Joseph D. Phillips

The significant role of mast cells in cancer

Mast cells (MC) are a bone marrow-derived, long-lived, heterogeneous cellular population that function both as positive and negative regulators of immune responses. They are arguably the most productive chemical factory in the body and influence other cells through both soluble mediators and cell-to-cell interaction. MC are commonly seen in various tumors and have been attributed alternatively with tumor rejection or tumor promotion. Tumor-infiltrating MC are derived both from sentinel and recruited progenitor cells. MC can directly influence tumor cell proliferation and invasion but also help tumors indirectly by organizing its microenvironment and modulating immune responses to tumor cells. Best known for orchestrating inflammation and angiogenesis, the role of MC in shaping adaptive immune responses has become a focus of recent investigations. MC mobilize T cells and antigen-presenting dendritic cells. They function as intermediaries in regulatory T cells (Treg)-induced tolerance but can also modify or reverse Treg-suppressive properties. The central role of MC in the control of innate and adaptive immunity endows them with the ability to tune the nature of host responses to cancer and ultimately influence the outcome of disease and fate of the cancer patient.

Expression of RORγt Marks a Pathogenic Regulatory T Cell Subset in Human Colon Cancer

Tregs that expand in human colon cancer have proinflammatory properties and contribute to tumor progression. A Treg Melting Pot Some things are not what they seem. Like the allegorical wolf in sheep’s clothing, cell populations that may seem homogeneous may actually contain subsets with different functions. Indeed, such hidden subpopulations may result in contradictory findings in different systems. Blatner et al. now find a subset of regulatory T cells (Tregs) in human colon cancer that may explain disparate clinical outcomes between studies. The authors found preferential expansion in human colon cancer of Tregs that can suppress T cells but are not anti-inflammatory like more classic Tregs. They then looked in a mouse model of hereditary polyposis and found that these cells, which express Foxp3 and RORγt, express the proinflammatory cytokine IL-17 and are directly associated with inflammation and disease progression. The balance between anti-inflammatory Tregs and these “pathogenic” proinflammatory Tregs may play a role in regulating cancer inflammation. Targeting these RORγt+ Tregs may influence disease outcome in colon cancer. The role of regulatory T cells (Tregs) in human colon cancer (CC) remains controversial: high densities of tumor-infiltrating Tregs can correlate with better or worse clinical outcomes depending on the study. In mouse models of cancer, Tregs have been reported to suppress inflammation and protect the host, suppress T cells and protect the tumor, or even have direct cancer-promoting attributes. These different effects may result from the presence of different Treg subsets. We report the preferential expansion of a Treg subset in human CC with potent T cell–suppressive, but compromised anti-inflammatory, properties; these cells are distinguished from Tregs present in healthy donors by their coexpression of Foxp3 and RORγt. Tregs with similar attributes were found to be expanded in mouse models of hereditary polyposis. Indeed, ablation of the RORγt gene in Foxp3+ cells in polyp-prone mice stabilized Treg anti-inflammatory functions, suppressed inflammation, improved polyp-specific immune surveillance, and severely attenuated polyposis. Ablation of interleukin-6 (IL-6), IL-23, IL-17, or tumor necrosis factor–α in polyp-prone mice reduced polyp number but not to the same extent as loss of RORγt. Surprisingly, loss of IL-17A had a dual effect: IL-17A–deficient mice had fewer polyps but continued to have RORγt+ Tregs and developed invasive cancer. Thus, we conclude that RORγt has a central role in determining the balance between protective and pathogenic Tregs in CC and that Treg subtype regulates inflammation, potency of immune surveillance, and severity of disease outcome.

Effect of Surgeon Training, Specialization, and Experience on Outcomes for Cancer Surgery: A Systematic Review of the Literature

BackgroundOutcomes after cancer resections have been shown to be better for high-volume surgeons compared with low-volume surgeons; however, reasons for this relationship have been difficult to identify. The objective of this study was to assess studies examining the effect of surgeon training and experience on outcomes in surgical oncology.MethodsA systematic review of the literature was performed to assess articles examining the impact of surgeon training, certification, and experience on outcomes. Studies were included if they examined cancer resections and performed multivariable analyses adjusting for relevant confounding variables.ResultsAn extensive literature search identified 29 studies: 27 examined surgeon training/specialization, 1 assessed surgeon certification, and 4 evaluated surgeon experience. Of the 27 studies examining training/specialization, 25 found that specialized surgeons had better outcomes than nonspecialized surgeons. One study found that American Board of Surgery (ABS)-certified surgeons had better outcomes than noncertified surgeons. Of the two studies examining time since ABS certification, both found that increasing time was associated with better outcomes. Of the four studies that examined experience, three studies found that increasing surgeon experience was associated with improved outcomes.ConclusionsAlthough numerous studies have examined the impact of surgeon factors on outcomes, only a few cancers have been examined, and outcome measures are inconsistent. Most studies do not appear robust enough to support major policy decisions. There is a need for better data sources and consistent analyses which assess the impact of surgeon factors on a broad range of cancers and help to uncover the underlying reasons for the volume–outcome association.

