Esophageal adenocarcinoma heterogeneity in clinicopathology and prognosis: A single center longitudinal study of 146 cases over a 20-year period.

Recent genomic studies suggest that esophageal adenocarcinoma (EAC) is not homogeneous and can be divided into true (tEAC) and probable (pEAC) groups. We compared clinicopathologic and prognostic features between the two groups of EAC. Based on endoscopic, radiologic, surgical, and pathologic reports, tumors with epicenters beyond 2 cm of the gastroesophageal junction (GEJ) were assigned to the tEAC group (N = 63), while epicenters within 2 cm of, but not crossing the GEJ, were allocated to the pEAC group (N = 83). All 146 consecutive patients were male (age: median 70 years, range: 51-88) and White-predominant (98.6 %). There was no significant difference in gastroesophageal reflux disease, obesity, comorbidity, and the prevalence of Barrett's esophagus, and cases diagnosed during endoscopic surveillance. However, compared to the pEAC group, the tEAC group had significantly more cases with hiatal hernia (P = 0.003); their tumors were significantly smaller in size (P = 0.007), more frequently with tubular/papillary adenocarcinoma (P = 0.001), had fewer cases with poorly cohesive carcinoma (P = 0.018), and demonstrated better prognosis in stage I disease (P = 0.012); 5-year overall survival (34.9 months) was significantly longer (versus 16.8 months in pEACs) (P = 0.043). Compared to the patients without resection, the patients treated with endoscopic or surgical resection showed significantly better outcomes, irrespective of stages. We concluded that EACs were heterogeneous with two distinct tEAC and pEAC groups in clinicopathology and prognosis; resection remained the better option for improved outcomes. CONDENSED ABSTRACT: Esophageal adenocarcinoma can be divided into true or probable groups with distinct clinicopathology and better prognosis in the former than in the latter. we showed that resection remained the better option for improved outcomes.

Clinical Implications of Colorectal Cancer Stem Cells in the Age of Single-Cell Omics and Targeted Therapies.

The cancer stem cell (CSC) concept emerged from the recognition of inherent tumor heterogeneity and suggests that within a given tumor, in analogy to normal tissues, there exists a cellular hierarchy composed of a minority of more primitive cells with enhanced longevity (ie, CSCs) that give rise to shorter-lived, more differentiated cells (ie, cancer bulk populations), which on their own are not capable of tumor perpetuation. CSCs can be responsible for cancer therapeutic resistance to conventional, targeted, and immunotherapeutic treatment modalities, and for cancer progression through CSC-intrinsic molecular mechanisms. The existence of CSCs in colorectal cancer (CRC) was first established through demonstration of enhanced clonogenicity and tumor-forming capacity of this cell subset in human-to-mouse tumor xenotransplantation experiments and subsequently confirmed through lineage-tracing studies in mice. Surface markers for CRC CSC identification and their prospective isolation are now established. Therefore, the application of single-cell omics technologies to CSC characterization, including whole-genome sequencing, RNA sequencing, and epigenetic analyses, opens unprecedented opportunities to discover novel targetable molecular pathways and hence to develop novel strategies for CRC eradication. We review recent advances in this field and discuss the potential implications of next-generation CSC analyses for currently approved and experimental targeted CRC therapies.

Socioeconomic Disparities in Pancreas Cancer Resection and Survival in the Veterans Health Administration.

BACKGROUND: Disparities based on socioeconomic factors such as race, ethnicity, marital status, and insurance status are associated with pancreatic cancer resection, but these disparities are usually not observed for survival after resection. It is unknown if there are disparities when patients undergo their treatment in a non-fee-for-service, equal-access healthcare system such as the Veterans Health Administration (VHA). METHODS: Patients having T1-T3 M0 pancreatic adenocarcinoma diagnosed between 2006 and 2017 were identified from the VHA Corporate Data Warehouse. Socioeconomic, demographic, and tumor variables associated with resection and survival were assessed. RESULTS: In total, 2580 patients with early-stage pancreatic cancer were identified. The resection rate was 36.5%. Surgical resection was independently associated with younger age [odds ratio (OR) 0.94, p < 0.001], White race (OR 1.35, p = 0.028), married status (OR 1.85, p = 0.001), and employment status (retired vs. unemployed, OR 1.41, p = 0.008). There were no independent associations with Hispanic ethnicity, geographic region, or Social Deprivation Index. Resection was associated with significantly improved survival (median 21 vs. 8 months, p = 0.001). Among resected patients, survival was independently associated with younger age (HR 1.019, p = 0.002), geographic region (South vs. Pacific West, HR 0.721, p = 0.005), and employment (employed vs. unemployed, HR 0.752, p = 0.029). Race, Hispanic ethnicity, marital status, and Social Deprivation Index were not independently associated with survival after resection. CONCLUSIONS: Race, marital status, and employment status are independently associated with resection of pancreatic cancer in the VHA, whereas geographic region and employment status are independently associated with survival after resection. Further studies are warranted to determine the basis for these inequities.

