Ifosfamide/carboplatin/etoposide (ICE), an effective salvaging therapy for recurrent malignant non-Hodgkin lymphoma of childhood: a Pediatric Oncology Group phase II study.
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Adolescent↗
Biomedical subjects
M B Harris
Publications and source records attributed to M B Harris.
Transcriptional repression of Stat6-dependent interleukin-4-induced genes by BCL-6: specific regulation of iepsilon transcription and immunoglobulin E switching.
The BCL-6 proto-oncogene encodes a POZ/zinc-finger transcription factor that is expressed in B cells and a subset of CD4(+) T cells within germinal centers. Recent evidence suggests that BCL-6 can act as a sequence-specific repressor of transcription, but the target genes for this activity have not yet been identified. The binding site for BCL-6 shares striking homology to the sites that are the target sequence for the interleukin-4 (IL-4)-induced Stat6 (signal transducers and activators of transcription) signaling molecule. Electrophoretic mobility shift assays demonstrate that BCL-6 can bind, with different affinities, to several DNA elements recognized by Stat6. Expression of BCL-6 can repress the IL-4-dependent induction of immunoglobulin (Ig) germ line epsilon transcripts, but does not repress the IL-4 induction of CD23 transcripts. Consistent with the role of BCL-6 in modulating transcription from the germ line epsilon promoter, BCL-6(-/-) mice display an increased ability to class switch to IgE in response to IL-4 in vitro. These animals also exhibit a multiorgan inflammatory disease characterized by the presence of a large number of IgE(+) B cells. The apparent dysregulation of IgE production is abolished in BCL-6(-/-) Stat6(-/-) mice, indicating that BCL-6 regulation of Ig class switching is dependent upon Stat6 signaling. Thus, BCL-6 can modulate the transcription of selective Stat6-dependent IL-4 responses, including IgE class switching in B cells.
Animals↗
Acute exercise can improve cardioprotection without increasing heat shock protein content.
The aim of this study was to determine the effects of acute bouts of exercise on myocardial recovery after ischemia and heat shock protein expression. Adult female Sprague-Dawley rats were divided into five groups: 1) 1-day run (1DR; n = 6) and 2) 3-day run (3DR; n = 7), in which rats ran for 100 min at a speed of 20 m/min up a 6 degrees grade for 1 or 3 consecutive days; 3) 1-day cold run (1CR), in which rats ran the same as 1DR but with wet fur at 8 degrees C, which prevented an elevation of core temperature (n = 8); 4) heat shock sedentary (HS), in which rats had their core temperatures raised to 42 degrees C one time for 15 min (n = 5); and 5) sedentary control (n=15). Cardiac function was analyzed 24 h after the last treatment using an isolated, working heart model. Nonpaced hearts were initially perfused under normoxic conditions, then underwent 17 min of global, normothermic (37 degrees C) ischemia, and, finally, were allowed to recover for 30 min under normoxic conditions. The concentration of the 72-kDa heat shock protein (HSP 72) was measured in each left ventricle. Compared with that in the sedentary group, recovery of cardiac output x systolic pressure (CO x SP) was enhanced (P < 0.05) in all treatment groups when the postischemic value was covaried with the preischemic value. No differences in CO x SP were found (P > 0.05) between the following groups: 1DR vs. 3DR, 1DR vs. HS, and 1DR vs. 1CR. Heat shock protein concentration was significantly greater (P < 0.05) than that in the sedentary controls in HS, 1DR, and 3DR groups, but not for 1CR. The concentration of HSP 72 was not significantly correlated with postischemic CO x SP (R2 = 0.197, P > 0.05). We conclude that acute bouts of exercise can produce cardioprotective effects without an elevation of HSP 72.
Animals↗
Treatment of metastatic osteosarcoma at diagnosis: a Pediatric Oncology Group Study.
