The use of fluoroscopy to guide needle placement in interstitial gynecological brachytherapy.

PURPOSE: Interstitial brachytherapy is generally performed for gynecological malignancies with extensive parametrial involvement, by inserting the needles through a transperineal template. Often, the implanted needles are not parallel, and the multiple sources can be difficult to identify on localization radiographs, especially if obtained with a portable X-ray unit. We have used fluoroscopy to guide the needles for interstitial brachytherapy to treat various gynecological malignancies. Because the resultant needles are parallel, dosimetry can be performed based on the template hole positions used, rather than identifying individual sources. This report focuses on the technique; the outcome of patients implanted with this technique will be reported separately. METHODS: Seventy-one patients were implanted transperineally with 192iridium using a Syed template under fluoroscopic guidance, from September 1989 to May 1995, for bulky parametrial disease, narrow vagina, extensive vaginal involvement, recurrent disease after previous course of pelvic radiation therapy, or in cases in which the patient had previously undergone hysterectomy. 137Cesium was added in a central tandem in cases with a cervical os. Thirty patients were treated for primary cervical or vaginal carcinoma; 41 patients were treated for recurrent disease from endometrial or cervical cancers. The brachytherapy dose (prescribed to the periphery of the implant) was 40 to 55 Gy when used alone (15 patients) and 22-40 Gy when used as a boost to 34.2 to 59.4 Gy of pelvic external-beam radiotherapy (56 patients). The patients were followed for 6 to 63 months. RESULTS: In all cases, some of the needles had to be repositioned to improve the alignment. Hence, the use of fluoroscopy aided in achieving parallel placement of the needles in all implants as seen on anterior-posterior radiographs. Because the 192iridium sources were ordered beforehand based on the preplan, and the dosimetry was based on idealized geometry of the template hole positions, all patients were loaded on the same day of implant. CONCLUSION: Fluoroscopically guided perineal interstitial brachytherapy is a feasible technique for use in various gynecological malignancies. The use of fluoroscopic guidance helped to achieve parallel needle placement in all of our implants, but it required repositioning of some of the needles in all cases. The parallel positioning allowed the use of preplanned dosimetry, minimizing the delay in loading of the patients. The outcome of the patients treated using this technique is currently undergoing analysis and will be reported separately.

Anticonvulsant activity of piperidinol and (dialkylamino)alkanol esters.

Aromatic and heterocyclic esters of 1-methyl-4-piperidinol and 1,4-dimethyl-4-piperidinol and aromatic esters of (dialkylamino)alkanols were prepared and evaluated for antiepileptic activity by the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole seizure threshold (scMet) assays and for minimal central neurotoxicity by the rotorod ataxia test. The most potent compound, namely the 2-phenylbenzoate (57) of 3-(diethylamino)propanol, was slightly more potent than diphenylhydantoin in the MES assay, while the 2-phenylbenzoate (24) of 1-methyl-4-piperidinol and the 2-phenylbenzoate (56) of (diethylamino)ethanol displayed activity comparable to that of diphenylhydantoin. The 2-phenethylbenzoate ester (6) of 1-methyl-4-piperidinol exhibited one-third the activity of diphenylhydantoin. The 2,4,5-trimethylbenzoate 40 and 2,4,6-trimethylbenzoate 41 of 1-methyl-4-pieridinol were even less potent, but did display activity in the phenobarbital-methsuximide range. Certain compounds interact with sites associated with the GABA receptor-chloride channel complex, but their potencies as anticonvulsant agents do not correlate with interaction at sites on the channel complex. Certain analogues antagonize binding of a batrachotoxin analogue to sodium channel sites, a property indicative of local anesthetic activity. There are structural similarities between 2-phenylbenzoates 57, 56, and 24 and diphenylhydantoin, and the latter anticonvulsant also antagonizes binding of the batrachotoxin analogue.

[3H]Batrachotoxinin A 20 alpha-benzoate binding to voltage-sensitive sodium channels: a rapid and quantitative assay for local anesthetic activity in a variety of drugs.

