A cost comparison of two strategies for treating stage IB2 cervical cancer.

Patients with stage IB2 cervical cancer at our institution are treated primarily with definitive chemoradiation, or chemoradiation followed by adjuvant hysterectomy. We sought to compare the cost differences associated with these two strategies. We identified all patients with stage IB2 cervical cancer who received their entire treatment regimen at our institution between 1995 and 2004. All patients received a combination of chemotherapy, external beam radiation, and one brachytherapy procedure, followed by either a second brachytherapy procedure or a simple hysterectomy. We retrieved cost data associated with hospitalization for the completion of respective treatment, including pharmacy, laboratory and pathology, radiation, and operating room services, as well as the costs of supplies and room and board. We identified 46 patients with stage IB2 cervical cancer, 23 who received a second brachytherapy procedure and 23 who underwent simple hysterectomy. Patients displayed similar demographics and similar disease characteristics including initial tumor diameter and histology. The cost of care for adjuvant hysterectomy group was greater ($8,316.70 vs 5,508.70, P < 0.0001). Specific differences included higher operating room costs ($1520 vs 414, P < 0.0001), pharmacy costs ($675 vs 342, P < 0.0001), and laboratory/pathology costs ($597 vs 89, P < 0.0001). We conclude that definitive chemoradiation appears to be associated with lower costs for management of stage IB2 cervical cancer when compared to simple adjuvant hysterectomy.

Chemoradiation with and without adjuvant extrafascial hysterectomy for IB2 cervical carcinoma.

The optimal treatment strategy for stage IB2 cervical carcinoma that maximizes survival while minimizing toxicity remains controversial. The purpose of this study was to compare survival and toxicity in stage IB2 cervical cancer patients treated with chemoradiation and adjuvant extrafascial hysterectomy (cRT + H) versus definitive chemoradiation (cRT). Data were abstracted from patients with IB2 cervical carcinoma primarily treated at a single institution from January 1994 to December 2004. All patients received chemotherapy concurrent with external beam radiation therapy. Patients were subsequently treated with either a single low-dose rate brachytherapy applicator followed by adjuvant extrafascial hysterectomy (n = 24) or a second brachytherapy application to complete full-dose definitive chemoradiation (n = 30). Analyses were conducted using Kaplan-Meier survival and Chi-square statistics. Groups did not differ demographically with the exception of smoking. Smokers were significantly (P = 0.04) more likely to have been treated with definitive chemoradiation. Median tumor size was similar between groups. There was no difference in overall or disease-free survival between patients who received cRT + H versus cRT (P = 0.82 and 0.75, respectively). All recurrences in the cRT arm were in smokers. There were two grade 3-4 toxicities in each group. No treatment-related deaths occurred. In this small retrospective cohort study, we observed no difference in survival between patients treated with cRT + H versus cRT. These data complement published results of Gynecologic Oncology Group studies in patients with IB2 cervical cancer. Definitive comparison between the two treatment strategies would require a randomized prospective trial with stratification based on smoking.

Failure of the subcallosal sling to develop after embryonic X-irradiation is correlated with absence of the cavum septi.

During embryonic development of the rodent forebrain, a cavity normally appears at the midline just below the corpus callosum. This cavity, the cavum septi, is present in mice by gestational day 18, but is subsequently obliterated by growth of the septal nuclei and neuropil. After x-irradiation of pregnant mice with 125r on gestational day 14.5, the cavum septi did not develop. This dramatic developmental abnormality was accompanied by delayed fusion of the septum, and a reduction in the population of subventricular cells that normally migrate to form a sling of cells extending from the medial aspect of the lateral ventricles to the midline. In normal animals formation of the cavum septi involves degeneration of this subcallosal sling of SV cells. Thus absence of the cavum after x-irradiation may be due to the premature killing of subventricular cells before their migration toward the midline.

Death of the subcallosal glial sling is correlated with formation of the cavum septi pellucidi.

In this study we have examined the developmental fate of a population of cells that is located beneath the rostral corpus callosum during the perinatal period. These cells form a distinct slinglike structure along the geographically defined corticoseptal boundary (CSB) and may play a role in guiding callosal axons across the midline. The sling is a transient structure present in fetal and neonatal animals but not in adults. Here we show that the CSB cells die and that this debris is removed by macrophages. The sequence of cell degeneration in the CSB is highly stereotyped and follows a spatiotemporal pattern that is correlated with fusion of the cerebral hemispheres and subsequent growth across the midline of the callosal axons. The subcallosal location of the resorbing CSB is found in the exact place in which a fluid-filled cavity (the cavum septi pellucidi) is transiently found during the perinatal period. The tight temporal and spatial correlation between callosal axon decussation, degeneration of the CSB, and cavum septi formation suggests that these three phenomena may be causally related.

