MRI-guided Real-time Online Gated Stereotactic Body Radiation Therapy for Liver Tumors.

BACKGROUND: Liver tumors are commonly encountered in oncology. The study aimed to assess the impact of magnetic resonance imaging (MRI)-guided stereotactic body radiation therapy (SBRT) (MRgSBRT) on disease-related outcomes and the toxicity profile. METHODS: Patients who received MRgSBRT from 2019 to 2021 for primary and metastatic liver tumors were included in this analysis. The protocol for treatment simulation included Gadoxetate disodium injection followed by a single-dimensional post-exhale MRI (0.35-T MRI linear accelerator) and computed tomography simulation. The patient demographics and treatment-related outcomes were assessed. The time-to-event curves were analyzed for freedom from local progression (FFLP) and overall survival (OS). RESULTS: A total of 35 patients were eligible for analysis with a median age of 70 years (range 25 to 95). The median follow-up was 19.4 months (range 1 to 37 mo). The one-year OS was 77.7%, with an estimated 3 years of 47.9%. Patients with the locally controlled disease had a better median OS of 27.8 months (95% CI [23.8-31.6]) compared with 13.5 months (95% CI [5.6-21.3], P =0.007) in patients with local disease progression. The 1-year FFLP was 95.6%, and 3-year estimated FFLP was 87.1%. Patients who received a radiation dose of biologically equivalent dose≥100 Gy had FFLP of 30.9 months (95% CI [28.7-33.1]) compared with 13.3 months (95% CI [5.3-21.3], P =0.004) in patients who received <100 Gy biologically equivalent dose. CONCLUSION: MRI-guided SBRT provides optimal local control, associated with improved OS in a heavily morbid, pretreated older cohort of patients with reasonable safety profiles.

Impact of sociodemographic factors on outcomes in patients with peritoneal malignancies following cytoreduction and chemoperfusion.

BACKGROUND AND OBJECTIVES: Sociodemographic factors have been shown to impact surgical outcomes. However, the effects of these factors on patients undergoing cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) are not well known. This study aims to evaluate the impact of sociodemographic factors on patients undergoing CRS/HIPEC. METHODS: Adult patients at a tertiary center who underwent CRS/HIPEC were evaluated. Perioperative variables were collected and analyzed. A national database was also used to evaluate patients undergoing CRS/HIPEC. RESULTS: There were 90 patients who underwent CRS/HIPEC (32% non-White). There was no statistically significant difference in postoperative complications, length of stay, or discharge disposition based upon race (white vs. non-White patients), socioeconomic status (SES), or insurance type. Nationally, we found that Black and Hispanic patients were less likely to undergo CRS/HIPEC than Non-Hispanic white patients (Black: odds ratio [OR]: 0.60, [confidence interval {CI}: 0.39-0.94]; Hispanic: OR: 0.52, [CI: 0.28-0.98]). However, there were no significant differences in postoperative complications based upon race/ethnicity. CONCLUSION: Sociodemographic factors including race, SES, and insurance status did not impact postoperative outcomes in patients undergoing CRS/HIPEC at our single institution. On a national level, Black and Hispanic patients underwent CRS/HIPEC at lower rates compared to white patients.

Octogenarians undergoing pancreaticoduodenectomy: Assessing outcomes, disposition, and timing of chemotherapy.

