Outcomes of immediate perforator flap reconstruction after skin-sparing mastectomy following neoadjuvant chemotherapy.

BACKGROUND: The impact of neoadjuvant chemotherapy (NACT) on immediate free flap breast reconstruction remains controversial. Furthermore, the oncological outcomes of immediate free flap breast reconstruction after skin-sparing mastectomy (SSM) following NACT remain unclear. This study aimed to investigate the surgical complications and oncological outcomes of immediate perforator flap reconstruction after SSM following NACT. METHODS: A total of 201 consecutive patients with indications for immediate perforator flap reconstruction after SSM were included between 2004 and 2012. Surgical and oncological outcomes were compared between patients with and without NACT. RESULTS: There were 38 patients in the NACT group and 163 in the non-NACT control group. The median age of the NACT group was 39.5 years, which was significantly younger than the control group (43.0 years; P < 0.05). Patients in the NACT group also had more advanced and aggressive disease (P < 0.05). There was no significant difference in the frequency of surgical complications between the groups, no difference in the type of complications, and no significant difference in the frequencies of major and minor complications. No patients in the NACT group had delayed adjuvant therapy. Eight patients (4%) developed recurrences, with a median follow-up time of 3.0 years. Local recurrences occurred in three control patients but no patients in the NACT group. CONCLUSION: NACT does not affect short-term or interim outcomes after immediate perforator flap reconstruction and may thus represent a safe and practical treatment option for the multidisciplinary treatment of breast cancer.

Low FOXA1 expression predicts good response to neo-adjuvant chemotherapy resulting in good outcomes for luminal HER2-negative breast cancer cases.

BACKGROUND: FOXA1 expression is a good prognostic marker for endocrine therapy in hormone-positive breast cancer. We retrospectively examined breast cancer patients with luminal human epidermal growth factor receptor 2 (HER2)-negative tumours, as defined by immunohistochemistry, who received neo-adjuvant chemotherapy (NAC) and investigated the relationship between treatment effects and FOXA1 expression. METHODS: Biopsy specimens from 103 luminal HER2-negative tumours were immunohistochemically examined. FOXA1 effects on chemo-sensitivity were also investigated employing in vitro experiments. RESULTS: FOXA1 and Ki67 expressions independently predicted a pathological complete response (pCR). Knockdown of FOXA1 by siRNA boosted the chemo-effect in oestrogen receptor-positive cells. The Cox hazards model revealed a pCR to be the strongest factor predicting a good patient outcome. CONCLUSIONS: Our present study showed low FOXA1 expression to be associated with a good response to NAC in luminal HER2-negative breast cancer. Improved outcomes of these patients suggest that NAC should be recommended to patients with low FOXA1 tumours.

Effects of long-term training on neutrophil function in male university judoists.

OBJECTIVES: To clarify the effects of high-intensity and high-frequency long-term/chronic training on neutrophil function and serum levels of myogenic enzymes in male university judoists. METHODS: The subjects were 24 male judoists who had stopped judo training for 6 months and then restarted their training. The following parameters were examined before and after a 2 h unified exercise loading (UEL) at the beginning of the restarted quotidian training (pre-training) and at 2 months, 4 months and 6 months thereafter: myogenic enzymes, neutrophil and leucocyte counts, and neutrophil phagocytic activity (PA) and oxidative burst activity as a measure of reactive oxygen species (ROS) production capability. RESULTS: Myogenic enzymes that were measured after UEL at all four points significantly increased except for creatine kinase at the 2-month point (p<0.01 in each) and neutrophil counts significantly increased after UEL at the pre-training, 2-month and 4-month points (p<0.01 in each), but these changes became smaller from the 2-month point. PA significantly decreased after UEL at the pre-training and 2-month points (p<0.01 in each), but no change was seen at the 4-month and 6-month points. On the other hand, no change in ROS production per cell after UEL was seen at the pre-training point, but it significantly increased after UEL at the 2-month, 4-month and 6-month points (p<0.01 in each). CONCLUSION: The changing rate of the levels of UEL-mediated myogenic enzymes, neutrophil mobilisation and neutrophil function was seen to decrease at the 2-month, 4-month and 6-month assessments, compared with the pre-training point: these may comprise at least some of the long-term training effects.

