The genetic identity of the earliest human-made hybrid animals, the kungas of Syro-Mesopotamia.

Before the introduction of domestic horses in Mesopotamia in the late third millennium BCE, contemporary cuneiform tablets and seals document intentional breeding of highly valued equids called kungas for use in diplomacy, ceremony, and warfare. Their precise zoological classification, however, has never been conclusively determined. Morphometric analysis of equids uncovered in rich Early Bronze Age burials at Umm el-Marra, Syria, placed them beyond the ranges reported for other known equid species. We sequenced the genomes of one of these ~4500-year-old equids, together with an ~11,000-year-old Syrian wild ass (hemippe) from Göbekli Tepe and two of the last surviving hemippes. We conclude that kungas were F1 hybrids between female domestic donkeys and male hemippes, thus documenting the earliest evidence of hybrid animal breeding.

Isotope evidence for agricultural extensification reveals how the world's first cities were fed.

This study sheds light on the agricultural economy that underpinned the emergence of the first urban centres in northern Mesopotamia. Using δ13C and δ15N values of crop remains from the sites of Tell Sabi Abyad, Tell Zeidan, Hamoukar, Tell Brak and Tell Leilan (6500-2000 cal bc), we reveal that labour-intensive practices such as manuring/middening and water management formed an integral part of the agricultural strategy from the seventh millennium bc. Increased agricultural production to support growing urban populations was achieved by cultivation of larger areas of land, entailing lower manure/midden inputs per unit area-extensification. Our findings paint a nuanced picture of the role of agricultural production in new forms of political centralization. The shift towards lower-input farming most plausibly developed gradually at a household level, but the increased importance of land-based wealth constituted a key potential source of political power, providing the possibility for greater bureaucratic control and contributing to the wider societal changes that accompanied urbanization.

Determining the optimal number of lymph nodes harvested during esophagectomy.

BACKGROUND: We examined the impact of the number of lymph nodes (LNs) removed during esophagectomy on outcomes in esophageal cancer (EC). METHODS: From a comprehensive EC database we identified patients who underwent curative resection from 1994 to 2011. The impact of total LNs retrieved on disease-free survival (DFS) and overall survival (OS) was investigated. RESULTS: In total, 635 patients were identified. Patients were divided on the basis of total number of LNs removed (<8, 9-12, 13-20, and >20). The 5-year OS and DFS rates for the group by LN category were (43%, 42%, 55%, and 36%, P=0.1836) and (44%, 37%, 46%, and 36%, P=0.5166), respectively. Total number of LNs assessed did not correlate with reduced risk of recurrence or improved survival. On multivariate analysis controlling for age, sex, histology, neoadjuvant therapy, only removal of 13-20 LN's correlated to improved oncologic outcomes. CONCLUSIONS: In a tertiary cancer center, we demonstrated that only removal of 13-20 LNs during esophagectomy correlated to improved survival. While the importance of standardized pathologic examination and adequate nodal staging is of utmost importance for patients with EC undergoing esophagectomy the optimum number of LNs removed clearly warrants further investigation.

Body Mass Index and Perioperative Complications After Esophagectomy for Cancer.

BACKGROUND: Given the increasing rate of obesity, the effects of excessive body weight on surgical outcomes constitute a relevant quality of care concern. Our aim was to determine the relationship between preoperative body mass index (BMI) on perioperative complications after esophagectomy for cancer. METHODS: From our comprehensive esophageal cancer database consisting of 510 patients, we identified 166 obese (BMI ≥30), 176 overweight (BMI 25-29), and 148 normal-weight (BMI 20-24) patients. Malnourished patients (BMI of <20) were excluded. Incidence of preoperative risk factors and perioperative complications in each group were analyzed. RESULTS: The patient group consists of 420 men and 70 women with a mean age at time of surgery were 64 years (range 28-86 years). The categories of patients (obese, overweight, and normal-weight) were similar in terms of demographics and comorbidities, with the exception of a younger age (62.5 years vs 66.2 years vs 65.3 years, P = 0.002), and a higher incidence of diabetes (23.5% vs 11.4% vs 10.1%, P = 0.001) and hiatal hernia (28.3% vs 14.8% vs 20.3%, P = 0.01) for obese patients. More patients with BMI >24 were found with adenocarcinoma, compared with the normal-weight group (90.8% vs 90.9% vs 82.5%, P = 0.03). Despite similar preoperative stage, obese patients were less likely to receive neoadjuvant treatment (47.6% vs 54.5% vs 66.2%, P = 0.004). The type of surgery performed, overall blood loss, extent of lymphadenectomy, rate of resections with negative margins, and postoperative complications were not influenced by BMI on univariate and multivariate analysis. CONCLUSIONS: In our experience, BMI did not affect number of harvested lymph-nodes, rates of negative margins, and morbidity and mortality after esophagectomy for cancer. In our experience, esophagectomy could be performed safely and efficiently in mildly obese patients.

