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Hereditary diffuse gastric cancer (HDGC) syndrome results from a germline CDH1 mutation, and microscopic foci of signet-ring carcinoma cells (SRCC) are present in nearly all gastrectomy specimens. 1 The lifetime risk of invasive gastric cancer (GC) has been thought to be 70%, 2 but recent data have suggested a lower risk of 37%. 3 Prophylactic total gastrectomy is considered the standard of care, but many patients choose surveillance endoscopy instead. We sought to define the outcomes in CDH1-positive individuals who pursued endoscopic surveillance., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: A general surgery resident may have competing clinical responsibilities that limit the ability to participate in educational didactics. Social media is an alternative delivery method for educational content that can be viewed at a resident's convenience. We sought to assess the feasibility of using social media to provide educational content for surgical residents., Materials and Methods: We created a novel, supplemental surgical curriculum consisting of two-minute videos based on the This Week in SCORE modules. Videos were posted to Twitter weekly, indexed with the #SurgEdVidz hashtag and uploaded to YouTube to create a catalog of videos. Twitter and YouTube analytics were used to calculate public viewership and impact., Results: A total of 43 videos were disseminated between January 30, 2019 and January 31, 2020. An average of 6.9 h (SD: 1.4; range: 5.0-10.0) was required to generate each video, including 1.5 h (SD: 0.6; range: 0-2.0) for content review and 5.4 h (SD: 1.1; range: 4.0-8.0) for video production. Between the two platforms, videos generated a total of 51,313 views with an average of 1193 views (SD: 715; range: 412-4096) per video. Account followers are geographically distributed across 28 states, 28 countries, and six continents., Conclusions: Social media can serve as an effective tool for the distribution of surgical educational content. Twitter, in conjunction with YouTube, allows for rapid dissemination of didactic content packaged into brief videos that is flexible in viewership with low time commitment. Social media offers visibility and engagement beyond the classroom without geographical or temporal borders., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: In this series from the Transatlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG), the authors examined longitudinal outcomes of patients with a second recurrence of retroperitoneal sarcoma (RPS) after complete resection of a first local recurrence (LR)., Methods: Data from patients undergoing resection of a first LR from January 2002 to December 2011were collected from 22 sarcoma centers. The primary outcome was overall survival (OS) after second recurrence., Results: Second recurrences occurred in 400 of 567 patients (70.5%) after an R0/R1 resection of a first locally recurrent RPS. Patterns of disease recurrence were LR in 323 patients (80.75%), distant metastases (DM) in 55 patients (13.75%), and both LR and DM in 22 patients (5.5%). The main subtype among the LR group was liposarcoma (77%), whereas DM mainly were leiomyosarcomas (43.6%). In patients with a second LR only, a total of 200 patients underwent re-resection (61.9%). The 5-year OS rate varied significantly based on the pattern of failure (P < .001): 45.6% for the LR group, 25.5% for the DM group, and 0% for the group with LR and DM. The only factors found to be associated with improved OS on multivariable analysis were both time between second surgery and the development of the second recurrence (32 months vs 8 months: hazard ratio, 0.44 [P < .001]) and surgery for second recurrence (yes vs no: hazard ratio, 3.25 [P < .001]). The 5-year OS rate for patients undergoing surgery for a second LR was 59% versus 18% in the patients not deemed suitable for surgical resection., Conclusions: Survival rates after second recurrence of RPS varied based on patterns of disease recurrence and treatment. Durable disease-free survivors were identified after surgery for second LR in patients selected for this intervention., (© 2020 American Cancer Society.)

Objective: To determine whether pursuit of an advanced degree during dedicated research time (DRT) in a general surgery residency training program impacts a resident's research productivity., Design: A retrospective, multi-institutional cohort study., Setting: General surgery residency programs that were approved to graduate more than 5 categorical residents per year and that offered at least 1 year of DRT were contacted for participation in the study. A total of 10 general surgery residency programs agreed to participate in the study., Participants: Residents who started their residency between 2000 and 2012 and spent at least one full year in DRT (n = 511) were included. Those who completed an advanced degree were compared on the following parameters to those who did not complete one: total number of papers, first-author papers, the Journal Citation Reports impact factors of publication (2018, or most recent), and first position after residency or fellowship training., Results: During DRT, 87 (17%) residents obtained an advanced degree. The most common degree obtained was a Master of Public Health (MPH, n = 42 (48.8%)). Residents who did not obtain an advanced degree during DRT published fewer papers (median 8, [interquartile range 4-12]) than those who obtained a degree (9, [6-17]) (p = 0.002). They also published fewer first author papers (3, [2-6]) vs (5, [2-9]) (p = 0.002) than those who obtained a degree. Resident impact factor (RIF) was calculated using Journal Citation Reports impact factor and author position. Those who did not earn an advanced degree had a lower RIF (adjusted RIF, 84 ± 4 vs 134 ± 5, p < 0.001) compared to those who did. There was no association between obtaining a degree and pursuit of academic surgery (p = 0.13) CONCLUSIONS: Pursuit of an advanced degree during DRT is associated with increased research productivity but is not associated with pursuit of an academic career., (Copyright © 2020 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Purpose: Disparities in surgical care persist. To mitigate these disparities, we are implementing and testing the Provider Awareness and Cultural dexterity Toolkit for Surgeons (PACTS), a curriculum to improve surgical residents' cultural dexterity during clinical encounters. We analyzed baseline data to look for concordance between residents' self-perceived cultural dexterity skills and patients' perceptions of their skills. We hypothesized that residents would rate their skills in cultural dexterity higher than patients would perceive those skills., Methods: Prior to the implementation of the curriculum, surgical residents at 5 academic medical centers completed a self-assessment of their skills in culturally dexterous patient care using a modified version of the Cross-Cultural Care Survey. Randomly selected surgical inpatients at these centers completed a similar survey about the quality of culturally dexterous care provided by a surgery resident on their service. Likert scale responses for both assessments were classified as high (agree/strongly agree) or low (neutral/disagree/strongly disagree) competency. Resident and patient ratings of cultural dexterity were compared. Assessments were considered dexterous if 75% of responses were in the high category. Univariate and multivariate analysis was conducted using STATA 16., Results: A total of 179 residents from 5 surgical residency programs completed self-assessments prior to receiving the PACTS curriculum, including 88 (49.2%) women and 97 (54.2%) junior residents (PGY 1-2s), of whom 54.7% were White, 19% were Asian, and 8.9% were Black/African American. A total of 494 patients with an average age of 55.1 years were surveyed, of whom 238 (48.2%) were female and 320 (64.8%) were White. Fifty percent of residents viewed themselves as culturally dexterous, while 57% of patients reported receiving culturally dexterous care; this difference was not statistically significant (p = 0.09). Residents who perceived themselves to be culturally dexterous were more likely to self-identify as non-White as compared to White (p < 0.05). On multivariate analysis, White patients were more likely to report highly dexterous care, whereas Black patients were more likely to report poorly dexterous care (p < 0.05)., Conclusions: At baseline, half of patients reported receiving culturally dexterous care from surgical residents at 5 academic medical centers in the United States. This was consistent with residents' self-assessment of their cultural dexterity skills. White patients were more likely to report receiving culturally dexterous care as compared to non-White patients. Non-White residents were more likely to feel confident in their cultural dexterity skills. A novel curriculum has been designed to improve these interactions between patients and surgical residents., (Copyright © 2020 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: This study aims to understand the perspectives of surgical residents who completed a Research Residents as Teachers Program (RRATP)., Methods: Our RRATP included a 6 h workshop followed by formal teaching opportunities across one academic year. Resident teachers participated in semi-structured interviews, which were inductively analyzed for prominent themes., Results: Eight surgical research residents completed the RRATP workshop and taught 330 h (median = 26 h, range: 8-105). Interview participation rate was 100%; kappa was 0.81. Residents reported four themes: 1) increased knowledge of teaching principles with subsequent teaching changes, specific factors that contributed to their development as a teacher, numerous personal benefits to participation, and broad positive consequences for the surgical department including improved culture and patient care., Conclusion: A RRATP can generate a significant number of formal teaching hours by surgical research residents, who perceive a high value of formal education training to themselves and their surgical residency program., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Competing Interests: Disclosure The authors have nothing to disclose.