Clock and ATF4 transcription system regulates drug resistance in human cancer cell lines.

The mechanisms underlying cellular drug resistance have been extensively studied, but little is known about its regulation. We have previously reported that activating transcription factor 4 (ATF4) is upregulated in cisplatin-resistant cells and plays a role in cisplatin resistance. Here, we find out a novel relationship between the circadian transcription factor Clock and drug resistance. Clock drives the periodical expression of many genes that regulate hormone release, cell division, sleep-awake cycle and tumor growth. We demonstrate that ATF4 is a direct target of Clock, and that Clock is overexpressed in cisplatin-resistant cells. Furthermore, Clock expression significantly correlates with cisplatin sensitivity, and that the downregulation of either Clock or ATF4 confers sensitivity of A549 cells to cisplatin and etoposide. Notably, ATF4-overexpressing cells show multidrug resistance and marked elevation of intracellular glutathione. The microarray study reveals that genes for glutathione metabolism are generally downregulated by the knockdown of ATF4 expression. These results suggest that the Clock and ATF4 transcription system might play an important role in multidrug resistance through glutathione-dependent redox system, and also indicate that physiological potentials of Clock-controlled redox system might be important to better understand the oxidative stress-associated disorders including cancer and systemic chronotherapy.

Visualization of the motor activation area using SPECT in neurosurgical patients with lesions near the central sulcus.

UNLABELLED: The purpose of this study was to visualize the motor area related to finger movement and a fist-making task using SPECT in patients with lesions near the central sulcus. METHODS: Eleven patients (9 with a brain tumor, 1 with cerebral infarction, and 1 with an arteriovenous malformation) were investigated. The first intravenous injection of 99mTc-ethyl cysteinate dimer (ECD) for the motor activation SPECT images was administered 2 min after completion of the fist-making task with the hand contralateral to the brain lesion. The movement was stopped 2 min after injection, and activation SPECT was performed. After the scan, the second dose of 99mTc-ECD was injected into resting patients, and a second set of SPECT images was acquired. The first set of images was subtracted from the second set to obtain control images. Regions of interest were set bilaterally on the sensorimotor hand area; the supplementary motor area; the frontal, temporal, and occipital lobes; and the cerebellar hemispheres. The results of activation SPECT were expressed as positive or negative for a high-count area, and the regional percentage change for activation images relative to resting images was calculated. RESULTS: Visual assessment of activation images was positive in 9 patients for the sensorimotor hand area and 7 patients for the supplementary motor area. The regional percentage change between activation and resting images for the high-count areas was 19.7% for the sensorimotor hand area and 18.2% for the supplementary motor area. Both values were significantly higher than those for other areas (P<0.05). CONCLUSION: Motor activation SPECT using a 99mTc-ECD split-dose method is easy to perform and may be helpful for presurgical visualization and identification of the sensorimotor hand area or the supplementary motor area.

Effects of thromboxane synthetase inhibitor (RS-5186) on experimentally-induced cerebral vasospasm.

RS-5186, which inhibits thromboxane A2 (TXA2) synthetase activity, ameliorated delayed cerebral vasospasm in a canine two-hemorrhage model. Subarachnoid hemorrhage was induced in 15 dogs, which were divided into two groups. In the RS-5186-treated group (9 dogs), 50 mg kg-1 of RS-5186 was administered twice a day for seven days. The remaining six dogs without administration of RS-5186 were used as a control group. In the RS-5186-treated group, the angiographic diameter of the basilar artery on Day 7 after subarachnoid hemorrhage was constricted to 60.9% +/- 11.6% (n = 9, mean +/- SD) of that on Day 0, before subarachnoid hemorrhage. The corresponding value was 42.8% +/- 6.1% (n = 6) in the control group. There was a statistically significant difference between these percentages. In the RS-5186-treated group, plasma thromboxane B2 level on Day 7 was 144.3 +/- 28.1 pg ml-1 (n = 4), which was lower than the 815.5 +/- 162.0 pg ml-1 (n = 4) in the control group (p < 0.0005). The plasma 6-keto-prostaglandin F1 alpha level on Day 7 was 180.5 +/- 66.5 pg ml-1 (n = 4) in the RS-5186-treated group, and higher than 107.3 +/- 12.4 pg ml-1 (n = 4) in the control group (p = 0.0734). Thus, administration of RS-5186 reduced TXA2 plasma level and had a beneficial effect on angiographically-detected delayed vasospasm.

