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Background: Increasing opioid-related deaths have heightened focus on combating the opioid epidemic. The impact of surgical trainees on opioid-related deaths is unclear, and there is little data examining the association between trainee pain management education and opioid prescribing practices. Methods: An anonymous, online survey was distributed to members of the Resident and Associate Society of the American College of Surgeons. The survey covered five themes: education and knowledge, prescribing practices, clinical case scenarios, policy, and beliefs and attitudes. Linear mixed models were used to evaluate the influence of respondent characteristics on reported morphine milligram equivalents (MME) prescribed for common general surgery clinical scenarios. Results: Of 427 respondents, 54 percent indicated receiving training in postoperative pain management during medical school and 66 percent during residency. Only 35 percent agreed that they had received adequate training in prescribing opioids. There was a significant association between undergoing formal pain management training in medical school and prescribing fewer MME for common outpatient general surgery scenarios (94 ± 15.2 vs 108 ± 15.0; p = 0.003). Similarly, formal pain management training in residency was associated with prescribing fewer MME in the survey scenarios (92.6 ± 15.2 vs 109 ± 15.2; p = 0.002). Conclusion: In this survey, nearly two-thirds of surgical residents felt that they were inadequately trained in opioid prescribing. Our findings additionally suggest that improving education may result in increased resident comfort with managing surgical pain, potentially leading to more responsible opioid prescribing. Further work will facilitate residency programs’ development of educational curricula for opioid prescribing best practices.

Effective chimeric antigen receptor-modified T-cell (CAR-T) therapy for liver metastases (LM) will require innovative solutions to ensure efficient delivery and minimization of systemic toxicity. We previously demonstrated the safety of CAR-T hepatic artery infusions (HAI). We subsequently conducted the phase 1b HITM-SIR trial, in which six patients (pts) with CEA+ LM received anti-CEA CAR-T HAIs and selective internal radiation therapy (SIRT). The primary endpoint was safety with secondary assessments of biologic activity. Enrolled pts had a mean LM size of 6.4 cm, 4 pts had >10 LM, and pts received an average of two lines of prior systemic therapy. No grade 4 or 5 toxicities were observed, and there were no instances of severe cytokine-release syndrome (CRS) or neurotoxicity. The mean transduction efficiency was 60.4%. Following CAR-T HAI, reduced levels of GM-CSF-R, IDO, and PD-L1 were detected in LM, and serum CEA levels were stable or decreased in all subjects. Median survival time was 8 months (mean 11, range 4–31). Anti-CEA CAR-T HAI with subsequent SIRT was well tolerated, and biologic responses were demonstrated following failure of conventional therapy. HAI of CAR-T was once again confirmed not to be associated with severe CRS or neurotoxicity.

Metastatic liver tumors have presented challenges with the use of checkpoint inhibitors (CPIs), with only limited success. We hypothesize that regional delivery (RD) of CPIs can improve activity in the liver and minimize systemic exposure, thereby reducing immune-related adverse events (irAE). Using a murine model of colorectal cancer liver metastases (LM), we confirmed high levels of PD-L1 expression on the tumor cells and liver myeloid-derived suppressor cells (L-MDSC). In vivo, we detected improved LM response at 3 mg/kg on PTD7 via portal vein (PV) regional delivery as compared to 3 mg/kg via tail vein (TV) systemic delivery (p = 0.04). The minimal effective dose at PTD7 was 5 mg/kg (p = 0.01) via TV and 0.3 mg/kg (p = 0.02) via PV. We detected 6.7-fold lower circulating CPI antibody levels in the serum using the 0.3 mg/kg PV treatment compared to the 5 mg/kg TV cohort (p &lt, 0.001) without increased liver toxicity. Additionally, 3 mg/kg PV treatment resulted in increased tumor cell apoptotic signaling compared to 5 mg/kg TV (p &lt, 0.05). Therefore, RD of an anti-PD-1 CPI therapy for CRCLM may improve the therapeutic index by reducing the total dose required and limiting the systemic exposure. These advantages could expand CPI indications for liver tumors.