BACKGROUND: Inclusion of pancreaticoduodenectomy has demonstrated higher rates of curative treatment in pancreatic cancer, yet prior research has suggested increased postoperative complications in octogenarians (patients older than 80 years). This study aimed to understand the impact of age on patients undergoing a pancreaticoduodenectomy, focusing on postoperative outcomes and return to intended oncologic treatment. MATERIALS AND METHODS: We conducted a single-institution retrospective cohort study for patients undergoing pancreaticoduodenectomy from 2007 to 2018. Collected data included demographics, preoperative comorbidities, and postoperative data (length of stay, 30-day mortality, 1-year mortality, infection, discharge location). Data were separated into 2 cohorts: octogenarians (≥ 80 years) and nonoctogenarians (< 80). χ2 and independent-sample t tests were used for analysis. RESULTS: A total of 649 patients underwent pancreaticoduodenectomy from 2007 to 2018; 63 (9.7%) were octogenarians. No differences were found in infectious complications (P = .607), 30-day mortality (P = .363), or 1-year mortality (P = .895). Octogenarians had a longer length of stay (P = .003) and were more likely to be discharged to skilled nursing facilities (P < .001). There was no significant difference in neoadjuvant chemotherapy administration, although octogenarians were less likely to receive adjuvant chemotherapy (P = .048) and declined adjuvant therapy at a higher rate (P = .003). CONCLUSION: Performing a pancreaticoduodenectomy in octogenarians can be safe and effective in a properly selected cohort. Although postoperative morbidity and mortality are similar to younger patients, elderly patients are more likely to be discharged to nursing facilities and less likely to receive adjuvant chemotherapy. This study suggests that age alone should not be a discriminating factor when discussing surgical therapy for pancreatic cancer treatment in octogenarians.

Impact of angiotensin system inhibitors on esophageal cancer survival.

INTRODUCTION: Angiotensin system inhibitors are associated with improved prognosis in patients with gastrointestinal and hepatobiliary cancers. Data suggest that renin-angiotensin system signaling stimulates the tumor's immune microenvironment to impact overall survival. The goal of this study is to investigate the role of angiotensin system inhibitor use on the overall survival and disease-free survival of esophageal cancer patients. METHODS: Retrospective review of esophagectomy patients with esophageal adenocarcinoma and squamous cell cancer at a single institution tertiary care center from 2007 to 2018 was performed. Outcomes include overall survival and disease-free survival. Patient characteristics were compared with t test and χ2 test. Survival was analyzed with Kaplan-Meier and Cox proportional-hazards regression. RESULTS: One hundred seventy-one patients were identified and 123 underwent esophagectomy for cancer. No significant differences in patient demographics were found between angiotensin system inhibitor users and non-angiotensin system inhibitor users except for the rates of hypertension (40% vs 94%, P < .01) and diabetes (16% vs 47%, P < .01). Distributions of tumor neoadjuvant therapy, adjuvant therapy, pathology, staging, margins, and surgical approach were similar. Postoperatively, there was no difference in major adverse cardiovascular events or infection rates. This study did not find any differences in overall survival and disease-free survival between angiotensin system inhibitor users and non-angiotensin system inhibitor users. CONCLUSION: Angiotensin system inhibitors have been shown to improve survival and decrease relative risk for several types of cancers; however, our data do not support the same effect on esophageal cancer patients undergoing curative intent surgery. Further research is needed to investigate potential nuances in angiotensin system inhibitor dose, chronicity of use, esophageal pathology, and applicability to nonsurgical candidates.

Pancreatic neuroendocrine tumors: Surgical outcomes and survival analysis.

BACKGROUND: Pancreatic neuroendocrine tumors are rare, with rising incidence and limited clinicopathological studies. METHODS: Adult patients with pNET at a single tertiary care center were retrospectively evaluated. RESULTS: In total, 87 patients with histologically confirmed pNET who underwent resection were evaluated. 11% of patients had functioning pNETs: 9 insulinoma and 1 VIPoma. The majority (88.5%) were nonfunctioning. The most common surgical procedure performed was distal pancreatectomy with splenectomy (36.8%). 35.6% of cases were performed with minimally invasive surgery (MIS). MIS patients had fewer postoperative complications, shorter length of stay, and fewer ICU admissions.Disease-free survival (DFS) was unaffected by tumor size (p = 0.5) or lymph node status (p = 0.62). Patients with high-grade (G3) tumors experienced significantly shorter DFS (p = 0.02). CONCLUSIONS: This series demonstrates that survival in patients with pNET is driven mostly by tumor grade, though overall most have long-term survival after surgical resection. Additionally, an MIS approach is efficacious in appropriately selected cases.