The impact of pathologic nodal status on survival following neoadjuvant chemoradiation for locally advanced rectal cancer.

PURPOSE: For patients with locally advanced rectal cancer, the accuracy rates of preneoadjuvant therapy nodal staging and potential nodal downstaging make the prognostic significance of nodal status unclear. We therefore sought to review our experience in order to better understand the impact of clinical and pathologic nodal status upon patient outcomes. METHODS: 174 patients were identified as having undergone neoadjuvant chemoradiation and resection for rectal cancer. For analytic purposes, patients were grouped into four nodal categories (uN( 0)· pN( 0), uN( 0)· pN( +), uN (+) · pN( 0), and uN (+) · pN( +)). Univariate and multivariate analyses were performed. RESULTS: 104 men and 70 women of median age 60 years (29-85 years) were followed for a median of 31 months (1-121 months). Nodal staging was available for 129 patients, with a median of 8 lymph nodes (range 0-39) evaluated. Disease recurred in 3 of 41 (7%) uN (0) ·pN ( 0), 10 of 52 (20%) uN ( +)·pN ( 0), 7 of 18 (41%) uN ( 0)·pN ( +), and 6 of 17 (35%) uN ( +)·pN ( +) patients. Those patients having nodal downstaging (uN ( +)·pN ( 0)) experienced superior overall survival (p = 0.03). Only pathologic nodal status was a significant predictor of both disease-free and overall survival in multivariate modeling. Adjuvant chemotherapy did not impact disease-free or overall survival for patients with pN0. CONCLUSIONS: Pathologic nodal status may represent a superior predictor of survival for patients with local advanced rectal cancers. Our findings may have potential implications for the application of adjuvant therapy.

Above-Label Doses of Octreotide-LAR in Patients With Metastatic Small Intestinal Carcinoid Tumors.

BACKGROUND: Octreotide LAR is indicated for treatment of malignant carcinoid syndrome and has been studied at doses of 10 to 30 mg intramuscularly every 4 weeks. In clinical practice, higher doses are often prescribed for patients who experience refractory carcinoid syndrome (flushing and/or diarrhea) or tumor growth while on the maximum label-recommended dose. METHODS: We performed a retrospective, longitudinal review of octreotide LAR administration at a tertiary institution to determine the frequency of above-label dosing and outcomes. RESULTS: Three hundred thirty-eight patients were considered evaluable, among whom 100 (30%) underwent at least 1 increase in dose or frequency of octreotide-LAR above the standard label dose. The most common maximum doses were 40 mg every 4 weeks (n = 37 patients), 60 mg every 4 weeks (n = 34), and 30 mg every 3 weeks (n = 18). The indications for dose increase were worsening carcinoid syndrome (n = 60), radiographic progression (n = 33), and rising urine 5-HIAA (n = 6). Of the patients whose doses were increased for refractory carcinoid syndrome, 62% (n = 34) experienced improvement in diarrhea, and 56% (n = 28) experienced improvement in flushing. CONCLUSIONS: In conclusion, octreotide LAR is commonly prescribed in doses or schedules above the recommended dose and frequency. Patients with refractory carcinoid syndrome appear to experience a clinical benefit from this change. Prospective data may be used to further evaluate this strategy.

Extent of lymphadenectomy does not predict survival in patients treated with primary esophagectomy.

