Tofogliflozin, a sodium/glucose cotransporter 2 inhibitor, attenuates body weight gain and fat accumulation in diabetic and obese animal models.

OBJECTIVE: Tofogliflozin, a highly selective inhibitor of sodium/glucose cotransporter 2 (SGLT2), induces urinary glucose excretion (UGE), improves hyperglycemia and reduces body weight in patients with Type 2 diabetes (T2D). The mechanisms of tofogliflozin on body weight reduction were investigated in detail with obese and diabetic animal models. METHODS: Diet-induced obese (DIO) rats and KKAy mice (a mouse model of diabetes with obesity) were fed diets containing tofogliflozin. Body weight, body composition, biochemical parameters and metabolic parameters were evaluated. RESULTS: In DIO rats tofogliflozin was administered for 9 weeks, UGE was induced and body weight gain was attenuated. Body fat mass decreased without significant change in bone mass or lean body mass. Food consumption (FC) increased without change in energy expenditure, and deduced total calorie balance (deduced total calorie balance=FC-UGE-energy expenditure) decreased. Respiratory quotient (RQ) and plasma triglyceride (TG) level decreased, and plasma total ketone body (TKB) level increased. Moreover, plasma leptin level, adipocyte cell size and proportion of CD68-positive cells in mesenteric adipose tissue decreased. In KKAy mice, tofogliflozin was administered for 3 or 5 weeks, plasma glucose level and body weight gain decreased together with a reduction in liver weight and TG content without a reduction in body water content. Combination therapy with tofogliflozin and pioglitazone suppressed pioglitazone-induced body weight gain and reduced glycated hemoglobin level more effectively than monotherapy with either pioglitazone or tofogliflozin alone. CONCLUSION: Body weight reduction with tofogliflozin is mainly due to calorie loss with increased UGE. In addition, tofogliflozin also induces a metabolic shift from carbohydrate oxidation to fatty acid oxidation, which may lead to prevention of fat accumulation and inflammation in adipose tissue and liver. Tofogliflozin may have the potential to prevent obesity, hepatic steatosis and improve insulin resistance as well as hyperglycemia.

Observational study of blue dye-assisted four-node sampling for axillary staging in early breast cancer.

BACKGROUND: The use of radioisotopes (RIs) is regulated and not all institutions have nuclear medicine facilities for sentinel node biopsy (SNB). We previously reported blue dye-assisted four-node axillary sampling (4NAS/dye) to be a suitable method for detecting sentinel nodes (SNs) without RIs. Here, we present an interim report on an observational study of this technique. METHODS: From May 2003 to June 2008, 234 early breast cancer patients underwent SNB with 4NAS/dye. Lymphatic mapping was performed by injection of patent blue, and axillary sampling was performed until 4 SNs were detected. Patients with metastatic SNs underwent axillary lymph node dissection (ALND) at levels I and II, while SN-negative patients did not undergo further axillary procedures. RESULTS: The SN identification rate was 99%. In total, 44 patients were diagnosed with metastatic disease by using the 4NAS/dye technique and underwent ALND; the remaining 189 patients did not undergo ALND (the SNB group). After a median follow-up period of 54 months, only 1 patient (0.5%) in the SNB group developed axillary recurrence. For the 4NAS/dye procedure, blue SNs were harvested in 220 patients (94%) and only unstained SNs were harvested in 13 patients (6%). Among the 44 patients with SN metastases, foci were found in blue SNs in 37 patients (84%), while they were found in only unstained SNs in 7 patients (16%). CONCLUSIONS: SNB with 4NAS/dye is a safe and reliable technique for treatment of early breast cancer patients. This technique may be particularly useful for surgeons who do not have access to radioisotope facilities.

Extent of pontine pyramidal tract Wallerian degeneration and outcome after supratentorial hemorrhagic stroke.

BACKGROUND AND PURPOSE: Pyramidal tract Wallerian degeneration has been detected on magnetic resonance imaging (MRI) as T2-weighted high-intensity areas. We analyzed the relation between the extent of brain stem Wallerian degeneration and activities of daily living (ADL) after supratentorial hemorrhagic stroke. METHODS: Twenty-six patients with supratentorial hemorrhage were examined on the coronal T2-weighted image of the pons 3 months or later after stroke, and the percentage of Wallerian degeneration in the pons was calculated. The patients were divided into three groups. In group A (n = 6), MR films were taken 3 to 6 months from the onset, and the ADL assessment was done within 2 months from the MRI. In group B (n = 11), MR films were taken 3 to 6 months from the onset, and the ADL assessment was done within 10 months from the MRI (mean, 15.5 months from the onset). In group C (n = 9), MR films were taken after 10 to 17 months (mean, 12.0 months) from the ictus, and the ADL assessment was done simultaneously. Barthel Index score was used for quantitative ADL assessment. RESULTS: All patients showed various degrees of pontine pyramidal tract Wallerian degeneration associated with capsular involvement by the hematoma. In group A, the percentage of degeneration did not correlate with the Barthel Index score (r = .2101, P = .6895). An inverse relation between percentage of degeneration and Barthel Index score was seen in groups B (r = .7354, P = .0099) and C (r = .888, P = .0014). In groups B and C, Wallerian degeneration was higher in patients with Barthel scores less than 60 (P = .005). CONCLUSIONS: The extent of pontine Wallerian degeneration on MRI 3 months or later after the stroke correlated with the patient's Barthel Index score 1 year after the stroke.

