A review of response in neoadjuvant therapy for exocrine pancreatic cancer.

Despite overall advances in cancer therapy, patients with pancreatic ductal adenocarcinoma continue to have a poor prognosis. While adjuvant therapy is still considered standard, there is mounting evidence that neoadjuvant therapy confers similar benefits in patients with locally advanced disease. The primary measures of response are radiographic, biochemical, margin status, and pathologic. Given overall low response rates and the need for new treatment strategies, standard metrics remain important to the investigation of new systemic agents.

Adequate Lymphadenectomy as a Quality Measure in Esophageal Cancer: Is there an Association with Treatment Approach?

BACKGROUND: The national comprehensive cancer network defines adequate lymphadenectomy as evaluation of ≥ 15 lymph nodes in esophageal cancer. However, varying thresholds have been suggested following neoadjuvant therapy. OBJECTIVES: Our objectives were to (1) explore trends in adequate lymphadenectomy rates over time; (2) evaluate unadjusted lymphadenectomy yield by treatment characteristics; and (3) identify independent factors associated with adequate lymphadenectomy. METHODS: The National Cancer Data Base was used to identify patients who underwent esophagectomy for cancer from 2004 to 2015. Adequate lymphadenectomy trends over time were evaluated using the Cochrane-Armitage test, and lymph node yield by treatment approach was compared using the Mann-Whitney U and Kruskal-Wallis tests. Associations with treatment factors were assessed by multivariable logistic regression. RESULTS: Among 24,413 patients, 9919 (40.6%) had adequate lymphadenectomy. Meeting the nodal threshold increased over time (52.6% in 2015 vs. 26.0% in 2004; p < 0.01). Lymph node yield did not differ based on neoadjuvant therapy (median 12 [interquartile range 7-19] with and without neoadjuvant therapy; p = 0.44). Adequate lymphadenectomy was not associated with neoadjuvant therapy (40.5% vs. 40.8%, odds ratio [OR] 0.94, 95% confidence interval [CI] 0.82-1.07), but was associated with surgical approach (52.7% of laparoscopic cases, OR 1.28, 95% CI 1.06-1.56; 61.2% of robotic cases, OR 1.71, 95% CI 1.34-2.19, vs. 43.5% of open cases), and increasing annual esophagectomy volume (55.6% in the fourth quartile vs. 32.6% in the first quartile; OR 3.57, 95% CI 2.35-5.43). CONCLUSIONS: Despite increases over time, only 50% of patients undergo adequate lymphadenectomy during esophageal cancer resection. Adequate lymphadenectomy was not associated with neoadjuvant therapy. Focusing on surgical approach and esophagectomy volume may further improve adequate lymphadenectomy rates.

Near-Infrared Fluorescent Endoscopic Image-Guided Photothermal Ablation Therapy of Colorectal Cancer Using Dual-Modal Gold Nanorods Targeting Tumor-Infiltrating Innate Immune Cells in a Transgenic TS4 CRE/APC loxΔ468 Mouse Model.

Colorectal cancer (CRC) is diagnosed with colonoscopy and treated with focal therapies. CRC is a good candidate for nanoparticle-mediated photothermal ablation (PTA) therapy. Herein, we developed a near-infrared fluorescent (NIRF) endoscopic image-guided PTA approach using a nanoparticle capable of simultaneously diagnosing and treating CRC. Dual-modal NIR heating and fluorescent gold nanorods (dual-modal GNRs) were synthesized by conjugation of GNRs to an NIRF probe. To validate the translational potential of our approach, a well-characterized transgenic TS4 CRE/APC loxΔ468 colon cancer mouse model was used to carry out NIRF image-guided PTA using our dual-modal GNRs under clinically relevant conditions. Intravenously infused dual-modal GNRs were effectively targeted at colon polyps by immunogenic capturing of the GNRs within tumor-infiltrating innate immune cells. NIRF endoscopic image-guided PTA using the GNRs permitted successful detection and ablation of inflammatory colon polyps. NIRF endoscopy image-guided PTA using dual-modal GNRs can be utilized for diagnosis and treatment of CRC and various inflammatory diseases.