BACKGROUND: The number of lymph nodes resected and its impact on survival for patients with esophageal cancer remains undefined. Current guidelines recommend extended lymphadenectomy in patients not receiving neoadjuvant therapy. We reviewed our single institutional experience with nodal harvest for esophageal cancer in a non-neoadjuvant therapy setting. METHODS: Patients who underwent esophagectomy as primary therapy were indentified from a prospectively maintained database consisting of 704 patients who underwent esophagectomy. Patients were stratified by number of lymph nodes (LN) resected: >5, 10, 12, 15, or 20. Survival, clinical, and pathologic parameters were analyzed with Kaplan-Meier curves, chi-square, or Fisher's exact tests where appropriate. RESULTS: We identified 246 patients who underwent esophagectomy as initial treatment. The mean age was 65 ±10 years. The majority of patients were male (87%). Ivor-Lewis esophagectomy was performed for 71%, minimally invasive esophagectomy for 15%, transhiatal esophagectomy for 12%, and three-field esophagectomy for 2%. At 60 months follow-up, there was no statistically significant difference in overall survival (OS) or disease-free survival (DFS) between patients with < vs. >5 LN resected (p = 0.74 and p = 0.67, respectively) or in the < vs. >10 (p = 0.33, p = 0.11), 12 (p = 0.82, p = 0.90), 15 (p = 0.45, p = 0.79), or 20 (p = 0.72, p = 0.86) resected LN groups. Patients were then subdivided into node-positive and node-negative cohorts and stratified by nodal harvest. In the subgroups of patients with node-negative and node-positive disease, OS and DFS also did not significantly differ between groups with respect to number of nodes resected (p > 0.05). A total of 49 (20%) patients developed recurrent disease; however, recurrence was not statistically associated with number of LN resected (p > 0.05). CONCLUSION: We found no impact of extent of lymphadenectomy on overall or disease-free survival in patients treated with esophagectomy without neoadjuvant therapy. In addition, the number of nodes resected at esophagectomy did not affect recurrence rates. Current recommendations for increased nodal resection during esophagectomy in patients not receiving neoadjuvant therapy may not improve patient outcomes, and this phenomenon warrants further investigation.

Intensity-Modulated Radiation Therapy vs. 3D Conformal Radiation Therapy for Squamous Cell Carcinoma of the Anal Canal.

PURPOSE: We compared our institutional experience using 3D conformal radiation therapy (3DCRT) vs. IMRT (intensity-modulated radiation therapy) for anal cancer. METHODS: We performed a single-institution retrospective review of all patients with squamous cell carcinoma anal cancer treated from September 2000 through September 2011, using definitive chemoradiation with curative intent. RESULTS: This study included 89 consecutive patients (37 3DCRT, 52 IMRT). Median follow-up for all patients, IMRT patients alone, and CRT patients alone was 26.5 months (range, 3.5-133.6), 20 months (range, 3.5-125.5), and 61.9 months (range, 7.6-133.6), respectively. Three-year overall survival (OS), progression-free survival (PFS), locoregional control (LRC), and colostomy-free survival (CFS) were 91.1%, 82.3%, 90.8%, and 91.3% in the IMRT cohort and 86.1%, 72.5%, 91.9%, and 93.7% in the 3DCRT group (all P > .1). More patients in the 3DCRT group required a treatment break (11 vs. 4; P = .006), although the difference in median treatment break duration was not significant (12.2 vs. 8.0 days; P = .35). Survival did not differ based on whether a treatment break was needed (all P > .1). Acute grade ≥3 nonhematologic toxicity was decreased in the IMRT cohort (21.1 vs. 59.5%; P < .0001). Acute grade ≥3 skin toxicity was worse in the 3DCRT group (P < .0001), whereas an improvement in late grade ≥3 gastrointestinal (GI) toxicity was observed in the IMRT patients (P = .012). CONCLUSIONS: This study is the largest thus far to compare 3DCRT and IMRT for definitive treatment of anal cancer. Although long-term outcomes did not significantly differ based on RT technique, a marked decrease in adverse effects and the need for a treatment break was achieved with IMRT.

Adjuvant radiation therapy and lymphadenectomy in esophageal cancer: a SEER database analysis.

