Early breast cancer: predictors of breast recurrence for patients treated with conservative surgery and radiation therapy

The identification of factors associated with breast recurrence following conservative surgery (CS) and radiation therapy (RT) is of potential use in refining patient selection criteria and treatment technique. In an attempt to define such factors we examined the relationship between various clinical, pathologic and treatment characteristics and the likelihood of breast recurrence in 783 patients with clinical stage I or II breast cancer treated between July 1968 and December 1982. Treatment consisted of complete gross excision of the primary tumor and RT to a total dose of at least 60 Gy to the primary site. During this period, pre-treatment mammograms and detailed histologic assessment of the margins of resection were not routinely performed. Median follow-up for surviving patients was 80 months. Thirteen patients (1.6%) were lost to follow-up. Ninety-one patients (12%) have developed a breast recurrence, corresponding to 5- and 10-year actuarial rates of 10 and 18%, respectively. The major feature associated with breast recurrence was the presence of an "extensive intraductal component" (EIC+). An EIC+ tumor was seen in 28% of evaluable cases with infiltrating ductal carcinoma and accounted for 60% of breast recurrences. Forty-three of 166 patients (26%) with EIC+ tumors developed a breast recurrence compared with 29 of 418 patients (7%) without an EIC (EIC-) (p = 0.0001). The 5-year actuarial rates of breast relapse were 24 and 6%, respectively (p = 0.0001). Very young age (defined as 34 years of age or younger) was also a significant factor associated with the risk of breast recurrence. Very young patients comprised 8% of the patient population and accounted for 16% of breast recurrences. Fifteen of 61 very young patients (25%) developed a breast recurrence compared with 76 of 722 older patients (11%) (p = 0.001). The corresponding 5-year actuarial rates of breast recurrence were 21 and 9% (p = 0.005). None of the other clinical or pathological factors examined by univariate analysis were significantly correlated with recurrence in the breast. A multivariate model of site of first failure (polychotomous logistic regression) also showed that EIC+ tumors and very young age were the main factors associated with a high relative risk of breast recurrence. We conclude that EIC+ tumors and very young age are associated with a high risk of breast recurrence for patients treated with limited excision prior to RT.     

Effects of dietary fish oil on fatty acids and eicosanoids in metastasizing human breast cancer cells

We examined the relationships between the suppressive effects of dietary fish oil on growth and metastasis of MDA-MB-435 human breast cancer cells in female nude mice and the primary tumor phospholipid fatty acid concentrations, phospholipase A2 activity, and eicosanoid levels. Mice (n = 120) were fed a 23% (wt/wt) corn oil (CO) linoleic acid (LA)-rich diet for seven days before and after 10(6) tumor cells were injected into a mammary fat pad, and then the mice receive one of three isocaloric diets containing 23% total fat but different proportions of CO and menhaden oil (MO) (18% CO-5% MO, 11.5% CO-11.5% MO, 5% CO-18% MO) or a 23% fat diet containing 18% deodorized fish oil supplemented with tocopherol and tert-butylhydroquinone antioxidants (FAO). Primary tumor growth rate was significantly greater in mice fed the 18% CO diet than in the three diets containing higher levels of fish oil (all p < 0.05). The 18% MO diet, but not the 11.5% MO or the 18% FAO diet, suppressed the development of lung metastases compared with the 18% CO diet. Increasing the proportion of MO relative to CO in the diets produced corresponding increases in the primary tumor phospholipid eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) concentrations and reductions in LA and arachidonic acid. There was a significant positive correlation between the LA concentration in these tumors and the extent of lung metastasis (r = 0.504). Tumor phospholipase A2 activity was unaffected by dietary MO intake. Prostaglandin E2 concentration was inversely correlated with phospholipid EPA (r = -0.484) and DHA (r = -0.439), but there was no relationship with lung metastasis. Tumor leukotriene B4 and 5-hydroxyeicosatetraenoic acid levels were not reduced by dietary MO. The 18% FAO- and the 18% MO-fed mice showed similar relationships for the phospholipid fatty acids and prostaglandin E2, despite the lack of effect on metastasis. The strong correlation between phospholipid LA levels and metastasis and the lack of an association with tumor eicosanoids suggest that the 18% MO diet inhibited metastasis because dietary LA was replaced by other fatty acids.     

