Citations

BACKGROUNDRAS/RAF/mitogen‐activated protein kinase activation is common in myeloid malignancies. Trametinib, a mitogen‐activated protein kinase kinase 1 (MEK1)/MEK2 inhibitor with activity against multiple myeloid cell lines at low nanomolar concentrations, was evaluated for safety and clinical activity in patients with relapsed/refractory leukemias.METHODSThis phase 1/2 study accrued patients with any relapsed/refractory leukemia in phase 1. In phase 2, this study accrued patients with relapsed/refractory acute myeloid leukemia (AML) or high‐risk myelodysplastic syndromes (MDS) with NRAS or KRAS mutations (cohort 1); patients with AML, MDS, or chronic myelomonocytic leukemia (CMML) with a RAS wild‐type mutation or an unknown mutation status (cohort 2); and patients with CMML with an NRAS or KRAS mutation (cohorts 3).RESULTSThe most commonly reported treatment‐related adverse events were diarrhea, rash, nausea, and increased alanine aminotransferase levels. The phase 2 recommended dose for Trametinib was 2 mg orally daily. The overall response rates were 20%, 3%, and 27% for cohorts 1, 2, and 3, respectively, and this indicated preferential activity among RAS‐mutated myeloid malignancies. Repeated cycles of trametinib were well tolerated with manageable or reversible toxicities; these results were similar to those of other trametinib studies.CONCLUSIONSThe selective, single‐agent activity of trametinib against RAS‐mutated myeloid malignancies validates its therapeutic potential. Combination strategies based on a better understanding of the hierarchical role of mutations and signaling in myeloid malignancies are likely to improve the response rate and duration. Cancer 2016;122:1871–9. © 2016 American Cancer Society.

Abstract Background Surgical performance, provider health, and patient safety can be compromised when workload demands exceed individual capability on the surgical team. The purpose of this study is to quantify and compare intraoperative workload among surgical team members. Methods Observations were conducted for an entire surgical day for 33 participating surgeons and their surgical team at one medical institution. Workload (mental, physical, case complexity, distractions, and case difficulty) was measured for each surgical team member using questions from validated questionnaires. Statistical analyses were performed with a mixed effects model. Results A total of 192 surgical team members participated in 78 operative cases, and 344 questionnaires were collected. Procedures with high surgeon mental and physical workload included endovascular and gastric surgeries, respectively. Ratings did not differ significantly among surgeons and residents, but scrub nurses physical demand ratings were 14–22 (out of 100) points lower than the surgeons, residents, and surgical assistants. Residents reported the highest mental workload, averaging 19–24 points higher than surgical assistants, scrub nurses, and circulating nurses. Mental and physical demands exceeded 50 points 28–45 % of the time for surgeons and residents. Workload did not differ between minimally invasive and open techniques. Conclusion The workload questionnaires are an effective tool for quantifying intraoperative workload across the surgical team to ensure mental and physical demands do not exceed thresholds where performance may decrease and injury risk increase. This tool has the potential to measure the safety of current procedures and drive design of workload interventions.

Refractory anemia with ring sideroblasts and thrombocytosis (RARS‐T) shares overlapping features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). RARS‐T is characterized by SF3B1 and JAK2 mutations and prognosis is considered to be better than MDS but not as good as MPN. The objective of the study was to identify predictors of survival in RARS‐T. We analyzed clinical and laboratory variables in 82 patients and applied a 27‐gene NGS assay to 48 marrow samples obtained at diagnosis. 94% of patients had ≥1 mutations; common mutations being: SF3B1 85%, JAK2 V617F 33%, ASXL1 29%, DNMT3A 13%, SETBP1 13% and TET2 10%. In a multivariable survival analysis ( n = 82), anemia ( P = 0.02) [HB< 10 gm/dl: HR 2.3, 95% CI 1.2–4.6] and abnormal karyotype ( P =.01) [HR 6.1, 95% CI 2.7‐13.8] were independently prognostic for inferior survival. In patients with NGS information ( n = 48), univariate analysis showed association between poor survival and presence of SETBP1 ( P = 0.04) or ASXL1 ( P = 0.08) mutations whereas the absence of these mutations ( ASXL1 wt/ SETBP1 wt) was favorable ( P = 0.04); the number of concurrent mutations did not provide additional prognostication ( P = 0.3). We developed a HR‐weighted prognostic model, with 2 points for an abnormal karyotype, 1 point for either ASXL1 and/or SETBP1 mutations, and 1 point for a HB level < 10 gm/dl, which effectively stratified patients into three risk categories; low (0 points), intermediate (1 point) and high (≥2 points), with median survivals of 80, 42 and 11 months respectively ( P = 0.01). In summary, we confirm the unique mutational landscape in RARS‐T and provide a novel mutation‐enhanced prognostic model. Am. J. Hematol. 91:492–498, 2016. © 2016 Wiley Periodicals, Inc.

