Biomedical subjects

C Greenwald

Publications and source records attributed to C Greenwald.

18 recordsLinked to original sources

PubMed2000

Delavirdine in combination with zidovudine in treatment of human immunodeficiency virus type 1-infected patients: evaluation of efficacy and emergence of viral resistance in a randomized, comparative phase III trial. The M/3331/0013B Study Group.

We compared the activity of delavirdine (DLV) plus zidovudine (AZT) (n = 300) with that of AZT (n = 297) against human immunodeficiency virus type 1 in a randomized, double-blind, placebo-controlled trial. DLV exerted a transient antiviral effect, and mutations for resistance to DLV were found in more than 90% of subjects at week 12. The K103N mutation, which confers nonnucleoside reverse transcriptase inhibitor cross-resistance, was found in 85% of the patients.

Anti-HIV Agents↗

PubMed2000

CNS involvement in children with newly diagnosed non-Hodgkin's lymphoma.

PURPOSE: To determine the frequency of CNS involvement at diagnosis of non-Hodgkin's lymphoma (NHL), to characterize its pattern of presentation, and to determine its prognostic significance. PATIENTS AND METHODS: We reviewed the records of 445 children (1975 through 1995) diagnosed with NHL (small noncleaved cell NHL/B-cell acute lymphoblastic leukemia [SNCC NHL/B-ALL], 201 patients; lymphoblastic, 113; large cell, 119; other, 12). Tumor burden was estimated by serum lactate dehydrogenase (LDH) measurement and reclassification of disease stage irrespective of CNS involvement (modified stage). RESULTS: Thirty-six of 445 children with newly diagnosed NHL had CNS involvement (lymphoma cells in the CSF [n = 23], cranial nerve palsy [n = 9], both features [n = 4]), representing 13%, 7%, and 1% of small noncleaved cell lymphoma, lymphoblastic lymphoma, and large-cell cases, respectively. By univariate analysis, CNS disease at diagnosis did not significantly impact event-free survival (P =. 095), whereas stage and LDH did; however, children with CNS disease at diagnosis were at 2.0 times greater risk of death than those without CNS disease at diagnosis. In a multivariate analysis, CNS disease was not significantly associated with either overall or event-free survival, whereas both serum LDH and stage influenced both overall and event-free survival. Among cases of SNCC NHL/B-ALL, CNS disease was significantly associated with event-free and overall survival (univariate analysis); however, in multivariate analysis, only LDH had independent prognostic significance. Elevated serum LDH or higher modified stage were associated with a trend toward poorer overall survival among children with CNS disease. CONCLUSION: A greater tumor burden at diagnosis adversely influences the treatment outcome of children with NHL and CNS disease at diagnosis, suggesting a need for ongoing improvement in both systemic and CNS-directed therapy.

Adolescent↗

PubMed1999

The elusive diploic veins: anthropological and anatomical perspective.

Diploic veins (Canales diploicae), which were identified in dogs by Dupuytren more than 200 years ago (Hecker [1845] Die anatomische Verhaltnisse und Krankheiten der Venae diploicae und Vasa emissaria. Erfahrungen und Abhandlungen im Gebiete der Chirurgie und Augenheilkunde. Erlangen), have remained inadequately understood and scantily referenced in the anatomical and anthropological literature. The tunnels formed by diploic veins are among the few known skeletal markers of soft tissue alteration. Protected by two bony laminae, diploic vein tunnels often resist postdepositional destruction and may provide a new way to assess living and extinct hominid populations. This basic research was carried out to enable future utilization of the diploic venous channels in anthropologic research. In the present study, diploic venous channels were observed radiographically in 108 human adults aged 19 years and above, 18 infants and children aged 1-18 years (Hamann-Todd Osteological Collection), eight fetuses aged 7-9 months (the Johns Hopkins Collection), and seven nonhuman primates (Hamann-Todd Osteological Collection). In addition, seven documented cases of parents and children were radiographed for genetic evaluation (Osteological Collection of The Hungarian Natural History Museum). Five distinct diploic distribution patterns were identified and described in this study. This was at variance with the impressions reported in dissection-based studies. Independence of diploic vein pattern from demographic (gender and age) and size factors and their tendency to be symmetrical make them amenable and reliable traits for skeletal population study. Diploic vein patterns appeared to be more complicated in humans than in nonhuman primates, raising the possibility of future phylogenetic applications.