OBJECTIVES: This study seeks to determine the effects of postoperative radiation therapy and lymphadenectomy on survival in esophageal cancer. METHODS: An analysis of patients with surgically resected esophageal cancer from the SEER database between 2004 and 2008 was performed to determine association of adjuvant radiation and lymph node dissection on survival. Survival curves were calculated according to the Kaplan-Meier method and log-rank analysis. Multivariate analysis (MVA) was performed by the Cox proportional hazard model. RESULTS: We identified 2109 patients who met inclusion criteria. Radiation was associated with increased survival in stage III patients (p = 0.005), no benefit in stage II (p = 0.075) and IV (p = 0.913) patients, and decreased survival in stage I patients (p < 0.0001). Univariate analysis revealed that radiation therapy was associated with a survival benefit node positive (N1) patients while it was associated with a detriment in survival for node negative (N0) patients. Removing >12 and >15 lymph nodes was associated with increased survival in N0 patients, while removing >8, >10, >12, >15, and >20 lymph nodes was associated with a survival benefit in N1 patients. MVA revealed that age, gender, tumor and nodal stage, tumor location, and number of lymph nodes removed were prognostic for survival in N0 patients. In N1 patients, MVA showed the age, tumor stage, number of lymph nodes removed, and radiation were prognostic for survival. CONCLUSION: The number of lymph nodes removed in esophageal cancer is associated with increased survival. The benefit of adjuvant radiation therapy on survival in esophageal cancer is limited to N1 patients.

Body mass index and perioperative complications after oesophagectomy for adenocarcinoma: a systematic database review.

OBJECTIVE: Given the increasing rate of obesity, the effects of excessive body weight on surgical outcomes constitute a relevant quality of care concern. Our aim was to determine the relationship between preoperative body mass index (BMI) on perioperative complications after oesophagectomy for adenocarcinoma of the oesophagus. DESIGN: Retrospective database review. SETTING: Single institution high volume oncological tertiary care referral centre. PARTICIPANTS: From our comprehensive oesophageal cancer database consisting of 709 patients, we stratified patients according to BMI: 155 normal-weight (BMI 20-24), 198 overweight (BMI 25-29) and 187 obese (BMI ≥30) patients. INTERVENTIONS: All patients underwent oesophagectomy for cancer. PRIMARY AND SECONDARY OUTCOME MEASURES: Incidences of preoperative risk factors and perioperative complications in each group were analysed. RESULTS: The patient cohort consisted of 474 men and 66 women with a mean age of 64.3 years (28-86). They were similar in terms of demographics and comorbidities, with the exception of a younger age (65.2 vs 65.4 vs 62.5 years, p=0.0094), and a higher incidence of diabetes (9.1% vs 13.2% vs 22.7%, p=0.001), hiatal hernia (16.8% vs 17.8% vs 28.8%, p=0.009) and Barrett oesophagus (24.7% vs 25.4% vs 36.2%, p=0.025) for obese patients. The type of surgery performed, overall blood loss, extent of lymphadenectomy, R0 resections and complications were not influenced by BMI on univariate and multivariate analysis. CONCLUSIONS: In our experience, patients with an elevated BMI and oesophageal adenocarcinoma do not experience an increase in morbidity and mortality after oesophagectomy as stated in previous reports, when performed at a high volume centre. Additionally, BMI did not affect the quality of oncological resection as determined by number of harvested lymph-nodes and rates of R0 resections. TRIAL REGISTRATION: MCC 15030, IRB 105286.

Defining the learning curve for robotic-assisted esophagogastrectomy.

INTRODUCTION: The expansion of robotic-assisted surgery is occurring quickly, though little is generally known about the "learning curve" for the technology with utilization for complex esophageal procedures. The purpose of this study is to define the learning curve for robotic-assisted esophagogastrectomy with respect to operative time, conversion rates, and patient safety. METHODS: We have prospectively followed all patients undergoing robotic-assisted esophagogastrectomy and compared operations performed at our institutions by a single surgeon in successive cohorts of 10 patients. Our measures of proficiency included: operative times, conversion rates, and complications. Statistical analyses were undertaken utilizing Spearman regression analysis and Mann-Whitney U test. Significance was accepted with 95 % confidence. RESULTS: Fifty-two patients (41 male: 11 female) of mean age 66.2 ± 8.8 years underwent robotic-assisted esophagogastrectomies for malignant esophageal disease. Neoadjuvant chemoradiation was administered to 30 (61 %) patients. A significant reduction in operative times (p <0.005) following completion of 20 procedures was identified (514 ± 106 vs. 397 ± 71.9). No conversions to open thoracotomy were required. Complication rates were low and not significantly different between any 10-patient cohort; however, no complications occurred in the final 10-patient cohort. There were no in-hospital mortalities. CONCLUSIONS: For surgeons proficient in performing minimally-invasive esophagogastrectomies, the learning curve for a robotic-assisted procedure appears to begin near proficiency after 20 cases. Operative complications and conversions were infrequent and unchanged across successive 10-patient cohorts.

