Rachel Rosenthal

The timing of surgical antimicrobial prophylaxis.

Objective:To obtain precise information on the optimal time window for surgical antimicrobial prophylaxis. Summary Background Data:Although perioperative antimicrobial prophylaxis is a well-established strategy for reducing the risk of surgical site infections (SSI), the optimal timing for this procedure has yet to be precisely determined. Under todays recommendations, antibiotics may be administered within the final 2 hours before skin incision, ideally as close to incision time as possible. Methods:In this prospective observational cohort study at Basel University Hospital we analyzed the incidence of SSI by the timing of antimicrobial prophylaxis in a consecutive series of 3836 surgical procedures. Surgical wounds and resulting infections were assessed to Centers for Disease Control and Prevention standards. Antimicrobial prophylaxis consisted in single-shot administration of 1.5 g of cefuroxime (plus 500 mg of metronidazole in colorectal surgery). Results:The overall SSI rate was 4.7% (180 of 3836). In 49% of all procedures antimicrobial prophylaxis was administered within the final half hour. Multivariable logistic regression analyses showed a significant increase in the odds of SSI when antimicrobial prophylaxis was administered less than 30 minutes (crude odds ratio = 2.01; adjusted odds ratio = 1.95; 95% confidence interval, 1.4–2.8; P < 0.001) and 120 to 60 minutes (crude odds ratio = 1.75; adjusted odds ratio = 1.74; 95% confidence interval, 1.0–2.9; P = 0.035) as compared with the reference interval of 59 to 30 minutes before incision. Conclusions:When cefuroxime is used as a prophylactic antibiotic, administration 59 to 30 minutes before incision is more effective than administration during the last half hour.

Surgical Glove Perforation and the Risk of Surgical Site Infection

HYPOTHESIS Clinically apparent surgical glove perforation increases the risk of surgical site infection (SSI). DESIGN Prospective observational cohort study. SETTING University Hospital Basel, with an average of 28,000 surgical interventions per year. PARTICIPANTS Consecutive series of 4147 surgical procedures performed in the Visceral Surgery, Vascular Surgery, and Traumatology divisions of the Department of General Surgery. MAIN OUTCOME MEASURES The outcome of interest was SSI occurrence as assessed pursuant to the Centers of Disease Control and Prevention standards. The primary predictor variable was compromised asepsis due to glove perforation. RESULTS The overall SSI rate was 4.5% (188 of 4147 procedures). Univariate logistic regression analysis showed a higher likelihood of SSI in procedures in which gloves were perforated compared with interventions with maintained asepsis (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.4-2.8; P < .001). However, multivariate logistic regression analyses showed that the increase in SSI risk with perforated gloves was different for procedures with vs those without surgical antimicrobial prophylaxis (test for effect modification, P = .005). Without antimicrobial prophylaxis, glove perforation entailed significantly higher odds of SSI compared with the reference group with no breach of asepsis (adjusted OR, 4.2; 95% CI, 1.7-10.8; P = .003). On the contrary, when surgical antimicrobial prophylaxis was applied, the likelihood of SSI was not significantly higher for operations in which gloves were punctured (adjusted OR, 1.3; 95% CI, 0.9-1.9; P = .26). CONCLUSION Without surgical antimicrobial prophylaxis, glove perforation increases the risk of SSI.

