Terminal-Phase Chronic Myelogenous Leukemia: Approaches to Treatment

The prognosis of patients with CML has improved little in the past 50 years. The relatively benign chronic phase invariably deteriorates to a refractory and rapidly fatal terminal phase. This terminal stage has been found to have two major subtypes as defined by morphologic, cytochemical, immunologic, and enzymatic criteria--myeloblastoid and lymphoblastoid. Aggressive combination chemotherapy has achieved minimal improvement in survival once the terminal phase has begun, perhaps because only Ph1-positive stem cells remain to repopulate the marrow at this stage. Bone marrow transplantation has also been unsuccessful as therapy for the terminal phase, possibly because the patients are too debilitated to tolerate transplantation once the terminal phase has begun. Combination chemotherapy has been applied in an effort to eliminate the Ph1 chromosome-containing clone during the chronic phase. This goal has not yet been consistently achieved. Chemotherapy has also not been able to delay the onset of the terminal phase nor to prolong survival. Even in those patients in whom the Ph1 chromosome-containing clone has been eliminated, relapse to the chronic phase with return of the Ph1 chromosome has generally occurred within a brief period of time. Bone marrow transplantation during the chronic phase may hold the promise of true cure for CML, with permanent elimination of the malignant clone. However, the chronic phase can be unpredictably long and patients in the chronic phase often have few, if any symptoms. Therefore, there has been a reluctance to employ drastic therapy during the chronic phase. Techniques to predict the transformation to the terminal phase prior to overt morphologic or clinical conversion are now being developed. It may be possible in the future to attempt HLA-matched sibling donor bone marrow transplantation at the earliest signs of transformation from the chronic to the terminal phase. In this manner, optimal survival might be achieved by allowing patients to be maintained in the chronic phase for as long as possible prior to the initiation of aggressive therapy. Until this is routinely possible, continued research designed to improve the therapy of the terminal phase must be pursued. These attempts are likely to include the development and evaluation of new chemotherapeutic agents, novel methods of administration of existing drugs to better exploit their pharmacokinetics (for example, continuous infusion), and the utilization of newly described treatment approaches (such as the use of "differentiating" agents in an attempt to prevent progression to blastic transformation).(ABSTRACT TRUNCATED AT 400 WORDS)     

Factors affecting ventricular volumes determined by a count-based equilibrium method

Using a 99mTc-filled source ("ventricle") in an elliptical torso phantom, we analyzed the effect of source depth, region of interest (ROI) size, background concentration and source shape on volumes determined by an attenuation-corrected count-based equilibrium method. The calculated volume of a 96 cc sphere decreased linearly from 103 to 82 cc with increasing depth from 4 to 18 cm [vol = -1.48 X depth (cm) + 109, r = 0.99]. The calculated volume of the same sphere imaged at a depth of 9 cm increased from 98 to 117 cc with ROI sizes increasing from 161 to 1,369 pixels (1 pixel = 0.17 cm2). With increasing background concentration from 0-2 microCi/ml calculated volumes decreased from 95 to 85 cc (vol = -5.3 X background concentration (microCi/ml) + 95, r = 0.97). However, with correction for over-subtraction of background, increasing background activity caused no decrease in calculated volume (mean = 95 cc, s.d. = 1). Calculated volumes for the sphere and various cylinders were accurate, while those for cones were up to 37% lower for actual volumes ranging from 56-608 cc. This study demonstrates that multiple factors produce variability in count-based determination of phantom volumes. A careful consideration of the interaction of these factors with the edge-detection and computational algorithms is required.     

Effects of characteristic x-rays on assay of I-123 by dose calibrator

Large differences in dose-calibrator readings are obtained if "high-purity" I-123 is assayed in different containers. Large correction factors are necessary for assaying another isotope of iodine, I-125, in a dose calibrator, because of absorption of the low-energy (28.4-keV, weighted mean) emissions. We found that up to 70% of the dose-calibrator response to I-123 can be due to characteristic x-rays with energies exactly the same as those emitted by I-125, and that dose-calibrator response to I-123 is also strongly affected by the absorption properties of the vial. An appropriate method to define I-123 activity uses a gamma camera with a medium-energy collimator to establish correction factors for dose-calibrator assay of I-123 in different containers. Correction factors for a plastic syringe and a thick-wall glass vial, were determined using this method. Measurement of I-123 activity in a copper absorber will eliminate the response to x-rays, and the gamma camera is useful in establishing the necessary correction factors.     

