Decreasing colorectal cancer screening disparities: A culturally tailored patient navigation program for Hispanic patients.

BACKGROUND: Colorectal cancer (CRC) is the second leading cause of cancer-related death in Hispanic patients. Screening colonoscopy has been shown to reduce the incidence and mortality of CRC. However, utilization among Hispanic patients and other minority groups is low. The objective of this study was to evaluate colonoscopy utilization among Hispanic patients with a culturally tailored patient navigation program (CTPNP) in place. METHODS: A CTPNP was designed to meet the needs of the authors' Hispanic patient population and their health care system characteristics. A CTPNP protocol was created, and a Spanish-speaking navigator/coordinator was hired. Enrolled patients received a Spanish-language introductory letter, an initial phone call for patient education, and follow-up calls to ensure that all potential barriers to colonoscopy were overcome. Colonoscopy completion (CC), colonoscopy cancellation (CN), and colonoscopy no-show (NS) rates were recorded and compared with historical rates in Rhode Island. RESULTS: Over a 28-month period, 773 patients were referred to the CTPNP, and 698 (53% female and 47% male) were enrolled in the program. The overall CC rate was 85% (n = 592) with no difference between males and females. The CN rate was 9% (n = 62), and the NS rate was 6% (n = 44). The most common reasons for CN and NS were cost and an inability to contact the patient after referral. Within the CC group, 43% (n = 254) of patients underwent polypectomy, and 1.3% (n = 8) required colectomy. Ninety percent (n = 530) of the CC group reported that they would not have completed colonoscopy without the CTPNP. CONCLUSIONS: Implementation of a CTPNP is an effective intervention to improve the CC rate and eliminate the historical gender gap in utilization among Hispanic patients.

Predictors of surgical non-referral for colorectal liver metastases.

BACKGROUND: Surgical resection is the only curative option for patients with colorectal liver metastases (CRLM). The objective of our study was to identify factors associated with failure to refer patients with CRLM to a surgeon with oncologic and hepatobiliary expertise. MATERIALS AND METHODS: Data were retrospectively reviewed on 75 patients with CRLM treated at our institution. Patients were divided into referred and nonreferred groups for comparison. Quantitative assessment of association was tabulated using the odds ratio (OR). Statistical comparison was performed using the chi-square test and multiple regression models. Overall survival (OS) was calculated using the Kaplan-Meier method. Multivariate analysis was done using Cox regression. RESULTS: Factors independently associated with lower surgical referral rates included age ≥ 65 y (OR 0.29, 95% confidence interval [CI] 0.09-0.89, P = 0.032), bilobar CRLM (OR 0.35, 95% CI 0.09-0.97, P = 0.048), and presence of >3 CRLM (OR 0.33, 95% CI 0.11-0.94, P = 0.044). The 5-y OS for referred patients was 33% compared with only 8% in patients who were not referred (P < 0.001). Factors independently associated with worse OS included age ≥ 65 y (hazard ratio [HR] 2.01, 95% CI 1.12-3.59, P = 0.019), bilobar hepatic metastases (HR 3.04, 95% CI 1.62-5.70, P < 0.001), and the presence of extrahepatic metastases (HR 2.11, 95% CI 1.02-4.16, P = 0.011). Referral to a surgeon was associated with improved OS (HR 0.42, 95% CI 0.24-0.74, P = 0.003). CONCLUSIONS: Failure to refer CRLM patients for surgical evaluation is associated with aggressive biologic features that do not necessarily preclude resection. Determination of resectability should be made with input from appropriately trained surgical experts.

Anti-KIT designer T cells for the treatment of gastrointestinal stromal tumor.

