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Biomedical subjects

J Blatt

Publications and source records attributed to J Blatt.

At least 37 records · Page 2Linked to original sources
PubMed1997

Neuroblastoma and related tumors in Turner's syndrome.

OBJECTIVES: The identification of constitutional cytogenetic abnormalities in patients with cancer may indicate loci of genes, abnormalities of which are responsible for tumor development or progression. This study was undertaken to determine whether girls with Turner's syndrome (TS) (partial or complete deletion of an X chromosome, short stature, gonadal dysgenesis) are at increased risk of neural crest-derived tumors. STUDY DESIGN: Medical records of 394 patients with TS who were followed up at Thomas Jefferson Hospital and Children's Hospital of Pittsburgh were reviewed for documentation of TS phenotype, constitutional cytogenetics, and history of neuroblastoma or related tumors. Informative cases were reviewed for tumor pathology, primary site, disease stage, associated symptoms, treatment, and outcome. RESULTS: Three patients were found to have neuroblastoma. A fourth child who died of neurofibrosarcoma was found to have extensive areas of ganglioneuroma, the benign counterpart of neuroblastoma, at autopsy. An additional four girls with TS and neuroblastoma were identified in the literature, as were two more patients with ganglioneuroma. These 10 patients ranged in age from 1 week to 16 10/12 years (median age, 3 years), and all but two of the children had localized lesions. Two of the seven children with neuroblastoma had courses complicated by opsoclonus-myoclonus, a syndrome found in fewer than 5% of all patients with neuroblastoma. CONCLUSIONS: These data strongly suggest that girls with TS are predisposed to the development of neuroblastoma and related tumors. Because these tumors are often of limited stage and may be underdiagnosed, screening of urine of patients with TS for elevated catecholamine metabolite levels may strengthen this association.

Adolescent↗
PubMed1997

Malignancy after retinoblastoma: secondary cancer or recurrence?

The risk of second malignancy after retinoblastoma is reported to be as high as 20% at 10 years after initial diagnosis. This incidence may be an overestimate because of difficulties in distinguishing a second malignancy from recurrent tumor. We encountered a patient with bilateral retinoblastoma who developed a temporal mass 3.5 years after initial treatment for what had first been diagnosed as rhabdomyosarcoma; further study suggested that it was recurrent retinoblastoma manifesting as primitive neuroectodermal tumor (PNET) with multilineage differentiation. Chromosome 13 abnormalities were compatible with either rhabdomyosarcoma or recurrent retinoblastoma. To determine how often second malignancies in retinoblastoma patients may be confused with recurrent primary tumor, we reviewed our experience at Children's Hospital of Pittsburgh. Of 43 retinoblastoma patients seen between 1951 and 1992, presumed second malignancies were documented in four, including the current case. Of the three other second tumors, one had both neural and skeletal muscle differentiation; another was diagnosed as rhabdomyosarcoma unclassifiable as embryonal or alveolar; the last was an osteosarcoma. Only the osteosarcoma was clearly a second neoplasm; two and perhaps three of the other cases may be recurrent retinoblastoma. The distinction between second malignancy and recurrent retinoblastoma may be difficult but is worth determining, because treatment may differ, depending on the correct designation.

Chromosome Banding↗
PubMed1997

The use of counterflow centrifugal elutriation for the depletion of T cells from unrelated donor bone marrow.

