The treatment patterns, efficacy, and safety of nab (®)-paclitaxel for the treatment of metastatic breast cancer in the United States: results from health insurance claims analysis.

BACKGROUND: nab-Paclitaxel is an albumin-bound formulation of paclitaxel approved for the treatment of metastatic breast cancer (MBC). This analysis was designed to characterize the treatment patterns, efficacy, and safety of nab-paclitaxel for MBC treatment using health claims data from US health plans associated with Optum. METHODS: Women aged ≥ 18 years who initiated nab-paclitaxel for MBC treatment from January 1, 2005, to September 30, 2012, and who met eligibility criteria were selected from the Optum Research Database for this analysis. Patients were required to have complete medical coverage and pharmacy benefits, ≥ 6 months of continuous enrollment, and a diagnosis of MBC prior to nab-paclitaxel initiation. The pattern of use for nab-paclitaxel (eg, regimen, schedule, duration, and administration) and claims-captured toxicities were characterized by line of therapy. Overall survival (OS) and time to next therapy or death (TNTD) were described by line of therapy, regimen, and schedule. RESULTS: Of the 664 nab-paclitaxel patients, 172 (25.9%) received it as first-line therapy, 211 (31.8%) as second-line therapy, and 281 (42.3%) as third-line or later therapy. Overall, the majority of patients received monotherapy (61%) and followed a weekly (71%) rather than an every 3 weeks treatment schedule. nab-Paclitaxel was often (31.7%) combined with targeted therapy (57.5% with bevacizumab and 23.9% with trastuzumab or lapatinib). The median duration of therapy was 128 days (4.2 months). For the overall population, median OS was 17.4 months (22.7, 17.4, and 15.1 months in first-, second-, and third-line or later therapy, respectively). Median TNTD was 6.1 months (7.1, 6.6, and 5.3 months in first-, second-, and third-line or later therapy, respectively). For patients aged ≤ 50 years or with ≥ 3 metastatic sites, median OS was 15.6 months. No new safety signal was identified. CONCLUSIONS: In this US healthcare system, the majority of patients received nab-paclitaxel as second-line or later therapy, monotherapy, and weekly treatment. The efficacy and safety outcomes of nab-paclitaxel observed in this real-world setting appear consistent with those from clinical trial data.

The cost-effectiveness of initial treatment of multiple myeloma in the U.S. with bortezomib plus melphalan and prednisone versus thalidomide plus melphalan and prednisone or lenalidomide plus melphalan and prednisone with continuous lenalidomide maintenance treatment.

The outlook for transplant-ineligible multiple myeloma patients has improved enormously over recent years with the incorporation of new agents into standard regimens. Novel regimens combine melphalan and prednisone (MP) with bortezomib (VMP), with thalidomide (MPT), and with lenalidomide with (MPR-R) and without (MPR) lenalidomide maintenance. The efficacy, safety, and cost-effectiveness of these regimens have not yet been compared; therefore, we conducted a pharmacoeconomic analysis using data from randomized controlled trials versus MP. Using a Markov model developed from a U.S. payer's perspective, we compared VMP with MPT and MPR-R over a lifetime horizon. MPT and MPR-R were chosen because, like VMP, they are superior to MP in response and outcomes. Data from the Velcade as Initial Standard Therapy in Multiple Myeloma (VISTA; VMP), Intergroupe Francophone du Myelome (IFM) 99-06 (MPT), and MM-015 (MPR-R) trials were used. The IFM 99-06 study was selected because of the superior activity in this study compared with other MPT studies. Using patient-level (VMP) and published (MPT, MPR-R) data, we estimated the health-state transition and adverse event probabilities for each regimen, related costs, and state-specific utility estimates. Costs (in 2010 U.S. dollars) and health outcomes were discounted at 3%. Discounted lifetime direct medical costs were lowest with VMP at $119,102. MPT cost $142,452 whereas MPR-R cost $248,358. Incremental cost-effectiveness ratio calculations projected that VMP would confer cost savings and better health outcomes relative to MPT and MPR-R. We conclude that VMP is highly likely to be cost-effective compared with MP, MPT, and MPR-R.

