Fabry Disease: prevalence of affected males and heterozygotes with pathogenic GLA mutations identified by screening renal, cardiac and stroke clinics, 1995-2017.

BACKGROUND: Fabry Disease (FD), an X linked lysosomal storage disease due to pathogenic α-galactosidase A (GLA) mutations, results in two major subtypes, the early-onset Type 1 'Classic' and the Type 2 'Later-Onset' phenotypes. To identify previously unrecognised patients, investigators screened cardiac, renal and stroke clinics by enzyme assays. However, some screening studies did not perform confirmatory GLA mutation analyses, and many included recently recognised 'benign/likely-benign' variants, thereby inflating prevalence estimates. METHODS: Online databases were searched for all FD screening studies in high-risk clinics (1995-2017). Studies reporting GLA mutations were re-analysed for pathogenic mutations, sex and phenotype. Phenotype-specific and sex-specific prevalence rates were determined. RESULTS: Of 67 studies, 63 that screened 51363patients (33943M and 17420F) and provided GLA mutations were reanalysed for disease-causing mutations. Of reported GLA mutations, benign variants occurred in 47.9% of males and 74.1% of females. The following were the revised prevalence estimates: among 36820 (23954M and 12866F) haemodialysis screenees, 0.21% males and 0.15% females; among 3074 (2031M and 1043F) renal transplant screenees, 0.25% males and no females; among 5491 (4054M and 1437F) cardiac screenees, 0.94% males and 0.90% females; and among 5978 (3904M and 2074F) stroke screenees, 0.13% males and 0.14% females. Among male and female screenees with pathogenic mutations, the type 1 Classic phenotype was predominant (~60%), except more male cardiac patients (75%) had type 2 Later-Onset phenotype. CONCLUSIONS: Compared with previous findings, reanalysis of 63 studies increased the screenee numbers (~3.4-fold), eliminated 20 benign/likely benign variants, and provided more accurate sex-specific and phenotype-specific prevalence estimates, ranging from ~0.13% of stroke to ~0.9% of cardiac male or female screenees.

Allogeneic stem cell transplantation as immunotherapy for nonhematological cancers.

Over the past two decades biologic therapy has played an increasing role in the treatment of cancer. While this field is still early in its development, there now exists compelling evidence that the immune system is capable of detecting and eliminating cancer cells. Although the majority of immunotherapy approaches for metastatic cancer involve strategies designed to enhance autologous immunity, most would agree that the graft-versus-leukemia reaction induced following allogeneic stem cell transplantation represents modern day's most potent form of cancer immunotherapy. While allogeneic stem cell transplantation has gained recognition as a potentially curative "immunotherapy" for a growing number of different hematological malignancies, its efficacy in inducing antimalignancy effects against nonhematological cancers has only recently begun to be investigated. The historical basis, development, and preliminary clinical results of allogeneic stem cell transplantation as a form of immunotherapy for treatment refractory solid tumors are reviewed.

Advances in allogeneic stem cell transplantation: directing graft-versus-leukemia at solid tumors.

Allogeneic stem cell transplantation was originally developed as a method to rescue hematopoietic function following high dose "myeloablative" therapy in the treatment of hematological malignancies. In the first two decades of its use, dose-intensive chemotherapy alone was credited with curing those patients who achieved sustained remission following this procedure. However, more recently investigators have come to recognize that antineoplastic effects mediated by immunocompetent donor T-cells transplanted with the stem cell allograft can be induced against hematological malignancies. Indeed, this graft-vs-leukemia (GVL) or graft-vs-tumor (GVT) effect is now felt to represent the principal modality required to sustain durable remissions of hematological malignancies following this approach. The powerful and potentially curative nature of the GVT effect in hematological cancers has recently lured oncologists into exploring the therapeutic potential of allogeneic stem cell transplantation as an investigational approach for treatment-refractory solid tumors. We review here the development and early clinical results of allogeneic stem cell transplantation as potential immunotherapy for solid tumors.