Research Spotlight

Jalali, P., M. Tahmasbi, R. A. Augsburger, N. K. Khalilkhani and K. Daghighi (2019). “Dynamics of Bone Loss in Cases with Acute or Chronic Apical Abscess.” J Endod 45(9): 1114-1118.

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INTRODUCTION: Acute and chronic apical abscesses are 2 dramatic ways that periradicular tissues may react to pulpal infection and necrosis. Although both of these clinical states are the response to pulpal infection, their clinical manifestations are significantly different. It is not clear why the body responds to root canal infection in one way or another. The objective of this study was to evaluate the size and pattern of bone loss in patients with acute apical abscess (AAA) and chronic apical abscess (CAA) using cone-beam computed tomographic images. METHODS: Twenty-three cone-beam computed tomographic images of cases with AAA and 25 cases with CAA were selected and evaluated. The presence and location of fenestration and the volume and pattern of the periradicular lesions were recorded and compared between the 2 groups using the Fisher exact and Mann-Whitney U tests. RESULTS: One hundred percent of cases with CAA had cortical fenestration, but only 47% of cases with AAA had cortical fenestration (P < .05). The median volume of the lesions was 233 mm(3) in the CAA group and 109 mm(3) in the AAA group (P > .05). CAA cases, in comparison with the AAA group, had a relatively larger cortical disruptions. CONCLUSIONS: Cortical fenestration is fundamental for the development of CAA. However, periradicular lesions without evident cortical fenestration can still cause AAA and fascial space involvement.

Nowak, A., H. D. Uyen, P. A. Krayenbuehl, F. Beuschlein, R. Schiffmann and F. Barbey (2019). “Fabry disease genotype, phenotype and migalastat amenability: insights from a national cohort.” J Inherit Metab Dis Aug 26. [Epub ahead of print].

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Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by alpha-galactosidase A (alpha-Gal A) deficiency. The progressive accumulation of globotriaosylceramide results in life-threatening complications, including renal, cardiac, and cerebrovascular diseases. The pharmacological chaperone migalastat was recently approved as an alternative to enzyme replacement therapy in patients with amenable mutations. In this paper we investigate the proportion of amenable mutations, related to phenotype, in a population of adult patients with FD in Switzerland. This study included 170 adult patients (n = 64 males) from 46 independent pedigrees with 39 different identified mutations over the last 59 years. Overall, 68% had the classic phenotype and 48% fulfilled the current amenability criteria. Migalastat was stopped in 2/11 (18%) patients: the only male classic patient, because of lack of efficacy based on lyso-Gb3 levels, and 1 patient with a benign variant. In males, the achieved enzyme activities in peripheral leucocytes under migalastat treatment differed from the activities in HEK-cells after incubation with migalastat (eg, 33% in PL vs 41% HEK-cells for p.F113 L; 43% in leucocytes vs 36% in HEK-cells for p.N215S, 24-30% in leucocytes vs 96% in HEK-cells for S238 N). In this national cohort, we found a relatively high proportion of patients with amenable GLA mutations, which, however, had heterogeneous extent of amenability: the higher the residual alpha-Gal A activity, the higher the chaperone effect. Further studies are required to investigate the long-term benefits of migalastat therapy depending on the achieved enzyme activities in different amenable mutations. This article is protected by copyright. All rights reserved.

Mack, M. J. (2019). “RESPONSE: Adapting to Change in a Time of Uncertainty.” J Am Coll Cardiol 74(6): 816-817.

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Historically, the specialty of thoracic surgery has always been, as Han states, one of “paradigm shifts” or, as euphemistically referred to within the specialty, “staying one operation ahead of extinction.” To wit, the specialty began as one to treat tuberculosis until the introduction of sulfa drugs greatly diminished the role of surgery for that disease. The specialty then evolved to the management of rheumatic heart disease for which surgery was a mainstay of treatment until penicillin dramatically reduced the incidence of the disease in developed countries. Next, the central role of surgical coronary revascularization in the treatment of coronary artery disease was significantly modulated by the introduction of percutaneous coronary intervention. Furthermore, many other procedures began as thoracic and cardiac surgical procedures, including bronchoscopy, esophagoscopy, permanent pacemaker, defibrillator implantation, and insertion of intra-aortic balloon pumps, only to have those procedures move to other specialties as the devices become smaller and more easily implanted without general anesthesia. Despite the evolution in the core treatments delivered by our specialty in different eras, we have not become extinct, nor has the specialty diminished; rather, it has survived and thrived . . . As I reflect on the types of operations I was performing when I finished training in 1982, they bear little resemblance to the procedures being performed today. However, that offers little solace to the trainee whose sands are now shifting beneath her/his feet. As the Greek philosopher Heraclitus stated, “the only constant is change.” You cannot worry too much that you chose the wrong career path or succumb to the fear that you will be left behind. Rather, embrace what you love to do and be cognizant of the changes in the ecosystem in which you work. Learn to lead change, embrace that which is currently good, have the vision to determine what needs to change, and have the wisdom to know the difference. To paraphrase Charles Darwin, it’s not the strongest of a species that survives, or the most intelligent, but the one most responsive to change. (Excerpts from text, p. 816-817.)