Transplantation of marrow from unrelated donors is associated with an increased incidence and severity of graft-versus-host disease (GVHD). In an attempt to minimize GVHD without compromising engraftment, unrelated donor marrow was depleted of lymphocytes by counterflow centrifugal elutriation (CCE), and a fixed dose of 0.5 x 10(6) CD3+ T cells/kg, as measured in real time by flow cytometry, was added back to the graft. Patients received cyclosporine (CYA) and corticosteroids for GVHD prophylaxis and to facilitate engraftment. In the first cohort (study I), 7 patients received busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) (CY) and one patient received CY (200 mg/kg) + 1260 cGy fractionated TBI. Of 6 who were evaluable for both engraftment and rejection, 4 rejected their graft. The study was terminated, and the protocol was modified (study II) by the addition of antithymocyte globulin (ATG) to the pre-BMT and post-BMT therapy. Twelve patients received CY + TBI as above plus ATG given pre-BMT and post-BMT. Ten of twelve who received ATG engrafted. Twelve patients from studies I and II were evaluable for acute GVHD. Two developed grade I acute GVHD. Two patients developed grade II acute GVHD, 2 patients developed grade III GVHD, and 1 patient developed grade IV acute GVHD. Two of three cases of acute GVHD (> grade II) occurred later than day 100 after BMT concomitant with reduction of immunosuppressive therapy. The rate of engraftment was significantly higher in study II (p = .054). In numbers of CD34+ cells infused, numbers of CFU-GM infused, and numbers of nucleated cells did not correlate with engraftment. We conclude that (a) in contrast to the results seen in recipients of marrow from HLA-matched sibling donors, the depletion of unrelated donor marrow of all but 0.5 x 10(6) CD34+ cells/kg together with CYA + corticosteroids was not sufficient to facilitate engraftment. The use of a more immunosuppressive regimen containing TBI and ATG appeared to improve engraftment. (b) The reduction of the graft T cell dose to 0.5 x 10(6) CD34+ cells/kg resulted in a higher incidence of acute GVHD than that seen in recipients of marrow from genotypically identical donors whose marrow was similarly processed.

Adolescent↗
PubMed1997

A phase I study of high-dose tamoxifen for the treatment of refractory malignant gliomas of childhood.

Recent studies have indicated that the proliferation of malignant gliomas is in part dependent on excessive activation of protein kinase C (PKC)-mediated pathways. Conversely, inhibiting PKC may provide a novel approach for blocking glioma growth. The antiestrogen tamoxifen, a moderately potent PKC inhibitor, has been shown in vitro to block the proliferation of malignant glioma cell lines at concentrations several-fold higher than those typically attained during the treatment of breast cancer; such serum concentrations may be achieved with doses > 40 mg/m2 b.i.d. The safety and efficacy of these high doses for producing disease control in patients with malignant gliomas has recently been noted anecdotally, although a rigorous study of this agent has been lacking. To address this issue, we examined the safety and efficacy of high-dose tamoxifen in a series of children with malignant gliomas that had progressed after conventional therapy. An initial group was treated with 60 mg/m2 p.o. b.i.d. and a second group with 100 mg/m2 b.i.d. Steady-state serum tamoxifen and metabolite levels were measured in most patients. Toxicity with the regimen was minimal; two patients treated at the higher dose required reduction to the lower dose because of asymptomatic prolongation of the QT interval on an electrocardiogram. Although none of the patients exhibited clear-cut tumor regression, 4 of 14 patients had stabilization of previously progressive disease for at least 3 months; the longest survivor lived for 17 months after beginning tamoxifen. The moderate efficacy of this agent in otherwise end-stage disease coupled with its low toxicity and the relative ease of oral administration provides a rationale for proceeding with larger studies of this agent in patients with malignant gliomas, possibly as a means for potentiating the effects of conventional chemotherapeutic agents, which to date have shown limited efficacy in the treatment of these tumors.

Administration, Oral↗
PubMed1996

Randomized comparison of moderate-dose methotrexate infusions to oral methotrexate in children with intermediate risk acute lymphoblastic leukemia: a Childrens Cancer Group study.

Methotrexate (MTX) infusions of 500--1,000 mg/m2 over 24 hours may improve survival and prevent relapse in children with acute lymphoblastic leukemia (ALL). Childrens Cancer Group (CCG) Study 139 compared weekly oral methotrexate 20 mg/m2/week (oral MTX) to MTX 500 mg/m2 infused over 24 hours (IV MTX) three times during consolidation and every 6 weeks during maintenance in 164 children with intermediate-risk ALL, i.e., those patients over age 1 year with white blood cell count 10,000 to 49,999/ml and no bulky extramedullary disease. Median follow-up for CCG-139 exceeded 75 months. Thirty-four events occurred among 80 patients receiving IV and oral MTX and 36 events among 84 patients receiving oral MTX. Two children died during induction and one did not enter remission. Remission induction rate is 98%. There have been 26 marrow relapses, 11 combined marrow and extramedullary relapses, 24 CNS relapses, and five testicular or other relapses. The frequency and distribution of relapses does not differ between the two regimens. For the entire group, overall event-free survival (EFS) at 6 years is 57.9% (standard deviation=4.0%) and actuarial survival is 80.0% (standard deviation =3.3%). Of the 29 patients with isolated extramedullary relapse, 18 survive free of a second event, a median of 42 months from relapse. In contrast to other trials, this trial does not show that IV MTX in this dose and schedule offers an advantage over standard therapy for this group of children.

