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Biomedical subjects

N K Foreman

Publications and source records attributed to N K Foreman.

At least 19 recordsLinked to original sources
PubMed2005

A study of sequential high dose cyclophosphamide and high dose carboplatin with peripheral stem-cell rescue in resistant or recurrent pediatric brain tumors.

PURPOSE: To determine the maximum tolerated dose (MTD) of carboplatin with autologous hematopoietic stem-cell rescue, in children with poor-prognosis brain tumors. PATIENTS AND METHODS: A previously determined dose of cyclophosphamide with stem-cell rescue was used as a first course. In a second course, carboplatin was given for 3 days with stem-cell rescue to 20 children. The starting dose of carboplatin was 400 mg/m2/day with increments of 75 mg/m2/day in subsequent cohorts. Toxicity and tumor response were recorded. RESULTS: There were two grade IV toxicities at the dose level of 775 mg/m2/day. There were no toxic deaths. Thus, the MTD of carboplatin was 700 mg/m2/day for 3 days. There were six complete responses (33%, 95% confidence interval [CI], 13-59%), two partial responses (11%; 95% CI, 1-35%), four with stable diseases (22%; 95% CI, 6-48%) and six progressed (33%; 95% CI, 13-59%) out of 18 assessable. Seven of the eight responses were in primitive neuroectodermal tumors (PNETs) or Germinomas. One child with a metastatic anaplastic astrocytoma had a CR. The median duration of tumor response was 10 months (range: 1.5-87 months) with two children disease free at 66 and 87 months. Actuarial survival is 21%. Median follow-up of survivors is 35 months (range: 15-87 months). CONCLUSION: The MTD of carboplatin with stem-cell rescue is 700 mg/m2/day for 3 days. Sequential stem-cell supported cyclophosphamide and carboplatin was tolerable in children with brain tumors and produced responses in PNETs and Germinomas.

Adolescent↗
PubMed2004

Intracranial germ cell tumors: a single institution experience and review of the literature.

There is little literature to guide therapy in children and young adults with intracranial germ cell tumors. We present 17 consecutively diagnosed intracranial germ cell tumors at The Children's Hospital, Denver, from 1995 to 2001. Of 17 patients, 3 had considerable delay in diagnosis. Two with suprasellar tumors presented with dementia, blindness and pan-hypopituitarism and another with recurrent subarachnoid hemorrhage. Seven had germinoma, three were metastatic at diagnosis. Ten had non-germinomatous germ cell tumors (NGGCT), 5/10 were alpha feto-protein (AFP) positive only, one beta-human chorionic growth (betaHCG) factor positive only, 3 positive for AFP and betaHCG, and 1 malignant teratoma. Therapy for metastatic patients consisted of chemotherapy followed by craniospinal radiation (CSI). Patients with localized disease received chemotherapy followed by focal radiation. Two patients received chemotherapy only, one because she died of sepsis while receiving chemotherapy and one because of neurologic injury incurred during surgery parents elected for no therapy. Three patients have died, one of tumor recurrence, one from a remote complication of surgery and one of sepsis. Twelve patients are alive without evidence of disease from 10 to 68 months (median 31.5 months). All five children with only AFP positivity, treated with chemotherapy and focal radiation are alive without evidence of disease at 10, 16, 22, 41 and 41 months. Thus, there is little evidence that CSI is necessary in non-metastatic germinomas and AFP positive NGGCTs when combined chemotherapy and radiation therapy is used. However, complications of delayed diagnosis, surgery and chemotherapy are important causes of mortality, with only one patient dying of tumor.

Adult↗
PubMed2001

Peripheral placement of apheresis catheters in children: feasibility, safety, and efficacy in the collection of blood stem cells--initial experience.

An 8-F 24-cm-long apheresis catheter was placed in the basilic vein with imaging-guided percutaneous technique in 15 children undergoing leukapheresis for collection of autologous peripheral blood stem cells. There were no immediate or long-term complications. This is a low-morbidity procedure requiring minimal sedation that results in successful collection of peripheral blood stem cells and allows flow rates comparable to those with surgically placed central catheters.

Adolescent↗
PubMed2000

Pattern of recurrence in children with midline posterior fossa malignant neoplasms.