Omega-3 Fatty Acids Prevent Early Pancreatic Carcinogenesis via Repression of the AKT Pathway.

Pancreatic cancer remains a daunting foe despite a vast number of accumulating molecular analyses regarding the mutation and expression status of a variety of genes. Indeed, most pancreatic cancer cases uniformly present with a mutation in the KRAS allele leading to enhanced RAS activation. Yet our understanding of the many epigenetic/environmental factors contributing to disease incidence and progression is waning. Epidemiologic data suggest that diet may be a key factor in pancreatic cancer development and potentially a means of chemoprevention at earlier stages. While diets high in ω3 fatty acids are typically associated with tumor suppression, diets high in ω6 fatty acids have been linked to increased tumor development. Thus, to better understand the contribution of these polyunsaturated fatty acids to pancreatic carcinogenesis, we modeled early stage disease by targeting mutant KRAS to the exocrine pancreas and administered diets rich in these fatty acids to assess tumor formation and altered cell-signaling pathways. We discovered that, consistent with previous reports, the ω3-enriched diet led to reduced lesion penetrance via repression of proliferation associated with reduced phosphorylated AKT (pAKT), whereas the ω6-enriched diet accelerated tumor formation. These data provide a plausible mechanism underlying previously observed effects of fatty acids and suggest that administration of ω3 fatty acids can reduce the pro-survival, pro-growth functions of pAKT. Indeed, counseling subjects at risk to increase their intake of foods containing higher amounts of ω3 fatty acids could aid in the prevention of pancreatic cancer.

National assessment of margin status as a quality indicator after pancreatic cancer surgery.

BACKGROUND: Surgical margin involvement is an important outcome after pancreatic cancer surgery; however, variation in pathologic review practices may limit its use as a quality indicator. Our objectives were to assess variation in hospital performance and the reliability of margin involvement after pancreatic cancer surgery. METHODS: From the National Cancer Data Base, patients who underwent pancreatic resection for stage I to III adenocarcinoma were identified. Risk-adjusted surgical margin involvement was evaluated using hierarchical regression methods, and variation in hospital performance and reliability was determined. RESULTS: From 1,002 hospitals, 14,889 patients underwent pancreatic resection for adenocarcinoma, and 3,573 (24.0 %) had an involved surgical margin (R1 22.8 %; R2 1.2 %). The strongest predictors associated with margin involvement were T stage [T3: odds ratio (OR) 2.08, 95 % confidence interval (CI) 1.68-2.59; T4: OR 7.26, 95 % CI 5.50-9.60; vs. T1] and tumor size (2-3.9 cm: OR 1.66, 95 % CI 1.39-1.98, ≥ 4 cm: OR 2.28, 95 % CI 1.90-2.74; vs. <2 cm). Factors associated with a decreased likelihood of margin involvement were the use of neoadjuvant therapy and hospital type (academic and National Cancer Institute-designated comprehensive cancer centers vs. community). At the hospital level, the mean risk-adjusted surgical margin involvement rate was 25.9 % and ranged 10.1 to 50.5 %. Twenty-one (2.1 %) hospitals had lower-than-expected and 17 (1.7 %) had higher-than-expected margin involvement. A minimum acceptable reliability of 0.4 was met after 13 cases and was achieved by 249 hospitals that performed 79 % of pancreatic resections assessed. CONCLUSIONS: Despite differences in pathologic evaluation practices, hospitals can be feasibly and reliably provided comparative data on surgical margin status after resection for pancreatic cancer.

PI3K/AKT signaling is essential for communication between tissue-infiltrating mast cells, macrophages, and epithelial cells in colitis-induced cancer.