Administration, Oral↗
PubMed1996

Self-instructional intervention for teaching generalized problem-solving within a functional task sequence.

Effects of an intervention that combined self-instruction with multiple exemplar training on the generalized problem solving of five high school students with severe mental retardation were examined. Innovative features of the intervention included (a) preteaching self-instruction to proficiency with one exemplar before introducing multiple exemplars and (b) embedding problem situations within a functional task sequence. Findings indicated that all students learned to perform five trained problem responses and five generalized responses while self-instructing. The self-instructional intervention appeared to decrease training time required to self-instruct as well as to decrease variability with which participants verbalized their self-instructions.

Adolescent↗
PubMed1995

Indolent course of advanced neuroblastoma in children older than 6 years at diagnosis.

BACKGROUND: An early observation suggests that children older than 6 years of age at diagnosis of neuroblastoma constitute a favorable prognostic group. METHODS: Kaplan-Meier plots of survival of all such patients diagnosed at the Children's Hospital of Pittsburgh 1975-1992 were compared with curves of concurrently treated patients with Stage IV disease who were 1-6 years of age at diagnosis ("younger patients"). Known prognostic features, including stage and primary site of disease, pattern of metastases, histopathology, MYCN gene amplification, and urinary catecholamine metabolite ratios, were reviewed. RESULTS: Of 17 children diagnosed after the age of 6 years ("older patients"), 13 patients had Evans' Stage IV disease and 4 had Stage III disease. The median survival was 3.24 years (range, 0.63-15.04 years) for the entire cohort and 3.07 years for those children with Stage IV disease. This compared with a median survival of 1.05 years in 34 concurrent younger patients (P < 0.01). In most cases, disease in these older patients was characterized by a short-lived complete or partial remission followed by aggressive recurrent disease that was partially and only transiently chemo- or radiosensitive. Only 3 patients (2 with Stage IV disease) are in continuous complete remission at 3, 5 10/12, and 14 1/2 years from diagnosis. Although poor prognostic factors were common, including the presence of bony metastases (12/17), biopsy material from pretreatment tumor specimens demonstrated a single MYCN gene copy number in all patients and favorable histology in 15 of 16 samples. CONCLUSION: Older children with neuroblastoma have a more indolent course than do younger patients, a finding that appears to be related to favorable histology and the absence of MYCN amplification. Examination of larger numbers of such patients from cooperative groups should lead to a better understanding of what appears to be a subset of pediatric patients with neuroblastoma who may benefit from specifically tailored treatment protocols.

Adolescent↗
PubMed1995

Progressive varicella presenting with pain and minimal skin involvement in children with acute lymphoblastic leukemia.

PURPOSE: Here we report the experience at the Children's Hospital of Pittsburgh (CHP) with varicella zoster virus (VZV) in children with acute lymphoblastic leukemia (ALL). This record review was prompted by a patient with ALL who died suddenly of varicella hepatitis within 24 hours of presentation with a single skin lesion. METHODS: We reviewed the medical records of children diagnosed with ALL at the CHP from January 1984 through December 1993, who subsequently developed VZV infection. RESULTS: Of 294 patients aged 0 to 15 years, 41 (14%) were identified as having had 42 episodes of VZV infection. Twenty patients (49%) had received prophylaxis with varicella zoster immunoglobulin (VZIG), and all 39 patients in whom the diagnosis was made premortem were treated with acyclovir. Twenty-nine of the 42 cases (70%) had disease limited to the skin. Thirteen cases (30%) had extracutaneous involvement, and five of these episodes (12% of all cases) ended in death. Risk factors for progressive varicella included age greater than 6 years and intensive immunosuppressive therapy at the time of exposure. Six of eight patients with progressive varicella, including two who died, had received VZIG. The clinical presentation in 10 of 13 patients with progressive disease and in four of five patients who died was dominated by severe abdominal and/or back pain. In seven cases, these symptoms preceded the development of skin lesions by several days, and in six patients were associated with extensive involvement of the spleen by varicella, as demonstrated histopathologically by the presence of Howell-Jolly bodies on peripheral-blood smear or radiographically. No patient with uncomplicated varicella was reported to have had premonitory pain. CONCLUSION: Recognition of these prodromes and suspicion of varicella even in the absence of skin lesions and even in children with a history of prior disease or VZIG administration should prompt early diagnostic and therapeutic measures.

