, MD; the GACI Study GroupBackground-Generalized arterial calcification of infancy has been reported to be frequently lethal, and the efficiency of any therapy, including bisphosphonates, is unknown. A phosphate-poor diet markedly increases survival of NPP1 null mice, a model of generalized arterial calcification of infancy. Methods and Results-We performed a multicenter genetic study and retrospective observational analysis of 55 subjects affected by generalized arterial calcification of infancy to identify prognostic factors. Nineteen (34%) patients survived the critical period of infancy. In all 8 surviving patients tested, hypophosphatemia due to reduced renal tubular phosphate reabsorption developed during childhood. Eleven of 17 (65%) patients treated with bisphosphonates survived. Of 26 patients who survived their first day of life and were not treated with bisphosphonates only 8 (31%) patients survived beyond infancy. Forty different homozygous or compound heterozygous mutations, including 16 novel mutations in ENPP1, were found in 41 (75%) of the 55 patients. Twenty-nine (71%) of these 41 patients died in infancy (median, 30 days). Seven of the 14 (50%) patients without ENPP1 mutations died in infancy (median, 9 days). When present on both alleles, the mutation p.P305T was associated with death in infancy in all 5 cases; otherwise, no clear genotype-phenotype correlation was seen. Conclusion-ENPP1 coding region mutations are associated with generalized arterial calcification of infancy in Ϸ75% of subjects. Except for the p.P305T mutation, which was universally lethal when present on both alleles, the identified ENPP1 mutations per se have no discernable effect on survival. However, survival seems to be associated with hypophosphatemia linked with hyperphosphaturia and also with bisphosphonate treatment. ENPP1 encodes a type II transmembrane glycoprotein ectoenzyme that forms homodimers of identical disulfidebonded subunits. 7 NPP1 has an extracellular catalytic domain as well as somatomedin B-like and substrate-binding or substrate-specifying nuclease-like domains. 8 NPP1 regulates soft tissue calcification and bone and joint cartilage mineralization by generating PP i , which not only serves as an essential physiological inhibitor of hydroxyapatite crystal growth 9 but also is a suppressor of chondrogenesis. 10 In artery smooth muscle cells, deficiencies of NPP1 (or of extracellular PP i without NPP1 deficiency in ank/ank mice homozygous for functional inactivation of the PP i transporter ANK) promote chondrogenic transdifferentiation in vivo and also in vitro under circumstances where excess of an inorganic phosphate (P i ) source is provided. 10,11 Although the pathophysiologic role of NPP1-mediated PP i generation in GACI has come to light within recent years, the factors accounting for the variation of the GACI phenotype including the presence or absence of intracerebral artery calcification and periarticular calcification, early death in utero and long-term survival are not known. 12 PP i and ...

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The emergence of acquired resistance against targeted drugs remains a major clinical challenge in lung adenocarcinoma patients. In a subgroup of these patients we identified an association between selection of EGFRT790M-negative but EGFRG724S-positive subclones and osimertinib resistance. We demonstrate that EGFRG724S limits the activity of third-generation EGFR inhibitors both in vitro and in vivo. Structural analyses and computational modeling indicate that EGFRG724S mutations may induce a conformation of the glycine-rich loop, which is incompatible with the binding of third-generation TKIs. Systematic inhibitor screening and in-depth kinetic profiling validate these findings and show that second-generation EGFR inhibitors retain kinase affinity and overcome EGFRG724S-mediated resistance. In the case of afatinib this profile translates into a robust reduction of colony formation and tumor growth of EGFRG724S-driven cells. Our data provide a mechanistic basis for the osimertinib-induced selection of EGFRG724S-mutant clones and a rationale to treat these patients with clinically approved second-generation EGFR inhibitors.

These findings indicate an influence of blood group differences in PBPCT on survival and must be studied in further detail.

Low-dose rectal sulindac maintenance therapy is highly effective in achieving complete adenoma reversion without relapse in 87 percent of patients after 33 months. Rectal FAP phenotype should be crucial for the surgical decision. Colectomy with ileorectal anastomosis and regular chemoprevention might proceed to be a promising alternative to pouch procedures. Chemoprevention with lower incidence of FAP-related tumors via dysplasia reversion may be possible in the future.