Preoperative Therapy Regimen Influences the Incidence and Implication of Nodal Downstaging in Patients with Gastric Cancer.

PURPOSE: Nodal downstaging after preoperative therapy for gastric cancer has been shown to impart excellent prognosis, but this has not been validated in a national cohort. The role of neoadjuvant chemoradiation (NACR) in nodal downstaging remains unclear when compared with that of neoadjuvant chemotherapy alone (NAC). Furthermore, it is unknown whether the prognostic implications of nodal downstaging differ by preoperative regimen. MATERIALS AND METHODS: Using the National Cancer Database, overall survival (OS) duration was compared among natural N0 (cN0/ypN0), downstaged N0 (cN+/ypN0), and node-positive (ypN+) gastric cancer patients treated with NACR or NAC. Factors associated with nodal downstaging were examined in a propensity score-matched cohort of cN+ patients, matched 1:1 by receipt of NACR or NAC. RESULTS: Of 7,426 patients (natural N0 [n=1,858, 25.4%], downstaged N0 [n=1,813, 24.4%], node-positive [n=3,755, 50.4%]), 58.2% received NACR, and 41.9% received NAC. The median OS durations of downstaged N0 (5.1 years) and natural N0 (5.6 years) patients were similar to one another and longer than that of node-positive patients (2.1 years) (P<0.001). In the matched cohort of cN+ patients, more recent diagnosis (2010-2015 vs. 2004-2009) (odds ratio [OR], 2.57; P<0.001) and NACR (OR, 2.02; P<0.001) were independently associated with nodal downstaging. The 5-year OS rate of downstaged N0 patients was significantly lower after NACR (46.4%) than after NAC (57.7%) (P=0.003). CONCLUSIONS: Downstaged N0 patients have the same prognosis as natural N0 patients. Nodal downstaging occurred more frequently after NACR; however, the survival benefit of nodal downstaging after NACR may be less than that when such is achieved by NAC.

Impact of tumor regression grade on recurrence after preoperative chemoradiation and gastrectomy for gastric cancer.

BACKGROUND AND OBJECTIVES: It is unknown whether the degree of response to preoperative therapy correlates with locoregional recurrence (LR) or distant recurrence (DR) after resection of gastric cancer. METHODS: Patients who underwent resection of gastric adenocarcinoma following chemotherapy and chemoradiation (1995-2015) were reviewed. The tumor regression grade (TRG) was defined by the percentage of viable tumor cells in the specimen (TRG0 = 0%; TRG1 = 1%-2%; TRG2 = 3%-50%; TRG3 ≥ 50%). The relationships among TRG, recurrence-free survival (RFS), LR, and DR were examined. RESULTS: Two hundred forty-seven patients met the inclusion criteria (TRG0, 52 [21%]; TRG1, 49 [20%]; TRG2, 98 [40%]; TRG3, 48 [19%]). LR and DR occurred in 6.1% and 32.0% of patients, respectively. No patient with TRG0 experienced LR. R1 resection (6%-15%) and LR (6%-8%) rates were similar among TRG1-3 patients. R1 resection was associated with LR (hazard ratio [HR], 17.85; P < .001). ypN status (HR, 2.44; P = .004) and linitis plastica (HR, 2.90; P < .001) were associated with DR. TRG was not independently associated with RFS, LR, or DR. CONCLUSIONS: TRG0 imparted excellent local control. However, TRG1-3 patients had similar R1 resection rates and therefore similar LR. DR is associated with ypN status and linitis plastica, not TRG.

Characteristics and Survival of Gastric Cancer Patients with Pathologic Complete Response to Preoperative Therapy.