Myogenic differentiation (MD) has been claimed to be a poor prognostic factor in dedifferentiated liposarcoma (DDLPS). To validate this, the prognostic significance of MD in a uniformly treated cohort of DDLPS was assessed. A cohort of patients that have been uniformly treated at one institution for DDLPS of the retroperitoneum and pelvis were stained with smooth muscle actin (SMA) and desmin and semiquantitatively scored for staining focality and strength. Clinical and survival data was collected, and the prognostic significance of MD was evaluated. A total of 50 patients with uniformly treated DDLPS were evaluated. SMA (P=0.052) and a combined score of MD (SMA+desmin) showed a statistically significant decrease in 5-year disease-free survival (P=0.002) in univariate analysis and in multivariate testing combined MD trended toward significance (P=0.052). Combined MD was associated with a decreased OS in multivariate analysis (P=0.004). In a uniformly treated cohort of DDLPS stained for myogenic markers, a combined myogenic score was associated with poor overall survival in multivariate analysis. However, the difference in groups was slight and the clinical application is limited.

Background: Despite an increasing number of women in the field of surgery, bias regarding cognitive or technical ability may continue to affect the experience of female trainees differently than their male counterparts. This study examines the differences in the degree of operative autonomy given to female compared with male general surgery trainees., Methods: A smartphone app was used to collect evaluations of operative autonomy measured using the 4-point Zwisch scale, which describes defined steps in the progression from novice ("show and tell") to autonomous surgeon ("supervision only"). Differences in autonomy between male and female residents were compared using hierarchical logistic regression analysis., Results: A total of 412 residents and 524 faculty from 14 general surgery training programs evaluated 8,900 cases over a 9-month period. Female residents received less autonomy from faculty than did male residents overall (P < .001). Resident level of training and case complexity were the strongest predictors of autonomy. Even after controlling for potential confounding factors, including level of training, intrinsic procedural difficulty, patient-related case complexity, faculty sex, and training program environment, female residents still received less operative autonomy than their male counterparts. The greatest discrepancy was in the fourth year of training., Conclusion: There is a sex-based difference in the autonomy granted to general surgery trainees. This gender gap may affect female residents' experience in training and possibly their preparation for practice. Strategies need to be developed to help faculty and residents work together to overcome this gender gap., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Patient satisfaction is an increasingly important quality metric nationwide. The impact that surgical trainees have on patient-reported satisfaction when they perform operations independently, however, has not been studied., Methods: We conducted a prospective study at a single academic institution from October 2016 to June 2017. An office-based, postprocedure survey was developed by adapting questions from the validated Consumer Assessment of Healthcare Providers and Systems Surgical Care Survey. Top-box scoring was used to determine satisfaction for categorical questions and a comparison of the means was used for overall quality ratings (scale 0-10). Patients indicated whether their operation was completed by an attending surgeon or a postgraduate year 3 general surgery resident. The primary outcome measured was patient satisfaction with overall quality of care. Individual questions were grouped by phase of care and composite scores were measured as a secondary outcome., Results: The survey response rate was 87.4% (n = 195). There were no differences in patient demographics or the types of procedures performed by residents or an attending surgeon. Excision of a soft tissue mass (ie, lipoma) accounted for 89.2% of all procedures performed (n = 174). There were no differences between preprocedure (resident = 92.5% vs attending = 94.2%) or postprocedure (resident = 95.3% vs attending = 97.7%) composite scores. There was, however, a significant difference in periprocedure satisfaction (resident = 78.7% vs attending = 90.7%, P = .02). There was no difference in overall ratings of quality of care given by patients who had their procedure performed by residents (9.8 ± 0.5) versus an attending surgeon (9.9 ± 0.3, P = .15). Finally, on adjusted analysis, resident care did not independently impact the likelihood of a "best possible care" rating for overall quality of care (odds ratio 0.84 ± 0.27, confidence interval 0.45-1.57, P = .58)., Conclusion: Patient satisfaction was very high when residents independently performed minor surgery operations in an office-based setting. Of note, there was no difference in satisfaction with overall quality of care compared with an attending surgeon. This study demonstrates that high resident operative autonomy and patient satisfaction are not mutually exclusive goals when postgraduate year 3 residents perform office-based outpatient procedures., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: We sought to understand the experiences of surgical residents and faculty with treating culturally diverse patients, and identify recommendations for establishing and implementing structured cultural competency training., Summary Background Data: Cultural competency training for medical professionals could reduce healthcare disparities, yet is currently not a standard part of surgical residency training. Few studies have explored the perspectives of surgical residents and faculty on the skills needed to provide cross-cultural care., Study Design: A purposeful sample of surgical residents and faculty from 4 academic institutions was recruited for semistructured qualitative interviews. We developed an in-depth interview guide and performed interviews to thematic saturation. Interviews were audio-recorded, transcribed, and analyzed using grounded theory methodology., Results: We interviewed 16 attending surgeons and 15 surgical residents. Participant demographics were: male (51.6%), White (58.1%), Black (9.7%), Asian (22.5%), and Hispanic (9.7%). Four main themes emerged from the data: 1) aspects of culture that can inform patient care; 2) specific cultural challenges related to surgical care, including informed consent, pain management, difficult diagnoses and refusal of treatment, emergency situations, and end-of-life issues; 3) need for culturally competent care in surgery to navigate cultural differences; 4) perceived challenges and facilitators to incorporating cultural competency into the current training paradigm., Conclusions: Surgeons identified the need to provide better cross-cultural care and proposed tenets for training. Based on these findings, we suggest the development and dissemination of a cultural dexterity training program that will provide surgeons with specific knowledge and skills to care for patients from diverse sociocultural backgrounds.