Effect of genetic background on the therapeutic effects of dehydroepiandrosterone (DHEA) in diabetes-obesity mutants and in aged normal mice

Dehydroepiandrosterone (DHEA) was fed at 0.1-0.4% in the diet to genetically diabetic (db/db) or obese (ob/ob) C57BL/KsJ (BL/Ks) or C57BL/6J (BL/6) mice. Treatment of BL/Ks-db/db or ob/ob mice with 0.4% DHEA prevented hyperglycemia, islet atrophy, and severe diabetes associated with this inbred background, but did not affect weight gain and food consumption. Homozygous obese (ob) or diabetes (db) mice on the BL/6 background were more sensitive to DHEA, and the mild, transient hyperglycemia associated with ob or db gene expression on the BL/6 inbred background could be prevented by 0.1% DHEA. Both body weight and food consumption were decreased in BL/6 mutants maintained on 0.1% DHEA whereas this effect was not seen in BL/Ks mutants fed up to 0.4% DHEA. Early therapy with 0.4% DHEA, initiated at 2 wk of age, prevented the development of most diabetes symptoms and decreased the rate of weight gain in pups of all genotypes. In addition to therapeutic effects on both obese mutants, DHEA effected significant changes in an aging study using normal BL/6 female mice. Four weeks of DHEA treatment initiated at 2 yr of age improved glucose tolerance and at the same time reduced plasma insulin to a "younger" level. This suggests that DHEA may act in insulin-resistant mutant mice and in aging normal mice to increase the sensitivity to insulin.     

Gestational Women’s Perceptions About the Harms of Cigarette and E-Cigarette Use During Pregnancy

Objectives

The purpose of this study was to examine differences between perceived harm of cigarette and electronic cigarette (e-cigarette) use while pregnant and differences between healthcare providers’ communication about these products during pregnancy.

Methods

A convenience sample of gestational women (n?=?218; ages 18–45) living in the US completed an online survey between May and December 2017. Participants reported perceived likelihood of adverse health outcomes (e.g., low birth weight, sudden infant death syndrome) among infants/children born to mothers who used cigarettes/e-cigarettes. T-tests and two-way ANOVAs examined differences between risk perceptions of using cigarettes/e-cigarettes while pregnant based on pregnancy status (previously pregnant, currently pregnant, future pregnant). Chi-square analyses examined differences between healthcare provider communication about cigarette/e-cigarette use during pregnancy.

Results

Overall, participants believed adverse health outcomes were significantly more likely to be caused by maternal use of cigarettes than e-cigarettes. Participants who planned to be pregnant reported higher endorsement that smoking combustible cigarettes would cause a miscarriage (p?<?.05) or increased blood pressure (p?<?.05) for a child than currently pregnant participants. Participants reported healthcare providers asked about (p?<?.05), advised them not to use (p?<?.001), and talked to them about health effects of smoking combustible cigarettes while pregnant (p?<?.001) significantly more than e-cigarettes.

Conclusions for Practice

Healthcare providers working with pregnant women should perform the 5As behavioral intervention method to provide pregnant women with tobacco cessation care. They should also discuss the absolute harm nicotine exposure (via cigarettes or e-cigarettes) can have on fetal health and development.

     

Success Rates of Debridement,Antibiotics, and Implant Retention in 230 Infected Total Knee Arthroplasties: Implications for Classification of Periprosthetic Joint Infection

BackgroundProsthetic joint infection (PJI) is the most common cause of failure following total knee arthroplasty (TKA). This study aimed to determine the success of debridement, antibiotics, and implant retention (DAIR) in a large cohort of TKA PJIs and assess the utility of current classification systems in predicting DAIR outcomes in early postoperative, late hematogenous, and chronic PJIs.MethodsIn a multicenter review over 15 years, 230 patients underwent DAIR for first episode PJI following primary TKA. Patient demographics, disease and surgical factors, treatment regime, and outcomes were identified. Univariate and multivariate survival analyses were performed to identify factors associated with successful DAIR. Continuous variables with predictive value were further analyzed using receiver operating characteristic curves. The ability to predict DAIR outcomes of multiple classification systems was also assessed.ResultsPatients were followed for an average of 6.9 years. The overall success rate of DAIR was 53.9%. On receiver operating characteristic analysis, 3 months (area under the curve = 0.63) and 1-year age (area under the curve = 0.66) of implant cut-offs was similarly predictive of outcomes. On multivariate survival analysis, DAIR was successful in 64% of “early” PJIs (implant <1 year) vs 38% of “late hematogenous” PJIs (implant >1 year; odds ratio [OR] 1.78, P = .01). For late PJIs (implant >1 year), Staphylococcus aureus (OR 4.70, P < .001) and gram-negative infections (OR 2.56, P = .031) were risk factors for DAIR failure.ConclusionDAIR has a high failure rate in all PJIs occurring more than a year post primary TKA, particularly when caused by S aureus or gram-negative bacteria. The age of implant is an important predictor of DAIR outcomes.     