BACKGROUND: Pathologic complete response of a primary tumor (ypT0) after preoperative therapy is associated with improved overall survival (OS). However, whether other variables are associated with outcome for gastric cancer patients with ypT0 status is unknown. METHODS: This study reviewed an institutional database of patients who underwent resection of gastric or gastroesophageal adenocarcinoma after preoperative therapy and identified patients with ypT0 status. Cox regression models were used to identify clinicopathologic predictors of OS. RESULTS: Of 77 patients with ypT0 status identified in this study, 36 (47%) had gastroesophageal junction tumors. At presentation, 62 patients (81%) had clinical T3 disease, and 7 (9%) had clinical T4 disease. The clinical nodal status was positive (cN+) for 45 patients (58%). Preoperative chemoradiation was administered to 75 patients (97%). The median follow-up duration was 3.54 years. The median OS was 10 years, and the 5-year OS rate was 61%. Univariable analysis identified age of 65 years or older at the time of diagnosis, histologic grade, and ypN status as significant predictors of OS. Multivariable analysis confirmed age of 65 years or older [hazard ratio (HR), 4.26; p < 0.001] and persistent nodal disease (ypN+ status; HR, 5.12; p < 0.001) to be independently associated with OS. Clinical stage was not associated with survival. In the subset of ypT0N0 patients, no clinicopathologic feature was predictive of survival. CONCLUSION: For gastric or gastroesophageal adenocarcinoma patients with ypT0 status after preoperative therapy, ypN+ status substantially reduced survival. Pretreatment clinical stage had no impact on OS for patients with a pathologic complete response.

Long-term survival in patients with pancreatic ductal adenocarcinoma.

BACKGROUND: Long-term survival (LTS) is uncommon for patients with pancreatic ductal adenocarcinoma (PDAC). We sought to identify factors that predict 10-year, LTS after resection of PDAC. METHODS: We identified all patients with PDAC who underwent resection at UCLA after 1990 and included all patients eligible for observed LTS (1/1/1990-12/31/2004). An independent pathologist reconfirmed the diagnosis of PDAC in patients with LTS. Logistic regression was used to predict LTS on the basis of patient and tumor characteristics. RESULTS: Of 173 included patients, 53% were male, median age at diagnosis was 66 years, and median survival was 23 months. The rate of observed LTS was 12.1% (n = 21). Age, sex, number of lymph nodes evaluated, margin status, lymphovascular invasion, and adjuvant chemotherapy and radiation were not associated with LTS. The following were associated with LTS on bivariate analysis: low AJCC stage (Ia, Ib, IIa) (P = .034), negative lymph node status (P = .034), low grade (well-, moderately-differentiated) (P = .001), and absence of perineural invasion (P = .019). Only low grade (odds ratio 7.17, P = .012) and absent perineural invasion (odds ratio 3.28, P = .036) were independently associated with increased odds of LTS. Our multivariate model demonstrated good discriminatory power for LTS, as indicated by a c-statistic of 0.7856. CONCLUSION: Absence of perineural invasion and low tumor grade were associated with greater likelihood of LTS. Understanding the tumor biology of LTS may provide critical insight into a disease that is typically marked by aggressive behavior and limited survival.

Robust Early Inflammation of the Peripancreatic Visceral Adipose Tissue During Diet-Induced Obesity in the KrasG12D Model of Pancreatic Cancer.

OBJECTIVES: Obesity increases the incidence of multiple types of cancer. Our previous work has shown that a high-fat, high-calorie diet (HFCD) leads to visceral obesity, pancreatic inflammation, and accelerated pancreatic neoplasia in KrasG12D (KC) mice. In this study, we aimed to investigate the effects of an HFCD on visceral adipose inflammation with emphasis on potential differences between distinct visceral adipose depots. METHODS: We examined the weight and visceral obesity in both wild-type and KC mice on either control diet (CD) or HFCD. After 3 months, mice were killed for histological examination. Multiplex assays were also performed to obtain cytokine profiles between different adipose depots. RESULTS: Both wild-type and KC mice on an HFCD exhibited significantly increased inflammation in the visceral adipose tissue, particularly in the peripancreatic fat (PPF), compared with animals on a CD. This was associated with significantly increased inflammation in the pancreas. Cytokine profiles were different between visceral adipose depots and between mice on the HFCD and CD. CONCLUSIONS: Our results clearly demonstrate that an HFCD leads to obesity and inflammation in the visceral adipose tissue, particularly the PPF. These data suggest that obesity-associated inflammation in PPF may accelerate pancreatic neoplasia in KC mice.

An Early Warning Score Predicts Risk of Death after In-hospital Cardiopulmonary Arrest in Surgical Patients.