BACKGROUND: Imatinib mesylate is an effective treatment for metastatic gastrointestinal stromal tumor (GIST). However, most patients eventually develop resistance and there are few other treatment options. Immunotherapy using genetically modified or designer T cells (dTc) has gained increased attention for several malignancies in recent years. The aims of this study were to develop and test novel anti-KIT dTc engineered to target GIST cells. METHODS: Human anti-KIT dTc were created by retroviral transduction with novel chimeric immune receptors (CIR). The gene for stem cell factor (SCF), the natural ligand for KIT, was cloned into 1st generation (SCF-CD3ζ, 1st gen) and 2nd generation (SCF-CD28-CD3ζ, 2nd gen) CIR constructs. In vitro dTc proliferation and tumoricidal capacity in the presence of KIT+ tumor cells were measured. In vivo assessment of dTc anti-tumor efficacy was performed by treating immunodeficient mice harboring subcutaneous GIST xenografts with dTc tail vein infusions. RESULTS: We successfully produced the 1st and 2nd gen anti-KIT CIR and transduced murine and human T cells. Average transduction efficiencies for human 1st and 2nd gen dTc were 50% and 42%. When co-cultured with KIT+ tumor cells, both 1st and 2nd gen dTc proliferated and produced IFNγ. Human anti-KIT dTc were efficient at lysing GIST in vitro compared to untransduced T cells. In mice with established GIST xenografts, treatment with either 1st or 2nd gen human anti-KIT dTc led to significant reductions in tumor growth rates. CONCLUSIONS: We have constructed a novel anti-KIT CIR for production of dTc that possess specific activity against KIT+ GIST in vitro and in vivo. Further studies are warranted to evaluate the therapeutic potential and safety of anti-KIT dTc.

Obstructive jaundice expands intrahepatic regulatory T cells, which impair liver T lymphocyte function but modulate liver cholestasis and fibrosis.

Although obstructive jaundice has been associated with a predisposition toward infections, the effects of bile duct ligation (BDL) on bulk intrahepatic T cells have not been clearly defined. The aim of this study was to determine the consequences of BDL on liver T cell phenotype and function. After BDL in mice, we found that bulk liver T cells were less responsive to allogeneic or syngeneic Ag-loaded dendritic cells. Spleen T cell function was not affected, and the viability of liver T cells was preserved. BDL expanded the number of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg), which were anergic to direct CD3 stimulation and mediated T cell suppression in vitro. Adoptively transferred CD4(+)CD25(-) T cells were converted into Treg within the liver after BDL. In vivo depletion of Treg after BDL restored bulk liver T cell function but exacerbated the degrees of inflammatory cytokine production, cholestasis, and hepatic fibrosis. Thus, BDL expands liver Treg, which reduce the function of bulk intrahepatic T cells yet limit liver injury.

The effects of sorafenib on liver regeneration in a model of partial hepatectomy.

BACKGROUND: Sorafenib is currently approved for advanced hepatocellular carcinoma (HCC) and is presently being studied as an adjuvant treatment for HCC following resection. The effects of sorafenib on liver regeneration have not been clearly defined. Our objective was to identify the effects of sorafenib on liver regeneration in a murine partial hepatectomy (PH) model. MATERIALS AND METHODS: We performed PH in C57Bl/6 mice treated with a range of sorafenib doses with assessments at several time points. Liver sinusoidal endothelial cells (LSEC) and hepatocyte DNA synthesis and proliferation were assessed with 5-bromo-2'-deoxyuridine (BrdU) and Ki67 by flow cytometry and immunohistochemistry. RESULTS: Treatment with sorafenib did not result in any deaths following PH. When we measured BrdU uptake to assess DNA synthesis, there was a statistically significant increase at 48 h post-PH for nonfibrotic LSEC following treatment with 60 mg/kg of sorafenib. However, BrdU and Ki67 staining among LSEC and hepatocytes was not significantly affected by sorafenib at any of the other doses or time points. BrdU and Ki67 flow cytometry data correlated with immunohistochemistry findings and postoperative liver weights. CONCLUSION: In a murine PH model, sorafenib did not alter the repair response of normal or fibrotic livers following PH as measured by changes in liver weight, DNA synthesis, and cellular proliferation. These findings suggest sorafenib administered following hepatic resection does not impair liver regeneration.

