NEJM Highlights for May 2016: Referral for surgery, and a miscellany of interesting biochemistry

Surgical volume and referral for surgery:

The impact of surgical volume on outcomes has been well documented, but is it top of mind with physicians referring patients to surgery? Readers of the Journal were polled on a hypothetical scenario whereby a community physician would be referring a patient in need of a major surgical procedure to either a nearby community hospital with a well-respected general surgeon doing approximately 5 of these cases a year versus a tertiary medical center 40 miles away. The great majority of readers chose the option to refer to the tertiary medical center. This does not bode well for the independent survival of small community hospitals.   Clinical Effect of Surgical Volume (free access)


A first proof of concept that telomeres can be a therapeutic target:

About 15 years ago, there was considerable interest in the therapeutic potential of manipulating telomeres (non-coding DNA repeat sequences at the end of chromosomes), especially in cancer and aging, but nothing much came of it.  The androgen hormone danazol is typically used for Ob/Gyn issues, but is also known to enhance the activity of telomerase which increases telomere length. In this study 27 patients with diseases thought to be at least partly due to telomere shortening (cases of bone marrow failure, pulmonary fibrosis, cirrhosis) received danazol which increased the telomere length in 11/12 patients at 24 months (leading to early termination of the study due to achieving the primary end-point) but also led to clinical improvement in most cases (e.g. cessation of transfusion dependence). We are starting to mess with chromosomes (aside from breaking them to bits with chemotherapy). Danazol Treatment for Telomere Diseases; Telomeres on Steroids — Turning Back the Mitotic Clock? (free access)


Bispecific antibodies are coming of age:

Naturally produced antibody molecules look like a Y with the two top ends binding to specific identical targets. The idea that you could make bispecific antibody where the top ends of the Y bind to two different targets has been around for a while – it is technically difficult to implement, and the few attempts have focused on immuno-oncology application whereby one binding site has affinity for tumor cells and the other to immune cells.  In hemophilia A, patients lack a functional component of the clotting cascade called factor VIII which acts by bringing together factor X and factor IX. This can be treated by intravenous administration of factor VIII but often leads to alloantibodies against factor VIII created by the immune system of the recipient. In a study testing a bispecific antibody binding to factors X and IX on 18 patients, bleeding rates were low. Key advantages are that the administration is subcutaneous, and that it bypasses the alloantibody problems.  More generally, it is further validation of a versatile tool that can impact physiology by simply bringing any two molecular targets together. Factor VIII–Mimetic Function of Humanized Bispecific Antibody in Hemophilia A (free access)


Will ASGR1 be the PCSK9 of tomorrow?

There is a history of large scale analysis of genetics of the Icelandic population with the general idea that the correlation of genetics and a complete health record database would yield valuable insights. Unfortunately, the company deCODE pursuing this approach was ahead of its time (it went bankrupt), but in this article the fruits of this work is evident in a general search of correlation between a genetic variants, levels of LDL cholesterol, and incidence of coronary artery disease.  Coming up with a strong signal is ASGR1, encoding a subunit of the hepatic asialoglycoprotein receptor, but well-known PCSK9 shows up as well. One has to imagine that a dozen Biopharma Discovery labs are currently hard at work designing drugs to hit this target. But more generally, it is a demonstration of principle that a big data approach can create a sieve to capture many targets for a given disease state in one go. Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease; The Sialylation Pathway and Coronary Artery Disease (free access)


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