Research Spotlight

Wesson, D. E., V. Mathur, N. Tangri, Y. Stasiv, D. Parsell, E. Li, G. Klaerner and D. A. Bushinsky (2019). “Veverimer versus placebo in patients with metabolic acidosis associated with chronic kidney disease: a multicentre, randomised, double-blind, controlled, phase 3 trial.” Lancet 393(10179): 1417-1427.

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BACKGROUND: Patients with advanced chronic kidney disease lose the capacity to fully excrete endogenous acid, resulting in chronic metabolic acidosis that increases the risk of disease progression and causes muscle catabolism and bone resorption. Veverimer, a non-absorbed, counterion-free, polymeric drug, selectively binds and removes hydrochloric acid from the gastrointestinal lumen, unlike current oral sodium bicarbonate therapy for metabolic acidosis that only neutralises accumulated acid. We assessed the efficacy and safety of veverimer as a treatment for metabolic acidosis in patients with chronic kidney disease. METHODS: We did a multicentre, parallel, randomised, double-blind, placebo-controlled study at 37 sites (hospitals and specialty clinics) in Bulgaria, Croatia, Georgia, Hungary, Serbia, Slovenia, Ukraine, and the USA. Eligible participants were patients aged 18-85 years with non-dialysis-dependent chronic kidney disease (estimated glomerular filtration rate of 20-40 mL/min per 1.73 m(2)) and metabolic acidosis (serum bicarbonate concentration of 12-20 mmol/L). Patients were randomly assigned (4:3) to veverimer 6 g/day or placebo for 12 weeks while they consumed their typical diet. Both drugs were taken as oral suspensions in water with lunch. Randomisation was done by study site personnel with a computer-generated randomisation code with balanced permuted blocks (block size of seven) and stratified by baseline bicarbonate (18 mmol/L). Patients and investigators were masked to treatment allocation; however, because the appearance of placebo differed from veverimer, a non-masked site staff member who had no other role in the study dispensed, prepared, and supervised dosing of the study drugs. The composite primary efficacy endpoint was the difference (veverimer-placebo) in the proportion of patients achieving at week 12 either an increase of 4 mmol/L or more from baseline in serum bicarbonate concentration or serum bicarbonate in the normal range of 22-29 mmol/L, assessed in the modified intention-to-treat population (all patients with a baseline and at least one post-baseline serum bicarbonate value). Patients fasted for at least 4 h (consuming only water) before measurements of bicarbonate. Safety was assessed in all patients who received any amount of study drug. This trial is registered with ClinicalTrials.gov, number NCT03317444. FINDINGS: Between Sept 26, 2017, and Feb 9, 2018, we randomly assigned 124 participants to veverimer and 93 to placebo. The composite primary endpoint was met by 71 (59%) of 120 patients in the veverimer group versus 20 (22%) of 89 patients in the placebo group (a difference of 37%, 95% CI 23-49; p<0.0001). The most common body system in which adverse events in the veverimer group occurred was gastrointestinal; of these, non-treatment limiting diarrhoea was the most common event (11 [9%] vs three [3%] in the veverimer and placebo groups, respectively). The most common treatment-related adverse events were gastrointestinal (diarrhoea, flatulence, nausea, and constipation) occurring in 16 (13%) patients with veverimer and five (5%) patients with placebo. Two deaths occurred during the study, both in the placebo group (unstable angina and pneumonia). INTERPRETATION: Veverimer effectively and safely corrected metabolic acidosis. Longer-term studies are warranted to assess the effects of veverimer on physical functioning and to assess other deleterious consequences of metabolic acidosis including progression of chronic kidney disease and bone health. FUNDING: Tricida.