Feasibility of purely laparoscopic resection of locally advanced rectal cancer in obese patients.

BACKGROUND: Totally laparoscopic (without hand-assist) resection for rectal cancer continues to evolve, and both obesity and locally advanced disease are perceived to add to the complexity of these procedures. There is a paucity of data on the impact of obesity on perioperative and oncologic outcomes for totally-laparoscopic rectal cancer resection (TLRR) for locally advanced disease. METHODS: In order to identify potential limitations of TLRR, a single-institution database was queried and identified 26 patients that underwent TLRR for locally advanced rectal cancers (T3/T4) over a three-year period. Patients were classified as normal-weight (NW, body mass index (BMI)=18.5 to 24.9 kg/m2), overweight (OW, BMI=25 to 29.9 kg/m2) and obese (OB, BMI >/= 30 kg/m2). Perioperative outcomes, lymph node harvest and margin status were assessed. RESULTS: Seven patients were classified as NW (26.9%), 12 as OW (46.2%) and 7 as OB (26.9%). Age, tumor stage, gender and American Society of Anesthesiologists (ASA) scores were similar. OB had more co-morbidities (median 3.0, range 0.0 to 5.0 vs. 2.0, range 0.0 to 3.0 for NW and 1.0, range 0.0 to 3.0 for OW). Five patients had tumors <5 cm from anal verge (NW=2; OW=1; OB=2). A median of 19.0, range 9.0 to 32.0; 20.0, range 9.0 to 46.0 and 19.0, range 15.0 to 31.0 lymph nodes were retrieved in the NW, OW and OB, respectively (Not Significant (NS)). Median node ratios for NW, OW and OB were 0.32, 0.13 and 0.00, respectively. All groups had negative proximal and distal margins. Radial margins were negative for 100% of NW, 83.3% of OW and 85.7% of OB (NS). Conversion rates were 14.3% for NW, 16.7% for OW & 0% for OB (NS). NW, OW and OB had complication rates of 28.3%, 33.3% and 14.3%, respectively. Median operative time, median estimated blood loss and median length of hospital stay were similar for all groups. CONCLUSION: The perceived limitation that obesity would have on TLRR was not demonstrated by the analyzed data. Although our findings are limited by the modest sized cohort, the results suggest that it is reasonable to offer TLRR to obese patients with rectal cancer.

Laparoscopic spleen-preserving distal pancreatectomy in elderly subjects: splenic vessel sacrifice may be associated with a higher rate of splenic infarction.

BACKGROUND: Laparoscopic spleen-preserving distal pancreatectomy has gained popularity in recent years. Splenic preservation can be achieved with or without splenic vessel preservation (SVP). The potential morbidity of this approach in patients aged >70 years has not been well defined. METHODS: Ten patients aged >70 years underwent attempted laparoscopic spleen-preserving distal pancreatectomy within a 2-year period. Multiple patient parameters were examined and chi-squared analysis was used to evaluate the association between the operative technique (SVP or splenic vessel division [SVD]) and splenic infarction. The Mann-Whitney test was used to compare the SVP and SVD groups with regard to age, estimated blood loss (EBL), operating time, splenic volume and length of stay (LoS). RESULTS: Median age was 81 years (range: 71-92 years). Operating room time, LoS, EBL and complication rates were similar to those reported in published series of younger patients. In four patients, the splenic vessels were divided in a manner relying on short gastric collateral flow; SVP was achieved in all other patients. All four patients who underwent SVD developed splenic infarcts and three required splenectomy to manage this (P=0.002). Median LoS was increased in the SVD group (9.3 days vs. 4.3 days; P=0.053). Estimated blood loss was higher in the SVP group (200 ml vs. 100 ml; P=0.091). One pancreatic leak occurred. There were no mortalities. CONCLUSIONS: Spleen-preserving laparoscopic distal pancreatectomy can be performed safely in elderly patients, with results comparable with those achieved in younger subjects. However, elderly patients undergoing division of the splenic artery and vein may be at higher risk for splenic infarct and the aetiology of this is unclear.