Stereotactic body radiation therapy for locally advanced and borderline resectable pancreatic cancer is effective and well tolerated.

PURPOSE: Stereotactic body radiation therapy (SBRT) provides high rates of local control (LC) and margin-negative (R0) resections for locally advanced pancreatic cancer (LAPC) and borderline resectable pancreatic cancer (BRPC), respectively, with minimal toxicity. METHODS AND MATERIALS: A single-institution retrospective review was performed for patients with nonmetastatic pancreatic cancer treated with induction chemotherapy followed by SBRT. SBRT was delivered over 5 consecutive fractions using a dose painting technique including 7-10 Gy/fraction to the region of vessel abutment or encasement and 5-6 Gy/fraction to the remainder of the tumor. Restaging scans were performed at 4 weeks, and resectable patients were considered for resection. The primary endpoints were overall survival (OS) and progression-free survival (PFS). RESULTS: Seventy-three patients were evaluated, with a median follow-up time of 10.5 months. Median doses of 35 Gy and 25 Gy were delivered to the region of vessel involvement and the remainder of the tumor, respectively. Thirty-two BRPC patients (56.1%) underwent surgery, with 31 undergoing an R0 resection (96.9%). The median OS, 1-year OS, median PFS, and 1-year PFS for BRPC versus LAPC patients was 16.4 months versus 15 months, 72.2% versus 68.1%, 9.7 versus 9.8 months, and 42.8% versus 41%, respectively (all P>.10). BRPC patients who underwent R0 resection had improved median OS (19.3 vs 12.3 months; P=.03), 1-year OS (84.2% vs 58.3%; P=.03), and 1-year PFS (56.5% vs 25.0%; P<.0001), respectively, compared with all nonsurgical patients. The 1-year LC in nonsurgical patients was 81%. We did not observe acute grade ≥3 toxicity, and late grade ≥3 toxicity was minimal (5.3%). CONCLUSIONS: SBRT safely facilitates margin-negative resection in patients with BRPC pancreatic cancer while maintaining a high rate of LC in unresectable patients. These data support the expanded implementation of SBRT for pancreatic cancer.

Initial experience from a large referral center with robotic-assisted Ivor Lewis esophagogastrectomy for oncologic purposes.

BACKGROUND: We report our initial experience of patients undergoing robotic-assisted Ivor Lewis esophagogastrectomy (RAIL) for oncologic purposes at a large-referral center. METHODS: A retrospective review of all consecutive patients undergoing RAIL from 2010-2011 was performed. Basic demographics were recorded. Oncologic variables recorded included: tumor type, location, postoperative tumor margins, and nodal harvest. Immediate 30-day postoperative complications also were analyzed. RESULTS: Fifty patients underwent RAIL with median age of 66 (range 42-82) years. The mean body mass index was 28.6 ± 0.7 kg/m(2); 54% and the majority had an American Society of Anesthesiologists classification of 3. The mean and median number of lymph nodes retrieved during surgery was 20 ± 1.4 and 18.5 respectively. R0 resections were achieved in all patients. Postoperative complications occurred in 14 (28%) patients, including atrial fibrillation in 5 (10%), pneumonia in 5 (10%), anastomotic leak in 1 (2%), conduit staple line leak in 1 (2%), and chyle leak in 2 (4%). The median ICU stay and length of hospitalization (LOH) were 2 and 9 days respectively. Total mean operating time calculated from time of skin incision to wound closure was 445 ± 85 minutes; however, operative times decreased over time. Similarly, there was a trend toward lower complications after the first 29 cases but this did not reach statistical significance. There were no in-hospital mortalities. CONCLUSIONS: We demonstrated that RAIL for esophageal cancer can be performed safely and may be associated with fewer complications after a learning curve, shorter ICU stay, and LOH.

Minimally invasive surgery for esophageal cancer: review of the literature and institutional experience.

