Polychlorinated biphenyls promote 1-nitropyrene-induced lung tumorigenesis without the induction of K-ras gene mutation in A/J mice.

Although the effects of polychlorinated biphenyls (PCBs) on human lung carcinogenesis are suggested from the massive PCBs poisoning that occurred in Japan designated "Yusho," the detailed molecular mechanism are unknown. 1 nitropyrene (1-NP), an ubiquitous and abundant environmental pollutant, is known to be detected in lung tissues derived from patients with lung cancer in Japan, and its relation to lung carcinogenesis is also suggested. We investigated the effects of PCBs (Kanechlor-400) on 1-NP-induced lung tumorigenesis in A/J mice. PCBs were administered intraperitoneally followed by ip injection of 1-NP. The lung lesions were examined 18 weeks after the final treatment. In the control group, no neoplastic lesions were induced in the lung. In the PCB group, preneoplastic lesions such as hyperplasia and adenoma were induced in 2/10 (20%) mice. In 1-NP group and in PCB + 1-NP group, lung lesions including adenocarcinoma were induced in 16/20 (80%) and 13/13 (100%) mice, respectively. Both the number and the size of tumors in PCB + 1-NP group were significantly greater than those in 1-NP group. K-ras gene mutation, CAA to CGA in codon 61 or GGT to GAT in codon 12, was found in either 1-NP group or PCB + 1-NP group but not in the PCB group. There was no difference in the pattern of K-ras mutation associated with the pretreatment with PCBs. These results suggest that PCBs promote 1-NP-induced lung tumorigenesis and may support, at least in part, the mechanism of the high incidence of lung cancer in patients with Yusho.

Diagnostic value of bone-turnover metabolites in the diagnosis of bone metastases in patients with lung carcinoma.

BACKGROUND: Several biochemical markers of bone formation and bone resorption have been developed recently. The authors evaluated the usefulness of new biomarkers, such as urinary deoxypyridinoline (D-PYD), serum pyridinoline cross-linked C-telopeptides of Type I collagen (1CTP), and urinary pyridinoline cross-linked N-telopeptides of Type I collagen (NTx), in the assessment of bone metastases in patients with lung carcinoma. METHODS: The serum concentrations of 1CTP and the urinary concentrations of D-PYD and NTx were measured in 100 lung carcinoma patients, of whom 20 patients had bone metastases and 80 patients did not. Receiver operating characteristic (ROC) curves were drawn for these markers to compare their usefulness in detecting bone metastases originating in lung carcinoma. RESULTS: Urinary concentrations of NTx in patients with bone metastases were significantly greater than in patients without bone metastases (147.1 +/- 129.3 pmol bone collagen equivalents [BCE]/micromol Cr vs. 47.2 +/- 29.9 pmol BCE/micromol Cr; P < 0.0001). Urinary concentrations of D-PYD in patients with bone metastases also were significantly greater than in patients without bone metastases (10.0 +/- 3.6 BCE/micromol Cr vs. 6.6 +/- 2.2 pmol BCE/micromol Cr; P = 0.0001). No significant difference was observed in serum concentrations of 1CTP between patients with and without bone metastases. A moderate but significant correlation was seen between NTx and D-PYD (correlation coefficient [R] = 0.435; P < 0.0001) and between D-PYD and 1CTP (R = 0.525; P < 0.0001). NTx had a better ROC curve than D-PYD and 1CTP (the areas under the ROC curve were 0.84, 0.79, and 0.62, respectively). Using the threshold of 62.5 pmol BCE/micromol Cr for NTx, sensitivity, specificity, and accuracy were 0.800, 0.737, and 0.750, respectively. CONCLUSIONS: In the current study, the measurement of NTx appeared to be most useful as a marker of bone metastases in patients with lung carcinoma.

Polycyclic aromatic hydrocarbon carcinogens increase ubiquitination of p21 protein after the stabilization of p53 and the expression of p21.

Polycyclic aromatic hydrocarbon carcinogens (PAHs) and their metabolites have been found to result in a rapid accumulation of p53 gene product in human and mouse cells. However, the induced p53 protein was reported to be transcriptionally inactive. In the present study, the induction of p53 target gene expression after the treatment with either benzo(a)pyrene (B[a]P) or 1-nitropyrene (1-NP) was investigated. A marked induction of messenger RNA (mRNA) expressions of Mdm2, Bax, and p21 was detected in wild-type p53-expressing cells after the treatment with either B[a]P or 1-NP, whereas no significant change in mRNA expression of these genes was observed in p53-negative and mutant cells. 1-NP activated the p21 promoter in a p53-dependent manner. Binding activity of p53 to a p53 consensus sequence increased after the treatment in wild-type p53-expressing cells. Nevertheless, the induced mRNA levels of the p21 did not result in a proportional p21 protein increase, indicating the possibility of post-transcriptional regulation of the protein. With the addition of MG-132, a proteasome inhibitor, to B[a]P or 1-NP treatments, both p21 and p53 protein levels were increased; however, the increase in p21 protein levels was significantly larger than the increase in p53 protein levels. PAHs treatment increased the level of ubiquitinated p21. These results suggest that the p21 product is degraded by the ubiquitin-proteasome system. We conclude that PAHs-induced p53 protein is transcriptionally active.

[Interstitial pneumonia treated with intermittent cyclophosphamide pulse therapy].