Does resection improve overall survival for intrahepatic cholangiocarcinoma with nodal metastases?

BACKGROUND: The potential benefit of surgical resection of intrahepatic cholangiocarcinoma in patients with locoregionally advanced disease has not been definitively determined. METHODS: The National Cancer Database was queried to identify patients with clinical evidence of node-positive intrahepatic cholangiocarcinoma. Resected patients were stratified by margin status and lymph node ratio (nodes positive to nodes harvested). Risk of death was determined using Cox regression models and Kaplan-Meier survival functions. RESULTS: A total of 1,425 patients with T(any)N1M0 intrahepatic cholangiocarcinoma were identified. Two hundred twelve (14.9%) underwent surgical resection. On multivariable Cox regression, R0 resection afforded a survival benefit regardless of lymph node ratio (lymph node ratio > 0.5: hazard ratio 0.466, 95% confidence interval 0.304-0.715; lymph node ratio ≤ 0.5: hazard ratio 0.444, 95% confidence interval 0.322-0.611), whereas a survival benefit was only seen in R1 patients with lymph node ratio ≤ 0.5 (hazard ratio 0.470, 95% confidence interval 0.316-0.701). On Kaplan-Meier, median survival was 11.6 months with chemotherapy, 15.7 months with R0 resection in lymph node ratio > 0.5, and 22.2 months with R0 resection in lymph node ratio ≤ 0.5 (P < .001). DISCUSSION: Margin negative resection is associated with a risk-adjusted survival benefit for patients with clinically N1 intrahepatic cholangiocarcinoma regardless of the degree of regional lymph node involvement.

Antimicrobial susceptibility of biliary stents do not predict infectious complications after whipple.

BACKGROUND: Postoperative infectious complications after a pancreaticoduodenectomy remain a significant cause of morbidity. Studies have demonstrated that a preoperative biliary stent increases the risk of postoperative infectious complications. Few studies have investigated the specific preoperative biliary stent bacterial sensitivities to preoperative antibiotics and the effect on infectious complications. The goal of this study was to investigate if the presence of a preoperative biliary stent increases the risk of postoperative infectious complications in patients undergoing a pancreaticoduodenectomy. Additionally, we aimed to investigate biliary stent culture sensitivities to preoperative antibiotics and determine if those sensitivities impacted postoperative infectious complications after a pancreaticoduodenectomy. METHODS: A retrospective chart review of patients who had undergone a pancreaticoduodenectomy at a single institution tertiary care center from 2007 to 2018 was performed. Perioperative variables including microbiology cultures from biliary stents were collected and analyzed. RESULTS: A total of 244 patients underwent a pancreaticoduodenectomy. A preoperative biliary stent was present in 45 (18%) patients. Infectious complications occurred in 25% of those patients with a preoperative biliary stent, and 19% of those without (P = .37). Of those patients with a stent that was cultured intraoperatively, 92% grew bacteria and 61% of those were resistant to the preoperative antibiotics administered. Of the patients with a preoperative biliary stent and bacteria resistant to the preoperative antibiotics, 17% developed a postoperative infectious complication, compared with 20% if the bacteria cultured was susceptible to the preoperative antibiotics (P = .64). CONCLUSION: Infectious complications after pancreaticoduodenectomy are a significant cause of morbidity. Stent bacterial sensitivities to preoperative antibiotics did not reduce the postoperative infectious complications in the preoperative biliary stent group suggesting a multifactorial cause of infections.

Total gastrectomy in patients with gastric adenocarcinoma: Is there an advantage to the minimally invasive approach?

