Research Spotlight

Baselga, J., S. M. Morales, A. Awada, J. L. Blum, A. R. Tan, M. Ewertz, J. Cortes, B. Moy, K. J. Ruddy, T. Haddad, E. M. Ciruelos, P. Vuylsteke, S. Ebbinghaus, E. Im, L. Eaton, K. Pathiraja, C. Gause, D. Mauro, M. B. Jones and H. S. Rugo (2017). “A phase ii study of combined ridaforolimus and dalotuzumab compared with exemestane in patients with estrogen receptor-positive breast cancer.” Breast Cancer Res Treat: 2017 Mar [Epub ahead of print].

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PURPOSE: Combining the mTOR inhibitor ridaforolimus and the anti-IGFR antibody dalotuzumab demonstrated antitumor activity, including partial responses, in estrogen receptor (ER)-positive advanced breast cancer, especially in high proliferation tumors (Ki67 > 15%). METHODS: This randomized, multicenter, international, phase II study enrolled postmenopausal women with advanced ER-positive breast cancer previously treated with a nonsteroidal aromatase inhibitor (NCT01234857). Patients were randomized to either oral ridaforolimus 30 mg daily for 5 of 7 days (once daily [qd] x 5 days/week) plus intravenous dalotuzumab 10 mg/kg/week or oral exemestane 25 mg/day, and stratified by Ki67 status. Due to a high incidence of stomatitis in the ridaforolimus-dalotuzumab group, two sequential, nonrandomized, reduced-dose cohorts were explored with ridaforolimus 20 and 10 mg qd x 5 days/week. The primary endpoint was progression-free survival (PFS). RESULTS: Median PFS was 21.4 weeks for ridaforolimus 30 mg qd x 5 days/week plus dalotuzumab 10 mg/kg (n = 29) and 24.3 weeks for exemestane (n = 33; hazard ratio = 1.00; P = 0.5). Overall survival and objective response rates were similar between treatment arms. The incidence of drug-related, nonserious, and serious adverse events was higher with ridaforolimus/dalotuzumab (any ridaforolimus dose) than with exemestane. Lowering the ridaforolimus dose reduced the incidence of grade 3 stomatitis, but overall toxicity remained higher than acceptable at all doses without improved efficacy. CONCLUSIONS: The combination of ridaforolimus plus dalotuzumab was no more effective than exemestane in patients with advanced ER-positive breast cancer, and the incidence of adverse events was higher. Therefore, the combination is not being further pursued.

Askar, M. (2017). “The killer immunoglobulin-like receptor dilemma: How do we harness the power of killer immunoglobulin-like receptors?” Biol Blood Marrow Transplant 23(4): 535-536.

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Alloreactive natural killer (NK) cells have been reported to significantly impact allogeneic hematopoietic cell transplantation (HCT) outcomes. How the interactions between killer immunoglobulin-like receptors (KIR) and HLA influence human NK cell functions has been demonstrated by elegant in vitro experiments [1]. Since the early 2000s, the published literature has been populated with numerous studies investigating the association between KIR genotype/haplotype and clinical outcomes of HCT, both independently and in the context of interaction with corresponding HLA ligands. Meanwhile, additional models for KIR modulation of NK cell functions have been proposed [2]. The method of KIR typing adds another layer of complexity in studying the associations between KIR and HCT outcomes. Most published studies in this domain rely on logistically attractive genotyping methods that allow identification of all KIR genes from archived DNA samples collected routinely for HLA typing and typically tested in large batches. In contrast, flow cytometry–based phenotyping and RNA-based transcription profile testing require freshly collected samples and are more technically involved. Leung et al. have demonstrated significant heterogeneity in the level of KIR expression by NK cells with more than 10-fold difference observed among individuals with similar genotype; they have also demonstrated that transcripts of only 2 of 12 KIR genes tested (KIR2DL3 and KIR3DL2) were consistently detectable by real time PCR [3]. These results suggest the potential relevance of phenotyping, rather than genotyping, in KIR-based selection of HCT donors. Lastly, different alleles of a KIR gene were reported to have different functional properties, such as licensing capability, durability of surface expression after ligand interaction, and intracellular signaling [4].

Roberts, W. C., P. A. Grayburn and B. L. Hamman (2017). “Lipoma of the Mitral Valve.” Am J Cardiol 119(7): 1121-1123.

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Described herein is a 67-year-old morbidly obese man who had a lipoma excised from his posterior mitral leaflet after it was found by echocardiogram. Findings in 6 other previously reported cases are reviewed.

McCullough, P. A., J. Zhang and C. Ronco (2017). “Volume expansion and contrast-induced acute kidney injury.” Lancet: 2017 Feb [Epub ahead of print].

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There is an ever-increasing population at risk of being exposed to intravascular iodinated contrast because of the increasingly popular practice of imaging techniques in medicine and surgery. Despite efforts to improve the safety of these agents, there has been no fundamental improvement in contrast product development since the introduction of iso-osmolar contrast more than 20 years ago.1; 2 ; 3 Thus, clinicians have focused on strategies to decrease the risk of contrast-induced acute kidney injury by limiting contrast volume, giving adjuvant agents, and providing supportive care once the renal damage has occurred. It has been suggested that intravascular volume expansion with isotonic crystalloid solution can decrease the incidence and the severity of contrast-induced acute kidney injury.4 This approach is attractive because the short-term administration of intravenous fluid results in an increase in renal blood flow, glomerular filtration, and increased volume of urine flow through the tubular segments of the nephron. Forced diuresis has been associated with a lesser rise in serum creatinine especially when higher rates (>150 ml/h) of urine flow have been achieved.5

Fordtran, J. S. and A. F. Hofmann (2017). “Seventy years of polyethylene glycols in gastroenterology: The journey of peg 4000 and 3350 from nonabsorbable marker to colonoscopy preparation to osmotic laxative.” Gastroenterology 152(4): 675-680.

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The history of polyethylene glycols (PEGs) began in 1859 when Laurenco heated ethylene glycol and 1,2-dibromoethane and isolated oligo(ethylene glycol)s by fractional distillation.1 PEGs are synthetic, uncharged, nonbranched, hydrophilic polymers made by joining units of ethylene glycol by an ether linkage. PEGs thus have the formula of H(OCH2CH2)nOH, where n denotes the number of individual ethylene oxide units. Molecular weights vary by time of the polymerization process. When the process is stopped, the result is a relatively narrow range of ethylene oxide units, and the molecular weight given for a particular PEG is a weighted average of the individual PEG molecules.