Abdominal Pain↗
PubMed1995

FK506 (tacrolimus) in the treatment of steroid-resistant acute graft-versus-host disease in children undergoing bone marrow transplantation.

Steroid-resistant graft-versus-host disease (GVHD) is an often lethal complication of bone marrow transplantation (BMT). FK506 (tacrolimus) is a new potent immunosuppressant which has been shown to be superior to conventional immunosuppression in the prevention and treatment of graft rejection in recipients of solid organ transplants. To determine whether FK506 is effective in the treatment of steroid-resistant acute GVHD, 6 children with biopsy-proven severe GVHD were studied. FK506 was administered as intravenous or oral therapy and the dose was adjusted to achieve serum levels between 0.5 and 1.0 microgram/ml by ELISA. Steroid doses were tapered based on clinical grading in each organ. Within 1-2 days, improvement occurred in skin and gut in all patients, and in liver in 3 patients. Toxicity attributable to FK506 was similar to that described in solid organ transplant patients and included neurotoxicity, nephrotoxicity and gastrointestinal effects. While FK506 is effective in the treatment of steroid-resistant acute GVHD, toxicity may limit its use. Further studies evaluating FK506 as GVHD prophylaxis and treatment of less advanced GVHD are needed.

Adolescent↗
PubMed1994

Catecholamine metabolites in ganglioneuroma.

With rare exception, ganglioneuroma (GN) is a benign lesion which presents as a localized mass without metastatic potential and which is chemotherapy resistant. Thus, its distinction from neuroblastoma (NB) may be important. The diagnosis of GN implies the absence of neuroblastic elements. Incomplete resection prevents complete microscopic examination and raises the possibility that focal NB was not sampled. In an attempt to determine what features other than histology distinguish these two entities, we reviewed the charts of 25 patients with GN with regard to patient age and sex, tumor location and size, and urine catecholamine metabolite levels. One patient with GN (5%) and gross total resection had elevated quantitative vanillylmandelic acid (VMA) and homovanillic acid (HVA) levels (2.4 x upper limit of normal for age), and two others had positive spot analyses for VMA. An additional patient with a large mass, multiple biopsies of which documented GN, also had greatly elevated (approximately 5 x normal) VMA and HVA levels. However, a subsequent attempt at resection disclosed several gross foci of NB. Even excluding this patient, there was a trend for elevated values in GN patients to correlate with tumor size (P = .07 and .14 for VMA and HVA, respectively). The incidence of elevated values appears to increase as a function of tumor size, and small tumors are not likely to result in positive urinary measurements. We conclude that while elevations of VMA and HVA are consistent with a well-documented diagnosis of GN, extreme elevations (> 3 x nl) should prompt careful serial evaluation for occult NB.

Adolescent↗
PubMed1994

Pancytopenia and vacuolation of marrow precursors associated with necrotizing encephalopathy.

Subacute necrotizing encephalopathy (SNE) or Leigh disease is an autosomal recessive disorder associated with various defects of oxidative phosphorylation. Two reports have described the concurrence of SNE with pancytopenia and vacuolation of bone marrow precursors, and have raised the possibility that this symptom complex may be part of a spectrum of diseases which includes Pearson's syndrome (vacuolation of bone marrow precursors, sideroblastic anaemia, exocrine pancreatic dysfunction). We describe a case of Pearson's syndrome in which haematological manifestations antedated progressive neurological deterioration by several years. Cytogenetic studies showed an inverted duplication of chromosome 9 (qh) [inv dup (9) (qh)]. We suggest that cytopenia associated with vacuolation of bone marrow precursors even without clinically apparent central nervous system pathology should prompt consideration of SNE, or related diseases. Conversely, a diagnosis of SNE should prompt evaluation of other organ system functions including bone marrow. Cytogenetic evaluation of other patients with SNE may determine whether the 9 (qh) findings are pathogenetic.