Adolescent↗

PubMed1999

Hyperostosis frontalis interna: an anthropological perspective.

Hyperostosis frontalis interna (HFI) is manifested by the accretion of bone on the inner table of the frontal bone. Despite the vast literature on HFI, ambiguity exists as to its etiology, osteogenesis, demography, and history. This stimulated the present broad-scale study of HFI which included the evaluation of 1,706 early 20th century skulls (1,007 males and 699 females) from the Hamann-Todd and Terry human osteological collections, as well as 2,019 pre-19th century East-Mediterranean, Amerindian, and Central European skulls. In addition, 72 cadavers were dissected for gross inspection and histology. Special attention was paid to the relationship of the brain and meninges to endocranial lesions. HFI is an independent condition, not a symptom of a more generalized syndrome as suggested in the past. It can appear in a variety of forms but each is the result of the same process and probably of the same etiology. Investigators' previous failure to recognize the mild stages of HFI (types A and B) as an early form of the general HFI process led to erroneous statistics and interpretations of observations. HFI should also be considered a phenomenon separate from HCI, hyperostosis cranialis diffusa (HCD), and other endostoses, even when it appears in association with them. To avoid ambiguity and facilitate the description of cranial hyperostoses, uniform nomenclature (HFI, HCD) has been recommended. HFI is rarely seen in historic populations, regardless of geographical origin. It is most commonly found among females and is believed to be associated with prolonged estrogen stimulation. While its magnitude of manifestation and frequency are much higher in females, HFI is not a purely female phenomenon. Males with hormonal disturbances such as atrophic testis were found to manifest HFI type D. HFI is associated with age insofar as it is much less frequent in females under 40 years of age. Although advanced cases of HFI (types C and D) have been observed in individuals as young as 40 years of age, it is more frequently found after age 60. The frequency of HFI type D will not increase from age 60. Type-predicted analysis by cohort reveals significant ethnic differences. Changes in African American (AA) females appear earlier in life and progress more rapidly than in European American (EA) females. Analysis of radiographs shows a discrepancy between the anatomic prevalence of HFI and its radiological recognition, which is very poor for mild cases. This apparently resulted in the misconceptions that HFI is entirely an old-age phenomenon, and that it is exclusively female. Histological analysis shows that the inner table along with the closely attached dural layer play a major role in the osteogenesis of HFI. Contrary to previous models, no evidence for diploe or ectocranial plate involvement was found. Cadaver study suggests that the predilection for the frontal area may be related to an altered blood supply and/or vascular stretching.

Adult↗

PubMed1999

Feasibility of implementing health promotion interventions to improve health-related quality of life.

Survivors of childhood cancer are a growing and vulnerable population. Cure rates for pediatric cancers now exceed 60% and, by the year 2000, an estimated 1 of every 1,000 young adults will be a cancer survivor. Because this population is at increased risk for late medical and neoplastic complications that impact adversely on health-related quality of life, it is important to investigate methods to promote risk reduction by motivating survivors to practice health-promoting behaviors. With this background, we initiated a prospective, randomized, controlled feasibility study in which survivors attending a long-term follow-up clinic were randomized to receive standard care or standard care plus an educational intervention. Our objectives were to determine if the intervention would improve the survivors' knowledge about their cancer treatment and risks of late effects and increase their practice of health-protective behaviors. Since July 1995, 272 of 318 families (86%) approached about the study agreed to participate. Of these, 266 are evaluable for assessment of baseline knowledge and health behaviors. Demographic features, baseline knowledge, health perceptions and health behaviors did not differ among randomized groups. Assessment of the intervention's efficacy at changing health behaviors of survivors randomized to the intervention group will be available when the 1-year follow-up evaluations are completed for the study cohort. Our preliminary experience with this pilot study supports the feasibility of educational intervention research in a specialty clinic dedicated to monitoring long-term childhood cancer survivors. Int. J. Cancer Suppl. 12:138-142, 1999.