[3H]Batrachotoxinin A benzoate ( [3H]BTX-B) binds with high affinity to sites on voltage-dependent sodium channels in a vesicular preparation from guinea pig cerebral cortex. In this preparation, local anesthetics competitively antagonize the binding of [3H]BTX-B. The potencies of some 40 classical local anesthetics and a variety of catecholamine, histamine, serotonin, adenosine, GABA, glycine, acetylcholine, and calcium antagonists, tranquilizers, antidepressants, barbiturates, anticonvulsants, steroids, vasodilators, antiinflammatories, anticoagulants, analgesics, and other agents have been determined. An excellent correlation with the known local anesthetic activity of many of these agents indicate that antagonism of binding of [3H]BTX-B binding provides a rapid, quantitative, and facile method for the screening and investigation of local anesthetic activity.

Synthesis and adrenergic activity of ring-fluorinated phenylephrines.

2-Fluoro-, 4-fluoro-, and 6-fluorophenylephrine (6-FPE) were synthesized from the corresponding fluorinated 3-hydroxybenzaldehydes. New routes to 2-fluoro- and 6-fluoro-3-hydroxybenzaldehydes were developed based on regioselective lithiation of 2- and 4-[(dimethyl-tert-butylsilyl)oxy]fluorobenzene ortho to fluorine. As with norepinephrine and isoproterenol analogues, the adrenergic properties of phenylephrine were markedly altered by ring fluorination. The order of potency of the fluoro analogues as alpha 1-adrenergic agonists in the stimulation of contraction of aortic strips and of phosphatidylinositol turnover and potentiation of cyclic AMP accumulation in guinea pig synaptoneurosomes was 6-FPE greater than PE greater than 4-FPE greater than 2-FPE. The same pattern was observed for the displacement of radioligands specific for alpha 1- and alpha 2-adrenergic receptors on brain membranes. The order of potency for the displacement of [3H]dihydroalprenolol, a beta-specific adrenergic ligand from brain membranes, was 2-FPE greater than 4-FPE = PE much greater than 6-FPE. 6-FPE was much more selective for alpha-adrenergic receptors compared to beta-receptors than was phenylephrine. A rationale for the observed fluorine-induced alterations in potency and selectivity of the FPEs for alpha- and beta-adrenergic systems is presented based on fluorine-induced conformations due to electrostatic repulsion of fluorine and the benzyl hydroxyl group.

Evidence for deficiencies in intracerebral cytokine production, adhesion molecule induction, and T cell recruitment in herpes simplex virus type-2 infected mice.

We examined the intracerebral T cell response in mice infected with neurovirulent HSV-2 strains and an avirulent HSV-1. In HSV-2-infected brains, (i) IL-1beta, TNF-alpha and IFN-gamma mRNA expression was low, (ii) ICAM-1 and VCAM-1 were not induced, (iii) few CD4+ or CD8+ cells were detected. By contrast, in HSV-1-infected brains, (i) cytokine mRNA expression was high, (ii) adhesion molecules were strongly expressed, (iii) many T cells were detected. We suggest that deficient T cell extravasation into HSV-2-infected brain regions is caused by negligible ICAM-1 and VCAM-1 expression, which is due to low expression of critical cytokines.

Evidence that deficient IFN-gamma production is a biological basis of herpes simplex virus type-2 neurovirulence.

Although immune response control of herpes simplex virus (HSV) has been well demonstrated, numerous HSV-2 strains are neurovirulent in immunocompetent mice. Using an RNase protection assay and an ELISA, we found that HSV-2-infected mice exhibited a deficient IFN-gamma response, an inability to clear virus, and eventual death. An HSV-based amplicon vector expressing mouse IFN-gamma was constructed and packaged into HSV-1-helper virus (HSV(pIFN-gamma)). In mice treated with HSV(pIFN-gamma), (i) the LD50 of HSV-2(G) increased 5000-fold, (ii) intracerebral IFN-gamma expression increased 10-fold, and (iii) HSV titer rapidly decreased. We suggest that the deficient IFN-gamma response is a basis for HSV-2 neurovirulence in mice.

