Menstrual timing of breast cancer surgery.

PURPOSE AND DESIGN: This is a critical review of the growing body of data, 32 retrospective studies of the outcomes of 9,665 women published since 1989, relevant to the possibility that the timing of primary breast cancer resection within the menstrual cycle impacts breast cancer recurrence and/or spread and patient survival. This article evaluates and contrasts the adequacy of information and data analysis presented in each publication. The overall purpose of this exercise is to rigorously determine the relative strength of the hypothesis that the menstrual cycle timing of operation impacts outcome and, thereby, to determine whether or not a specific change in the practice of breast surgical oncology can be recommended. RESULTS: The single most completely reported and thoroughly analyzed series, involving 1,175 young women, indicates that surgical resection timing is likely to be relevant to outcome. Seven additional high-quality studies involving 2,864 women have been most completely reported. While two of these eight find no impact, six (75%) of these studies find that breast cancer outcome is affected by operative timing. Nine of the remaining 24 less-complete studies report a statistically significant effect of operative timing. Among these 15 studies of the fates of more than 5,000 women, the opportune menstrual cycle phase almost invariably includes the putative luteal phase. A large number of retrospective studies of widely varying quality find no outcome difference as a function of resection timing. The adequacy of design of each of four ongoing prospective studies is found lacking. CONCLUSIONS: Although it is likely that the menstrual cycle phase of operation is relevant to outcome, the nature of the available data cannot allow a clear recommendation of precisely when to operate. It is, therefore, concluded that current retrospective data are inadequate to recommend an immediate change in practice. Prospective studies of this potentially important question are essential. The prospective trials initiated to date will not be able to definitively answer this question because of inadequate chronobiological design. The minimal requirements for adequate prospective study are delineated.

Experimental diabetes: reduction of serotonin-induced vasoconstriction by meclofenamic acid in vitro.

In diabetes the sensitivity of isolated rat aortae to serotonin is greatly diminished and the dose-response curve is shifted to the right. The maximal response is reduced to 37% of control, the threshold dose is approximately tenfold greater, and the ED50 is about fourfold greater than control. This decrease in sensitivity may be due, in part, to a reduction in the synthesis of prostaglandins because serotonin-induced responses in normal and diabetic arteries treated with meclofenamate are also significantly diminished. In addition, there is evidence that both receptor-operated Ca2+ and potential-operated Ca2+ channels may be impaired because the responses to norepinephrine and KCl are both dampened in diabetic aortae. The greatly diminished effect of serotonin may be a sensitive tool to study the nature of diabetes better and to monitor its development.

Effect of nonsteroid anti-inflammatory drugs on subarachnoid hemorrhage in dogs.

The effects of two long-acting anti-inflammatory agents on behavioral changes and cerebral vasospasm were evaluated in a canine model of chronic subarachnoid hemorrhage (SAH). The agent with the longest half-life, sudoxicam, clearly reduced both the incidence and the magnitude of the vasopasm, and prevented the usual behavior changes caused by the stimulated SAH. The results obtained with the other agent, naproxen, suggested that it was better than the administration of saline. These agents were studied because of reports indicating that prostaglandins and thromboxane may play a role in the pathogenesis of the effects of SAH and because of nonsteroid anti-inflammatory agents exert pharmacological effects by reducing an excessive synthesis of these lipids. The findings suggest that some of these agents may afford an alternative treatment for the deterious consequences of SAH.

Levels and disappearance of prostaglandin F2alpha in cerebral spinal fluid: a clinical and experimental study.

The concentration of prostaglandin F2alpha (PGF2alpha) was measured in cerebrospinal fluid (CSF) obtained by lumbar puncture in patients with subarachnoid hemorrhage and compared to control values. The level of this prostaglandin was elevated at some time in most patients during the course of their illness. However, this could not be correlated with the severity of neurological deficits observed. The possibility that the concentration of PGF2alpha in lumbar fluid may not reflect that present intracranially was tested experimentally in anesthetized dogs. In these experiments only a small fraction of the radioactive PGF2alpha injected into the cisterna magna appeared in lumbar CSF. Prostaglandin F2alpha rapidly disappeared from the cisterna magna, half time 8 minutes, and radioactivity was present in blood from the jugular vein indicating that normally this prostaglandin rapidly egresses from the CSF into blood. These findings suggest that PGF2alpha can be rapidly transported away from the brain. This could explain the low concentrations of PGF2alpha in CSF of normal individuals and in some patients who have severe cerebral vasospasm. Conversely, the elevation of PGF2alpha in lumbar CSF noted in some patients might be due, in part, to an impairment of transport caused by the size and location of the hemorrhage.

Pleocytosis and elevation of prostaglandins F2a and E2 in cerebrospinal fluid following intracisternal injection of thrombin.

A marked pleocytosis and increase in the levels of prostaglandin F2a (PGF2a) and prostaglandin E2 (PGE2) were noted in cerebrospinal fluid of dogs within two hours following the intracisternal injection of thrombin. Quantitation of the prostaglandins (PG's) was done by gas chromatography-mass spectroscopy using deuterated PGF2a and PGE2 as internal standards. Whereas the levels of these prostaglandins were below the sensitivity of the method in control animals, a marked increase was noted following thrombin. PGF2a levels were 15-21 ng/ml and the PGE2 levels were 55-72 ng/ml. This concentration of the PG's is adequate to cause spasm of the cerebral vessels and could explain the spasm which occurs following the intracisternal injection of thrombin. These two effects, a pleocytosis and elevation of PG levels, may be specific to thrombin.

Chromosome alterations produced in germ cells of dogs by progesterone.

PIP: The morphological alterations of the chromosomes in male dogs caused by long-termed progesterone treatment were studied in male dogs receiving either 1, 5, 10 or 25 mg progesterone injected in every other day for 6 weeks, followed by an 8 week recovery period. For comparison, several other dogs received medroxyprogesterone acetate, estradiol-17beta, chorionic gonadotropin and testosterone. Testes were biopsied prior to treatment and at 1, 2, 4, 6, 10 and 14 weeks after the first injection. Characteristic chromosomal changes were seen in all dogs receiving progesterone including stickiness and clumping and prominent aneuploidy and polypoidy, with the extent of the damage directly related to the dose level. These alterations were found in all phases of meiosis studied as well as in the spermatogonial metaphases. By Week 6 spermatogenesis had been halted in all animals and as early as Week 2 in the dogs receiving the 25 mg dose. Regrowth during the recovery period was incomplete and variable and the dose relationship was less well-defined. Administration of medroxyprogesterone acetate resulted in similar chromosomal alterations but the tissues were not affected by the other nonprogestational hormones tested. Further research is needed into the mechanism of progesterone's antispermatogenetic effect and the long-range effect of such progesterone treatment on fertility.^ieng