Background: We investigated attending surgeon decisions regarding resident operative autonomy, including situations where operative autonomy was discordant with performance quality., Methods: Attending surgeons assessed operative performance and documented operative autonomy granted to residents from 14 general surgery residency programs. Concordance between performance and autonomy was defined as "practice ready performance/meaningfully autonomous" or "not practice ready/not meaningfully autonomous." Discordant circumstances were practice ready/not meaningfully autonomous or not practice ready/meaningfully autonomous. Resident training level, patient-related case complexity, procedure complexity, and procedure commonality were investigated to determine impact on autonomy., Results: A total of 8,798 assessments were collected from 429 unique surgeons assessing 496 unique residents. Practice-ready and exceptional performances were 20 times more likely to be performed under meaningfully autonomous conditions than were other performances. Meaningful autonomy occurred most often with high-volume, easy and common cases, and less complex procedures. Eighty percent of assessments were concordant (38% practice ready/meaningfully autonomous and 42% not practice ready/not meaningfully autonomous). Most discordant assessments (13.8%) were not practice ready/meaningfully autonomous. For fifth-year residents, practice ready/not meaningfully autonomous ratings (9.7%) were more frequent than not practice ready/meaningfully autonomous ratings (7.5%). Ten surgeons (2.3%) failed to afford residents meaningful autonomy on any occasion., Conclusion: Resident operative performance quality is the most important determinant in attending surgeon decisions regarding resident autonomy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Approximately 25-30% of patients with renal cell carcinoma (RCC) have metastatic disease at the time of diagnosis, where the most common sites of metastasis are the lung (50-60% of patients with metastatic disease), bones (30-40%), liver (30-40%), and brain (5%). Although RCC metastasis to the small intestine is thought to be exceedingly rare, with predominantly isolated case reports and a few case series in the literature, we present below three additional cases at our institution of metastatic RCC to the small bowel presenting as GI bleeding. A literature review demonstrates that the number of published case reports has been increasing in recent years. We hypothesize that in the era of targeted chemotherapy and VEGF inhibitors to treat RCC that patients are living longer and have more time for their primary tumors to metastasize to the small bowel and become symptomatic, causing metastatic RCC to the small bowel to be less rare than previously thought.

Background: We evaluated the efficacy and safety of risk-adapted, proton-based stereotactic body radiation therapy (SBRT) for liver metastases from solid tumors., Methods: This single-arm phase II single institutional study (NCT01239381) included patients with limited extrahepatic disease, 800 mL or greater of uninvolved liver, and no cirrhosis or Child-Pugh A, who had received proton-based SBRT to one to four liver metastases from solid tumors. Treatment comprised 30 to 50 Gray equivalent (GyE) in five fractions based on the effective volume of liver irradiated. Sample size was calculated to determine if local control (LC) at one year was greater than 70%. The cumulative incidence of local failure was used to estimate LC. The association of tumor characteristics, including genetic alterations in common cancer genes such as BRAF, EGFR, HER2, KRAS, NRAS, PIK3CA, and TP53 with local tumor control, was assessed. All statistical tests were two-sided., Results: Eighty-nine patients were evaluable (colorectal, n = 34; pancreatic, n = 13; esophagogastric, n = 12; other, n = 30). Median tumor size was 2.5 cm (range = 0.5-11.9 cm). Median dose was 40 GyE (range = 30-50 GyE), and median follow-up was 30.1 months (range = 14.7-53.8 months). There was no grade 3 to 5 toxicity. Median survival time was 18.1 months. The one- and three-year LC rates were 71.9% (95% confidence limit [CL] = 62.3% to 80.9%) and 61.2% (95% CL = 50.8% to 71.8%), respectively. For large tumors (≥6 cm), one-year LC remained high at 73.9% (95% CL = 54.6% to 89.8%). Mutation in the KRAS oncogene was the strongest predictor of poor LC (P = .02). Tumor with both mutant KRAS and TP53 were particularly radioresistant, with a one-year LC rate of only 20.0%, compared with 69.2% for all others (P = .001)., Conclusions: We report the largest prospective evaluation to date of liver SBRT for hepatic metastases, and the first with protons. Protons were remarkably well tolerated and effective even for metastases that were 6 cm or larger. KRAS mutation is a strong predictor of poor LC, stressing the need for tumor genotyping prior to SBRT and treatment intensification in this patient subset., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Purpose: To conduct phase 1 and 2 trials with photon intensity modulated radiation therapy and intensity modulated proton therapy (IMPT) arms to selectively escalate the retroperitoneal sarcoma preoperative radiation dose to tumor volume (clinical target volume [CTV] 2) that is judged to be at a high risk for positive margins and aim to reduce local recurrence. We report on the IMPT study arm in phase 1., Methods and Materials: Patients aged ≥18 years with primary or locally recurrent retroperitoneal sarcoma were treated with preoperative IMPT, 50.4 GyRBE in 28 fractions, to CTV1 (gross tumor volume and adjacent tissues at risk of subclinical disease) with a simultaneous integrated boost to CTV2 to doses of 60.2, 61.6, and 63.0 GyRBE in 28 fractions of 2.15, 2.20, and 2.25 GyRBE, respectively. The primary objective of the phase 1 study was to determine the maximum tolerated dose to CTV2, which will be further tested in the phase 2 study., Results: Eleven patients showed increasing IMPT dose levels without acute dose limiting toxicities that prevented dose escalation to maximum tolerated dose. Acute toxicity was generally mild with no radiation interruptions. No unexpected perioperative morbidity was noted. Eight months postoperatively, one patient developed hydronephrosis that was treated by stent with ureter dissected off tumor and received 57.5 GyRBE. Retained ureter(s) was (were) subsequently constrained to 50.4 GyRBE without further problem. With an 18-month median follow-up, there were no local recurrences., Conclusions: IMPT dose escalation to CTV2 to 63 GyRBE was achieved without acute dose limiting toxicities. The phase 2 study of IMPT will accrue patients to that dose. Parallel intensity modulated radiation therapy phase 1 arm is currently accruing at the initial dose level. Ureters that undergo a high dose radiation and/or surgery are at risk for late hydro-ureter. Future studies will constrain retained ureters to 50.4 GyRBE to avoid ureteral stricture.