Alteration of intracerebral cytokine production in mice infected with herpes simplex virus types 1 and 2.

Previously we reported that a lethal strain of herpes simplex virus type 2 (HSV-2) infects the brain following ocular inoculation of mice. We now demonstrate that HSV-2 mediates an unusual intracellular sequestering of class II major histocompatibility complex (MHC) antigens. With use of an RNase protection assay, we observed a selective inhibition of IFN-gamma and IL-6 gene transcription in brains of mice infected with HSV-2. It is likely that the inhibition of cytokine gene expression was mediated through a failure to activate CD4+ lymphocytes. These data suggest that the infecting herpesvirus can influence the profile of intracerebrally produced cytokines, which in turn may determine the outcome of the infection.

Recent declines in breast-feeding in the United States, 1984 through 1989.

Ongoing surveys performed by Ross Laboratories demonstrate recent declines both in the initiation of breast-feeding and continued breast-feeding at 6 months of age. Comparing rates in 1984 and 1989, the initiation of breast-feeding declined approximately 13% (from 59.7% to 52.2%), and there was a 24% decline in the rate of breast-feeding at 6 months of age (from 23.8% to 18.1%). The decline in breast-feeding was seen across all groups studied but was greater in some groups than in others. Logistic regression analysis indicates that white ethnicity, some college education, increased maternal age, and having an infant of normal birth weight were all positively associated with the likelihood of both initiating breast-feeding and continuing to breast-feed to at least 6 months of age. Women who were black and who were younger, no more than high school educated, enrolled in the Women, Infants and Children supplemental food program, working outside the home, not living in the western states, and who had an infant of low birth weight were less likely either to initiate breast-feeding or to be nursing when their children were 6 months of age. The factors influencing the decline in breast-feeding were not uniform. There were fewer sociodemographic factors associated with the decline in the initiation of breast-feeding than in the decline in prolonged breast-feeding. While the disparity between older and younger mothers in initiating breast-feeding increased, there was an offsetting trend as the disparity associated with parity decreased.(ABSTRACT TRUNCATED AT 250 WORDS)

Local anesthetic properties of opioids and phencyclidines: interaction with the voltage-dependent, batrachotoxin binding site in sodium channels.

[3H]Batrachotoxinin-A 20-alpha-benzoate ([3H]BTX-B) binds specifically and with high affinity (Kd = 30 nM) to a site on voltage-dependent Na+ channels. Compounds with local anesthetic activity inhibit the binding of [3H]BTX-B by a mutually exclusive, allosteric mechanism. The potential local anesthetic potency of a series of 23 opioids and phencyclidine-like compounds has been estimated by their inhibition of [3H]BTX-B binding to Na+ channels in a preparation of synaptoneurosomes from guinea pig cerebral cortex. The potency of these compounds were also tested as inhibitors of the specific binding of [3H]phencyclidine ([3H]PCP) to a high affinity site on rat brain membranes. Opioids such as morphine and codeine show little affinity for the [3H]BTX-B binding site or for the [3H]PCP binding site. Other analgesics, many of the PCP-like compounds and dioxadrol derivatives are potent versus [3H]BTX-B binding and display both stereospecificity and high affinity towards the PCP-binding site. However, there was no correlation between local anesthetic potency assessed as antagonism of [3H]BTX-B binding and affinity towards the PCP site. Five classical local anesthetics had no affinity for the PCP-site, but did displace [3H]BTX-B from its binding site.

Surgical issues in the management of carcinoma of the cervix in pregnancy.