BACKGROUND: Previous evaluations of the oncologic efficacy of minimally invasive approaches to total gastrectomy in gastric adenocarcinoma have been limited by sample size and duration of follow-up. METHODS: We queried the National Cancer Database to identify patients undergoing robotic and laparoscopic or open total gastrectomy for gastric adenocarcinoma between 2010 and 2015. Propensity score matching was used to adjust for patient, tumor, and treating facility factors. Kaplan-Meier survival functions were used to compare overall survival. Secondary outcomes included margin status, lymph node sampling, mortality, readmission, and length of stay. RESULTS: In the study, 3,213 (72.2%) patients underwent open total gastrectomy; 1,238 (27.8%) minimally invasive total gastrectomy. Patients undergoing minimally invasive total gastrectomy were more likely to be treated at academic (49.5% vs 57.8%, P < .05) and high-volume centers (21.6% vs 28.4%, P < .05). Propensity score matching yielded 1,238 open and 1,238 minimally invasive well-matched total gastrectomies. Minimally invasive was associated with a decreased median length of stay (10 vs 9 days; P < .01). Rates of positive surgical margins, 30-day readmission, 90-day mortality and overall survival were identical between matched cohorts (P > .1). CONCLUSION: Minimally invasive approaches to total gastrectomy provide perioperative oncologic outcomes and overall survival rates that are identical to those for open total gastrectomy but are associated with reduced length of stay.

Perceptions Regarding Mentorship Among General Surgery Trainees With Academic Career Intentions.

OBJECTIVE: Effective mentorship may be an opportunity to mitigate career de-prioritization, improve stress management, and bolster professional growth. Relatively few studies address specific challenges that occur for general surgery trainees. We conducted a focus group-based investigation to determine facilitators/barriers to effective mentorship among general surgery residents, who are intending to pursue an academic career. DESIGN: A semistructured focus group study was conducted to explore residents' attitudes and experiences regarding (1) needs for mentorship, (2) barriers to identifying mentors, and (3) characteristics of successful mentor-mentee interactions. Subjects self-identified and were characterized as either "Mentored" or "Nonmentored." Transcriptions were independently reviewed by 3 coders. Inter-rater reliability between the coders was evaluated by calculating Cohen's kappa for each coded item. SETTING: General surgery residents from 2 academic tertiary hospitals, University of Pittsburgh Medical Center, and University of Washington, participated. PARTICIPANTS: Thirty-four general surgery trainees were divided into 8 focus groups. RESULTS: There were no gender-based differences in mentoring needs among residents. Barriers to establishing a relationship with a mentor, such as lack of exposure to faculty, and time and determination on the part of both mentor and mentee, were exacerbated by aspects of surgical culture including gender dynamics, criticism, and hierarchy. Successful relationships between mentee and mentor were perceived to require personal/professional compatibility and a feeling that the mentor is invested in the mentee, while conflicts of interest and neglect detracted from a successful relationship. CONCLUSIONS: Our investigations demonstrate the importance of surgical hierarchy and culture in facilitating interpersonal interactions with potential mentors. Further studies will be necessary to determine how best to address these barriers.

Towards standardized robotic surgery in gastrointestinal oncology.

PURPOSE: Minimally invasive techniques have revolutionized the field of surgery over the past several decades. Specifically, robotic surgery is increasingly being used for complex operations, although the appreciable learning curve required to become proficient has deterred many surgeons. We describe how use of a proficiency-based training program can decrease the learning curve and lead to standardized robotic surgery. METHODS: The steps of a proficiency-based robotic training program are described, including (1) a proficiency-based virtual reality simulation curriculum, (2) an inanimate biotissue curriculum, (3) a video library training, (4) intraoperative evaluation, and (5) skill maintenance with ongoing assessment. The learning curve for robotic gastrointestinal surgery is explored, as well as outcomes compared to laparoscopic and open techniques. RESULTS: The implementation of a proficiency-based robotic training program is feasible. Surgical oncology fellows who participated in the program demonstrated improvement in both the simulation and biotissue curricula. Analyzed as a group, the participants improved in time and errors after the biotissue curriculum. CONCLUSIONS: Published outcomes from robotic gastrointestinal surgery have demonstrated safety, feasibility, and preserved oncologic resections. A proficiency-based robotic curriculum is ideal to enable surgeons to achieve mastery in robotic surgery while minimizing the learning curve required.

