Relationships between the in vitro cytotoxicity and transport characteristics of pirarubicin and doxorubicin in M5076 ovarian sarcoma cells, and comparison with those in Ehrlich ascites carcinoma cells

PURPOSE: We sought to determine whether the de novo resistance of M5076 ovarian sarcoma cells, which show sensitivity to pirarubicin (THP), to doxorubicin (DOX) is due to differences in the transport characteristics between THP and DOX, and the results were compared with those for drug-sensitive Ehrlich ascites carcinoma cells. METHODS: The in vitro cytotoxicity of the drugs was assessed by means of the tetrazolium dye assay. Transport experiments were performed by the rapid centrifugation method. RESULTS: In an in vitro cytotoxicity experiment, M5076 cells showed lower sensitivity to DOX than to THP, and the cytotoxicity of THP and DOX toward M5076 cells was lower than toward Ehrlich cells, and these results were similar to those of an in vivo experiment. This was due to the much lower expression of topoisomerase II in M5076 cells than in Ehrlich cells. The amount of intracellular DOX was found to be significantly lower than that of THP in both cell types, and furthermore, little free intracellular DOX was observed in M5076 cells, indicating that the low sensitivity of M5076 cells to DOX was partially a result of the low amount of intracellular DOX. There was no difference in the efflux rate, but there was an apparent difference in the uptake efficiency of the carrier between THP and DOX. CONCLUSIONS: These findings suggest that the cytotoxicities of THP and DOX toward M5076 and Ehrlich cells depend, at least in part, on the uptake efficiency of the carrier.     

A patient with advanced gastric cancer in the gastric tube whose QOL was improved by TS-1

We present the case of a 72-year-old man with gastric tube cancer accompanied by multiple liver metastases, after esophagectomy for esophageal cancer, whose quality of life (QOL) was improved with a small dosage of TS-1. The patient's high serum AFP level suggested alpha-fetoprotein-producing gastric cancer. He was treated with half the standard dose of TS-1, because the patient's poor general condition necessitated chemotherapy with low toxicity and high efficacy. The daily dose was 40 mg for the first three courses and 50 mg for the last two. Each treatment course consisted of a four-week administration followed by two drug-free weeks. The patient received five courses of chemotherapy at our outpatient clinic before his death from re-progression of liver metastasis. No serious side effect except temporary stomatitis was observed. A decrease in tumor markers, alpha-fetoprotein and carcinoembryonic antigen, was obtained after 4 weeks. After 2 cycles, computed tomography and endoscopy examinations showed regression of the primary tumor and liver metastases, and tumor markers were decreased remarkably. The patient's QOL improved gradually after the treatment. His performance status before the chemotherapy was 3, and improved to 1 after two cycles. The small dosage of TS-1 was effective without any adverse effects, and improved the patient's QOL, for 6 months.     

Intra-arterial chemotherapy with gemcitabine (GEM) for unresectable pancreatic cancer

PURPOSE: Most patients with pancreatic cancer are unresectable because of local invasion and liver metastasis at the time of diagnosis. To date, no treatment has had a significant impact on this disease. To deliver a high concentration of drug to the cancer, intra-arterial chemotherapy with GEM was performed in two patients with unresectable advanced cancer. PATIENTS AND METHODS: One patient, a 70-year-old man with liver metastasis, was treated with arterial infusion of GEM 1,000 mg/body. Another patient, a 55-year-old woman with local invasion and distant metastatic lymphadenopathy, was given intra-arterial infusion of GEM 400 mg and intra-venous infusion of GEM 1,000 mg/body. The patients were given GEM weekly for 3 weeks followed by a week of rest. RESULTS: In the first patient, the pain went away and CEA was decreased for 6 months. After that, the patient died due to intra-abdominal dissemination within 4 months. In the other patient, the pain went away. Tumor markers, such as CEA and CA19-9, were normalized and primary pancreatic cancer was reduced locally. The patient currently has a metastatic liver tumor, but she has had a significant improvement in performance status. CONCLUSION: Intra-arterial chemotherapy with GEM may be tolerated in patients with unresectable pancreatic cancer.     