Dermatofibrosarcoma protuberans (DFSP) is a rare dermal soft tissue sarcoma characterized by a typically indolent clinical course. The greatest clinical challenge in management of DFSP is achieving local control. There is vigorous debate in the literature as to the optimal surgical approach to these tumors. The choice between wide local excision and Mohs micrographic surgery for DFSP should be governed by the attainment of three goals: (1) to completely excise the tumor with negative margins, tantamount to cure; (2) to preserve function, optimize cosmesis, and minimize morbidity of resection; and (3) to minimize cost and inconvenience to the patient and the health care system at large., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: The benefit of surgical resection in patients with incurable gastric adenocarcinoma is controversial., Methods: A total of 289 patients who presented with advanced or metastatic gastric cancer from 1995 to 2010 were retrospectively reviewed., Results: Ten patients (3.5 %) required emergent surgery at presentation and were excluded from further analyses. Patients who underwent nonemergent surgery at presentation (n = 110, 38.1 %) received either gastric resection (group A, n = 46, 42 %) or surgery without resection (group B, n = 64, 58 %). Procedures in group A included distal gastrectomy (n = 25, 54 %), total gastrectomy (n = 17, 37 %), and proximal/esophagogastrectomy (n = 4, 9 %). Procedures in group B included laparoscopy (n = 17, 27 %), open exploration (n = 25, 39 %), gastrostomy and/or jejunostomy tube (n = 12, 19 %), and gastrojejunostomy (n = 10, 16 %). Group A required a stay in the intensive care unit or additional invasive procedure significantly more often than group B (15 vs. 2 %, p = 0.009). Four patients in group A (8.7 %) and three patients in group B (4.7 %) died within 30 days of surgery (p = 0.45). When the 110 patients who underwent nonemergent surgery (groups A and B) were compared to nonoperatively managed patients (group C, n = 169, 58 %), median overall survival did not significantly differ (8.6 vs. 9.2 vs. 7.7 months; p > 0.05). Three patients in group B (4.7 %) and three in group C (1.8 %) ultimately required an operation for their primary tumor., Conclusions: Patients with gastric adenocarcinoma who present with advanced or metastatic disease not amenable to curative resection infrequently require emergent surgery. Noncurative resection is associated with significant perioperative morbidity and mortality as well as limited overall survival, and should therefore be performed judiciously.

Background: The AJCC recommends examination of >16 nodes to stage gastric adenocarcinoma. D2 lymphadenectomy (LAD) followed by surgical ex vivo dissection (SEVD) into nodal stations is standard at many high-volume Asian centers, but potential increases in morbidity and mortality have slowed adoption of D2 LAD in some Western centers., Methods: A total of 331 patients with gastric adenocarcinoma who underwent surgical resection at one Western institution from 1995 to 2010 were examined., Results: Median age of patients was 69 years old, 65% were male, and 84% were white. D1 LAD was performed in 285 patients (86%) and D2 LAD in 46 patients (14%), with SEVD being performed in 17 patients (37%) in the D2 group. D2 LAD with or without SEVD was performed much more commonly between 2006 and 2010. For the D1, D2 without SEVD, and D2 with SEVD groups, the median number of examined nodes and percentage with >16 examined nodes were 16 and 51%, 27 and 93%, and 40 and 100%, respectively. Major complications occurred in 16% of the D1 group and 17% of the D2 group (p>0.05), and 30-day mortality was 3% for the D1 group and 0% for the D2 group. D2 LAD was a positive prognostic factor for overall survival on univariate (p=0.027) and multivariate analyses (p=0.005), but there were several possible confounding variables., Conclusions: D2 LAD at our Western institution was performed with low morbidity and no mortality. Optimal staging occurred after D2 LAD combined with SEVD, where a median of 40 nodes were examined and all patients had >16 examined nodes.

Background: Patients with large, high-grade extremity and truncal soft tissue sarcomas (STS) are at considerable risk for recurrence. A regimen of pre-operative chemotherapy consisting of mesna, adriamycin, ifosfamide and dacarbazine (MAID), interdigitated with radiotherapy (RT), followed by resection and post-operative chemotherapy with or without RT, has demonstrated high rates of local and distant control. The goal of this study is to assess outcomes in a recent cohort of patients treated on this regimen., Methods: We retrospectively reviewed records of 66 consecutive patients with STS of the extremity or trunk who were treated with the aforementioned regimen from May 2000 to April 2011. Clinicopathologic characteristics and patient outcomes were analysed., Results: Sixty-six patients were analysed and were equally divided between grade 2 and 3 tumours. Margins were negative in 57 (89%) patients and positive in seven (11%) patients. At a median follow-up of 46 months, there were six (9%) locoregional and 20 (30%) distant recurrences. The locoregional and distant 5-year recurrence-free survival (RFS) rates were 91% and 64%, respectively. The 5-year overall (OS) and disease-specific survival rates were 86% and 89%, respectively. There were no treatment-related deaths or secondary myelodysplasias. Thirty-four (52%) patients had grade 3 or 4 acute haematologic chemotherapy-related toxicity. There were no statistically significant predictors of OS or RFS., Conclusions: For a contemporary cohort of patients with high-risk extremity and truncal STS, a regimen of neoadjuvant chemoradiotherapy and surgery continues to result in high rates of survival with tolerable short- and long-term toxicity., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Myxofibrosarcomas (MFS) are a historically heterogeneous group of tumors that exhibit a propensity for local recurrence. The objectives of this study were to analyze the prognostic factors and outcomes of patients with MFS treated at a single institution., Methods: We retrospectively reviewed the records of 69 consecutive patients with pathologically confirmed MFS of the extremities or superficial trunk who underwent surgery from August 1995 to November 2010. Clinicopathologic features, treatments, and patient outcomes were reviewed., Results: Sixty-nine patients were identified, of whom 38 were men (55%). The median age was 62 years. Sixty-four patients (93%) presented with primary tumors, and 5 patients (7%) presented with locally recurrent tumors. Median tumor size was 6.0 cm, and 44 patients (64%) had grade 3 tumors (FNCLCC [Fédération Nationale des Centres de Lutte Contre le Cancer] classification). Margins were microscopically positive in 14 patients (20%) and negative in 55 patients (80%), including close margins (<1 mm) in 14 patients (20%). Fifty-three patients (77%) received radiotherapy. At a median follow-up of 41 months, there were 11 local (16%) and 11 distant (16%) recurrences. The local and distant 5-year recurrence-free survival rates were 72% and 82%, and the 5-year overall survival was 61%. Increased age (scaled by 0.1; hazard ratio [HR] 1.80, P=0.002) and tumor size (HR 1.12, P=0.004) were negatively correlated with overall survival. Positive/close (<1 mm) margin status (HR 4.34, P=0.030) predicted worsened local recurrence-free survival., Conclusions: MFS exhibit a propensity for local recurrence, which is predicted by resection with positive or close margins. Aggressive surgery combined with radiotherapy may contribute to more effective local control.