Cancer Cell Invasion in Three-dimensional Collagen Is Regulated Differentially by Gα13 Protein and Discoidin Domain Receptor 1-Par3 Protein Signaling.

Cancer cells can invade in three-dimensional collagen as single cells or as a cohesive group of cells that require coordination of cell-cell junctions and the actin cytoskeleton. To examine the role of Gα13, a G12 family heterotrimeric G protein, in regulating cellular invasion in three-dimensional collagen, we established a novel method to track cell invasion by membrane type 1 matrix metalloproteinase-expressing cancer cells. We show that knockdown of Gα13 decreased membrane type 1 matrix metalloproteinase-driven proteolytic invasion in three-dimensional collagen and enhanced E-cadherin-mediated cell-cell adhesion. E-cadherin knockdown reversed Gα13 siRNA-induced cell-cell adhesion but failed to reverse the effect of Gα13 siRNA on proteolytic invasion. Instead, concurrent knockdown of E-cadherin and Gα13 led to an increased number of single cells rather than groups of cells. Significantly, knockdown of discoidin domain receptor 1 (DDR1), a collagen-binding protein that also co-localizes to cell-cell junctions, reversed the effects of Gα13 knockdown on cell-cell adhesion and proteolytic invasion in three-dimensional collagen. Knockdown of the polarity protein Par3, which can function downstream of DDR1, also reversed the effects of Gα13 knockdown on cell-cell adhesion and proteolytic invasion in three-dimensional collagen. Overall, we show that Gα13 and DDR1-Par3 differentially regulate cell-cell junctions and the actin cytoskeleton to mediate invasion in three-dimensional collagen.

Preferential expansion of pro-inflammatory Tregs in human non-small cell lung cancer.

OBJECTIVES: Lung cancer is the leading cause of cancer-related death in the USA. Regulatory T cells (Tregs) normally function to temper immune responses and decrease inflammation. Previous research has demonstrated different subsets of Tregs with contrasting anti- or pro-inflammatory properties. This study aimed to determine Treg subset distributions and characteristics present in non-small cell lung cancer (NSCLC) patients. METHODS: Peripheral blood was collected from healthy controls (HC) and NSCLC patients preceding surgical resection, and mononuclear cells were isolated, stained, and analyzed by flow cytometry. Tregs were defined by expression of CD4 and CD25 and classified into CD45RA(+)Foxp3(int) (naïve, Fr. I) or CD45RA(-)Foxp3(hi) (activated Fr. II). Activated conventional T cells were CD4(+)CD45RA(-)Foxp3(int) (Fr. III). RESULTS: Samples from 23 HC and 26 NSCLC patients were collected. Tregs isolated from patients with NSCLC were found to have enhanced suppressive function on naive T cells. Cancer patients had significantly increased frequencies of activated Tregs (fraction II: FrII), 17.5 versus 3.2% (P < 0.001). FrII Tregs demonstrated increased RORγt and IL17 expression and decreased IL10 expression compared to Tregs from HC, indicating pro-inflammatory characteristics. CONCLUSIONS: This study demonstrates that a novel subset of Tregs with pro-inflammatory characteristics preferentially expand in NSCLC patients. This Treg subset appears identical to previously reported pro-inflammatory Tregs in human colon cancer patients and in mouse models of polyposis. We expect the pro-inflammatory Tregs in lung cancer to contribute to the immune pathogenesis of disease and propose that targeting this Treg subset may have protective benefits in NSCLC.

GLI2-dependent c-MYC upregulation mediates resistance of pancreatic cancer cells to the BET bromodomain inhibitor JQ1.