PURPOSE: To estimate the duration of survival (S) of patients with metastatic osteosarcoma (MOS) at diagnosis treated with a multiagent, ifosfamide-containing chemotherapeutic and surgical regimen and to evaluate the toxicity of this regimen. PATIENTS AND METHODS: Thirty patients aged younger than 30 years received two courses of ifosfamide followed by surgery on the primary tumor and metastatic sites. Patients then received a postsurgical multiagent chemotherapeutic regimen that consisted of high-dose methotrexate (HDMTX), ifosfamide, doxorubicin, and cisplatin. RESULTS: The 5-year event-free survival (EFS) rate was 46.7% (95% confidence interval [CI]; 28.5 to 64.9) and 5-year S rate was 53.3% (95% CI; 35.1 to 71.5). Three patients with bone metastases and one patient with lymph node metastases died. Twenty-six patients presented with pulmonary metastatic nodules only. Eight of these patients had at least eight nodules at diagnosis and had an estimated 5-year EFS rate of 25.0% compared with 66.7% for the 18 patients with less than eight nodules (P=.06). Fourteen patients presented with bilateral lung metastases and had a 5-year EFS rate of 35.7% compared with the 12 patients who presented with unilateral involvement and had a 5-year EFS rate of 75.0% (P=.03). The hematopoietic toxicity experienced by the patients during the entire regimen was relatively mild. Seven patients had renal toxicity characterized by hypophosphatemia and/or hypokalemia. CONCLUSION: This ifosfamide-containing regimen is tolerable and effective in the treatment of patients with osteosarcoma (OS) who present with lung metastases. However, better regimens are required for this group of patients.
Adult↗
Consolidation therapy with antimetabolite-based therapy in standard-risk acute lymphocytic leukemia of childhood: a Pediatric Oncology Group Study.
PURPOSE: To develop antimetabolite-based consolidation regimens that minimize acute and long-term toxicities and improve the survival rate of children with standard-risk B-lineage acute lymphocytic leukemia (ALL). PATIENTS AND METHODS: Seven hundred twenty-seven eligible patients with standard-risk early pre-B ALL were registered onto the study. Seven hundred sixteen patients attained a complete remission (CR) after induction therapy. Of these, 114 patients were randomized to a different regimen and were the subject of a separate report. Six hundred two patients were randomized to receive one the following regimens: intermediate-dose methotrexate (IDMTX) with leucovorin rescue on weeks 7, 10, 13, 16, 19, and 22 (regimen A); regimen A plus asparaginase (ASP) administered intramuscularly (i.m.) weekly for 24 weeks (regimen B); or regimen A plus a 24-hour infusion of cytarabine (AraC) with each IDMTX (regimen C). After consolidation, patients were placed on maintenance therapy through week 156. Regimens A and C were opened in February 1986, and regimen B in May 1987. Comparisons are based on concurrently randomized patients (May 1987 to January 1991 between regimens A and B, and February 1986 to January 1991 between regimens A and C). RESULTS: The 5-year continuous CR (CCR) rates were not significantly different: A versus B, 78.1% (3.9 +/- SE) versus 83.3% +/- 3.5% and A versus C, 79.4% +/- 3.2% versus 83.5% +/- 2.9%; P by one-sided log-rank tests were .27 and .34, respectively. Significant treatment differences were not found with regard to sex, rate of testicular and CNS relapse, or CNS complications. During consolidation, regimen C had significantly more bacterial infections (P = .0032) and days spent in the hospital (P < .001) compared with regimen A. CONCLUSION: We were unable to show a statistical advantage of adding either ASP or AraC to IDMTX in terms of improvement in event-free survival (EFS).
Antimetabolites, Antineoplastic↗
Do descending influences alternate to produce episodic breathing?
This study examines the episodic breathing patterns of three disparate groups of vertebrates. In an in vitro bullfrog brainstem-spinal cord preparation, episodic breathing was replaced by uniformly spaced breaths following transection caudal to the optic chiasma. The same effect was produced in hibernating squirrels by inhalation of mild anesthesia. Preliminary data suggest that a similar conversion is also produced in hibernating squirrels by vagotomy, in conjunction with blockade of central NMDA-type glutamate receptors. In all cases, even though overall breathing frequency increased, due to elimination of periods of apnea, instantaneous breathing frequency slowed. Seals breathe episodically in sleep and when these animals awaken after the start of a breathing episode, breathing also immediately slows. The data presented here are consistent with the suggestion that in all vertebrates, higher centres can modulate the central rhythm generator for breathing, in both a positive and a negative fashion. During episodic breathing, in the species studied here, these modulating influences alternate in a fashion that produces periods of apnea alternating with periods of relatively high frequency ventilation.
