Shaun C. Daly

Development and validation of a plasma biomarker panel for discerning clinical significance of indeterminate pulmonary nodules.

Introduction: The recent findings of the National Lung Screening Trial showed 24.2% of individuals at high risk for lung cancer having one or more indeterminate nodules detected by low-dose computed tomography–based screening, 96.4% of which were eventually confirmed as false positives. These positive scans necessitate additional diagnostic procedures to establish a definitive diagnosis that adds cost and risk to the paradigm. A plasma test able to assign benign versus malignant pathology in high-risk patients would be an invaluable tool to complement low-dose computed tomography–based screening and promote its rapid implementation. Methods: We evaluated 17 biomarkers, previously shown to have value in detecting lung cancer, against a discovery cohort, comprising benign (n = 67) cases and lung cancer (n = 69) cases. A Random Forest method based analysis was used to identify the optimal biomarker panel for assigning disease status, which was then validated against a cohort from the Mayo Clinic, comprising patients with benign (n = 61) or malignant (n = 20) indeterminate lung nodules. Results: Our discovery efforts produced a seven-analyte plasma biomarker panel consisting of interleukin 6 (IL-6), IL-10, IL-1ra, sIL-2R&agr;, stromal cell-derived factor-1&agr;+&bgr;, tumor necrosis factor &agr;, and macrophage inflammatory protein 1 &agr;. The sensitivity and specificity of our panel in our validation cohort is 95.0% and 23.3%, respectively. The validated negative predictive value of our panel was 93.8%. Conclusion: We developed a seven-analyte plasma biomarker panel able to identify benign nodules, otherwise deemed indeterminate, with a high degree of accuracy. This panel may have clinical utility in risk-stratifying screen-detected lung nodules, decrease unnecessary follow-up imaging or invasive procedures, and potentially avoid unnecessary morbidity, mortality, and health care costs.

The use of laparoscopic ultrasound in difficult cholecystectomy cases significantly decreases morbidity.

BACKGROUND Laparoscopic ultrasound (LUS) is a method of intraoperative bile duct imaging that can be used prior to any potentially hazardous dissection. The purpose of this study was to determine whether LUS could permit safe laparoscopic completion of difficult cholecystectomy (LC) cases and to assess whether its use had any impact on clinical outcome. METHODS We identified prospectively 44 patients with severe cholecystitis in whom LUS was considered critical for intraoperative identification of the bile ducts. LC patients were compared, on an intention to treat basis, with 41 contemporaneous patients with severe cholecystitis who had planned open cholecystectomy (OC). RESULTS LUS identified the extrahepatic bile ducts in all cases. Of the cases, 40 (91%) were completed laparoscopically. OC patients had a higher rate of acute cholecystitis and preoperative percutaneous cholecystostomy tubes and a higher mean ASA classification. Intraoperatively, LC patients had significantly less estimated blood loss and fewer drains were placed. Postoperatively, LC patients had significantly fewer total complications, Clavien-Dindo grade 3 complications, biliary complications, biliary reinterventions, intra-abdominal abscesses, and bleeding complications. LC patients had significantly fewer ICU admissions and shorter LOS. CONCLUSION By allowing identification of the extrahepatic bile ducts during difficult cholecystectomy, LUS results in a high rate of successful laparoscopic completions. Laparoscopic cholecystectomy is associated with better clinical outcomes than OC for patients with severe cholecystitis.

Value of circulating insulin-like growth factor-associated proteins for the detection of stage I non-small cell lung cancer.