Occult carcinoma discovered after simple hysterectomy treated with postoperative radiotherapy.

PURPOSE: Treatment of patients with occult carcinoma of the cervix discovered after simple hysterectomy is controversial. The purpose of this review is to examine our results with postoperative radiotherapy and to compare them to similar reports and to reports of treatment with radical parametrectomy. METHODS AND MATERIALS: Between November 1979 and April:, 18 patients were treated with radiotherapy at the University of Virginia for invasive carcinoma of the cervix discovered after simple hysterectomy. Simple hysterectomy was performed in all 18 patients for a variety of indications. After surgery gross residual carcinoma remained in four patients; and microscopic disease was present at the surgical margins in two patients. The remaining patients had no evidence of residual disease. All 18 patients had postoperative radiotherapy with or without brachytherapy. The endpoints for this study were local control, survival, and treatment-related toxicity. Actuarial rates were calculated using the Life Table method. RESULTS: Median follow-up for all 18 patients was 42 months (range 2-202 months). Both the 5 and the 10-year actuarial local control rates were 88%. Five and 10-year actuarial overall survival rates were both 93%. Two patients had both local and distant cancer recurrences. There were no recurrences among the six patients treated with external beam alone. The remaining patients are all alive without evidence of disease, including two patients who had gross residual disease after surgery, and one patient with both microscopic positive margin and a positive lymph node (the only patient to undergo lymph node sampling). There was no severe acute morbidity and only one patient had severe late morbidity. CONCLUSIONS: Invasive carcinoma found after simple hysterectomy may be treated safely and effectively with postoperative radiotherapy. Patients with known residual disease following surgery do poorly with either radiotherapy or reoperation, but treatment with radiotherapy alone may be less morbid. Also, for the treatment of minimal disease external beam radiation to the pelvis appears to be as effective and possibly less morbid than radical reoperation.

Cytogenetic abnormalities in primary bronchopulmonary leiomyosarcoma of childhood.

Primary bronchopulmonary leiomyosarcoma (PBLMS) is a rare malignant neoplasm in all age groups and only 10 pediatric cases of PBLMS have been reported. This report presents cytogenetic findings of a PBLMS from an 8-year-old boy. Tumor diagnosis was established by using routine histopathology, immunohistochemistry, and electron microscopy. The karyotype was highly complex, demonstrating consistent structural abnormalities of chromosomes 1, 5, 6, and 7, relative gain of chromosomes 2 and 11, and relative loss of chromosomes 9, 19, 20, and 22, along with the presence of multiple marker chromosomes. Cytogenetic results of previously reported leiomyosarcomas are reviewed and compared with the present case.

Loss of chromosomes 22 and 14 in the malignant progression of meningiomas. A comparative study of fluorescence in situ hybridization (FISH) and standard cytogenetic analysis.

The majority of meningiomas are classified as typical and have a relatively benign course. However, approximately 10% are diagnosed as atypical, anaplastic, or malignant and have a worse prognosis. The genetic differences between the typical and higher grade meningiomas are not well characterized, although there appear to be increasingly complex karyotypic changes associated with the higher grade tumors. Because higher grade meningiomas are not common tumors, and because of the inherent problems associated with the culturing of tumors, the use of interphase cytogenetic techniques with paraffin-embedded archival material is desirable for studying these neoplasms. To determine its accuracy in detecting aneuploidy, we performed fluorescence in situ hybridization (FISH) on 2-micron paraffin sections of nine previously karyotyped meningiomas using an alpha-satellite probe for chromosomes 14 and 22. Sections of normal tissue from six patients without malignancy were used as controls. FISH analysis detected all of the chromosome losses in the meningioma cases that had been characterized cytogenetically. In five cases, cell lines not detected by standard cytogenetics were identified by FISH. These results indicate that FISH is a reliable method for detecting chromosomal loss and may be more sensitive than standard cytogenetics alone. Furthermore, the results of this study support the concept that loss of chromosome 14 is associated with malignant progression in meningiomas.

Acquisition of acoustic startle shows a dose-response to serum free T4.

Methimazole, administered to rats in drinking water (0.1 and 0.05%) from embryonic day 17 to postnatal day 10, caused a dose-dependent decrease in serum Free T4 and an accompanying dose dependent delay in acquisition of acoustic startle reflex. In conjunction with other studies showing the specific dependence of acoustic startle development on thyroid hormone, this study suggests that the acoustic startle system may be a useful model for determining thyroid hormone requirements for normal neurologic development.