Adolescent↗

PubMed1999

Chemotherapy dose-intensification for pediatric patients with Ewing's family of tumors and desmoplastic small round-cell tumors: a feasibility study at St. Jude Children's Research Hospital.

PURPOSE: To evaluate the feasibility of dose-intensification for patients with Ewing's family of tumors (EFT) and desmoplastic small round-cell tumors. PATIENTS AND METHODS: From February 1992 to June 1996, we treated 53 consecutive patients on our Ewing's protocol. Induction comprised three cycles of ifosfamide/etoposide on days 1 to 3 and cyclophosphamide (CTX)/doxorubicin on day 5, followed by granulocyte colony-stimulating factor. Local control using surgery and/or radiotherapy started at week 9 along with vincristine/dactinomycin. Maintenance included four alternating cycles of ifosfamide/etoposide and doxorubicin/CTX, with randomization to one of two CTX dose levels to determine the feasibility of dose-intensification during maintenance. RESULTS: Patients had a median age of 13.4 years (range, 4.5 to 24.9 years); 34 patients were male and 43 patients were white. Nineteen patients presented with metastatic disease, 29 had tumors greater than 8 cm in diameter, and 26 had primary bone tumors. These patients received 155 induction cycles, 91% of which resulted in grade 4 neutropenia, 68% in febrile neutropenia, and 68% in grade 3 to 4 thrombocytopenia. During maintenance, grade 4 neutropenia and grade 3 to 4 thrombocytopenia occurred in 81% and 85% of cycles, respectively. Thirty-five patients (66%) completed all therapy, only 13 without significant delays; three developed secondary myeloid malignancies. The toxicity and time to therapy completion were similar in both CTX arms. Estimated 3-year survival and event-free survival were 72%+/-8% and 60%+/-9%, respectively. CONCLUSION: Although intensifying therapy seems feasible for 25% of patients on this study, toxicity was considerable. Therefore, the noninvestigational use of dose-intensification in patients with EFT should await assessment of its impact on disease-free survival.

Adolescent↗

PubMed1998

Clues to recognition of fungal origin of lytic skeletal lesions.

The present study addresses the specificity of lytic osseous impact for distinguishing among metastatic cancer, tuberculosis, and fungal disease. Osseous impact is used in this manuscript as a convention to describe the macroscopic appearance of defleshed bones affected by the disease. Osseous changes in the skeleton of a 47-year-old black male, diagnosed in life as having blastomycosis, were characterized and compared to lytic lesions observed in ten individuals with tuberculosis and six with metastatic cancer in the Terry and Hamman-Todd Collections. Apparent distinguishing characteristics are identified. Eroded areas, present as fronts of resorption or the result of space-occupying masses in blastomycosis, with protruding, short, blunt, 1 x 2 mm spicules of new bone, are surrounded by periosteal reaction. These differed from smooth zones of resorption and coalesced lesions, with a smoothed marginal zone and space-occupied appearance--bone-displacing mass--in tuberculosis and lytic (nonpermeative) lesions of metastatic cancer. Displacing is a convention (an artificial term) denoting bone resorption and reformation at the outer edge of the tumor mass, giving the impression that the surrounding bone had expanded beyond its original margins. Irregular trabeculae are occasionally preserved in the margins, but remodeling in the form of blunting of those trabeculae is not observed macroscopically in either tuberculosis or metastatic cancer. Two apparently specific lesion types are noted in blastomycosis. Periosteal reaction surrounding fronts of resorption appears specific, at least for nonarticular osseous lytic lesions, among the three entities studied. Remodeling of isolated internal trabeculae in the space-occupying mass lesions of blastomycosis also appears unique among the three disorders studied. Comparison with coccidioidomycosis suggests that extrapolation of blastomycosis findings to other fungal diseases is feasible; description of additional clinically diagnosed cases is awaited.

