William A. Smithson

Mutations in RECQL4 cause a subset of cases of Rothmund-Thomson syndrome

Rothmund-Thomson syndrome (RTS; also known as poikiloderma congenitale) is a rare, autosomal recessive genetic disorder characterized by abnormalities in skin and skeleton, juvenile cataracts, premature ageing and a predisposition to neoplasia. Cytogenetic studies indicate that cells from affected patients show genomic instability often associated with chromosomal rearrangements causing an acquired somatic mosaicism. The gene(s) responsible for RTS remains unknown. The genes responsible for Werner and Bloom syndromes (WRN and BLM, respectively) have been identified as homologues of Escherichia coli RecQ, which encodes a DNA helicase that unwinds double-stranded DNA into single-stranded DNAs. Other eukaryotic homologues thus far identified are human RECQL (Refs 13, 14), Saccharomyces cerevisiae SGS1 (Refs 15,16) and Schizosaccharomyces pombe rqh1+ (ref. 17). We recently cloned two new human helicase genes, RECQL4 at 8q24.3 and RECQL5 at 17q25, which encode members of the RecQ helicase family. Here, we report that three RTS patients carried two types of compound heterozygous mutations in RECQL4. The fact that the mutated alleles were inherited from the parents in one affected family and were not found in ethnically matched controls suggests that mutation of RECQL4 at human chromosome 8q24.3 is responsible for at least some cases of RTS.

Extraosseous Ewing's sarcoma. A study of 42 cases

Fifty patients at the Mayo Clinic (Rochester, MN) from 1935 to 1985 met the histologic criteria for extraosseous Ewings sarcoma. Forty‐two had soft tissue primaries without bony involvement and formed the basis for this retrospective study of the clinical behavior and management of extraosseous Ewings sarcoma. There were 19 male and 23 female patients (mean age, 22 years). Metastases were documented in 30 of the patients, six at the time of presentation and 24 occurring up to 11 years later, most commonly to lungs or bone. Three patients were lost to follow‐up. Sixteen of 35 patients (46%) had local recurrence. Overall survival was 15 of 39 (38.5%) at 5 years. Decreased survival was noted with pelvic tumors, incomplete resections, and presence of metastatic disease, whereas increased survival was associated with wide surgical resection with negative microscopic margins, adjuvant local radiation therapy, and presentation since 1970 (48% 5‐year survival compared with 28% before 1970).

A controlled pilot study of high-dose methotrexate as postsurgical adjuvant treatment for primary osteosarcoma.

Thirty-eight patients whose primary extremity or limb girdle osteosarcomas had been completely excised (37 amputations, one limb sparing procedure) were allocated at random to two treatment groups receiving respectively regular follow-up examinations plus a high-dose methotrexate (HDMTX) regimen or regular follow-up without primary adjuvant chemotherapy. Although the vincristine, HDMTX, leucovorin regimen was generally quite tolerable when given at three-week intervals for one year and most of the chemotherapy patients followed the planned HDMTX dose escalations from 3 to 6 to 7.5 g/m2, delayed methotrexate excretion limited dosage escalations in 25%. An estimated 52% of the 38 patients were surviving five years after randomization and an estimated 42% remained continuously relapse-free after five years. No significant differences between the outcomes of the 20 treated and the 18 untreated patients were apparent; however, power to detect differences was low. Furthermore, no significant differences in postmetastasis survival were apparent between the 12 treated and 10 untreated patients who relapsed. Approximately 20% of these failing patients appear to have been salvaged for long-term survival. This pilot study of HDMTX confirms the continuing need for controlled clinical trials in determining the therapeutic value of adjuvant chemotherapy programs for patients with primary osteosarcoma.

Rothmund‐Thomson syndrome in siblings: evidence for acquired in vivo mosaicism

Rothmund‐Thomson syndrome (RTS) is an autosomal recessive disorder characterized by skin abnormalities that appear in infancy, skeletal abnormalities, juvenile cataracts and other manifestations of premature aging, and a predisposition to malignancy. The diagnosis is made on clinical grounds as no consistent laboratory test has been identified. Chromosome studies have been reported for only three patients with RTS and in two of these three, trisomy 8 mosaicism was found. We performed a variety of cytogenetic and molecular genetic studies on two siblings with RTS and on their phenotypically normal parents. Two chromosomally abnormal clones involving either trisomy 8 or i(8q) were found in both patients with RTS. These clones were present in vivo, as they were seen in interphase buccal smears and lymphocytes from unstimulated preparations using both conventional cytogenetic studies and fluorescence in situ hybridization (FISH) with a centromere probe for chromosome 8. These results suggest that RTS is associated with in vivo clonal chromosomal rearrangements causing an acquired somatic mosaicism.

Neuropsychologic follow-up study of children with acute lymphocytic leukemia. A preliminary report.

ABSTRACT Thirty-three children with acute lymphocytic leukemia who were in remission and who did not have central nervous system (CNS) leukemia were studied in an effort to detect effects of CNS prophylaxis on brain function. Nineteen children had received intrathecal methotrexate plus cranial radiation, eight had intrathecal methotrexate alone, and six had intrathecal plus intravenous methotrexate. Intrathecal methotrexate, 12 mg/m2, was given six times over 2 months. The dosage of cranial irradiation was 2400 rads in 12 divided doses over 16 days. Intravenous methotrexate, 500 mg/m2, was given at 21-day intervals three times. All except two patients had been in remission for more than 1 year, 10 for 1–2 years, nine for 2–4 years, and 12 for more than 4 years. Computed tomography of the head, electroencephalograms, neurologic examination, and a modified form of the Halsted-Reitan neuropsychologic test battery revealed 13 patients with an abnormal finding, but only one of these patients had an abnormality in more than one area. There was thus no correlation between the observed structural and functional abnormalities. These preliminary results fail to confirm any significant difference in neuropsychologic function related to the various CNS regimens and do not indicate a need to modify presently accepted methods of CNS prophylaxis. A prospective longer-term follow-up study with a larger patient sample is needed to assess the long-range relationship of measurable abnormalities to CNS prophylaxis and to help establish a preferred method of prophylaxis.