BACKGROUND: Esophageal cancer represents a major public health problem in the world. Several minimally invasive esophagectomy (MIE) techniques have been described and represent a safe alternative for the surgical management of esophageal cancer in selected centers with high volume and surgeons experienced in minimally invasive procedures. METHODS: The authors reviewed the most recent and largest studies published in the medical literature that reported the outcomes for MIE techniques. RESULTS: In larger series, MIE has proven to be equivalent in postoperative morbidity and mortality to the open esophagectomy. However, MIE has been associated with less blood loss, reduced postoperative pain, decreased time in the intensive care unit, and shortened length of hospital stay compared with the conventional open approaches. Despite limited data, no significant difference in survival stage for stage has been observed between open esophagectomy and MIE. CONCLUSIONS: The myriad of MIE techniques complicates the debate for defining the optimal surgical approach for the treatment of esophageal cancer. Randomized controlled trials comparing MIE with conventional open esophagectomy are needed to clarify the ideal procedure with the lowest postoperative morbidity, best quality of life after surgery, and long-term survival.

Lymph node harvest in esophageal cancer after neoadjuvant chemoradiotherapy.

BACKGROUND: This study was designed to determine the effects of lymph node (LN) harvest on survival in esophageal cancer after neoadjuvant chemoradiation (nCRT). METHODS: An analysis of surgically resected esophageal cancer patients after nCRT was performed to determine an association between the number of LNs resected and survival. Overall survival (OS) and disease-free survival (DFS) curves were calculated according to the Kaplan-Meier method and log-rank analysis. Multivariate analysis (MVA) was performed by the Cox proportional hazard model. RESULTS: We identified 358 patients with a mean follow-up of 27.3 months. The number of LN removed was not impacted by the type of surgical procedure. The number of LNs removed (<10 vs. ≥10, <12 vs. ≥12, and <15 vs. ≥15) did not impact OS or DFS. We found a significant difference in OS and DFS by pathologic response. The median and 5-year OS for patients with complete, partial, and no response was 65.6 months and 52.7%, 29.7 months and 30.4%, and 17.7 months and 25.4% (p=0.0002). However, the number of LN harvested did not impact OS and DFS when patients were stratified by pathologic response. MVA also revealed that the number of lymph nodes removed was not prognostic for OS or DFS. Higher age, higher stage, and less than a complete response were associated with a decreased OS. Higher stage and less than a complete response were prognostic for worse DFS. CONCLUSIONS: The number of LNs harvested during esophagectomy does not impact survival after nCRT. Stage and pathologic response continue to be the strongest prognostic factors for survival in esophageal cancer after nCRT.

Quantitative measures of visceral adiposity and body mass index in predicting rectal cancer outcomes after neoadjuvant chemoradiation.

BACKGROUND: The association between body mass index as a measure of obesity and rectal cancer outcomes has been inconsistent. Radiologic measures of visceral adiposity using CT scans have not been well characterized among rectal cancer patients. The objective of this study was to examine quantitative radiologic measures of visceral obesity compared with body mass index in predicting patient outcomes among patients undergoing neoadjuvant chemoradiation and resection for locally advanced rectal cancers. STUDY DESIGN: We identified 99 rectal adenocarcinoma patients treated with neoadjuvant chemoradiation and surgical resection. Visceral and subcutaneous fat areas, as well as perinephric fat thickness (PNF), were recorded and categorized as obese (body mass index ≥30, visceral fat area to subcutaneous fat area ratio [V/S] ≥0.4, or median PNF). The Kaplan-Meier method, log-rank test, and Cox proportional hazards models evaluated overall and disease-free survival differences by adiposity. RESULTS: Viscerally obese rectal cancer patients (V/S >0.4 or PNF) were more likely to be older, male, and have pre-existing obesity-related conditions (eg, diabetes, hypertension, and/or hypercholesterolemia). Elevated V/S or PNF was associated with shorter disease-free survival (p = 0.02) or overall survival time (p = 0.047), respectively. Among patients with well to moderately differentiated tumors, visceral obesity was associated with poorer disease-free survival (V/S >0.4: adjusted hazard ratio = 5.0; 95% CI, 1.2-22.0). CONCLUSIONS: Visceral fat area to subcutaneous fat area ratio and PNF were strongly associated with key preoperative metabolic comorbidities, and body mass index was not. Findings suggests that elevated visceral adiposity was associated with an increased risk of recurrence, which was most evident among patients with well to moderately differentiated tumors and those with incomplete response to neoadjuvant chemoradiation treatment. Quantitative measures of visceral adiposity warrant large-scale prospective evaluation.

