Treatment of acute lymphoblastic leukemia. 30 years' experience at St. Jude Children's Research Hospital

BACKGROUND: Therapy for childhood lymphoblastic leukemia has evolved during the past three decades, but key questions about what are the least toxic, most effective forms of treatment remain unanswered because of the lack of comprehensive follow-up information. METHODS: To assess long-term outcome in the series of clinical trials conducted at St. Jude Hospital, we compared the results of treatment typical of four eras: exploratory combination chemotherapy (era 1, 1962 to 1966; 91 patients), regimens for the control of meningeal leukemia (era 2, 1967 to 1979; 825 patients), limited intensification of therapy (era 3, 1979 to 1983; 428 patients), and extended intensification of therapy (era 4, 1984 to 1988; 358 patients). ("Intensification" refers to strategies of systemic chemotherapy that are more aggressive than conventional ones.) The major end points were survival and event-free survival; we also calculated the relative risk of treatment failure and the rate of relapse or death after treatment ended (post-treatment failure rate). RESULTS: The probability of event-free survival improved significantly in each successive era (P < 0.001 by the log-rank test), reaching 71 percent in era 4. There was a decrease of approximately 50 percent in the risk of treatment failure from one era to the next in each subgroup of patients defined according to different combinations of the leukocyte count, race, age, and sex. Leukemia appeared to be eradicated in patients who remained in complete remission for three years or more after treatment in era 4. The incidence of death due to nonleukemic causes remained 4 to 6 percent despite the trend toward more intensive treatment. An estimated 765 patients (45 percent) are long-term survivors; most of them (80 percent) have no health problems related to leukemia or its treatment. CONCLUSIONS: The development and successful application of preventive therapy for meningeal leukemia, followed by the intensification of systemic chemotherapy, has progressively improved the rate of cure of childhood lymphoblastic leukemia, with relatively few adverse sequelae.     

Effect of set-up error on the dose across the junction of matching cranial-spinal fields in the treatment of medulloblastoma

PURPOSE: The effect of systematic and stochastic setup error on the dose delivered to the gap region for the three field radiation treatment of medulloblastoma is studied. The consequences of such setup error is discussed. METHODS AND MATERIALS: The treatment of medulloblastoma is typically a 3 field technique, in which two lateral cranial fields are matched with a spine field. The x-ray dose delivered to the region between the matched fields depends upon the gap size. The choice of the gap width between the cranial and spinal fields is controversial. It is currently a compromise between minimizing the risk of dose hot spots to the spine, and the associated clinical complications, as well as the magnitude of cold spots (underdosing) across the gap, with the associated risk of disease recurrence. In this paper, we examine the effect of gap width with a moving junction, referred to as "field feathering", on the dose across the field junction for a 6MV photon beam. In addition, we have studied 129 portal films and 40 simulation films to assess the accuracy and precision of patient setup during treatment with a plan involving feathered fields. Selected landmarks observable on both portal and simulation films were identified and the variation in the distances to the field edges measured. The distribution of patient setup error was convoluted with the beam profiles for a 6MV linac. These convoluted field edges were used obtain dose profiles across the gap region as a function of gap separation. The consequences for therapy are discussed. In addition, analysis of patient setup error on an alternative treatment involving beam modifiers to broaden the beam penumbra is discussed. RESULTS: The magnitude of the spatial stochastic and systematic setup error was determined to be approximately three and two millimeters respectively. The dosimetric consequences of patient setup error lead to over and under dosing in the spinal gap region for the three field technique. The degree of under or over dose depends on the nature and magnitude of the patient setup error. CONCLUSIONS: The effect of patient setup error can lead to significant dosimetric errors in the dose to the gap region depending on the magnitude of the setup errors. The effective over and under dose can be compensated by the use beams modifiers such as a beam spoiler or vibrating jaws.     

Hofmann degradation of acrylamide copolymer: Synthesis of amine functionalized thermoplastic hydrogel

The amine functionalization of an acrylamide copolymer was achieved via Hofmann degradation. The starting material, poly(acrylamide-co-methyl methacrylate), was synthesized by radical precipitation polymerization. Using this copolymer, Hofmann degradation at 0°C in a water-dioxane mixture was done using sodium hypochlorite and NaOH. The resulting hydrogel could be dissolved in water-tetrahydrofuran mixtures, and the cast film had a water content of 73%. It was found that the conversion to primary amine was lower, and the extent of a side reaction was higher, compared to those of an acrylamide homopolymer. This was presumed to be due to the lack of the neighboring group effect among acrylamide units since it was a random copolymer. Further modification of this polymer by reacting the amine group is considered to obtain the desired properties for biomedical applications. © 1996 John Wiley & Sons, Inc.     

Detection of extrathoracic metastases by positron emission tomography in lung cancer

BACKGROUND: Accurate staging of non-small cell lung cancer is essential for treatment planning. We evaluated in a prospective study the role of whole-body 2-[18F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) in mediastinal nodal staging with a positive predictive value of 96%. The study was continued to further evaluate the value of whole-body FDG PET in detecting unexpected extrathoracic metastases (ETMs) in patients qualifying for surgical treatment by conventional staging. METHODS: One hundred patients underwent clinical evaluation, chest and upper abdominal computed tomography scan, mediastinoscopy (lymph nodes greater than 1 cm on computed tomography), and routine laboratory tests. In 94 patients with stage IIIa or less and 6 with suspected N3 a whole-body FDG PET was performed. If clinical signs of ETMs were present additional diagnostic methods were applied. All findings in the FDG PET were confirmed histologically or radiologically. RESULTS: Unexpected ETMs were detected in 13 (14%) of 94 patients (stage IIIa or less) at 14 sites. In addition 6 of 94 patients were restaged up to N3 after PET. The suspected N3 disease (stage IIIb) on computed tomography was confirmed by PET in all 6 patients. There was no false positive finding of ETM. Weight loss was correlated with the occurrence of ETM: more than 5 kg, 5 of 13 patients (38%); more than 10 kg, 4 of 6 patients (67%). Pathologic laboratory findings were not predictive for ETM. CONCLUSIONS: Whole-body FDG PET improves detection of ETMs in patients with non-small cell lung cancer otherwise elegible for operation. In 14% of patients (stage IIIa or less), ETMs were detected, and in total, 20% of the patients were understaged.     

