Efficacy of tacrolimus rescue therapy in refractory acute rejection after lung transplantation.

BACKGROUND: Encouraging results in transplantation of other solid organs led to investigation of the use of tacrolimus in lung transplantation as a salvage immunosuppressant in persistent acute rejection. METHODS: The incidence and severity of acute rejection and the number of steroid pulses were analyzed in 20 lung recipients who were converted from a cyclosporine- to a tacrolimus-based immunosuppressive regimen because of refractory biopsy-proven acute rejection. RESULTS: Tacrolimus was started 12.0 +/- 13.0 months after transplantation, and the mean follow-up was 25.0 +/- 13.7 months. After shifting to tacrolimus, a significant decline was observed in both the number of acute rejections per patient (3.0 +/- 1.56 to 0.85 +/- 1.14, p < 0.0001), and the incidence of acute rejection per 100 patient-days (1.52 +/- 0.99 to 0.14 +/- 0.21, p < 0.0001). Furthermore, the average histologic grade of rejection decreased from 1.9 +/- 0.8 to 0.4 +/- 0.5 (p < 0.0001). Methylprednisolone pulses similarly decreased from 1.9 +/- 1.3/patient to 0.3 +/- 0.7/patient (p < 0.0001). During cyclosporine immunosuppression, the mean forced expiratory volume in 1 second decreased to 84.4% +/- 13.3% of individual best value. The average lung function parameters were stable 3 months after the change of medication, and then began to improve. After an average follow-up of 36.5 +/- 19.2 months, 2 patients have developed bronchiolitis obliterans syndrome (one has Stage 1 and one has Stage 3). CONCLUSION: Conversion to a tacrolimus-based immunosuppressive regimen for refractory acute lung rejection is associated with reduced incidence and severity of acute rejection episodes, steroid sparing, and stabilization or improvement of pulmonary function.     

Extent of liver resection influences the outcome in patients with cirrhosis and small hepatocellular carcinoma

BACKGROUND: The long-term outcome after resection of hepatocellular carcinoma (HCC) is influenced by parameters related to the tumor and the underlying liver disease. However, the extent of the resection, which can be limited or anatomical (including the tumor and its portal territory), is controversial. METHODS: Among 64 Child-Pugh A patients with cirrhosis who underwent curative liver resection for small HCC (< or = 4 cm) between 1990 and 1996, 34 patients underwent limited resection with a margin width of at least 1 cm, and 30 patients underwent anatomic resection of at least 1 liver segment with complete removal of the portal area containing the tumor. The 2 groups were comparable in terms of epidemiologic and pathologic parameters. The major end points were: (1) in-hospital mortality and morbidity; (2) overall and disease-free survival; and (3) rate and topography of recurrence. RESULTS: The 30-day mortality (6% vs 7%) and morbidity (52% vs 47%) rates after limited and anatomic liver resection were not statistically different. The 5- and 8-year overall survival rates after limited versus anatomic resection were, respectively, 35% versus 54% (P <.05) and 6% versus 45% (P <.05). The 5- and 8-year disease-free survival rates were, respectively, 26% versus 45% and 0% versus 21% (P <.05). Local recurrence was more frequently observed after limited resections than after anatomic resections (50% vs 10%, P <.05). CONCLUSIONS: In patients with cirrhosis and a small HCC, anatomic resection achieves better disease-free survival than limited resection without increasing the postoperative risk. Therefore, anatomical resection should be the treatment of choice and considered as the reference surgical treatment compared with other treatments.     

The neurovascular triad: mixed cavernous, capillary, and venous malformations of the brainstem

OBJECT: The four types of cerebrovascular malformations may sometimes be combined and more often occur in pairs; triads are exceptional. The authors present six patients with the clinicoradiographic profile of mixed vascular malformations of the brainstem, including cavernous malformation (CM), capillary telangiectasia, and developmental venous anomaly (DVA). METHODS: Five patients (one of whom was a child) suffered from hemorrhage, suggesting that this complex association has a high bleeding potential. Progressive growth, rebleeding, and de novo occurrence of the associated CM were documented in three cases. Magnetic resonance imaging of the brain was obtained in all patients by using one or more of the following modalities: T1-weighted sequences before and after gadolinium administration; T2-weighted sequences; T2-weighted fluid attenuated Inversion recovery; T1-weighted fast spin echo; and diffusion weighted, diffusion tensor, and perfusion imaging in three cases. RESULTS: Three patients were surgically treated with the intention of excising the hemorrhagic lesion, but only two patients had their malformations successfully removed. In the third case, diffuse pontine telangiectasia precluded the safe excision of the CM. Histological examination demonstrated a blended pathological milieu characterized by coalescent telangiectasia and venules associated with loculated endothelial chambers resembling an immature or de novo CM. Three patients were treated conservatively; recurrent minor hemorrhage occurred in one case. The authors found these malformations to be arranged in two basic relationships: CM inside the telangiectasia and CM in the radicles of the DVA. Stenosis of the main venous collector and dilation of the medullary veins were important findings. CONCLUSIONS: The pathogenesis of this malformation may be referred to a developmental deviance of the brainstem capillary-venous network associated with transitional vessels and loculated endothelial vascular spaces related to genetic and acquired origins, probably in a restrictive venous outflow milieu.     

