Peritoneal carcinomatosis in gastric cancer: Are Hispanics at higher risk?

BACKGROUND: A recent study from our group identified Hispanic race/ethnicity as an independent predictor of peritoneal carcinomatosis (PC) in gastric cancer. We sought to identify the tumor factors that might contribute to this strong association in Hispanics. METHODS: California Cancer Registry data were used to identify patients diagnosed with gastric adenocarcinoma from 2004 to 2014. Logistic regression analyses were performed to determine odds ratios for cancer stage, tumor location, grade, histology, and PC. RESULTS: Of 16,275 patients with gastric adenocarcinoma who met inclusion criteria, 6463 (39.7%) were non-Hispanic White (NHW), 4953 (30.4%) were Hispanic, 1020 (6.3%) were non-Hispanic Black (NHB), and 3915 (23.6%) were Asian/other. Compared to NHW, Hispanics were more likely to have a poorly differentiated grade (65.9% vs. 57.6%; p < .001), signet ring adenocarcinoma (28.1% vs. 17.6%; p < .001) and stage IV (51.9% vs. 45.0%; p < .001) gastric cancer. The proportion of stage IV patients with PC was also significantly higher in Hispanics compared to NHW, NHB, and Asian/other (28.5% vs. 16.6%, 20.5%, and 25.2%, respectively; p < .001). CONCLUSIONS: Hispanic ethnicity is an independent predictor of aggressive tumor phenotype and PC. Disproportionate incidence of signet ring adenocarcinoma and PC highlight the need to explore the genomic differences in Hispanic gastric cancer.

Rate of Peritoneal Carcinomatosis in Resected Stage II and III Colon Cancer.

INTRODUCTION: Incidence of peritoneal carcinomatosis (PC) after curative resection of stage II and III colon cancer varies widely. Although certain features are considered high risk for PC, the impact of these features on PC incidence is unclear. METHODS: A retrospective analysis was performed on patients ≥ 18 years old with resected stage II and III colonic adenocarcinoma treated at two academic institutions from 2007 to 2018. Clinicopathologic features, treatment and outcomes data were recorded. Patients with reported high-risk features (pT3N0-2 with mucinous/signet ring components, pT4, pN1c, perforation) were identified. The remaining stage II and III patients were used for comparison. RESULTS: Of 219 eligible patients, 93/219 (42.5%) were stage II and 126/219 (57.5%) were stage III. Median follow-up time was 25 (1-146) months. Adjuvant systemic treatment was administered to 133/219 (60.7%) patients. Overall incidence of PC was 14/219 (6.4%) and the median time to PC was 18 (1-37) months. The high-risk and comparison groups contained 113 and 106 patients, respectively. Incidence of PC was significantly different between groups (high-risk 9.7% vs comparison 2.8%, p = 0.04). Median time to PC was not significantly different between the groups [high-risk 17 (1-37) months vs comparison 20 (7-36) months, p = 0.88]. CONCLUSION: Overall PC incidence in patients with resected stage II and III colon cancer was 6.4%. Although the high-risk group developed PC at a significantly higher rate, the rate of PC in this group was still below 10%. The results of this study represent real-world rates of PC and should be taken into account when designing future studies.

Identification of Tissue-Specific DNA Methylation Signatures for Thyroid Nodule Diagnostics.

PURPOSE: Thyroid cancer is frequently difficult to diagnose due to an overlap of cytologic features between malignant and benign nodules. This overlap leads to unnecessary removal of the thyroid in patients without cancer. While providing some improvement over cytopathologic diagnostics, molecular methods frequently fail to provide a correct diagnosis for thyroid nodules. These approaches are based on the difference between cancer and adjacent thyroid tissue and assume that adjacent tissues are the same as benign nodules. However, in contrast to adjacent tissues, benign thyroid nodules can contain genetic alterations that can be found in cancer.Experimental Design: For the development of a new molecular diagnostic test for thyroid cancer, we evaluated DNA methylation in 109 thyroid tissues by using genome-wide single-base resolution DNA methylation analysis. The test was validated in a retrospective cohort containing 65 thyroid nodules. RESULTS: By conducting reduced representation bisulfite sequencing in 109 thyroid specimens, we found significant differences between adjacent tissue, benign nodules, and cancer. These tissue-specific signatures are strongly linked to active enhancers and cancer-associated genes. Based on these signatures, we developed a new epigenetic approach for thyroid diagnostics. According to the validation cohort, our test has an estimated specificity of 97% [95% confidence interval (CI), 81-100], sensitivity of 100% (95% CI, 87-100), positive predictive value of 97% (95% CI, 83-100), and negative predictive value of 100% (95% CI, 86-100). CONCLUSIONS: These data show that epigenetic testing can provide outstanding diagnostic accuracy for thyroid nodules.See related commentary by Mitmaker et al., p. 457.