Acquisition of acoustic startle response in relation to growth and thyroid function in rats.

Thiourea was administered by gavage to pregnant and lactating rats from gestational day 18 until postnatal day 10, at doses of 100 or 250 mg per day (approximately 350 or 900 mg/kg/day). From the day after birth until postnatal day 14 the neonates were weighed, and beginning on postnatal day 10 acquisition of acoustic startle reflex was assessed. Serum thyroxine and thyrotropin were measured on postnatal day 14. High dose thiourea severely inhibited thyroid function in pups, significantly depressed body growth, and retarded development of the acoustic startle response. At the low dose there was a significant reduction in growth, but no effect on acquisition of acoustic startle reflex. Low dose pups appeared to be functionally euthyroid (free T4 and thyrotropin were not significantly different from control). In conjunction with other studies, these results strongly suggest that, while development of acoustic startle is dependent upon thyroid hormone, it is not readily affected by retarded body growth.

Histopathology of arteriovenous malformations after gamma knife radiosurgery.

Stereotactic radiosurgery effectively obliterates many arteriovenous malformations (AVMs). Hemodynamic changes in AVMs after radiosurgery have been illustrated using magnetic resonance imaging and angiography, but there have been no detailed reports describing the underlying histopathological changes. This study examines AVMs at various times after gamma knife radiosurgery (GKRS) and describes the histopathological changes that lead to vessel occlusion. The authors examined nine AVM specimens obtained 10 months to more than 5 years after GKRS, by using routine histopathological stains as well as immunohistochemical techniques to detect smooth-muscle actin, factor VIII, and type IV collagen. Blood vessels within the AVMs showed progressive changes leading to narrowing or obliteration of the lumen. The earliest changes after gamma knife irradiation appear to be damage to endothelial cells, followed by progressive thickening of the intimal layer caused by proliferation of smooth-muscle cells that elaborate an extracellular matrix that includes type IV collagen. Finally, cellular degeneration and hyaline transformation occur. For statistical correlation analyses, the specimens were graded according to the degree of histopathological change and the relative number of vessels showing such changes. Both of these parameters were significantly correlated with time after GKRS and with AVM size reduction shown on follow-up imaging studies. Gamma knife radiosurgery of AVMs causes endothelial damage, which induces the proliferation of smooth-muscle cells and the elaboration of extracellular collagen by these cells, which leads to progressive stenosis and obliteration of the AVM nidus. This series of pathological changes in AVMs after GKRS is essentially similar to the response-to-injury model of atherosclerosis.

Postnatal behavioral changes in prenatally irradiated rats.

Rats were exposed on gestational day 15 to 125 r X-irradiation, a treatment known to severely alter brain morphology. At 4-6 weeks of age the behavior of these animals was studied using two methods: (1) measurement of circadian locomotor activity, (2) photographic analysis of behavioral acts. The circadian locomotor activity of irradiated rats was similar to that of controls tested individually or as groups in a residential unit. After morphine sulfate, 2 mg/kg, the increase in locomotor activity was greater for the irradiated than control groups. Successive frames of photographic film were analyzed to determine the frequency, duration, sequencing of behavioral acts. No significant differences were present in these parameters of behavioral acts of control and irradiated rats. After morphine, irradiated rats showed a greater increase than controls in frequency and initiations of some behavioral acts, and these acts were more randomly dispersed in the sequences of acts. In this experiment activity was little affected by an agent which severely alters brain morphology, but the latent behavioral effects of the permanent brain damage became manifest, when the testing situation included challenge with a low dose of a drug which caused hyperactivity.

Neuronal damage in chick and rat embryos following X-irradiation.

Exposure of rat and chick embryos to X-irradiation at the time of development of neurons at the telencephalic-diencephalic border results in prolonged damage to neurons in this area as measured by neuronal nuclear size. A dose of 100 rads to the seven-day-old chick embryo has about the same effect as 125 rads to the 15-day-old rat fetus. The nuclear volume of large, multipolar neurons in the chick paleostriatum primitivum and the rat lateral preoptic area are reduced from 10 to 15%. Larger doses of X-irradiation to the chick (150 and 200 rads) cause progressively greater reductions in nuclear size. The large neurons which were measured in the rat and chick are morphologically similar in the two species. Both contain cytoplasmic acetylcholinesterase and have several branched, spiny dendritic processes. The similarity of response of chick and rat neurons to X-irradiation diminishes the significance of maternal factors as the cause of the effects of fetal irradiation in these experiments.