Early results on the use of biomaterials as adjuvant to abdominal wall closure following cytoreduction and hyperthermic intraperitoneal chemotherapy.

BACKGROUND: Hyperthermic chemotherapy applies thermal energy to both abdominal wall as well as the intra-abdominal viscera. The combination of the hyperthemia, chemotherapy and cytoreductive surgery (CRS) is associated with a defined risk of abdominal wall and intestinal morbidity reported to be as high as 15%, respectively to date, no studies have evaluated the use of biomaterial mesh as adjuvant to abdominal wall closure in this group of patients. In the present report, we hypothesized that post HIPEC closure with a biomaterial can reduce abdominal wall morbidity after CRS and hyperthermic intraperitoneal chemotherapy. MATERIALS AND METHODS: All patients treated with HIPEC in a tertiary care center over 12 months (2008-2009) period were included. Eight patients received cytoreductive surgery followed by HIPEC for 90 minutes using Mitomycin C (15 mg q 45 minutes x 2). Abdominal wall closure was performed using Surgisis (Cook Biotech.) mesh in an underlay position with 3 cm fascial overlap-closure. Operative time, hospital length of stay (LOS) as well as postoperative outcome with special attention to abdominal wall and bowel morbidity were assessed. RESULTS: Eight patients, mean age 59.7 ys (36-80) were treated according to the above protocol. The primary pathology was appendiceal mucinous adenocarcinoma (n = 3) colorectal cancer (n = 3), and ovarian cancer (n = 2). Four patients (50%) presented initially with abdominal wall morbidity including incisional ventral hernia (n = 3) and excessive abdominal wall metastatic implants (n = 1). The mean peritoneal cancer index (PCI) was 8.75. Twenty eight CRS were performed (3.5 CRS/patient). The mean operating time was 6 hours. Seven patients had no abdominal wall or bowel morbidity, the mean LOS for these patients was 8 days. During the follow up period (mean 6.3 months), one patient required exploratory laparotomy 2 weeks after surgery and subsequently developed an incisional hernia and enterocutaneous fistula. CONCLUSION: The use of biomaterial mesh in concert with HIPEC enables the repair of concomitant abdominal wall hernia and facilitates abdominal wall closure following the liberal resection of abdominal wall tumors. Biomaterial mesh prevents evisceration on repeat laparotomy and resists infection in immunocompromised patients even when associated with bowel resection.

T cell infiltrate and outcome following resection of intermediate-grade primary neuroendocrine tumours and liver metastases.

BACKGROUND: Tumour-infiltrating lymphocytes (TILs) have been shown to predict survival in numerous malignancies. The importance of TILs in primary pancreatic neuroendocrine tumours (NETs) and NET liver metastases (NETLMs) has not been defined. METHODS: We identified 87 patients with NETs and 39 with NETLMs who had undergone resection. Immunohistochemistry was performed to determine TIL counts. Recurrence-free survival (RFS) and overall survival (OS) were determined using the log-rank test. RESULTS: The median follow-up time was 62 months in NET patients and 48 months in NETLM patients. Vascular invasion and histologic grade were the only independent predictors of outcome for NETs and NETLMs, respectively. Analysis of intermediate-grade NETs indicated that a dense T cell (CD3+) infiltrate was associated with a median RFS of 128 months compared with 61 months for those with low levels of intratumoral T cells (P= 0.05, univariate analysis). Examination of NETLMs revealed that a low level of infiltrating regulatory T cells (Treg, FoxP3+) was a predictor of prolonged survival (P < 0.01, univariate analysis). CONCLUSIONS: A robust T cell infiltrate is associated with improved RFS following resection of intermediate-grade NETs, whereas the presence of more Treg correlated with shorter OS after treatment of NETLMs. Further study of the immune response to intermediate-grade NETs and NETLMs is warranted.