Isolation and characterization of the glycoprotein fraction with a proliferation-promoting activity on human and hamster cells in vitro from Aloe vera gel.

Fractions of leaf gel from Aloe barbadensis Mill. were prepared by gel permeation using DEAE Sephadex A-25, Sepharose 6B, and Sephadex G-50 columns. These were then tested by in vitro assays for proliferation of human normal dermal and baby hamster kidney cells. The glycoprotein fraction promoted cell growth, while the neutral polysaccharide fraction did not show any growth stimulation. Moreover, the polar-colored glycoprotein fraction strongly inhibited the in vitro assays. An active glycoprotein fraction (protein 82%, carbohydrate 11%) examined on polyacrylamide gel electrophoresis (PAGE) and SDS-PAGE showed a single band. Its molecular weight was 29 kD on a Sephadex G-50 column and its isoelectric point was pH 6.8. Immunoblotting after SDS-PAGE showed that the glycoprotein was composed of two subunits (14 kD). Deglycosylation of glycoprotein (Pg21-2b fraction) by trifluoromethanesulphonic acid provided a protein band with a molecular weight of 13 kD on SDS-PAGE. The colored glycoprotein fraction was shown on SDS-PAGE to be a mixture with a molecular weight of 18 kD-15 kD. It was later hydrolyzed with 10% H2SO4 to produce phenolic substances.

[Portal embolization using lipiodol-gelatin sponge].

Gelatin sponge moistened with lipiodol was prepared for use in portal embolization to improve percutaneous transhepatic portal embolization as preoperative management of patients undergoing extensive liver resection. For one sheet of gelatin sponge (20 x 60 x 7mm)0.5ml of lipiodol was used. Five sheets cut to 2mm square pieces and mixed with physiological saline solution were injected into the right portal vein. This embolic material proved safer and more reliable than gelatin sponge mixed with water-soluble contrast medium, because it provided sufficient opacification to grasp the extent of embolization and prevented back flow.

[Experimental investigation of 201TlCl-scintigraphy in evaluating therapeutic effect of hyperthermia].

We investigated the usefulness of 201Tl-scintigraphy in the evaluation of therapeutic effect of hyperthermia. Satoh's experimental lung cancer tumors implanted in the right thighs of donryu rats were treated with hyperthermia using water bath. Tumors were heated at 44 degrees C or 46 degrees C for 15 min. 201Tl-scintigraphy was obtained before, immediately after and 24 hrs after treatment. Counts ratio of the tumor to the normal muscle (T/N ratio) was measured by gamma camera. We examined blood flow of the tumor, and relative tumor growth rate, and performed autoradiogram and histopathological examination of the tumor after 201Tl-scintigraphy. Immediately after hyperthermia, T/N ratio and blood flow of the tumor significantly decreased (p < 0.05). Autoradiogram showed that the accumulation of 201TlCl in the tumor decreased diffusely. Histopathological finding showed congestion, thrombosis, and swelling of endothelial cells. These results suggest that the decrease in T/N ratio may be caused by the vascular damage due to hyperthermia. The T/N ratio recovered 24 hrs after hyperthermia but was still lower than that for the control. Autoradiogram showed that 201TlCl greatly accumulated in the viable tumor tissue but was hardly seen in the necrotic tumor tissue. These results suggest that the decrease in T/N ratio may be caused by increase of necrotic areas. The T/N ratio 24 hrs after hyperthermia correlated (r = 0.83) with relative tumor growth rate on 7th day after hyperthermia and, therefore, can be used as an indicator of relative tumor growth rate. 201Tl-scintigraphy can be useful for prediction of therapeutic effect of hyperthermia.

[A comparative clinical study on the treatment of head and neck tumors by adjuvant chemotherapy with HCFU--Second Study by Kinki Head and Neck Tumor Study Group].

In the first study by the "Kinki Head and Neck Tumor Study Group," we performed a comparative study to investigate intergroup difference between a control group consisting of patients given radical treatment only, and a HCFU group consisting of patients receiving long-term administration of HCFU after radical treatment. We earlier reported that subsequent observations by stratification revealed a favorable tendency in the cumulative disease-free rate in Stage II and Stage III patients in the HCFU group. In the second study, the same methods of treatment as in the first study were compared in a prospective control study. No differences were found between the two groups in Stage II patients. In Stage III patients, however, the disease-free rate tended to increase significantly in the HCFU group as in the first study.