A randomized study of alglucosidase alfa in late-onset Pompe's disease.

BACKGROUND: Pompe's disease is a metabolic myopathy caused by a deficiency of acid alpha glucosidase (GAA), an enzyme that degrades lysosomal glycogen. Late-onset Pompe's disease is characterized by progressive muscle weakness and loss of respiratory function, leading to early death. We conducted a randomized, placebo-controlled trial of alglucosidase alfa, a recombinant human GAA, for the treatment of late-onset Pompe's disease. METHODS: Ninety patients who were 8 years of age or older, ambulatory, and free of invasive ventilation were randomly assigned to receive biweekly intravenous alglucosidase alfa (20 mg per kilogram of body weight) or placebo for 78 weeks at eight centers in the United States and Europe. The two primary end points were distance walked during a 6-minute walk test and percentage of predicted forced vital capacity (FVC). RESULTS: At 78 weeks, the estimated mean changes from baseline in the primary end points favored alglucosidase alfa (an increase of 28.1+/-13.1 m on the 6-minute walk test and an absolute increase of 3.4+/-1.2 percentage points in FVC; P=0.03 and P=0.006, respectively). Similar proportions of patients in the two groups had adverse events, serious adverse events, and infusion-associated reactions; events that occurred only in patients who received the active study drug included anaphylactic reactions and infusion-associated reactions of urticaria, flushing, hyperhidrosis, chest discomfort, vomiting, and increased blood pressure (each of which occurred in 5 to 8% of the patients). CONCLUSIONS: In this study population, treatment with alglucosidase alfa was associated with improved walking distance and stabilization of pulmonary function over an 18-month period. (ClinicalTrials.gov number, NCT00158600.)

Long-term monitoring of patients with infantile-onset Pompe disease on enzyme replacement therapy using a urinary glucose tetrasaccharide biomarker.

PURPOSE: To investigate the correlation of the urinary glucose tetrasaccharide, Glcalpha1-6Glcalpha1-4Glcalpha1-4Glc, (Glc4) with skeletal muscle glycogen content and the long-term clinical response to enzyme replacement therapy with recombinant human acid alpha glucosidase in infantile Pompe disease. METHODS: Eighteen patients, < or =6 months old, were enrolled in a clinical trial of enzyme replacement therapy for up to 142 weeks. Urinary Glc4, skeletal muscle glycogen, and other clinical and laboratory assessments were made at baseline and at regular intervals. Urinary Glc4 was determined using an isotope-dilution tandem mass spectrometric assay. The clinical response to treatment was defined according to the motor function response. Trends in urinary Glc4 were correlated with the clinical response and compared with serum enzyme markers of skeletal muscle damage, creatine kinase, aspartate aminotransferase, and alanine aminotransferase. RESULTS: Urinary Glc4, in contrast to the serum markers, correlated closely with skeletal muscle glycogen content and with the clinical response. Patients with the best response to treatment maintained the lowest levels of Glc4 throughout the trial. CONCLUSION: The results from this study support the use of urinary Glc4 for monitoring patients with infantile-onset Pompe disease on therapy.

Long-Term Retrospective Analysis of Gene Therapy with Alipogene Tiparvovec and Its Effect on Lipoprotein Lipase Deficiency-Induced Pancreatitis.

