Sean C. Wightman

Surgical Training, Duty-Hour Restrictions, and Implications for Meeting the Accreditation Council for Graduate Medical Education Core Competencies Views of Surgical Interns Compared With Program Directors

OBJECTIVE To describe the perspectives of surgical interns regarding the implications of the new Accreditation Council for Graduate Medical Education (ACGME) duty-hour regulations for their training. DESIGN We compared responses of interns and surgery program directors on a survey about the proposed ACGME mandates. SETTING Eleven general surgery residency programs. PARTICIPANTS Two hundred fifteen interns who were administered the survey during the summer of 2011 and a previously surveyed national sample of 134 surgery program directors. MAIN OUTCOME MEASURES Perceptions of the implications of the new duty-hour restrictions on various aspects of surgical training, including the 6 ACGME core competencies of graduate medical education, measured using 3-point scales (increase, no change, or decrease). RESULTS Of 215 eligible surgical interns, 179 (83.3%) completed the survey. Most interns believed that the new duty-hour regulations will decrease continuity with patients (80.3%), time spent operating (67.4%), and coordination of patient care (57.6%), while approximately half believed that the changes will decrease their acquisition of medical knowledge (48.0%), development of surgical skills (52.8%), and overall educational experience (51.1%). Most believed that the changes will improve or will not alter other aspects of training, and 61.5% believed that the new standards will decrease resident fatigue. Surgical interns were significantly less pessimistic than surgery program directors regarding the implications of the new duty-hour restrictions on all aspects of surgical training (P < .05 for all comparisons). CONCLUSIONS Although less pessimistic than program directors, interns beginning their training under the new paradigm of duty-hour restrictions have significant concerns about the effect of these regulations on the quality of their training.

Investigation of the essential role of platelet-tumor cell interactions in metastasis progression using an agent-based model

BackgroundMetastatic tumors are a major source of morbidity and mortality for most cancers. Interaction of circulating tumor cells with endothelium, platelets and neutrophils play an important role in the early stages of metastasis formation. These complex dynamics have proven difficult to study in experimental models. Prior computational models of metastases have focused on tumor cell growth in a host environment, or prediction of metastasis formation from clinical data. We used agent-based modeling (ABM) to dynamically represent hypotheses of essential steps involved in circulating tumor cell adhesion and interaction with other circulating cells, examine their functional constraints, and predict effects of inhibiting specific mechanisms.MethodsWe developed an ABM of Early Metastasis (ABMEM), a descriptive semi-mechanistic model that replicates experimentally observed behaviors of populations of circulating tumor cells, neutrophils, platelets and endothelial cells while incorporating representations of known surface receptor, autocrine and paracrine interactions. Essential downstream cellular processes were incorporated to simulate activation in response to stimuli, and calibrated with experimental data. The ABMEM was used to identify potential points of interdiction through examination of dynamic outcomes such as rate of tumor cell binding after inhibition of specific platelet or tumor receptors.ResultsThe ABMEM reproduced experimental data concerning neutrophil rolling over endothelial cells, inflammation-induced binding between neutrophils and platelets, and tumor cell interactions with these cells. Simulated platelet inhibition with anti-platelet drugs produced unstable aggregates with frequent detachment and re-binding. The ABMEM replicates findings from experimental models of circulating tumor cell adhesion, and suggests platelets play a critical role in this pre-requisite for metastasis formation. Similar effects were observed with inhibition of tumor integrin αV/β3. These findings suggest that anti-platelet or anti-integrin therapies may decrease metastasis by preventing stable circulating tumor cell adhesion.ConclusionCirculating tumor cell adhesion is a complex, dynamic process involving multiple cell-cell interactions. The ABMEM successfully captures the essential interactions necessary for this process, and allows for in-silico iterative characterization and invalidation of proposed hypotheses regarding this process in conjunction with in-vitro and in-vivo models. Our results suggest that anti-platelet therapies and anti-integrin therapies may play a promising role in inhibiting metastasis formation.