Anthropology, Physical↗

PubMed1997

Outcome of treatment for pediatric sarcoma of the foot: a retrospective review over a 20-year period.

Soft tissue sarcomas (STS) arising in the foot are rare in children. From 1975 to 1994, 18 children (median age, 13.5 years) were treated at St Jude Children's Research Hospital for STS of the foot. Five children had rhabdomyosarcoma (RMS), with alveolar histology in four cases. All of these patients presented with metastatic disease, which proved fatal within 9 to 24 months despite combined modality treatment with chemotherapy, radiation, and surgery. Thirteen patients had nonrhabdomyosarcoma soft tissue sarcoma (NRSTS). The most common histological variant was synovial sarcoma (7 patients). Of the 10 who presented with localized disease, seven survived 1 to 12 years (median, 7 years). Surgical treatment for these consisted of local excision (n = 2), wide local excision (n = 3), below knee amputation (n = 1 ), ray amputation (n = 1). Three received supplemental radiation, and one was also treated with chemotherapy. Local or distant recurrence proved fatal in the three other children who had localized disease. Three children who presented with metastatic NRSTS died 8 to 14 months after diagnosis. All surviving patients are without significant functional disability. In our experience, pediatric RMS of the foot has a poor outcome, attributable to both alveolar histology and presence of metastatic disease at diagnosis. In contrast, NRSTS of the foot is more often localized, and limited surgery with adjuvant radiation in the absence of clear margins should be the treatment of choice.

Adolescent↗

PubMed1996

Local control in synchronous bilateral Wilms tumor.

PURPOSE: To evaluate the role of radiation therapy (RT), chemotherapy (CT), and surgery in the local control of synchronous bilateral Wilms Tumor (WT). METHODS AND MATERIALS: Between 1962 to 1993, 45 children were treated for bilateral WT; 38 patients with synchronous tumors were reviewed. Initial surgery depended on the era of treatment and included unilateral nephrectomy (N)/partial nephrectomy (PN) and contralateral PN in 6, unilateral N/PN alone in 7, and biopsy only in 25. Chemotherapy (CT) consisted of vincristine, actinomycin-D, and adriamycin in 32 and vincristine/ actinomycin-D in 6. Radiation therapy (RT) was given to 32 patients. Treatment included both kidneys in 20, unilateral kidney plus contralateral renal bed in 9, unilateral kidney in 2, and unilateral renal bed in 1. Follow-up was 16 months to 25 years (median: 6.3 years). RESULTS: Local control (LC) has been maintained in 66 out of 76 sites (87%). For Stage I-II disease with initial N/PN, LC was 10 out of 12 with RT and 11 out of 11 without RT; for Stage III with initial N/PN, LC was 8 out of 9 with RT and 1 out of 1 without RT. Initial CT and RT was followed by delayed N/PN for 20 sites; LC was 15 out of 17 in post induction Stage I-II and 1 out of 3 in postinduction Stage III. In 23 sites undergoing biopsy and chemotherapy, LC was 19 out of 20 with RT and 1 out of 3 without RT. Seven of 23 sites had a complete response (CR) after induction CT, and LC was maintained in four out of four with RT and one out of three without RT. Univariate Cox Regression analysis demonstrated that sites receiving two drugs had a statistically significant increase in loco-regional relapse when compared to sites receiving three drugs (p = 0.004). Major morbidities related to multimodality therapy have included renal failure in one patient and small bowel obstruction requiring lysis of adhesions in two patients. CONCLUSIONS: Local control does not seem to be compromised by renal conservation therapy. Local control is excellent in sites treated with radiation therapy in combination with three drug chemotherapy.

