Absence of t(12;15) associated ETV6-NTRK3 fusion transcripts in pediatric acute leukemias.
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Child↗
Biomedical subjects
J A Mathers
Publications and source records attributed to J A Mathers.
Molecular detection of the ETV6-NTRK3 gene fusion differentiates congenital fibrosarcoma from other childhood spindle cell tumors.
Congenital fibrosarcoma (CFS) is a pediatric spindle cell tumor of the soft tissues that usually presents before the age of 2 years. Although these tumors display histologic features of malignancy and frequently recur, they have a relatively good prognosis and only rarely metastasize. CFS must therefore be differentiated from more aggressive spindle cell sarcomas that occur during childhood, particularly adult-type fibrosarcoma (ATFS), which can have an identical morphology. CFS must also be distinguished from benign but cellular fibroblastic lesions of the same age group, including infantile fibromatosis (IFB) and myofibromatosis (MFB). Unfortunately, standard pathologic examination often does not differentiate CFS from these other conditions. The authors recently identified a novel chromosomal translocation in CFS, t(12;15)(p13;q25), which gives rise to an ETV6-NTRK3 gene fusion. They subsequently developed reverse transcription-polymerase chain reaction (RT-PCR) assays that can detect ETV6-NTRK3 fusion transcripts in CFS frozen or paraffin-embedded tumor specimens. To confirm the use of this assay in the differential diagnosis of CFS, they have screened a larger series of childhood pediatric spindle cell lesions for ETV6-NTRK3 gene fusions, including 11 cases of CFS, 13 malignant spindle cell tumors (including ATFS), and 38 benign spindle cell tumors (including IFB and MFB). Of the 11 cases diagnosed as CFS, 10 showed the ETV6-NTRK3 gene fusion, whereas none of the 51 other malignant or benign spindle cell tumors demonstrated this fusion gene. They also compared their RT-PCR findings with those of conventional cytogenetics and with immunohistochemical detection of the ETV6-NTRK3 protein using antisera to NTRK3. They conclude that RT-PCR analysis is superior to these techniques for the detection of the ETV6-NTRK3 gene fusion in pediatric spindle cell tumors, and it is a reliable and specific modality for the diagnosis of CFS.
Adolescent↗
Absence of detectable EWS/FLI1 expression after therapy-induced neural differentiation in Ewing sarcoma.
Ewing sarcoma and other peripheral primitive neuroectodermal tumors (pPNETs) display limited neural differentiation and are thought to have a neural crest origin Greater than 95% of these tumors share common t(11;22)(q24;q12) ort(21;22)(q22;q12) chromosomal translocations leading to ES/FLI1 or EWS/ERG gene fusions, respectively. The resulting chimeric oncoproteins seem to function as aberrant transcription factors. However, whether these molecules contribute to the limited neural differentiation observed in pPNETs or actually inhibit differentiation remains unclear. We report a Ewing sarcoma case from the forearm of a 10-year-old girl which expressed EWS/FLI1 fusion transcripts. The tumor was treated with surgery, chemotherapy, and local radiation, but residual tumor was detected within a year as a well-differentiated peripheral neural tumor lacking detectable EWS/FLI1 expression. Further studies suggested that the primary and residual tumors were clonally related. This association between apparent therapy-induced differentiation in Ewing sarcoma and absence of detectable fusion transcripts in the residual tumor provides presumptive evidence that EWS/FLI1 expression may inhibit differentiation in tumour cells.
Bone Neoplasms↗
Peripheral primitive neuroectodermal tumors in adults: documentation by molecular analysis.