Anesthesia↗
The role of the nucleus isthmi in respiratory pattern formation in bullfrogs.
The nucleus isthmi (NI) is a mesencephalic structure of the amphibian brain located between the roof of the midbrain and the cerebellum. From a neuroanatomical perspective, the NI can be compared with the pons which, in mammals, contributes to the control of breathing pattern. This study tested the hypothesis that the NI plays a critical role in breathing pattern formation in the bullfrog. More specifically, we postulated that this nucleus was the site responsible for clustering breaths into distinct episodes of breathing. This hypothesis was tested by comparing the respiratory motor output of decerebrate, paralyzed and artificially ventilated bullfrogs before and after bilateral lesions of the NI by pressure microinjections of lidocaine or kainic acid (KA) into this area. Bilateral microinjections of lidocaine or KA into the NI transformed the breathing pattern from episodic (many breaths per episode) to one of evenly spaced single breaths, without affecting the amplitude of the fictive breaths. These changes in breathing pattern were associated with an overall decrease in breathing frequency and a reduction in CO2-chemosensitivity. Breathing episodes of more than one breath reappeared during hypercarbia (3.5% CO2 in air) after KA lesioning. Bilateral lesions to the NI did not affect the changes in the timing or the amplitude of the respiratory-related bursts elicited by pulmonary stretch receptor feedback, indicating that mechanoreflexes do not require NI input. We conclude that the NI is not responsible for the genesis of breathing episodes, but provides a tonic excitatory input to respiratory centers in the lower brainstem. The NI also plays an important role in either CO2 chemodetection or, more probably, integration of CO2 chemoreceptor information. This, in turn, contributes to the production of episodes of more than one breath.
Afferent Pathways↗
Biomechanical analysis of nonreamed tibial intramedullary nailing after simulated transverse fracture and fibulectomy.
A tibial shaft fracture model was created to study the effects of an intramedullary nail and partial fibulectomy on fracture loading. Cadaveric lower extremities were instrumented with strain gages and subjected to biomechanical testing. A nonreamed nail was inserted into each tibia using only the proximal locking screws. Each specimen was tested under six conditions: intact tibia; intact tibia with nail; fractured tibia with nail removed and fibula intact; fractured tibia with nail and fibula intact; fractured tibia with nail and partial fibulectomy; and fractured tibia with partial fibulectomy and nail removed. In the intact tibia the anterior cortices were in relative tension compared with the posterior cortex. After transverse fracture this relative tension was increased. Inserting the nail after fracture significantly increased anteromedial and anterolateral compressive strains and decreased posterior strains. Performing a partial fibulectomy in the fractured tibia with a nail had no significant effect on the strain patterns. These results confirm the relative anterior tension present in the intact tibia and demonstrate an increase in this anterior tension following transverse fracture. Performing a partial fibulectomy or inserting an intramedullary nail increased anterior compressive loading. This loading alteration may be responsible for the clinical success seen using these treatment methods.
Analysis of Variance↗
Atypical mycobacterial vertebral osteomyelitis in an immunocompetent patient.
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Adult↗
'Clearing' cervical spine injuries in polytrauma patients: is it really safe to remove the collar?
Polytrauma patients are at increased risk for occult cervical spine injuries. Those unable to provide clinical clues to injury either remain in hard collars until they are able to cooperate with the physical examination or are deemed "clear of cervical injury" if the emergency room screening radiographs are without obvious bony abnormality. Cervical immobilization for a lengthy period of time is not without morbidity. Missed ligamentous injuries can lead to cervical instability, which in turn can result in permanent neurologic sequelae. This article reviews the current methodologies to "clear the cervical spine" and highlights the inadequacies.