Associations of gender, race, and ethnicity with disparities in short-term adverse outcomes after pancreatic resection for cancer.

BACKGROUND: Several studies have identified disparities in pancreatic cancer treatment associated with gender, race, and ethnicity. There are limited data examining disparities in short-term adverse outcomes after pancreatic resection for cancer. The aim of this study is to evaluate associations of gender, race, and ethnicity with morbidity and mortality after pancreatic resection for malignancy. METHODS: The American College of Surgeons National Surgical Quality Improvement database was retrospectively reviewed. The χ2 test and Student's t-test were used for univariable analysis and hierarchical logistic regression for multivariable analysis. RESULTS: Morbidity and major morbidity after pancreaticoduodenectomy are associated with male gender, Asian race, and Hispanic ethnicity, whereas 30-day mortality is associated with the male gender. Morbidity and major morbidity after distal pancreatectomy are associated with the male gender. Morbidity after pancreaticoduodenectomy is independently associated with male gender, Asian race, and Hispanic ethnicity; major morbidity is independently associated with male gender and Asian race, and mortality is independently associated with Hispanic ethnicity. CONCLUSIONS: Gender, race, and ethnicity are independently associated with morbidity after pancreaticoduodenectomy for cancer; gender and race are independently associated with major morbidity; and ethnicity is independently associated with mortality. Further studies are warranted to determine the basis of these associations.

The improvement in post-operative mortality following pancreaticoduodenectomy between 2006 and 2016 is associated with an improvement in the ability to rescue patients after major morbidity, not in the rate of major morbidity.

BACKGROUND: The postoperative mortality rate of pancreaticoduodenectomy is decreasing over time. It is unknown whether this is related to reduction in incidence of major morbidity or failure to rescue. We aimed to make this determination. METHODS: ACS-NSQIP was retrospectively reviewed from 2006 to 2016. Comparisons were assessed with Spearman's rank-order correlation test, chi-square test with linear-by-linear association, and multivariable hierarchical logistic regression. RESULTS: Mortality decreased significantly from 2.9% to 1.5% (p < 0.001). This decrease was independent of preoperative variables on multivariable analysis (odds ratio [OR] 2.55, 95% confidence interval [CI] 1.55-5.21, p < 0.001). In contrast, no change in incidence of major morbidity was seen on univariable (26.8% to 25.9%, p = 1.00) or multivariable analysis (OR 1.22, 95% CI 1.03-1.45, p = 0.060). Failure to rescue was observed to decrease on univariable (9.8% to 4.1%, p < 0.001) and multivariable analysis (OR 3.65, 95% CI 2.07-6.76, p < 0.001). CONCLUSION: There has been a sizeable reduction in the mortality rate after pancreaticoduodenectomy from 2006 to 2016. This predominantly results from a reduction in failure to rescue rate rather than a decrease in incidence of major morbidity.

Discharge destination following rectal cancer resection: an analysis of preoperative and intraoperative factors.