Prevalence, Characteristics, and Publication of Discontinued Randomized Trials

IMPORTANCE The discontinuation of randomized clinical trials (RCTs) raises ethical concerns and often wastes scarce research resources. The epidemiology of discontinued RCTs, however, remains unclear. OBJECTIVES To determine the prevalence, characteristics, and publication history of discontinued RCTs and to investigate factors associated with RCT discontinuation due to poor recruitment and with nonpublication. DESIGN AND SETTING Retrospective cohort of RCTs based on archived protocols approved by 6 research ethics committees in Switzerland, Germany, and Canada between 2000 and 2003. We recorded trial characteristics and planned recruitment from included protocols. Last follow-up of RCTs was April 27, 2013. MAIN OUTCOMES AND MEASURES Completion status, reported reasons for discontinuation, and publication status of RCTs as determined by correspondence with the research ethics committees, literature searches, and investigator surveys. RESULTS After a median follow-up of 11.6 years (range, 8.8-12.6 years), 253 of 1017 included RCTs were discontinued (24.9% [95% CI, 22.3%-27.6%]). Only 96 of 253 discontinuations (37.9% [95% CI, 32.0%-44.3%]) were reported to ethics committees. The most frequent reason for discontinuation was poor recruitment (101/1017; 9.9% [95% CI, 8.2%-12.0%]). In multivariable analysis, industry sponsorship vs investigator sponsorship (8.4% vs 26.5%; odds ratio [OR], 0.25 [95% CI, 0.15-0.43]; P < .001) and a larger planned sample size in increments of 100 (-0.7%; OR, 0.96 [95% CI, 0.92-1.00]; P = .04) were associated with lower rates of discontinuation due to poor recruitment. Discontinued trials were more likely to remain unpublished than completed trials (55.1% vs 33.6%; OR, 3.19 [95% CI, 2.29-4.43]; P < .001). CONCLUSIONS AND RELEVANCE In this sample of trials based on RCT protocols from 6 research ethics committees, discontinuation was common, with poor recruitment being the most frequently reported reason. Greater efforts are needed to ensure the reporting of trial discontinuation to research ethics committees and the publication of results of discontinued trials.

Differential effects of the tryptophan metabolite 3-hydroxyanthranilic acid on the proliferation of human CD8 + T cells induced by TCR triggering or homeostatic cytokines

Production of indoleamine 2,3‐dioxygenase (IDO) by tumor cells, leading to tryptophan depletion and production of immunosuppressive metabolites, may facilitate immune tolerance of cancer. IDO gene is also expressed in dendritic cells (DC) upon maturation induced by lipopolysaccarides or IFN. We investigated IDO gene expression in melanoma cell lines and clinical specimens as compared to mature DC (mDC). Furthermore, we explored effects of L‐kynurenine (L‐kyn) and 3‐hydroxyanthranilic acid (3‐HAA) on survival and antigen‐dependent and independent proliferation of CD8+ cells. We observed that IDO gene expression in cultured tumor cells and freshly excised samples is orders of magnitude lower than in mDC, providing highly efficient antigen presentation to CD8+ T cells. Non toxic concentrations of L‐kyn or 3‐HAA did not significantly inhibit antigen‐specific CTL responses. However, 3‐HAA, but not L‐kyn markedly inhibited antigen‐independent proliferation of CD8+ T cells induced by common receptor γ‐chain cytokines IL‐2, ‐7 and ‐15. Our data suggest that CD8+ T cell activation induced by antigenic stimulation, a function exquisitely fulfilled by mDC, is unaffected by tryptophan metabolites. Instead, in the absence of effective T cell receptor triggering, 3‐HAA profoundly affects homeostatic proliferation of CD8+ T cells.

Cancer/testis antigen expression and specific cytotoxic T lymphocyte responses in non small cell lung cancer.