Incorporating effective screening into preventive health care for women would theoretically eliminate the diagnosis of cervical cancer in pregnancy. Until this goal is reached, our management decisions are limited by the relatively small and retrospective studies that form the basis for our pertinent knowledge and the ethical issues that would complicate randomized trials of treatment in pregnancy. Limited data suggest that radical hysterectomy with pelvic lymphadenectomy might carry a more favorable therapeutic index than radiation therapy in early-stage disease. In general, improvements in neonatal management may allow earlier intervention, shortening the time between diagnosis and treatment in hope of improving maternal outcome. The actual survival impact of this information remains to be demonstrated. An algorithm has been provided in Figure 3 which summarizes the salient features of the clinical management of significantly abnormal cervical cytology in pregnancy. At many institutions the rate of "atypical" or other nonspecified cytologic abnormalities exceeds 10%, and low-grade dysplastic changes are common and less threatening. These conditions place the responsibility for cervical cancer detection firmly upon the clinician and his or her index of suspicion that a significant abnormality exists. Those directing prenatal care must remain compulsive in the proper use of cytologic screening and careful clinical examination. A diagnosis should be rapidly and vigorously pursued when a diagnosis of cancer is suspected, with timely referral when needed. These practices may have the most immediate impact upon both maternal and fetal outcome when facing cervical cancer in pregnancy.

Second-look laparotomy in epithelial ovarian cancer.

The absence of a reliable noninvasive means of detecting persistent clinically occult ovarian cancer is the basis for performing repetitive operative procedures, usually called a second-look. Although controversy persists regarding whether second-look surgery contributes to an improved survival, it is well established that the second-look findings are of prognostic value. Patients with no pathologic evidence of tumor at second-look surgery (negative second-look) are much more likely to experience a prolonged disease-free interval than are patients with evidence of gross tumors at second-look (macroscopic positive second-look). Likewise, patients without gross tumor but with pathologic or cytologic disease (microscopic positive second-look) tend to survive longer than patients with a macroscopic positive second-look, but they do more poorly than patients with a negative second-look. It is also well known, however, that there are other prognostic features that influence clinical outcomes. For example, patients who have a negative second-look after treatment for a stage IIIC, grade 3 epithelial ovarian carcinoma should be considered at higher risk (50%) for an earlier clinical relapse than patients with low-grade tumors (grade 1 or low malignant potential) who have microscopic or small-volume gross tumors at second-look surgery. Much attention has been directed to whether second-look surgery has a favorable impact on survival. Unfortunately, no blind randomized trials have addressed this question. The conduct of a trial to evaluate the impact of second-look surgery on survival would be most difficult and essentially impossible because of an inability to standardize or control the treatment for recurrent tumors. Even measuring the interval of progression-free disease from completion of primary chemotherapy would be a challenging clinical trial to execute.

Applications of DAPI cytochemistry to neurobiology.

4',6-Diamidino-2-phenylindole hydrochloride (DAPI) is a fluorescent dye with high affinity for DNA. We have employed it as a fluorescent chromatin counterstain on sections immunofluorescent-stained using rhodamine and on tissues enzymatically stained using beta-galactosidase. DAPI also allows easy identification of mitotic figures and can be used to supplement cytochemical studies involving cell division in the nervous system.

Carcinoma of the vulva. Significance of surgical margin involvement in assessing prognosis.

Repeat pathologic analysis was completed in order to independently assign surgical margin status in a group of 61 patients from the Ohio State University gynecologic oncology tumor registry. Patients were entered into the study group after having undergone simple or radical vulvectomy for squamous carcinoma of the vulva. A statement regarding margin status was made following a detailed pathologic review, and parameters--including stage, grade and lymph node involvement--were assigned without regard to outcome. There was no statistically significant difference in the survival or recurrence rate with involved margins. Mean lesion size was significantly larger with involved margins (P less than .05). The survival and recurrence data support a primary surgical attempt at complete excision regardless of the microscopic margin status.

Vulvar condylomas and squamous vestibular micropapilloma. Differences in appearance and response to treatment.