PURPOSE: Rectal cancer resections can be associated with long and complicated postoperative recoveries. Many patients undergoing these operations are discharged to rehabilitation or skilled nursing facilities. The purpose of this study was to identify preoperative and intraoperative factors associated with increased risk for non-home discharge after rectal cancer resection. METHODS: Rectal cancer resections were identified in the National Surgical Quality Improvement Program Targeted Proctectomy Dataset (years 2016 through 2017) by ICD code. Patients with unknown discharge destination or who experienced in-hospital mortality were excluded. Univariate and multivariate logistic regression analyses were performed to identify preoperative and intraoperative variables associated with non-home discharge destination. Multiple imputation was used to account for missing values. RESULTS: Among the 3637 patients comprising the study sample, 292 (8.0%) patients were discharged to rehabilitation, skilled care, or acute care facilities. Preoperative factors associated with non-home discharge on multivariate analysis included older age, non-independent functional status, insulin-dependent diabetes, and hypoalbuminemia (all p < 0.05). Having received neoadjuvant chemotherapy was associated with home discharge (OR 0.625, 95% CI 0.427-0.914, p = 0.015). Intraoperative factors associated with non-home discharge on multivariate analysis were concurrent cystectomy (p = 0.004) and myocutaneous flap reconstruction (p < 0.001). Patients discharged to non-home facilities had longer initial lengths of stay (14.1 versus 7.0 days, p < 0.001) and higher reoperation rates (12.7 versus 5.0%, p < 0.001), but similar readmission rates (14.7 versus 15.0%, p = 1.0). CONCLUSION: Several preoperative and intraoperative factors are associated with increased risk for non-home discharge after rectal cancer resection. These data can aid in perioperative planning and discharge optimization.

Twenty-Three-Hour-Stay Colectomy Without Increased Readmissions: An Analysis of 1905 Cases from the National Surgical Quality Improvement Program.

BACKGROUND: Isolated case series from highly specialized centers suggest the feasibility of a 23-h hospital stay after colectomy. We sought to determine preoperative variables associated with discharge within 23 h after colectomy to identify patients best suited for a short-stay model. METHODS: The American College of Surgeons NSQIP Colectomy-Targeted database was used to identify patients who underwent elective colectomy from 2012 to 2017. All cases with missing length of stay or inpatient death were excluded. Patients with a postoperative hospital stay ≤1 day were identified. Univariate and multivariate analyses were conducted to identify factors associated with early discharge. RESULTS: A total of 1905 patients were discharged within 23 h after surgery (1.6%). These patients were noted to be younger (59 versus 61 years, p < 0.001) and less likely to have insulin-dependent diabetes (3.0 versus 4.4%, p < 0.001), preoperative dyspnea (2.2 versus 6.0%, p < 0.001), COPD (3.0 versus 4.2%, p = 0.011), and hypertension (40.7 versus 46.9%, p < 0.001) than patients who stayed longer. Shorter operative time (OR 0.986, 95% CI 0.985-0.987, p < 0.001), minimally invasive techniques (OR 2.969, 95% CI 2.686-3.282, p < 0.001), lack of ostomy (OR 0.614, 95% CI 0.478-0.788, p < 0.001), and lack of ureteral stenting (OR 0.641, 95% CI 0.500-0.821, p < 0.001) were associated with early discharge in multivariable analysis. There was no increased incidence of readmission in patients discharged within 23 h. CONCLUSIONS: Twenty-three-hour-stay colectomy is feasible on a national level and does not result in an increased incidence of readmission. Patients undergoing elective procedures without significant medical comorbidities may be eligible for early discharge. Preoperative factors may be used to select patients best suited for this short-stay model.

ATP-binding cassette member B5 (ABCB5) promotes tumor cell invasiveness in human colorectal cancer.

ABC member B5 (ABCB5) mediates multidrug resistance (MDR) in diverse malignancies and confers clinically relevant 5-fluorouracil resistance to CD133-expressing cancer stem cells in human colorectal cancer (CRC). Because of its recently identified roles in normal stem cell maintenance, we hypothesized that ABCB5 might also serve MDR-independent functions in CRC. Here, in a prospective clinical study of 142 CRC patients, we found that ABCB5 mRNA transcripts previously reported not to be significantly expressed in healthy peripheral blood mononuclear cells are significantly enriched in patient peripheral blood specimens compared with non-CRC controls and correlate with CRC disease progression. In human-to-mouse CRC tumor xenotransplantation models that exhibited circulating tumor mRNA, we observed that cancer-specific ABCB5 knockdown significantly reduced detection of these transcripts, suggesting that the knockdown inhibited tumor invasiveness. Mechanistically, this effect was associated with inhibition of expression and downstream signaling of AXL receptor tyrosine kinase (AXL), a proinvasive molecule herein shown to be produced by ABCB5-positive CRC cells. Importantly, rescue of AXL expression in ABCB5-knockdown CRC tumor cells restored tumor-specific transcript detection in the peripheral blood of xenograft recipients, indicating that ABCB5 regulates CRC invasiveness, at least in part, by enhancing AXL signaling. Our results implicate ABCB5 as a critical determinant of CRC invasiveness and suggest that ABCB5 blockade might represent a strategy in CRC therapy, even independently of ABCB5's function as an MDR mediator.