Alipogene tiparvovec (Glybera) is a gene therapy product approved in Europe under the "exceptional circumstances" pathway as a treatment for lipoprotein lipase deficiency (LPLD), a rare genetic disease resulting in chylomicronemia and a concomitantly increased risk of acute and recurrent pancreatitis, with potentially lethal outcome. This retrospective study analyzed the frequency and severity of pancreatitis in 19 patients with LPLD up to 6 years after a single treatment with alipogene tiparvovec. An independent adjudication board of three pancreas experts, blinded to patient identification and to pre- or post-gene therapy period, performed a retrospective review of data extracted from the patients' medical records and categorized LPLD-related acute abdominal pain events requiring hospital visits and/or hospitalizations based on the adapted 2012 Atlanta diagnostic criteria for pancreatitis. Both entire disease time period data and data from an equal time period before and after gene therapy were analyzed. Events with available medical record information meeting the Atlanta diagnostic criteria were categorized as definite pancreatitis; events treated as pancreatitis but with variable levels of laboratory and imaging data were categorized as probable pancreatitis or acute abdominal pain events. A reduction of approximately 50% was observed in all three categories of the adjudicated post-gene therapy events. Notably, no severe pancreatitis and only one intensive care unit admission was observed in the post-alipogene tiparvovec period. However, important inter- and intraindividual variations in the pre- and post-gene therapy incidence of events were observed. There was no relationship between the posttreatment incidence of events and the number of LPL gene copies injected, the administration of immunosuppressive regimen or the percent triglyceride decrease achieved at 12 weeks (primary end point in the prospective clinical studies). Although a causal relationship cannot be established and despite the limited number of individuals evaluated, results from this long-term analysis suggest that alipogene tiparvovec was associated with a lower frequency and severity of pancreatitis events, and a consequent overall reduction in health care resource use up to 6 years posttreatment.

Pathogenic classification of LPL gene variants reported to be associated with LPL deficiency.

BACKGROUND: Lipoprotein lipase (LPL) deficiency is a serious lipid disorder of severe hypertriglyceridemia (SHTG) with chylomicronemia. A large number of variants in the LPL gene have been reported but their influence on LPL activity and SHTG has not been completely analyzed. Gaining insight into the deleterious effect of the mutations is clinically essential. METHODS: We used gene sequencing followed by in-vivo/in-vitro and in-silico tools for classification. We classified 125 rare LPL mutations in 33 subjects thought to have LPL deficiency and in 314 subjects selected for very SHTG. RESULTS: Of the 33 patients thought to have LPL deficiency, only 13 were homozygous or compound heterozygous for deleterious mutations in the LPL gene. Among the 314 very SHTG patients, 3 were compound heterozygous for pathogenic mutants. In a third group of 51,467 subjects, from a general population, carriers of common variants, Asp9Asn and Asn291Ser, were associated with mild increase in triglyceride levels (11%-35%). CONCLUSION: In total, 39% of patients clinically diagnosed as LPL deficient had 2 deleterious variants. Three patients selected for very SHTG had LPL deficiency. The deleterious mutations associated with LPL deficiency will assist in the diagnosis and selection of patients as candidates for the presently approved LPL gene therapy.

Treatment of metastatic breast cancer with 𝑛𝑎𝑏-paclitaxel in the community practice setting: a US Oncology survey.

BACKGROUND: Different dosages-schedules of nab-paclitaxel have been assessed in trials of metastatic breast cancer (MBC). However, there is limited information on nab-paclitaxel dosing-scheduling in the community setting. OBJECTIVE: To report on experience with nab-paclitaxel for human epidermal growth factor receptor 2 (HER2)-negative MBC and identify patient characteristics affecting nab-paclitaxel treatment patterns in the community practice setting. METHODS: From September 6-October 21, 2013, a 35-question, web-based survey on nab-paclitaxel dosing, toxicities leading to dose modifications, management, and treatment duration was sent to US Oncology network oncologists. Respondents were categorized by percentage of their patients with HER2-negative MBC who received nab-paclitaxel. RESULTS: 104 of 428 oncologists responded; 84% were from large practices (≥16 oncologists), and 56% had a high level of experience using nab-paclitaxel. For first- and second-line treatment, 100 mg/m² weekly was the most common starting dosage-schedule, followed by 125 mg/m² weekly and 260 mg/m² every 3 weeks (q3w); 150 mg/m² weekly was used least frequently. Several factors, including select aggressive disease characteristics, were found to affect nab-paclitaxel dose selection. Weekly dosing was preferred in patients with select aggressive disease characteristics, whereas q3w dosing was commonly used in patients aged ≤50 years and those with good performance status. Differences in management styles among oncologists with high compared with infrequent nab-paclitaxel experience were also observed. Peripheral neuropathy and neutropenia were common dose-limiting toxicities. LIMITATIONS: Recall and response bias may be limitations of this study. CONCLUSIONS: In the community setting, nab-paclitaxel 100 mg/m² weekly was the most commonly used starting dose for patients with HER2-negative MBC, including those with aggressive disease characteristics.

