Research Spotlight

Voss, R. K., J. C. Lin, M. T. Roper, M. H. Al-Temimi, J. Ruan, W. Tseng, M. Tam, M. J. Sherman, D. D. Klaristenfeld and M. J. Tomassi (2020). “Adjuvant Chemotherapy Does Not Improve Recurrence-Free Survival in Patients with Stage 2 or Stage 3 Rectal Cancer After Neoadjuvant Chemoradiotherapy and Total Mesorectal Excision.” Dis Colon Rectum Jan 28. [Epub ahead of print].

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BACKGROUND: Current guidelines for locally advanced stage 2/3 rectal cancer recommend neoadjuvant chemoradiotherapy followed by total mesorectal excision and adjuvant chemotherapy. The oncologic benefit of adjuvant chemotherapy has not been consistently demonstrated. OBJECTIVE: Evaluate disease recurrence and survival in rectal cancer patients who received adjuvant chemotherapy after chemoradiotherapy and total mesorectal excision DESIGN:: Retrospective review of stage 2/3 rectal cancer patients after chemoradiotherapy and surgery, based on receipt of adjuvant chemotherapy SETTINGS:: Kaiser Permanente Southern California system of 14 hospitals and associated clinics PATIENTS:: 862 Stage 2/3 rectal cancer patients diagnosed and treated between 1/1/2005 and 12/31/2016 INTERVENTIONS:: Neoadjuvant chemoradiotherapy followed by total mesorectal excision +/- adjuvant chemotherapy MAIN OUTCOME MEASURES:: The primary endpoint was recurrence-free survival. RESULTS: 348 stage 2 and 514 stage 3 patients were included. 660 patients (76.6%) underwent adjuvant chemotherapy. Mean patient follow-up after surgery was 63.0 months (range 3-160). Multivariable analysis showed that yp stage (Hazard Ratio for yp stage 2=4.74 and yp stage 3=8.83) and en bloc resection (Hazard Ratio=1.76) were the only variables that significantly predicted disease recurrence. Neither pretreatment tumor stage nor receipt of adjuvant chemotherapy was significantly associated with recurrence-free survival. Log rank testing failed to demonstrate significant recurrence-free survival improvement after receipt of adjuvant chemotherapy in any patient subgroup. LIMITATIONS: Selection bias, due to retrospective study without patient randomization or predefined treatment protocol CONCLUSIONS:: In stage 2/3 rectal cancer treated with chemoradiotherapy and surgery, the addition of adjuvant chemotherapy was not associated with decreased recurrence-free survival in the entire cohort or in any subgroup, while tumor response to chemoradiotherapy is closely associated with disease recurrence. These findings have important consequences for treatment and surveillance decisions for rectal cancer patients. Pre-surgical efforts that maximize tumor downstaging, such as total neoadjuvant therapy, may produce better oncologic outcomes than traditional adjuvant chemotherapy.See Video Abstract at http://links.lww.com/DCR/B134.

Vaduganathan, M., B. L. Claggett, A. S. Desai, S. D. Anker, S. V. Perrone, S. Janssens, D. Milicic, J. L. Arango, M. Packer, V. C. Shi, M. P. Lefkowitz, J. J. V. McMurray and S. D. Solomon (2020). “Prior Heart Failure Hospitalization, Clinical Outcomes, and Response to Sacubitril/Valsartan Compared With Valsartan in HFpEF.” J Am Coll Cardiol 75(3): 245-254.

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BACKGROUND: The period shortly after hospitalization for heart failure (HF) represents a high-risk window for recurrent clinical events, including rehospitalization or death. OBJECTIVES: This study sought to determine whether the efficacy and safety of sacubitril/valsartan varies in relation to the proximity to hospitalization for HF among patients with HF with preserved ejection fraction (HFpEF). METHODS: In this post hoc analysis of PARAGON-HF (Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] with ARB [Angiotensin Receptor Blocker] Global Outcomes in HFpEF), we assessed the risk of clinical events and response to sacubitril/valsartan in relation to time from last HF hospitalization among patients with HFpEF (>/=45%). The primary outcome was composite total HF hospitalizations and cardiovascular death, analyzed by using a semiparametric proportional rates method, stratified by geographic region. RESULTS: Of 4,796 validly randomized patients in PARAGON-HF, 622 (13%) were screened during hospitalization or within 30 days of prior hospitalization, 555 (12%) within 31 to 90 days, 435 (9%) within 91 to 180 days, and 694 (14%) after 180 days; 2,490 (52%) were never previously hospitalized. Over a median follow-up of 35 months, risk of total HF hospitalizations and cardiovascular death was inversely and nonlinearly associated with timing from prior HF hospitalization (p < 0.001). There was a gradient in relative risk reduction in primary events with sacubitril/valsartan from patients hospitalized within 30 days (rate ratio: 0.73; 95% confidence interval: 0.53 to 0.99) to patients never hospitalized (rate ratio: 1.00; 95% confidence interval: 0.80 to 1.24; trend in relative risk reduction: pinteraction = 0.15). With valsartan alone, the rate of total primary events was 26.7 (180 days), and 7.9 (not previously hospitalized) per 100 patient-years. Compared with valsartan, absolute risk reductions with sacubitril/valsartan were more prominent in patients enrolled early after hospitalization: 6.4% (180 days or who were never hospitalized (trend in absolute risk reduction: pinteraction = 0.050). CONCLUSIONS: Recent hospitalization for HFpEF identifies patients at high risk for near-term clinical progression. In the PARAGON-HF trial, the relative and absolute benefits of sacubitril/valsartan compared with valsartan in HFpEF appear to be amplified when initiated in the high-risk window after hospitalization and warrant prospective validation. (PARAGON-HF; NCT01920711).

