Impact of radiation dose on locoregional control and survival on squamous cell carcinoma of anal canal

Purpose

To perform a systematic analysis of clinical data of presentation, treatment, outcome, toxicity, survival and other associated prognostic factors of the patients of anal canal who received treatment at our hospital.

Methods and materials

The medical records of 257 patients treated with radiotherapy with or without chemotherapy from the year 1985 to 2005 were studied.

Results

Median follow-up was 36 months. Complete clinical response after radiotherapy was 74.4% in the whole group. The 5 years overall (OAS) and disease-free (DFS) survival for the whole group was 71.5% and 61%, respectively. Patients with T1-2 tumors which received the radiation dose between 55 and 60 Gy had superior locoregional control, DFS and OAS. Similarly T3-4 tumors receiving radiation dose more than 60 Gy independently improved the locoregional control, DFS and OAS irrespective of the nodal status and addition of chemotherapy.

Conclusions

Radiation dose of 56-60 Gy for T1 and T2 and 65 Gy for T3 and T4 tumors along with concurrent chemotherapy is required to achieve better local control, disease-free survival and overall survival, with acceptable toxicity.     

Amenorrhea in premenopausal women on the doxorubicin-and-cyclophosphamide-followed-by-docetaxel arm of NSABP B-30 trial

The NSABP B-30 trial addresses whether amenorrhea after adjuvant chemotherapy increases survival. Preliminary to the trial outcome analysis, we examined the incidence of amenorrhea and its relationship to symptoms and quality of life (QOL) in the standard-care arm of this adjuvant breast cancer trial. Premenopausal women treated on the doxorubicin-and-cyclophosphamide-followed-by-docetaxel arm were included. Questionnaires assessing menstrual history, QOL, and symptoms were administered at baseline, day 1 of cycle 4 (or 9 weeks from start of chemotherapy for those who stopped chemotherapy early), and at 6, 12, and 24 months. Seven hundred and eight patients were evaluable for the analysis, with median potential follow-up of 57.5 months. Of these, 321 patients also participated in the QOL substudy. Of the 708 patients, 83% reported ≥1 episode of amenorrhea for ≥6 months. The estimated rate of resumption of menses at 24 months was 45.3% for women <40 years, 10.9% for women 40–50, and 3.2% for women >50 years. Those treated with tamoxifen were more likely to become amenorrheic (p = 0.003). Menstrual status was not significantly associated with QOL or symptoms. Prolonged amenorrhea is associated with a regimen that contains doxorubicin, cyclophosphamide, and docetaxel, and is age dependent and impacted by tamoxifen use. Vasomotor symptoms are common in this patient population but are not associated with menstrual status. These results can be used to inform premenopausal women about the risk and time course of amenorrhea associated with this common adjuvant therapy regimen, along with the effects on symptoms and QOL. This work represents original research by the authors. Previously presented at ASCO 2005 as a poster (abstr # 537).     

尿中麻黄碱类药物的气相色谱检测法

麻黄碱及其类似物有兴奋作用,属体育比赛禁用药。这类化合物的化学结构相似,故有相似的鉴别特征。本文报道了以气相色谱对尿中麻黄碱(ephedrine)、甲基麻黄碱(methylephedrine)、乙基麻黄碱(ethylephedrine)、去甲麻黄碱(norephedrine)及去甲伪麻黄碱(cathine)进行检测,最后以气质联用法进行确证。本法操作简便,灵敏度高,结果可靠。     

Mouse mammary tumor-like virus is associated with p53 nuclear accumulation and progesterone receptor positivity but not estrogen positivity in human female breast cancer.

PURPOSE: The purpose is to compare the presence of proteins with known associations with breast cancer-progesterone receptor (PgR), estrogen receptor, and p53, with the prevalence of mouse mammary tumor virus (MMTV)-like DNA sequences in human female breast cancers. EXPERIMENTAL DESIGN: A cohort of 128 Australian female breast cancers were screened for MMTV-like DNA sequences using PCR. The presence of PgR, estrogen receptor, and nuclear accumulation of p53 protein was assessed in the same samples using immunohistochemical staining. RESULTS: Nuclear accumulation of p53 was significantly more prevalent (P = 0.05) in archival human breast cancers containing MMTV-like DNA sequences. The presence of progesterone receptor was significantly higher in MMTV-positive than MMTV-negative breast cancers (P = 0.01). No correlation between estrogen receptor and MMTV-like DNA sequences was found. CONCLUSIONS: MMTV causes breast cancer in mice, and hormones up-regulate expression of virus in mice mammary tissue. It is unknown if this is the case in human breast cancers shown to contain DNA of MMTV-like viruses. The positive association between MMTV-like DNA sequences and PgR indicates hormones and MMTV may play a role in human breast cancer. Mutations of the tumor suppressor gene p53 are common in human breast cancer and are associated with higher grades of cancer. The association of MMTV-like DNA sequences with higher grades of cancer, and the positive association between p53 and MMTV-like DNA sequences clearly warrant additional investigation.     