Deletions involving genes WHSC1 and LETM1 may be necessary, but are not sufficient to cause Wolf-Hirschhorn Syndrome.

Wolf-Hirschhorn syndrome (WHS) is a complex genetic disorder caused by the loss of genomic material from the short arm of chromosome 4. Genotype-phenotype correlation studies indicated that the loss of genes within 4p16.3 is necessary for expression of the core features of the phenotype. Within this region, haploinsufficiency of the genes WHSC1 and LETM1 is thought to be a major contributor to the pathogenesis of WHS. We present clinical findings for three patients with relatively small (<400 kb) de novo interstitial deletions that overlap WHSC1 and LETM1. 3D facial analysis was performed for two of these patients. Based on our findings, we propose that hemizygosity of WHSC1 and LETM1 is associated with a clinical phenotype characterized by growth deficiency, feeding difficulties, and motor and speech delays. The deletion of additional genes nearby WHSC1 and LETM1 does not result in a marked increase in the severity of clinical features, arguing against their haploinsufficiency. The absence of seizures and typical WHS craniofacial findings in our cohort suggest that deletion of distinct or additional 4p16.3 genes is necessary for expression of these features. Altogether, these results show that although loss-of-function for WHSC1 and/or LETM1 contributes to some of the features of WHS, deletion of additional genes is required for the full expression of the phenotype, providing further support that WHS is a contiguous gene deletion disorder.

Clinical features of late-onset Pompe disease: a prospective cohort study.

The objective of this 12-month study was to describe the clinical features of late-onset Pompe disease and identify appropriate outcome measures for use in clinical trials. Assessments included quantitative muscle testing (QMT), functional activities (FAA), 6-min walk test (6MWT), and pulmonary function testing (PFT). Percent predicted values indicated quantifiable upper and lower extremity weakness, impaired walking ability, and respiratory muscle weakness. Significant declines in arm and leg strength and pulmonary function were observed during the study period. The outcome measures were demonstrated to be safe and reliable. Symptom duration was identified as the best predictor of the extent of skeletal and respiratory muscle weakness.

Sibling phenotype concordance in classical infantile Pompe disease.

Pompe disease (acid-alpha-glucosidase deficiency) encompasses a clinical spectrum, ranging from severe infantile-onset disease with clinical symptoms appearing before 1 year of age with rapid progression to an early death, to late-onset disease with a much more variable age at onset and disease course. Sibling phenotype discordance has been reported for late-onset Pompe disease, but has not been studied in classical infantile disease. We reviewed the medical literature for affected sibships in which at least one sibling had clinical and pathology or biochemical findings consistent with infantile Pompe disease including symptoms beginning in infancy, early hypotonia, cardiomegaly documented by 6 months of age, and early death. The age at symptom onset, age at death, and clinical course were compared between probands and affected siblings. Our results showed that since 1931, publications document 13 families with 31 affected infants (11 probands; 20 affected siblings). The median age at symptom onset for all affected infants was 3 months (range 0-6 months) with significant correlation (R = 0.60, P = 0.04) between probands and affected siblings. The median age at death for all affected infants was 6 months (range 1.5-13 months); probands were slightly older at death than their siblings. The median length of disease course for all affected infants was 3 months (0-10 months) and was slightly longer for probands. Unlike late-onset Pompe disease, there appears to be minimal phenotypic and lifespan variation among siblings with infantile Pompe disease. This prognostic information is vital for families with affected infants and allows for appropriate genetic counseling.

