Citations

Significance A hallmark of aging is chronic sterile inflammation, which is closely associated with frailty and age-related diseases. We found that senescent fat progenitor cells accumulate in adipose tissue with aging and acquire a senescence-associated secretory phenotype (SASP), with increased production of proinflammatory cytokines compared with nonsenescent cells. These cells provoked inflammation in adipose tissue and induced macrophage migration. The JAK pathway is activated in adipose tissue with aging, and the SASP can be suppressed by inhibiting the JAK pathway in senescent cells. JAK1/2 inhibitors reduced inflammation and alleviated frailty in aged mice. One possible mechanism contributing to reduced frailty is SASP inhibition. Our study points to the JAK pathway as a potential target for countering age-related dysfunction.

In complex health care situations, teamwork becomes immensely integral to favorable patient outcomes. This study examines an unusual prolonged resuscitation case to understand elements that contributed to the successful outcome of this patient. Through use of the Shared Mental Model Framework (SMMF), we highlighted the importance of multidisciplinary teamwork during resuscitation efforts by analyzing team members’ perceptions through surveys. An 11-item open-ended questionnaire was administered to clinicians (N=9) involved in the resuscitation effort. A case analysis technique was used to identify four key themes that contributed to the success of this resuscitation effort: (1) clear goals are essential to the team’s functioning; (2) strong and effective communication solidified longitudinally among team members; (3) provider’s expertise was paramount to the case’s success; and (4) resources readily available helped manage the team’s cohesiveness. Identifying key teamwork elements in successful resuscitation efforts further informs the valuable need for team cohesiveness in health care.

Mixed lineage kinase 3 (MLK3) deficiency reduces macrophage‐associated inflammation in a murine model of nonalcoholic steatohepatitis (NASH). However, the mechanistic links between MLK3 activation in hepatocytes and macrophage‐driven inflammation in NASH are uncharted. Herein, we report that MLK3 mediates the release of (C‐X‐C motif) ligand 10 (CXCL10)‐laden extracellular vesicles (EVs) from lipotoxic hepatocytes, which induce macrophage chemotaxis. Primary mouse hepatocytes (PMHs) and Huh7 cells were treated with palmitate or lysophosphatidylcholine (LPC). Released EVs were isolated by differential ultracentrifugation. LPC treatment of PMH or Huh7 cells induced release of EVs, which was prevented by either genetic or pharmacological inhibition of MLK3. Mass spectrometry identified the potent chemokine, CXCL10, in the EVs, which was markedly enriched in EVs isolated from LPC‐treated hepatocytes versus untreated cells. Green fluorescent protein (GFP)‐tagged CXCL10 was present in vesicular structures and colocalized with the red fluorescent protein (RFP)‐tagged EV marker, CD63, after LPC treatment of cotransfected Huh‐7 cells. Either genetic deletion or pharmacological inhibition of MLK3 prevented CXCL10 enrichment in EVs. Treatment of mouse bone‐marrow–derived macrophages with lipotoxic hepatocyte‐derived EVs induced macrophage chemotaxis, an effect blocked by incubation with CXCL10‐neutralizing antisera. MLK3‐deficient mice fed a NASH‐inducing diet had reduced concentrations of total plasma EVs and CXCL10 containing EVs compared to wild‐type mice. Conclusions: During hepatocyte lipotoxicity, activated MLK3 induces the release of CXCL10‐bearing vesicles from hepatocytes, which are chemotactic for macrophages. (Hepatology 2016;63:731–744)