In recent years, cell therapy technologies have resulted in impressive results in hematologic malignancies. Treatment of solid tumors with chimeric antigen receptor T-cells (CAR-T) has been less successful. Solid tumors present challenges not encountered with hematologic cancers, including high intra-tumoral pressure and ineffective CAR-T trafficking to the site of disease. Novel delivery methods may enable CAR-T therapies for solid tumor malignancies. A patient with liver metastases secondary to pancreatic adenocarcinoma received CAR-T targeting carcinoembryonic antigen (CEA). Previously we reported that Pressure-Enabled Drug Delivery (PEDD) enhanced CAR-T delivery to liver metastases 5.2-fold. Three doses of anti-CEA CAR-T were regionally delivered via hepatic artery infusion (HAI) using PEDD technology to optimize the therapeutic index. Interleukin-2 was systemically delivered by continuous intravenous infusion to support CAR-T in vivo. HAI of anti-CEA CAR-T was not associated with any serious adverse events (SAEs) above grade 3 and there were no on-target/off-tumor SAEs. Following CAR-T treatment, positron emission tomography-CT demonstrated a complete metabolic response within the liver, which was durable and sustained for 13 months. The response was accompanied by normalization of serum tumor markers and an abundance of CAR+ cells found within post-treatment tumor specimens. The findings from this report exhibit biologic activity and safety of regionally infused CAR-T for an indication with limited immune-oncology success to date. Further studies will determine how HAI of CAR-T may be included in multidisciplinary treatment plans for patients with liver metastases. ClinicalTrials.gov number, NCT02850536.

We studied prevalence and predictors of meaningful self-reflection among surgical residents and with prompting/structured interventions, sought to improve/sustain resident skills.Residents from six programs recorded 1032 narrative self-reflective comments (120 residents), using a web-based platform. If residents identified something learned or to be improved, self-reflection was deemed meaningful. Independent variables PGY level, resident/surgeon gender, study site/Phase1: July2014-August2015 vs. Phase2: September2015-September2016) were analyzed.Meaningful self-reflection was documented in 40.6% (419/1032) of entries. PGY5's meaningfully self-reflected less than PGY1-4's, 26.1% vs. 49.6% (p = 0.002). In multivariate analysis, resident narratives during Phase 2 were 4.7 times more likely to engage in meaningful self-reflection compared to Phase1 entries (p 0.001). Iterative changes during Phase2 showed a 236% increase in meaningful self-reflection, compared to Phase1.Surgical residents uncommonly practice meaningful self-reflection, even when prompted, and PGY5/chief residents reflect less than more junior residents. Substantial/sustained improvements in resident self-reflection can occur with both training and interventions.

Background Gender and/or gender-stereotypes might influence surgical education. We hypothesized that female surgeons might focus their learning and teaching differently from male surgeons. Methods Residents and surgeons (multi-institutional) individually recorded preoperatively discussed learning objectives (LO) for matching cases. Narratives were classified as knowledge-based, skill-based, or attitude-based. Multinomial logistic regression analyses, LO = dependent variable; independent variables = resident/surgeon gender, PGY level, timing of entry-to-procedure date, and quarters-of-year. Results 727 LOs from 125 residents (41% female) and 49 surgeons (20% female) were classified. Female residents were 1.4 times more likely to select knowledge over skill. With female surgeons, residents were 1.6 and 2.1 times more likely to select knowledge over skill and attitude over skill than if the surgeon was male. PGY 4/5 residents chose attitude-based LOs over junior residents. Conclusion Resident, surgeon gender and year-of-training influence learning objectives. Whether this reflects gender stereotyping by residents or differences in attending teaching styles awaits further exploration.

Resident and curriculum evaluation require tracking surgical resident operative performance, yet what and when to measure remains unclear.From a multi-institutional database, we reviewed 611 resident/surgeon-paired assessments of ACGME Milestones and modified OPRS ratings for different cases and postgraduate years.Faculty Milestone ratings increased with each PGY (p=0.001) and correlated with resident self-ratings (ICC = 0.83). Mean OPRS scores increased in small increments with substantial intra-year variability. Progression among individual OPRS subcategories was not apparent from more global analyses. Interestingly, male faculty offered lower ratings than female faculty.Milestones and modified mean OPRS ratings suggest residents are learning, yet lack sufficient discrimination for promotion or curricular analysis. Differential progression through OPRS subcategories suggests a taxonomy of surgical learning that can be tailored to focus on different skills at each point in the training continuum. The effect of faculty gender on resident ratings awaits further study.