Fast-Track Pancreaticoduodenectomy: Factors Associated with Early Discharge.

BACKGROUND: Pancreaticoduodenectomy is a complex surgery frequently associated with prolonged hospitalizations. However, there are a subset of patients discharged within 5 days from surgery; the preoperative and intraoperative characteristics of this subset are unknown. METHODS: The NSQIP Targeted Pancreatectomy Dataset was used from 2014 to 2016. Patients who died within 30 days were excluded. A total of 10,741 patients undergoing pancreaticoduodenectomy were identified. Univariable and multivariable logistic regression analyses were performed for preoperative and intraoperative ACS-NSQIP variables to identify predictors of early discharge. Early discharge was defined as discharge 3-5 days after surgery. RESULTS: A total of 1105 patients (10.3%) were discharged within 5 days following pancreaticoduodenectomy. On multivariable analysis, preoperative factors associated with early discharge included younger age (OR 0.988, p < 0.001), non-obesity (OR 0.737, p = 0.001), those receiving neoadjuvant chemotherapy (OR 1.424, p < 0.001), and lack of COPD (OR 0.489, p = 0.005) or hypertension (OR 0.805, p = 0.007). Intraoperative factors associated with early discharge on multivariable analysis were shorter operation duration (OR 0.999, p = 0.002), minimally invasive surgery (OR 3.537, p < 0.001), and hard pancreatic texture (OR 1.480, p < 0.001). Intraoperative factors associated with non-early discharge were epidural placement (OR 0.485, p < 0.001), drain placement (OR 0.308, p < 0.001), and jejunostomy tube placement (OR 0.278, p < 0.001). Patients discharged within 5 days had a 14.7% readmission rate compared to 17.0% for later discharges (p = 0.047). CONCLUSIONS: Multiple preoperative and intraoperative factors, including some that are potentially modifiable, were significantly associated with early discharge after pancreaticoduodenectomy. Patients with these characteristics may benefit from enhanced recovery after surgery programs and expedited disposition planning postoperatively.

Prediction of Discharge Destination Following Major Hepatectomy.

BACKGROUND: Anatomic hepatectomies can be associated with complicated post-operative recoveries, often with discharge to post-acute care facilities. This study identifies preoperative and intraoperative factors associated with increased risk for non-home discharge destination after major hepatectomy. METHODS: Patients undergoing major hepatectomy were identified in the NSQIP Targeted Hepatectomy Dataset (2014-2016). Multivariable logistic regression was performed. Patients from 2014 to 2015 were used for training cohort with nomogram generation and 2016 for validation cohort. RESULTS: Overall, 226 of 3750 patients (6.0%) were discharged to rehab, skilled care, or acute care facilities. Preoperative factors associated with non-home discharge on multivariable analysis were outside patient transfers, older age, presence of ascites, ASA physical status 3 or higher, and low preoperative hematocrit (all p < 0.05). Intraoperative factors significantly predictive were concurrent lysis of adhesions, Pringle maneuver, and biliary reconstruction (all p < 0.05). Predictors from testing cohort were validated in validation cohort. Nomograms based on preoperative variables alone and both preoperative and intraoperative variables were generated. CONCLUSION: We identify several preoperative and intraoperative factors that are associated with increased risk for non-home discharge after major hepatectomy. Preoperative anemia represents a potentially modifiable risk factor. Nomograms for preoperative planning as well as immediately following surgery were generated.

Low risk of lymph node metastasis in 495 early gastric cardiac carcinomas: a multicenter clinicopathologic study of 2101 radical gastrectomies for early gastric carcinoma.