Asymptomatic syringomyelia associated with cerebellopontine angle meningioma--case report.

A 66-year-old female with a 3-year history of left trigeminal neuralgia presented with an unusual left cerebellopontine angle meningioma associated with asymptomatic syringomyelia at the C2 to C4 levels diagnosed by magnetic resonance (MR) imaging. Two months after total tumor removal, the syringomyelia had diminished without shunting. MR images are useful as a basis for early diagnosis of syringomyelia.

Effectiveness of interferon-beta, ACNU, and radiation therapy in pediatric patients with brainstem glioma.

Sixteen pediatric patients with brainstem glioma were treated with a combination of interferon-beta, 1-(4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-chloroethyl)-3-nitroso ure a hydrochloride (ACNU), and radiation therapy (IAR therapy). All patients received 1-1.5 million IU/day of interferon-beta intravenously for 1 week of each 6-week cycle. In addition, ACNU (2-3 mg/kg) was given on the 2nd day of each cycle. Conventional focal irradiation (1.5-2 Gy/day for 5 days to a total dosage of 40-60 Gy) was administered beginning on day 3. Patients underwent at least two 6-week cycles. Adverse effects included nausea, vomiting, and myelosuppression, but were mild and transient. Response to treatment was evaluated by the reduction in tumor size measured on postcontrast computed tomographic scans and magnetic resonance images. Responses occurred in 10 of 11 patients with the intrinsic type of brainstem glioma, including three complete and seven partial responses. Two of five patients with exophytic type gliomas partially responded. The median survival was 15.7 months, a remarkable improvement over the natural course of this disease. These results indicate that IAR therapy is a useful primary treatment for pediatric patients with brainstem gliomas.

Intracerebral leukemic mass in acute myelogenous leukemia.

Leukemic intracranial space occupying lesions are rare. A 69 year old man with acute myelogenous leukemia was found to have an intracranial leukemic mass at the time of his remission period. Computed tomography and magnetic resonance imaging study demonstrated a large irregular mass in the right temporal lobe. After total removal of the tumor, the patient was treated with whole brain irradiation and intrathecal chemotherapy. After surviving for 7 months, the patient expired of hematologic relapse.

Liposomes coupled with monoclonal antibodies against glioma-associated antigen for targeting chemotherapy of glioma.

Liposomes have a variety of attributes as a drug delivery system. Targeting of liposomes to specific cells has been investigated by using appropriate cytophilic ligands such as monoclonal antibodies (MAb's). In the present study, liposomes with selective cytotoxicity toward glioma cells were obtained. An MAb which reacts with a glioma-associated antigen, G-22-MAb, was coupled with liposomes by the cross-linking reagent dipalmitoyl L-alpha-phosphatidylethanolamine 3-(2-pyridyldithio)propionate. Interaction of the liposomes with glioma cells was morphologically observed by fluorescence microscopy, and uptake of liposomal contents into glioma cells was analyzed by flow cytometry using carboxyfluorescein as a marker. It was demonstrated that G-22-MAb could be coupled with liposomes without altering its specificity toward glioma cells and that coupling with the MAb led to a significant increase in the uptake of liposomal contents into glioma cells. Liposomes containing an antitumor drug, methotrexate (MTX), were prepared and their cytotoxicity was examined by a colorimetric growth assay. Upon incorporation of MTX into the MAb-coupled liposomes, the cytotoxicity toward glioma cells was increased 100-fold as compared with free MTX. These results indicate that G-22-MAb-coupled liposomes containing MTX have selective cytotoxicity toward glioma cells and could be utilized for targeting the chemotherapy of gliomas.

Combination chemotherapy with cisplatin and etoposide for malignant intracranial germ-cell tumors. An experimental and clinical study.

Antitumor activity against intracranial malignant teratoma by combination chemotherapy with cisplatin and etoposide was evaluated in experimental and clinical studies. A human teratoma cell line (Tera 2) was exposed in vitro to cisplatin and/or etoposide, after which cell growth inhibition and alterations of deoxyribonucleic acid (DNA) histograms were observed. The results indicated that a synergistic cytotoxic effect was achieved by use of both agents in combination. Four cases of recurrent intracranial germ-cell tumor (three malignant teratomas and one germinoma) were treated with cisplatin and etoposide. With this combination therapy, regression of the tumor was observed in all four cases (three complete and one partial), for a total response rate of 100%. During a follow-up period of 9 to 22 months, no recurrence or progression has been noted in three of these cases.