Role of yttrium-90 selective internal radiation therapy in the treatment of liver-dominant metastatic colorectal cancer: an evidence-based expert consensus algorithm.

Surgical resection of colorectal liver metastases is associated with greater survival compared with non-surgical treatment, and a meaningful possibility of cure. However, the majority of patients are not eligible for resection and may require other non-surgical interventions, such as liver-directed therapies, to be converted to surgical eligibility. Given the number of available therapies, a general framework is needed that outlines the specific roles of chemotherapy, surgery, and locoregional treatments [including selective internal radiation therapy (SIRT) with Y-90 microspheres]. Using a data-driven, modified Delphi process, an expert panel of surgical oncologists, transplant surgeons, and hepatopancreatobiliary (HPB) surgeons convened to create a comprehensive, evidence-based treatment algorithm that includes appropriate treatment options for patients stratified by their eligibility for surgical treatment. The group coined a novel, more inclusive phrase for targeted locoregional tumor treatment (a blanket term for resection, ablation, and other emerging locoregional treatments): local parenchymal tumor destruction therapy. The expert panel proposed new nomenclature for 3 distinct disease categories of liver-dominant metastatic colorectal cancer that is consistent with other tumor types: (I) surgically treatable (resectable); (II) surgically untreatable (borderline resectable); (III) advanced surgically untreatable (unresectable) disease. Patients may present at any point in the algorithm and move between categories depending on their response to therapy. The broad intent of therapy is to transition patients toward individualized treatments where possible, given the survival advantage that resection offers in the context of a comprehensive treatment plan. This article reviews what is known about the role of SIRT with Y-90 as neoadjuvant, definitive, or palliative therapy in these different clinical situations and provides insight into when treatment with SIRT with Y-90 may be appropriate and useful, organized into distinct treatment algorithm steps.

HITM-SIR: phase Ib trial of intraarterial chimeric antigen receptor T-cell therapy and selective internal radiation therapy for CEA+ liver metastases.

Effective chimeric antigen receptor-modified T-cell (CAR-T) therapy for liver metastases (LM) will require innovative solutions to ensure efficient delivery and minimization of systemic toxicity. We previously demonstrated the safety of CAR-T hepatic artery infusions (HAI). We subsequently conducted the phase 1b HITM-SIR trial, in which six patients (pts) with CEA+ LM received anti-CEA CAR-T HAIs and selective internal radiation therapy (SIRT). The primary endpoint was safety with secondary assessments of biologic activity. Enrolled pts had a mean LM size of 6.4 cm, 4 pts had >10 LM, and pts received an average of two lines of prior systemic therapy. No grade 4 or 5 toxicities were observed, and there were no instances of severe cytokine-release syndrome (CRS) or neurotoxicity. The mean transduction efficiency was 60.4%. Following CAR-T HAI, reduced levels of GM-CSF-R, IDO, and PD-L1 were detected in LM, and serum CEA levels were stable or decreased in all subjects. Median survival time was 8 months (mean 11, range 4-31). Anti-CEA CAR-T HAI with subsequent SIRT was well tolerated, and biologic responses were demonstrated following failure of conventional therapy. HAI of CAR-T was once again confirmed not to be associated with severe CRS or neurotoxicity.

Extrahepatic cholangiocarcinoma: current surgical strategy.

Cholangiocarcinoma is a rare cancer. Although rare, it remains the second most common hepatobiliary cancer and its incidence is increasing worldwide. Extrahepatic cholangiocarcinoma can occur anywhere along the biliary tree and prognosis varies according to the location of disease.

STAT3 inhibition induces Bax-dependent apoptosis in liver tumor myeloid-derived suppressor cells.

