHODS: Simulated lesions (emphysema, mediastinal masses and interstitial pneumonia) in a chest phantom were scanned by a 320-row area detector CT. The scans were performed by 64-row and 160-row helical scans at various dose levels and were reconstructed by filtered back projection (FBP) and IR. Emphysema, honeycombing and reticular opacity were visually scored on a four-point scale by six thoracic radiologists. The ground-glass opacity as a percentage of total lung volume (%GGO), CT value and contrast-to-noise ratio (CNR) of mediastinal masses were calculated. These scores and values were compared between FBP and IR. Wilcoxon's signed-rank test was used (p < 0.05). Interobserver agreements were evaluated by κ statistics. RESULTS: There were no significant differences in visual assessment. Interobserver agreement was almost perfect. CT values were almost equivalent between FBP and IR, whereas CNR with IR was significantly higher than that with FBP. %GGO significantly increased at low-dose levels with FBP; however, IR suppressed the elevation. CONCLUSION: The confidence ratings of diagnoses of simulated lesions other than lung cancer on low-dose CT screening were not degraded with hybrid IR compared with FBP. ADVANCES IN KNOWLEDGE: Hybrid IR did not degrade the confidence ratings of diagnoses on visual assessment and differential diagnoses based on CT value of mediastinal masses, and it showed the advantage of higher GGO conspicuity at low-dose level. Radiologists can analyse images of hybrid IR alone on low-dose CT screening for lung cancer.

The presence of myoglobin in human thyroid tissue.

In the present study we sought to determine the presence of myoglobin in human thyroid tissue. When reacted with antihuman myoglobin antibody on the Ouchterlony plate, homogenates of human thyroid tissue formed a precipitation line. When the human thyroid extract was included in human myoglobin RIA, the dilution curve of thyroid extract was parallel to the standard curve of myoglobin. When the myoglobin immunoreactivity in thyroid extract was fractionated with Sephadex G 75 column, the immunoreactivity was eluted in a peak identical with authentic myoglobin. The position of the peak was different from that of thyroglobulin. Myoglobin concentration in thyroid tissue was estimated to be 0.7-110 mg/g wet wt, being about 1/6000 to 1/40 of that in skeletal muscle. Histochemical studies demonstrated the presence of myoglobin immunoreactivity in thyroid tissue, especially in the apical border of thyroid epithelial cells, implying a functional role in iodinating process or exocytotic-endocytotic process.

Prophylactic long-term treatment of bladder tumors with oral chemotherapy (tegafur).

A total of 107 patients with bladder tumor (from Ta to T2) was studied. Patients were treated with or without prophylactic intravesical chemotherapy using mitomycin C or doxorubicin hydrochloride (Adriamycin) after the excision of tumor. After the preliminary treatment, 55 patients were given tegafur 600 mg p.o. daily (study group), and the other 52 patients (control group) were treated without tegafur. Both groups were followed up with periodic cystoscopy every three months. Actuarial nonrecurrence rate of the two groups were examined statistically. The results revealed that tegafur was a good prophylaxis against recurrence of the bladder tumor, significant differences at P from less than 0.001 to 0.025 were noted at every observation period except at six months. A significant difference at P less than 0.005 was also recognized from an overall comparison between two nonrecurrence curves.

Intra-arterial adriamycin chemotherapy for bladder cancer. Semiselective intra-arterial chemotherapy with compression of the femoral arteries at the time of injection.

Twenty patients with bladder cancer were treated by semiselective intra-arterial chemotherapy with Adriamycin. Ten of them were given the agent while the femoral arteries were compressed, to prevent loss of the agent into the external iliac arteries. The other ten were given Adriamycin without this compression. Clinical and pathological responses of tumor and the side-effects were examined in these two groups. The results of the comparative study led us to the conclusion that the compression technique is a simple and valuable means of decreasing the side-effects of Adriamycin and increasing tumor response.

Role of the amino-terminal amino acid sequences determining the in vitro refolding process of prochymosin polypeptide.