PURPOSE: The Ewing tumor (ET) family of peripheral primitive neuroectodermal tumors (pPNETs) are primitive small round-cell tumors (SRCTs) of the bone and soft tissue that occur predominantly in children and adolescents. However, pPNETs only rarely enter the differential diagnosis of bone and soft tissue SRCTs in adults. Recently, gene fusions between the EWS gene and different members of the ETS transcription factor family have been shown to occur in virtually all pPNETs and thus constitute a pathognomonic marker for this tumor subclass. The aim of the present study was to document EWS/ETS fusion gene expression in suspected pPNETs of adults as objective evidence for the existence of this tumor family in older patients. PATIENTS AND METHODS: The three contributing molecular diagnostic laboratories retrospectively compiled a cohort of all SRCT cases in which EWS/ETS gene fusions had been shown by molecular analysis. This cohort was surveyed for cases that occurred in patients aged 40 years or older, which were then analyzed for their clinical and pathologic features. RESULTS: Nine patients between 40 and 65 years of age were found to have tumors positive for EWS/ETS gene fusions. Standard histopathologic and clinical features of these cases, other than age, were similar to those of childhood pPNETs. Patients were initiated on appropriate therapy after molecular analysis confirmed the diagnosis of pPNET. CONCLUSION: Identification of an EWS/ETS gene fusion is useful in providing objective evidence of the diagnosis of pPNET in patients over the age of 40 years. This diagnosis should be considered in adults who present with bone and soft tissue SRCTs and appropriate biopsy specimens should be collected for molecular analysis at the time of diagnosis.
Adult↗
Detection of the EWS/WT1 gene fusion by reverse transcriptase-polymerase chain reaction in the diagnosis of intra-abdominal desmoplastic small round cell tumor.
We report two cases of intra-abdominal desmoplastic small round cell tumor with characteristic clinical, histological, immunohistochemical, and ultrastructural features. Fusion of the EWS gene on chromosome 22 and the WT1 gene on chromosome 11, resulting from the chromosomal translocation t(11;22)(p13;q12), was detected by reverse transcriptase polymerase chain reaction (RT-PCR) in both cases. This translocation has been previously reported in this type of tumor using either cytogenetic or molecular biological techniques. Tumor tissue from both cases revealed no chimeric fusion transcripts characteristic of the Ewing sarcoma family of peripheral primitive neuroectodermal tumors or of alveolar rhabdomyosarcoma, two tumors in the differential diagnosis of intra-abdominal desmoplastic small round cell tumor. This report demonstrates the utility of molecular studies as an adjunct in the diagnosis of this rare and aggressive tumor.
Abdominal Neoplasms↗
Scintigraphy and radiography in oleic acid pulmonary microvascular injury: effects of positive end-expiratory pressure (PEEP).
Using computerized gamma scintigraphy, 10-cm H2O PEEP did not alter the rate of capillary protein leakage in dogs following pulmonary microvascular injury with 0.01 to 0.2 ml/kg oleic acid. A rising lung:heart radioactivity ratio, or 'slope of injury,' was seen during PEEP which paralleled the 'slope of injury' had PEEP not been used. A sudden decrease in lung and heart count activity (p less than 0.001) and decreased lung:heart radioactivity ratio (p less than 0.001) occurred with PEEP at all doses of oleic acid studied. An apparent improvement in the standard chest roentgenogram was seen within 2 minutes following PEEP in dogs given 0.2 ml/kg oleic acid. However, progression of the radiographic infiltrate occurred in these animals during 30 minutes of PEEP. When all vessels leading to and from the heart and lungs were ligated, PEEP produced a 60% fall in count activity over the lung without any change in cardiac radioactivity. The apparent radiographic improvement and 2/3 of the fall in lung radioactivity with PEEP were due to an increased pulmonary air volume and 1/3 due to a decreased pulmonary blood volume. The decreased cardiac output with PEEP must be secondary to decreased ventricular filling rather than decreased ventricular function.
Animals↗
Gastroplasty for respiratory insufficiency of obesity.
Three patients with the obesity hypoventilation syndrome and one patient with the sleep apnea syndrome underwent gastroplasty for weight reduction. A tracheostomy was also performed in the patient with sleep apnea. The PaO2 rose from an average of 51 +/- 9 to 71 +/- 5 torr and the PaCO2 fell from an average of 51 +/- 21 to 41 +/- 6 torr within two to ten months following bariatric surgery. The improved arterial blood gases were associated with an increased forced vital capacity in each patient. The change in maximum voluntary ventilation was variable. Sleep capneography demonstrated cure of the patient with sleep apnea permitting removal of the tracheostomy. All four patients have returned to productive lives in society. Given proper pre- and postoperative care, patients with respiratory insufficiency tolerate the operation well. Respiratory insufficiency associated with morbid obesity should be considered an indication for the gastroplasty procedure, rather than a contraindication as previously suggested.
Adult↗
Pulmonary microvascular and alveolar epithelial permeability characteristics in N-nitroso-N-methylurethane-injected dogs.