Endogenous Akt Activity Promotes Virus Entry and Predicts Efficacy of Novel Chimeric Orthopoxvirus in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with high recurrence rate and poor prognosis. Here, we describe a novel, chimeric orthopoxvirus (CF33) that efficiently kills TNBC. Cytotoxicity was assayed in vitro in four TNBC cell lines. Viral replication was examined through standard plaque assay. Two orthotopic TNBC xenograft models were generated in athymic nude mice and were injected with CF33 intratumorally. CF33 was effective in vitro with potent cytotoxicity and efficient intracellular replication observed in TNBC lines with phosphatidylinositol 3-kinase (PI3K)/Akt pathway mutations that resulted in endogenous phospho-Akt (p-Akt) activity (BT549, Hs578T, and MDA-MB-468). Relative resistance to CF33 by wild-type PI3K/Akt pathway cell line MDA-MB-231 was overcome using higher MOI. The virus was effective in vivo with significant tumor size reduction in both xenograft models. Mechanistically, CF33 appears to share similar properties to vaccinia virus with respect to Akt-mediated and low-pH-mediated viral entry. In summary, CF33 demonstrated potent antitumoral effect in vitro and in vivo, with the most potent effect predicted by the presence of endogenous Akt activity in the TNBC cell line. Further investigation of its mechanism of action as well as genetic modifications to enhance its natural viral tropism are warranted for preclinical development.

A Novel Oncolytic Chimeric Orthopoxvirus Encoding Luciferase Enables Real-Time View of Colorectal Cancer Cell Infection.

This study hypothesizes that a novel oncolytic chimeric orthopoxvirus CF33-Fluc is imageable and targets colorectal cancer cells (CRCs). A novel chimeric orthopoxvirus (CF33) was constructed. The thymidine kinase locus was replaced with firefly luciferase (Fluc) to yield a recombinant virus-CF33-Fluc. In vitro cytotoxicity and viral replication assays were performed. In vivo CRC flank xenografts received single doses of intratumoral or intravenous CF33-Fluc. Viral biodistribution was analyzed via luciferase imaging and organ titers. CF33-Fluc infects, replicates in, and kills CRCs in vitro in a dose-dependent manner. CF33 has superior secretion of extracellular-enveloped virus versus all but one parental strain. Rapid tumor regression or stabilization occurred in vivo at a low dose over a short time period, regardless of the viral delivery method in the HCT-116 colorectal tumor xenograft model. Rapid luciferase expression in virus-infected tumor cells was associated with treatment response. CRC death occurs via necroptotic pathways. CF33-Fluc replicates in and kills colorectal cancer cells in vitro and in vivo regardless of delivery method. Expression of luciferase enables real-time tracking of viral replication. Despite the chimerism, CRC death occurs via standard poxvirus-induced mechanisms. Further studies are warranted in immunocompetent models.

High-Risk Stage II Colon Cancer: Not All Risks Are Created Equal.