BACKGROUND: Surveillance imaging of the brain and spinal neuraxis in patients with posterior fossa malignant tumors is commonly performed, with the assumption that early detection of tumor recurrence will improve outcome. However, the benefit of this imaging has not been proven. PURPOSE: To evaluate the usefulness of spinal surveillance imaging in children with nonmetastatic (at diagnosis, M0) posterior fossa ependymoma and medulloblastoma. MATERIALS AND METHODS: This retrospective study included 65 children (3 months to 16 years, mean 5.7 years) treated between 1985 and 1997 for ependymoma (22) and medulloblastoma (43). Medical records were reviewed for pathology and treatment data. Serial imaging of the head and spine was reviewed for evidence of tumor recurrence. RESULTS: Twenty-four patients (37 %) had tumor recurrence, including 13 with ependymoma and 11 with medulloblastoma. Of the 17/24 recurrent patients initially diagnosed as M0 (6 medulloblastoma and 11 ependymoma), 13 (76 %) had a cranial recurrence only, and 4 (24 %) presented with concomitant cranial and spinal recurrence. No M0 patient presented solely with spinal metastases at recurrence. CONCLUSION: This study suggests that spinal surveillance imaging in patients with posterior fossa ependymoma or medulloblastoma initially staged as M0 may not be useful, as these patients initially recur intracranially. Thus, until an intracranial recurrence is detected, these patients may be spared the time, expense and sedation risk necessary for spinal imaging.

Adolescent↗
PubMed2000

Protein kinase C zeta isoform is critical for proliferation in human glioblastoma cell lines.

Previous studies have confirmed that proliferation in glioblastoma cell lines can be blocked by non-isoform specific protein kinase C (PKC) inhibitors, e.g calphostin C, staurosporine. However, the exact mechanism of PKC involvement is poorly understood. The aim of this study was to explore the role of specific PKC isoforms in the aberrant growth of glioblastoma. Identification of the isoform(s) critical for proliferation in glioblastoma would present a better target for the design of chemotherapeutic strategies. To this end, we screened expression on PKC isoforms in four human glioblastoma cell lines both when proliferating and in a quiescent state using western assays. PKC isoforms alpha, beta, betaII and zeta were found to be expressed in all cell lines. PKC epsilon was detected in three out of four cell lines and PKC eta was detected in one out of four cell lines. Quiescence of growth resulted in down-regulation of PKC epsilon. We examined the role of these isoforms by studying the effect of PKC isoform-specific inhibitors bisindolylmaleimide-I and Gö6976 on proliferation in a panel of four human glioblastoma cell lines. Inhibition of PKC alpha and epsilon had no effect on proliferation, suggesting that previous studies targeting PKC alpha may not be of therapeutic benefit. More significantly, it was shown that inhibition of PKC zeta blocked proliferation. This suggests that the inhibition of PKC zeta may be an important chemotherapeutic target for arresting growth in glioblastoma.

Blotting, Western↗
PubMed1999

Health status in 52 long-term survivors of pediatric brain tumors.

The percentage of children who survive childhood brain tumors is increasing. A number have neurological and other sequelae which impact on the quality of their survival. We reviewed long-term survivors using a standardized health status instrument. The mothers of 52 survivors of brain tumors were surveyed. Eight different aspects (attributes) of health status were scored. The first 6 of these attributes were scored in a health status index (HSI) developed at McMaster University. Subgroup analysis was performed. Limitation in the quality of life was found in one of the 8 attributes in all but 2 of the subjects. The health status index (HSI) score using the first 6 attributes of this survey had a median of 0.73 (range 0.16-1.00). This score is lower than that found in previously surveyed survivors of leukemia or other childhood cancers. Examination of age at diagnosis, extent of surgery, sex and therapeutic modalities used showed no correlation with HSI score. Those with supratentorial astrocytomas had a lower HSI score (0.65) than those with infratentorial astrocytomas (0.85) (p = 0.05). Children with craniopharyngiomas had a poor score (0.64). This survey shows that the survivors of brain tumors have an appreciable burden of morbidity. Most have deficits in health status that affect many areas of their lives. Apart from site of the primary tumor, there was little correlation between subgroups studied and health status. The health status of children who survive brain tumors is lower than that of survivors of other childhood malignancies.

Adolescent↗
PubMed1999

Successful use of intracavitary bleomycin for low-grade astrocytoma tumor cyst.

We report successful use of bleomycin in a low-grade astrocytoma tumor cyst of the tectal plate. A 6-year-old male underwent subtotal resection of a low-grade astrocytoma of the tectal plate followed by chemotherapy and proton beam radiation at age 2 and a half. Despite resolution of the solid portion of the tumor, serial MRI showed enlargement of a bilobar tumor cyst 3 years after the original diagnosis. The patient developed progressive ataxia, short-term memory loss and dysconjugate gaze. Following stereotactic placement of an Ommaya reservoir into the cyst, Isovue contrast and CT scan were used to confirm the integrity of the cyst. Five consecutive daily doses of 3.0 mg of bleomycin were instilled into the cyst after removal of cyst fluid. The therapy was well tolerated in the outpatient setting, and the clinical findings resolved. Subsequent CT and MRI at 4 months and 2 years after bleomycin confirmed no recurrence of the tumor or cyst.