Cervical Vertebrae↗
Radiology case of the month. Unfortunate Chance. Chance fracture at L3.
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Accidents, Traffic↗
The effect of anterior thoracolumbar plate application on the compressive loading of the strut graft.
STUDY DESIGN: In vitro biomechanical testing was performed using a simulated vertebral body bone graft instrumented with strain gauges. Strains were recorded from various locations on the graft during axial compressive loading. Comparisons were made of the strain patterns recorded before and after application of two different anterior plates. OBJECTIVES: To quantify the changes in axial compression experienced by the strut graft in the presence of an anterior plate. SUMMARY OF BACKGROUND DATA: The use of anterior instrumentation to augment anterior thoracolumbar grafting offers the potential advantage of saving additional motion segments while being performed in a single-stage surgery. Several biomechanical studies have compared the anteriorly grafted and instrumented spine to the compressive axial stiffness and torsional rigidity of the intact spine. No previous study has addressed the loading patterns experienced by the graft before and after plating. METHODS: Anterior spinal plates of two designs (Amset ALPS Anterior Locking Plate System; AMS, Hayward, California; Anterior Thoracolumbar Locking Plate System; Synthes Spine, Paoli, Pennsylvania) were evaluated to determine the axial compressive forces experienced by the bone graft before and after application of the plates. Bovine spines harvested from 8- to 12-week-old calves were used for testing. All plates were tested in axial compression to 500 N. Simultaneous recordings were made of the axial strains on the simulated bone graft and the load applied to the construct. Comparisons were made of the strain through the graft without any instrumentation (graft alone, or baseline), with the plate applied, and after removal of the caudal screws (dynamization). RESULTS: With the application of the ALPS plate, the compressive strain through the graft adjacent to the plate averaged 77% of the graft alone construct (range, 39% to 158%). After application of the Synthes plate, the compressive strain through the graft adjacent to the plate averaged 34% of the graft alone construct (range, -14% to 97%). Once the caudal screws were removed, the dynamized construct allowed near-baseline compression through the graft. CONCLUSIONS: Although the literature indicates that the anteriorly instrumented spine may restore the overall spinal structure to near-normal resistance to rotation and flexion forces, the current study demonstrates that a significant amount of compression through the graft is lost by its application. This decreased axial loading further supports the concept of device-related osteopenia observed clinically with such devices.
Animals↗
Life events and difficulties in relation to the onset of globus pharyngis.
Fifty patients with a diagnosis of globus pharyngis and 33 control patients attending the same ENT clinic were interviewed using the (Royal Holloway &) Bedford College Life Events and Difficulties Schedule (LEDS). Information was elicited concerning life events and difficulties over the 12 months before globus onset, and this was compared with the experiences of the control patients for the year before symptom onset or, where appropriate, before the interview. Globus patients had significantly more severe events than the control patients throughout the year. Moreover, globus patients had significantly fewer close confiding relationships with their partners than did controls. There is evidence, therefore, for both psychological diathesis and social stress factors in the etiology of globus pharyngis.
Adult↗
Pain sensitivity in patients with temporomandibular disorders: relationship to clinical and psychosocial factors.
OBJECTIVE: We have previously reported that patients with temporomandibular disorders (TMD) exhibit enhanced sensitivity to experimentally evoked pain (1); however, the clinical relevance of this increased pain sensitivity remains unclear. The purpose of this study was to investigate the relationship of experimental pain sensitivity to clinical and psychosocial variables among patients with TMD. DESIGN: Thirty-six TMD patients were studied, half of whom were pain sensitive (PS) and the other half pain tolerant (PT), based on their ability to tolerate an ischemic pain task. Responses to painful thermal and nonpainful visual stimuli as well as clinical/diagnostic symptoms and psychosocial variables were compared for the two groups (i.e., PS vs. PT). RESULTS: Results indicated that, compared with PT patients, the PS group exhibited greater sensitivity to thermal pain and rated innocuous visual stimuli as more intense. PS patients also reported greater clinical pain, but in general the groups did not differ on diagnostic and psychosocial measures. CONCLUSIONS: The results suggest that ischemic pain tolerance is a clinically relevant marker of pain sensitivity in TMD patients. These findings are consistent with the hypothesis that impairments in CNS inhibitory pathways may contribute to the pain associated with TMD.