JQ1 and I-BET151 are selective inhibitors of BET bromodomain proteins that have efficacy against a number of different cancers. Since the effectiveness of targeted therapies is often limited by development of resistance, we examined whether it was possible for cancer cells to develop resistance to the BET inhibitor JQ1. Here we show that pancreatic cancer cells developing resistance to JQ1 demonstrate cross-resistance to I-BET151 and insensitivity to BRD4 downregulation. The resistant cells maintain expression of c-MYC, increase expression of JQ1-target genes FOSL1 and HMGA2, and demonstrate evidence of epithelial-mesenchymal transition (EMT). However, reverting EMT fails to sensitize the resistant cells to JQ1 treatment. Importantly, the JQ1-resistant cells remain dependent on c-MYC that now becomes co-regulated by high levels of GLI2. Furthermore, downregulating GLI2 re-sensitizes the resistant cells to JQ1. Overall, these results identify a mechanism by which cancer cells develop resistance to BET inhibitors.

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.

Comparative effectiveness in esophagogastric cancer.

Cancer of the esophagus and the gastroesophageal junction (GEJ) continues to have a dismal prognosis, with the incidence of esophageal cancer increasing in the United States. Although radical resection was initially the primary treatment for this disease process, systemic chemotherapy and radiation have been shown to play a role in prolonging survival in most patient populations. This chapter explores the evidence that guides treatment for esophageal and GEJ cancer today. Chemotherapy and radiation therapy were introduced as treatment modalities for esophageal and GEJ cancers when it became evident that surgical therapy alone provided poor long-term survival rates. A variety of treatment strategies have been explored including preoperative (neoadjuvant) and postoperative (adjuvant) chemotherapy, with and without radiation. The evidence suggests that neoadjuvant chemotherapy or chemoradiotherapy provides better outcomes compared to surgery alone for esophageal, GEJ, and gastric cancers. Studies indicate a trend towards improved survival when neoadjuvant chemoradiotherapy is compared to chemotherapy alone. When patients have undergone resection with node-positive disease without receiving neoadjuvant therapy, some form of adjuvant treatment is recommended. This chapter also explores the surgical management of esophageal, GEJ, and gastric cancers including the extent of the gastric lymph node dissection. It also includes a discussion about adherence to national guidelines in terms of gastric cancer treatment and esophageal and gastric lymph node examinations.

Ablation of 5-lipoxygenase mitigates pancreatic lesion development.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC), which continues to have a dismal prognosis, is associated with a pronounced fibroinflammatory response. Inflammation in vivo can be mediated by 5-lipoxygenase (5LO), an enzyme that converts omega-6 fatty acids (FA) to eicosanoids, including leukotriene B4 (LTB4). We have previously shown that diets rich in omega-6 FA increase pancreatic lesions and mast cell infiltration in EL-Kras mice. In this study, we evaluated the role of 5LO in generating higher levels of LTB4 from human cells and in mediating lesion development and mast cell infiltration in EL-Kras mice. MATERIALS AND METHODS: Human pancreatic ductal epithelial and cancer cells were treated with omega-6 FA in vitro. EL-Kras mice lacking 5LO (EL-Kras/5LO(-/-)) mice were generated and fed standard chow or omega-6 FA diets. Pancreatic lesion frequency and mast cell infiltration were compared with EL-Kras/5LO(+/+) mice. Human PDAC tumors were evaluated for 5LO expression and mast cells. RESULTS: Human pancreatic ductal epithelial and pancreatic cancer cells treated with omega-6 FA generated increased LTB4 levels in vitro. EL-Kras/5LO(-/-) mice developed fewer pancreatic lesions and had decreased mast cell infiltration when compared with EL-Kras/5LO(+/+) mice. Human PDAC tumors with increased 5LO expression demonstrate increased mast cell infiltration. Additionally, diets rich in omega-6 FA failed to increase pancreatic lesion development and mast cell infiltration in EL-Kras/5LO(-/-) mice. CONCLUSIONS: The expansion of mutant Kras-induced lesions via omega-6 FA is dependent on 5LO, and 5LO functions downstream of mutant Kras to mediate inflammation, suggesting that 5LO may be a potential chemopreventive and therapeutic target in pancreatic cancer.