Purpose Given that the clinical course of oxaliplatin-induced neuropathy is not well defined, the current study was performed to better understand clinical parameters associated with its presentation. Methods Acute and chronic neuropathy was evaluated in patients receiving adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) on study N08CB (North Central Cancer Treatment Group, Alliance). Acute neuropathy was assessed by having patients complete daily questionnaires for 6 days with each cycle of FOLFOX. Before each dose of FOLFOX and as long as 18 months after chemotherapy cessation, chronic neurotoxicity was assessed with use of the 20-item, European Organisation for Research and Treatment of Cancer quality-of-life questionnaire for patients with chemotherapy-induced peripheral neuropathy. Results Three hundred eight (89%) of the 346 patients had at least one symptom of acute neuropathy with the first cycle of FOLFOX; these symptoms included sensitivity to touching cold items (71%), sensitivity to swallowing cold items (71%), throat discomfort (63%), or muscle cramps (42%). Acute symptoms peaked at day 3 and improved, although they did not always resolve completely between treatments. These symptoms were about twice as severe in cycles 2 through 12 as they were in cycle 1. For chronic neurotoxicity, tingling was the most severe symptom, followed by numbness and then pain. During chemotherapy, symptoms in the hands were more prominent than they were in the feet; by 18 months, symptoms were more severe in the feet than they were in the hands. Patients with more severe acute neuropathy during the first cycle of therapy experienced more chronic sensory neurotoxicity (P < .0001). Conclusion Acute oxaliplatin-induced neuropathy symptoms do not always completely resolve between treatment cycles and are only half as severe on the first cycle as compared with subsequent cycles. There is a correlation between the severities of acute and chronic neuropathies.

Abstract Background: Traditional adjuvant therapy for oropharyngeal squamous cell carcinoma (OPSCC) consists of 60-66 Gy of radiation therapy (XRT) given in 2 Gy daily fractions along with high dose cisplatin if the patient has high risk factors. Despite the excellent cure rates for HPV+ OPSCC, one in three patients treated with conventional treatment will develop grade &gt;3 long-term sequelae from therapy. There is intense interest in de-intensifying adjuvant therapy for this patient population in order to maximize quality of life while maintaining excellent historical rates of disease control. Methods: MC1273 is a phase II non-randomized trial open at Mayo Clinic Rochester testing a novel course of aggressive therapy de-escalation following surgery for HPV+ OPSCC. The primary endpoint is local/regional control at 2 years while secondary endpoints include toxicity and quality of life (QOL). The eligibility criteria include all patients with p16-positive OPSCC with less than a ten pack-year smoking history who have had a complete surgical resection. Exclusion criteria include positive surgical margins, prior history of malignancy, and history of connective tissue disorders. Patients are divided into two prospective cohorts depending upon risk factors found at surgery. Patients with intermediate risk disease (≥T3, ≥N2, lymphovascular invasion, or perineural invasion) are enrolled in MC1273A while patients with extracapsular extension (ECE) are enrolled in MC1273B. Patients on MC1273A receive 30 Gy of radiation delivered in 1.5 Gy twice-daily fractions over the course of two weeks along with weekly docetaxel (15 mg/m2) given on day 1 and day 8. Patients on MC1273B receive a similar treatment regimen but also have the nodal level with positive ECE concurrently boosted to 36 Gy in 1.8 Gy twice-daily fractions. In addition to standard of care follow-up, patients receive a swallowing assessment with speech therapy immediately before XRT, one month post-XRT, and one year post-XRT. Patients also have QOL assessment consisting of the XeQOLS, Eq-5D, FACT H&N (Vers 4) and Dermatology Life Quality Index assessed at pre-XRT and 3, 12, and 24 months post-XRT. Results: Each cohort of MC1273 is powered to detect a 10% local/regional failure rate with 85% confidence. Each cohort will accrue 35 evaluable patients and 5 additional patients to account for ineligibilities and violations (40 patients total per cohort.) MC1273A began accrual in September 2013. The first five patients were monitored for grade ≥4 acute toxicities before proceeding to open accrual. MC1273B began accrual in May 2014 and has also proceeded to open accrual. Accrual will also begin in Mayo Clinic Scottsdale in the first quarter of 2015. Conclusions: MC1273 is meeting its accrual targets and should finish accrual by 2016. We anticipate that preliminary results for toxicity will be available by 2017 and local/regional data will be available by 2018. Citation Format: Daniel J. Ma, Katharine A. Price, Eric J. Moore, Joaquin J. Garcia, Scott H. Okuno, Daniel L. Price, Jeff A. Sloan, Nathan R. Foster, Robert L. Foote. MC1273: Phase II evaluation of aggressive dose de-escalation for adjuvant chemoradiation in HPV associated oropharynx cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT227. doi:10.1158/1538-7445.AM2015-CT227