Non small cell lung cancers (NSCLC) express cancer/testis antigens (CTA) genes and MAGE‐A expression correlates with poor prognosis in squamous cell carcinomas. We addressed cytotoxic T lymphocytes (CTL) responses to HLA class I restricted CTA epitopes in TIL from NSCLC in an unselected group of 33 patients consecutively undergoing surgery. Expression of MAGE‐A1, ‐A2, ‐A3, ‐A4, ‐A10, ‐A12 and NY‐ESO‐1 CTA genes was tested by quantitative RT‐PCR. Monoclonal antibodies (MAb) recognizing MAGE‐A and NY‐ESO‐1 CTA were used to detect CTA by immunohistochemistry. CD8+ TIL obtained from tumors upon culture with anti CD3 and anti CD28 mAb and IL‐2 were stimulated with autologous mature DC (mDC) and HLA‐A*0101 restricted MAGE‐A1161–169 or MAGE‐A3168–176 peptides or HLA‐A*0201 restricted MAGE‐A4230–239, MAGE‐A10254–262, NY‐ESO‐1157–165 or multi‐MAGE‐A (YLEYRQVPV) peptides or a recombinant vaccinia virus (rVV) encoding MAGE‐A and NY‐ESO‐1 HLA‐A*0201 restricted epitopes and CD80 co‐stimulatory molecule. Specificity was assessed by 51Cr release and multimer staining. At least one CTA gene was expressed in tumors from 15/33 patients. In 10 specimens, at least 4 CTA genes were concomitantly expressed. These data were largely confirmed by immunohistochemistry. TIL were expanded from 26/33 specimens and CTA‐specific CTL activity was detectable in 7/26 TIL. In 6, however, specific cytotoxicity was weak, (<40% lysis at a 50:1 E:T ratio) and multimer staining was undetectable. In one case, high (>60% lysis at 50:1 E:T ratio) MAGE‐A10254–262 specific, HLA‐A*0201 restricted response was observed. Supportive evidence was provided by corresponding multimer staining. Although CTA genes are frequently expressed in NSCLC, detection of CTL reactivity against CTA epitopes in TIL from nonimmunized NSCLC patients represents a rare event.

Can skills assessment on a virtual reality trainer predict a surgical trainee’s talent in laparoscopic surgery?

BackgroundA number of studies have investigated several aspects of feasibility and validity of performance assessments with virtual reality surgical simulators. However, the validity of performance assessments is limited by the reliability of such measurements, and some issues of reliability still need to be addressed. This study aimed to evaluate the hypothesis that test subjects show logarithmic performance curves on repetitive trials for a component task of laparoscopic cholecystectomy on a virtual reality simulator, and that interindividual differences in performance after considerable training are significant. According to kinesiologic theory, logarithmic performance curves are expected and an individual’s learning capacity for a specific task can be extrapolated, allowing quantification of a person’s innate ability to develop task-specific skills.MethodsIn this study, 20 medical students at the University of Basel Medical School performed five trials of a standardized task on the LS 500 virtual reality simulator for laparoscopic surgery. Task completion time, number of errors, economy of instrument movements, and maximum speed of instrument movements were measured.ResultsThe hypothesis was confirmed by the fact that the performance curves for some of the simulator measurements were very close to logarithmic curves, and there were significant interindividual differences in performance at the end of the repetitive trials.ConclusionsAssessment of perceptual motor skills and the innate ability of an individual with no prior experience in laparoscopic surgery to develop such skills using the LS 500 VR surgical simulator is feasible and reliable.

Subgroup analyses in randomised controlled trials: cohort study on trial protocols and journal publications

Objective To investigate the planning of subgroup analyses in protocols of randomised controlled trials and the agreement with corresponding full journal publications. Design Cohort of protocols of randomised controlled trial and subsequent full journal publications. Setting Six research ethics committees in Switzerland, Germany, and Canada. Data sources 894 protocols of randomised controlled trial involving patients approved by participating research ethics committees between 2000 and 2003 and 515 subsequent full journal publications. Results Of 894 protocols of randomised controlled trials, 252 (28.2%) included one or more planned subgroup analyses. Of those, 17 (6.7%) provided a clear hypothesis for at least one subgroup analysis, 10 (4.0%) anticipated the direction of a subgroup effect, and 87 (34.5%) planned a statistical test for interaction. Industry sponsored trials more often planned subgroup analyses compared with investigator sponsored trials (195/551 (35.4%) v 57/343 (16.6%), P<0.001). Of 515 identified journal publications, 246 (47.8%) reported at least one subgroup analysis. In 81 (32.9%) of the 246 publications reporting subgroup analyses, authors stated that subgroup analyses were prespecified, but this was not supported by 28 (34.6%) corresponding protocols. In 86 publications, authors claimed a subgroup effect, but only 36 (41.9%) corresponding protocols reported a planned subgroup analysis. Conclusions Subgroup analyses are insufficiently described in the protocols of randomised controlled trials submitted to research ethics committees, and investigators rarely specify the anticipated direction of subgroup effects. More than one third of statements in publications of randomised controlled trials about subgroup prespecification had no documentation in the corresponding protocols. Definitive judgments regarding credibility of claimed subgroup effects are not possible without access to protocols and analysis plans of randomised controlled trials.