Intrinsic angiotensin II-generating system in human pancreatic cancer tissues

To clarify whether an intrinsic angiotensin II-generating system exists in human advanced pancreatic cancer tissues, we measured angiotensin II concentration and angiotensin converting enzyme (ACE) activity in tissues of normal pancreas, pancreatic cancers, colon cancers and hepatocellular carcinomas. After the surgically resected specimens were homogenized, angiotensin II concentration and ACE activity in tissues were measured using the florisil method and Kasahara's method, respectively. Tissue angiotensin II levels in pancreatic cancers (n = 13) were significantly higher than those of normal pancreas (n = 7), colon cancers (n = 7), or hepatocellular carcinomas (n = 7). However, there was no significant difference in tissue ACE activity between them. This study provides in vivo evidence of ACE-independent angiotensin II-generating system in human pancreatic cancer tissues and suggests that this locally-formed angiotensin II influences the microenvironment of pancreatic cancer tissues in a paracrine fashion.     

Developmental changes in KCC1, KCC2 and NKCC1 mRNAs in the rat cerebellum

Cation chloride cotransporters are considered to play pivotal roles in controlling the intracellular and extracellular ionic environments of neurons, hence controlling neuronal function. To establish how these cotransporters are involved in cerebellum development, we investigated the expression of KCC1, KCC2 and NKCC1 mRNAs in the developing rat cerebellum using in situ hybridization histochemistry. In the external germinal layer, where premature cells exist, we found substantial KCC1 and NKCC1 mRNA expression on P7 and P14, while KCC2 mRNA was not detected. In contrast, KCC2 mRNA was already expressed in Purkinje cells on P1. We also observed KCC2 mRNA expression in postmigratory granule cells after P7. The expression of KCC1, KCC2, and NKCC1 mRNAs reached adult patterns by P21. In the adult cerebellum, KCC2 mRNA was expressed in most neurons, including Purkinje cells, granule cells, and stella/basket cells, while KCC1 and NKCC1 mRNAs were only detected in granule cells and glial cells. These findings suggest that in the rat cerebellum KCC2 mRNA expression is induced when neurons arrive their final destinations.     

Dyslipidemia in young Japanese children: its relation to familial hypercholesterolemiaand familial combined hyperlipidemia

BACKGROUND: Most cases of dyslipidemia found in adults are non-familial. However, in children, especially young children, dyslipidemias other than familial hypercholesterolemia (FH) have not yet been characterized. METHODS: From April 1990 to March 1999, 56 181 children were screened, and 1380 showed abnormal levels of apolipoprotein B (more than 2.5 standard deviations above the mean). Among these, 1198 were re-examined and further characterized by measuring lipids and apolipoproteins, and by their familial histories. RESULTS: Seventy-seven percent of the children (928 of 1198) recalled were diagnosed as being dyslipidemic. Ninety-one children were FH, 423 were type IIa, 128 were type IIb, 98 were type IV, and 188 were hypoalphalipoproteinemia. The presumed incidence of FH was 0.19%, IIa 0.87%, IIb 0.26%, IV 0.20%, and hypoalphalipoproteinemia 0.39%, taking into account the percentage of subjects who refused recall. At regular follow-ups, in many children with type IIb, the phenotypic expression changes from type IIb to IIa or IV. Thus, lipid and apolipoprotein levels were determined in 77 family members in 34 families of children with type IIb. Forty-five family members were dyslipidemic (type IIa 18, type IIb 11, type IV 16). As a result, 27 children (79%) with type IIb met the criteria for familial combined hyperlipidemia. CONCLUSIONS: Children with dyslipidemia had more family or genetic background than adults. Unexpectedly, children with type IIb were mostly familial combined hyperlipidemia. Thus, setting appropriate eating patterns during childhood might be important for normalizing risk factors for atherosclerotic coronary heart disease, especially in children with FH or type IIb.     