Immunosuppressive myeloid-derived suppressor cells (MDSC) subvert antitumor immunity and limit the efficacy of chimeric antigen receptor T cells (CAR-T). Previously, we reported that the GM-CSF/JAK2/STAT3 axis drives liver-associated MDSC (L-MDSC) proliferation and blockade of this axis rescued antitumor immunity. We extended these findings in our murine liver metastasis (LM) model, by treating tumor-bearing mice with STAT3 inhibitors (STATTIC or BBI608) to further our understanding of how STAT3 drives L-MDSC suppressive function. STAT3 inhibition caused significant reduction of tumor burden as well as L-MDSC frequencies due to decrease in pSTAT3 levels. L-MDSC isolated from STATTIC or BBI608-treated mice had significantly reduced suppressive function. STAT3 inhibition of L-MDSC was associated with enhanced antitumor activity of CAR-T. Further investigation demonstrated activation of apoptotic signaling pathways in L-MDSC following STAT3 inhibition as evidenced by an upregulation of the pro-apoptotic proteins Bax, cleaved caspase-3, and downregulation of the anti-apoptotic protein Bcl-2. Accordingly, there was also a decrease of pro-survival markers, pErk and pAkt, and an increase in pro-death marker, Fas, with activation of downstream JNK and p38 MAPK. These findings represent a previously unrecognized link between STAT3 inhibition and Fas-induced apoptosis of MDSCs. Our findings suggest that inhibiting STAT3 has potential clinical application for enhancing the efficacy of CAR-T cells in LM through modulation of L-MDSC.

Lipopolysaccharide-stimulated RAW 264.7 macrophage inducible nitric oxide synthase and nitric oxide production is decreased by an omega-3 fatty acid lipid emulsion.

BACKGROUND: Omega-3 fatty acids (omega-3 FA) have been demonstrated to have anti-inflammatory properties, postulated to occur through several principal mechanisms, including (1) displacement of arachidonic acid from the cellular membrane; (2) shifting of prostaglandin E(2) and leukotriene B(4) production; and (3) molecular level alterations including decreased activation of nuclear factor kappa B and activator protein-1. An additional regulator that is likely associated is the production of nitric oxide (NO) by nitric oxide synthetase. NO is a short-lived free radical involved in many biological functions. However, excessive NO production can lead to complications, suggesting that decreased NO production is a potential target for some inflammatory diseases. We hypothesized that pretreating with an omega-3 FA lipid emulsion would decrease the production of NO in macrophages and that this effect would occur through alterations in inducible nitric oxide synthetase (iNOS). MATERIALS AND METHODS: Greiss reagent was used to assess NO production in RAW 264.7 macrophages following omega-3 or omega-6 FA treatment alone or in combination with lipopolysaccharide (LPS) stimulation for 12 h/24 h. iNOS levels were determined by Western blot. Tumor necrosis factor-alpha levels were determined by enzyme-linked immunosorbent assay. RESULTS: Following LPS-stimulation, omega-3 FA pretreatment at 12 and 24 h produced significantly less NO (P < 0.05) compared to omega-6 FA or media-only conditions. omega-3 FA pretreatment at 12 and 24 h also had less iNOS protein expression compared to omega-6 FA or media-only conditions. Tumor necrosis factor-alpha production was significantly decreased with omega-3 FA treatment compared to omega-6 FA treatment (P < 0.05) after 24 h LPS stimulation. CONCLUSION: These experiments demonstrate that, in addition to other anti-inflammatory effects, omega-3 FA lipid emulsions also significantly lower NO production in LPS-stimulated macrophages through altered iNOS protein expression.

Feasibility evaluation of emodin (rhubarb extract) as an inhibitor of pancreatic cancer cell proliferation in vitro.

