Citations

Purpose Physical impairments cause profound functional declines in patients with cancer. Although common rehabilitation measures can address many impairments, the extent of their delivery is unknown. We studied these issues by quantifying physical impairments in patients with metastatic breast cancer and by assessing how they are addressed. Patients and Methods A consecutive sample of 163 community-dwelling patients with metastatic breast cancer was stratified by Karnofsky performance score and administered the Medical Outcomes Study Physical Function Subscale and the Older Americans Resource Study Activities of Daily Living subscales. Cancer-related physical impairments were identified through a physical examination, the 6-Minute Walk Test, and the Functional Independence Measure Mobility Subscale. Patients were questioned regarding the nature, type, and setting of treatments for impairments. Physical rehabilitation needs were determined through a consensus process involving physiatrists and physical/occupational therapists specializing in cancer. Results Ninety-two percent of patients (150 of 163) had at least one physical impairment. Among 530 identified impairments, 484 (92%) required a physical rehabilitation intervention and 469 (88%) required physical therapy (PT) and/or occupational therapy (OT). Only 30% of impairments requiring rehabilitation services and 21% of those requiring PT/OT received treatment. Impairments detected during hospitalization were overwhelmingly more likely to receive a rehabilitation intervention (odds ratio [OR] = 87.9; 95% CI, 28.5 to 271.4), and PT/OT (OR = 558.8; 95% CI, 187.0 to 1,669.6). Low socioeconomic and minority status were significantly associated with nontreatment. Conclusion Remediable physical impairments were prevalent and poorly addressed among patients with metastatic breast cancer, drastically so in the outpatient setting. Undertreatment was particularly prominent among minority and socioeconomically disadvantaged groups.

Background— Long-QT syndrome (LQTS) is an inherited disorder associated with sudden cardiac death. The cytoskeletal protein syntrophin-α 1 (SNTA1) is known to interact with the cardiac sodium channel (hNa v 1.5), and we hypothesized that SNTA1 mutations might cause phenotypic LQTS in patients with genotypically normal hNa v 1.5 by secondarily disturbing sodium channel function. Methods and Results— Mutational analysis of SNTA1 was performed on 39 LQTS patients (QTc≥480 ms) with previously negative genetic screening for the known LQTS-causing genes. We identified a novel A257G- SNTA1 missense mutation, which affects a highly conserved residue, in 3 unrelated LQTS probands but not in 400 ethnic-matched control alleles. Only 1 of these probands had a preexisting family history of LQTS and sudden death with an additional intronic variant in KCNQ1. Electrophysiological analysis was performed using HEK-293 cells stably expressing hNa v 1.5 and transiently transfected with either wild-type or mutant SNTA1 and, in neonatal rat cardiomyocytes, transiently transfected with either wild-type or mutant SNTA1. In both HEK-293 cells and neonatal rat cardiomyocytes, increased peak sodium currents were noted along with a 10-mV negative shift of the onset and peak of currents of the current-voltage relationships. In addition, A257G-SNTA1 shifted the steady-state activation ( V h ) leftward by 9.4 mV, whereas the voltage-dependent inactivation kinetics and the late sodium currents were similar to wild-type SNTA1. Conclusion— SNTA1 is a new susceptibility gene for LQTS. A257G- SNTA1 can cause gain-of-function of Na v 1.5 similar to the LQT3.