INTRODUCTION: Adjuvant chemotherapy is recommended in patients with stage II colon cancer with high-risk features (HRF). However, there is no quantification of the amount of risk conferred by each HRF or the overall survival (OS) benefit gained by chemotherapy based on the risk factor. OBJECTIVE: To assess survival benefits associated with adjuvant chemotherapy among stage II colon cancer patients having one or more HRF [T4 tumors, less than 12 lymph nodes examined (< 12LN), positive margins, high-grade tumor, perineural invasion (PNI), and lymphovascular invasion (LVI)]. METHODS: Patients diagnosed with stage II colon cancer between 2010 and 2013 were identified from California Cancer Registry. Propensity score weighted all-cause mortality hazard ratios (HR) were calculated for combinations of HRF. RESULTS: A total of 5160 stage II colon cancer patients were identified, of which 2398 had at least one HRF and 510 of 2398 (21%) received adjuvant chemotherapy. Compared with patients with a single HRF, presence of any 2 or ≥ 3 HRF showed increasingly poorer survival [HR 1.42, 95% confidence interval (CI) 1.16-1.73 and HR 2.50, 95% CI 1.96-3.20, respectively]. Chemotherapy was associated with improved overall survival only among patients with T4 as the single HRF (HR 0.51, 95% CI 0.34-0.78) or combinations involving T4 as T4/< 12 LN (HR 0.31, 95% CI 0.11-0.90), T4/high grade (HR 0.26, 95% CI 0.11-0.61), and T4/LVI (HR 0.16, 95% CI 0.04-0.61). CONCLUSIONS: Not all high-risk features have similar adverse effects on OS. T4 tumors and their combination with other HRF achieve the most survival benefit with adjuvant therapy. Type and number of high-risk features should be taken into consideration when recommending adjuvant chemotherapy in stage II colon cancer.

Novel oncolytic chimeric orthopoxvirus causes regression of pancreatic cancer xenografts and exhibits abscopal effect at a single low dose.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has been increasing by 0.5% per year in the United States. PDAC portends a dismal prognosis and novel therapies are needed. This study describes the generation and characterization of a novel oncolytic chimeric orthopoxvirus for the treatment of pancreatic cancer. METHODS: After chimerization and high-throughput screening, CF33 was chosen from 100 new chimeric orthopoxvirus isolates for its ability to kill pancreatic cancer cells. In vitro cytotoxicity was assayed in six pancreatic cancer cell lines. In vivo efficacy and toxicity were evaluated in PANC-1 and MIA PaCa-2 xenograft models. RESULTS: CF33 caused rapid killing of six pancreatic cancer cells lines in vitro, releasing damage-associated molecular patterns, and regression of PANC-1 injected and non-injected distant xenografts in vivo after a single low intratumoral dose of 103 plaque-forming units. Using luciferase imaging, CF33 was noted to preferentially replicate in tumors which corresponds to the low viral titers found in solid organs. CONCLUSION: The low dose of CF33 required to treat pancreatic cancer in this preclinical study may ease the manufacturing and dosing challenges currently facing oncolytic viral therapy.

Novel chimeric parapoxvirus CF189 as an oncolytic immunotherapy in triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer is an aggressive subtype of breast cancer with high recurrence rate and poor prognosis. Here we describe a novel, genetically engineered parapoxvirus that efficiently kills triple-negative breast cancer. METHODS: A novel chimeric parapoxvirus (CF189) was generated via homologous recombination and identified through high-throughput screening. Cytotoxicity was assayed in vitro in 4 triple-negative breast cancer cell lines. Viral replication was examined through standard plaque assay. Orthotopic triple-negative breast cancer xenografts were generated by MDA-MB-468 implantation into the 2nd and 4th mammary fat pads of athymic nude mice and treated with the virus. RESULTS: Chimeric parapoxvirus (CF189) demonstrated dose-dependent cytotoxicity at low multiplicity of infection, with > 80% cell death 6 days after treatment. Significant reductions in tumor size were observed 2 weeks after intratumoral injection at doses as low as 103 plaque-forming units (PFU) compared with control (P < 0.01). In addition, abscopal effect (shrinkage of noninjected remote tumors) was clearly demonstrated. CONCLUSION: Chimeric parapoxvirus (CF189) demonstrated efficient cytotoxicity in vitro and potent antitumor effect in vivo at doses as low as 103 PFU. These are data encouraging of clinical development for this highly potent agent against triple-negative breast cancer.

A rising trend in the incidence of advanced gastric cancer in young Hispanic men.