Extremity Soft Tissue Sarcoma: Adding to the Prognostic Meaning of Local Failure

Background We explored the prognostic meaning of local relapse and surgical margins in adult soft tissue sarcoma of the extremities. Methods Out of a series of 1017 patients with extremity soft tissue sarcoma treated over 20 years, we picked a group of 238 patients operated on at our institution for their first local relapse: 88 after their primary operation performed at the same center and 150 elsewhere. At operation for relapse, margins were microscopically negative in 77% and 75% of patients, respectively. Median follow-up was 107 months. Results The 10-year mortality rate was 22% in the absence of local relapse, whereas in locally relapsing patients it was 54% and 43%, respectively, for patients first operated on at our institute and for those who were not. The hazard ratio of positive versus negative surgical margins was 1.7 for cause-specific death and 2.1 for distant metastases in patients first operated on at our institute, as opposed to 1.2 and 1.3 for the others. Conclusions Local relapse was an unfavorable prognostic factor. In the face of a consistent surgical policy for local relapse in a single-institution setting, patients relapsing after the first operation performed at our institution received rescue treatment less frequently than those previously operated on outside a referral center. This is likely due to an inherently higher tumor aggressiveness. In the presence of such a higher aggressiveness, the adequacy of surgical margins at operation for first relapse seemed more critical prognostically. This may have clinical and speculative implications. Presented at the Annual Meeting of the American Society of Clinical Oncology, June 2–6, 2006, Atlanta, GA (USA) (abstract 9565).     

AKI Recovery Induced by Mesenchymal Stromal Cell-Derived Extracellular Vesicles Carrying MicroRNAs

Phenotypic changes induced by extracellular vesicles have been implicated in mesenchymal stromal cell–promoted recovery of AKI. MicroRNAs are potential candidates for cell reprogramming toward a proregenerative phenotype. The aim of this study was to evaluate whether microRNA deregulation inhibits the regenerative potential of mesenchymal stromal cells and derived extracellular vesicles in a model of glycerol-induced AKI in severe combined immunodeficient mice. We generated mesenchymal stromal cells depleted of Drosha to alter microRNA expression. Drosha-knockdown cells produced extracellular vesicles that did not differ from those of wild-type cells in quantity, surface molecule expression, and internalization within renal tubular epithelial cells. However, these vesicles showed global downregulation of microRNAs. Whereas wild-type mesenchymal stromal cells and derived vesicles administered intravenously induced morphologic and functional recovery in AKI, the Drosha-knockdown counterparts were ineffective. RNA sequencing analysis showed that kidney genes deregulated after injury were restored by treatment with mesenchymal stromal cells and derived vesicles but not with Drosha-knockdown cells and vesicles. Gene ontology analysis showed in AKI an association of downregulated genes with fatty acid metabolism and upregulated genes with inflammation, matrix-receptor interaction, and cell adhesion molecules. These alterations reverted after treatment with wild-type mesenchymal stromal cells and extracellular vesicles but not after treatment with the Drosha-knockdown counterparts. In conclusion, microRNA depletion in mesenchymal stromal cells and extracellular vesicles significantly reduced their intrinsic regenerative potential in AKI, suggesting a critical role of microRNAs in recovery after AKI.     

Distinguishing androgenetic alopecia from chronic telogen effluvium when associated in the same patient: a simple noninvasive method

BACKGROUND: Distinguishing chronic telogen effluvium (CTE) from androgenetic alopecia (AGA) may be difficult especially when associated in the same patient. OBSERVATIONS: One hundred consecutive patients with hair loss who were clinically diagnosed as having CTE, AGA, AGA + CTE, or remitting CTE. Patients washed their hair in the sink in a standardized way. All shed hairs were counted and divided "blindly" into 5 cm or longer, intermediate length (>3 to <5 cm), and 3 cm or shorter. The latter were considered telogen vellus hairs, and patients having at least 10% of them were classified as having AGA. We assumed that patients shedding 200 hairs or more had CTE. The kappa statistic revealed, however, that the best concordance between clinical and numerical diagnosis (kappa = 0.527) was obtained by setting the cutoff shedding value at 100 hairs or more. Of the 100 patients, 18 with 10% or more of hairs that were 3 cm or shorter and who shed fewer than 100 hairs were diagnosed as having AGA; 34 with fewer than 10% of hairs that were 3 cm or shorter and who shed at least 100 hairs were diagnosed as having CTE; 34 with 10% or more of hairs that were 3 cm or shorter and who shed at least 100 hairs were diagnosed as having AGA + CTE; and 14 with fewer than 10% of hairs that were 3 cm or shorter and who shed fewer than 100 hairs were diagnosed as having CTE in remission. CONCLUSION: This method is simple, noninvasive, and suitable for office evaluation.     

Safety and tolerability of injectable lipid-lowering drugs: an update of clinical data

Introduction: Cardiovascular (CV) diseases are the leading cause of death and disability in the developed countries. Lipid-lowering therapy is a cornerstone of the CV risk modification strategy. The first line treatment for hyperlipidemia is statins, which decrease low-density lipoprotein cholesterol (LDL-C) by 30–50% and proportionally reduce the CV events. However, they are not always enough to achieve LDL-C goals in many patients, and some patients are statin intolerant. For this reason, new powerful injectable lipid-lowering drugs have been developed.

Areas covered: The aim of this narrative review was to summarize the more recent clinical data on safety and tolerability of injectable lipid-lowering drugs. After an attentive literature search, the authors resumed here information on proprotein convertase subtilisin/kexin 9 inhibitors (evolocumab and alirocumab), small interfering RNA molecule inclisiran, antisense oligonucleotides (mipomersen, volanesorsen, ISIS 681257), and drugs targeting angiopoietin-like protein 3 (evinacumab, IONIS-ANGPTL3_Rx).

Expert opinion: Injectable lipid-lowering therapy for patients at high risk for CV disease complications or with severe inherited hypercholesterolemias can be an important element of the available therapeutic armamentarium. Clinical data prove the favorable risk-benefit profile of evolocumab, alirocumab, and inclisiran. Mipomersen, volanesorsen, ISIS 681257, evinacumab, and IONIS-ANGPTL3_Rx safety is currently less extensively studied, especially in patients with comorbidities and polypharmacotherapy.