Mast cell 5-lipoxygenase activity promotes intestinal polyposis in APC Δ468 mice

Arachidonic acid metabolism has been implicated in colon carcinogenesis, but the role of hematopoietic 5-lipoxygenase (5LO) that may impact tumor immunity in development of colon cancer has not been explored. Here we show that tissue-specific deletion of the 5LO gene in hematopoietic cells profoundly attenuates polyp development in the APC(Δ468) murine model of colon polyposis. In vitro analyses indicated that mast cells in particular utilized 5LO to limit proliferation of intestinal epithelial cells and to mobilize myeloid-derived suppressor cells (MDSCs). Mice lacking hemapoietic expression of 5LO exhibited reduced recruitment of MDSCs to the spleen, mesenteric lymph nodes, and primary tumor site. 5LO deficiency also reduced the activity in MDSCs of arginase-1, which is thought to be critical for MDSC function. Together, our results establish a pro-tumorigenic role of hematopoietic 5LO in the immune microenvironment and suggest 5LO inhibition as an avenue for future investigation in treatment of colorectal polyposis and cancer.

Laparoscopic versus open resection of gastric gastrointestinal stromal tumors

ObjectivesGastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. There is some controversy as to the effectiveness and feasibility of laparoscopic versus open resection of these tumors. We hypothesized that laparoscopic resection of gastric GISTs would offer better perioperative outcomes compared with the traditional open approach. MethodsA retrospective review was conducted of all GISTs treated at a tertiary care urban teaching hospital between January 1999 and August 2008. The medical records were examined for demographic and clinicopathological features. ResultsForty-six gastric GISTs were identified (17 treated laparoscopically and 29 treated via laparotomy). The median age of patients in these groups were comparable at 62 and 60, respectively. Body mass index of these patients were also similar at 28.2 kg/m2 for the laparoscopic and 29.9 kg/m2 for the open group. The average size of tumor was slightly smaller in the laparoscopic group at 4.27 cm versus the open group at 6.39 cm (NS). The estimated blood loss for the laparoscopic group was lower at 94 mL versus 169 mL (P = 0.059). Operative times for the 2 surgical approaches were not significantly different at 135 minutes for laparoscopic and 157.4 minutes for open. Laparoscopic resection yielded a significantly shorter length of stay compared with open at 2.68 versus 6.25 days (P < 0.001). ConclusionsLaparoscopic resection of gastric GISTs offers a decreased length of stay, a trend to decreased blood loss, and comparable oncologic outcomes indicating that a laparoscopic approach should be considered in all patients with gastric GISTs who do not have a contraindication to this approach.

Short-term outcomes after esophagectomy at 164 American College of Surgeons National Surgical Quality Improvement Program hospitals: effect of operative approach and hospital-level variation.

HYPOTHESIS When assessing the effect of operative approach on outcomes, it may be less relevant whether a transhiatal or an Ivor Lewis esophagectomy was performed and may be more important to focus on patient selection and the quality of the hospital performing the operation. DESIGN Observational study. SETTING Hospitals participating in the American College of Surgeons National Surgical Quality Improvement Program. PATIENTS Individuals undergoing esophagectomy were identified from January 1, 2005, to December 31, 2010. The following 4 groups were created based on operative approach: transhiatal, Ivor Lewis, 3-field, and any approach with an intestinal conduit. MAIN OUTCOME MEASURES Risk-adjusted 30-day outcomes and hospital-level variation in performance. RESULTS At 164 hospitals, 1738 patients underwent an esophageal resection: 710 (40.9%) were transhiatal, 497 (28.6%) were Ivor Lewis, 361 (20.8%) were 3-field, and 170 (9.8%) were intestinal conduits. Compared with the transhiatal approach, Ivor Lewis esophagectomy was not associated with increased risk for postoperative complications; however, 3-field esophagectomy was associated with increased likelihood of postoperative pneumonia (odds ratio [OR], 1.88; 95% CI, 1.28-2.77) and prolonged ventilation exceeding 48 hours (OR, 1.68; 95% CI, 1.16-2.42). Intestinal conduit use was associated with increased 30-day mortality (OR, 2.65; 95% CI, 1.08-6.47), prolonged ventilation exceeding 48 hours (OR, 1.61; 95% CI, 1.01-2.54), and return to the operating room for any indication (OR, 1.85; 95% CI, 1.16-2.96). Patient characteristics were the strongest predictive factors for 30-day mortality and serious morbidity. After case-mix adjustment, hospital performance varied by 161% for 30-day mortality and by 84% for serious morbidity. CONCLUSIONS Compared with transhiatal dissection, Ivor Lewis esophagectomy did not result in worse postoperative complications. After controlling for case-mix, hospital performance varied widely for all outcomes assessed, indicating that reductions in short-term outcomes will likely result from expanding other aspects of hospital quality beyond a focus on specific technical maneuvers.

Zileuton, 5-lipoxygenase inhibitor, acts as a chemopreventive agent in intestinal polyposis, by modulating polyp and systemic inflammation.