PURPOSE: To understand signaling pathways that shape inflamed tissue and predispose to cancer is critical for effective prevention and therapy for chronic inflammatory diseases. We have explored phosphoinositide 3-kinase (PI3K) activity in human inflammatory bowel diseases and mouse colitis models. EXPERIMENTAL DESIGN: We conducted immunostaining of phosphorylated AKT (pAKT) and unbiased high-throughput image acquisition and quantitative analysis of samples of noninflamed normal colon, colitis, dysplasia, and colorectal cancer. Mechanistic insights were gained from ex vivo studies of cell interactions, the piroxicam/IL-10(-/-) mouse model of progressive colitis, and use of the PI3K inhibitor LY294002. RESULTS: Progressive increase in densities of pAKT-positive tumor-associated macrophages (TAM) and increase in densities of mast cells in the colonic submucosa were noted with colitis and progression to dysplasia and cancer. Mast cells recruited macrophages in ex vivo migration assays, and both mast cells and TAMs promoted invasion of cancer cells. Pretreatment of mast cells with LY294002 blocked recruitment of TAMs. LY294002 inhibited mast cell and TAM-mediated tumor invasion, and in mice, blocked stromal PI3K, colitis, and cancer. CONCLUSION: The PI3K/AKT pathway is active in cells infiltrating inflamed human colon tissue. This pathway sustains the recruitment of inflammatory cells through a positive feedback loop. The PI3K/AKT pathway is essential for tumor invasion and the malignant features of the piroxicam/IL-10(-/-) mouse model. LY294002 targets the PI3K pathway and hinders progressive colitis. These findings indicate that colitis and progression to cancer are dependent on stromal PI3K and sensitive to treatment with LY294002.

Wait times for cancer surgery in the United States: trends and predictors of delays.

BACKGROUND: Patients frequently voice concerns regarding wait times for cancer treatment; however, little is known about the length of wait times from diagnosis to surgery in the United States. Our objectives were (1) to assess changes in wait times over the past decade and (2) to identify patient, tumor, and hospital factors associated with prolonged wait times for initial cancer treatment. METHODS: Using the National Cancer Data Base (1995-2005), 1,228,071 patients were identified who underwent resection for nonmetastatic breast, colon, esophageal, gastric, liver, lung, pancreatic, and rectal cancer at 1443 hospitals. Multivariable models were developed to assess factors associated with time to treatment. RESULTS: From 1995 to 2005, the median time from diagnosis to treatment increased for all cancers (P < 0.0001). The time from diagnosis to treatment was significantly longer at National Cancer Institute Comprehensive Cancer Centers and Veterans' Administration institutions versus community hospitals (P < 0.0001). On multivariable analysis, patients were significantly more likely to undergo initial treatment > 30 days from diagnosis if older (6 of 8 cancers), black (5 of 8 cancers), had more comorbidities (6 of 8 cancers), had Stage I disease (7 of 8 cancers), or were treated at National Cancer Institute Comprehensive Cancer Centers or Veterans' Affairs institutions (all cancers). CONCLUSIONS: Wait times for cancer treatment have increased over the last decade. As case loads increase, wait times for treatment are likely to continue increasing, potentially resulting in additional treatment delay. Additional resources and strategies are needed to reduce wait times for cancer treatment in the United States.

A high omega-3 fatty acid diet mitigates murine pancreatic precancer development.

BACKGROUND: Diets containing omega-3 (ω-3) fat have been associated with decreased tumor development in the colon, breast, and prostate. We assessed the effects of a diet rich in ω-3 fat on the development of pancreatic precancer in elastase (EL)-Kras transgenic mice and examined the effect of an ω-3 fatty acid on pancreatic cancer cells in vitro. MATERIALS AND METHODS: Two cohorts of EL-Kras mice were fed a high ω-3 fat diet (23% menhaden oil) for 8 and 11 mo and compared with age-matched EL-Kras mice fed standard chow (5% fat). Pancreata from all mice were scored for incidence and frequency of precancerous lesions. Immunohistochemistry was performed for proliferating cell nuclear antigen (PCNA) to assess proliferative index in lesions of mice fed either a high ω-3 or standard diet. In vitro, the effect of the ω-3 fatty acid, docosahexaenoic acid (DHA), on two pancreatic cancer cell lines was assessed. Cancer cell proliferation was assessed with an MTT assay; cell cycle analysis was performed by flow cytometry; and apoptosis was assessed with annexin/PI staining. RESULTS: The incidence, frequency, and proliferative index of pancreatic precancer in EL-Kras mice was reduced in mice fed a high ω-3 fat diet compared with mice fed a standard chow. In vitro, DHA treatment resulted in a concentration-dependent decrease in proliferation through both G1/G0 cell cycle arrest and induction of apoptosis. CONCLUSIONS: A high ω-3 fat diet mitigates pancreatic precancer by inhibition of cellular proliferation through induction of cell cycle arrest and apoptosis.