Emodin is a commonly used traditional herbal treatment in China, including use for pancreatic malignancy. In this study, the potential for emodin to inhibit pancreatic cancer cell proliferation was examined using 4 human pancreatic adenocarcinoma cell lines: Mia Paca-2, BxPC-3, Panc-1, and L3.6pl. WST-1 proliferation, propidium iodide flow cytometry cell cycle analysis, and poly-ADP-ribose polymerase (PARP) Western blot analysis were performed. Forty-eight-hour treatment with 50 muM emodin inhibited proliferation in Mia Paca-2 cells by 42%, BxPc-3 by 38%, L3.6pl by 56%, and Panc-1 by 18% (all P < .01). In three-fourths of the cell lines, emodin treatment resulted in an increase (from 4.7% to 22%) in the cell population number in apoptosis when measured by flow cytometric analysis. Mia Paca-2 revealed a significant PARP cleavage product when compared with control. These feasibility experiments provide initial evidence that emodin exerts an antiproliferative effect, likely through apoptosis induction-related mechanism(s), that is reproducible in various human pancreatic cancer cell lines.

Gastric adenocarcinoma arising from fundic gland polyps in a patient with familial adenomatous polyposis syndrome.

Familial adenomatous polyposis (FAP) is a rare hereditary syndrome characterized by multiple colorectal polyps and early development of colorectal cancer. Although FAP uniformly involves the large bowel, it may also produce lesions in the stomach and upper intestinal tract. Fundic gland polyps are the most common gastric lesion in FAP. In the general population, these polyps are considered benign and have no malignant potential. However, in FAP patients, fundic gland polyps have been occasionally recognized as precursor lesions from which invasive cancer may develop. Herein, we present a case of gastric adenocarcinoma arising from fundic gland polyps in an FAP patient. We also review reported cases of gastric cancer in FAP and FAP variant patients in an effort to better understand the pathology, clinical course, and optimal screening and treatment strategies for this disease manifestation.

Efficacy and Tolerability of 5-Year Adjuvant Imatinib Treatment for Patients With Resected Intermediate- or High-Risk Primary Gastrointestinal Stromal Tumor: The PERSIST-5 Clinical Trial.

Importance: Three years of adjuvant imatinib mesylate therapy is associated with reduced recurrence rates and improved overall survival in patients with high-risk primary gastrointestinal stromal tumor (GIST) compared with patients who receive 1 year of treatment. The impact of a longer duration of therapy is unknown. Objective: To determine whether adjuvant treatment for primary GIST with imatinib for 5 years is tolerable and efficacious. Design, Setting, and Participants: This prospective, single-arm, phase 2 clinical trial (Postresection Evaluation of Recurrence-free Survival for Gastrointestinal Stromal Tumors With 5 Years of Adjuvant Imatinib [PERSIST-5]) included adult patients with primary GIST (expressing KIT) at 21 US institutions who underwent a macroscopically complete resection and were at intermediate or high risk of recurrence, defined as primary GIST at any site measuring 2 cm or larger with 5 or more mitoses per 50 high-power field or nongastric primary GIST measuring 5 cm or larger. Data were collected from August 5, 2009, through December 20, 2016. Interventions: Imatinib, 400 mg once daily, orally for 5 years or until discontinuation of therapy because of progression or intolerance. Main Outcomes and Measures: The primary end point was recurrence-free survival (RFS). The secondary end point was overall survival. Results: Of the 91 patients enrolled, 48 (53%) were men with a median age of 60 years (range, 30-90 years). Median tumor size was 6.5 cm (range, 2.3-30.0 cm). Median treatment duration was 55.1 months (range, 0.5-60.6 months); 46 patients (51%) completed 5 years of imatinib therapy. Estimated 5-year RFS was 90% (95% CI, 80%-95%), and overall survival was 95% (95% CI, 86%-99%). Recurrence was noted in 7 patients: 1 had disease recur while receiving imatinib (PDGFRA D842V mutation) and died; 6 had disease recur after discontinuation of imatinib therapy. Two additional deaths were unrelated to treatment or tumor progression. Forty-five patients (49%) stopped treatment early because of patient choice (10 [21%]), adverse events (15 [16%]), or other (11 [12%]). All 91 patients experienced at least 1 adverse event, and 17 (19%) experienced grade 3 or 4 adverse events. Conclusions and Relevance: In this first adjuvant trial, to our knowledge, of patients with resected primary GIST who received 5 years of imatinib therapy, no patient with imatinib-sensitive mutations had disease recur during therapy. For patients in whom disease recurred, recurrence was within 2 years of discontinuation of imatinib therapy. Approximately half of the patients discontinued treatment early, most commonly because of patient choice, thus emphasizing the importance of close clinical monitoring to continue imatinib treatment for patients at appropriate risk. Trial Registration: ClinicalTrials.gov identifier: NCT00867113.