Outcomes associated with surgery for T4 esophageal cancer.

BACKGROUND: T4 esophageal cancer often portends a dismal prognosis even after surgical resection. Historical incomplete resections and poor survival rates often make surgery palliative rather than curative. METHODS: Using a comprehensive esophageal cancer database, we identified patients who underwent an esophagectomy for T4 tumors between 1994 and 2011. Neoadjuvant treatment (NT) and pathologic response variables were recorded, and response was denoted as complete response (pCR), partial response (pPR), and nonresponse (NR). Clinical and pathologic data were compared. Survival was calculated using Kaplan-Meier curves with log-rank tests for significance. RESULTS: We identified 45 patients with T4 tumors all who underwent NT. The median age was 60 years (range, 31-79 years) with a median follow-up of 27 months (range, 0-122 months). There were 19 pCR (42 %), 22 pPR (49 %), and 4 NR (9 %). R0 resections were accomplished in 43 (96 %). There were 18 recurrences (40 %) with a median time to recurrence of 13.5 months (2.2-71 months). In this group pCR represented 7 (38.9 %), whereas pPR and NR represented 10 (55.5 %), and 1 (5.5 %) respectively. The overall and disease-free survival for all patients with T4 tumors were 35 and 36 %, respectively. Patients achieving a pCR had a 5 year overall and disease-free survival of 53 and 54 %, compared with pPR 23 and 28 %, while there were no 5 year survivors in the NR cohort. CONCLUSION: We have demonstrated that neoadjuvant therapy and downstaging of T4 tumors leads to increased R0 resections and improvements in overall and disease-free survival.

Increased survival associated with surgery and radiation therapy in metastatic gastric cancer: a Surveillance, Epidemiology, and End Results database analysis.

BACKGROUND: Patients with metastatic gastric cancer have poor survival. The purpose of this study was to compare outcomes of metastatic gastric cancer patients stratified by surgery and radiation therapy. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was accessed to identify patients with AJCC M1 stage IV gastric cancer (based on the American Joint Committee on Cancer Cancer Staging Manual, 6th edition) between 2004 thru 2008. Patients were divided into 4 groups: group 1, no surgery or radiation; group 2, radiation alone; group 3, surgery alone; group 4, surgery and radiation. Survival analysis was determined by Kaplan-Meier and log-rank analysis. Multivariate analysis (MVA) was analyzed by the Cox proportional hazard ratio model. RESULTS: A total of 5072 patients were identified. Surgery and/or radiation were associated with a survival benefit. Median and 2-year survival for groups 1, 2, 3, and 4 was 7 months and 8.2%, 8 months and 8.9%, 10 months and 18.2%, and 16 months and 31.7%, respectively (P < .00001). MVA for all patients revealed that surgery and radiation were associated with decreased mortality whereas T-stage, N-stage, age, signet ring histology, and peritoneal metastases were associated with increased mortality. In patients treated with surgery, MVA showed that radiation was associated with decreased mortality, whereas T-stage, N-stage, age, removal of < 15 lymph nodes, signet ring histology, and peritoneal metastases was associated with increased mortality. Age was the only prognostic factor in patients who did not undergo surgery. CONCLUSIONS: Surgery and radiation are associated with increased survival in a subset of patients with metastatic gastric cancer. Prospective trials will be needed to address the role and sequence of surgery and radiation in metastatic gastric cancer.

Prognostic validity of the American Joint Committee on Cancer staging classification for midgut neuroendocrine tumors.