Rapid diagnosis of late-onset Pompe disease by fluorometric assay of alpha-glucosidase activities in dried blood spots.

The enzymatic defect in Pompe disease is insufficient lysosomal acid alpha-glucosidase (GAA) activity which leads to lysosomal glycogen accumulation. We recently introduced a simple and reliable method to measure GAA activity in dried blood spots using Acarbose, a highly selective alpha-glucosidase inhibitor, to eliminate isoenzyme interference. Here we demonstrate that this method efficiently detects late-onset Pompe patients who are frequently misdiagnosed by conventional methods due to residual GAA activity in other tissue types.

Cardiac arrhythmias following anesthesia induction in infantile-onset Pompe disease: a case series.

BACKGROUND: Patients with infantile-onset Pompe disease suffer from marked hypertrophic cardiomyopathy and an increased risk of arrhythmia. A noncompliant left ventricle predisposes these infants to diastolic heart failure with elevated left ventricular enddiastolic pressure (LVEDP); these patients also commonly develop systolic heart failure. Given this baseline cardiac physiology, coronary perfusion pressure becomes highly sensitive to abrupt changes in diastolic blood pressure (DBP). METHODS: We retrospectively reviewed the experiences of 139 patients enrolled in clinical trials investigating the treatment of infantile-onset Pompe disease with recombinant human acid alpha-glucosidase (rhGAA). Adverse events were screened for those involving anesthesia. RESULTS: Nine patients (6%) with infantile-onset Pompe disease experienced an arrhythmia or cardiopulmonary arrest soon after the induction of general anesthesia. Of these events, propofol was involved in four arrhythmias; sevoflurane without propofol was associated with an additional two. Deaths resulting from arrhythmia appeared to correlate with left ventricular mass indices >350 g x m(-2). CONCLUSIONS: With the advent of enzyme replacement therapy (ERT) using rhGAA, and increased survivability, more infantile Pompe patients will likely present for surgical procedures. Additional care in maximizing coronary perfusion pressure and minimizing arrhythmia risk must be given. For these reasons, it is recommended that anesthesia for infantile Pompe patients specifically avoid propofol or high concentrations of sevoflurane and, instead, use an agent such as ketamine as the cornerstone for induction in order to better support coronary perfusion pressure and to avoid decreasing DBP with vasodilatory agents.

Fractures in children with Pompe disease: a potential long-term complication.

BACKGROUND: Pompe disease (glycogen storage disease type II or acid maltase deficiency) is an autosomal recessive disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). Classic infantile-onset disease, characterized by cardiomegaly and profound weakness, leads to death in the first year of life from cardiorespiratory failure. Reversal of cardiomyopathy and improved motor function have been shown in clinical trials of rhGAA enzyme replacement therapy (ERT) with alglucosidase alfa (Myozyme), recently approved for clinical use. Increased survival potentially unmasks long-term complications of this previously lethal disease, including risk of skeletal fracture, recently identified at our institution and not previously reported in children with Pompe disease. OBJECTIVE: To report the risk of fracture in children with Pompe disease with increased survival with ERT. MATERIALS AND METHODS: We present four cases of fracture in patients with classic infantile Pompe disease treated with ERT at our institution, and review a study database for additional reports of fracture in this population. RESULTS: We review 19 fractures in 14 children with Pompe disease on ERT. CONCLUSION: Radiologists should be familiar with and vigilant for the association of fractures and increased survival on ERT in children with Pompe disease. We discuss potential mechanisms, implications for radiographic surveillance, potential intervention, and needs for further research.

A retrospective, multinational, multicenter study on the natural history of infantile-onset Pompe disease.