Adolescent↗

PubMed1996

Epithelioid sarcoma in children.

Literature regarding the natural history and prognosis of epithelioid sarcoma in the pediatric population is sparse. During the past 11 years, eight patients with epithelioid sarcoma were treated at St Jude Children's Research Hospital. Of the eight children, six of whom were male, seven presented with localized disease and one with metastatic disease. The primary tumor was located in the upper extremity in four patients; the other sites were the scalp, external ear, back, and mediastinum. The mean duration of symptoms before diagnosis was 8.3 months (range, 1 to 12 months). Surgical treatment comprising amputation or wide local excision was performed in six patients, three of whom had additional lymph node dissection. Three patients received multiagent chemotherapy, and four patients were treated with supplementary radiation. Two patients died of progressive local and distant disease within 9 months of diagnosis. The other six patients are alive and have no evidence of disease 12 months to 10 years 6 months after the completion of treatment.

Adolescent↗

PubMed1995

A phase II trial evaluating selective use of altered radiation dose and fractionation in patients with unresectable rhabdomyosarcoma.

PURPOSE: Between 1987 and 1991, 25 children with advanced rhabdomyosarcoma (20 with IRS Group 3 disease and 5 with Group 4 disease) were entered on a prospective study evaluating selective use of hyperfractionated irradiation (HFI) and reduced-dose conventionally fractionated irradiation (CFI), based on disease status following induction chemotherapy (ifosfamide or melphalan, followed by vincristine, adriamycin, and cyclophosphamide combination) with or without delayed surgery. METHODS AND MATERIALS: Patients with gross disease following induction chemotherapy with or without delayed surgery, and whose primary tumor sites did not involve the central nervous system, received HFI (n = 12) at 1.1 Gy twice-a-day to 59.4-63.8 Gy total. Patients with parameningeal primaries and intracranial disease extension received HFI with initiation of therapy (n = 2). Those with microscopic disease following induction chemotherapy with or without delayed surgery (n = 11) received reduced-dose CFI to 40 Gy. Active follow-up ranges from 28-75 months (median = 43 months) with no patient lost to follow-up. RESULTS: Eighteen patients (72%) are alive and without evidence of disease, including 8 of the children with gross residual disease postinduction therapy. The absolute 2-year continuous local tumor control rate is 86% for all patients. Among the 14 who received HFI, the absolute 2-year continuous local tumor control rate is 75% at 33 to 67 months (median = 38 months) postirradiation. Hyperfractionated irradiation was associated with expected enhancement of acute reactions, which all resolved with conservative medical management. Grade 4 or 5 acute toxicities were not seen. Significant late radiation morbidity has, thus far, been minimal and limited to Grade 1 and 2 events. Among the 11 who received reduced-dose CFI, the absolute 2-year continuous local tumor control rate is 100% at 25 to 70 months (median = 40 months) postirradiation. CONCLUSION: This limited experience suggests that HFI to a dose level of 60 Gy can be used selectively in children with advanced rhabdomyosarcoma left with gross disease following induction chemotherapy, with or without delayed surgery, with an apparent improvement in local control, and minimization of potential late radiation toxicity. Concurrently, those left with microscopic disease following induction therapy can be selectively treated with reduced-dose CFI with excellent local control.

Adolescent↗

PubMed1995

Health-related behaviors of survivors of childhood cancer.