BACKGROUND: Although the incidence of gastric cancer has been decreasing, recent reports suggest an increased rate in select populations. We sought to evaluate trends in gastric cancer incidence to identify high-risk populations. METHODS: Gastric cancer incidence rates from 1992 to 2011 were computed with use of the Surveillance, Epidemiology, and End Results (SEER) registry. We evaluated trends in incidence rates by calculating the annual percent change (APC) across three age groups (20-49 years, 50-64 years, and 65 years or older) and four racial/ethnic groups (Hispanics, non-Hispanic whites, blacks, and Asian/Pacific Islanders). RESULTS: We identified 41,428 patients with gastric cancer. For the entire cohort during the study period, the APC was decreased. When patients were grouped according to sex, the APC was flat or decreased in women regardless of age or race/ethnicity. The APC was also flat or decreased for all men except young Hispanic men (20-49 years), who had an increased APC of nearly 1.6 % (1.55 %, 95 % confidence interval 0.26-2.86 %). Furthermore, young Hispanic men were the only group to have increased incidence of stage IV disease (APC 4.34 %, 95 % confidence interval 2.76-5.94 %) and poorly differentiated tumors (APC 2.08 %, 95 % confidence interval 0.48-3.70 %). CONCLUSIONS: The APC of the incidence of gastric cancer in young Hispanic men places it among the top cancers with rising incidence in the USA. This is concomitant with increased incidence of advanced disease at presentation. This major public health concern warrants additional research to determine the cause of the increasing incidence in this group.

Complications of Feeding Jejunostomy Tubes in Patients with Gastroesophageal Cancer.

BACKGROUND: Feeding jejunostomy tubes (FJT) in patients undergoing resection of gastroesophageal cancers facilitate perioperative nutrition. Data regarding FJT use and complications are limited. STUDY DESIGN: A single institution review was performed for patients who underwent perioperative FJT placement for gastrectomy or esophagogastrectomy from 2007 to 2015. FJT-related and unrelated complications were evaluated. RESULTS: FJTs were inserted for total/completion gastrectomy (n = 49/117, 41.9 %), proximal gastrectomy (n = 7/117, 6.0 %), or esophagogastrectomy (n = 61/117, 52.1 %). Ninety percent (n = 106/117) of patients used an FJT at some time point. Although the majority of patients (75.2 %) used FJTs after discharge, 8.5 % (n = 10/117) never used the FJT and 10.3 % (n = 12/117) used the FJT only during hospitalization. Overall, 44.4 % (n = 52/117) had FJT-related complications, including dislodgement (n = 22), clogging (n = 13), and leakage (n = 6). The majority of FJT complications were resolved by telephone triage (13.5 %) or bedside/clinic intervention (57.7 %), but 3.4 % required operative intervention for small bowel obstruction (n = 3) and hemorrhage (n = 1). FJT complications were more common with gastrectomy than esophagogastrectomy (53.6 vs. 36.0 %), perhaps related to longer FJT use in gastrectomy patients (71 vs. 38 days). CONCLUSIONS: FJT-related complications are common, occurring more frequently after gastrectomy than esophagogastrectomy. In most patients, complications can be managed by simple measures, rarely requiring operative intervention. Nevertheless, the need for FJTs should be carefully considered to balance nutritional benefits with the risks of insertion and usage.

Assessment of the Double-Staple Technique for Esophagoenteric Anastomosis in Gastric Cancer.

INTRODUCTION: Reports on outcomes after double-staple technique (DST) for total and proximal gastrectomy are limited, originating mostly from Asian centers. Our objective was to examine anastomotic leak and stricture with DST for esophagoenteric anastomosis in gastric cancer patients. METHODS: A single institution review was performed for patients who underwent total/proximal gastrectomy with DST between 2006 and 2015. DST was performed using transoral anvil delivery (OrVil) with end-to-end anastomosis. Clinical characteristics and outcomes, including anastomotic leak and stricture, were recorded. RESULTS: Overall, DST was performed in 60 patients [total gastrectomy (81.7%, n = 49/60), proximal gastrectomy (10.0%, n = 6/60), and completion gastrectomy (8.3%, n = 5/60)]. Neoadjuvant chemotherapy was administered to 21 patients (35.0%), and 6 patients (10.0%) received external beam radiation therapy prior to completion gastrectomy. Operative approach was open (51.7%, n = 31/60), laparoscopic (43.3%, n = 26/60), or robotic (5.0%, n = 3/60). Anastomotic leak occurred in 6.7% (n = 4/60), while stricture independent of leak was identified in 19.0% (n = 11/58) of patients. Complications occurred in 38.3% (n = 23/60) of patients, of which 52% were classified as Clavien-Dindo grades III-V complications. CONCLUSION: In the largest Western series of DST for esophagoenteric anastomoses in gastric cancer surgery, our experience demonstrates that DST is safe and effective with low rates of leak and stricture.

From Benchtop to Bedside: A Review of Oncolytic Virotherapy.