OBJECTIVE: To characterize the natural progression of infantile-onset Pompe disease. STUDY DESIGN: Retrospective chart reviews of 168 patients with documented acid alpha-glucosidase deficiency and symptom onset by 12 months of age; Kaplan-Meier analysis of total and ventilator-free survival time; Cox proportional hazards regression modeling of mortality risk factors. RESULTS: The median age at symptom onset was 2.0 months (range 0 to 12 months), 4.7 months at diagnosis (range: prenatal to 4.2 months), 5.9 months at first ventilator support (range 0.1 to 31.1 months), and 8.7 months at death (range 0.3 to 73.4 months). Survival rates at 12 months of age were 25.7% overall and 16.9% ventilator-free; at 18 months 12.3% and 6.7%. Cardiomegaly (92%), hypotonia (88%), cardiomyopathy (88%), respiratory distress (78%), muscle weakness (63%), feeding difficulties (57%), and failure to thrive (53%) appeared after a median age of approximately 4.0 months. Multiple covariate analysis confirmed that early symptom onset increased risk of early death. CONCLUSION: Despite frequent therapeutic interventions, infantile-onset Pompe disease remains lethal.

Chinese hamster ovary cell-derived recombinant human acid alpha-glucosidase in infantile-onset Pompe disease.

OBJECTIVE: To conduct an open-label, multinational, multicenter study examining the safety and efficacy of recombinant human acid alpha-glucosidase (rhGAA) in treatment of infantile-onset Pompe disease. STUDY DESIGN: We enrolled 8 infant patients who had Pompe disease with GAA activity <1% of normal, cardiomyopathy, and hypotonia. In the 52-week initial phase, rhGAA was infused intravenously at 10 mg/kg weekly; an extension phase continued survivors' treatment with 10 to 20 mg/kg of rhGAA weekly or 20 mg/kg every 2 weeks for as long as 153 weeks. Safety measurements included adverse events, laboratory tests, and anti-rhGAA antibody titers. Efficacy evaluations included survival, ventilator use, echocardiograms, growth, and motor and cognitive function. RESULT: After 52 weeks of treatment, 6 of 8 patients were alive, and 5 patients were free of invasive ventilator support. Clinical improvements included ameliorated cardiomyopathy and improved growth and cognition. Five patients acquired new motor milestones; 3 patients walked independently. Four patients died after the initial study phase; the median age at death or treatment withdrawal for all patients was 21.7 months, significantly later than expected for patients who were not treated. Treatment was safe and well tolerated; no death was drug-related. CONCLUSION: rhGAA improved ventilator-free survival, cardiomyopathy, growth, and motor function in patients with infantile-onset Pompe disease compared with outcomes expected for patients without treatment.

A computer adaptive testing approach for assessing physical functioning in children and adolescents.

The purpose of this article is to demonstrate: (1) the accuracy and (2) the reduction in amount of time and effort in assessing physical functioning (self-care and mobility domains) of children and adolescents using computer-adaptive testing (CAT). A CAT algorithm selects questions directly tailored to the child's ability level, based on previous responses. Using a CAT algorithm, a simulation study was used to determine the number of items necessary to approximate the score of a full-length assessment. We built simulated CAT (5-, 10-, 15-, and 20-item versions) for self-care and mobility domains and tested their accuracy in a normative sample (n=373; 190 males, 183 females; mean age 6y 11mo [SD 4y 2m], range 4mo to 14y 11mo) and a sample of children and adolescents with Pompe disease (n=26; 21 males, 5 females; mean age 6y 1mo [SD 3y 10mo], range 5mo to 14y 10mo). Results indicated that comparable score estimates (based on computer simulations) to the full-length tests can be achieved in a 20-item CAT version for all age ranges and for normative and clinical samples. No more than 13 to 16% of the items in the full-length tests were needed for any one administration. These results support further consideration of using CAT programs for accurate and efficient clinical assessments of physical functioning.

Nephrotic syndrome complicating alpha-glucosidase replacement therapy for Pompe disease.