Oncogenic CXCL10 signalling drives metastasis development and poor clinical outcome

Background:The CXCL10/CXCR3 signalling mediates paracrine interactions between tumour and stromal cells that govern leukocyte trafficking and angiogenesis. Emerging data implicate noncanonical CXCL10/CXCR3 signalling in tumourigenesis and metastasis. However, little is known regarding the role for autocrine CXCL10/CXCR3 signalling in regulating the metastatic potential of individual tumour clones.Methods:We performed transcriptomic and cytokine profiling to characterise the functions of CXCL10 and CXCR3 in tumour cells with different metastatic abilities. We modulated the expression of the CXCL10/CXCR3 pathway using shRNA-mediated silencing in both in vitro and in vivo models of B16F1 melanoma. In addition, we examined the expression of CXCL10 and CXCR3 and their associations with clinical outcomes in clinical data sets derived from over 670 patients with melanoma and colon and renal cell carcinomas.Results:We identified a critical role for autocrine CXCL10/CXCR3 signalling in promoting tumour cell growth, motility and metastasis. Analysis of publicly available clinical data sets demonstrated that coexpression of CXCL10 and CXCR3 predicted an increased metastatic potential and was associated with early metastatic disease progression and poor overall survival.Conclusion:These findings support the potential for CXCL10/CXCR3 coexpression as a predictor of metastatic recurrence and point towards a role for targeting of this oncogenic axis in the treatment of metastatic disease.

Extremes of body mass index and postoperative complications after esophagectomy

Obesity has been variously associated with reduced or similar rates of postoperative complications compared to normal weight patients undergoing esophagectomy for cancer. In contrast, little is known about esophagectomy risks in the underweight population. The relationship between the extremes of body mass index (BMI) and postoperative complications after esophagectomy was evaluated. Consecutive esophagectomy patients (2000-2013) were reviewed. The patients were stratified based on BMI at the time of diagnosis: underweight (<18.5), normal (18.5-24.9), overweight (25-29.9), obese I (30-34.9), and obese II or III (≥35). Hospital length of stay as well as postoperative complications and their accordion severity grading were evaluated according to the BMI category. Of 388 patients, 78.6% were male with a median age of 62 years at the time of operation. Pathologic cancer stage was 0 to I in 53%. BMI distribution was as follows: 5.6% underweight, 28.7% normal, 31.4% overweight, 22.8% obese I, and 11.5% obese II or III. Performance status was 0 or 1 in 99.2%. Compared to normal BMI patients, underweight patients had increased pulmonary complications (odds ratio (OR) 3.32, P = 0.014) and increased other postoperative complications (OR 3.00, P = 0.043). Patients who were overweight did not have increased complications compared to normal BMI patients. BMI groups did not differ in mortality rates or complication accordion severity grading. Hospital length of stay trended toward a longer duration in the underweight population (P = 0.06). Underweight patients are at increased risk for postoperative pulmonary and other complications. Underweight patients may benefit from preoperative nutritional repletion and mitigation for sarcopenia. Aggressive postoperative pulmonary care may help reduce complications in these patients. In contrast, the operative risk in overweight and obese patients is similar to normal BMI patients.

In Vivo Delivery and Therapeutic Effects of a MicroRNA on Colorectal Liver Metastases

Multiple therapeutic agents are typically used in concert to effectively control metastatic tumors. Recently, we described microRNAs that are associated with the oligometastatic state, in which a limited number of metastatic tumors progress to more favorable outcomes. Here, we report the effective delivery of an oligometastatic microRNA (miR-655-3p) to colorectal liver metastases using nanoscale coordination polymers (NCPs). The NCPs demonstrated a targeted and prolonged distribution of microRNAs to metastatic liver tumors. Tumor-targeted microRNA miR-655-3p suppressed tumor growth when co-delivered with oxaliplatin, suggesting additive or synergistic interactions between microRNAs and platinum drugs. This is the first known example of systemically administered nanoparticles delivering an oligometastatic microRNA to advanced metastatic liver tumors and demonstrating tumor-suppressive effects. Our results suggest a potential therapeutic strategy for metastatic liver disease by the co-delivery of microRNAs and conventional cytotoxic agents using tumor-specific NCPs.