PURPOSE: The American Joint Committee on Cancer (AJCC) staging manual has introduced a TNM staging classification for jejunal-ileal (midgut) neuroendocrine tumors (NETs). This classification has not been validated in a population consisting solely of midgut NETs. The purpose of this study was to test the prognostic validity of the classification in such a population. METHODS: Patients with jejunal and ileocecal NETs who were treated at the Moffitt Cancer Center between 2000 and 2010 were assigned stages (I through IV). Kaplan-Meier analyses for overall survival (OS) were performed on the basis of TNM stage and pathologic grade. Multivariate modeling was performed using Cox proportional hazards regression. RESULTS: We identified 691 patients with jejunal-ileocecal NETs. The AJCC classification in aggregate was highly prognostic for OS (P < .001). Five-year OS rates for stages I through IV were 100%, 100%, 91%, and 72%, respectively. The survival difference between stages III and IV was significant (P < .001); the difference between stages I/II versus III was not statistically significant (P = .1). Among patients with stage IIIB tumors, 5-year survival rates were 95% for resectable tumors versus 78% for unresectable mesenteric tumors (P = .02). A proliferative threshold of five mitoses per 10 high-power fields (HPF) was of greater prognostic value than a threshold of two mitoses per 10 HPF for discriminating between low- and intermediate-grade tumors. CONCLUSION: Stage I and II midgut NETs are associated with identical survival rates. Stage IIIB tumors are heterogeneous, with significant differences in survival observed between resectable mesenteric lymph nodes versus unresectable masses in the root of the mesentery. A higher mitotic cutoff of five per 10 HPF may lead to improved prognostic differentiation between low- and intermediate-grade tumors. Revisions to the current AJCC staging and grading classification may be warranted.

High-grade dysplasia and adenocarcinoma are frequent in side-branch intraductal papillary mucinous neoplasm measuring less than 3 cm on endoscopic ultrasound.

BACKGROUND: Surgical resection for intraductal papillary mucinous neoplasm (IPMN) of the pancreas has increased over the last decade. While IPMN with main duct communication are generally recommended for resection, indications for resection of side-branch IPMN (SDIPMN) have been less clear. We reviewed our single institutional experience with SDIPMN and indications for resection. METHODS: Patients who underwent resection for IPMN were identified from a prospectively maintained IRB-approved database. Patients with main pancreatic duct communication were excluded. Outcome, clinical and pathologic characteristics were correlated with endoscopic ultrasound (EUS) findings. RESULTS: From 2000 to 2010, 105 patients who underwent preoperative EUS evaluation and resection for SDIPMN were identified. The mean age was within the sixth decade of life, and there was a slight female predominance (55 vs. 45 %). The most common presenting symptom was abdominal pain (N = 47, 45 %), followed by jaundice (N = 24, 23 %) and weight loss (N = 24, 23 %). Only ten patients (10 %) were asymptomatic at presentation; seven (70 %) had suspicious features on EUS. Of the total cohort, few patients had intracystic septations (N = 27, 26 %) or presence of mural nodules (N = 2, 2 %) on EUS. Of 39 patients who had invasive pancreatic ductal adenocarcinoma (PDAC) on final pathology, EUS-fine needle aspiration (EUS-FNA) demonstrated malignancy in only 21 (54 %). An additional seven (18 %) had EUS-FNA findings of atypia or concern for mucinous neoplasm. EUS evaluation of cyst size was correlated with final pathology. Of 70 patients with EUS cyst size <3 cm, 12 (17 %) had a preoperative EUS diagnosis of malignancy. Final pathology revealed 24 (34 %) to have PDAC: 1 of 7 (14 %) patients with cyst size <1 cm, 2 of 19 (11 %) with cyst size 1-2 cm, and 21of 44 (48 %) with cyst size 2-3 cm. Fifteen of 35 (43 %) patients with cyst size >3 cm had PDAC on final pathology. Of the patients with cyst size <3 cm, 16 (23 %) had high-grade dysplasia on final pathology: 3 of 7 (43 %) with cyst size <1 cm, 3 of 19 (16 %) with cyst size 1-2 cm, and 10 of 44 (23 %) with cyst size 2-3 cm. Seven of 35 (20 %) patients with cyst size >3 cm had high-grade dysplasia on final pathology. Although overall survival (OS) at 48 months stratified by EUS cyst size did not significantly differ between groups, patients with PDAC on final pathology had significantly worse OS compared to noninvasive pathology. A total of eight patients (8 %) developed recurrent disease, all of whom had PDAC on final pathology. CONCLUSION: EUS is a helpful modality for the diagnostic evaluation of SDIPMN. Considering the high incidence of malignancy as well as high-grade dysplasia in SDIPMN greater than 2 cm, EUS features should be used in conjunction with other clinical criteria to guide management decisions. Patients with SDIPMN greater than 2 cm that do not undergo surgical resection may benefit from more intensive surveillance.