Prochymosin, a zymogen of an aspartic proteinase chymosin, is produced as inclusion bodies in the recombinant Escherichia coli cells. Solubilization of the inclusion bodies with 8 M urea followed by dialysis at pH 10.5 achieves correctly refolded prochymosin to some extent, which is then activated by self-processing at acidic pHs. Analyses of the alkaline dialysates by anion exchange chromatography revealed broad distribution of prochymosin polypeptides with different conformations. Stepwise dialysis with a slower decreasing rate of urea resulted in marked improvement of the yield of correctly refolded molecules. A hybrid prochymosin (CR601) possessing a short NH2-terminal replacement with the trp-leader peptide was not refolded into the correct conformation by one-step dialysis, but it was by stepwise dialysis. Replacement of Lys at the NH2-terminal second position of CR601 with Asp or Glu caused marked enhancement of correct refolding. These findings suggest that the amino acid sequence in the NH2-terminal region of prochymosin plays a crucial role in determining the whole refolding process of the polypeptide.

Radiation response of apoptosis in C57BL/6N mouse spleen after whole-body irradiation.

PURPOSE: Primary conditioning low dose irradiation suppresses the molecular responses against secondary challenge high dose irradiation; this phenomenon has been termed the radioadaptive response. The mechanism of the radioadaptive response is not yet clear. This study was undertaken to elucidate the radiation response of apoptosis in mouse spleen after whole-body irradiation. MATERIALS AND METHODS: The induction of apoptosis was analysed in the spleens of C57BL/6N mice after chronic irradiation with gamma-rays at 1.5 Gy (0.001 Gy/min for 25 h) followed by challenge irradiation with X-rays at 3.0Gy (1 Gy/min). RESULTS: Accumulation of p53 and Bax, and the induction of apoptosis were observed dose-dependently in mouse spleen 12 h after acute irradiation at a high dose-rate. However, it was found that there was significant suppression of the accumulation of p53 and Bax, and induction of apoptosis 12 h after challenge irradiation at 3.0Gy at a high dose-rate following chronic preirradiation at 1.5Gy at a low dose-rate. In addition, the combination of pre-irradiation at 1.5Gy at a high dose-rate and challenge irradiation at 3.0Gy at a high dose-rate could not suppress the accumulation of p53 and Bax or the induction of apoptosis. CONCLUSIONS: Chronic pre-irradiation at a low dose-rate suppressed Bax-mediated apoptosis. These findings suggest that the radioadaptive response in mouse spleen may be due to a suppression of p53-mediated apoptosis.

Two types of X-ray-induced radioresistance in mice: presence of 4 dose ranges with distinct biological effects.

Preirradiation with 0.05 Gy of X rays 2 months before a second exposure to a mid-lethal dose significantly enhanced the survival rate in both female and male ICR strain mice. The radioresistance was observed between 2-2.5 months after exposure to 0.05 Gy. It did not appear within 1.5 months, and disappeared after 3 months. This radioresistance was induced only by whole-body preirradiation (not by partial irradiation of the head or the trunk). On the other hand, preirradiation with 0.30 Gy as well as 0.50 Gy resulted in radioresistance 2 weeks later, but not 2 months later. The radioresistance was induced by whole-body preirradiation or partial preirradiation of the trunk. No radioresistance was evident after exposure of intermediate preirradiation doses of 0.15 and 0.20 Gy administered before 2 months and 2-5 weeks, respectively. The present and previous results show that the biological effects of ionizing radiation may be distinguished with the following four radiation dose ranges; (1) below 0.025 Gy: no radioresistance after 2 months; (2) 0.05-0.10 Gy: significant radioresistance after 2-2.5 months; (3) 0.20 Gy: no radioresistance after 2-5 weeks; and (4) 0.30-0.50 Gy or more: significant radioresistance after 2 weeks. These results conflict with previous findings of the biological effects of ionizing radiation in which the radiation hazard increases in relation to increasing accumulated doses. Some stimulation, in addition to adaptation, by low dose irradiation may have occurred.

Radiation protection by Shigoka extract on split-dose irradiation in mice.

Radioprotective effect of a Shigoka extract was studied on split-dose irradiation. Mice were exposed to 4 Gy X 4 or 3 Gy X 4 for examining survival ratio or hemogram, respectively. The extract was i.p. injected immediately after each irradiation. The extract significantly (p less than 0.001) increased the survival ratio, and it increased leukocyte count within the period of the death (days 2-12 after the final exposure). Cerebral hemorrhage after 4 Gy X 4 was diminished by the extract. Recovery of leukocytogenesis seems much more important for survival at split-dose irradiation than at single acute irradiation.