Lack of microsatellite instability in human prostate-cancer

DNA replication errors are especially frequent in repetitive DNA sequences, including microsatellites. Thus, microsatellites are sensitive indicators of the genetic instability observed in many types of human cancers, particularly colorectal cancer. We tested prostate carcinomas for the presence of microsatellite alleles not present in normal tissue from the same individuals. Analysis of 7 microsatellites in each of 30 patients revealed instability at only one microsatellite in one tumor. This level of microsatellite instability, considerably lower than that reported previously, may reflect differences in patient pools. We discuss the implications of the genetic stability of prostate cancers relative to other cancers.     

CD18-mediated neutrophil recruitment contributes to the pathogenesis of reperfused but not nonreperfused stroke

BACKGROUND AND PURPOSE: Neutrophil (PMN) recruitment mediated by increased expression of intercellular adhesion molecule-1 expression (ICAM-1, CD54) in the cerebral microvasculature contributes to the pathogenesis of tissue injury in stroke. However, studies using blocking antibodies against the common beta2-integrin subunit on the PMN, the counterligand for ICAM-1 (CD18), have demonstrated equivocal efficacy. The current study tested the hypothesis that mice deficient in CD18 would be protected in the setting of reperfused but not nonreperfused stroke. METHODS: Two groups of mice were studied, those whose PMNs could express CD18 (CD18 +/+) and those mice hypomorphic for the CD-18 gene (CD18 -/-). PMNs obtained from CD18 -/- or CD18 +/+ mice were fluorescently labeled and tested for binding to murine brain endothelial monolayers. Using a murine model of focal cerebral ischemia in which an occluding suture placed in the middle cerebral artery (MCA) is removed after 45 minutes (transient ischemia, reperfused stroke) or left in place (permanent ischemia, nonreperfused stroke), cerebral infarct volumes (% ipsilateral hemisphere by TTC staining), cerebral blood flow (CBF, % contralateral hemisphere by laser-Doppler flowmetry), and survival (%) were examined 24 hours after the initial ischemic event. Adoptive transfer studies used 111In-labeled PMNs (from either CD18 +/+ or CD18 -/- mice) to examine the relative accumulation of PMNs in the ischemic region. RESULTS: PMNs obtained from CD18 -/- mice exhibit reduced adhesivity (compared with CD18 +/+ PMNs) for both quiescent and cytokine-activated endothelial monolayers. CD18 -/- mice (n=14) subjected to transient focal cerebral ischemia demonstrated a 53% decrease in infarct volumes versus CD18 +/+ mice (n=26, P<0.05), improved penumbral CBF at 24 hours (1.8-fold, P=0.02), and a 3.7-fold decrease in mortality (P=0.02). However, when CD18 -/- mice (n=12) were subjected to permanent focal cerebral ischemia, no differences were noted in infarct volume, mortality, or CBF versus similarly treated CD18 +/+ mice (n=10). There was a greater accumulation of CD18 +/+ PMNs in the ischemic zone of CD18 +/+ animals than CD18 -/- animals subjected to reperfused stroke (82% increase, P=0.02), although there was no difference between groups when subjected to permanent MCA occlusion. CONCLUSIONS: Deficiency for the CD18 gene confers cerebral protection in a murine model of reperfused stroke, but this benefit does not extend to CD18-deficient animals subjected to permanent MCA occlusion. These data suggest that anti-PMN strategies should be targeted to reperfused stroke and may perhaps be used in conjunction with thrombolytic therapy that establishes reperfusion.     

Laparoscopic Splenectomy

Splenectomy is a powerful tool for treatment of hematologic disease, with 70% to 90% of patients achieving long-term improvement. In recent years laparoscopic splenectomy has gained acceptance as a viable alternative to open splenectomy. This review summarizes the indications for laparoscopic splenectomy, the operative techniques, and the most recent results. Laparoscopic splenectomy is evolving and may become the standard operative method for the treatment of the problem spleen.     