月橘烯碱抗着床作用及其激素活性的研究

小鼠于妊娠第1～3天,po或sc月橘烯碱(yuehchukene)2mg或4mg/kg·d有明显的抗着床作用。金黄地鼠于妊娠1～3天,sc月橘烯碱4mg/kg·d却无此作用。月橘烯碱有明显的雌激素活性,与雌二醇合用有协同作用。该化合物无雄激素或抗雄激素活性;无孕激素或抗孕激素活性。放射受体竞争实验测得月橘烯碱对[³H]-雌二醇与雌激素受体特异性结合抑制50%的浓度(IC₅₀)为4.2×10^-6mol/L,表观解离常数(KI)为1.24×10^-6mol/L。说明月橘烯碱与雌激素受体有一定的亲和力。     

The Effect of Denture Cleansing Solutions on the Retention of Yellow Hader Clips: An In Vitro Study

PURPOSE: To evaluate the retention of yellow Hader clips after exposure to various denture cleansers. METHODS: Seven groups of 18 yellow Hader clips each were soaked for the equivalent of 6 months of clinical use in the following denture cleansing solutions: Polident Regular, Polident Overnight, Efferdent, 5.25% Sodium Hypochlorite (NaOCl, 1:10 dilution) 15 min/day, NaOCl (1:10 dilution) 8 hours/day, water and dry (control) group. A Universal Testing Machine, set at a crosshead speed of 2 in/min, pulled each clip once, and the peak load-to-dislodgement was recorded and used as a measure to reflect changes in the retention of the Hader clips. Data were analyzed by a one-way analysis of variance followed by Tukey's HSD test. A p value < or = 0.05 was considered significant. RESULTS: Denture cleansing solutions affected the retentive values of yellow Hader clips (F= 6.102, p< or = .0001). Sodium hypochlorite solution, 15 min/day for 6 months, caused an increase in the retentive values of the clips tested with a mean peak load-to-dislodgement of 22.63 +/- 1.29 N. In addition, clips soaked in water showed no difference in retentive values when compared with all other groups. Furthermore, Polident Regular, Polident Overnight, Efferdent, and NaOCl (8 hours/day) had no effect on the retentive values of yellow Hader clips. CONCLUSION: This in vitro study demonstrated that the retention of yellow Hader clips used in implant overdentures is unaffected when soaked in commercial effervescent denture cleansers (Polident 5 Minute, Polident Overnight, and Efferdent) for six simulated months. Sodium hypochlorite statistically increased the single-pull retentive values of the clips, an effect that may not be beneficial. Increased retentive values may be associated with reduced durability of clips; further research is needed to address this issue.     

Weight Loss May Reverse Blunted Sympathetic Neural Responsiveness to Glucose Ingestion in Obese Subjects With Metabolic Syndrome

OBJECTIVE

The purpose of this study was to examine the effects of weight loss on sympathetic nervous system responsiveness to glucose ingestion in obese subjects with metabolic syndrome, in whom such responses are reportedly blunted.

RESEARCH DESIGN AND METHODS

Thirty four subjects, 19 insulin resistant and 15 insulin sensitive and aged 55 ± 1 years (mean ± SE) with BMI 31.6 ± 0.6 kg/m², who fulfilled the Adult Treatment Panel III criteria for metabolic syndrome participated. Simultaneous measurements of whole-body norepinephrine spillover rate, calf blood flow, and intra-arterial blood pressure were made at times 0, 30, 60, 90, and 120 min postglucose (75 g). The experiment was repeated after a 3-month hypocaloric diet with or without an exercise program.

RESULTS

Body weight decreased by 8.1 ± 0.9 and 8.4 ± 1.1 kg and resting norepinephrine spillover by 94 ± 31 and 166 ± 58 ng/min (all P ≤ 0.01) in insulin-resistant and insulin-sensitive subjects, respectively. Weight loss was accompanied by a marked increase in sympathetic responsiveness after glucose but only in insulin-resistant subjects. In this subgroup, comparative increases in norepinephrine spillover rates at baseline and after weight loss averaged −3 ± 25 versus 73 ± 24 ng/min at 30 min (P = 0.039), 36 ± 21 versus 115 ± 28 ng/min at 60 min (P = 0.045), 9 ± 21 versus 179 ± 50 ng/min at 90 min (P < 0.001), and 40 ± 48 versus 106 ± 39 ng/min at 120 min (P = 0.24).