Functionalized 1,3-teraryls as a new class of hepatoprotectants. Part V

A 29-year-old man was admitted to the hospital because of a high fever and dyspnea. He had a history of bronchial asthma and had had a bullectomy of the right lung at 15 years of age. He had visited a family physician because of fever and non productive coughing. Medications had no effect on his symptoms, and dyspnea developed. A chest X-ray film showed total collapse of the right lung, and he was referred to our hospital. Laboratory data showed eosinophilia and a high titer of IgE. Total obstruction of the right main stem bronchus by mucous plug was found during fiberoptic bronchoscopy. Aspergillus was detected by pathological examination of bronchial lavage fluid. Tests for aspergillus-specific IgE and IgG antibody were positive, as was immediate skin reactivity to Aspergillus. Allergic bronchopulmonary aspergillosis (ABPA) was diagnosed. Infusion and inhalation of a corticosteroid and fluconazole were effective; the symptoms resolved and X-ray findings improved. While migratory infiltration, proximal bronchiectasis and segmental or subsegmental atelectasis caused by a mucous plug are common X-ray findings in allergic bronchopulmonary aspergillosis, total collapse is rare.     

Enhancement of the transient-evoked otoacoustic emission produced by the addition of a pure tone in the guinea pig

Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase implicated in cell-matrix interaction and integrin signaling. It is well established that Tyr-397 is the FAK autophosphorylation site and Tyr-407, -576/577, -861, and -925 are the sites on murine FAK that are mediated by Src family kinases. To study how FAK is regulated by tyrosine phosphatase(s), cells overexpressing chicken FAK are treated with sodium vanadate. Both the phosphotyrosine content and the enzymatic activity of FAK are increased in response to vanadate. Interestingly, sustained FAK Tyr-576/577 and -863 phosphorylations are detected in vanadate-treated FAK overexpressors and are dependent on FAK autophosphorylation. Further analysis of sodium vanadate-treated FAK overexpressors reveals that the enhanced FAK kinase activity parallels its elevated Tyr-576/577 phosphorylation. Thus, we conclude that Src-mediated FAK phosphorylation is regulated by a tyrosine phosphatase(s) and may be of physioligical significance.     

DSEF-1 is a member of the hnRNP H family of RNA-binding proteins and stimulates pre-mRNA cleavage and polyadenylation in vitro

DSEF-1 protein selectively binds to a G-rich auxiliary sequence element which influences the efficiency of processing of the SV40 late polyadenylation signal. We have obtained cDNA clones of DSEF-1 using sequence information from tryptic peptides isolated from DSEF-1 protein purified from HeLa cells. DSEF-1 protein contains three RNA-binding motifs and is a member of the hnRNP H family of RNA-binding proteins. Recombinant DSEF-1 protein stimulated the efficiency of cleavage and polyadenylation in an AAUAAA-dependent manner in in vitro reconstitution assays. DSEF-1 protein was shown to be able to interact with several poly(A) signals that lacked a G-rich binding site using a less stringent, low ionic strength gel band shift assay. Recombinant DSEF-1 protein specifically stimulated the processing of all of the poly(A) signals tested that contained a high affinity G-rich or low affinity binding site. DSEF-1 specifically increased the level of cross-linking of the 64 kDa protein of CstF to polyadenylation substrate RNAs. These observations suggest that DSEF-1 is an auxiliary factor that assists in the assembly of the general 3'-end processing factors onto the core elements of the polyadenylation signal.     

Evaluation of anti-nociceptive effects of neuronal nicotinic acetylcholine receptor (NAChR) ligands in the rat tail-flick assay

In the present investigation, anti-nociceptive effects of neuronal nicotinic acetylcholine receptor (NAChR) ligands, (+)- and (-)-nicotine, cytisine, methylcarbamylcholine (MCC), dimethylphenylpiperazinium iodide (DMPP), and (+/-)-epibatidine were evaluated in the rat tail-flick assay both after subcutaneous (s.c.) and intracerebroventricular (i.c.v.) administration. The pharmacology of the tail-flick response to NAChR ligands after s.c. and i.c.v. routes was similar. Epibatidine was the most potent ligand examined with a longer duration of action than any other agonist. (-)-Nicotine was more active than (+)-nicotine indicating stereospecificity. ICV administration studies indicated an apparent partial agonist activity for (+)-nicotine in the tail-flick response. Tail-flick responses to NAChR agonists are independent of opioid and muscarinic pathways and appear to be mediated both by central and peripheral NAChR recognition sites. Central administration of MCC activates both NAChR and muscarinic anti-nociceptive mechanisms. Studies employing the alpha-adrenergic receptor alkylating agent, phenoxybenzamine or the noradrenergic neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), suggested that the NAChR-noradrenergic and NAChR-serotoninergic interactions play an important role in the tail-flick response. Studies employing a selective alpha-bungarotoxin-sensitive NAChR receptor antagonist, methyllycaconitine (MLA), suggested a minimal role for these receptors in the tail-flick response. The biochemical studies also indicated that a sub-population of NAChR receptors are located pre-synaptically on noradrenergic and/or serotoninergic pathways in the hippocampus.