Tew, B. Y., C. Legendre, M. A. Schroeder, T. Triche, G. C. Gooden, Y. Huang, L. Butry, D. J. Ma, K. Johnson, R. A. Martinez, M. Pierobon, E. F. Petricoin, J. O’Shaughnessy, C. Osborne, C. Tapia, D. N. Buckley, J. Glen, M. Bernstein, J. N. Sarkaria, S. A. Toms and B. Salhia (2020). “Patient-derived xenografts of central nervous system metastasis reveal expansion of aggressive minor clones.” Neuro Oncol 22(1): 70-83.

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BACKGROUND: The dearth of relevant tumor models reflecting the heterogeneity of human central nervous system metastasis (CM) has hindered development of novel therapies. METHODS: We established 39 CM patient-derived xenograft (PDX) models representing the histological spectrum, and performed phenotypic and multi-omic characterization of PDXs and their original patient tumors. PDX clonal evolution was also reconstructed using allele-specific copy number and somatic variants. RESULTS: PDXs retained their metastatic potential, with flank-implanted PDXs forming spontaneous metastases in multiple organs, including brain, and CM subsequent to intracardiac injection. PDXs also retained the histological and molecular profiles of the original patient tumors, including retention of genomic aberrations and signaling pathways. Novel modes of clonal evolution involving rapid expansion by a minor clone were identified in 2 PDXs, including CM13, which was highly aggressive in vivo forming multiple spontaneous metastases, including to brain. These PDXs had little molecular resemblance to the patient donor tumor, including reversion to a copy number neutral genome, no shared nonsynonymous mutations, and no correlation by gene expression. CONCLUSIONS: We generated a diverse and novel repertoire of PDXs that provides a new set of tools to enhance our knowledge of CM biology and improve preclinical testing. Furthermore, our study suggests that minor clone succession may confer tumor aggressiveness and potentiate brain metastasis.

Tague, L. K., D. E. Byers, R. Hachem, D. Kreisel, A. S. Krupnick, H. S. Kulkarni, C. Chen, H. J. Huang and A. Gelman (2020). “Impact of SLCO1B3 polymorphisms on clinical outcomes in lung allograft recipients receiving mycophenolic acid.” Pharmacogenomics J 20(1): 69-79.

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Single-nucleotide polymorphisms (SNPs) in genes involved in mycophenolic acid (MPA) metabolism have been shown to contribute to variable MPA exposure, but their clinical effects are unclear. We aimed to determine if SNPs in key genes in MPA metabolism affect outcomes after lung transplantation. We performed a retrospective cohort study of 275 lung transplant recipients, 228 receiving mycophenolic acid and a control group of 47 receiving azathioprine. Six SNPs known to regulate MPA exposure from the SLCO, UGT and MRP2 families were genotyped. Primary outcome was 1-year survival. Secondary outcomes were 3-year survival, nonminimal (>/=A2 or B2) acute rejection, and chronic lung allograft dysfunction (CLAD). Statistical analyses included time-to-event Kaplan-Meier with log-rank test and Cox regression modeling. We found that SLCO1B3 SNPs rs4149117 and rs7311358 were associated with decreased 1-year survival [rs7311358 HR 7.76 (1.37-44.04), p = 0.021; rs4149117 HR 7.28 (1.27-41.78), p = 0.026], increased risk for nonminimal acute rejection [rs4149117 TT334/T334G: OR 2.01 (1.06-3.81), p = 0.031; rs7311358 GG699/G699A: OR 2.18 (1.13-4.21) p = 0.019] and lower survival through 3 years for MPA patients but not for azathioprine patients. MPA carriers of either SLCO1B3 SNP had shorter survival after CLAD diagnosis (rs4149117 p = 0.048, rs7311358 p = 0.023). For the MPA patients, Cox regression modeling demonstrated that both SNPs remained independent risk factors for death. We conclude that hypofunctional SNPs in the SLCO1B3 gene are associated with an increased risk for acute rejection and allograft failure in lung transplant recipients treated with MPA.

Tabachnick, D., B. Obokhae, K. Harrington and D. L. Brown (2020). “Assessing the risk of an anomalous circumflex artery using balloon aortic valvuloplasty prior to transcatheter aortic valve replacement.” Catheter Cardiovasc Interv Jan 20. [Epub ahead of print].

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Anomalous origin of the left circumflex coronary artery from the right sinus of Valsalva or proximal right coronary artery (RCA) is a well-known anatomic variation. Although the condition is usually benign, there is risk for compression of the anomalous artery by a prosthetic valve in patients undergoing aortic valve replacement (AVR). In more recent years, balloon aortic valvuloplasty (BAV) has been performed prior to transcatheter aortic valve replacement (TAVR) to serve as a diagnostic tool in the evaluation of symptom relief and procedural risks prior to definitive therapy with TAVR. However, the literature regarding BAV utilization in the assessment of coronary artery anomalies prior to TAVR is scarce. Our case illustrates the importance of performing preoperative BAV to assess the safety of a TAVR procedure in patients with coronary anomalies. Herein, we present a case of a patient who underwent BAV with selective angiography of her anomalous circumflex artery. During balloon inflation, the anomalous circumflex artery was transiently occluded, with complete resolution with balloon deflation. Given these findings, the patient was deemed to be unsuitable for TAVR and offered surgical AVR. This case demonstrates that patients with anomalous coronary circulation may require BAV with selective angiography to fully evaluate risk of coronary occlusion with TAVR.