A 52-year-old woman was admitted to the hospital because of polyarthralgia and dry coughing. A chest X-ray film showed bilateral diffuse reticulo-nodular shadows. A specimen obtained by transbronchial lung biopsy revealed alveolar septal thickening and infiltration by mononuclear cells. Interstitial pneumonia associated with rheumatoid arthritis was diagnosed. Interstitial pneumonia relapsed soon after the first pulse of corticosteroid therapy. Cyclophosphamide pulse therapy was given in addition to a second pulse of corticosteroid therapy; 700 mg of cyclophosphamide (500 mg/m2) was administered intravenously every month and the dose of steroids was gradually reduced. Cyclophosphamide pulse therapy was repeated three times and the dose of oral corticosteroids was reduced from 60 mg to 35 mg. There was no bone marrow suppression or hemorrhagic cystitis after the cyclophosphamide pulses. Eventually, corticosteroid therapy was stopped with no clinical deterioration. This case suggests that intermittent cyclophosphamide pulse therapy can be effective for treatment of interstitial pneumonia unresponsive to corticosteroids.

Hydrocephalus due to villous hypertrophy of the choroid plexus in the lateral ventricles. Case report.

A case is reported of hydrocephalus due to overproduction of cerebrospinal fluid (CSF) caused by villous hypertrophy of the choroid plexus in the lateral ventricles. A 7-year-old girl with mental retardation developed gait disturbance; hydrocephalus and a Dandy-Walker cyst were detected on computerized tomography. She was initially treated with a ventriculoperitoneal shunt; however, shunting failed to control the hydrocephalus. The excessive outflow of CSF suggested choroid plexus abnormality, and magnetic resonance (MR) imaging revealed enlargement of the choroid plexus in both lateral ventricles. The patient was therefore diagnosed as having hydrocephalus induced by overproduction of CSF, which was controlled by resection of the choroid plexus. Histological examination showed the structure typical of normal choroid plexus. This is a rare case of villous hypertrophy of the choroid plexus in which MR imaging assisted in the diagnosis.

[Macroscopic and histological studies on the gastric carcinoma having arisen from the cardiac gland mucosa--concerning to the esophageal invasion and the reliable surgical cut-line].

Cardiac carcinoma is defined as the carcinoma whose center of the mucosal lesion is located at the area of the stomach within 2.0cm from the esophago-gastric junction. Histological and macroscopical examination was performed concerning to the frequency of macroscopic type, the direction of the mucosal invasion, the tendency of the submucosal invasion and the esophageal invasion by using these cardiac carcinomas. The objects of this study are a hundred and thirty-nine cases of cardiac carcinomas. The conclusions are as follows: 1) Depressed type (Type II c) in early carcinoma, Type Borrmann 2 and Borrmann 3 in advanced carcinoma are the most frequent form of macroscopic types. 2) The majority (87.7%) of the early carcinomas was situated at the lesser curvature and the posterior wall of the cardiac mucosa (Figure 1). 3) The early cardiac carcinoma had a tendency to invade in the mucosal layer along the esophago-gastric junction (Table 2). 4) The cardiac carcinoma was thought to invade into the submucosa in its early phase, comparing to the carcinoma on the other area of the stomach (Table 3). Twenty-four out of thirty-five (68.6%) cases of cardiac carcinoma ranged from 11 to 20mm in diameter invaded into the submucosa (Table 3). 5) Twelve out of seventy-three (16.4%) of early cases and fifty-seven out of sixty-six (86.4%) of advanced cases showed the infiltration into the esophagus (Table 4, Figure 6). The reliable and surgical cut-line of the oral site can be established at the area over 11 mm in the distance from the oral margin of the mucosal invasion in the cases of early cardiac carcinoma, over 25mm in the cases of advanced differentiated type, and over 30mm in the cases of advanced undifferentiated type (Figure 6).

A correlation between arterial ketone body ratio and concentration of beta-hydroxybutyrate as an indicator of hepatic functional reserve.

We have investigated the correlation between the arterial blood ketone body ratio (AKBR) and beta-hydroxybutyric acid (HBAC) in the course of a 75 g glucose tolerance test. The correlation was revealed to be represented by an equation of Y = A + BX [X = log(HBAC), Y = log(AKBR)] with high significance. This expression existed in both normal individuals and patients with liver, biliary tract or pancreas disease. The postoperative course was unsatisfactory because of liver dysfunction in cases whose value B was more than -0.6 in bisegmentectomy and more than -0.45 in uni- or subsegmentectomy. The coefficient B in the equation was suggested to contribute to the evaluation of hepatic functional reserve.

[Intraoperative ABR monitoring during cerebello-pontine angle surgery].

Intraoperative auditory brainstem response (ABR) monitoring was performed in 27 patients undergoing C-P angle surgery (12: hemifacial spasm, 10: trigeminal neuralgia, 2: glossopharyngeal neuralgia, 3: C-P angle tumor, 2 epidermoid, 1 meningioma). Because of the introduction of this method, no patient suffered from postoperative hearing disturbance in this series. During C-P angle surgery, the wave V of ABR changes according to the retraction of the cerebellum and the manipulation of the eighth cranial nerve. Many authors have discussed this change, however the timing and the mechanism of disappearance of wave V is unclear. Accordingly, the authors discussed the correlation between the prolongation of wave V latency and its amplitude. The wave V amplitude was measured from the positive peak of wave V to the next negative peak. Then, the correlation between the prolongation of wave V latency and its reduction ratio (%) of amplitude was represented as a parabola. The wave V reduces its amplitude when the prolongation of the latency is from 1.5 ms to 2.0 ms. Once the prolongation of the latency is over 1.5 ms, the amplitude of wave V seems to be reduced suddenly, because it takes over 1'30'' to finish each record. But the authors demonstrated the gradual reduction of the amplitude of wave V in Figure 3. As mentioned above, the prolongation of wave V latency must be less than 1.5 ms, and the neurosurgeon must recognize this turning point during C-P angle surgery.