Four cases of arthritis associated with Mycoplasma pneumoniae infection

Background: Mycoplasma pneumoniae infection is diagnosed commonly by marked elevation of serum antibodies, but this requires several days and consequently M. pneumoniae infection might be overlooked in some cases. Recently an ImmunoCard Mycoplasma rapid diagnosis test (IC) has been developed and used clinically. One of the advantages of this diagnosis test is that clinicians can recognize the infection by a single administration at the beginning of treatment.
Methods: A total of 1033 children aged 1–15 years (average 2.0 years) were examined. The diagnosis of M. pneumoniae infection was made mainly on the basis of a positive reaction to the IC. Also where possible, particle agglutination (PA) was performed as a confirmatory test. Diagnosis was made on the basis of a fourfold or greater rise in the PA antibody titer by paired sera or an initial single PA titer >1:320. Arthritis was diagnosed mainly on clinical symptoms. Additionally, ultrasonography (US) was conducted to confirm arthritis. In using US, arthritis was defined as an enlargement of the low echoic section or fluid retention inside the articular capsule.
Results: IC was used in 1033 patients and results were positive in 348 (33.6%). Of these 348, there were 70 cases of pneumonia (20.1%) and four cases of arthritis (1.1%). IC was positive in all of the cases of arthritis, and in two of the four arthritis patients the PA titers were also useful for diagnoses. In three of four cases, US was performed and lesions were observed in two of three cases. Three of the four arthritis patients were infants and only one of these three had pneumonia.
Conclusions: Using IC as a screening test, occult M. pneumoniae infections were discovered that would otherwise have been overlooked. These included two patients with US-proved arthritis. Arthritis in the absence of pneumonia may not be an unusual manifestation in infants infected by this organism.     

Cytomegalovirus infection and wheezing in infants

Background: Bronchial asthma‐like symptoms such as wheezing are commonly associated with respiratory tract infection including respiratory syncytial virus (RSV) infection in infants. No study on the association of wheezing with cytomegalovirus (CMV) infection in infancy has been reported, although CMV infection has been observed to play some role in prolonged and intractable wheezing in limited cases. Methods: The present study investigated 40 hospitalized infants who presented with first‐episode wheezing between October 2003 and September 2004. Nasopharyngeal aspirates were tested for RSV, and serum antibodies against CMV were measured. As controls, age‐matched infants with no wheezing were examined for CMV serostatus. Results: RSV‐antigen was detected in 21 subjects (53%), and seven (18%) were considered primary CMV infection serologically. Primary CMV infection was found more often in the wheezers than in the controls although the difference was not statistically significant (P = 0.06). The incidence of splenomegaly was significantly higher in wheezers with CMV infection (86%) than in those with RSV infection or without either infection. The duration of wheezing, fever, and radiographic and laboratory findings during hospitalization were not significantly different. Conclusions: CMV infection based on serologic diagnosis should be considered in infants with first wheezing episode and particularly those with splenomegaly.     

Mother-to-child transmission of human T-lymphotropic virus type I (HTLV-I): An extended follow-up study on children between 18 and 22-24 years old in Okinawa,Japan

The significant difference observed between the seroprevalence of HTLV-I in adults and in children is as yet unexplained. To evaluate a hypothetical explanation of the existence of seroconversion cases of ?seronegative carriers”? for this phenomenon, 21 of 55 children who had been born to seropositive mothers and who remained seronegative until the age of 18 years were further followed up at the ages of 22 and/or 24 years. None of the 21 seronegative children born to seropositive mothers seroconverted, either at 22 years or at 24 years. In addition, the polymerase-chain-reaction (PCR) technique could not prove the existence of the HTLV-I provirus genome in peripheral mononuclear cells (PBMC) of 10 of these children. Our results fail to prove the possibility of viral latency of HTLV-I in mother-to-child transmission. Therefore, the hypothetical seroconversion of ?seronegative carriers”? after adulthood can not be an explanation.     

Effect of Mass Screening for Breast Cancer from the Aspect of Psychosocial Assessment of the Quality of Life

To assess the quality of life (QOL) in patients with breast cancer receiving mass screening, a collaborative matched case-control study was conducted in nine hospitals throughout Japan. A total of 122 patients detected by mass screening (study group) and 226 patients found in out-patient clinics (control group) were assessed psychosocially on the basis of questionnaire information. The incidence of patients with early stage breast cancer was significantly higher in the study group than in the control group ( P <0.05). Chest wall pain was observed in 35.2% of the study group and in 46.5% of the control group ( P <0.05). Although control patients were more optimistic than study group patients, disturbed daily life and anxiety about recurrence were a little more frequent in the former group than in the latter. In particular, shoulder stiffness was frequently seen in the control group ( P <0.05). Early detection and information do not create anxiety in mass screening patients ( P <0.01). We should recommend mass screening to patients to detect early stage breast cancer and provide better QOL.