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Penn Evidence-Based Literature Review (PEBLR)
Summarized highlights from contemporary literature in surgical and allied disciplines for general surgery residents.
March - June 2017
  1. Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma
    Faries MB et al, MSLT-2 investigators. N Engl J Med. 2017 June (PDF)
    Contributor: Jash Datta
    Discipline: Endocrine & Oncologic Surgery

Brief Summary
Synopsis: In the first Multicenter Selective Lymphadenectomy Trial (MSLT-1), among patients with intermediate thickness melanomas (1.2-3.5 mm) and nodal metastases, early surgical treatment guided by sentinel-node biopsy (SNB) was associated with increased melanoma-specific survival (MSS). The goal of the MSLT-2 trial was to evaluate whether immediate completion nodal dissection (CND) improved MSS compared with nodal observation (and nodal dissection if needed in those with clinically detected nodal relapse). The authors randomized 1755 pts (per-protocol analysis) to CND vs observation; primary end-point was MSS, and secondary end-points included disease-free survival (DFS) and the cumulative rate of nonsentinel-node metastasis. At a median follow-up of 43 months, the mean 3-year rate of MSS was similar in CND vs observation groups (86% in both, p=0.42). DFS was slightly higher in CND vs observation group (68±1.7% vs. 63±1.7%), but this was driven largely by increased rate of disease control in regional nodes. Lymphedema was observed in 24.1% in the CND group and in 6.3% in the observation group. These data provide rather definitive evidence that immediate CND should be abandoned as routine practice in SNB-positive melanoma. Moreover, nodal recurrence does not equate to loss of regional control, so interval CND can still be applied to patients with nodal relapse while undergoing active surveillance. A significant limitation of this study is that authors do not comment on the distinction between node-only and node-any recurrence-- identification of patients with biologically "nodotrophic" disease (vs concomitant systemic failure) at the time of SNB could potentially allow selective application of immediate CND in this subset. Finally, all current adjuvant therapy trials assume knowledge of non-sentinel nodal status, so selection of adjuvant therapies in patients with SNB-positive melanoma who do NOT undergo immediate CND remains a fertile arena for further investigation.    
  1. Mismatch-repair deficiency predicts response of solid tumors to PD-1 blockade
    Le DT et al., Science 2017 May (PDF)
    Contributor: Brett Ecker
    Discipline: Cancer Biology/Immunotherapy

Brief Summary
Synopsis: Therapy response to immune checkpoint inhibitors (e.g., anti-PD- 1 antibody) is hypothesized to be dependent upon recognition of tumor-specific antigens by the adaptive immune system. Mismatch-repair (MMR) deficient cancers have a large number of mutation-derived tumor antigens, and thus may be an effective target for checkpoint inhibitors. In a prospective Phase II trial of pembrolizumab therapy, 86 patients with metastatic MMR-deficient cancers (12 cancer types; 47% colorectal) were evaluated for radiographic response (RECIST), progression-free survival (PFS) and overall survival (OS) at 20 weeks. Twenty-one percent achieved a complete radiographic response, and disease control (stable/regressing disease) was achieved in 77%. At a median of 12.5 months, median PFS nor median OS has yet been reached. In a subset of therapy-responsive patients (n=3), intratumoral T cell clones were identified that were often undetectable in the peripheral blood before treatment, but rapidly increased after pembrolizumab initiation. A major limitation of this study is the small numbers of each tumor type represented (excluding colon cancer), although these preliminary data suggest that MMR-deficiency might be considered to guide rationale therapy paradigms, regardless of tumor type.
  1. Time to Appendectomy and Risk of Complicated Appendicitis and Adverse Outcomes in Children
    Serres SK et al., JAMA Pediatrics 2017 June (PDF)
    Contributor: Robert Swendiman
    Discipline: Pediatric Surgery