A study of 37 women with typical condylomas and so-called squamous micropapilloma was undertaken to determine their response to systemic interferon and/or podophyllin treatment. Thirty lesions were classified as condylomas and 9 as squamous micropapillomas; two women had both lesions. Twenty-six (87%) of 30 condylomas responded, whereas only 1 (11%) of the 9 cases of micropapillomatosis showed a partial response (P less than .001) to podophyllin and/or interferon. Twenty-six biopsies from condylomas in which sufficient DNA was available for analysis contained human papillomavirus (HPV) DNA sequences that hybridized to an HPV 6 + 16 probe mix under nonstringent conditions. In contrast, HPV DNA sequences could not be detected in any of the nine cases of micropapillomatosis. Immunoperoxidase studies performed on these lesions failed to demonstrate viral capsid antigen. Thus, despite certain similarities in the clinical presentation and microscopic features of condylomas and squamous micropapillomas, it is not clear at present whether micropapillomas are HPV-related lesions.

Biodegradation of mixed wastes in continuously operated cyclic reactors.

The problem of simultaneous biodegradation of two dissimilar substrates in a continuously operated cyclic reactor was studied both at the theoretical and experimental levels using a simple model system. The system involved media containing mixtures of glucose and phenol as carbon sources. A pure culture of Pseudomonas putida (ATCC 17514) was employed. Independent kinetic experiments have revealed that glucose and phenol are involved in a crossinhibitory uncompetitive kinetic interaction. The dynamics of a cyclically operated reactor were analyzed using the principles of bifurcation theory for forced systems. Experimental results have confirmed the theoretical predictions. Implications of the results for the design of waste-treating facilities are discussed.

Immunohistochemical examination of intracerebral T cell recruitment and adhesion molecule induction in herpes simplex virus-infected mice.

Herpes simplex virus type 1 (HSV-1) infection in the nervous system is tightly controlled by the T-cell-mediated response. This report describes the temporal relationships among HSV-1 infection, intracerebral adhesion molecule induction, and T cell migration in intravitreally inoculated mice. HSV-1 immunoreactivity, initially detected at 3 days, increased in area and intensity in the superior colliculus, oculomotor nucleus, and geniculate through 5 days. By 6 days, HSV-1 was nearly undetectable in the same regions and the mice survive the infection. At the peak of HSV-1 immunoreactivity, ICAM-1 and VCAM-1 were strongly expressed in all infected brain regions. Additionally, in these region a few CD4+ and CD8+ T cells were detected. The heaviest T cell migration and adhesion molecule expression occurred at 6 days, coinciding with the decrease in HSV-1 immunoreactivity. However, in SCID and athymic mice, HSV-1 was not cleared from the brain and the mice died. Together, these data suggest that HSV-1 infection of the brain is followed by adhesion molecule induction in and T cell extravasation into the infected brain regions. Most importantly, an efficient T cell response was required to eradicate infectious HSV-1 from the brain.

A potential role for intensive chemotherapy in the treatment of small cell neuroendocrine tumors of the cervix.

Small cell neuroendocrine (SCNE) tumors of the cervix constitute a group of malignancies with a predilection for early systemic metastasis which likely contributes to the poor outcome reported to date. Histologic and immunocytochemical similarities exist between SCNE cervical tumors and small cell (oat cell) tumors of the lung. Notable clinical responses to chemotherapy have been reported in both small cell lung tumors and in poor-risk squamous cervical cancers, suggesting the potential for a similar role in the management of SCNE cervical tumors. In this report, four cases are described in which intensive chemotherapy with etoposide, doxorubicin, and cisplatin was used in patients with SCNE tumors. Marked reduction in tumor volume was a feature in three evaluable patients, two of whom received neoadjuvant therapy (one complete and one near-complete pathologic response). The fourth patient received adjuvant chemotherapy and remains without evidence of disease 47 months from diagnosis. Management details of each case have been provided along with a review of the use of chemotherapy in SCNE cervical tumors.

Mechanism and mode of action of 5-iodo-2-pyrimidinone 2'-deoxyribonucleoside, a potent anti-herpes simplex virus compound, in herpes simplex virus-infected cells.