OBJECTIVE Circulating biomarkers related to insulin-like growth factor (IGF) signaling are associated with disease progression in multiple carcinomas, but their potential diagnostic value for lung cancer screening has been inadequately examined. We evaluated 9 circulating IGF-related factors for their ability to assign clinical significance to indeterminate pulmonary nodules identified via computed tomography-based radiologic studies. METHODS Patients (n = 224 stage I non-small cell lung cancer; n = 123 benign) were enrolled by Rush University and the Mayo Clinic and had pretreatment serum evaluated for levels of IGF-1, IGF-2, and insulin-like growth factor binding proteins (IGFBPs) 1-7. The Mann-Whitney rank-sum test and receiver-operator characteristics curves were used to assess differences in biomarker concentrations relevant to malignant versus benign pathology. These targets were used to help refine our companion blood test for assigning clinical significance to computed tomography-detected solitary nodules (discovery cohort, n = 94) and were validated against an independent cohort from the Mayo Clinic (n = 81). RESULTS Patients with benign pulmonary nodules were found to have serum concentrations of IGFBP-3, IGFBP-5, IGF-1, and IGF-2 that were higher (P = .001, P < .001, P = .002, and P = .011, respectively) than those with non-small cell lung cancer, with distinct associations with histologic subtypes observed. Refinement of our multianalyte classification algorithm using IGF-related factors provided a new panel consisting of interleukin-6, interleukin-1 receptor antagonist, interleukin-10, stromal cell-derived factor-1(α + β), IGFBP-4, IGFBP-5, and IGF-2 with improved assay performance-achieving a (validated) negative predictive value of 100%. CONCLUSIONS Our findings suggest a divergent role for IGF signaling in the biology of benign and malignant pulmonary nodules. Upon further validation, these observations may help identify cases of false positives resulting from computed tomography-based screening studies.

Long-term efficacy of laparoscopic cholecystectomy for the treatment of biliary dyskinesia

BACKGROUND Laparoscopic cholecystectomy is the treatment of choice for biliary dyskinesia; however, long-term outcomes remain unclear. METHODS A retrospective review of patients diagnosed with biliary dyskinesia and treated with laparoscopic cholecystectomy at a single institution between 2001 and 2012 was conducted. Long-term outcome data were obtained by telephonic interview using a modified Likert scale. RESULTS Sixty-seven patients met inclusion criteria, of which 34 patients (51%) had long-term follow-up data. Mean time of follow-up was 65 (range: 6 to 134) months. Long-term follow-up demonstrated symptom response in 88% (n = 30) of patients (responders), compared to no response in 12% (n = 4) of patients (nonresponders). Responders underwent a mean of 1.56 preoperative diagnostic procedures, compared to 2.5 for nonresponders (P = .01). CONCLUSION This represents the longest mean time of follow-up study demonstrating the success of laparoscopic cholecystectomy to improve symptoms in patients with biliary dyskinesia.

A Subjective Assessment of Medical Student Perceptions on Animal Models in Medical Education

BACKGROUND There remains increasing societal pressure to limit the use of animals in medical education. The purpose of this study was to explore the subjective perceptions that medical students exposed to an animal model curriculum feel about the laboratory and its continued use. METHODS A 6-month prospective study was performed during the medical college core surgical clerkship. Medical students participated in both a trainer-based simulation workshop (dry laboratory) and a live-tissue animal laboratory (wet laboratory) in addition to their operative experience. Students completed a 23-question Likert survey at the end of the surgical clerkship. Data were compared using the chi-square test. RESULTS More students reported increased subjective stress levels in the wet laboratory (32.4%) compared with the dry laboratory (5.4%, p < 0.001). In addition, more students felt the wet laboratory (vs dry laboratory) prepared them for the anxiety (55.4% vs 24.3%, p < 0.001) and technical demands (67.6% vs 44.6%, p = 0.005) of the operating room. The majority of medical students (>90%) felt the wet laboratory was an important experience and should be continued. CONCLUSIONS The results of this study show a subjective benefit perceived by medical students when it comes to participation in an animal laboratory during their surgical clerkship. As such, over 90% of participating medical students feel the animal laboratory is important in medical education and should be continued in their surgical curriculum.

Permanent mesh results in long-term symptom improvement and patient satisfaction without increasing adverse outcomes in hiatal hernia repair.

BACKGROUND The purpose of this study is to evaluate symptom relief, patient satisfaction, and safety of permanent mesh following Nissen fundoplication and hiatal hernia repair. METHODS Patients who underwent Nissen fundoplication and hiatal hernia repair with permanent mesh (Crurasoft; Davol, Inc, Bard, Warwick, RI) between 2005 and 2011 were identified. A retrospective chart review was conducted. Long-term follow-up data were obtained via telephone interviews using a modified 5-point Likert scale. RESULTS Forty-one patients were identified. Twenty-six patients (63%) had complete follow-up data. Mean follow-up period was 65 months (14 to 96 months). Symptomatic improvement occurred in 23 patients (88%). Twenty-three patients (88%) reported overall satisfaction with the procedure as either excellent or good, and 23 of 26 patients (89%) would undergo surgery again. Three patients (12%) reported hernia recurrence. There were no mesh erosions. CONCLUSION The use of permanent (Crurasoft; Davol, Inc) mesh resulted in symptom improvement as well as patient satisfaction, and no mesh erosions were seen.