Bone Marrow↗
PubMed1993

Severe acne and hyperandrogenemia following dactinomycin.

The etiology of dactinomycin-associated acne has not previously been studied. An 81/2 year old girl with embryonal rhabdomyosarcoma of the left petrous bone was prepubertal at the time of presentation. Treatment according to a current Intergroup Rhabdomyosarcoma Study regimen consisted of vincristine, dactinomycin, and cyclophosphamide at 3 to 6 week intervals, as well as hyperfractionated radiotherapy to the tumor bad. Severe acne of the forehead developed within 10 days of starting therapy and resolved over the next 2 months. Serial measurements of serum hormones documented periodic increases in androgen levels coincident with courses of dactinomycin. These observations support a relationship between drug, dermatitis, and hormone levels. Study of other patients will be of interest to document the frequency, degree, and mechanism of hyperandrogenemia following dactinomycin.

Acne Vulgaris↗
PubMed1993

Toxicity following concurrent intrathecal and moderate-dose intravenous methotrexate.

To evaluate factors predisposing children with non-Hodgkin's lymphoma to toxicity from moderate dose methotrexate (MTX) (300 mg/m2 per 4 hours), we reviewed the medical records of 15 patients treated at our institution according to two similar protocols. Five patients experienced hyperemesis and/or severe mucositis. In two of these patients, pharmacokinetic analysis demonstrated delayed terminal excretion of methotrexate with a half-life of 3-3.5 days, compared to a previously reported t1/2 of 8-15 hours in subjects with normal clearance. All affected patients were large (body surface area 1.6-1.9 m2), and MTX toxicity was seen only during courses where intravenous MTX was given concurrently with intrathecal MTX. Four patients also received simultaneous prophylactic doses of oral trimethoprim-sulfamethoxazole (trimethoprim 5 mg/kg per day). We recommend that, in protocol design, consideration be given to avoiding concurrent use of intravenous and intrathecal MTX, and possibly trimethoprim-sulfamethoxazole. Where high doses of MTX are given based on large body surface area, urine alkalinization may be indicated.

Adolescent↗
PubMed1992

Second malignancies in very-long-term survivors of childhood cancer.

PURPOSE: Although most second malignancies are treatment related, their occurrence also may be due to an underlying systemic disease or chromosomal abnormalities shared by multiple organs in which they are tumorigenic. We attempted to identify unusual tumor pairs that might provide a clue to shared genetic etiologies. PATIENTS AND METHODS: Medical records and tumor registry correspondence of 1,743 patients (0 to 18 years at diagnosis) were reviewed. For those said to have a second malignancy, biopsy and autopsy records and slides were reviewed to confirm initial and secondary diagnoses. RESULTS: Two hundred fifty-eight patients had follow-up of at least 10 years and 157 of at least 20 years. Second malignancies were identified in 14 patients. The estimated cumulative incidence of a second cancer was approximately 1% within 10 years. At 20 years after diagnosis, the actuarial estimate was 3%. Although most second cancers were likely treatment related, several tumor pairs could not clearly be explained on that basis, including thyroid carcinoma followed by an ovarian sarcoma, and acute lymphoblastic leukemia associated with renal leiomyosarcoma. Based on one case in this series and a review of the literature, associations between Wilms' tumor, abdominal radiation, and adenocarcinoma of the colon and hepatocellular carcinoma are suggested. CONCLUSIONS: We conclude that continued surveillance of very-long-term survivors of childhood cancer, which is usually accomplished by internists, family practitioners, and adult oncologists, may be one approach to defining the life-time incidence of second malignancies. In addition, although the yield is likely to be small, descriptions of unexpected tumor pairs may target families for studies of pleiotropic genetic abnormalities.

Adolescent↗