Thuijs, D., A. P. Kappetein, P. W. Serruys, F. W. Mohr, M. C. Morice, M. J. Mack, D. R. Holmes, Jr., N. Curzen, P. Davierwala, T. Noack, M. Milojevic, K. D. Dawkins, B. R. da Costa, P. Juni and S. J. Head (2019). “Percutaneous coronary intervention versus coronary artery bypass grafting in patients with three-vessel or left main coronary artery disease: 10-year follow-up of the multicentre randomised controlled SYNTAX trial.” Lancet Aug 30. [Epub ahead of print].

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BACKGROUND: The Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) trial was a non-inferiority trial that compared percutaneous coronary intervention (PCI) using first-generation paclitaxel-eluting stents with coronary artery bypass grafting (CABG) in patients with de-novo three-vessel and left main coronary artery disease, and reported results up to 5 years. We now report 10-year all-cause death results. METHODS: The SYNTAX Extended Survival (SYNTAXES) study is an investigator-driven extension of follow-up of a multicentre, randomised controlled trial done in 85 hospitals across 18 North American and European countries. Patients with de-novo three-vessel and left main coronary artery disease were randomly assigned (1:1) to the PCI group or CABG group. Patients with a history of PCI or CABG, acute myocardial infarction, or an indication for concomitant cardiac surgery were excluded. The primary endpoint of the SYNTAXES study was 10-year all-cause death, which was assessed according to the intention-to-treat principle. Prespecified subgroup analyses were performed according to the presence or absence of left main coronary artery disease and diabetes, and according to coronary complexity defined by core laboratory SYNTAX score tertiles. This study is registered with ClinicalTrials.gov, NCT03417050. FINDINGS: From March, 2005, to April, 2007, 1800 patients were randomly assigned to the PCI (n=903) or CABG (n=897) group. Vital status information at 10 years was complete for 841 (93%) patients in the PCI group and 848 (95%) patients in the CABG group. At 10 years, 244 (27%) patients had died after PCI and 211 (24%) after CABG (hazard ratio 1.17 [95% CI 0.97-1.41], p=0.092). Among patients with three-vessel disease, 151 (28%) of 546 had died after PCI versus 113 (21%) of 549 after CABG (hazard ratio 1.41 [95% CI 1.10-1.80]), and among patients with left main coronary artery disease, 93 (26%) of 357 had died after PCI versus 98 (28%) of 348 after CABG (0.90 [0.68-1.20], pinteraction=0.019). There was no treatment-by-subgroup interaction with diabetes (pinteraction=0.66) and no linear trend across SYNTAX score tertiles (ptrend=0.30). INTERPRETATION: At 10 years, no significant difference existed in all-cause death between PCI using first-generation paclitaxel-eluting stents and CABG. However, CABG provided a significant survival benefit in patients with three-vessel disease, but not in patients with left main coronary artery disease. FUNDING: German Foundation of Heart Research (SYNTAXES study, 5-10-year follow-up) and Boston Scientific Corporation (SYNTAX study, 0-5-year follow-up).

Chari, A., D. T. Vogl, M. Gavriatopoulou, A. K. Nooka, A. J. Yee, C. A. Huff, P. Moreau, D. Dingli, C. Cole, S. Lonial, M. Dimopoulos, A. K. Stewart, J. Richter, R. Vij, S. Tuchman, M. S. Raab, K. C. Weisel, M. Delforge, R. F. Cornell, D. Kaminetzky, J. E. Hoffman, L. J. Costa, T. L. Parker, M. Levy . . . and S. Jagannath (2019). “Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma.” New England Journal of Medicine 381(8): 727-738.

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BACKGROUND: Selinexor, a selective inhibitor of nuclear export compound that blocks exportin 1 (XPO1) and forces nuclear accumulation and activation of tumor suppressor proteins, inhibits nuclear factor kappaB, and reduces oncoprotein messenger RNA translation, is a potential novel treatment for myeloma that is refractory to current therapeutic options. METHODS: We administered oral selinexor (80 mg) plus dexamethasone (20 mg) twice weekly to patients with myeloma who had previous exposure to bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent and had disease refractory to at least one proteasome inhibitor, one immunomodulatory agent, and daratumumab (triple-class refractory). The primary end point was overall response, defined as a partial response or better, with response assessed by an independent review committee. Clinical benefit, defined as a minimal response or better, was a secondary end point. RESULTS: A total of 122 patients in the United States and Europe were included in the modified intention-to-treat population (primary analysis), and 123 were included in the safety population. The median age was 65 years, and the median number of previous regimens was 7; a total of 53% of the patients had high-risk cytogenetic abnormalities. A partial response or better was observed in 26% of patients (95% confidence interval, 19 to 35), including two stringent complete responses; 39% of patients had a minimal response or better. The median duration of response was 4.4 months, median progression-free survival was 3.7 months, and median overall survival was 8.6 months. Fatigue, nausea, and decreased appetite were common and were typically grade 1 or 2 (grade 3 events were noted in up to 25% of patients, and no grade 4 events were reported). Thrombocytopenia occurred in 73% of the patients (grade 3 in 25% and grade 4 in 33%). Thrombocytopenia led to bleeding events of grade 3 or higher in 6 patients. CONCLUSIONS: Selinexor-dexamethasone resulted in objective treatment responses in patients with myeloma refractory to currently available therapies. (Funded by Karyopharm Therapeutics; STORM ClinicalTrials.gov number, NCT02336815.).