AbstractD-cyclins are regulators of cell division that act in a complex with cyclin-dependent kinases to commit cells to a program of DNA replication. D-cyclins are overexpressed in many tumors, including multiple myeloma and leukemia, and contribute to disease progression and chemoresistance. To better understand the role and impact of D-cyclins in hematologic malignancies, we conducted a high throughput screen for inhibitors of the cyclin D2 promoter and identified the drug cyproheptadine. In myeloma and leukemia cells, cyproheptadine decreased expression of cyclins D1, D2, and D3 and arrested these cells in the G0/G1 phase. After D-cyclin suppression, cyproheptadine induced apoptosis in myeloma and leukemia cell lines and primary patient samples preferentially over normal hematopoietic cells. In mouse models of myeloma and leukemia, cyproheptadine inhibited tumor growth without significant toxicity. Cyproheptadine-induced apoptosis was preceded by activation of the mitochondrial pathway of caspase activation and was independent of the drug's known activity as an H1 histamine and serotonin receptor antagonist. Thus, cyproheptadine represents a lead for a novel therapeutic agent for the treatment of malignancy. Because the drug is well tolerated and already approved in multiple countries for clinical use as an antihistamine and appetite stimulant, it could be moved directly into clinical trials for cancer.

Background— Previous studies that assessed the risk of life-threatening cardiac events in patients with congenital long-QT syndrome (LQTS) have focused mainly on the first 4 decades of life, whereas the clinical course of this inherited cardiac disorder in the older population has not been studied. Methods and Results— The risk of aborted cardiac arrest or death from age 41 though 75 years was assessed in 2759 subjects from the International LQTS Registry, categorized into electrocardiographically affected (corrected QT interval [QTc] ≥470 ms), borderline (QTc 440 to 469 ms), and unaffected (QTc <440 ms) subgroups. The affected versus unaffected adjusted hazard ratio for aborted cardiac arrest or death was 2.65 ( P <0.001) in the age range of 41 to 60 years and 1.23 ( P =0.31) in the age range of 61 to 75 years. The clinical course of study subjects displayed gender differences: Affected LQTS women experienced a significantly higher cumulative event rate (26%) than borderline (16%) and unaffected (12%) women ( P =0.001), whereas event rates were similar among the 3 respective subgroups of men (29%, 26%, and 27%; P =0.16). Recent syncope (<2 years in the past) was the predominant risk factor in affected subjects (hazard ratio 9.92, P <0.001), and the LQT3 genotype was identified as the most powerful predictor of outcome in a subset of 871 study subjects who were genetically tested for a known LQTS mutation (hazard ratio 4.76, P =0.02). Conclusions— LQTS subjects maintain a high risk for life-threatening cardiac events after age 40 years. The phenotypic expression of affected subjects is influenced by age-specific factors related to gender, clinical history, and the LQTS genotype.

Background— The congenital long-QT syndrome (LQTS) is an important cause of sudden cardiac death in children without structural heart disease. However, specific risk factors for life-threatening cardiac events in children with this genetic disorder have not been identified. Methods and Results— Cox proportional-hazards regression modeling was used to identify risk factors for aborted cardiac arrest or sudden cardiac death in 3015 LQTS children from the International LQTS Registry who were followed up from 1 through 12 years of age. The cumulative probability of the combined end point was significantly higher in boys (5%) than in girls (1%; P <0.001). Risk factors for cardiac arrest or sudden cardiac death during childhood included corrected QT interval [QTc] duration >500 ms (hazard ratio [HR]; 2.72; 95% confidence interval [CI], 1.50 to 4.92; P =0.001) and prior syncope (recent syncope [<2 years]: HR, 6.16; 95% CI 3.41 to 11.15; P <0.001; remote syncope [≥2 years]: HR, 2.67; 95% CI, 1.22 to 5.85; P =0.01) in boys, whereas prior syncope was the only significant risk factor among girls (recent syncope: HR, 27.82; 95% CI, 9.72 to 79.60; P <0.001; remote syncope: HR, 12.04; 95% CI, 3.79 to 38.26; P <0.001). β-Blocker therapy was associated with a significant 53% reduction in the risk of cardiac arrest or sudden cardiac death ( P =0.01). Conclusions— LQTS boys experience a significantly higher rate of fatal or near-fatal cardiac events than girls during childhood. A QTc duration >500 ms and a history of prior syncope identify risk in boys, whereas prior syncope is the only significant risk factor among girls. β-Blocker therapy is associated with a significant reduction in the risk of life-threatening cardiac events during childhood.