[A comparative clinical study of adjuvant chemotherapy of tumors in the head and neck areas by means of HCFU].

In order to evaluate the efficacy of HCFU as an adjuvant chemotherapy agent for squamous cell carcinoma of the head and neck areas, a randomized comparative study was performed with cooperative facilities. 191 patients who had undergone radical therapy were randomly assigned to the following two groups: Group A was the control group, which underwent radical therapy only, and Group B was a group which received long-term HCFU administration (300-600 mg/day x 12 weeks or more). In the comparison of non-recurrence rate in both groups, Group B had better results among patients who were at the advanced clinical stages such as N1 through N3, Stage II (p = 0.0583) and Stage III (p = 0.0970). The adverse reactions to HCFU included pollakiuria, feverishness, and digestive symptoms, but these were mild and the recovery was possible.

[Targeting anticancer chemotherapy dispersed in lipid contrast medium in hepatoblastoma in childhood].

Fourteen cases of malignant liver tumor in childhood were experienced in our department during past 14 years. Since 1984 we have performed preoperative targeting anticancer chemotherapy using oily anticancer agents such as THP-adriamycin 30 mg/m2. These oil emulsion was making with 20 mg amounts of THP-adriamycin dissolved in 5 ml urographin and 15 ml volume of lipiodol. These mixture were administered by catheterizing the hepatic artery under X-ray monitoring in 6 cases with hepatoblastoma. Remarkable anticancer effects of this targeting chemotherapy were achieved, the serum AFP level and tumor size both showing a decrease in all cases, and the resectability of tumor showing a increase in 5 among 6 cases in comparison with 50% resectability before 1983.

[Anti-tumor promoting activities and inhibitory effects on Epstein-Barr virus activation of Shi-un-kou and its constituents].

The Kampo-prescription, Shi-un-kou, and its constituent crude drugs [Lithospermum erythrorhizon (1), Macrotomia euchroma (2) and Angelica acutiloba (3)] were assayed for their inhibitory effects on Epstein-Barr virus activation induced by the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA). The crude drugs exhibited inhibitory activity singly and in combinations. In particular, the combination of 2 and 3 yielded enhanced inhibition and lower cytotoxicity. The anti-tumor promoter activity suggested by these results was further investigated in an in vivo study, which demonstrated that Shi-un-kou markedly inhibited TPA-induced skin tumor formation in mice.

Preventive effect of a quinonyl derivative of N-acetylmuramyl dipeptide, QMDP-66, against adriamycin-induced ECG abnormalities in rats.

The effects on adriamycin cardiotoxicity of an immunoadjuvant, 2-[2-acetamido-2-deoxy-6-0-[10-(2,3-dimethoxy-5-methyl-1, 4-benzo-quinon-6-yl) decanoyl]-D-glucopyranos-3-0-yl]-D-propionyl-L-valyl D-isoglutamine methyl ester (QMDP-66), and a reference compound, ubiquinone-10, were studied in Wistar Kyoto (WKY) rats. Adriamycin, 1 mg/kg/day intra-peritoneally (i.p.) for 23 days, elicited cardiotoxicity, as judged by widening of the QRS complexes in ECGs. Electron microscopic examination of myocytes from the treated rats revealed many cytoplasmic vacuoles possibly originating from deranged endoplasmic reticula or mitochondria. In addition, the treatment significantly inhibited body weight gain, and decreased ventricular weight. QMDP-66 alone, 1 mg/kg/day i.p. for 23 days, had no effect on the parameters described above. When QMDP-66 (1 mg/kg/day, i.p.) or ubiquinone-10 (3 mg/kg/day, i.p.) was administered together with adriamycin, the widening of the QRS complexes was significantly depressed, and cytoplasmic vacuoles in myocytes were rarely observed. The QMDP-66 or ubiquinone-10 treatment, however, did not alleviate the decrease in body weight gain or ventricular weight due to adriamycin. Heart rate was not significantly changed by any of the treatments. These findings suggest that QMDP-66 is an effective antidote against adriamycin cardiotoxicity.