Background: Mutations in the gene-encoding β-catenin, CTNNB1, are highly prevalent in sporadic desmoid tumors and may predict the risk for recurrence. We sought to determine the prevalence of CTNNB1 mutations in a large cohort of sporadic desmoid tumors and to determine whether CTNNB1 mutation status correlates with disease outcome., Methods: Single-base extension genotyping of the CTNNB1 gene was performed on 145 sporadic, paraffin-embedded desmoid tumor specimens. Correlation of mutation status with outcome was performed on a subset of 115 patients who underwent macroscopically complete surgical resection., Results: CTNNB1 mutations were detected in 106 of 145 (73%) tumor specimens and in 86 of 115 (75%) specimens from patients who underwent curative-intent surgical resection, including discrete mutations in the following codons of CTNNB1 exon 3: T41A (46%), S45F (25%), S45P (1.7%), and S45C (0.9%). Desmoid tumors of the superficial trunk were significantly less likely to harbor CTNNB1 mutations than tumors located elsewhere, but none of the other examined clinicopathologic factors were found to be associated with CTNNB1 mutation status. At a median follow-up of 31 months, 5-year recurrence-free survival was slightly, although not statistically significantly, worse for patients with β-catenin-mutated tumors than for those with wild-type tumors (58% vs. 74%, respectively). The specific CTNNB1 codon mutation did not correlate with the risk for recurrence., Conclusion: CTNNB1 mutations are indeed common in sporadic desmoid tumors. However, our study did not detect a statistically significant difference in recurrence risk according to either the CTNNB1 mutation status or the specific CTNNB1 mutation.

Objective: To understand the study habits of general surgery residents as well as their motivating factors for study., Design: A survey was mailed to general surgical residents. Performance on the American Board of Surgery In-Training Examination (ABSITE) was correlated with reported study habits using the Pearson's correlation coefficient., Setting: Massachusetts General Hospital and Brigham and Women's Hospital, 2 urban tertiary referral academic training institutions in Boston, Massachusetts., Participants: Fifty-eight general surgical residents of all training levels (including research)., Results: On average, surgical residents studied for 3 ± 1 days per week, the average duration of each study session being 1.3 ± 0.6 hours. The average total number of study hours per week was 3.4 ± 2.3. There were strong positive correlations between increased study frequency and high overall ABSITE score (Pearson's r = 0.339; p = 0.02) and between the total number of study hours per week and high overall ABSITE score (Pearson's r = 0.423; p < 0.005). Only 10% and 3% reported complete satisfaction with current study materials and routine, respectively. Most residents (96%) reported a willingness to try a new type of study method and 75% were willing to enroll in a trial comparing study methods., Conclusions: Increased study frequency and overall increased study duration are positively correlated with ABSITE performance. Dissatisfaction with current study materials and study routine is high, as is willingness to adopt new methods and enroll in investigational trials comparing study methods., (Copyright © 2012 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Desmoid tumors are rare and exhibit a highly unpredictable natural history. We sought to analyze prognostic factors associated with recurrence in a large single-institution study of patients with desmoid tumors., Methods: We performed a retrospective review of 177 patients with desmoid tumor who underwent macroscopically complete surgical resection, with or without the addition of radiotherapy (RT) or systemic therapy, from 1970 to 2009. We examined patterns of presentation, all known risk factors for recurrence, and their association with recurrence-free survival (RFS)., Results: Twenty-two patients (12 %) had intra-abdominal desmoid tumors, and 155 (88 %) had extra-abdominal tumors. Patterns of presentation included primary (n = 133, 75 %) and locally recurrent (n = 44, 25 %) disease. Treatment was surgery alone in 125 patients (71 %), surgery and RT in 36 (20 %), and surgery and systemic therapy with or without RT in 20 (11 %). Median follow-up was 40 months. Overall, the local relapse rate was 29 %, and 10-year RFS was 60 %. R0 resection status was the only predictor of freedom from local recurrence on multivariate analysis (odds ratio 0.32; 95 % confidence interval 0.15-0.66; P = 0.002). The selective use of adjuvant RT appeared to improve local control in patients with positive margins., Conclusions: For patients with desmoid tumors undergoing surgery, wide excision with negative margins should be the goal, but not at the expense of function, as fewer than half of patients with positive margins will experience recurrence.

Background: Patients with large, high-grade, extremity soft tissue sarcomas (STS) are at significant risk for distant recurrence and death. A regimen of preoperative chemotherapy consisting of mesna, Adriamycin (doxorubicin), ifosfamide, and dacarbazine (MAID), interdigitated with radiotherapy (RT) and followed by resection and postoperative chemotherapy with or without RT, has demonstrated high rates of local and distant control. We report the long-term follow-up data on 48 patients treated with this regimen compared to an historical matched-control patient population., Methods: Adult patients with high-grade extremity STS ≥ 8 cm were treated with 3 cycles of preoperative chemotherapy combined with 44 Gy of RT followed by surgery. Three cycles of postoperative MAID were planned. For patients with positive surgical margins, 16 Gy of RT was delivered postoperatively., Results: Patients received the MAID/RT regimen from 1989 through 1999. After a median follow-up of 9.3 years in surviving patients in the MAID group and 13.2 years in surviving patients in the control group, the 7-year disease-specific and overall survival rates were 81% and 50% (P = .004) and 79% and 45% (P = .003) for the MAID and control patients, respectively. Five of 11 patients in the MAID group and 7 of 25 control patients died of sarcoma ≥5 years after treatment. One patient in the MAID group developed a fatal myelodysplasia at 53 months., Conclusions: For patients with high-risk, extremity STS, the significant survival benefits conferred by an intense regimen of neoadjuvant chemoradiotherapy and surgery are sustained even with long-term follow-up., (Copyright © 2011 American Cancer Society.)