Brief Summary
Synopsis: Appendicitis is the most common and most costly surgical disease in the pediatric population. Complicated appendicitis is particularly costly, and is observed in approximately 30% of patients treated operatively. Increasingly, appendicitis is being treated as an "urgent" rather than "emergent" operation in children. Prior data has been conflicting on whether delayed surgical care increases the likelihood of complicated disease. Thus, the authors designed a retrospective cohort study using the Pediatric National Surgical Quality Improvement Program (P-NSQUIP) database, including 2,429 patients <18 years who underwent appendectomy within 24 hours of presentation at 23 children’s hospitals over a two year period. Median time to appendectomy (TTA) was 7.4 hours in 23 hospitals. In all hospitals but one, TTA within 24 hours was not associated with an increased risk of complicated appendicitis or post-complications, suggesting that operative treatment of appendicitis can be performed urgently rather than emergently. These data also suggest that timely administration of antibiotics play an important role in halting the progression of early appendicitis to more complicated presentations, which has been demonstrated in other studies. It is important to note, however, that ~4,000 patients were excluded from the study due to patient transfer from an outside hospital, those who underwent CT as part of their evaluation, or due to missing medical record data. Prehospital delay may be much more important in the development of complicated appendicitis than TTA.
  1. Intraoperative ketamine for prevention of postoperative delirium or pain after major surgery in older adults: an international, multicentre, double-blind, randomised clinical trial
    Avidan et al., Lancet 2017 May (PDF)
    Contributor: Grace Lee
    Discipline: Perioperative Medicine

Brief Summary
Synopsis: The pathophysiology of postoperative delirium, the most common perioperative neurological complication, is poorly understood, restricting prevention efforts. In systematic reviews of smaller studies assessing subanesthetic doses of IV ketamine, inflammation, pain, opioid consumption, and rates of delirium are decreased. The authors conducted an international double-blind randomized placebo-controlled trial (PODCAST) assessing the effect of two different intraoperative doses of subanesthetic IV ketamine on postoperative delirium (primary outcome) and postoperative pain and opioid consumption (secondary outcome) in patients age >60 yrs undergoing major surgery (cardiac or non-cardiac). Results demonstrated no statistical difference in both the primary and secondary outcomes of the study between placebo group and any dose of IV ketamine. The rate of delirium ranged from 19.82% in placebo versus 17.65% and 21.30% in the two ketamine groups. The patients receiving ketamine had a higher rate of hallucinations (18% placebo versus 20% and 28% in ketamine groups) and nightmares compared to placebo. The findings and implications of this study are fairly convincing, generalizable, and the most methodologically rigorous of any study assessing the effect of intraoperative ketamine on delirium in elderly surgical patients. The major point of caution in this study is that the findings of no effect on postoperative pain and opioid consumption are contrary to a significant body of previous literature. The study did not undertake this outcome as a primary outcome and was not designed to answer this specific question, warranting further research.  
  1. Trends in Reoperation After Initial Lumpectomy for Breast Cancer: Addressing Overtreatment in Surgical Management
    Morrow M et al., JAMA Oncology 2017 June  (PDF)
    Contributor: Andrew Newton
    Discipline: Endocrine & Oncologic Surgery
Brief Summary
Synopsis: This is a population based cohort survey analysis of trends in surgical treatment of breast cancer since 2014 consensus guidelines defined a negative margin in patients treated with lumpectomy and radiation as “no ink on tumor.” The study included 3729 women aged 20-79 with stage I or II invasive unilateral breast cancer diagnosed between 2013 and 2015 from the Georgia and LA County, California SEER databases and 342 of their surgeons. Patients reported their surgical treatment sequence while surgeons gave opinions on adequate lumpectomy margins in 2 clinical scenarios. The initial lumpectomy rate of 67% did not change over time after adjusting for covariates. Meanwhile, the rate of final lumpectomy increased from 52% to 65% and the rates of unilateral and bilateral mastectomy decreased from 27% to 18% and 21% to 16%, respectively, from 2013-2015. The rates of post-lumpectomy re-excision and post-lumpectomy mastectomy decreased from 21% to 14% and 13% to 4%, respectively, from 2013-2015. Surgeons who performed more breast surgery were more likely to consider “no ink on tumor” an adequate margin in the 2 clinical scenarios. The major limitation is the reliance on patient report of surgical procedures. The long-term oncologic impact of this more limited surgical resection strategy remains to be seen.

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