The health-related beliefs and behaviors of long-term survivors of childhood cancer are important because of vulnerability to adverse late effects from their primary malignancy and its therapy. A health behavior survey was completed by 110 parents of long-term survivors ranging in age from 11-17 years, and by 40 adult long-term survivors of childhood cancer ranging in age from 18-29 years. The survey included questions on the former patient's frequency of alcohol and tobacco use, as well as diet, exercise, sleep, dental, and seatbelt habits. The reported prevalence of tobacco and alcohol use was less than 10% among those less than 18 years old. Among the adults, tobacco (17.5%) and alcohol (72.5%) use was greater, but problem drinking was infrequently reported. In order to assess their perceived vulnerability, we asked the parents and the young adult patients to rate the strength of their belief that it is more important for the patient to keep healthy compared to most other children or young adults. Contrary to our expectation, demographic factors such as the patient's gender, socioeconomic level, or time elapsed since completion of therapy exerted minimal influence on their responses. Over 80% of parents and 60% of young adult survivors believed that it was more important for the former patient to remain healthy compared to most other people. However, this shared belief in increased vulnerability was inconsistently expressed in the patient's health behaviors. These results suggest that specific changes are needed in the health assessment and education of long-term survivors of childhood cancer.

Adolescent↗

PubMed1995

Subsequent malignancies in children and adolescents after treatment for Hodgkin's disease.

PURPOSE: We assessed the cumulative risk of malignancies following treatment for Hodgkin's disease in childhood and adolescence and investigated related patient and treatment characteristics. PATIENTS AND METHODS: Medical records of 499 Hodgkin's disease patients treated between 1962 and 1993 were reviewed. There were 385 adolescents (> or = 10 years of age at diagnosis) and 114 preadolescents (< 10 years). Most patients (n = 346) were treated with radiation plus multiagent chemotherapy, while 30 received only chemotherapy and 123 only radiation therapy. Radiation doses ranged from 20 to 42 Gy. RESULTS: At a median follow-up duration of 9 years (range, 0.1 to 27.4), 25 patients have had second malignancies: 19 solid tumors, four acute nonlymphoblastic leukemias (ANLLs), 1 non-Hodgkin's lymphoma (NHL), and one chronic myeloid leukemia (CML). Three patients have had a third malignancy. The estimated cumulative risk of second malignancies increased from 1.5% at 5 years to 7.7% at 15 years. All but two of the patients with second malignancies were > or = 10 years of age at initial diagnosis, which reflects the higher risk among patients treated for Hodgkin's disease as adolescents (P = .01). Second malignancies were more common among female patients (P = .0002), even when those breast cancer were excluded (P = .007), and in those treated for recurrent Hodgkin's disease (P = .02). Patients with ANLL/NHL were older at diagnosis of Hodgkin's disease than those with solid tumors, (median age, 18.3 v 13.8 years; P = .04). There was no difference between groups treated with radiation therapy alone, chemotherapy alone, or radiation plus multiagent chemotherapy. CONCLUSION: Adolescents treated for Hodgkin's disease are at greater at risk of second malignancies than younger patients. Overall, adolescent females treated for recurrent Hodgkin's disease appear to be at greatest risk, while preadolescents appear to be protected from this late complication.

Adolescent↗

PubMed1995

Preirradiation chemotherapy with carboplatin and etoposide in newly diagnosed embryonal pediatric CNS tumors.

PURPOSE: We evaluated the clinical efficacy of preirradiation carboplatin (CARBO) and etoposide (VP-16) in 25 patients with newly diagnosed embryonal CNS tumors. PATIENTS AND METHODS: Sixteen patients with high-risk medulloblastoma and nine with other embryonal tumors were treated with two daily doses of CARBO 350 mg/m2 and VP-16 100 mg/m2 (CARBO/VP) every 21 days for four cycles before standard craniospinal irradiation. Patients with disease progression (PD) before radiation therapy were additionally treated with intensive postirradiation cyclophosphamide (CYCLO) and vincristine (VINC). RESULTS: Among 23 assessable patients, 48% (95% confidence interval, 27% to 69%) had a complete response (CR) or partial response (PR) to CARBO/VP; eight had PD. Among the subgroup of 15 assessable patients with medulloblastoma, 53% had a CR or PR (95% confidence interval, 27% to 79%) and five PD. The toxicity of CARBO/VP was predominantly hematologic; although grade IV neutropenia was common, only five episodes of febrile neutropenia occurred. Only thrombocytopenia was a more common toxicity than in other reported chemotherapy regimens; ototoxicity was less common than in cisplatin (CDDP) regimens. CONCLUSION: The responses and survival associated with neoadjuvant CARBO/VP are similar to those with CDDP-containing and other neoadjuvant drug regimens. Although the rate of progression with this regimen may be higher than with similar CDDP-containing regimens, the numbers of patients in other published studies of these agents are too small to detect meaningful statistical differences. Future studies must balance the apparently comparable efficacy of CARBO and CDDP with their differing toxicities.