Equivalent ages in rat, mouse and chick embryos.

Data for estimating equivalent ages of rat, mouse and chick embryos are presented, using several sources from the literature. When the time of development of various embryonic structures is matched for the three species, the differences in time for the stages are primarily due to delays in development of the preimplantation blastulas of the rat and mouse in comparison with the incubated chick egg. Development from the blastula stage to completion of major organogenesis proceeds at approximately the same rate for all three species.

Axonal shortening and the mechanisms of axonal motility.

Axons in tissue culture retract and shorten if their tips are detached from the substrate. The shortening reaction of the axon involves contractile forces that also arise during normal axonal motility, elongation, and retraction. We studied shortening in axonal segments isolated from their parent axons by transecting the axon between the growth cone and the most distal point of adhesion to the substrate. Within 15-20 minutes after transection, an isolated axonal segment shortened and pulled its tail end toward the growth cone. During the shortening process, long sinusoidal bends arose along the axon. The identical shortening reaction occurs without transection, when the axon tip is detached from the substrate. Pharmacological studies with inhibitors of glycolysis indicate that the shortening mechanisms utilize metabolic energy, presumably ATP. The rate of sinusoidal shortening is similar to both the rate of polymer translocation in the axon by slow axonal transport and the rate of normal axonal elongation. Taxol inhibits the shortening reaction with a similar dose dependence to its inhibition of axonal growth. Together, all these observations suggest that the same basic intracellular motility mechanisms are involved in normal axonal growth, in slow axonal transport, and in the shortening reaction: the intracellular dynamic system that utilizes ATP to generate longitudinal movements of polymers within the axon may be the same mechanism underlying both the retraction and the elongation of the axon.

Sarcoid myopathy presenting with diaphragm weakness.

Sarcoidosis involving muscle occurs frequently, but it is infrequently symptomatic. The clinical, electromyographic, and histologic features of sarcoidosis involving muscle in a 63-year-old woman presenting with diaphragm weakness are described. An electromyogram revealed wide-spread myotonia and an inflammatory myopathic process, suggestive of adult-onset acid maltase deficiency disease. Muscle biopsy showed noncaseating granulomas consistent with sarcoidosis. Clinical improvement followed the initiation of oral prednisone therapy. This case illustrates that muscular sarcoidosis may mimic adult-onset acid maltase deficiency in both its clinical and electromyographic features.

Prenatal diagnosis of Turner syndrome using cells cultured from cystic hygromas in two pregnancies with normal maternal serum alpha-fetoprotein.

In two cases of prenatally detected cystic hygroma with oligohydramnios, successful cytogenetic diagnosis of Turner syndrome was achieved using cells obtained from direct aspiration of the cystic hygroma. Exceptionally high levels of alpha-fetoprotein were found in the cystic hygroma fluid, as might be expected. However, the maternal serum alpha-fetoprotein levels were within normal limits. Elevated alpha-fetoprotein levels in 'amniotic fluid' noted previously in the literature may have resulted because of inadvertent tapping of the cystic hygroma. It is clear from our cases that maternal serum levels of alpha-fetoprotein will not necessarily be elevated and will not serve as a screening mechanism for cystic hygromas.

Membranous glomerulonephritis associated with testicular seminoma.

Proteinuria, often nephrotic in range, is a recognized paraneoplastic syndrome of solid tumours, with membranous glomerulonephritis (MGN) the most common histopathological lesion seen on renal biopsy. A 56-year-old male was found to have proteinuria on routine medical examination. History, physical and serological evaluation failed to reveal an aetiology and subsequent renal biopsy showed MGN, presumed to be idiopathic. Prednisone therapy was begun but this proteinuria did not resolve (> 1 g 24 h-1). Eleven months later the patient discovered a testicular mass which was found to be a stage I seminoma upon excision and metastatic evaluation. His proteinuria rapidly normalized after orchectomy and regional lymph node radiotherapy. This is the first known case of MGN associated with testicular seminoma.

Extradural failure in glioblastoma multiforme: MRI demonstration.

Glioblastoma multiforme is invariably associated with intracranial failure following conventional therapy. Extracranial as well as metastatic failure are rarely seen. Subtle extracranial abnormalities in most patients with glioblastoma multiforme are not indicative of convexity failure. However, in patients with high p53 and Ki67 immunoreactivity and in whom the dura was not closed at the time of craniotomy, the possibility of early extradural failure should be considered.