Research Spotlight

Agtarap, S., E. Carl, M. C. Reynolds, K. Roden-Foreman, M. Bennett, E. Rainey, M. B. Powers, S. Driver and A. M. Warren (2018). “Caregiver expectations of recovery among persons with spinal cord injury at three and six months post-injury: A brief report.” J Spinal Cord Med Aug 21: 1-4. [Epub ahead of print].

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OBJECTIVE: Caregivers of patients with spinal cord injury (SCI) have increased risk of depression, anxiety, and diminished quality of life. Unmet expectations for recovery may contribute to poorer outcomes. DESIGN: Prospective, longitudinal observation study. SETTINGS: Trauma/Critical care ICU at baseline, telephone for follow-ups. PARTICIPANTS: Caregivers of patients with SCI (n = 13). INTERVENTIONS: None. OUTCOME MEASURES: Expectations for recovery were assessed across four primary domains identified in a review of the literature including: pain severity, level of engagement in social/recreational activities, sleep quality, and ability to return to work/school. Caregivers’ forecasts of future recovery were compared to later perceived actual recovery. RESULTS: At three months, 75% of caregivers had unmet expectations for social engagement recovery, 50% had unmet expectations for pain decrease, and 42% had unmet expectations for sleep improvement and resuming work. Rates of unmet expectations were similar at six months, with 70% of caregivers reporting unmet expectations for social engagement recovery, 50% with unmet expectations for pain decrease, and 40% with unmet expectations for sleep improvement. CONCLUSION: Unmet caregiver expectations for recovery could pose a risk for caregiver recovery and adjustment. Our results show that caregiver expectations merit further investigation for their link with caregiver mental health.

Fleshman, J., M. E. Branda, D. J. Sargent, A. M. Boller, V. V. George, M. A. Abbas, W. R. Peters, Jr., D. C. Maun, G. J. Chang, A. Herline, A. Fichera, M. G. Mutch, S. D. Wexner, M. H. Whiteford, J. Marks, E. Birnbaum, D. A. Margolin, D. W. Larson, P. W. Marcello, M. C. Posner, T. E. Read, J. R. T. Monson, S. M. Wren, P. W. T. Pisters and H. Nelson (2018). “Disease-free Survival and Local Recurrence for Laparoscopic Resection Compared With Open Resection of Stage II to III Rectal Cancer: Follow-up Results of the ACOSOG Z6051 Randomized Controlled Trial.” Ann Surg Aug 3. [Epub ahead of print].

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OBJECTIVE: To determine the disease-free survival (DFS) and recurrence after the treatment of patients with rectal cancer with open (OPEN) or laparoscopic (LAP) resection. BACKGROUND: This randomized clinical trial (ACOSOG [Alliance] Z6051), performed between 2008 and 2013, compared LAP and OPEN resection of stage II/III rectal cancer, within 12 cm of the anal verge (T1-3, N0-2, M0) in patients who received neoadjuvant chemoradiotherapy. The rectum and mesorectum were resected using open instruments for rectal dissection (included hybrid hand-assisted laparoscopic) or with laparoscopic instruments under pneumoperitoneum. The 2-year DFS and recurrence were secondary endpoints of Z6051. METHODS: The DFS and recurrence were not powered, and are being assessed for superiority. Recurrence was determined at 3, 6, 9, 12, and every 6 months thereafter, using carcinoembryonic antigen, physical examination, computed tomography, and colonoscopy. In all, 486 patients were randomized to LAP (243) or OPEN (243), with 462 eligible for analysis (LAP = 240 and OPEN = 222). Median follow-up is 47.9 months. RESULTS: The 2-year DFS was LAP 79.5% (95% confidence interval [CI] 74.4-84.9) and OPEN 83.2% (95% CI 78.3-88.3). Local and regional recurrence was 4.6% LAP and 4.5% OPEN. Distant recurrence was 14.6% LAP and 16.7% OPEN.Disease-free survival was impacted by unsuccessful resection (hazard ratio [HR] 1.87, 95% CI 1.21-2.91): composite of incomplete specimen (HR 1.65, 95% CI 0.85-3.18); positive circumferential resection margins (HR 2.31, 95% CI 1.40-3.79); positive distal margin (HR 2.53, 95% CI 1.30-3.77). CONCLUSION: Laparoscopic assisted resection of rectal cancer was not found to be significantly different to OPEN resection of rectal cancer based on the outcomes of DFS and recurrence.

Sankaranarayanan, G., L. Wooley, D. Hogg, D. Dorozhkin, J. Olasky, S. Chauhan, J. W. Fleshman, S. De, D. Scott and D. B. Jones (2018). “Immersive virtual reality-based training improves response in a simulated operating room fire scenario.” Surg Endosc 32(8): 3439-3449.