Oncolytic viruses (OVs) demonstrate the ability to replicate selectively in cancer cells, resulting in antitumor effects by a variety of mechanisms, including direct cell lysis and indirect cell death through immune-mediate host responses. Although the mechanisms of action of OVs are still not fully understood, major advances have been made in our understanding of how OVs function and interact with the host immune system, resulting in the recent FDA approval of the first OV for cancer therapy in the USA. This review provides an overview of the history of OVs, their selectivity for cancer cells, and their multifaceted mechanism of antitumor action, as well as strategies employed to augment selectivity and efficacy of OVs. OVs in combination with standard cancer therapies are also discussed, as well as a review of ongoing human clinical trials.

Rates of lymph node metastasis and survival in T1a gastric adenocarcinoma in Western populations.

BACKGROUND AND AIMS: EMR and endoscopic submucosal dissection (ESD) are widely accepted in Asia for treatment of early gastric cancer (EGC). Few studies have examined lymph node (LN) metastasis of EGC in Western populations. We sought to examine EGC and LN metastasis in a heterogeneous Western population. METHODS: Patients with surgically resected, histologically confirmed American Joint Committee on Cancer T1a gastric adenocarcinoma were identified in the Surveillance, Epidemiology, and End Results (SEER) database from 2002 to 2012. Patients were excluded if they had stage IV disease, had multiple primary cancers, or received neoadjuvant therapy. Rates of LN metastasis were calculated, and survival analyses were performed. RESULTS: Of 923 patients in the cohort, 72 (7.8%) had at least 1 positive LN on final pathology. When stratified by race, Asian/Pacific Islanders (APIs) demonstrated the lowest rate of LN metastases (n = 17/327, 5.2%), followed by Hispanics (n = 12/171, 7.0%), whites (n = 27/278, 9.7%), and blacks (n = 16/147, 10.9%). The highest rates of stage IA disease were observed in API (93.9%) and Hispanic (92.4%) patients, followed by white (89.9%) and black (87.1%) patients (P = .04). Survival analysis of T1a gastric cancer patients by race/ethnicity showed that 5-year overall survival was highest for API patients (API, 88%; Hispanic, 81%; black, 79%; and white, 77%; P < .01). CONCLUSIONS: The rate of LN metastasis in T1a gastric cancers in the United States is higher than the rates reported in Asia. Survival outcomes in T1a gastric cancers varied significantly by race, suggesting that definitive endoscopic treatment may not be appropriate for all patients in the United States.

Epidermal Growth Factor Receptor Signaling to the Mitogen Activated Protein Kinase Pathway Bypasses Ras in Pancreatic Cancer Cells.

OBJECTIVE: Epidermal growth factor (EGF) receptor (EGFR/HER1) is overexpressed in human pancreatic cancers. However, anti-EGFR therapy does not exhibit significant therapeutic activity with oncogenic K-ras mutation. We sought to assess the signaling relationship between EGFR and mutant K-ras, which is commonly detected in pancreatic cancer. METHODS: Pancreatic cancer cells harboring mutated K-ras were treated with EGF to assess signaling from EGFR to mitogen-activated protein kinase (MAPK) pathway. The role of Ras family of proteins in transducing EGFR signals was assessed using short interfering RNA. Other components of MAPK and PI3K (phosphoinositide 3-kinase) pathways were examined for their roles in EGFR signaling. RESULTS: First, EGF signaling in pancreatic cancer cells occurs selectively through HER1. Second, knockdown of all Ras isoforms failed to block EGF-mediated phosphorylation of extracellular signal-regulated kinase (ERK). Inhibition of Raf was observed to partially abrogate ERK phosphorylation, whereas MEK inhibition resulted in complete attenuation of EGF-mediated ERK phosphorylation. Finally, inhibition of phosphoinositide 3-kinase/AKT and CDC42/PAK pathways did not block EGFR signaling. CONCLUSIONS: Our study results demonstrate that EGFR-mediated signaling in mutant K-ras pancreatic cancer cells does not follow canonical MAPK signaling. Our novel findings suggest the existence of alternate signaling pathways to downstream MAPK in the presence of mutant K-ras.

Size of Extranodal Extension on Sentinel Lymph Node Dissection in the American College of Surgeons Oncology Group Z0011 Trial Era.