Integrated molecular subtyping defines a curable oligometastatic state in colorectal liver metastasis

The oligometastasis hypothesis suggests a spectrum of metastatic virulence where some metastases are limited in extent and curable with focal therapies. A subset of patients with metastatic colorectal cancer achieves prolonged survival after resection of liver metastases consistent with oligometastasis. Here we define three robust subtypes of de novo colorectal liver metastasis through integrative molecular analysis. Patients with metastases exhibiting MSI-independent immune activation experience the most favorable survival. Subtypes with adverse outcomes demonstrate VEGFA amplification in concert with (i) stromal, mesenchymal, and angiogenic signatures, or (ii) exclusive NOTCH1 and PIK3C2B mutations with E2F/MYC activation. Molecular subtypes complement clinical risk stratification to distinguish low-risk, intermediate-risk, and high-risk patients with 10-year overall survivals of 94%, 45%, and 19%, respectively. Our findings provide a framework for integrated classification and treatment of metastasis and support the biological basis of curable oligometastatic colorectal cancer. These concepts may be applicable to many patients with metastatic cancer.The oligometastasis hypothesis suggests certain metastases are limited in extent and curable with focal therapies. Here they identify three integrated molecular subtypes of colorectal cancer liver metastasis, which complement clinical risk stratification to distinguish the subset of oligometastatic patients.

Imaging of tumor clones with differential liver colonization

We present a model of hepatic colorectal metastases which represents monoclonal cell lines double-labeled by luciferase and tdTomato. These cells form liver metastasis in varying numbers and patterns similar to those observed in patients. Using in vivo and ex vivo luminescent and fluorescent imaging we determine the growth kinetics and clonogenic frequency of tumor cells colonizing liver. Molecular profiling detected stable expressional differences between clones consistent with their phenotypes. The data indicate that clinically relevant phenotypes of liver metastases can be modeled in vivo.

An organized approach to complex ethical cases on a surgical service.

Ethical scenarios, such as the one above, frequently arise in surgical specialties. The surgical environment often is saturated with complicated decisions, critically ill patients, and delivering bad news. Ethics is central to both medical and surgical practice. However, surgical ethics is different from other areas of medical ethics in that surgeons are necessarily an active part of the patient’s treatment. When a surgical plan is created, there is always an action by a person, the surgeon, upon another person, the patient. If the surgeon is removed from the operative plan, the treatment falls apart. The fact that a surgeon is required to complete surgical procedures differs greatly from other medical specialties where once a plan is generated, it can continue without the direct involvement of the physician. Across the field of bioethics, four principles can frequently be identified as central to most ethical situations and decisions: respect for persons—allowing the patient to play an active role in making decisions regarding their own medical care [1]; nonmaleficence—avoiding harm to a patient; beneficence—maximizing benefits and minimizing harms to patients; and justice—being fair and equitable [2]. These principles guide the evaluation and interpretation of the ethical issues in patient care. Surgical care most commonly occurs when a patient is sick and vulnerable as patients often present when acutely ill or with a malignancy or other condition that requires operative resolution. The vulnerability of the patient requires the surgeon to exercise additional caution in caring for patients who are in dire need of assistance and may be willing to consent to extreme procedures. When the surgeon and patient discuss an operative plan, it is the surgeon’s responsibility to effectively communicate the indications, risks, and alternatives of the operation to the patient. Although official documentation of informed consent occurs through signing a form, the actual consent process is the conversation between the surgeon and patient [3]. This conversation is a critical component of any surgical procedure. It is in this interaction that the relationship is established with the patient; confidence and trust are instilled, the usual postoperative course defined, and possible complications are explained. For high-risk procedures, the surgeon should go further than the informed consent conversation and discuss what the patient might want done if complications arise. This conversation should outline what the patient would want in specific and unlikely, but still possible scenarios; e.g., not regaining baseline mental status or not being able to be extubated. Beyond the consent process itself, surgeons must continually communicate with patients S. C. Wightman (&) P. Angelos Department of Surgery, University of Chicago Medicine, 5841 S. Maryland Avenue, MC6040, Chicago, IL 60637, USA e-mail: sean.wightman@uchospitals.edu

Ethical aspects of a video-assisted thoracoscopic surgery practice

Thoracic surgery is a field encompassing many diverse operative techniques ranging from open surgeries involving thoracotomies and sternotomies to less invasive operations such as video-assisted thoracoscopic surgery (VATS), endoscopy, and bronchoscopy. The popularity and acceptance of VATS has been increasing over time. Ethical considerations must be used to navigate patient misconceptions of VATS surgery, creating an appropriate informed consent process, determining appropriate patients for VATS, training future thoracic surgeons in VATS, and advancing thoracic surgery innovation. Thoracic surgeons are the gateway to determine what operation and what technique is appropriate to offer to each patient. This requires strict adherence to ethical standards as well as self-regulation.