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BACKGROUND: SAGES FUSE curriculum provides didactic knowledge on OR fire prevention. The objective of this study is to evaluate the impact of an immersive virtual reality (VR)-based OR fire training simulation system in combination with FUSE didactics. METHODS: The study compared a control with a simulation group. After a pre-test questionnaire that assessed the baseline knowledge, both groups were given didactic material that consists of a 10-min presentation and reading materials about precautions and stopping an OR fire from the FUSE manual. The simulation group practiced on the OR fire simulation for one session that consisted of five trials within a week from the pre-test. One week later, both groups were reassessed using a questionnaire. A week after the post-test both groups also participated in a simulated OR fire scenario while their performance was videotaped for assessment. RESULTS: A total of 20 subjects (ten per group) participated in this IRB approved study. Median test scores for the control group increased from 5.5 to 9.00 (p = 0.011) and for the simulation group it increased from 5.0 to 8.5 (p = 0.005). Both groups started at the same baseline (pre-test, p = 0.529) and reached similar level in cognitive knowledge (post-test, p = 0.853). However, when tested in the mock OR fire scenario, 70% of the simulation group subjects were able to perform the correct sequence of steps in extinguishing the simulated fire whereas only 20% subjects in the control group were able to do so (p = 0.003). The simulation group was better than control group in correctly identifying the oxidizer (p = 0.03) and ignition source (p = 0.014). CONCLUSIONS: Interactive VR-based hands-on training was found to be a relatively inexpensive and effective mode for teaching OR fire prevention and management scenarios.

Zeidan, A. M., H. A. Knaus, T. M. Robinson, A. M. H. Towlerton, E. H. Warren, J. F. Zeidner, A. L. Blackford, A. S. Duffield, D. Rizzieri, M. G. Frattini, Y. M. Levy, M. A. Schroeder, A. Ferguson, K. E. Sheldon, A. E. DeZern, I. Gojo, S. D. Gore, H. Streicher, L. Luznik and B. D. Smith (2018). “A Multi-center Phase I Trial of Ipilimumab in Patients with Myelodysplastic Syndromes following Hypomethylating Agent Failure.” Clin Cancer Res 24(15): 3519-3527.

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Purpose: After failure of hypomethylating agents (HMA), patients with myelodysplastic syndromes (MDS) have dismal survival and no approved treatment options.Patients and Methods: We conducted a phase 1b investigator-initiated trial of ipilimumab in patients with higher risk MDS who have failed HMAs. Patients received monotherapy at two dose levels (DL; 3 and 10 mg/kg) with an induction followed by a maintenance phase. Toxicities and responses were evaluated with CTCAE.4 and IWG-2006 criteria, respectively. We also performed immunologic assays and T-cell receptor sequencing on serial samples.Results: Twenty-nine patients from 7 centers were enrolled. In the initial DL1 (3 mg), 3 of 6 patients experienced grade 2-4 immune-related adverse events (IRAE) that were reversible with drug discontinuation and/or systemic steroids. In DL2, 4 of 5 patients experienced grade 2 or higher IRAE; thus, DL1 (3 mg/kg) was expanded with no grade 2-4 IRAEs reported in 18 additional patients. Best responses included marrow complete response (mCR) in one patient (3.4%). Prolonged stable disease (PSD) for >/=46 weeks occurred in 7 patients (24% of entire cohort and 29% of those treated with 3 mg/kg dose), including 3 patients with more than a year of SD. Five patients underwent allografting without excessive toxicity. Median survival for the group was 294 days (95% CI, 240-671+). Patients who achieved PSD or mCR had significantly higher frequency of T cells expressing ICOS (inducible T-cell co-stimulator).Conclusions: Our findings suggest that ipilimumab dosed at 3 mg/kg in patients with MDS after HMA failure is safe but has limited efficacy as a monotherapy. Increased frequency of ICOS-expressing T cells might predict clinical benefit. Clin Cancer Res; 24(15); 3519-27.

Wu, T. C., K. Xu, J. Martinek, R. R. Young, R. Banchereau, J. George, J. Turner, K. I. Kim, S. Zurawski, X. Wang, D. Blankenship, H. M. Brookes, F. Marches, G. Obermoser, E. Lavecchio, M. K. Levin, S. Bae, C. H. Chung, J. L. Smith, A. M. Cepika, K. L. Oxley, G. J. Snipes, J. Banchereau, V. Pascual, J. O’Shaughnessy and K. Palucka (2018). “IL-1 receptor antagonist controls transcriptional signature of inflammation in patients with metastatic breast cancer.” Cancer Res Jul 16. [Epub ahead of print].

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Inflammation affects tumor immune surveillance and resistance to therapy. However, no approved treatments aimed at decreasing chronic tumor-associated inflammation are available, largely due to incomplete understanding of pathogenesis. Here we show that production of interleukin (IL)-1beta in primary breast cancer (BC) tumors is linked to advanced disease and originates from tumor-infiltrating CD11c+ myeloid cells. IL-1beta production was triggered by cancer cell membrane-derived TGF-beta, and neutralizing TGF-beta or IL-1 receptor prevented BC progression in a humanized mouse model. Patients with metastatic HER2-negative BC displayed a transcriptional signature of inflammation in the blood leukocytes, which was attenuated by IL-1 blockade. When present in primary BC tumors, this signature discriminated patients with poor clinical outcomes in two independent public datasets (TCGA and METABRIC).