IMPORTANCE: Based on the American College of Surgeons Oncology Group Z0011 trial exclusion criteria, patients with T1N0 or T2N0 breast cancer with 1 or 2 positive sentinel lymph nodes (SLNs) are recommended to undergo axillary lymph node dissection if extranodal extension (ENE) is present. OBJECTIVE: To determine the effect of ENE size on residual axillary nodal burden, disease recurrence, and survival in patients meeting Z0011 criteria. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study between January 1, 2000, and December 31, 2012, at a single tertiary cancer center. Patients had T1 or T2 breast cancer with 1 or 2 positive SLNs. The ENE was classified as 2 mm or smaller or as larger than 2 mm. MAIN OUTCOMES AND MEASURES: Nodal burden, disease recurrence, and overall survival. RESULTS: Of 208 patients, 149 (71.6%) had no ENE, 21 (10.1%) had ENE 2 mm or smaller, and 38 (18.3%) had ENE larger than 2 mm on SLN dissection. The median follow-up time was 60 months (range, 1-158 months). The mean (SD) total number of positive lymph nodes differed significantly for the group with no ENE (1.72 [1.39]) vs the group with ENE 2 mm or smaller (3.22 [2.09]; P < .001) and vs the group with ENE larger than 2 mm (4.26 [5.01]; P < .001). Similar patterns were observed for mean (SD) nonsentinel lymph node metastases: 0.48 (1.30) for no ENE vs 1.91 (2.07) with ENE 2 mm or smaller (P = .02) and vs 2.95 (4.95) with ENE larger than 2 mm (P < .001). For the group without ENE vs the group with ENE 2 mm or smaller, there were no significant differences in recurrence (distant recurrence, 4 patients [2.7%] vs 1 patient [4.8%], respectively; P = .62) or in mortality (18 patients [12.1%] vs 4 patients [19.1%], respectively; P = .48). For the group without ENE vs the group with ENE larger than 2 mm, there were no significant differences in recurrence (distant recurrence, 4 patients [2.7%] vs 4 patients [10.5%], respectively; P = .19) or in mortality (18 patients [12.1%] vs 9 patients [23.7%], respectively; P = .07). CONCLUSIONS AND RELEVANCE: Presence of ENE on SLN dissection is associated with N2 disease. Despite increased nodal burden, patients with 1 or 2 positive SLNs and ENE 2 mm or smaller demonstrated recurrence and survival rates similar to those of patients without ENE. Reporting of ENE size should be standardized and required.

Accuracy of computed tomography in nodal staging of colon cancer patients.

AIM: To predict node-positive disease in colon cancer using computed tomography (CT). METHODS: American Joint Committee on Cancer stage I-III colon cancer patients who underwent curavtive-intent colectomy between 2007-2010 were identified at a single comprehensive cancer center. All patients had preoperative CT scans with original radiology reports from referring institutions. CT images underwent blinded secondary review by a surgeon and a dedicated abdominal radiologist at our institution to identify pericolonic lymph nodes (LNs). Comparison of outside CT reports to our independent imaging review was performed in order to highlight differences in detection in actual clinical practice. CT reviews were compared with final pathology. Results of the outside radiologist review, secondary radiologist review, and surgeon review were compared with the final pathologic exam to determine sensitivity, specificity, positive and negative predictive values, false positive and negative rates, and accuracy of each review. Exclusion criteria included evidence of metastatic disease on CT, rectal or appendiceal involvement, or absence of accompanying imaging from referring institutions. RESULTS: From 2007 to 2010, 64 stageI-III colon cancer patients met the eligibility criteria of our study. The mean age of the cohort was 68 years, and 26 (41%) patients were male and 38 (59%) patients were female. On final pathology, 26 of 64 (40.6%) patients had node-positive (LN+) disease and 38 of 64 (59.4%) patients had node-negative (LN-) disease. Outside radiologic review demonstrated sensitivity of 54% (14 of 26 patients) and specificity of 66% (25 of 38 patients) in predicting LN+ disease, whereas secondary radiologist review demonstrated 88% (23 of 26) sensitivity and 58% (22 of 38) specificity. On surgeon review, sensitivity was 69% (18 of 26) with 66% specificity (25 of 38). Secondary radiology review demonstrated the highest accuracy (70%) and the lowest false negative rate (12%), compared to the surgeon review at 67% accuracy and 31% false negative rate and the outside radiology review at 61% accuracy and 46% false negative rate. CONCLUSION: CT LN staging of colon cancer has moderate accuracy, with administration of NCT based on CT potentially resulting in overtreatment. Active search for LN+ may improve sensitivity at the cost of specificity.