Adolescent↗

PubMed1994

Predominance of pilocytic histology in dorsally exophytic brain stem tumors.

We report the magnetic resonance imaging (MRI) and clinico-histologic characterization of dorsally exophytic brain stem gliomas (DEBSGs). Between 1983 and 1991, 12 of 51 patients evaluated for the diagnosis of brain stem glioma were found to have DEBSGs emanating from the pons, pontomedullary junction or medulla. Eleven of the 12 patients had classic juvenile pilocytic astrocytomas. Unlike most other brain stem tumors, these patients were young (median 38 months, range 17-75), had a relatively long duration of symptoms (median 7 months, range 2-24) and displayed signs of increased intracranial pressure with limited cranial nerve paresis, absence of pyramidal tract findings, and near normal brain stem auditory-evoked potentials. MRI characteristically showed sharply demarcated lesions with decreased signal intensity on T1, and increased intensity on T2 sequences. Except for cystic areas, these tumors showed bright, uniform enhancement after gadolinium-DTPA. In all patients, 50-100% of the tumor volume could be resected. Three of 10 patients who received no immediate postoperative treatment eventually demonstrated disease progression, and 2 patients with subtotal resections who were treated with radiation and/or chemotherapy postoperatively remain disease-free for extended periods of time. The only death occurred in the 1 patient treated with chemotherapy who died of secondary leukemia. The overall and progression-free survival of these patients at 2 years is 100 and 67% as compared to 18 and 21%, respectively, for other concomitantly treated nonexophytic brain stem gliomas.2+ the ability to achieve significant degrees of resection.

Astrocytoma↗

PubMed1993

Haloperidol and clozapine treatment and their effect on M-chlorophenylpiperazine-mediated responses in schizophrenia: implications for the mechanism of action of clozapine.

Since clozapine is, in contrast to conventional neuroleptics, effective in treatment refractory schizophrenic patients its mechanism of action may be different from that of typical neuroleptics. Clozapine has been shown to display the highest binding affinity of all neuroleptics to one of the serotonin (5-hydroxytryptamine, 5HT) receptor subtypes, i.e., the 5HT1c receptor. Furthermore, clozapine, in contrast to conventional neuroleptics, blocks the effect of 5HT agonists on ACTH and corticosterone release in animals. This study hypothesized that clozapine, but not haloperidol would block ACTH and prolactin release induced by the 5HT agonist, m-chlorophenylpiperazine (MCPP). MCPP (0.35 mg/kg PO) was administered after a 3-week drug-free period, after 5 weeks of haloperidol treatment (20 mg/day) and finally after 5 weeks of clozapine treatment (> 400 mg/day) in ten male schizophrenic patients. Clozapine, but not haloperidol, blocked the effect of MCPP on ACTH and prolactin release. These results suggest that clozapine, in contrast to haloperidol, is a functional 5HT antagonist. Since MCPP-induced ACTH and prolactin release may be (partially) 5HT1c mediated, these results suggest that clozapine is a potent antagonist at the 5HT1c receptor.

Adrenocorticotropic Hormone↗

PubMed1993

Efficacy and toxicity of multiagent chemotherapy and low-dose involved-field radiotherapy in children and adolescents with Hodgkin's disease.