Recovery of motor function after spinal-cord injury--a randomized, placebo-controlled trial with GM-1 ganglioside

BACKGROUND. Spinal-cord injury is devastating; until recently, there was no medical treatment to improve recovery of the initial neurologic deficit. Studies in animals have shown that monosialotetrahexosylganglioside (GM-1) ganglioside enhances the functional recovery of damaged neurons. METHODS. A prospective, randomized, placebo-controlled, double-blind trial of GM-1 ganglioside was conducted in patients with spinal-cord injuries. Of 37 patients entered into the study, 34 (23 with cervical injuries and 11 with thoracic injuries) completed the test-drug protocol (100 mg of GM-1 sodium salt or placebo intravenously per day for 18 to 32 doses, with the first dose taken within 72 hours of the injury) and a one-year follow-up period. Neurologic recovery was assessed with the Frankel scale (comprising five categories) and the American Spinal Injury Association (ASIA) motor score (a scale of scores from 0 to 100, derived from strength tests of 20 specific muscles, each scored from 0 to 5). RESULTS. There was a significant difference between groups in the distribution of improvement of Frankel grades from base line to the one-year follow-up (improvement of 0, 1, 2, and 3 grades in 13, 4, 1, and 0 patients, respectively, in the placebo group and 8, 1, 6, and 1 patients, respectively, in the GM-1 group; P = 0.034 by the Cochran-Mantel-Haenszel chi-square test). The GM-1-treated patients also had a significantly greater mean improvement in ASIA motor score from base line to the one-year follow-up than the placebo-treated patients (36.9 vs. 21.6 points; P = 0.047 by analysis of covariance with the base-line ASIA motor score as the covariate). An analysis of individual muscle recoveries revealed that the increased recovery in the GM-1 group was attributable to initially paralyzed muscles that regained useful motor strength rather than to strengthening of paretic muscles. CONCLUSIONS. This small study provides evidence that GM-1 enhances the recovery of neurologic function after one year. A larger study must be conducted, however, before GM-1 is considered efficacious and safe in treating spinal-cord injury.     

Nasogastric and intravenous infusions of (+)-4-propyl-9-hydroxynaphthoxazine (PHNO) in Parkinson's disease.

(+)-4-propyl-9-hydroxynaphthoxazine (PHNO) is a new dopamine agonist which is capable of producing a sustained response in parkinsonian patients with "on-off" fluctuations when given as a continuous infusion either nasogastrically or intravenously. These data suggest that a sustained release formulation of PHNO may provide a significant, new treatment for patients with "on-off" fluctuations.     

Improved methodology for analyzing local and distant recurrence

Studies of radiation therapy and/or surgery in the treatment of cancer frequently use actuarial methods to estimate curves of time to local failure and compare two such curves with statistical methods originally developed for survival data. In such analyses, patients who fail first in distant sites or die before local failure are considered censored for time to local failure. While the arithmetic of these calculations is usually correct, the interpretation of the results is almost universally incorrect. For example, an actuarial Kaplan-Meier curve of time to breast recurrence after breast conserving treatment consistently overestimates the percentage of patients who would benefit from a subsequent mastectomy. Actuarial methods require the assumption that time to local failure and time to distant failure are statistically independent. For most human malignancies this is not a reasonable assumption, since there are always some patient subgroups at high risk of both local and distant failure and some patient subgroups at low risk for either type of failure. Without the assumption of independence, the time to local failure distribution is not well defined. The basic problem is that estimating time to local failure falls into the category of analyzing "competing risks," since the various causes of failure are competing for the same patient. For this reason, the effects of a particular treatment on local failure cannot be assessed separately from its effects on distant failure. This report explains the concepts of statistical independence, nonidentifiability, and competing risks and illustrates the pitfalls of using actuarial methods to assess local tumor control.(ABSTRACT TRUNCATED AT 250 WORDS)