Involvement of eicosanoids in the pathogenesis of pancreatic cancer: the roles of cyclooxygenase-2 and 5-lipoxygenase.

The interplay between inflammation and cancer progression is a growing area of research. A combination of clinical, epidemiological, and basic science investigations indicate that there is a relationship between inflammatory changes in the pancreas and neoplastic progression. Diets high in ω-6 polyunsaturated fatty acids provide increased substrate for arachidonic acid metabolism by cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) to form eicosanoids. These eicosanoids directly contribute to pancreatic cancer cell proliferation. Both COX-2 and 5-LOX are upregulated in multiple cancer types, including pancreatic cancer. In vitro studies using pancreatic cancer cell lines have demonstrated upregulation of COX-2 and 5-LOX at both the mRNA and protein levels. When COX-2 and 5-LOX are blocked via a variety of mechanisms, cancer cell proliferation is abrogated both in vitro and in vivo. The mechanism of COX-2 has been shown to include effects on apoptosis as well as angiogenesis. 5-LOX has been implicated in apoptosis. The use of COX-2 and 5-LOX inhibitors in clinical studies in patients with pancreatic cancer has been limited. Patient enrollment has been restricted to those with advanced disease which makes evaluation of these drugs as chemopreventive agents difficult. COX-2 and 5-LOX expression have been shown to be present during the early neoplastic changes of pancreatic cancer, well before progression to invasive disease. This indicates that the ideal role for these interventions is early in the disease process as preventive agents, perhaps in patients with chronic pancreatitis or hereditary pancreatitis.

HOIL-1L functions as the PKCζ ubiquitin ligase to promote lung tumor growth.

RATIONALE: Protein kinase C zeta (PKCζ) has been reported to act as a tumor suppressor. Deletion of PKCζ in experimental cancer models has been shown to increase tumor growth. However, the mechanisms of PKCζ down-regulation in cancerous cells have not been previously described. OBJECTIVES: To determine the molecular mechanisms that lead to decreased PKCζ expression and thus increased survival in cancer cells and tumor growth. METHODS: The levels of expression of heme-oxidized IRP2 ubiquitin ligase 1L (HOIL-1L), HOIL-1-interacting protein (HOIP), Shank-associated RH domain-interacting protein (SHARPIN), and PKCζ were analyzed by Western blot and/or quantitative real-time polymerase chain reaction in different cell lines. Coimmunoprecipitation experiments were used to demonstrate the interaction between HOIL-1L and PKCζ. Ubiquitination was measured in an in vitro ubiquitination assay and by Western blot with specific antibodies. The role of hypoxia-inducible factor (HIF) was determined by gain/loss-of-function experiments. The effect of HOIL-1L expression on cell death was investigated using RNA interference approaches in vitro and on tumor growth in mice models. Increased HOIL-1L and decreased PKCζ expression was assessed in lung adenocarcinoma and glioblastoma multiforme and documented in several other cancer types by oncogenomic analysis. MEASUREMENTS AND MAIN RESULTS: Hypoxia is a hallmark of rapidly growing solid tumors. We found that during hypoxia, PKCζ is ubiquitinated and degraded via the ubiquitin ligase HOIL-1L, a component of the linear ubiquitin chain assembly complex (LUBAC). In vitro ubiquitination assays indicate that HOIL-1L ubiquitinates PKCζ at Lys-48, targeting it for proteasomal degradation. In a xenograft tumor model and lung cancer model, we found that silencing of HOIL-1L increased the abundance of PKCζ and decreased the size of tumors, suggesting that lower levels of HOIL-1L promote survival. Indeed, mRNA transcript levels of HOIL-1L were elevated in tumor of patients with lung adenocarcinoma, and in a lung adenocarcinoma tissue microarray the levels of HOIL-1L were associated with high-grade tumors. Moreover, we found that HOIL-1L expression was regulated by HIFs. Interestingly, the actions of HOIL-1L were independent of LUBAC. CONCLUSIONS: These data provide first evidence of a mechanism of cancer cell adaptation to hypoxia where HIFs regulate HOIL-1L, which targets PKCζ for degradation to promote tumor survival. We provided a proof of concept that silencing of HOIL-1L impairs lung tumor growth and that HOIL-1L expression predicts survival rate in cancer patients suggesting that HOIL-1L is an attractive target for cancer therapy.