The association of preoperative anemia and perioperative allogeneic blood transfusion with the risk of surgical site infection

BACKGROUND: The purpose of the study was to investigate allogeneic blood transfusion (ABT) and preoperative anemia as risk factors for surgical site infection (SSI).

Comparison of randomized controlled trial registry entries and content of reports in surgery journals.

Objective:To evaluate discrepancies between trial registry entries and final reports of randomized controlled trials (RCTs) published in major general surgical journals. Background:Health care decisions are based on published results in peer-reviewed journals. Mandatory trial registration was introduced to increase transparency and reduce publication and outcome reporting bias. Methods:The discrepancy rate between trial registry entries and final reports of all RCTs published during 2010 in the Annals of Surgery, Archives of Surgery, and British Journal of Surgery was evaluated. Results:Of 596 identified studies, 545 were excluded because they were not RCTs or interim reports/secondary analysis of RCTs or because of missing trial registry information.In the remaining 51 RCTs, prospective registration was found in 9.8% (n = 5), registration during trial conduct in 33.3% (n = 17), and retrospective registration in 56.9% (n = 29), respectively.For the primary and secondary outcomes, there was no discrepancy in 54.9% and 33.3%, complete omission in 7.8% and 31.3%, new introduction in 7.8% and 39.2%, a change in definition in 9.8% and 5.8%, downgrading from primary to secondary in 21.6%, and upgrading from secondary to primary in 13.7%. There were few discrepancies in randomization, blinding, and intervention and some in targeted sample size and inclusion/exclusion criteria. Conclusions:When interpreting the results of surgical RCTs, the possibility of selective reporting, and thus outcome reporting bias, has to be kept in mind. For future trials, prospective registration should be strictly respected with the ultimate goal to increase transparency and contribute to high-level evidence reports for optimal patient care in surgery.

Intranodal immunization with a vaccinia virus encoding multiple antigenic epitopes and costimulatory molecules in metastatic melanoma.

Recombinant vaccinia virus (rVV) encoding tumor-associated antigens (TAAs) and adhesion or costimulatory molecules may represent important immunogenic reagents for cancer immunotherapy. Recently, intranodal (IN) antigen administration was suggested to be more immunogenic than intradermal (ID) vaccination. However, IN rVV administration has not been attempted so far. We used a rVV encoding gp100(280-288), Melan-A/MART-1(27-35) and tyrosinase(1-9) HLA-A0201 restricted epitopes and CD80 and CD86 costimulatory molecules in stage III and IV melanoma patients in a phase 1/2 trial. Of 15 patients initiating treatment, including two cycles of IN immunization, each comprising one rVV administration and three recall injections of the corresponding peptides, accompanied by subcutaneous granulocyte macrophage-colony stimulating factor supplementation, five withdrew due to progressing disease. Of 10 remaining patients seven showed evidence of induction of cytotoxic T lymphocytes (CTLs) directed against at least one epitope under investigation, as detectable by limiting dilution analysis (LDA) of specific precursors and multimer staining. Adverse reactions were mild (National Cancer Institute (NCI) grade 1-2) and mainly represented by fever, skin rashes, and pruritus. These data indicate that IN administration of rVV encoding melanoma-associated epitopes and costimulatory molecules is safe and immunogenic.