Comparison of commission on cancer-approved and -nonapproved hospitals in the United States: implications for studies that use the National Cancer Data Base.

BACKGROUND: The Commission on Cancer (CoC) designates cancer programs on the basis of the ability to provide a wide range of oncologic services and specialists. All CoC-approved hospitals are required to report their cancer diagnoses to the National Cancer Data Base (NCDB), and the cancer diagnoses at these hospitals account for approximately 70% of all new cancers diagnosed in the United States annually. However, it is unknown how CoC-approved programs compare with non-CoC-approved hospitals. METHODS: By using the American Hospital Association Annual Survey Database (2006), CoC-approved and non-CoC-approved hospitals were compared with respect to structural characteristics (ie, accreditations, geography, and oncologic services provided). RESULTS: Of the 4,850 hospitals identified, 1,412 (29%) were CoC-approved hospitals, and 3,438 (71%) were not CoC-approved hospitals. The proportion of CoC-approved hospitals varied at the state level from 0% in Wyoming to 100% in Delaware. Compared with non-CoC-approved hospitals, CoC-approved programs were more frequently accredited by the Joint Commission, designated as a Comprehensive Cancer Center by the National Cancer Institute, and affiliated with a medical school or residency program (P < .001). CoC-approved hospitals were less likely to be critical access hospitals or located in rural areas (P < .001). CoC-approved hospitals had more total beds and performed more operations per year (P < .001). CoC-approved programs more frequently offered oncology-related services, including screening programs, chemotherapy and radiation therapy services, and hospice/palliative care (P < .001). CONCLUSION: Compared with non-CoC-approved hospitals, CoC-approved hospitals were larger, were more frequently located in urban locations, and had more cancer-related services available to patients. Studies that use the NCDB should acknowledge this limitation when relevant.

Lymph node evaluation as a colon cancer quality measure: a national hospital report card.

BACKGROUND: Examination of 12 or more regional lymph nodes for colon cancer is associated with improved staging and survival, and the National Quality Forum recently endorsed lymph node examination for colon cancer as a quality surveillance measure. However, information regarding the extent of hospital compliance with the 12-node measure in the United States is lacking. METHODS: From the National Cancer Data Base, 1296 hospitals that performed 156 789 colectomies in 1996-1997 and 2004-2005 were identified, and rates of hospital-level compliance (defined as examination of >or=12 nodes in >or=75% of patients) in these two time periods were compared. Multivariable models were developed to determine if hospital type, volume, or differences in case mix were associated with 12-node measure compliance. All statistical tests were two-sided. RESULTS: In 1996-1997, 15% of hospitals were compliant with the 12-node measure; in 2004-2005 the percentage of compliant hospitals had increased to 38%. From 1996-1997 to 2004-2005, 12-node measure compliance increased at 980 hospitals, remained unchanged at 6 hospitals, and decreased at 310 hospitals. In 2004-2005, National Cancer Institute-designated Comprehensive Cancer Centers were more frequently compliant with the 12-node measure than other academic hospitals, Veterans' Administration hospitals, or community hospitals (78.1% versus 52.4%, 53.1%, and 33.7%, respectively, all P < .001), even after adjustment for differences in characteristics of the colon cancer patients at these hospitals. CONCLUSIONS: This study provides a national report card of nearly 1300 hospitals showing that more than 60% of institutions failed to achieve a compliance benchmark for the 12-node measure. Considerable improvement is needed in colon cancer nodal evaluation in the United States.