Inoperable Plasma Cell Granuloma of the Heart: Spontaneous Decrease in Size During an 11-Month Period

Plasma cell granuloma occurs in children, typically as an intrapulmonary mass. Surgical excision is the treatment of choice and is usually curative. We report an atypical and unresectable plasma cell granuloma that occurred asymptomatically in the heart of a child and spontaneously decreased in size by 40% during an 11-month period. Thus, plasma cell granuloma should be considered in the differential diagnosis of any child who has a cardiac mass. Observation should be considered a treatment option because this case demonstrated that the cardiac mass can spontaneously recede without therapy.

Successful Treatment of Intrathecal Methotrexate Overdose by Using Ventriculolumbar Perfusion and Intrathecal Instillation of Carboxypeptidase G2

Prompt and appropriate management measures are critical in order to achieve a favorable outcome after a major overdose of intrathecally (IT) administered methotrexate (MTX). Published information available to guide clinicians in the immediate management of this medical emergency is scant. Herein we describe a 6-year-old boy with acute lymphoblastic leukemia who received an inadvertent overdose of 600 mg of IT administered MTX instead of the intended dose of 12 mg. Severe acute neurotoxicity developed rapidly. Lumbar puncture and drainage of 15 mL of cerebrospinal fluid 2 hours after administration resulted in removal of 32% of the administered drug. Ventriculolumbar perfusion with 240 mL of warmed isotonic saline through ventricular and lumbar catheters for 3 hours resulted in removal of a total of 90% of the drug within 8 1/2 hours after administration. IT administration of 2,000 U of carboxypeptidase G2 (CPDG2), an enzyme that inactivates MTX, resulted in a further 150-fold reduction in cerebrospinal fluid MTX concentration. The patient experienced complete recovery. To our knowledge, this is the first reported case of the use of IT instillation of CPDG2 for the treatment of an overdose of IT administered MTX in a human, and it is only the second reported favorable outcome after an IT overdose of more than 500 mg of MTX. Minor IT overdoses of MTX can be managed by immediate lumbar drainage alone. Major overdoses may also necessitate prompt ventriculolumbar perfusion, IT instillation of CPDG2, and further supportive measures for a successful outcome after this infrequent but potentially catastrophic event.

Neuropsychologic performance among children in remission from acute lymphocytic leukemia

Comprehensive neuropsychologic assessments were done for children in continuous remission from acute lymphocytic leukemia (ALL) following either chemotherapy alone (N = 14) or chemotherapy combined with prophylactic cranial radiation (N = 19). Only 5 of 75 neuropsychologic variables were found to differ at the .05 level for these two groups; trends were seen (p<. 10) on two additional variables. The data indicate few if any meaningful differences related to the presence or absence of radiation therapy, although the differences that were seen occurred on tasks for which other authors have suggested diminished ability as a result of cranial radiation. Additional analysis failed to reveal any effects related to the age at which prophylactic radiation was received.

Ewing's sarcoma of the proximal femur

The cases of 16 patients with Ewings sarcoma of the proximal femur treated in the era of multiagent chemotherapy were reviewed, with emphasis on the mechanical problem of tumor involvement in this structurally demanding site. Fourteen patients received chemotherapy and local radiotherapy as the initial primary treatment. One patient had chemotherapy and radiotherapy, followed by wide local resection. One patient had amputation, followed by chemotherapy, for pathologic fracture and extensive soft tissue involvement at presentation. Two local recurrences occurred. Excluding the 2 patients whose femurs were fixed prophylac-tically, the pathologic fracture rate was 79%. In addition, by excluding the 2 patients who died before fracture, the pathologic fracture rate was 92%. Nonunion occurred in 5 (71%) of the 7 pathologic fractures not treated by resection and required as many as 5 additional surgical procedures to obtain union. At latest followup evaluation (average, 6.3 years), 10 patients had no evidence of disease, 1 was alive with disease, and 5 had died of their disease. Options for management should include primary resection and reconstruction or prophylactic internal fixation after completion of chemotherapy plus or minus radiotherapy.

Activity of indicine N-oxide in refractory acute leukemia.

Indicine N‐oxide, the first pyrrolizidine alkaloid N‐oxide to be studied in the treatment of cancer in humans, was administered to ten patients: four children and two adolescents with refractory acute lymphocytic leukemia and four adults with refractory acute nonlymphocytic leukemia (three acute myelocytic, one myelomonocytic). Two patients, a 4‐year‐old boy with acute lymphocytic leukemia and a 22‐year‐old man with acute myelocytic leukemia, achieved complete remission lasting 3 and 5+ months, respectively. Another 15‐year‐old male with acute lymphocytic leukemia had a partial remission for four months. Toxicities included bone marrow suppression, mild anorexia and nausea, and transient elevation of liver enzymes. Jaundice and liver failure, presumably induced by drug, occurred in two patients.