CONCLUSIONS

Weight loss reverses blunted sympathetic responsiveness to glucose ingestion in insulin-resistant subjects with metabolic syndrome, which is relevant to postprandial energy utilization and body weight homeostasis.There is much evidence to indicate that the sympathetic nervous system (SNS) is activated by food intake and particularly by carbohydrate ingestion (1–3). Oral glucose elicits a marked and sustained increase in SNS activity over a 2-h period in healthy humans, as assessed by measurements of plasma norepinephrine concentration, by regional norepinephrine spillover, and by direct microneurographic recordings of muscle sympathetic nerve activity (MSNA) (1–3). At least two mechanisms are thought to contribute to this neurophysiological response: the postprandial increase in plasma insulin and the entrance of a nutrient into the gastrointestinal tract (4). Insulin exerts its sympathoexcitatory effects either directly by facilitating central sympathetic outflow or indirectly by activation of the baroreceptor reflex in response to its peripheral vasodilatory effects (5). The observation that C-peptide–negative diabetic patients retain a blunted MSNA responsiveness to oral glucose, even in the absence of endogenous insulin (6), suggests that insulin-independent factors such as hemodynamic adjustment to splanchnic vasodilation and gastrointestinal distension may also contribute to sympathetic activation after carbohydrate ingestion (4). Postprandial SNS stimulation is physiologically important in the regulation of facultative thermogenesis or the rise in energy expenditure after dietary intake (7).A growing body of data suggests that obesity and the insulin-resistant state are accompanied by impaired sympathetic neural responsiveness to physiological hyperinsulinemia, glucose ingestion, and changing energy states. Vollenweider et al. (8) showed that in lean young subjects MSNA increased by 94% in response to euglycemic hyperinsulinemia, whereas in age-matched obese subjects the increase was only 9%. MSNA responses to oral glucose are diminished in insulin-resistant Pima Indians (9), and short-term under- and overfeeding is accompanied by blunted sympathetic responsiveness in obese subjects (10). The metabolic syndrome is an increasingly prevalent multidimensional risk factor for cardiovascular disease and type 2 diabetes. Several indexes of SNS activity, such as norepinephrine spillover from sympathetic nerves and MSNA at rest, are known to be increased in subjects with the metabolic syndrome even in the absence of hypertension (11,12). We have recently demonstrated that obese insulin-resistant subjects with metabolic syndrome have both blunted and delayed norepinephrine spillover and MSNA responses to oral glucose compared with obese insulin-sensitive subjects with metabolic syndrome (13). Sympathetic responsiveness related inversely to measures of central adiposity and the insulin response and positively to fitness level (13).Weight loss and exercise are recommended as first-line treatments for the metabolic syndrome, and both lifestyle modalities are known to reduce SNS activity and improve metabolic syndrome components (11). No study to date has examined whether weight loss alters the dynamic sympathetic neural response to glucose ingestion. The aims of the present investigation were twofold: 1) to test the hypothesis that weight loss would reverse the blunted SNS response to glucose in obese individuals with metabolic syndrome and 2) to compare the benefits of weight loss in insulin-resistant and insulin-sensitive subjects. To accomplish these aims, we simultaneously measured plasma glucose, insulin, leptin, whole-body norepinephrine kinetics, calf blood flow, intra-arterial blood pressure, and heart rate during a standard oral glucose tolerance test (OGTT) at baseline and after a 12-week weight loss program.     

Immunological cell type characterization and Th1-Th17 cytokine production in a mouse model of Gaucher disease

Gaucher disease is a lysosomal storage disease resulting from insufficient acid β-glucosidase (glucocerebrosidase, GCase, EC 4.2.1.25) activity and the resultant accumulation of glucosylceramide. Macrophage (M?) lineage cells are thought to be the major disease effectors because of their secretion of numerous cytokines and chemokines that influence other poorly defined immunological cell populations. Increases in several such populations were identified in a Gba1 mouse model (D409V/null; 9V/null) of Gaucher disease including antigen presenting cells (APCs), i.e., M?, dendritic cells (DCs), neutrophils (PMNs), and CD4(+) T cells. FACS analyses showed increases in these cell types in 9V/null liver, spleen lung, and bone marrow. T-cells or APCs enhanced activations were evident by positivity of CD40L, CD69, as well as CD40, CD80, CD86, and MHCII on the respective cells. M?, and, unexpectedly, DCs, PMNs, and T cells, from 9V/null mice showed excess glucosylceramides as potential bases for activation of APCs and T cells to induce Th1 (IFNγ, IL12, TNFα,) and Th17 (IL17A/F) cytokine production. These data imply that excess glucosylceramides in these cells are pivotal for activation of APCs and T cell induction of Th1 and Th17 responses and PMN recruitment in multiple organs of this model of Gaucher disease.