Antibiotics, Antineoplastic↗
PubMed1999

Tamoxifen radiosensitization in human glioblastoma cell lines.

OBJECT: A combined tamoxifen and radiation therapy is being used in clinical trials to treat glioblastoma multiforme (GBM). The rationale behind this therapy is that tamoxifen is a radiosensitizer. However, the evidence for this is weak. The authors, therefore, examined the effect of combined radiation-tamoxifen therapy in three GBM cell lines of human origin. METHODS: The GBM cell lines were exposed to different concentrations (0.3-5 microg/ml) of tamoxifen and subsequently irradiated at varying doses (0.8-5 Gy). Tumor growth inhibition was measured using a proliferation assay. The interaction of tamoxifen and radiation therapies was quantified using the combination index method, which distinguishes whether a combined antitumor effect is synergistic, additive, or antagonistic. At high doses of tamoxifen or radiation there was significant inhibition of tumor cell proliferation. At low doses of either therapeutic agent, there was little effect. In one cell line, synergism occurred at high doses of tamoxifen and radiation. In the other two cell lines, an additive effect was observed. In only one of the three cell lines was there synergy between tamoxifen and radiation at doses that significantly inhibited tumor proliferation. CONCLUSIONS: Because synergy could not be demonstrated in all three cell lines at active dosages, the clinical combination of tamoxifen and radiation therapies may not be of benefit to all patients.

Dose-Response Relationship, Drug↗
PubMed1998

Adenovirus mediated gene therapy in a glioblastoma vaccine model; specific antitumor immunity and abrogation of immunosuppression.

Clinical trials are being performed using tumor genetically engineered to produce cytokines as a vaccine. The design of such a vaccine may be made more effective by further study using in-vitro as well as in-vivo models. We studied an in-vitro tumor 'vaccine' model in glioblastoma. We have demonstrated high efficiency transfection of the Interleukin-2 (IL-2) gene into glioblastoma cell lines using adenoviral vectors. Glioblastoma cell lines transduced with this vector could produce high levels of IL-2 for up to 2 weeks, long enough to elicit an antitumor immune response. We studied tumor/effector cell interactions using cytotoxicity assays coupled with flow cytometric analysis. Activation of CD8+ and expansion of CD3+/CD16+ effector cell subpopulations were observed, suggesting the generation of a specific anti-tumor response and the potential for systemic immunity. We demonstrated that glioblastoma produce immunosuppressive factors which reduce the antitumor response by peripheral blood effector cells. These immunosuppressive factors could be neutralized to improve antitumor response. A better understanding of tumor/effector cell interactions may improve the design of gene therapy trials.

Adenoviridae↗
PubMed1997

Congenital malignant rhabdoid tumour of the gum margin.

The case of an infant born with a large polypoid tumour arising from the mouth is described. The tumour had the histological, immunohistochemical and ultrastructural phenotype of an extrarenal malignant rhabdoid tumour and followed an aggressive clinical course. This is one of the few reported cases of malignant rhabdoid tumour to present at birth. The oral tumour was associated with a mass in the posterior cranial fossa. This was most likely to be a simultaneous second primary tumour.

Fatal Outcome↗
PubMed1997

Second-look surgery for incompletely resected fourth ventricle ependymomas: technical case report.

OBJECTIVE AND IMPORTANCE: The prognosis for patients with ependymomas is related to the adequacy of surgical clearance. It is, however, often not possible to obtain a macroscopically complete resection of tumors arising in the posterior fossa. This may be because of the involvement of structures, the sacrifice of which would result in unacceptable morbidity, or because of metastatic lesions at diagnosis. For those patients in whom initial surgery was incomplete, elective second-look surgery may allow more complete clearance of tumor. INTERVENTION: We have performed second-look surgery for fourth ventricle ependymomas in five patients: two women, aged 26 and 27 years, and three male patients, aged 4 months, 19 months, and 18 years. The 19-month-old male patient underwent early second-look surgery without receiving any interim chemotherapy. Second-look surgery on the other four patients was performed after they had received chemotherapy. No additional major morbidity was associated with the subsequent surgery, which achieved macroscopically complete clearances in four of the five patients. Three of four patients who underwent macroscopically complete resections were well, without clinical or radiological evidence of recurrent tumor, at 23, 25, and 34 months after their second operations. The 10-month-old patient who underwent early second-look complete resection relapsed locally at 33 months after surgery. Complete resection was not possible in one patient who had progressive tumor 8 months after second-look surgery. CONCLUSION: For patients in whom complete excision of fourth ventricle ependymomas is not possible at initial surgery, second-look procedures may enable macroscopic clearance to be achieved with little morbidity. A larger study is needed to evaluate this approach to treatment.