Perioperative chemotherapy for resectable gastric cancer: MAGIC and beyond.

Over the last 15 years, there have been major advances in the multimodal treatment of gastric cancer, in large part due to several phase III studies showing the treatment benefits of neoadjuvant and adjuvant chemotherapy and chemoradiation protocols. The objective of this editorial is to review the current high-level evidence supporting the use of chemotherapy, chemoradiation and anti-HER2 agents in both the neoadjuvant and adjuvant settings, as well as to provide a clinical framework for use of this data based on our own institutional protocol for gastric cancer. Major studies reviewed include the SWOG/INT 0116, Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC), CLASSIC, ACTS-GC, Adjuvant Chemoradiation Therapy in Stomach Cancer (ARTIST) and Trastuzumab for Gastric Cancer trials. Although these studies have demonstrated that multiple approaches in terms of the timing and therapy for gastric cancer are effective, no standard of care is widely accepted and questions regarding the optimal timing of chemotherapy, the benefit of radiotherapy, the minimum required extent of lymphadenectomy and optimal chemotherapy regimen still exist. Protocols from the upcoming ARTIST II, CRITICS, TOPGEAR, Neo-AEGIS and MAGIC-B studies are outlined, and results from these studies will provide critical information regarding optimal timing and treatment regimen. Additionally, the future directions of gastric cancer research predicated on molecular profiling and tailored therapies based on targetable genetic alterations in individual patient's tumors are addressed.

CCR9-mediated signaling through ß-catenin and identification of a novel CCR9 antagonist.

Elevated levels of chemokine receptor CCR9 expression in solid tumors may contribute to poor patient prognosis. In this study, we characterized a novel CCR9-mediated pathway that promotes pancreatic cancer cell invasion and drug resistance, indicating that CCR9 may play a critical role in cancer progression through activation of ß-catenin. We noted that the CCL25/CCR9 axis in pancreatic cancer cells induced the activation of ß-catenin, which enhanced cell proliferation, invasion, and drug resistance. CCR9-mediated activation of ß-catenin and the resulting downstream effects were effectively inhibited by blockade of the PI3K/AKT pathway, but not by antagonism of Wnt. Importantly, we discovered that CCR9/CCL25 increased the lethal dose of gemcitabine, suggesting decreased efficacy of anti-cancer drugs with CCR9 signaling. Through in silico computational modeling, we identified candidate CCR9 antagonists and tested their effects on CCR9/ß-catenin regulation of cell signaling and drug sensitivity. When combined with gemcitabine, it resulted in synergistic cytotoxicity. Our results show that CCR9/ß-catenin signaling enhances pancreatic cancer invasiveness and chemoresistance, and may be a highly novel therapeutic target.

Underreporting of Gastrointestinal Stromal Tumors: Is the True Incidence Being Captured?

BACKGROUND: Hospital cancer registries are only required to report gastrointestinal stromal tumors (GISTs) if labeled malignant or metastatic, leading to potential loss of cases in national cancer registries. Our objective was to determine whether GISTs are underreported in the US. METHODS: Retrospective review of pathology reports between 2010 and 2013 with diagnosis of GIST was performed at two academic medical centers. Recurrent GISTs were excluded. Pathology reports were cross-referenced to cases reported by each cancer registry. Risk for metastasis/death was determined according to National Comprehensive Cancer Network (NCCN) guidelines. RESULTS: Forty-nine cases of non-recurrent GIST were identified. Only 19/49 (38.8%) cases were reported. None of the 30 non-reported cases were labeled malignant/metastatic on final pathology. To illustrate malignant potential, these tumors were risk stratified. Most (60%) of the non-reported cases were low risk, but there were 4 (13.3%) cases each in the intermediate, high, and unknown risk groups. Additionally, 7/30 (23.0%) cases were treated with tyrosine kinase inhibitors, highlighting clinical concern of malignant GIST. CONCLUSIONS: Our results show that nearly two thirds of GIST cases have been underreported, suggesting that current reporting practices underestimate its true incidence. Revision of reporting guidelines may result in a more accurate estimation of the US disease burden of GIST.