Reduction of Immunosuppression for Transplant-Associated Skin Cancer: Rationale and Evidence of Efficacy

BACKGROUND: Solid organ transplant recipients may develop numerous or life-threatening skin cancers. In addition to aggressive standard treatment of skin cancer, reduction of immunosuppression has been considered an adjuvant therapeutic strategy, albeit without direct proof of efficacy. OBJECTIVE: To review the rationale for and evidence supporting the efficacy of reduction of immunosuppression for severe skin cancer in transplant recipients. METHODS: Review of the literature regarding direct and indirect evidence on reduction of immunosuppression for transplant-associated skin cancer. RESULTS: Although there are no randomized controlled trials of reduction of immunosuppression as a therapeutic intervention for transplant patients with skin cancer, multiple lines of evidence suggest that this strategy may be an effective adjuvant therapy. A randomized trial has demonstrated a lower incidence of skin cancer in transplant recipients after reduction of immunosuppression, albeit in a cohort not previously affected by skin cancer. Case series of reduction or cessation of immunosuppression demonstrate a lower incidence of skin cancer or improved outcomes of preexisting skin cancer. Lower overall immunosuppression is associated with a lower incidence of skin cancer. Multiple cancers affecting the skin have been shown to regress with reduction of immunosuppression. CONCLUSIONS: Reduction of immunosuppression may be an effective adjuvant therapeutic strategy when confronting severe transplant-associated skin cancer. The risks of reduction of immunosuppression must be better defined, and randomized trials of this strategy are necessary.     

药物动力学入门(三)

重复给药许多药物不仅投药一次。病人在接受药物治疗时,通常是经多次的药物应用。这样每一剂量给予的次数和多少则称为给药方案。通过给药方案的调整,则可以显著地改变药物治疗的效果。口服给药如果口次剂量每次给药的间隔相当长,则由每一次剂量所给的药物已几乎完全消除,所以这些分次给药的行为相互将无何影响,如图33所示。     

Serum fractions and related agonists with calcium-mobilizing activity in the bovine growth plate chondrocyte

Longitudinal growth of bone involves a complex sequence of cellular events in the cartilaginous epiphysis. Whole blood serum has been shown previously to be a potent stimulus to the cells of the growth plate, as demonstrated by its ability to activate the inositol phosphate-calcium second messenger system resulting in a rise in intracellular Ca²⁺. By manipulating the preparation of serum to functionally separate it into its constituent parts, we have shown that the processes of platelet lysis and activation of the clotting cascade are responsible for the generation of factors that stimulate this signaling mechanism in isolated bovine growth plate chondrocytes. Through a subsequent trial of bioactive agents generated in these processes, we identified and partially characterized several novel agonists of growth plate chondrocytes: adenosine triphosphate and adenosine diphosphate, the purine energy substrates, and bradykinin, the bioactive peptide generated in a side reaction of the clotting cascade, each induces a rise in intracellular Ca²⁺ via release from intracellular ion stores. Additionally, the three distinct isoforms of platelet-derived growth factor (AA, AB and BB), also released on platelet lysis, were compared with respect to their ability to stimulate the inositol phosphate-calcium second messenger system in growth plate chondrocytes.     

Inherited Neurodegenerative Disorders Caused by CAG/Polyglutamine Tract Expansions: Symposium Introduction

At the beginning of this decade, the American Association of Neurology decided that the 1990's should be labelled "the decade of the brain" for expected advances in our understanding of neurological disorders and neuroscience. By the end of this decade, clinicians and researchers who work in the field of inherited neurological disorders might well remember the 1990's as "the decade of the trinucleotide repeat". At the time of writing this introduction, eleven inherited neurological disorders have been found to be caused by expansions of trinucleotide repeats, and a twelfth trinucleotide repeat expansion mutation has been identified (6), although the gene containing this mutant triplet repeat has not been cloned to our knowledge (Table 1).     