Inhibition of proliferation by omega-3 fatty acids in chemoresistant pancreatic cancer cells.

BACKGROUND: Pancreatic cancer-gemcitabine (GEM) chemoresistance has been demonstrated to be associated with enhanced NF-kB activation and antiapoptotic protein synthesis. The well-known capacity of omega-3 fatty acids (n-3 FAs) to inhibit NF-kB activation and promote cellular apoptosis has the potential to restore or facilitate gemcitabine chemosensitivity. METHODS: Four pancreatic cancer cell lines (MIA PaCa-2, BxPC-3, PANC-1, and L3.6), each with distinct basal NF-kB and differing GEM sensitivity profiles, were administered: 100 uM of (1) n-3FA, (2) n-6FA, (3) GEM, (4) n-3FA + GEM, or (5) n-6FA + GEM for 24 and 48 hours. Proliferation was assessed using the WST-1 assay. To define the mechanism(s) of altered proliferation, electron mobility shift assay for NF-kB activity, western blots of phoshoStat3, phosphoIkappaB, and poly(ADP-ribose) polymerase (PARP) cleavage were performed in the MIA PaCa-2 cell line. RESULTS: All cell lines demonstrated a time/dose-dependent inhibition of proliferation in response to n-3FA. For MIA PaCa-2 cells, n-3FA and n-3FA + GEM treatment resulted in reduction of I-kB phosphorylation and NF-kB activation when compared with n-6FA control. n-3FA and combination treatment also significantly decreased Stat3 phosphorylation, whereas GEM alone had no effect. n-3FAs and n-3FA + GEM groups demonstrated increased PARP cleavage, mirroring NF-kB activity and Stat3 phosphorylation. CONCLUSIONS: n-3 FA treatment is specifically associated with inhibition of proliferation in these four pancreatic cell lines irrespective of varied gemcitabine resistance. An experimental paradigm to screen for potential contributory mechanism(s) in altered pancreatic cancer cellular proliferation was defined, and using this approach the co-administration of n-3 FA with GEM inhibited GEM-induced NF-kB activation and restored apoptosis in the MIA PaCa-2 cell-line.

Complete eradication of hepatic metastasis from colorectal cancer by Yttrium-90 SIRT.

Yttrium-90 (Y-90) radioembolization, also known as selective internal radiation therapy (SIRT), is a regional hepatic therapy used in the treatment of unresectable colorectal cancer (CRC) liver metastases. In SIRT, Y-90 impregnated microspheres are injected into the VASCULAR SUPPLY of hepatic tumor, leading to selective irradiation and necrosis of tumor TISSUE. While several studies demonstrate improved local control and survival with SIRT, the specific indications for this therapy have yet to be defined. Typically, SIRT is given in combination with chemotherapy as multimodal treatment for unresectable hepatic CRC. However, it has also found increasing use as a salvage therapy in chemo-refractory patients. Herein, the authors describe their experience with SIRT as "stand alone" therapy in a surgically-prohibitive, chemotherapy naive patient with hepatic CRC metastasis. The results suggest that Y-90 SIRT may have potential applications beyond its usual role as a palliative or salvage therapy for unresectable hepatic CRC.