Adrenocortical oncocytic neoplasms are rare tumors, generally regarded as benign and hormonally nonfunctional. We performed a systematic review to update the literature on adrenocortical oncocytic neoplasms by reviewing patient and tumor characteristics, as well as management trends, because the literature is composed of predominately single-case reports.A systematic search was performed in PubMed, Embase, and Cochrane Library through June 2017. Malignant potential was determined by applying the Lin-Weiss-Bisceglia criteria to cases.Included for analysis were 84 citations describing 140 adrenocortical oncocytic neoplasms, including our own case. These were diagnosed predominantly in females (66%), on the left side (64%), and were nonfunctional (66%). Average age at diagnosis was 44 years (2.5-77), and median tumor size was 80 mm (16-285). A total of 35% of adrenocortical oncocytic neoplasms were benign, 41% borderline, and 24% malignant. Male patients were more likely to have a malignant tumor compared with females (36% versus 18%, P = .035). The 5-year overall survival for benign adrenocortical oncocytic neoplasms was 100%, borderline 88%, and malignant 47%. Hormonal function did not discriminate malignant from benign lesions. Adrenocortical oncocytic neoplasms that stained positive for synaptophysin (50%, P.001) and negative for vimentin (62%, P = .009) are more often benign.We found that the majority of adrenocortical oncocytic neoplasms (65%) were either malignant or had malignant potential, contrary to the previous literature. The Lin-Weiss-Bisceglia criteria are useful in identifying those patients for whom closer surveillance is warranted, because their prognosis is dependent on the Lin-Weiss-Bisceglia diagnosis.

It is increasingly important for faculty to teach deliberately and provide timely, detailed, and formative feedback on surgical trainee performance. We initiated a multicenter study to improve resident evaluative processes and enhance teaching and learning behaviors while engaging residents in their education.Faculty from 7 US postgraduate training programs rated resident operative performances using the perioperative briefing, intraoperative teaching, debriefing model, and rated patient visits/academic performances using the entrustable professional activities model via a web-based platform. Data were centrally analyzed and iterative changes made based on participant feedback, individual preferences, and database refinements, with trends addressed using the Plan, Do, Check, Act improvement methodology.Participants (92 surgeons, 150 residents) submitted 3,880 assessments during July 2014 through September 2017. Evidence of preoperative briefings improved from 33.9% ± 2.5% to 95.5% ± 1.5% between April and September 2014 compared with April and September 2017 (p0.001). Postoperative debriefings improved from 10.6% ± 2.7% to 90.2% ± 2.5% (p0.001) for the same period. Meaningful self-reflection by residents improved from 28.6% to 67.4% (p0.001). The number of assessments received per resident during a 6-month period increased from 6.4 ± 6.2 to 13.4 ± 10.1 (p0.003). Surgeon-entered assessments increased from 364 initially to 685 in the final period, and the number of resident assessments increased from 308 to 445. We showed a 4-fold increase in resident observed activities being rated.By adopting recognized educational models with repeated Plan, Do, Check, Act cycles, we increased the quality of preoperative learning objectives, showed more frequent, detailed, and timely assessments of resident performance, and demonstrated more effective self-reflection by residents. We monitored trends, identified opportunities for improvement and successfully sustained those improvements over time, applying a team-based approach.

Primary neonatal T cell responses comprise both T helper (Th) cell subsets, but Th1 cells express high levels of interleukin 13 receptor alpha1 (IL-13R alpha 1), which heterodimerizes with IL-4R alpha. During secondary antigen challenge, Th2-produced IL-4 triggers the apoptosis of Th1 cells via IL-4R alpha/IL-13R alpha 1, thus explaining the Th2 bias in neonates. We show that neonates acquire the ability to overcome the Th2 bias and generate Th1 responses starting 6 d after birth. This transition was caused by the developmental maturation of CD8 alpha(+)CD4(-) dendritic cells (DCs), which were minimal in number during the first few days of birth and produced low levels of IL-12. This lack of IL-12 sustained the expression of IL-13R alpha 1 on Th1 cells. By day 6 after birth, however, a significant number of CD8 alpha(+)CD4(-) DCs accumulated in the spleen and produced IL-12, which triggered the down-regulation of IL-13R alpha 1 expression on Th1 cells, thus protecting them against IL-4-driven apoptosis.

Aman aged 54 years,who had not seen a physician for nearly 10 years, presented to the emergency department with a 1-month history of generalized weakness and bilateral lower extremity swelling that had progressed to his upper abdomen. Physical examination revealed at least 4 lower extremity edemas and an abdomen that was large, taut, and distended (Figure 1A). A computed tomographic scan of the chest, abdomen, and pelvis was obtained (Figure 1B). A