Higher clinical performance during a surgical clerkship is independently associated with matriculation of medical students into general surgery.

BACKGROUND The purpose of our study was to determine the predictive impact of individual academic measures for the matriculation of senior medical students into a general surgery residency. METHODS Academic records were evaluated for third-year medical students (n = 781) at a single institution between 2004 and 2011. Cohorts were defined by student matriculation into either a general surgery residency program (n = 58) or a non-general surgery residency program (n = 723). Multivariate logistic regression was performed to evaluate independently significant academic measures. RESULTS Clinical evaluation raw scores were predictive of general surgery matriculation (P = .014). In addition, multivariate modeling showed lower United States Medical Licensing Examination Step 1 scores to be independently associated with matriculation into general surgery (P = .007). CONCLUSIONS Superior clinical aptitude is independently associated with general surgical matriculation. This is in contrast to the negative correlation United States Medical Licensing Examination Step 1 scores have on general surgery matriculation. Recognizing this, surgical clerkship directors can offer opportunities for continued surgical education to students showing high clinical aptitude, increasing their likelihood of surgical matriculation.

Resident training in single-incision compared with traditional cholecystectomy.

These data support the supposition that senior surgical residents can be trained to complete a single-incision laparoscopic cholecystectomy with the same efficacy as traditional laparoscopic cholecystectomy.

Abstract 1730: Expression of serum biomarkers related to epithelial-to-mesenchymal transition in non-small cell lung cancer recurrence

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Objective: Recurrent disease in stage I non-small cell lung cancer (NSCLC) is primarily attributed to metastatic dissemination at the time of surgery undetected by current staging practices. We hypothesized that metastatic progression is driven by epithelial-to-mesenchymal transition (EMT) resulting in differences in tumor-shed protein biomarkers. The objective of this study was to evaluate the difference in expression of these biomarkers in patients with recurrent stage 1 NSCLC. Methods: We used the Luminex immunobead platform, including the MILLIPLEX map human angiogenesis/growth factor magnetic bead panel, to evaluate 80 biomarkers related to EMT against a total of 75 patients who underwent a complete anatomic resection. Patients were divided into the following cohorts: a) stage I NSCLC without recurrence in 2 years (n=50), and b) stage I NSCLC with recurrence within 2 years of follow up (n=25). Peripheral blood was collected and processed using standard phlebotomy techniques. Specimens were obtained in compliance with institutional IRB standards and consent. The Mann-Whitney test and receiver operator characteristics (ROC) curves were used to assess differences in biomarker concentrations between cohorts. Results: Univariate analysis revealed 19 biomarkers with significant (ROC >0.6) differences in expression between the patient cohorts including: angiopoietin 2, MCP-1, MIP-IB, TNF-R1, IGFBP-5, VEGF-D, IGF-1, IGFBP-3, follistatin, sICAM-1, sE-SELECTIN, CYFRA 21.1, RANTES, IL-Ira, M-CSF, IGFBP-1, IGFBP-6, HB-EGF, and PGF. The Mann-Whitney test revealed five biomarkers highly significant (p<0.05) for recurrence in stage 1 NSCLC, including MCP-1, VEGF-D, follistatin, sICAM-1, and placental growth factor (PGF). Evaluation of these biomarkers with the Ingenuity Pathway Analysis (IPA) suite identified several highly significant (p<1x10−5) biological themes, including ten IPA-defined processes associated with development (e.g. embryonic development and cardiovascular system development), seven processes associated with pathological processes (e.g. cancer, cell death, and respiratory disease), and seven processes associated with metastasis (e.g. cellular movement, immune cell trafficking, and cell-to-cell signaling and interaction). Random Forest analysis generated a 6-analyte panel consisting of MCP-1, IP-10, sICAM-1, IGFBP2, RANTES, and IGFBP3 that provided 71.1% classification accuracy with 66.1% sensitivity and 73.3% specificity. Conclusions: Here we report observations concerning the expression of EMT pathway members that may provide key insights into the role of circulating biomarkers related to recurrence in stage 1 NSCLC. Upon further validation, these biomarkers may serve as convenient surrogates to help guide molecular diagnostics and treatment strategies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1730. doi:1538-7445.AM2012-1730