Abstract Rationale The 2002 American Thoracic Society/European Respiratory Society classification of idiopathic interstitial pneumonias identified nonspecific interstitial pneumonia (NSIP) as a provisional diagnosis. Concern was expressed that NSIP was a “wastebasket” category, difficult to distinguish from other idiopathic interstitial pneumonias. Objectives The following questions were addressed: (1) Is idiopathic NSIP a distinct entity? 2) If so, what are its clinical, radiologic and pathologic characteristics? (3) What is the role of radiology and pathology in establishing the diagnosis? (4) To make a diagnosis of idiopathic NSIP, what other disorders need to be excluded and how should this be done? Methods Investigators who had previously reported cases of idiopathic NSIP were invited to submit cases for review (n = 305). After initial review, cases with complete clinical, radiologic, and pathologic information (n = 193) were reviewed in a series of workshops. Measurements and Main Results Sixty-seven cases were identified as NSIP. Mean age was 52 years, 67% were women, 69% were never-smokers, and 46% were from Asian countries. The most common symptoms were dyspnea (96%) and cough (87%); 69% had restriction. By high-resolution computed tomography, the lower lung zones were predominantly involved in 92% of cases; 46% had a peripheral distribution; 47% were diffuse. Most showed a reticular pattern (87%) with traction bronchiectasis (82%) and volume loss (77%). Lung biopsies showed uniform thickening of alveolar walls with a spectrum of cellular to fibrosing patterns. Five-year survival was 82.3%. Conclusions Idiopathic NSIP is a distinct clinical entity that occurs mostly in middle-aged women who are never-smokers. The prognosis of NSIP is very good.

Prior studies have suggested the possibility of immune-mediated death of xenogeneic hepatocytes in a bioartificial liver (BAL) during hemoperfusion. This study was designed to elucidate how immunity may cause death of xenogeneic hepatocytes in the BAL. Healthy dogs were treated with a BAL containing hollow fiber membranes with large pores (200 nm) or small pores (400 kDa). The immune response of recipient dogs to BAL therapy was monitored over 3 h of treatment. We observed significantly greater loss of viability of hepatocytes in the 200 nm group compared with the 400 kDa group (p < 0.001). Low viability after treatment with the large pore membrane was associated with positive staining for dog IgG, dog IgM, and dog complement on dead hepatocytes. Significant levels of dog antibody were detected in samples of BAL medium from the 200 nm group. These canine antibodies were cytotoxic to porcine hepatocytes. In contrast, medium from the 400 kDa group contained only trace levels of dog IgG and were noncytotoxic. We conclude that antibody-mediated cytotoxicity contributed to the death of hepatocytes during treatment with a xenogeneic BAL. Immune-mediated death of hepatocytes was reduced by increasing selectivity of the BAL membrane.

Langerhans' cell histiocytosis is a disease of the dendritic histiocytes with a wide variety of clinical manifestations. This report describes a boy with Langerhans' cell histiocytosis who presented with primarily neurologic and endocrinologic findings, without pain. The diagnosis of Langerhans' cell histiocytosis was not made until 10 years after symptom onset. The pathology database at Mayo Clinic was searched for cases of Langerhans' cell histiocytosis between 1985 and 1999 under 19 years of age (65 children), and information regarding clinical presentation was abstracted. Database review found a range of 1 day to 156 weeks (mean 13.8 weeks) from symptom onset to diagnosis. No other patients with primarily neurologic symptoms were found. The diagnosis of Langerhans' cell histiocytosis was made significantly sooner after onset if pain was present (chi-square = 19.1, P < . .001, two-tailed, phi coefficient 0.54). Our findings indicate that neurologic manifestations of Langerhans' cell histiocytosis are rare, and the combination of diabetes insipidus, ataxia, skin rash, or osseous pain should alert the clinician to the possibility of Langerhans' cell histiocytosis and avoid delayed diagnosis. (J Child Neurol 2001;16: 535-538).