Shi, Y., W. Gao, N. K. Lytle, P. Huang, X. Yuan, A. M. Dann, M. Ridinger-Saison, K. E. DelGiorno, C. E. Antal, G. Liang, A. R. Atkins, G. Erikson, H. Sun, J. Meisenhelder, E. Terenziani, G. Woo, L. Fang, T. P. Santisakultarm, U. Manor, R. Xu, C. R. Becerra, E. Borazanci, D. D. Von Hoff, P. M. Grandgenett, M. A. Hollingsworth, M. Leblanc, S. E. Umetsu, E. A. Collisson, M. Scadeng, A. M. Lowy, T. R. Donahue, T. Reya, M. Downes, R. M. Evans, G. M. Wahl, T. Pawson, R. Tian and T. Hunter (2019). “Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring.” Nature 569(7754): 131-135.

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Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis largely owing to inefficient diagnosis and tenacious drug resistance. Activation of pancreatic stellate cells (PSCs) and consequent development of dense stroma are prominent features accounting for this aggressive biology(1,2). The reciprocal interplay between PSCs and pancreatic cancer cells (PCCs) not only enhances tumour progression and metastasis but also sustains their own activation, facilitating a vicious cycle to exacerbate tumorigenesis and drug resistance(3-7). Furthermore, PSC activation occurs very early during PDAC tumorigenesis(8-10), and activated PSCs comprise a substantial fraction of the tumour mass, providing a rich source of readily detectable factors. Therefore, we hypothesized that the communication between PSCs and PCCs could be an exploitable target to develop effective strategies for PDAC therapy and diagnosis. Here, starting with a systematic proteomic investigation of secreted disease mediators and underlying molecular mechanisms, we reveal that leukaemia inhibitory factor (LIF) is a key paracrine factor from activated PSCs acting on cancer cells. Both pharmacologic LIF blockade and genetic Lifr deletion markedly slow tumour progression and augment the efficacy of chemotherapy to prolong survival of PDAC mouse models, mainly by modulating cancer cell differentiation and epithelial-mesenchymal transition status. Moreover, in both mouse models and human PDAC, aberrant production of LIF in the pancreas is restricted to pathological conditions and correlates with PDAC pathogenesis, and changes in the levels of circulating LIF correlate well with tumour response to therapy. Collectively, these findings reveal a function of LIF in PDAC tumorigenesis, and suggest its translational potential as an attractive therapeutic target and circulating marker. Our studies underscore how a better understanding of cell-cell communication within the tumour microenvironment can suggest novel strategies for cancer therapy.

Wells, K. and J. Fleshman (2019). “Screening Colonoscopy Should Be Available to All.” JAMA Surg Apr 17. [Epub ahead of print].

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In a retrospective review of 16,000 patients in a systemwide experience of screening colonoscopy, Sarvepalli et al determined that the association of endoscopist specialty (surgeon or gastroenterologist) with adenoma detection rate was insignificant. This counters previously reported lower quality for colonoscopies and increased risk of missed adenomas and interval cancers by surgeons and confirms that colonoscopic quality indicators are adequately met by both gastroenterologists and nongastroenterologists. Sarvepalli et al do report differences between specialties not owing to random features of the endoscopists and other confounders, specifically, a decrement in the proximal sessile serrated adenoma (SSA) detection rate of 2.3% by surgeons vs 5.6% by gastroenterologists. The clinical significance of a 3.3% difference in the proximal SSA detection rate is questionable. Proximal SSAs arise via CpG island methylator phenotype pathway, with higher rates of methylation and carcinogenesis occurring in an age-dependent pattern. In a pathology series of 2416 SSAs, SSA-associated carcinoma was diagnosed at a mean age of 76 years vs 67 years among those with carcinoma arising in conventional adenomas. The SSAs do not progress as often or as quickly as conventional adenomas, accounting for their presence in the elderly cohort. In longitudinal computed tomographic colonographic assessment, 22% of SSAs progress vs 41% of conventional adenomas at an annual volumetric growth rate of 12.7% vs 36.4% in conventional adenomas (P = .03). The difference in median age between patients with SSA and SSA-associated carcinoma is 15 years vs a 5-year difference from tubular adenoma to conventional carcinoma, suggesting a 3-fold longer rate of progression to malignancy in SSA. Therefore, a second screening colonoscopy in 10 years would likely detect an early cancer or larger SSA. An SSA-harboring carcinoma represented only 1% of all specimens, which, if applied to the Sarvepalli et al study’s difference of 3.3%, translates into a miss rate of 3 SSA-associated carcinomas per 10 000 colonoscopies. In view of a slower progression of SSA to cancer in most cases, allowing a slightly higher miss rate in surveillance colonoscopy performed by nongastroenterologists might be acceptable. Eventual polypectomy, as less aggressive SSA lesions become larger, would be akin to the management of anal intraepithelial neoplasia III, where frequent observation of an affected mucosal field to remove visible lesions preserves the organ and effectively prevents progression to cancer. This study validates the surgeon in providing a high-quality screening and, more importantly, broadens the limited pool of clinicians to address low national screening rates. The question becomes whether well-trained nonspecialty clinicians with an acceptable adenoma detection rate could also provide screening. (Excerpt from text, p. e1; no abstract available.)