Evaluating problem-based learning in a multilingual student population

OBJECTIVES: The University of Natal Medical School in South Africa provides training for a student body composed of two groups: one with English as a first language and the other with an African language as a first language and English as the second. A new methodology was developed to evaluate an innovative course using modified problem-based learning techniques in this heterogeneous environment. DESIGN: The learning model proposed required achieving a balance of three components: content, enquiry/learning process and social interaction/group process. A multidimensional system, felt to be consistent with this educational philosophy, was developed using seven different quantitative and qualitative techniques. SETTING: The University of Natal Medical School. SUBJECTS: First-year multilingual medical students. RESULTS: The results revealed that social interaction was highly successful in reducing barriers between the student groups and between students and facilitators. However, the emphasis on group participation may have overshadowed the enquiry process, leading to superficial discussions of problems and feelings of repetitiveness. During the course students and facilitators expressed concern that the innovative assessments used did not assess the course content adequately. While the group presentations and projects were useful exercises for consolidation and group interaction, they did not enable facilitators to identify struggling students. CONCLUSIONS: The outcome of the evaluation stressed the need of achieving an appropriate balance both in the curriculum and assessments of the three components of the learning model, particularly in a setting where student backgrounds and language ability differ. Multidimensional methodology is needed for effective evaluation that promotes critical reflection.     

The effect of therapy on the concentration and occupancy of androgen receptors in human prostatic cytosol

With a protamine sulphate precipitation method, total and free cytosol AR was assayed in BPH and prostatic carcinoma tissue, in order to investigate possible differences in AR concentration that might relate to the histo-pathology of the tissue or to endocrine manipulation of the patients. Similar ranges of total cytosol AR concentrations were observed in BPH and untreated prostatic carcinoma, but the latter tended to have a higher proportion of apparently free sites. Moreover, the proportion of "free" sites in the untreated carcinoma tissue appeared to be related to the proportion of poorly differentiated carcinoma in the specimen. In patients whose endogenous androgen levels had been lowered by treatment, the proportion of free sites tended to be higher, but a considerable proportion of sites appeared to be still occupied. Carcinoma tissue from some estrogen-treated patients had high cytosol AR concentrations. It is suggested that, in some treated patients, androgens of adrenal origin may occupy some AR sites and that some carcinomas may contain a considerable concentration of nonfunctional AR.     

Jefferson fracture resulting in Collet-Sicard syndrome

STUDY DESIGN: A case report and review of the literature. OBJECTIVE: To increase awareness of and add to the spectrum of injury that can result from Jefferson fractures, to suggest a possible mechanism of injury, and to give a brief review of pertinent facts regarding C1 burst fractures and the Collet-Sicard Syndrome. SUMMARY OF BACKGROUND DATA: To the author's knowledge, this is the first reported case of a Jefferson fracture resulting in Collet-Sicard Syndrome. It represents only the second reported case of cranial nerve palsy caused by Jefferson fracture. METHODS: A 56-year-old man sustained a C1 burst fracture in a rollover motor vehicle accident. Repeated neurologic examinations over the ensuing days revealed lesions of cranial nerves IX, X, XI, and XII on the left side. RESULTS: Two weeks of traction, 10 weeks in a halo vest, and 2 weeks in a cervical collar resulted in adequate fracture healing and almost complete resolution of the patient's neurologic symptoms. CONCLUSION: Although this is the first reported case of Collet-Sicard Syndrome caused by Jefferson fracture, the authors' review of the literature suggests that cranial nerve injuries may go unrecognized in some patients with C1 burst fractures. The importance of a thorough neurologic examination, including examination of the cranial nerves, in all cases of cervical spine injury cannot be overemphasized.     

Radiographic evidence and surgical confirmation of a saccular aneurysm on a hypoplastic duplicated A1 segment of the anterior cerebral artery: case report

OBJECTIVE AND IMPORTANCE: True duplication of the A1 segment of the anterior cerebral artery is extremely rare, as is finding a true A1 segment saccular aneurysm. We report the angiographic and surgical findings of such a case with the additional association of a hypoplastic ipsilateral M1 segment of the middle cerebral artery. CLINICAL PRESENTATION: A 68-year-old man presented with a Hunt and Hess Grade II subarachnoid hemorrhage and symptoms of headache, nuchal rigidity, and facial paresis. INTERVENTION: Angiographic evaluation with superselective exploration revealed a small ruptured aneurysm located on a duplicated hypoplastic A1 segment of the left anterior cerebral artery with associated middle cerebral artery stenosis and secondary early moyamoya changes. Surgical clipping of the aneurysm was performed successfully while sparing the hypoplastic A1 segment. CONCLUSION: A1 aneurysms occurring on a duplicated anterior cerebral artery segment probably develop from a congenital weakness of the parent vessel and increased local shear stress. Superselective angiography was helpful in the preoperative planning and facilitated the decision to treat with surgical clipping instead of embolization.