Research Spotlight

Wells, K. O. and A. Senagore (2019). “Minimally Invasive Colon Cancer Surgery.” Surg Oncol Clin N Am 28(2): 285-296.

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Colon cancer is the second leading cause of cancer death in the United States. Advances in surgical resection techniques, including minimally invasive colectomy, are becoming a standard of care. The oncologic principles of colectomy have included adequate lymphadenectomy, proximal ligation of primary vessels, and resection with adequate longitudinal margins. More recently, complete mesocolic excision has been advocated. Open and minimally invasive approaches must accomplish the same outcomes. This article focuses on the surgical principles of colon cancer, perioperative considerations, and technical aspects of minimally invasive colectomy. We review the current literature regarding oncologic and short-term outcomes of minimally invasive surgery.

Wells, K. O. and W. R. Peters (2019). “Minimally Invasive Surgery for Locally Advanced Rectal Cancer.” Surg Oncol Clin N Am 28(2): 297-308.

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Total mesorectal excision (TME) can be safely performed through a minimally invasive approach by experienced surgeons and may offer patients benefit in certain short-term outcomes. Long-term oncologic outcomes and meta-analysis of the most recent randomized controlled trials may offer additional clarity regarding the role of laparoscopic TME and those patients for whom the approach is most appropriate. Until then, laparoscopic TME should be used judiciously. As the landscape of rectal cancer surgery evolves, the necessary constant needs to be multidisciplinary oversight of rectal cancer surgery performed by surgeons and surgical centers experienced in this critically important procedure.

Bodei, L., E. Liu, S. Paulson, A. Gulati, J. Freudman, W. Grosh, S. Kafer, P. C. Wickremesinghe and R. R. Salem (2019). “Time for a change and to adopt a novel molecular genomic approach in NETs.” Nat Rev Clin Oncol 16(4): 269-270.

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There is a reply to this correspondence by Rindi, G. & Wiedenmann, B., in Nature Reviews Clinical Oncology 16(4): 270-270: Despite the concerns raised by these experts, the clinical utility of the NETest liquid biopsy assay in the ‘real-world’ setting2. NETest scores enabled accurate prediction (100%) of disease progression and had a 98% correlation with response to therapy, reducing the requirement to perform an imaging test in 40% of patients. NETest is the first blood-based multianalyte gene transcript (mRNA-based) test for neuroendocrine tumours (NETs). The genomic validity of this assay was independently confirmed in an NIH-funded study evaluating the gene expression profiles of >10,000 tumours from The Cancer Genome Atlas (TCGA) database, with the results indicating that the NETest gene signature accurately captured the NET phenotype. Our registry study confirms the clinical utility of this signature . . . Iconoclastic views of novel sophisticated technologies has culminated in the management of NETs falling behind other oncological disciplines (such as the management of breast cancer), which ultimately is detrimental to patients. Rindi and Wiedenmann disappointingly reiterate the tautology “reaching perfection is almost impossible in the real world.” On the contrary, only through the thoughtful adoption of novel advances rather than clinging to dogma can medicine reach for perfection and thereby provide the best care for our patients. (Excerpt from text, p. 269; no abstract available.)

Alvarez Villela, M., C. Y. Guerrero-Miranda, T. Chinnadurai, S. R. Patel and U. P. Jorde (2019). “Rate Response Pacing in Left Ventricular Assist Device Patients.” ASAIO Journal Mar 19. [Epub ahead of print].

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Chronotropic incompetence (II) is common in advanced heart failure and is associated with worse functional capacity. This impaired heart rate (HR) response during exercise is ameliorated but persists after left ventricular assist device (LVAD) implantation. Patients with continuous flow LVAD (CF-LVAD) suffer from significant exercise limitation despite restoration of resting cardiac output. Whether CI contributes to exercise limitation in this setting is unknown. We examined the role of CI and the effect of rate response pacing (RRP) on functional capacity in a group of stable patients with LVAD . . . Our findings demonstrate the association between CI and poor functional capacity in patients with advanced heart failure and CF-LVAD, in line with one small prior study. Findings in this cohort point out the inadequacy of current RRP technologies for sensing signals other than atrial rate during different types of physical activity. When RRP increased the HR promptly and in a sustained manner, replicating the activity of the sinus node, the effect on aerobic capacity was substantial, but this occurred in only a minority of patients. In contrast to the heterogeneous effect of RRP during treadmill-based CPX, its effect on 6 MWD was more homogeneous. This could represent a difference in CIED sensing efficacy since all of the employed devices in this study have an accelerometer-based RRP system. Ambulation, producing linear displacement of the body during 6 MWT could be more easily sensed by accelerometer-based systems than the more static motion during treadmill exercise. These findings warrant further exploration to allow for improvement of current RRP technologies. An efficacious sensing system that can replicate sinus nodal function during different types of physical and emotional activity may lead to important improvements in the quality of life of the growing durable CFLVAD population. (Excerpt from text, p. 1-2; no abstract available.)E

Schwarz, M. E. Sanders, T. C. Dugger, M. R. Cruz, A. Behdad, M. Cristofanilli, A. Bardia, J. O’Shaughnessy, R. J. Nagy, R. B. Lanman, N. Solovieff, W. He, M. Miller, F. Su, Y. Shyr, I. A. Mayer, J. M. Balko and C. L. Arteaga (2019). “Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer.” Nat Commun 10(1): 1373.

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Using an ORF kinome screen in MCF-7 cells treated with the CDK4/6 inhibitor ribociclib plus fulvestrant, we identified FGFR1 as a mechanism of drug resistance. FGFR1-amplified/ER+ breast cancer cells and MCF-7 cells transduced with FGFR1 were resistant to fulvestrant +/- ribociclib or palbociclib. This resistance was abrogated by treatment with the FGFR tyrosine kinase inhibitor (TKI) lucitanib. Addition of the FGFR TKI erdafitinib to palbociclib/fulvestrant induced complete responses of FGFR1-amplified/ER+ patient-derived-xenografts. Next generation sequencing of circulating tumor DNA (ctDNA) in 34 patients after progression on CDK4/6 inhibitors identified FGFR1/2 amplification or activating mutations in 14/34 (41%) post-progression specimens. Finally, ctDNA from patients enrolled in MONALEESA-2, the registration trial of ribociclib, showed that patients with FGFR1 amplification exhibited a shorter progression-free survival compared to patients with wild type FGFR1. Thus, we propose breast cancers with FGFR pathway alterations should be considered for trials using combinations of ER, CDK4/6 and FGFR antagonists.