Clinical decision-making on endoscopic vs. surgical resection of early gastric cardiac carcinoma remains challenging because of uncertainty on risk of lymph node metastasis. The aim of this multicenter study was to investigate risk factors of lymph node metastasis in early gastric cardiac carcinoma. Guided with the World Health Organization diagnostic criteria, we studied 2101 radical resections of early gastric carcinoma for risk factors associated with lymph node metastasis, including tumor location, gross pattern, size, histology type, differentiation, invasion depth, lymphovascular, and perineural invasion. We found that the risk of lymph node metastasis was significantly lower in early gastric cardiac carcinomas (6.7%, 33/495), compared with early gastric non-cardiac carcinomas (17.1%, 275/1606) (p < 0.0001). In early gastric cardiac carcinoma, no lymph node metastasis was identified in intramucosal carcinoma (0/193) and uncommon types of carcinomas (0/24), irrespective of the gross pattern, size, histologic type, differentiation, and invasion depth. Ulceration, size > 3 cm, and submucosal invasion were not significant independent risk factors for lymph node metastasis. In 33 early gastric cardiac carcinomas with lymph node metastasis, either lymphovascular invasion or poor differentiation was present in 16 (48.5%) cases and together in six cases. By multivariate analysis, independent risk factors of lymph node metastasis in early gastric cardiac carcinoma included lymphovascular invasion (Odds Ratio (OR): 7.6, 95% Confidence Interval (CI): 2.8-20.2) (p < 0.0001) and poor differentiation (OR: 6.0, 95% CI: 1.4-25.9) (p < 0.05). In conclusion, lymph node metastasis was not identified in early gastric cardiac intramucosal carcinoma and uncommon types of carcinoma. The risk of lymph node metastasis was also significantly lower in tumors with submucosal invasion, especially for cases without lymphovascular invasion or poor differentiation. These results lend support to the role of endoscopic therapy in the treatment of patients with early gastric cardiac carcinoma.

Unplanned reoperation after hepatectomy: an analysis of risk factors and outcomes.

BACKGROUND/PURPOSE: Reoperation is being increasingly utilized as a metric for surgical care quality. The aim of this study was to identify the incidence of and risk factors for unplanned reoperation following index hepatectomy. METHODS: Pre, intra- and post-operative information of patients who underwent partial hepatectomy in 435 hospitals participating in the American College of Surgeons National Surgical Quality Improvement Program from 2011 to 2013 were analyzed. RESULTS: 343 (4%) of 9195 patients required reoperation within 30 days of index hepatectomy. The index procedures with the highest incidence of reoperation (%) were trisectionectomy (7%) and right hepatectomy (5%). Patients who underwent reoperation had increased index operative duration (323 ± 174 min versus 243 ± 125 min, p < 0.001), postoperative transfusion (57% versus 23%, p < 0.001), wound complications, cardiorespiratory, renal, thromboembolic, and infectious events. Hemorrhage was the most common indication for reoperation (10%). Male gender, ASA class 4, and right hepatectomy or trisectionectomy were independent predictors of reoperation (OR 1.4 [1.1-1.7], p = 0.007; 2.0 [1.3-3.1], p = 0.003; 1.6 [1.2-2.0], p = 0.001 and 2.5 [1.8-3.4], p < 0.001, respectively). All reoperations occurred during index hospitalization and resulted in longer mean length of stay (19 ± 17 days versus 7 ± 7 days, p < 0.001). CONCLUSION: Reoperation is associated with several patient characteristics and procedural factors in this national sample. Knowledge of these factors can increase awareness of patients at risk for reoperation.

Risk Factors of Reoperation After Pancreatic Resection.

BACKGROUND: Pancreatic resection is associated with a high incidence of postoperative complications, some of which require reoperation. AIMS: To analyze the incidence of and risk factors for reoperation following pancreatectomy. METHODS: Pre- and postoperative information and procedure characteristics of 15,549 patients having undergone pancreatectomy in 435 hospitals participating in the American College of Surgeons National Surgical Quality Improvement Program from 2011 to 2014 were analyzed. RESULTS: A total of 773 (5.0%) patients required reoperation within 30 days of their index pancreatectomy. Patients requiring reoperation were more likely to be younger (mean ± standard deviation, 62.6 ± 13.2 vs. 64.1 ± 12.2 years, p < 0.001), male (60 vs. 49%, p < 0.001), to have respiratory comorbidities, lower preoperative serum albumin (3.7 ± 0.68 vs. 3.8 ± 0.62 mg/dl, p < 0.001), higher total bilirubin (1.7 ± 2.7 vs. 1.5 ± 2.4 mg/dl, p = 0.02), and higher American Society of Anesthesiologists (ASA) class than those who did not undergo reoperation. Other factors associated with increased incidence of reoperation included longer mean operative duration at the index procedure, postoperative transfusion requirement, wound complications, and cardiorespiratory, renal, thromboembolic, and infectious events. Multivariate regression analysis identified male sex, preoperative serum albumin <3.5 mg/dl, ASA class of 3 or 4, pancreaticoduodenectomy, and total pancreatectomy as the strongest predictors for reoperation after index pancreatic resection. Complication and readmission rates were significantly higher for those undergoing reoperation. CONCLUSION: Patient characteristics and procedural factors contribute to reoperation after pancreatectomy in this largest and most diverse sample to date. Further investigation to identify perioperative strategies for mitigating this risk is required to improve the safety of pancreatic resection.