Adolescent↗
PubMed1997

High-dose cyclophosphamide for poor-prognosis and recurrent pediatric brain tumors: a dose-escalation study.

PURPOSE: To determine the maximum-tolerated dose (MTD) of cyclophosphamide (CTX) when administered over 2 consecutive days followed by hematopoetic stem-cell rescue given as two sequential courses to children with glioblastoma multiforme, poor-prognosis pontine gliomas, and other recurrent CNS tumors. PATIENTS AND METHODS: Two identical doses of CTX were administered 24 hours apart to 14 children and followed by hematopoetic stem-cell rescue. This treatment was repeated immediately following hematologic recovery. The starting dose of CTX was 2.5 g/m2/d with increments of 0.5 g/m2/d. CTX pharmacokinetics and metabolism were measured during 22 courses of treatment. Toxicity and tumor response were recorded. RESULTS: There were two toxic deaths at the dose level of 4 g/m2/d. These were not clearly related to cardiac toxicity and may have been due to generalized capillary leak syndrome. Thus, the MTD of CTX was 3.5 g/m2/ d. There were six complete responses (CRs) (46%; (95% confidence interval [CI], 19% to 73%) and four partial responses (PRs) (31%; 95% CI, 6% to 56%), and one patient achieved stable disease. All children with intracranial primitive neuroectodermal tumors (PNETs) improved following CTX. The median duration of tumor response was 6 months (range, 4 to 29) and only one patient remains disease-free following CTX alone. Overall survival is 21% (95% CI, 13% to 29%) at a median follow-up time of 27 months (range, 12 to 34). CONCLUSION: The MTD of CTX when followed by hematopoetic stem-cell rescue is 3.5 g/m2 administered on each of 2 consecutive days. This treatment was tolerable in children with poor-prognosis brain tumors and produced complete responses in children with recurrent PNETs.

Adolescent↗
PubMed1996

Variation in survival of children with cancer within a region of the United Kingdom.

BACKGROUND: A population-based study of survival of 678 children, age less than 15 years, diagnosed with cancer in the Southwest region of the United Kingdom showed an improvement in 5-year survival from 53% between 1976 and 1980 to 64% between 1981 and 1985 (P = 0.008). Survival varied significantly among the five counties that make up the region (P = 0.0008); the differences were greatest for central nervous system (CNS) tumors. METHODS: The expertise of local hospitals and entrance into national trials was examined. The region has nine hospitals acting as primary treatment hospitals for children with cancer, two neurosurgical units, and one regional oncology unit. Four of the primary hospitals saw more than six children per year and were designated "large" centers. Five saw fewer than six patients per year and were designated "small" hospitals. RESULTS: There was a significant difference in survival of patients according to the number of patients treated per year per hospital. A hospital that treated fewer than six patients per year was designated "small" and six or more designated "large." At 5 years, patients with CNS tumors experienced a 58% survival rate in large hospitals and a 41% survival rate in small hospitals. (P = 0.03). The rate of entrance into trials for all malignancies did not differ between large (30%) and small (27%) centers. Only 5% of children with CNS tumors were placed on national trials. There was no difference in survival rates for CNS tumors in the two neurosurgical centers. CONCLUSIONS: There were significant differences in survival by county for children with cancer, especially those with CNS tumors. In the first half of the study decade, in hospitals treating fewer than six cases of childhood cancer per year, children with CNS tumors were rarely placed on national protocols and did poorly.

Adolescent↗
PubMed1996

Radon in Devon and Cornwall and paediatric malignancies.

Exposure to radon in dwellings may cause cancer including paediatric malignancies. Devon and Cornwall have the highest exposure to radon of the counties of England. However, within these counties there is considerable variation in exposure. Exposure to radon in the 283 postcode sectors of the two counties has been published. The incidence of childhood malignancies between 1976 and 1985 was studied to compare postcode sectors of radon exposures > or = 100 Bq/m3 with sectors < 100 Bq/m3. No significant difference in the incidence rate of 106.7 per million child years in the high radon postcode sectors and 121.7 in the low (P = 0.29) was found. When the incidences of individual tumours were examined, a significantly increased rate of neuroblastoma (P = 0.02) and a non-significant increased rate of acute myeloid leukaemia were found in the high exposure postcode sectors. No association between radon exposure and overall rate of childhood malignancy was found.

Acute Disease↗