Background: Carcinoid tumors of the appendix are rare, and as such there are few data guiding their optimal treatment., Methods: The analysis included all patients with malignant, typical carcinoid tumor of the appendix for whom complete data were available in the Surveillance, Epidemiology, and End Results database between 1988 and 2003. Clinicopathologic factors predicting lymph node (LN) involvement and survival were determined., Results: LN metastases were present in 44 of 89 patients (49%), including 4 of 27 patients (15%) with tumors ≤ 1.0 cm, 16 of 34 patients (47%) with tumors > 1.0 cm but ≤ 2.0 cm, and 24 of 28 patients (86%) with tumors >2.0 cm. Increasing tumor size predicted LN involvement, whereas age, gender, and depth of tumor invasion did not. Excluding patients with distant metastasis (DM), the 10-year overall survival rates of patients with positive LNs and tumor sizes ≤1.0 cm, >1.0 cm but ≤2.0 cm, and >2.0 cm were 100%, 92%, and 91%, respectively., Conclusions: Right hemicolectomy should be considered for patients with appendiceal carcinoid tumors >1.0 cm in size given their high incidence of LN metastases and limited data concerning the natural history of unresected LN metastases. Wiley-Liss, Inc., (Copyright © 2011 Wiley-Liss, Inc.)

Objective: We sought to examine the effect of body mass index (BMI) on 30-day morbidity and mortality in a large cohort of patients undergoing nonbariatric general surgery., Summary Background Data: Obesity has long been considered a risk factor for poor outcomes from a variety of surgical procedures, yet recent studies of critically and chronically ill patients suggest that overweight and obese patients may paradoxically have better outcomes than "normal" weight patients., Methods: A prospective, multi-institutional, risk-adjusted cohort study of 118,707 patients undergoing nonbariatric general surgery who were included in the National Surgical Quality Improvement Program Participant Use database in 2005 and 2006 was performed. Outcomes and risk variables were compared across NIH-defined BMI class using analysis of variance, Bonferroni multiple comparisons of means tests, and multivariable logistic regression., Results: After adjusting for all significant perioperative risk factors, the risk of death according to BMI exhibited a reverse J-shaped relationship, with the highest rates in the underweight and morbidly obese extremes and the lowest rates in the overweight and moderately obese. Overweight (odds ratio, 0.85; 95% CI, 0.75-0.99) and moderately obese (odds ratio, 0.73; 95% CI, 0.57-0.94) patients had a significantly lower risk of death than normal weight patients. There was a progressive increase in the likelihood of a complication with increasing BMI class, almost entirely due to increasing rates of wound infection., Conclusions: Overweight and moderately obese patients undergoing nonbariatric general surgery have paradoxically "lower" crude and adjusted risks of mortality compared with patients at a "normal" weight. This finding is in contrast to observations from the general population, confirming the existence of an "obesity paradox" in this patient population.

Background: The pancreas is a rare location for metastatic disease, with only 2-11% of all pancreatic tumours being of non-primary origin. It is also uncommon for renal cell carcinoma (RCC) to metastasize to the pancreas (1-3% of cases) and, when it does, it typically occurs substantially after index nephrectomy. It is not known whether all pancreatic metastases need be resected because today's chemo- and biological therapies are increasingly effective in controlling advanced disease., Methods: Six patients with a variety of symptoms are discussed. Four patients presented with recurrent gastrointestinal bleeding, ranging from occult to life-threatening in severity., Results: The four patients with gastrointestinal bleeding had RCC metastases that had eroded into the duodenum and were successfully controlled by palliative pancreaticoduodenectomy or completion pancreatectomy. The other two patients were treated using different chemotherapeutic or biological agents., Conclusions: Renal cell carcinoma metastases to the pancreas typically occur long after index nephrectomy. Although clinical presentation is variable, palliative resection should be reserved for those who develop complications, such as upper gastrointestinal bleeding, and, in other series, obstructive jaundice. Routine debulking resections do not appear to be indicated because current biological therapies effectively and reliably control disease over long periods.

Background: Obesity is an increasingly common serious chronic health condition. We sought to determine the impact of body mass index (BMI) on perioperative outcomes in patients undergoing major intra-abdominal cancer surgery., Methods: A prospective, multi-institutional, risk-adjusted cohort study of patients undergoing major intra-abdominal cancer surgery was performed from the 14 university hospitals participating in the Patient Safety in Surgery Study of the National Surgical Quality Improvement Program (NSQIP). Demographic, clinical, and intraoperative variables and 30-day morbidity and mortality were prospectively collected in standardized fashion. Analysis of variance, Bonferroni multiple comparisons of means tests, and multivariable logistic regression analysis were performed., Results: We identified 2258 patients who underwent esophagectomy (n = 29), gastrectomy (n = 223), hepatectomy (n = 554), pancreatectomy (n = 699), or low anterior resection/proctectomy (n = 753). Patients were stratified by National Institutes of Health (NIH)-defined BMI obesity class, with 573 (25.4%) patients classified as obese (BMI > 30 kg/m(2)). There were no differences in mean work relative value units, total time of operation, or length of stay amongst the BMI classes. After adjusting for other risk factors, obesity was not a risk factor for death or major complications but was a risk factor for wound complications. The risk of postoperative death was greatest in underweight patients (odds ratio [OR] 5.24; 95% confidence interval [CI] 1.7-16.2)., Conclusion: In patients undergoing major intra-abdominal cancer surgery, obesity is not a risk factor for postoperative mortality or major complications. Importantly, underweight patients have a fivefold increased risk of postoperative mortality, perhaps a consequence of their underlying nutritional status.

Background: Two-stage hepatectomy has been proposed for patients with bilateral colorectal liver metastases (CLM). The aim of this study was to compare the outcome of patients with CLM treated with preoperative chemotherapy followed by one- or two-stage hepatectomy., Methods: From a prospective database, 214 consecutive patients who received preoperative systemic chemotherapy (fluoropyrimidine with irinotecan or oxaliplatin) followed by planned one- or two-stage hepatectomy were retrospectively analyzed (1998-2006). In patients undergoing two-stage procedures, minor hepatectomy (wedge or segmental resection[s]) was systematically performed before major (more than three segments), second-stage hepatectomy. Preoperative portal vein embolization (PVE) was performed if indicated., Results: One- (group I) and two-stage (group II) hepatectomies were performed in 184 and 21 patients, respectively. Median number of metastases in groups I and II were two (range 1-20) and seven (range 2-20). All patients in group II had bilateral disease vs 39% in group I. Major hepatectomy was performed in all patients in group II and 79% in group I. PVE was performed in 18 group I and 12 group II patients without increase in morbidity. For group I, group II first stage, and group II second stage, respectively, morbidity (24%, 24%, 43%), median hospital stay (7 days, 6 days, 6.5 days) and 30 days postoperative mortality (2%, 0%, 0%) were not significantly different (P = NS). Median follow-up was 25 months; median survival has not been reached. One- and 3-year overall and disease-free survival rates from the time of hepatic resection were 95% and 75%, 63% and 39%, respectively in group I; 95% and 86%, 70% and 51%, respectively in group II (P = NS)., Conclusions: Two-stage hepatectomy with preoperative chemotherapy results in comparable morbidity and survival rates as one-stage hepatectomy. This approach enables selection and treatment of patients with multiple, bilateral CLM who will benefit from aggressive surgery with good outcomes.