In-hospital cardiopulmonary arrest can contribute significantly to publicly reported mortality rates. Systems to improve mortality are being implemented across all specialties. A review was conducted for all surgical patients >18 years of age who experienced a "Code Blue" event between January 1, 2013 and March 9, 2014 at a university hospital. A previously validated Modified Early Warning Score (MEWS) using routine vital signs and neurologic status was calculated at regular intervals preceding the event. In 62 patients, the most common causes of arrest included respiratory failure, arrhythmia, sepsis, hemorrhage, and airway obstruction, but remained unknown in 27 per cent of cases. A total of 56.5 per cent of patients died before hospital discharge. In-hospital death was associated with American Society of Anesthesiologists status (P = 0.039) and acute versus elective admission (P = 0.003). Increasing MEWS on admission, 24 hours before the event, the event-day, and a maximum MEWS score on the day of the event increased the odds of death. Max MEWS remained associated with death after multivariate analysis (odds ratio 1.39, P = 0.025). Simple and easy to implement warning scores such as MEWS can identify surgical patients at risk of death after arrest. Such recognition may provide an opportunity for clinical intervention resulting in improved patient outcomes and hospital mortality rates.

E-cadherin expression in obesity-associated, Kras-initiated pancreatic ductal adenocarcinoma in mice.

BACKGROUND: The epithelial-mesenchymal transition (EMT) is critical in the development of invasive epithelial malignancies. EMT is accelerated by inflammation and results in decreased E-cadherin expression. Diet-induced obesity is an inflammatory state that accelerates pancreatic carcinogenesis; its effect on EMT and E-cadherin expression in the development of pancreatic ductal adenocarcinoma is unclear. METHODS: Conditional Kras(G12D) mice were fed a control diet or a high-fat, high-calorie diet for 3 or 9 months (n = 10 each). Immunohistochemistry with anti-E-cadherin antibody was performed. E-cadherin expression was characterized by staining intensity, location, and proportion of positive cells. In vitro expression of E-cadherin and Slug in primary pancreatic intraepithelial neoplasia (PanIN) and cancer cells was determined by Western blot. RESULTS: The HFCD led to increased weight gain in both 3- (15.8 vs 5.6 g, P < .001) and 9-month (19.8 vs 12.9 g, P = .007) mice. No differences in E-cadherin expression among various stages of preinvasive PanIN lesions were found--regardless of age or diet. In invasive cancer, E-cadherin expression was aberrant, with loss of membranous staining and prominent cytoplasmic staining, associated with strong, cytoplasmic expression of ß-catenin. In vitro expression of E-cadherin was greatest in primary PanIN cells, accompanied by absent Slug expression. Cancer cell lines demonstrated significantly decreased E-cadherin expression in the presence of upregulated Slug. CONCLUSION: Despite increased pancreatic inflammation and accelerated carcinogenesis, the high-fat, high-calorie diet did not induce changes in E-cadherin expression in PanIN lesions of all stages. Invasive lesions demonstrated aberrant cytoplasmic E-cadherin staining. Loss of normal membranous localization may reflect a functional loss of E-cadherin.

A pilot study to evaluate knowledge and attitudes of Illinois pediatricians toward newborn screening for sickle cell disease and cystic fibrosis.

In Illinois, newborn screening (NBS) for sickle cell disease (SCD) began in 1989 and for cystic fibrosis (CF) in 2008. We measured pediatricians' knowledge and attitudes regarding CF and SCD, the significance of carrier status, and NBS methodologies. Of 730 eligible Illinois pediatricians randomly selected from the American Academy of Pediatrics Web-based directory, 391 (54%) fully or partially completed the survey. Approximately three-fifths were women, two-thirds were Caucasians, and one-quarter had specialty training. Ninety-seven percent (377/390) and 93% (364/391) of respondents have at one point cared for a patient with SCD and CF, respectively, and virtually all support NBS for SCD (389/391, 99.5%) and CF (382/389, 98%). Overall mean knowledge of SCD (81.2%) and CF (84.5%) was high but did not correlate with self-reported familiarity. Questions regarding the interpretation of NBS results were less well understood, with 37% of our respondents unaware that Illinois NBS identifies all infants with sickle cell trait, and 28% unaware that Illinois NBS does NOT identify all infants who are CF carriers. Pediatricians support NBS but need additional education about the meaning of a positive and negative screen with respect to carrier detection to effectively counsel or appropriately refer.