Acquired radioresistance after low dose X-irradiation in mice.

Low doses (2.5-15 cGy) of X-irradiation two months prior to a second exposure to a sublethal dose enhanced the survival rate in mice. Optimal and significant increase was observed with 5-10 cGy. Endogenous spleen colony counts (endo-CFUs) after 7 Gy increased by a factor of about 1.7 in mice pre-irradiated with 5-10 cGy, while the number of blood forming stem cells (CFUs) in the pre-irradiated group did not exceed that in the sham-irradiated control group at the period of the second exposure (two months after irradiation with 5 cGy). The low dose exposure seems to stimulate recovery of blood forming stem cells after the second irradiation and favors a decrease in the incidence of bone marrow death.

Factors related to resistance to hematopoietic death in mice.

Mouse strain difference in the radiosensitivity to hematopoietic death is thought to be determined by several factors besides radiosensitivity and the initial number of hematopoietic stem cells. Factors related to the survival of mice exposed to X-irradiation were analyzed using BALB/cHeA and STS/A strains whose LD50/30 values differ markedly (BALB/cHeA, 5.55 Gy; STS/A, 8.45 Gy). STS/A mice exposed to 4 Gy of X-irradiation showed a small reduction but rapid recovery of blood cells (leukocytes, erythrocytes, and thrombocytes) when compared with BALB/cHeA mice. The survival of endogenous and exogenous CFU-S was much higher, by a magnitude of one log or more, in STS/A mice than those in BALB/cHeA mice; whereas the initial numbers of femoral CFU-S were similar for the two strains. The recovery of exogenous CFU-S was much more rapid in STS/A mice than it was in BALB/cHeA mice after 4 Gy of X-irradiation. Furthermore, spleen colonies produced by the transfusion of STS/A marrow cells into syngeneic recipients were significantly larger than those produced by BALB/cHeA marrow cells, regardless of whether the mice used for sources of marrow cells had been irradiated. But, there was no such difference when unirradiated marrow cells from the two strains were transfused into (BALB/cHeA X STS/A) F1 recipients. These results indicate the possible contribution of a host factor (s) that stimulates the growth of spleen colonies after radiation to the radioresistance of STS/A mice, in addition to the primary effect of higher number of survivals of endogenous and exogenous CFU-S in STS/A mice.

Hodgkin's disease in a killer whale (Orcinus orca).

Hodgkin's disease (HD) is reported in a killer whale (Orcinus orca). Generalized lymphadenopathy and splenomegaly were noted at necropsy and histopathological examination revealed diffuse proliferation of atypical large cells with huge eosinophilic nucleoli. They were often multinucleated, and binucleated forms characteristic of Sternberg-Reed cells of human HD were occasionally present. There was no cytological atypia in the background lymphocytes. Thus, the lesion was identified as analogous to HD in man. To our knowledge, this is the first recorded case of HD in the killer whale.

A new treatment of aneurysmal bone cyst by endoscopic curettage without bone grafting.

Curettage and bone grafting are the accepted methods of treatment of aneurysmal bone cysts. Unfortunately, recurrence is common. We treated 4 patients with atypical aneurysmal bone cysts that lacked aneurysmal dilatation by endoscopic curettage without bone grafting. New bone formation and remodeling were observed in all patients. In the patients in whom the follow-up was longer than 30 months, there was no evidence of recurrence. Endoscopic curettage without bone grafting is a simple and effective treatment for aneurysmal bone cysts.

Localization and developmental change of indoleamine 2,3-dioxygenase activity in the human placenta.

Previously, we pointed out the importance of the kynurenine metabolism in fetuses and neonates. We examined localization and developmental change of indoleamine 2,3-dioxygenase activity in human placenta. The indoleamine 2,3-dioxygenase was found localized in syncytiotrophoblast in the placenta. The indoleamine 2,3-dioxygenase activity was not detected in placenta in the early stage of gestation. It was first detected at around 14 weeks of gestation, increased rapidly thereafter and was maintained at high levels till near term. The indoleamine 2,3-dioxygenase activity was significantly lower in placenta with retarded intrauterine development. These results suggest the importance of placental indoleamine 2,3-dioxygenase during fetal development.