Background: To establish a reliable definition of postoperative hepatic insufficiency (PHI) in noncirrhotic patients undergoing major hepatectomy. No standard definition of PHI has been established, but one is essential for meaningful comparison of outcomes data across studies., Methods: Data from 1,059 noncirrhotic patients who underwent major hepatectomy (3 or more liver segments) at 3 centers from 1995 to 2005 were analyzed. Receiver operating characteristics (ROC) analysis of peak postoperative bilirubin ((Peak)Bil) and international normalized ratio ((Peak)INR) were used to define PHI., Results: A total of 669 patients (63%) underwent resection of 3 to 4 liver segments; 390 (37%) underwent resection of 5 or more segments. Complications occurred in 453 (43%). The 90-day all-cause mortality rate was 4.7%, which is 47% higher than the 30-day rate (3.2%). Twenty (1.9%) patients died of causes unrelated to the liver. Of the remaining 1,039 patients, 30 (2.8%) died a median 36 days from liver-related causes (liver failure with or without multiorgan failure). ROC analysis revealed cut-offs that predict liver-related death are (Peak)Bil 7.0 mg/dL (area under the curve 0.982; sensitivity 93.3%; specificity 94.3%) and (Peak)INR 2.0 (area under the curve 0.846; sensitivity 76.7%; specificity 82.0%). (Peak)Bil > 7.0 mg/dL was the most powerful predictor of any (odds ratio [OR] = 83.3) or major complication (OR = 10.0), 90-day mortality (OR = 10.8), and 90-day liver-related mortality (OR = 250) (all p < 0.0001)., Conclusions: PHI defined as (Peak)Bil > 7.0 mg/dL accurately predicts liver-related death and worse outcomes after major hepatectomy. Standardized reporting of complications, PHI, and 90-day mortality is essential to accurately determine the risk of major hepatectomy and to compare outcomes data.

Background: The standard treatment for epidermoid carcinoma of the anal canal consists of combined radiation and chemotherapy. For patients who present with persistent or locally recurrent disease, salvage abdominoperineal resection is the treatment of choice. The purpose of this study is to review our experience with salvage surgery in this group of patients., Methods: From 1990-2002, 31 patients underwent radical salvage surgery with curative intent after failure of initial sphincter-conserving therapy, and the medical records of these patients were retrospectively reviewed. Clinicopathologic variables were determined and comparisons performed with the Cox proportional hazards model. Survival was calculated by the Kaplan-Meier method., Results: Eleven patients underwent radical salvage surgery for persistent disease and 20 patients for recurrent disease. The median follow-up time was 29 months. The actuarial 5-year overall survival was 64%. Twelve patients developed recurrent disease after radical salvage surgery. Patients who received an initial radiation dose of less than 55 Gy had a significantly worse survival than those who received at least 55 Gy as part of their initial treatment (5-year overall survival 37.5% vs. 75%; age-adjusted hazard ratio 8.2 [95% CI: 1.1-59.8], P = .037). The presence of positive lymph nodes at presentation also adversely affected survival (P < .05). Factors that were not found to have an impact on survival included the presence of persistent versus recurrent disease, tumor (T) stage, and margin status of resection., Conclusions: Long-term survival following salvage surgery for persistent or locally recurrent epidermoid carcinoma of the anal canal can be achieved in the majority of patients. However, patients who initially present with node-positive disease and patients who receive a radiation dose of less than 55 Gy as part of their initial chemoradiation therapy regimen have a worse prognosis after radical salvage surgery.

Background: Unlike its more common non-invasive form, invasive squamous cell carcinoma (SCC) of the skin can be biologically aggressive and is prone to recur. The objectives of this study were to identify relevant clinicopathologic prognostic factors associated with the outcomes of patients with invasive SCC in order to define a high-risk group., Methods: We retrospectively reviewed the records of patients with invasive cutaneous SCC of the trunk or extremities who received surgical treatment at a tertiary care cancer center over the past 10 years. We examined the patterns of presentation, all known clinical and histological risk factors for recurrence, and their association with survival., Results: 136 patients were identified, of whom 102 (74%) were male. Patterns of presentation included primary (n = 91), locally recurrent (n = 16), regional nodal (n = 24), and distant (n = 5) disease. Univariate analysis identified poorly differentiated carcinomas (hazard ratio [HR] = 2.92, P = .016), scar carcinomas (HR = 3.12, P = .008), tumor size > 2 cm (HR = 3.79, P = .006), and regional nodal disease (HR = 5.77, P < .0001) as significant risk factors for recurrence or death. On multivariate analysis, however, only regional nodal disease at presentation (HR = 7.64, P < .0001) was found to be significant., Conclusions: Patients with invasive SCCs metastatic to regional nodes constitute a group at high risk for recurrence and death. Such patients should be considered for adjuvant therapy trials.

Some investigators have suggested that wedge resection (WR) confers a higher incidence of positive margins and an inferior survival compared with anatomic resection (AR) of colorectal liver metastases (CLM). We sought to investigate the margin status, pattern of recurrence, and overall survival of patients with CLM treated with WR or AR. We identified 253 consecutive patients, in a multi-institutional database from 1991 to 2004, who underwent either WR or AR. WR was defined as a nonanatomic resection of the CLM, and AR was defined as single or multiple resections of one or two contiguous Couinaud segments. Clinicopathologic factors were analyzed with regard to pattern of recurrence and survival. One hundred six WRs were performed in 72 patients and 194 ARs in 181 patients. There was no difference in the rate of positive surgical margin (8.3%), overall recurrence rates, or patterns of recurrence between patients treated with WR vs. AR. Patients who had a positive surgical resection margin were more likely to recur at the surgical margin regardless of whether they underwent WR or AR. The median survival was 76.6 months for WR and 80.8 months for AR, with 5-year actuarial survival rates of 61% and 60%, respectively. AR is not superior to WR in terms of tumor clearance, pattern of recurrence, or survival. WR should remain an integral component of the surgical treatment of CLM.