Deficiency of IL-17A, but not the prototypical Th17 transcription factor RORγt, decreases murine spontaneous intestinal tumorigenesis.

While inflammation has been associated with the development and progression of colorectal cancer, the exact role of the inflammatory Th17 pathway remains unclear. In this study, we aimed to determine the relative importance of IL-17A and the master regulator of the Th17 pathway, the transcription factor RORγt, in the sporadic intestinal neoplasia of APC(MIN/+) mice and in human colorectal cancer. We show that levels of IL-17A are increased in human colon cancer as compared to adjacent uninvolved colon. Similarly, naïve helper T cells from colorectal cancer patients are more inducible into the Th17 pathway. Furthermore, IL-17A, IL-21, IL-22, and IL-23 are all demonstrated to be directly mitogenic to human colorectal cancer cell lines. Nevertheless, deficiency of IL-17A but not RORγt is associated with decreased spontaneous intestinal tumorigenesis in the APC(MIN/+) mouse model, despite the fact that helper T cells from RORγt-deficient APC(MIN/+) mice do not secrete IL-17A when subjected to Th17-polarizing conditions and that Il17a expression is decreased in the intestine of RORγt-deficient APC(MIN/+) mice. Differential expression of Th17-associated cytokines between IL-17A-deficient and RORγt-deficient APC(MIN/+) mice may explain the difference in adenoma development.

Trends and predictors of resection of the primary tumor for patients with stage IV colorectal cancer.

BACKGROUND AND OBJECTIVES: Over 130,000 patients are diagnosed with colorectal cancer annually, with approximately 20% presenting with unresectable metastatic disease. Recent consensus guidelines recommend against primary tumor resection for asymptomatic patients with unresectable metastases. Our goal was to examine the trends and predictors of surgical resection. METHODS: Cases of colorectal cancer with synchronous metastases diagnosed between 1988-2010 were identified using the Surveillance, Epidemiology and End Results (SEER) Database. Associations between resection and clinicopathologic variables were sought using univariate and multivariate logistic regression. RESULTS: Overall, 68% of patients with synchronous metastatic colorectal cancer underwent primary tumor resection. Resection rates were as high as 76% in the earliest time period (1988-1992) and steadily dropped to 60% in the most recent period (2008-2010). Socioeconomic factors associated with resection on univariate analysis included age, race, gender, marital status, insurance status, and geographic region. Clinicopathologic characteristics associated with resection included tumor location, grade, size, and CEA level. In the multivariate model, gender, geographic region, insurance status, tumor location, grade and CEA level were independent predictors of primary tumor resection. CONCLUSIONS: Surgical resection of the primary site remains common practice for patients with synchronous metastatic colorectal cancer. Treatment disparities are associated with socioeconomic as well as clinicopathologic factors.

Prognostic factors in clinicopathology of oesophagogastric adenocarcinoma: a single-centre longitudinal study of 347 cases over a 20-year period.