The anti-herpes simplex virus type 2 (-HSV-2) action of 5-iodo-2-pyrimidinone deoxyribonucleoside (IPdR) was found to be exerted through inhibition of HSV DNA synthesis. The inhibition of viral DNA synthesis was not caused by inhibition of the synthesis of HSV-2-specified proteins or HSV-2 mRNA species involved with viral DNA synthesis or by depletion of deoxynucleotides. The inhibition of viral DNA synthesis may be due to damage to the DNA template in the nuclei or to an action at the DNA replication complex, because nuclei isolated from HSV-2-infected cells treated with IPdR could not support DNA synthesis in vitro. Moreover, the addition of exogenous template to the reaction enabled nuclear DNA synthesis to occur at the level of control. The major cellular metabolite of IPdR in HeLa S3 cells infected with HSV-2 was IPdR monophosphate, which was formed through virally specified kinase. Attempts to either identify or synthesize IPdR diphosphate and triphosphate were unsuccessful. The accumulation of IPdR monophosphate was dependent on the extracellular concentration of IPdR. IPdR monophosphate did not have any inhibitory effect on nuclear DNA synthesis, even at 200 microM. Thus, the action of IPdR could be due to an unidentified metabolite of IPdR or the depletion of a cellular metabolite that is essential for viral DNA synthesis.

Interference with major histocompatibility complex class II-restricted antigen presentation in the brain by herpes simplex virus type 1: a possible mechanism of evasion of the immune response.

Host survival of herpes simplex virus type 1 (HSV-1) infection depends on the establishment of latent infections in both peripheral and central nervous systems. Strains of HSV-1 that are successful in escaping the immune response produce a lethal infection. We now report a possible mechanism of immune response evasion used by HSV-1. After intraocular inoculation of mice, HSV-1 strain F established a latent infection in the brain, whereas strain KOS did not. The immune response to HSV-1 infection (strains KOS and F) in the brain was characterized by induction of major histocompatibility complex class II expression and recruitment of CD4+ and CD8+ cells to highly restricted sites of intracerebral viral infection. Major histocompatibility complex class II antigen expression was primarily intracellular in strain KOS infection centers and at the cell surface in strain F infection centers. We propose that major histocompatibility complex class II-restricted viral-antigen presentation to T cells is interrupted during strain KOS infections, thereby allowing KOS infection to evade T-cell-mediated events that would normally protect the host from a lethal infection. Immunocompromised mice (athymic or irradiate mice) could not survive strain F infections; however, latent F infections were established in irradiated mice reconstituted with naive lymph node and spleen cells. These data suggest that class II-restricted presentation of viral antigens is required for the control of HSV-1 infections in the nervous system.

Role of mycelium and extracellular protein in the biodegradation of 2,4,6-trichlorophenol by Phanerochaete chrysosporium.

The biodegradation of 2,4,6-trichlorophenol (2,4,6-TCP) by Phanerochaete chrysosporium was studied in batch systems. In experiments with mycelial suspension, the degradation of 2,4,6-TCP was found to occur in the absence of ligninase. Chloride ion was recovered in nearly stoichiometric amounts at the end of the process. The microorganism did not retain its degradation ability for more than 6 days under substrate-deficient conditions. Neither the mycelium nor the extracellular protein alone could degrade 2,4,6-TCP; both were required for complete degradation to occur. In experiments in which 2,4,6-TCP was exposed to the culture supernatant separated from its mycelium, negligible degradation was obtained and no chloride ion was recovered. No degradation was observed even when the supernatant was supplemented with hydrogen peroxide as a possible cosubstrate. In experiments performed with washed mycelium separated from its supernatant, no degradation took place until the mycelium released additional extracellular protein 5 to 6 h into the incubation. Additions of washed mycelium separated from its supernatant to active cultures also produced an increase in the rate of degradation in correspondence with the protein release. The protein release was independent of the presence of 2,4,6-TCP. The addition of cycloheximide to inhibit the synthesis of de novo proteins completely suppressed the release of protein by the mycelium and resulted in no 2,4,6-TCP degradation. Additions of culture supernatants containing a high concentration of extracellular protein to active cultures produced an increase in the rate of 2,4,6-TCP degradation.(ABSTRACT TRUNCATED AT 250 WORDS)