PURPOSE: Between May 1980 and September 1990, 85 patients with Hodgkin's disease were treated with a regimen designed to increase cure rates while reducing late toxicity. PATIENTS AND METHODS: Therapy consisted of five cycles of cyclophosphamide, Oncovin (vincristine; Eli Lilly and Co, Indianapolis, IN), and procarbazine (COP), alternated with four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and low-dose (20 Gy) regional radiotherapy. Vincristine and cyclophosphamide were administered as tolerated during irradiation and during the 2- to 4-week rest period between radiation volumes. The need for staging laparotomy was defined by clinical presentation. RESULTS: The median age at diagnosis was 14 years (range, 4 to 20), and 56% of patients were male. The majority (67%) had stage III or IV disease and 68% (19 of 28) of stage II patients had bulky mediastinal disease. Nodular sclerosing histology predominated (67%). Ninety-three percent of patients were alive without disease with a median follow-up of 4.1 years. Abnormalities were detected on chest roentgenograms and/or pulmonary function tests in 58% and 25% of clinically asymptomatic patients who were tested at least 1 year after completion of therapy. The only symptomatic patient had pulmonary fibrosis after treatment with bleomycin (20 U/m2) and mantle (20 Gy)/lung (13 Gy) irradiation, and developed multiple spontaneous pneumothoraces that required cortical stripping. One patient had congestive heart failure 19 months post-treatment, and two had abnormalities on echocardiograms. Thyroid abnormalities occurred in 21 (27%) patients who were assessable for late toxicity. The majority of female patients have had regular menstrual cycles. Six developed ovarian failure, and 10 have had a total of 17 pregnancies. Other than one documented case of oligospermia, information was not available on male fertility. CONCLUSION: The results demonstrate excellent disease control for the COP/ABVD regimen, with acceptable toxicity.

Adolescent↗

PubMed1993

Acute hypersensitivity reactions to etoposide in a VEPA regimen for Hodgkin's disease.

PURPOSE: We report an unexpectedly high incidence of hypersensitivity to etoposide among 45 patients with newly diagnosed Hodgkin's disease treated with vinblastine, etoposide, prednisone, and doxorubicin (VEPA) plus radiation. PATIENTS AND METHODS: Twenty-three of 45 patients (51%) had one or more acute hypersensitivity reactions to etoposide administration. The 23 patients were 8 to 18 years of age (median, 15 years); 12 were males. Four patients had experienced prior allergic reactions to antibiotics or intravenous contrast media. RESULTS: Hypersensitivity reactions followed the first or second dose of VEPA in most cases. The reactions occurred at a median time of 5 minutes (range, 3 to 120) from the start of the etoposide infusion. Fifteen patients reacted early (within 10 minutes), four midway through the infusion, and four after completion of the infusion. Signs and symptoms included flushing, respiratory problems, changes in blood pressure, and abdominal pain with or without nausea and vomiting. Respiratory problems included dyspnea, chest pain/tightness, bronchospasm, and cyanosis. Symptoms were alleviated by discontinuing the etoposide infusions and administering diphenhydramine and/or hydrocortisone; epinephrine was required to reverse bronchospasm in three cases. All 23 patients recovered without adverse sequelae and were rechallenged with etoposide. Fifteen patients tolerated subsequent etoposide infused at a slower rate, with antihistamine and/or corticosteroid premedication; five had recurrent hypersensitivity despite these measures. Three of these five developed similar symptoms when teniposide was substituted for etoposide. Three patients who had isolated episodes of hypotension on completion of the etoposide infusion successfully received subsequent infusions without premedication or change in infusion rate or concentration. CONCLUSION: Despite this unexpectedly high incidence of hypersensitivity among Hodgkin's disease patients treated with etoposide, rechallenge with the drug was successful in 78% of cases.

Acute Disease↗