Effect of hospital type and volume on lymph node evaluation for gastric and pancreatic cancer.

HYPOTHESIS: For gastric and pancreatic cancer, regional lymph node evaluation is important to accurately stage disease in a patient and may be associated with improved survival. We hypothesized that National Comprehensive Cancer Network (NCCN), National Cancer Institute (NCI)-designated institutions, and high-volume hospitals examine more lymph nodes for gastric and pancreatic malignant neoplasms than do low-volume centers and community hospitals. DESIGN: Volume-outcome study. SETTING: Academic research. PATIENTS: Using the National Cancer Data Base (January 1, 2003, to December 31, 2004), patients were identified who underwent resection for gastric (n = 3088) and pancreatic (n = 1130 [pancreaticoduodenectomy only]) cancer. MAIN OUTCOME MEASURES: Multivariable logistic regression analysis was used to assess the effect of hospital type and volume on nodal evaluation (>or=15 nodes). RESULTS: Only 23.2% of patients with gastric cancer and 16.4% of patients with pancreatic cancer in the United States underwent evaluation of at least 15 lymph nodes. Patients undergoing surgery had more lymph nodes examined at NCCN-NCI hospitals than at community hospitals (median, 12 vs 6 for gastric cancer and 9 vs 6 for pancreatic cancer; P < .001). Patients at highest-volume hospitals had more lymph nodes examined than patients at low-volume hospitals (median, 10 vs 6 for gastric cancer and 8 vs 6 for pancreatic cancer; P < .001). On multivariable analysis, patients undergoing surgery at NCCN-NCI and high-volume hospitals were more likely to have at least 15 lymph nodes evaluated compared with patients undergoing surgery at community hospitals and low-volume centers (P < .001 and P =.02, respectively). CONCLUSIONS: Nodal examination is important for staging, adjuvant therapy decision making, and clinical trial stratification. Moreover, differences in nodal evaluation may contribute to improved long-term outcomes at NCCN-NCI centers and high-volume hospitals for patients with gastric and pancreatic cancer.

National failure to operate on early stage pancreatic cancer.

BACKGROUND: Despite studies demonstrating improved outcomes, pessimism persists regarding the effectiveness of surgery for pancreatic cancer. Our objective was to evaluate utilization of surgery in early stage disease and identify factors predicting failure to undergo surgery. METHODS: Using the National Cancer Data Base (1995-2004), 9559 patients were identified with potentially resectable tumors (pretreatment clinical Stage I: T1N0M0 and T2N0M0). Multivariate models were employed to identify factors predicting failure to undergo surgery and assess the impact of pancreatectomy on survival. RESULTS: Of clinical Stage I patients 71.4% (6823/9559) did not undergo surgery; 6.4% (616/9559) were excluded due to comorbidities; 4.2% (403/9559) refused surgery; 9.1% (869/9559) were excluded due to age; and 38.2% (3,644/9559) with potentially resectable cancers were classified as "not offered surgery." Of the 28.6% (2736/9559) of patients who underwent surgery, 96.0% (2630/2736) underwent pancreatectomy, and 4.0% (458/2736) had unresectable tumors. Patients were less likely to undergo surgery if they were older than 65 years, were black, were on Medicare or Medicaid, had pancreatic head lesions, earned lower annual incomes, or had less education (P < 0.0001). Patients were less likely to receive surgery at low-volume and community centers. Patients underwent surgery more frequently at National Cancer Institute/National Comprehensive Cancer Network-designated cancer centers (P < 0.0001). Patients who were not offered surgery had significantly better survival than those with Stage III or IV disease but worse survival than patients who underwent pancreatectomy for Stage I disease (P < 0.0001). CONCLUSIONS: This is the first study to characterize the striking underuse of pancreatectomy in the United States. Of early stage pancreatic cancer patients without any identifiable contraindications, 38.2% failed to undergo surgery.