The prevalence of autonomic neuropathy in the primary glaucomas

The results of systemic autonomic nerve function studies in patients with closed-angle glaucoma and ocular hypertension are reviewed. Autonomic neuropathy has been demonstrated in 58% of patients with closed-angle glaucoma and 42% of ocular hypertensive subjects, with significantly increased prevalence in ocular hypertensives with narrow iridocorneal angles. The implications are discussed, with particular reference to the pathogenesis of raised intraocular pressure.     

Comparative dermal carcinogenesis of shale and petroleum-derived distillates

Ten test materials derived from petroleum or hydrotreated shale oils were applied 3 times/week for up to 105 weeks to the shaved skin of 25 male and 25 female C3H/HeN mice per group. Mineral oil and benzo(a) pyrene (0.15%) were control materials. Clinical observations were recorded during the study. At death, histopathologic examination was conducted on skin, internal organs and any gross lesions. Exposures to some materials were ended midway in the study due to severe irritation. Chronic toxicity of all materials was limited to inflammatory and degenerative skin changes. Significant increases over control incidence of skin tumors (squamous cell carcinoma and fibrosarcoma) occurred with both petroleum and shale-derived naphtha (21%, 50%), Jet A (26%, 28%), JP-4 (26%, 50%), and crude oils (84%, 54%). Severely hydrotreated shale oil and petroleum and shale-derived diesel distillates were not considered tumorigenic. Results indicate that toxicity of comparable petroleum and shale-derived fractions was qualitatively similar and confirm earlier findings that hydrotreating reduces or eliminates carcinogenicity of raw shale oil.     

High alveolar surface tension increases clearance of technetium 99m diethylenetriamine-pentaacetic acid.

The effect of high alveolar surface tension on alveolar epithelial permeability was studied in anesthetized closed-chest mongrel dogs. Alveolar surface tension was elevated by displacement of pulmonary surfactant from the alveolar hypophase by the aerosolized detergent dioctyl sodium sulfosuccinate (OT). After measurement of baseline hemodynamics, arterial blood gases, and airway pressure, the dogs were separated into groups: Group I inhaled a 1% solution of OT (15 mg/kg) in a vehicle of equal parts saline and ethanol; group II inhaled the same volume of vehicle without OT. The pulmonary clearance of technetium 99m diethylenetriamine-pentaacetic acid (99mTc-DTPA) (half-time in minutes) was studied immediately after aerosol (OT and vehicle) delivery and compared with that of historical control values. No change was seen in arterial blood gases and airway pressure after vehicle inhalation, whereas OT caused a marked fall in arterial oxygen tension and increase in airway pressure. Vehicle inhalation effected only a slight increase in DTPA clearance, whereas OT significantly reduced half-time over control and group II. These data suggest that high alveolar surface tension increases alveolar epithelial permeability.     

Calcium decreases transparency of homogenate from lens cortex and has no effect on nucleus

We studied the effects of calcium on transparency in homogenates of cortical and nuclear cells from calf lenses. Calcium was mixed into samples of homogenate to final concentrations between 0 and 50 mM and the transparency of the calcium-treated homogenates was measured using laser transmittance. In the presence of 10 mM calcium, the transmittance of cortical homogenate decreased 50% while the nuclear homogenate lost less than 4% transmittance after 24 h at 37 degrees C. To better understand the contribution of cytoplasm and membranes to opacity, the nuclear and cortical homogenates were centrifuged to separate membranes from the cytoplasm. When 10 mM calcium was added to cortical homogenate which was then centrifuged, the transmittance of the membrane fraction decreased nearly 60%, while the fraction without membrane decreased only 10%. The strong effect of calcium on the membrane fraction was accompanied by an increase in specific gravity of membranes from 1.23 to 1.32. Ten- and 20 mM calcium had no effect on transparency of membranes or cytoplasm separated from nuclear homogenate, and 50 mM calcium produced only a slight opacity. The results indicate that an effect on membrane-protein interactions may be important in the loss of transparency produced by calcium in cells of lens cortex.