[Basic studies on chemotherapy of brain tumors by means of liposomes: affinity of sulfatide-inserted liposomes to human glioma cells].

In order to utilize liposomes for the treatment of brain tumors, we examined the interaction between the cells and the liposomes prepared from phosphatidylcholine, cholesterol, and sulfatide (molar ratio, 7:2:1), which were able to deliver the encapsulated materials into the brain through the blood-brain barrier. With a variety of human cell lines, the incorporation of the liposomes and the release of the liposomal contents into cells were studied by spectrofluorometry and flow cytometry by use of encapsulated 6-carboxy-fluorescein. It was found that the amounts of liposomes incorporated into cells were dependent on the dose of liposomes and type of cells. At the same concentration of liposomes, the highest incorporation was found for glioma cells, which was further confirmed by electron microscopy with ferritin-containing liposomes. These results indicate that the liposomes composed of sulfatide, phosphatidylcholine and cholesterol have a high affinity for human glioma cells and should be useful for the chemotherapy of glioma when antitumor drugs are encapsulated into them.

[Controlled multimodality treatment of brain stem gliomas].

Thirty-eight children were diagnosed as having a brain stem glioma at Nagoya University. Thirty-three patients in our previous series from 1957 to 1983, were treated traditionally with radiation and at late stage with shunting operation for hydrocephalus and/or suboccipital decompression, but not with direct operation for tumors. In general, tumors constantly grew regardless histology and their mean survival time was only 7.0 months even with transient neurological remission. On the other hand, recent five patients since 1984 were treated with prospective multimodality treatment. According to neuroradiological studies by X ray and/or NMR, CT scanning, the brain stem glioma cases were classified into subgroups of intrinsic and exophytic. Then the former were treated non-surgically with adjuvant therapy of Interferon-ACNU-Radiation (IAR) and the latter were treated surgically at first by resection of the tumor followed by adjuvant therapy of IAR or interferon-CDDP. Four out of five patients responded to adjuvant therapy (complete response = 2, partial response = 2, response rate = 80%) and they are all alive after 7-28 months follow-up period. It is concluded from our results that CT scanning can diagnose the accurate location and nature of brain stem gliomas, surgical therapy benefits at least in exophytic cases, and IAR adjuvant therapy may prolong the survival time of patients.

[Combination therapy with IFN-beta, ACNU and radiation (IAR) in malignant brain tumors].

In order to analyze the efficacy of combination therapy with Hu-IFN-beta, ACNU and radiation (IAR), nine patients with malignant glioma were treated as a control study. They received 100 X 10(4) IU Hu-IFN-beta daily for seven days intravenously or intratumorally, 3 mg/kg ACNU on day 2 and 5,000-6,000 rads of radiation from day 3. Four out of nine patients showed complete response and one partial response with this IAR therapy. Case 1 was a 64-year-old man who had glioblastoma in the left frontal lobe. Postoperative residual tumors disappeared completely with this therapy. Case 3 was a 8-year-old girl who had an enhanced high-density lesion in the medulla oblongata and pons. After IAR therapy, the high-density lesion was completely vanished and her clinical manifestations of multiple cranial nerve palsy and pyramidal sign were improved remarkably. The major side effects of IAR therapy were mild or moderate myelosuppression, and some patients also showed hepatic dysfunction, mild fever and gastrointestinal toxicities. However, all these side effects were mild and transient and soon recovered to normal levels. These results suggest that IAR therapy is effective and will prolong the survival time of patients with malignant glioma.

[Effect of MCNU on brain tumors. Part II: Clinical experience with MCNU on malignant brain tumors].

Ten patients with malignant brain tumor (8 cases with glioblastoma, 2 cases with medulloblastoma) were treated with a new water-soluble nitrosourea, MCNU. Objective tumor regression of tumor (CR & PR) on computerized tomography was observed in four patients (2 complete and 2 partial) after MCNU, chemotherapy showing a response rate of 40%. The major side effects of MCNU were mild or moderate myelosuppression, and some cases also showed gastrointestinal toxicities and impairment of hepatic function. However, all these side effects were mild and transient and soon recovered to normal levels. One patient with glioblastoma multiforme recurrence was treated with a high-dose chemotherapy of MCNU (400 mg) associated with autologous bone marrow transplantation. Myelosuppression began to appear from 15th day of MCNU administration and normalized within 30 days afterwards. These results suggest that MCNU therapy is effective for patients with malignant brain tumors.