Purpose Skin metastases of breast cancer remain a therapeutic challenge. Toll-like receptor 7 agonist imiquimod is an immune response modifier and can induce immune-mediated rejection of primary skin malignancies when topically applied. Here we tested the hypothesis that topical imiquimod stimulates local anti-tumor immunity and induces the regression of breast cancer skin metastases. Methods A prospective clinical trial was designed to evaluate the local tumor response rate of breast cancer skin metastases treated with topical imiquimod, applied 5 days/week for 8 weeks. Safety and immunological correlates were secondary objectives. Results Ten patients were enrolled and completed the study. Imiquimod treatment was well tolerated, with only grade 1-2 transient local and systemic side effects consistent with imiquimod's immunomodulatory effects. Two patients achieved a partial response (20%; 95% CI 3% - 56%). Responders showed histological tumor regression with evidence of an immune-mediated response, demonstrated by changes in the tumor lymphocytic infiltrate and locally produced cytokines. Conclusion Topical imiquimod is a beneficial treatment modality for breast cancer metastatic to skin/chest wall and is well tolerated. Importantly, imiquimod can promote a pro-immunogenic tumor microenvironment in breast cancer. Preclinical data generated by our group suggest even superior results with a combination of imiquimod and ionizing radiation and we are currently testing in patients whether the combination can further improve anti-tumor immune and clinical responses.

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: A randomized, double-masked, placebo-controlled study was designed to compare dexmedetomidine as a primary sedative agent with a commonly used drug combination in patients undergoing awake carotid endarterectomy (CEA). Sixty-six patients undergoing CEA (ASA II-IV) were randomly assigned to receive either dexmedetomidine (total dose of 97.5 +/- 54.7 mcg) or normal saline (control). Supplemental doses of midazolam, fentanyl, and/or propofol were administered as deemed necessary by the anesthesiologist. An observer blinded to the study drug assessed sedation level (Observer's Assessment of Alertness-Sedation [OAA/S] scale). The primary outcomes were defined as the number of patients with an OAA/S score of 4 intraoperatively and an OAA/S score of 5 postoperatively. The authors also compared cardiorespiratory parameters, intra- and postoperative side effects, and complications. Chi-square tests were used to analyze the primary endpoints. All secondary parameters were analyzed using the Wilcoxon rank sum test. Three patients in the dexmedetomidine group (10%) had an OAA/S score of 4 at all four time points assessed intraoperatively, while no patient in the control group had a score of 4 at all the time points considered. Thirteen patients in the dexmedetomidine group had a score of 4 at three or more time points (42%) compared with six patients (19%) in the control group. Four patients in the control group (13%) and one patient in the dexmedetomidine group (3%) did not achieve a score of 4 at any of the four critical intraoperative time points (chi for association = 9.9, P < 0.05; chi for a trend = 8.6, P < 0.004, with the trend favoring dexmedetomidine). More patients in the control group required treatment with metoprolol (26% vs. 6%, P = 0.04) and labetalol (48% vs/ 6%, P < 0.01). Plasma levels of norepinephrine were significantly lower in the dexmedetomidine group during and after surgery compared with the control group. Six patients (19%) in the dexmedetomidine group required intra-arterial shunts, while only two patients (6%) required shunts in the control group (P = 0.16). These data show that the use of dexmedetomidine in patients undergoing awake CEA resulted in fewer fluctuations from the desired sedation level. Patients receiving dexmedetomidine required less antihypertensive therapy compared with the midazolam/fentanyl/propofol combination. The effect of dexmedetomidine on cerebrovascular circulation in the study population needs further investigation.

tended to develop 5-year mortality rates. Accumulation of a total of 349 deaths, 149 of them sudden (deaths within minutes in the absence of symptoms or signs of acute MI), permits both examination of course of disease over the longer period and more detailed study of the role of specified qualitative features of the ventricular premature complexes in relation to risk of sudden death. MethodsOver a period of almost 4 years (March 1972 through December 1975, 2155 CHD patients were identified from a population of 120,000 men ages 35-74 years, insured in HIP, a prepaid group-practice plan providing comprehensive medical services. Standard baseline observations included interviews to establish personal characteristics and medical history, physical examination and laboratory determinations, a 12-lead ECG and 1 hour of single-lead ECG monitoring recorded on tape. A baseline examination was performed in 87% of the men identified as potential study subjects from case-finding procedures. Of those examined, 83% satisfied the study criteria for CHD12 and entered the follow-up phase of the study. Of these, 1739 men had had at least one MI before the baseline date and 416 had had unequivocal effort angina in the absence of historical or ECG evidence of MI.Computer processing of the monitoring tapes produced writeouts on ECG paper of all possibly abnormal beats. Double reading these sections by trained technicians and physicians then provided the basis for classification of patients by ventricular ectopic activity during the monitoring hour. Details of the method and data on validation have been published.7, 13 Follow-up of all patients is now complete, and mortality status as of the last observation due before April 1, 1978 is known for all patients. The final data, presented for the MI patients in this report, are based on an average observation period of 3.5 years. Patients have been followed for mortality up to periods of 5.5 years,