ABSTRACT Mengovirus, a member of the Picornaviridae family, has a broad cell tropism and can cause encephalitis and myocarditis in multiple mammalian species. Attenuation has been achieved by shortening the polycytidine tract in the 5′ noncoding region (NCR). A poly(C)-truncated strain of mengovirus, vMC 24 , resulted in significant tumor regression in immunocompetent BALB/c mice bearing syngeneic MPC-11 plasmacytomas, but the associated toxicities were unacceptable. To enhance its safety profile, microRNA target sequences complementary to miR-124 or miR-125 (enriched in nervous tissue), miR-133 and miR-208 (enriched in cardiac tissue), or miR-142 (control; enriched in hematopoietic tissues) were inserted into the vMC 24 NCRs. The microRNA-detargeted viruses showed reduced replication and cell killing specifically in cells expressing the cognate microRNAs, but certain insertions additionally were associated with nonspecific suppression of viral fitness in vivo. In vivo toxicity testing confirmed that miR-124 targets within the 5′ NCR suppressed virus replication in the central nervous system while miR-133 and miR-208 targets in the 3′ NCR suppressed viral replication in cardiac tissue. A dual-detargeted virus named vMC 24 -NC, with miR-124 targets in the 5′ NCR and miR-133 plus miR-208 targets in the 3′ NCR, showed the suppression of replication in both nervous and cardiac tissues but retained full oncolytic potency when administered by intratumoral (10 6 50% tissue culture infectious doses [TCID 50 ]) or intravenous (10 7 to 10 8 TCID 50 ) injection into BALB/c mice bearing MPC-11 plasmacytomas. Overall survival of vMC 24 -NC-treated tumor-bearing mice was significantly improved compared to that of nontreated mice. MicroRNA-detargeted mengoviruses offer a promising oncolytic virotherapy platform that merits further development for clinical translation. IMPORTANCE The clinical potential of oncolytic virotherapy for cancer treatment has been well demonstrated, justifying the continued development of novel oncolytic viruses with enhanced potency. Here, we introduce mengovirus as a novel oncolytic agent. Mengovirus is appealing as an oncolytic virotherapy platform because of its small size, simple genome structure, rapid replication cycle, and broad cell/species tropism. However, mengovirus can cause encephalomyelitis and myocarditis. It can be partially attenuated by shortening the poly(C) tract in the 5′ NCR but remains capable of damaging cardiac and nervous tissue. Here, we further enhanced the safety profile of a poly(C)-truncated mengovirus by incorporating muscle- and neuron-specific microRNA target sequences into the viral genome. This dual-detargeted virus has reduced pathogenesis but retained potent oncolytic activity. Our data show that microRNA targeting can be used to further increase the safety of an attenuated mengovirus, providing a basis for its development as an oncolytic platform.

Professionalism requires that doctors acknowledge their errors and figure out how to avoid making similar ones in the future. Over the last few decades, doctors have gotten better at acknowledging mistakes and apologizing to patients when a mistake happens. Such disclosure is especially complicated when one becomes aware of an error made by a colleague. We present a case in which consultant surgeons became aware that a colleague seemed to have made a serious error. Experts in surgery and bioethics comment on appropriate responses to this situation.

The presence and absence of distortion product otoacoustic emissions (DPOAEs) as well as DPOAE amplitudes were compared between college music majors and a control group of nonmusic majors. Participants included 28 music majors and 35 nonmusic majors enrolled at a university with ages ranging from 18-25 years. DPOAEs and hearing thresholds were measured bilaterally on all the participants. DPOAE amplitudes were analyzed at the following f2 frequencies: 1,187 Hz, 1,500 Hz, 1,906 Hz, 2,531 Hz, 3,031 Hz, 3812 Hz, 4,812 Hz, and 6,031 Hz. Significantly more music majors (7/28) than nonmusic majors (0/35) exhibited absent DPOAEs for at least one frequency in at least one ear. Both groups of students reported similar histories of recreational and occupational noise exposures that were unrelated to studying music, and none of the students reported high levels of noise exposure within the previous 48 h. There were no differences in audiometric thresholds between the groups at any frequency. At DPOAE f2 frequencies from 3,031 Hz to 6,031 Hz, nonsignificantly lower amplitudes of 2-4 dB were seen in the right ears of music majors versus nonmajors, and in the right ears of music majors playing brass instruments compared to music majors playing nonbrass instruments. Given the greater prevalence of absent DPOAEs in university music majors compared to nonmusic majors, it appears that early stages of cochlear damage may be occurring in this population. Additional research, preferably longitudinal and across multiple colleges/universities, would be beneficial to more definitively determine when the music students begin to show signs of cochlear damage, and to identify whether any particular subgroups of music majors are at a greater risk of cochlear damage.