Afzal, A., K. M. Tecson, A. K. Jamil, J. Felius, P. S. Garcha, S. A. Hall and S. A. Carey (2019). “The Effect of Obstructive Sleep Apnea on 3-Year Outcomes in Patients Who Underwent Orthotopic Heart Transplantation.” Am J Cardiol Apr 10. [Epub ahead of print].

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Despite the well-known association between obstructive sleep apnea (OSA) and cardiovascular disease, there is a paucity of data regarding OSA in orthotopic heart transplant (OHT) recipients and its effect on clinical outcomes. Hence, we sought to determine the association between OSA, as detected by polysomnography, and late graft dysfunction (LGD) after OHT. In this retrospective review of consecutive OHT recipients from 2012 to 2014 at our center, we examined LGD, i.e., graft failure >1 year after OHT, through competing risks analysis. Due to small sample size and event counts, as well as preliminary testing which revealed statistically similar demographics and outcomes, we pooled patients who had treated OSA with those who had no OSA. Of 146 patients, 29 (20%) had untreated OSA, i.e., OSA without use of continuous positive airway pressure therapy, at the time of transplantation. Patients with untreated OSA were significantly older, heavier, and more likely to have baseline hypertension than those with treated/no OSA. Although there were no differences between groups in regard to short-term complications of acute kidney injury, cardiac allograft vasculopathy, or primary graft dysfunction, there were significant differences in the occurrence of LGD. Those with untreated OSA were at 3 times the risk of developing LGD than those with treated/no OSA (hazard ratio 3.2; 95% confidence interval 1.3 to 7.9; p=0.01). Because OSA is a common co-morbidity of OHT patients and because patients with untreated OSA have an elevated risk of LGD, screening for and treating OSA should occur during the OHT selection period.

Roberts, W. C. (2019). “Proceedings of the Editorial Board Meeting of The American Journal of Cardiology on March 17, 2019, in New Orleans, Louisiana.” Am J Cardiol Apr 18. [Epub ahead of print].

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The year 2018 was a good one for the American Journal of Cardiology. The number of manuscripts submitted in 2018 increased 3.4% from the previous year (3,360 → 3,479), an average of 67 per week of which an average of 12 were accepted each week. The acceptance rate decreased from 19% in 2017 to 18% in 2018. The acceptance rate has continued to decrease during the present editorship even though the AJC publishes more manuscripts each year than any other cardiology journal in the world. A total of 573 articles were published in the AJC in 2018, a decrease from 700 published in 2017. This number excludes Readers’ Comments (Letters to the Editor). There is no limitation in the total number of tables and figures in articles published in the AJC, in contrast to the limitations (usually 8) of most cardiology journals. As a consequence, the AJC publishes more figures and tables than other major cardiovascular journals. The average length of the text of articles published in the AJC is almost certainly less than in other cardiology journals. The publisher of the AJC in 2018 provided a total of 3,891 editorial pages, of which 3735 (96%) were used for publishing articles and 42 for publishing Readers’ Comments. Total circulation of the AJC in 2018, according to the publisher, was just over 23,000. (Excerpt from text of article-in-press, p. 2; no abstract available.)