Purpose Leukotrienes and prostaglandins, products of arachidonic acid metabolism, sustain both systemic and lesion-localized inflammation. Tumor-associated Inflammation can also contribute to the pathogenesis of colon cancer. Patients with inflammatory bowel disease (IBD) have increased risk of developing colon cancer. The levels of 5-lipoxygenase (5-LO), the key enzyme for leukotrienes production, are increased in colon cancer specimens and colonic dysplastic lesions. Here we report that Zileuton, a specific 5-LO inhibitor, can prevent polyp formation by efficiently reducing the tumor-associated and systemic inflammation in APCΔ468 mice. Experimental Design In the current study, we inhibited 5-LO by dietary administration of Zileuton in the APCΔ468 mouse model of polyposis and analyzed the effect of in vivo 5-LO inhibition on tumor-associated and systemic inflammation. Results Zileuton-fed mice developed fewer polyps and displayed marked reduction in systemic and polyp-associated inflammation. Pro-inflammatory cytokines and pro-inflammatory innate and adaptive immunity cells were reduced both in the lesions and systemically. As part of tumor-associated inflammation Leukotriene B4 (LTB4), product of 5-LO activity, is increased focally in human dysplastic lesions. The 5-LO enzymatic activity was reduced in the serum of Zileuton treated polyposis mice. Conclusions This study demonstrates that dietary administration of 5-LO specific inhibitor in the polyposis mouse model decreases polyp burden, and suggests that Zileuton may be a potential chemo-preventive agent in patients that are high-risk of developing colon cancer.

Factors affecting selection of operative approach and subsequent short-term outcomes after anatomic resection for lung cancer.

BACKGROUND Previous studies evaluating video-assisted thoracoscopic surgery (VATS) for lung cancer are single-institution series, suffer from small sample size, or use administrative or self-reported databases. Using a multi-institutional, standardized, and audited surgical outcomes database, our objectives were to examine preoperative factors associated with undergoing VATS vs open resection and assess subsequent perioperative outcomes. STUDY DESIGN The American College of Surgeons National Surgical Quality Improvement Program Participant Use File was used to identify patients who underwent anatomic resection (eg, segmentectomy, lobectomy, and bi-lobectomy) for primary lung cancer (2005 to 2010). Multiple logistic regression models, including propensity scores, were developed to assess preoperative factors associated with undergoing VATS and the risk-adjusted association between operative approach and 30-day outcomes. RESULTS Of 2,353 patients undergoing resection, 74% underwent open thoracotomy (OT) and 26% underwent VATS. After regression for confounders, factors associated with undergoing a VATS were patient age older than 75 years (odds ratio [OR] = 1.41; 95% CI, 1.05-1.90), Hispanic ethnicity (OR = 2.52; 95% CI, 1.69-3.77), and cardiothoracic surgery training (OR = 1.68; 95% CI, 1.37-2.07). Patients undergoing OT had a higher likelihood of any adverse event developing (24% vs 14%; OR = 1.76; 95% CI, 1.35-2.29), specifically pneumonia and sepsis/septic shock. Median length of stay was significantly longer in the OT group (7 vs 4 days; p < 0.001). Mortality was not significantly different for VATS vs OT after regression for confounders. CONCLUSIONS In addition to patient factors, surgeon training can play a role in determining the operative approach offered to patients. Patients selected for VATS had a lower 30-day morbidity and shorter length of stay compared with OT anatomic resection for primary lung cancer.

Needs Assessment for an Errors-Based Curriculum on Thoracoscopic Lobectomy

BACKGROUND Research suggests a benefit from a skills curriculum emphasizing error prevention, identification, and management. Our purpose was to identify common errors committed by trainees during simulated thoracoscopic lobectomy for use in developing an error-based curriculum. METHODS Twenty-one residents (postgraduate years 1 to 8) performed a thoracoscopic left upper lobectomy on a previously validated simulator. Videos of the procedure were reviewed in a blinded fashion using a checklist listing 66 possible cognitive and technical errors. RESULTS Of the 21 residents, 15 (71%) self-reported completing the anatomic lobectomy; however, only 7 (33%) had actually divided all of the necessary structures correctly. While dissecting the superior pulmonary vein, 16 residents (76%) made at least one error. The most common (n=13, 62%) was dissecting individual branches rather than the entire vein. On the bronchus, 14 (67%) made at least one error. Again, the most common (n=9, 43%) was dissecting branches. During these tasks, cognitive errors were more common than technical errors. While dissecting arterial branches, 18 residents (86%) made at least one error. Technical and cognitive errors occurred with equal frequency during arterial dissection. The most common arterial error was excess tension on the vessel (n=10, 48%). CONCLUSIONS Curriculum developers should identify skill-specific technical and judgment errors to verify the scope of errors typically committed. For a thoracoscopic lobectomy curriculum, emphasis should be placed on correct identification of anatomic landmarks during dissection of the vein and airway and on proper tissue handling technique during arterial dissection.

Bronchial Carcinoid Secreting Insulin-Like Growth Factor-1 With Acromegalic Features

Acromegaly caused by a bronchial carcinoid tumor is rare. We report a patient with acromegaly caused by a bronchial carcinoid tumor secreting insulin-like growth factor-1. The patient was treated successfully with bilobectomy.