Breast conservation and prolonged chemotherapy for locally advanced breast cancer: the University of Michigan experience

PURPOSE: To determine whether breast conservation and prolonged neoadjuvant chemotherapy have efficacy in locally advanced breast cancer (LABC), as measured by survival and rate of breast conservation. MATERIALS AND METHODS: Eighty-nine patients with stage III disease were enrolled at the University of Michigan (UM) onto a prospective nonrandomized trial. Patients received nine 21-day cycles of neoadjuvant chemohormonal therapy that consisted of doxorubicin 30 mg/m2 and cyclophosphamide 750 mg/m2 intravenously on day 1, conjugated estrogens 0.625 mg orally twice daily on days 6 to 8, methotrexate 40 mg/m2 and fluorouracil 500 mg/m2 intravenously on day 8, and tamoxifen 10 mg orally twice daily on days 9 to 14. Patients with a negative biopsy received radiation only, while those with residual disease underwent mastectomy and postoperative radiotherapy. Eight more cycles of chemohormonal therapy were administered after local-regional therapy. RESULTS: The clinical response rate to neoadjuvant therapy was 97%, 28% of patients had a complete pathologic response evaluated at biopsy. Five-year overall and disease-free survival probabilities were 54% and 44%, respectively. The median disease-free survival time was 2.4 years. The 5-year actuarial rates of local-regional control with local failure as only first failure were 82% and 78% following radiotherapy, and mastectomy and radiotherapy, respectively (P = .99). CONCLUSION: Prolonged neoadjuvant chemohormonal therapy and biopsy-driven local therapy have efficacy in LABC, with 28% of patients being candidates for breast conservation and a 5-year overall survival rate of 54%.     

Effect of grain-boundary crystallization on the high-temperature strength of silicon nitride

Si₃N₄ specimens having the composition 88.7 wt% Si₃N₄-4.9wt% SiO₂-6.4wt% Y₂O₃ (85.1 mol% Si₃N₄-11.1 mol% SiO₂-3.8mol% Y₂O₃) were sintered at 2140° C under 25 atm N₂ for 1 h and then subjected to a 5 h anneal at 1500° C. Crystallization of an amorphous grainboundary phase resulted in the formation of Y₂Si₂O₇. The short-time 1370° C strength of this material was compared with that of material of the same composition having no annealing treatment. No change in strength was noted. This is attributed to the refractory nature of the yttrium-rich grain-boundary phase (apparently identical in both glassy and crystalline phases) and the subsequent domination of the failure process by common processing flaws.Chemical analysis of the medium indicated 5.25 wt% O₂, 0.46 wt% C, 0.8 wt% Al, and expressed in p.p.m. 670 Ca, 30 Cu, 2000 Fe, <2 Ti, 370 Cr, 130 Mg, 90 Mn, <10 V, <20 Zr, 2000 Mo, 240 Ni, 130 Zn, <30 Pb, <60 Sn.     

Specific sleepiness symptoms are indicators of performance impairment during sleep deprivation

Drivers are not always aware that they are becoming impaired as a result of sleepiness. Using specific symptoms of sleepiness might assist with recognition of drowsiness related impairment and help drivers judge whether they are safe to drive a vehicle, however this has not been evaluated. In this study, 20 healthy volunteer professional drivers completed two randomized sessions in the laboratory – one under 24 h of acute sleep deprivation, and one with alcohol. The Psychomotor Vigilance Task (PVT) and a 30 min simulated driving task (AusEdTM) were performed every 3–4 h in the sleep deprivation session, and at a BAC of 0.00% and 0.05% in the alcohol session, while electroencephalography (EEG) and eye movements were recorded. After each test session, drivers completed the Karolinska Sleepiness Scale (KSS) and the Sleepiness Symptoms Questionnaire (SSQ), which includes eight specific sleepiness and driving performance symptoms. A second baseline session was completed on a separate day by the professional drivers and in an additional 20 non-professional drivers for test–retest reliability. There was moderate test–retest agreement on the SSQ (r = 0.59). Significant correlations were identified between individual sleepiness symptoms and the KSS score (r values 0.50–0.74, p < 0.01 for all symptoms). The frequency of all SSQ items increased during sleep deprivation (χ² values of 28.4–80.2, p < 0.01 for all symptoms) and symptoms were related to increased subjective sleepiness and performance deterioration. The symptoms “struggling to keep your eyes open”, “difficulty maintaining correct speed”, “reactions were slow” and “head dropping down” were most closely related to increased alpha and theta activity on EEG (r values 0.49–0.59, p < 0.001) and “nodding off to sleep” and “struggling to keep your eyes open” were related to slow eye movements (r values 0.67 and 0.64, p < 0.001). Symptoms related to visual disturbance and impaired driving performance were most accurate at detecting severely impaired driving performance (AUC on ROC curve of 0.86–0.91 for detecting change in lateral lane position greater than the change at a BAC of 0.05%). Individual sleepiness symptoms are related to impairment during acute sleep deprivation and might be able to assist drivers in recognizing their own sleepiness and ability to drive safely.     

Hypoxia impairs vasodilation in the lung

Alveolar hypoxia causes pulmonary vasoconstriction; we investigated whether hypoxia could also impair pulmonary vasodilation. We found in the isolated perfused rat lung a delay in vasodilation following agonist-induced vasoconstriction. The delay was not due to erythrocyte or plasma factors, or to alterations in base-line lung perfusion pressure. Pretreating lungs with arachidonic acid abolished hypoxic vasoconstriction, but did not influence the hypoxia-induced impairment of vasodilation after angiotensin II, bradykinin, or serotonin pressor responses. Progressive slowing of vasodilation followed angiotensin II-induced constriction as the lung oxygen tension fell progressively below 60 Torr. KCl, which is not metabolized by the lung, caused vasoconstriction; the subsequent vasodilation time was delayed during hypoxia. However, catecholamine depletion in the lungs abolished this hypoxic vasodilation delay after KCl-induced vasoconstriction. In lungs from high altitude rats, the hypoxia-induced vasodilation impairment after an angiotensin II pressor response was markedly less than it was in lungs from low altitude rats. We conclude from these studies that (a) hypoxia impairs vasodilation of rat lung vessels following constriction induced by angiotensin II, serotonin, bradykinin, or KCl, (b) hypoxia slows vasodilation following KCl-induced vasoconstriction probably by altering lung handling of norepinephrine, (c) the effect of hypoxia on vasodilation is not dependent on its constricting effect on lung vessels, (d) high altitude acclimation moderates the effect of acute hypoxia on vasodilation, and (e) the hypoxic impairment of vasodilation is possibly the result of an altered rate of dissociation of agonists from their membrane receptors on the vascular smooth muscle.