The subcutaneous injection of 5 to 6 mg/kg of body weight of N-nitroso-N-methylurethane (NNNMU) has been reported to cause acute alveolar injury in animals. To determine the permeability characteristics of the alveolar epithelium, we employed the in vivo saline-filled dog lung model and determined the time to 50 percent equilibration in minutes of a specific tracer in the blood and the lung model and determined the time to 50 percent equilibration in minutes of a specific tracer in the blood and the lung liquid (T 1/2) for endogenous serum albumin (MW 69,000 daltons, molecular radius 35 A) and exogenously administered 500,000 MW polydispersed dextrans (molecular radius 200 A). Compared to control animals, T1/2 decreased (permeability increased) in NNNMU-injected dogs from 3,500 +/- 100 to 682 +/- 160 minutes for albumin and from 20,000 +/- 250 to 2,790 +/- 750 minutes for 500,000 MW dextran (P less than 0.001). To determine the permeability characteristics of the pulmonary microvasculature, we employed the right lymph duct cannulation dog model and measured lymph flow/30 minutes, lymph albumin and dextran concentration, and lymph/plasma albumin and dextran ratios in control and NNNMU-injected dogs. Compared to control animals, lymph flow was significantly greater in NNNMU dogs, 2.07 +/- 1.1 vs .71 +/- .50 ml/30 minutes (P less than 0.01), respectively. We conclude that NNNMU injection increases permeability in both the alveolar epithelium and the pulmonary microvasculature.
Albumins↗
Pulmonary embolism: a systematic clinical approach.
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Angiography↗
Gallium scans and serum angiotensin converting enzyme levels in talc granulomatosis and lymphocytic interstitial pneumonitis.
We have described two patients who had positive gallium lung scans with simultaneous elevation in serum angiotensin converting enzyme (SACE) levels. One patient had talc granulomatosis secondary to the intravenous injection of pentazocine, while the other patient had lymphocytic interstitial pneumonitis. We believe these are the first cases in which a positive gallium scan and elevated SACE levels were associated with these entities.
Adult↗
Sleep apnea syndrome: clinical features and treatment.
The sleep apnea syndrome is a relatively unappreciated but by no means rare cause of nocturnal hypercapnia and hypoxemia that sometimes persist into the waking hours. The authors describe their experience in diagnosing and treating this disease in seven patients who were characteristically overweight, tended to snore, and had daytime somnolence, intellectual deterioration and elevated hematocrits.
Humans↗
Combined aztreonam and gentamicin therapy for pseudomonal lower respiratory tract infections.
A multicenter, open-label study was performed to assess the efficacy and safety of aztreonam plus gentamicin in the treatment of lower respiratory tract infections due to Pseudomonas aeruginosa. Patients with documented P aeruginosa infections were given aztreonam 2 g every 8 hours (q8h) plus gentamicin 3 to 5 mg/kg per day in three equal doses. Clindamycin, 600 mg q8h, was added to the regimen for patients with infections also involving gram-positive and/or anaerobic bacteria. Therapy was continued for at least 5 days or until obvious failure to respond to treatment. Of 64 patients with suspected P aeruginosa infections, 57 were eligible for clinical evaluation and 51 for microbiologic evaluation. At entry, impaired host defense was present in 35% of patients, and chronic obstructive pulmonary disease in 28%, in addition to other predisposing conditions such as emphysema, history of tuberculosis, and pneumothorax. The clinical response rate for the combination regimen was 48/57 (84%), which included 27 (47%) cures and 21 (37%) partial responses. The microbiologic response rate was 35/51 (69%), of which 25 (49%) outcomes were classified as eradication and 10 (20%) as eradication with relapse. Superinfection was observed in 3 (6%) patients. The combination of aztreonam and gentamicin was synergistic in the initial isolates obtained from 33 (72%) patients. A total of 16 patients died of pulmonary or other underlying disease, for a mortality rate of 28%. The monobactam-aminoglycoside combination was generally well tolerated. Two other patients were withdrawn because rashes emerged on treatment. This study demonstrates that aztreonam can be administered as one component of a synergistic monobactam-aminoglycoside therapy in the treatment of nosocomial lower respiratory tract infections involving P aeruginosa.
Adult↗