Adult↗
Comparison of fluorescence in situ hybridization, cytogenetic analysis, and DNA index analysis to detect chromosomes 4 and 10 aneuploidy in pediatric acute lymphoblastic leukemia: a Pediatric Oncology Group study.
PURPOSE: Chromosome abnormalities are an important prognostic factor in childhood acute lymphoblastic leukemia (ALL). Recently, a subset of patients with hyperdiploid ALL and trisomy of chromosomes 4 and 10 has been reported to have a very favorable event-free survival. Rapid and accurate detection of these patients will allow them to be treated with highly effective and relatively nontoxic antimetabolite therapy. Because of inherent problems associated with conventional cancer cytogenetics, we examined the efficacy of fluorescence in situ hybridization (FISH) to identify this ALL subgroup. PATIENTS AND METHODS: Fifty uncultured bone marrow specimens from children with newly diagnosed ALL were examined for chromosomes 4 and 10 aneuploidy with FISH. These results were compared with routine cytogenetics and DNA Index (DI). RESULTS: Interphase FISH cytogenetics identified the abnormal cell line(s) in all cases in which cytogenetics showed aneuploidy of chromosomes 4 and 10. In cases in which cytogenetics was not informative, FISH identified the presence of an aneuploid chromosome 4 and/or 10 cell line in concordance with the DI. CONCLUSIONS: FISH interphase cytogenetics can accurately detect chromosome 4 and 10 aneuploidy in leukemic cells. It is a rapid and clinically applicable technique that can reliably identify childhood ALL cases who have trisomy of chromosomes 4 and 10 and who have very favorable event-free survival.
Aneuploidy↗
Charcot spinal arthropathy in congenital insensitivity to pain.
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Arthropathy, Neurogenic↗
Traumatic hip dislocation during childhood. A case report and review of the literature.
Traumatic hip dislocations rarely occur during childhood. Males sustain pediatric hip dislocations four times more often than do females. Posterior hip dislocations comprise 87% of all pediatric hip dislocations. A soft, pliable acetabulum and ligamentous laxity predispose the immature hip joint to a dislocation secondary to minimal trauma. Potential associated injuries include fractures and neurovascular injury, whereas avascular necrosis (AVN) and degenerative joint disease are potential sequelae. Optimal treatment should be prompt reduction of the hip in order to minimize the risk of AVN of the femoral head.
Accidental Falls↗
Treatment of osteosarcoma with ifosfamide: comparison of response in pediatric patients with recurrent disease versus patients previously untreated: a Pediatric Oncology Group study.
This study was designed to test if the activity of a phase II agent, ifosfamide, would have been underestimated if it was tested exclusively in a population of children and young adults with recurrent osteosarcoma. The response rate to ifosfamide was compared in patients younger than 30 years of age with previously untreated osteosarcoma with metastases at diagnosis and/or unresectable primary tumors (stratum 1) with that of patients with recurrent osteosarcoma following adjuvant chemotherapy who were not previously exposed to ifosfamide (stratum 2). Evaluation of response was conducted 3 weeks after two courses of ifosfamide (2400 mg/m2 x 5 days) were administered 3 weeks apart. Nine of 33 (27%) evaluable patients in stratum 1 responded (1 complete and 8 partial responses) to ifosfamide. Among 30 evaluable patients in stratum 2, only 3 (10%) responded (1 complete and 2 partial responses; P = .04) Both groups of patients received equal doses of ifosfamide and experienced comparable toxicities. Results from this study suggest that the activity of new agents will be underestimated if tested in a population of heavily pretreated patients with recurrent disease. When possible, new chemotherapeutic agents should be tested in patients with a poor prognosis who have not been exposed to chemotherapy.
Adolescent↗