We report a patient with Pompe disease who developed reversible nephrotic syndrome during prolonged, high-dose, experimental, enzyme replacement therapy with recombinant human acid alpha-glucosidase (rhGAA). Because of the development of antibodies to rhGAA and concomitant clinical decline, escalating doses of rhGAA were administered as part of an experimental immune tolerance regimen. Histologic evaluation of kidney tissue revealed glomerular deposition of immune complexes containing rhGAA itself, in a pattern of membranous nephropathy. To our knowledge, this is the first reported case of nephrotic syndrome occurring during enzyme replacement therapy. The nephrotic syndrome gradually resolved after the rhGAA dose was decreased, indicating that decreasing the antigenic load can ameliorate glomerular immune complex deposition associated with enzyme replacement in a highly sensitized patient.

Contiguous deletion of the X-linked adrenoleukodystrophy gene (ABCD1) and DXS1357E: a novel neonatal phenotype similar to peroxisomal biogenesis disorders.

X-linked adrenoleukodystrophy (X-ALD) results from mutations in ABCD1. ABCD1 resides on Xq28 and encodes an integral peroxisomal membrane protein (ALD protein [ALDP]) that is of unknown function and that belongs to the ATP-binding cassette-transporter superfamily. Individuals with ABCD1 mutations accumulate very-long-chain fatty acids (VLCFA) (carbon length >22). Childhood cerebral X-ALD is the most devastating form of the disease. These children have the earliest onset (age 7.2 +/- 1.7 years) among the clinical phenotypes for ABCD1 mutations, but onset does not occur at <3 years of age. Individuals with either peroxisomal biogenesis disorders (PBD) or single-enzyme deficiencies (SED) in the peroxisomal beta-oxidation pathway--disorders such as acyl CoA oxidase deficiency and bifunctional protein deficiency--also accumulate VLCFA, but they present during the neonatal period. Until now, it has been possible to distinguish unequivocally between individuals with these autosomal recessively inherited syndromes and individuals with ABCD1 mutations, on the basis of the clinical presentation and measurement of other biochemical markers. We have identified three newborn boys who had clinical symptoms and initial biochemical results consistent with PBD or SED. In further study, however, we showed that they lacked ALDP, and we identified deletions that extended into the promoter region of ABCD1 and the neighboring gene, DXS1357E. Mutations in DXS1357E and the ABCD1 promoter region have not been described previously. We propose that the term "contiguous ABCD1 DXS1357E deletion syndrome" (CADDS) be used to identify this new contiguous-gene syndrome. The three patients with CADDS who are described here have important implications for genetic counseling, because individuals with CADDS may previously have been misdiagnosed as having an autosomal recessive PBD or SED

Aspectos moleculares y usos terapéuticos del Sistema Interferón

El Sistema Interferón es una familia de páptidos con propiedades inmunomoduladoras, antiproliferativas, endocrinas, antitumorales y antivirales. Esta última le confiere características particulares que permiten diferenciarlo de otras sustancias pertenecientes al amplio grupo de citoquinas. Se describen aspectos generales sobre estructura, clasificación, receptores, mecanismo molecular de acción y usos terpéuticos, con particular énfasis en el tratamiento del cáncer y los procesos infecciosos. Los estudios actuales permiten dilucidar el espectro de aplicaciones dentro del cual el Sistema Interferón tiene otras posibilidaes de desarrollo

Alteraciones neurológicas primarias del SNC asociadas con infección por el VIH-1

La infección por el virus de inmunodeficiencia humana es considerada hoy una pandemia. Si bien las complicaciones neurológicas aparecieron casi a la par con los primeros casos de sindrome de inmunodeficiencia adquirida, solo desde finales de la pasada década se ha venido observando un aumento marcado en el compromiso del sistema nervioso tanto en los pacientes con manifestaciones clínicas evidentes, por lo que se considera que las alteraciones neurológicas primarias del sistema nervioso central, en especial la encefalopatía serán, las complicaciones mas importantes en estos pacientes. En la presente revisión, se describen los principales hallazgos neurovirológicos, los posibles mecanismos de neuropatogénesis que participarían en el daño neurológico primario y las principales características de los sindromes neurológicos primarios del sistema nervioso central presentes en los pacientes infectados con este retrovirus humano