Treatment trends, risk of lymph node metastasis, and outcomes for localized esophageal cancer.

BACKGROUND: Endoscopic resection is increasingly used to treat localized, early-stage esophageal cancer. We sought to assess its adoption, characterize the risks of nodal metastases, and define differences in procedural mortality and 5-year survival between endoscopic and surgical resection in the United States. METHODS: From the National Cancer Data Base, patients with T1a and T1b lesions were identified. Treatment patterns were characterized, and hierarchical regression methods were used to define predictors and evaluate outcomes. All statistical tests were two-sided. RESULTS: Five thousand three hundred ninety patients were identified and underwent endoscopic (26.5%) or surgical resection (73.5%). Endoscopic resection increased from 19.0% to 53.0% for T1a lesions (P < .001) and from 6.6% to 20.9% for T1b cancers (P < .001). The strongest predictors of endoscopic resection were depth of invasion (T1a vs T1b: odds ratio [OR] = 4.45; 95% confidence interval [CI] = 3.76 to 5.27) and patient age of 75 years or older (vs age less than 55 years: OR = 4.86; 95% CI = 3.60 to 6.57). Among patients undergoing surgery, lymph node metastasis was 5.0% for T1a and 16.6% for T1b lesions. Predictors of nodal metastases included tumor size greater than 2 cm (vs. <2 cm) and intermediate-/high-grade lesions (vs low grade). For example, 0.5% of patients with low-grade T1a lesions less than 2 cm had lymph node involvement. The risk of 30-day mortality was less after endoscopic resection (hazard ratio [HR] = 0.33; 95% CI = 0.19 to 0.58) but greater for conditional 5-year survival (HR = 1.63; 95% CI = 1.07 to 2.47). CONCLUSIONS: Endoscopic resection has become the most common treatment of T1a esophageal cancer and has increased for T1b cancers. It remains important to balance the risk of nodal metastases and procedural risk when counseling patients regarding their treatment options.

Snail cooperates with Kras G12D in vivo to increase stem cell factor and enhance mast cell infiltration.

UNLABELLED: Pancreatic ductal adenocarcinoma (PDAC) is associated with a pronounced fibro-inflammatory stromal reaction that contributes to tumor progression. A critical step in invasion and metastasis is the epithelial-to-mesenchymal transition (EMT), which can be regulated by the Snail family of transcription factors. Overexpression of Snail (Snai1) and mutant Kras(G12D) in the pancreas of transgenic mice, using an elastase (EL) promoter, resulted in fibrosis. To identify how Snail modulates inflammation in the pancreas, we examined the effect of expressing Snail in EL-Kras(G12D) mice (Kras(G12D)/Snail) on mast cell infiltration, which has been linked to PDAC progression. Using this animal model system, it was demonstrated that there are increased numbers of mast cells in the pancreas of Kras(G12D)/Snail mice compared with control Kras(G12D) mice. In addition, it was revealed that human primary PDAC tumors with increased Snail expression are associated with increased mast cell infiltration, and that Snail expression in these clinical specimens positively correlated with the expression of stem cell factor (SCF/KITLG), a cytokine known to regulate mast cell migration. Concomitantly, SCF levels are increased in the Kras(G12D)/Snail mice than in control mice. Moreover, overexpression of Snail in PDAC cells increased SCF levels, and the media conditioned by Snail-expressing PDAC cells promoted mast cell migration. Finally, inhibition of SCF using a neutralizing antibody significantly attenuated Snail-induced migration of mast cells. IMPLICATIONS: Together, these results elucidate how the EMT regulator Snail contributes to inflammation associated with PDAC tumors.