Oesophagogastric adenocarcinoma (EGA) includes oesophageal (EA), gastro-oesophageal junctional (GEJA), and gastric (GA) adenocarcinomas. The prognostic values of clinicopathological factors in these tumours remain obscure, especially for GEJA that has been inconsistently classified and staged. We studied the prognosis of EGA patients among the three geographic groups in 347 consecutive patients with a median age of 70 years (range 47-94). All patients were male, and 97.1% were white. Based on tumour epicentre location, EGAs were sub-grouped into EA (over 2 cm above the GEJ; n=3, 18.1%), GEJA (within 2 cm above and 3 cm below the GEJ; n=231, 66.6%), and GA (over 3 cm below the GEJ; n=53, 15.3%). We found that the median overall survival (OS) was the longest in EA (62.9 months), compared to GEJA (33.4), and GA (38.1) (p<0.001). Significant risk factors for OS included tumour location (p=0.018), size (p<0.001), differentiation (p<0.001), adenocarcinoma subtype (p<0.001), and TNM stage (p<0.001). Independent risk factors for OS comprised low-grade papillary adenocarcinoma [odds ratio (OR) 0.449, 95% confidence interval (CI) 0.214-0.944, p<0.05), mixed adenocarcinoma (OR 1.531, 95% CI 1.056-2.218, p<0.05), adenosquamous carcinoma (OR 2.206, 95% CI 1.087-4.475, p<0.05), N stage (OR 1.505, 95% CI 1.043-2.171, p<0.05), and M stage (OR 10.036, 95% CI 2.519-39.993, p=0.001)]. EGA was further divided into low-risk (common well-moderately differentiated tubular and low-grade papillary adenocarcinomas) and high-risk (uncommon adenocarcinoma subtypes, adenosquamous carcinoma) subgroups. In this grouping, the median OS was significantly longer in the low-risk (83 months) than in the high-risk (10 months) subgroups (p<0.001). In conclusion, the prognosis of EGA patients was significantly better in EA than in GEJA or GA and could be stratified into low and high-risk subgroups with significantly different outcomes.

Population-based outcome of stage IA-IIA resected gastric adenocarcinoma: who should get adjuvant treatment?

BACKGROUND: The benefit of adjuvant treatment in gastric adenocarcinoma was demonstrated by randomized, controlled trials of patients with locally advanced tumors. Thus, its role for stage IIB-IIIC disease is widely accepted. We aimed to identify patients with stage IA-IIA gastric adenocarcinoma who have a poor prognosis and thus may benefit from adjuvant treatment. METHODS: Patients with gastric adenocarcinoma who underwent surgical resection with pathological evaluation of ≥15 lymph nodes and had available disease-specific survival (DSS) data were identified from the Surveillance Epidemiology and End Results Registry. Survival differences were evaluated with the log-rank test and Cox multivariate analysis. RESULTS: Stage and TN grouping strongly predicted DSS (P < 0.001, P < 0.001). Stage IA tumors had an excellent outcome: 91 ± 1.2 % 5-year DSS. The TN groupings of stages IB and IIA had the next best outcomes with 5-year DSS from 66 ± 4.6 % to 81 ± 2.3 %. Older age (P < 0.001), higher grade (P = 0.004), larger tumor size (P < 0.001), and proximal tumor location (P < 0.001) were independent predictors of worse DSS in stage IB-IIA tumors. We devised a risk stratification scheme for stage IB-IIA tumors where 1 point was assigned for age >60 years, tumor size >5 cm, proximal tumor location, and grade other than well-differentiated. Five-year DSS was 100 % for patients with 0 points; 86 ± 4.3 %, 1 point; 76 ± 3 %, 2 points; 72 ± 2.8 %, 3 points; and 48 ± 4.9 %, 4 points (P < 0.001). CONCLUSIONS: Patients with stage IB-IIA gastric adenocarcinoma and ≥2 adverse features (age >60 years, tumor size >5 cm, proximal location, and high-grade) have 5-year DSS ≤76 %. Adjuvant therapy may be warranted for these patients.

Autoimmunity and tumor immunity induced by immune responses to mutations in self.

Little is known about the consequences of immune recognition of mutated gene products, despite their potential relevance to autoimmunity and tumor immunity. To identify mutations that induce immunity, here we have developed a systematic approach in which combinatorial DNA libraries encoding large numbers of random mutations in two syngeneic tyrosinase-related proteins are used to immunize black mice. We show that the libraries of mutated DNA induce autoimmune hypopigmentation and tumor immunity through cross-recognition of nonmutated gene products. Truncations are present in all immunogenic clones and are sufficient to elicit immunity to self, triggering recognition of normally silent epitopes. Immunity is further enhanced by specific amino acid substitutions that promote T helper cell responses. Thus, presentation of a vast repertoire of antigen variants to the immune system can enhance the generation of adaptive immune responses to self.