Background: Carcinoid tumors of the duodenum are rare, and their natural history has not been defined. Consequently, there is no consensus on the optimal extent of surgical treatment., Methods: The authors reviewed the records of all patients with primary carcinoid tumors of the duodenum treated at their institution from 1969 through 2004. Patients with primary periampullary tumors and gastrinomas were excluded., Results: Twenty-four patients had a pathologic diagnosis of duodenal carcinoid tumor. The majority (89%) of tumors measured less than 2 cm in diameter, and most (85%) were limited to the mucosa or submucosa. Lymph node metastases were identified in the surgical specimen in 7 (54%) of 13 patients in whom lymph nodes were examined, including 2 patients with tumors smaller than 1 cm and limited to the submucosa. At a mean follow-up of 46 months, the disease-specific survival rate was 100%, and only 2 patients have had recurrences in regional lymph nodes. No patient has had distant metastases or the carcinoid syndrome., Conclusions: Carcinoid tumors of the duodenum are indolent. The presence of regional lymph node metastases cannot be predicted reliably on the basis of tumor size or depth of invasion, and their impact on survival is uncertain.

Contemporary treatment programs for patients with potentially resectable pancreatic cancer often involve preoperative therapy. When the duration of preoperative therapy exceeds 2 months, the risk of plastic endobiliary stent occlusion increases. Metal stents have much better patency but may complicate subsequent pancreaticoduodenectomy (PD). We evaluated rates of perioperative morbidity, mortality, and stent complications in 272 consecutive patients who underwent PD at our institution from May 2001 to November 2004. Of these 272 patients, 29 (11%) underwent PD after placement of a metal stent, 141 underwent PD after placement of a plastic stent, 10 had PD after biliary bypass without stenting, and 92 had PD without any form of biliary decompression. No differences were found between the Metal Stent group and all other patients in median operative time, intraoperative blood loss, or length of hospital stay. No perioperative deaths occurred in the Metal Stent group versus 3 (1.2%) deaths in the other 243 patients. The incidence of major perioperative complications was similar between the two groups, including the rates of pancreatic fistula, intra-abdominal abscess, and wound infection. Furthermore, there were no differences in the perioperative morbidity or mortality rates between patients who underwent preoperative biliary decompression with a stent of any kind (metal or plastic) and those patients who underwent no biliary decompression at all. Metal stent-related complications occurred in 2 (7%) of 29 patients during a median preoperative interval of 4.1 months; in contrast, 75 (45%) of the 166 patients who had had plastic stents experienced complications, including 98 stent occlusions, during a median preoperative interval of 3.9 months (P < 0.001). We conclude that the use of expandable metal stents does not increase PD-associated perioperative morbidity or mortality, and as such an expandable metal stent is our preferred method of biliary decompression in patients with symptomatic malignant distal bile duct obstruction in whom surgery is not anticipated, or in whom there is a significant delay in the time to surgery.

Background: In preclinical models, infection of tumors by oncolytic strains of herpes simplex virus 1 (HSV-1) resulted in the destruction of tumor cells by viral replication and release of progeny virion that infected and destroyed adjacent tumor cells. However, complete tumor regression was rarely observed., Methods: To augment the antitumor effect of viral oncolysis, a replication conditional HSV-1 mutant (HSV-Endo) was constructed in which the murine endostatin gene was incorporated into the HSV-1 genome., Results: Replication of HSV-Endo effectively destroyed several colon carcinoma cell lines in vitro. Secretion of endostatin by HSV-Endo-infected HT29 human colon carcinoma cells was confirmed by Western blot analysis. The secreted endostatin was biologically active as assessed in a chick chorioallantoic membrane assay. Importantly, endostatin production at the site of viral replication did not inhibit viral replication. Direct injection of HSV-Endo into flank tumors caused tumor destruction, and some of the HSV-Endo-treated flank tumors completely sloughed. Immunohistochemical staining of the tumors revealed a decreased number of blood vessels in the HSV-Endo-treated group versus the control group., Conclusions: The oncolytic HSV-1 mutant HSV-Endo provided a two-pronged therapy; namely, inhibition of angiogenesis and direct tumor cell destruction by viral replication., (Copyright 2004 American Cancer Society.)

Replication-conditional viruses destroy tumors in a process referred to as viral oncolysis. An important prerequisite for this cancer therapy strategy is use of viruses that replicate preferentially in neoplastic cells. In this study the DF3/MUC1 promoter/enhancer sequence is used to regulate expression of gamma(1)34.5 to drive replication of a Herpes simplex virus 1 (HSV-1) mutant (DF3gamma34.5) preferentially in DF3/MUC1-positive cells. HSV-1 gamma(1)34.5 functions to dephosphorylate elongation initiation factor 2alpha, which is an important step for robust HSV-1 replication. After DF3gamma34.5 infection of cells, elongation initiation factor 2alpha phosphatase activity and viral replication were observed preferentially in DF3/MUC1-positive cells but not in DF3/MUC1-negative cells. Regulation of gamma(1)34.5 function results in preferential replication in cancer cells that express DF3/MUC1, restricted biodistribution in vivo, and less toxicity as assessed by LD(50). Preferential replication of DF3gamma34.5 was observed in DF3/MUC1-positive liver tumors after intravascular perfusion of human liver specimens. DF3gamma34.5 was effective against carcinoma xenografts in nude mice. Regulation of gamma(1)34.5 by the DF3/MUC1 promoter is a promising strategy for development of HSV-1 mutants for viral oncolysis.

Viral oncolysis represents a unique strategy to exploit the natural process of viral replication to kill tumor cells. Although this concept dates back nearly a century, recent advances in the fields of molecular biology and virology have enabled investigators to genetically engineer viruses with greater potency and tumor specificity. In this article we review the general mechanisms by which oncolytic viruses achieve their antineoplastic efficacy and specificity. We focus on the development of several classes of oncolytic viruses for the treatment of malignant liver tumors, including adenoviruses, vaccinia viruses, and herpes simplex viruses, and discuss the results of clinical trials for these viruses. We also describe results from our laboratory research program, which is focused on developing effective, liver tumor-specific Herpes simplex virus 1 mutants.

Objective: To investigate use of transcriptional regulatory elements (promoters) for tumor-associated antigens to achieve HSV-1 replication preferentially in cells that overexpress the tumor-associated antigens., Summary Background Data: An important advantage of replicating viruses for cancer therapy is their ability to simultaneously destroy tumor cells by replication and release progeny virion to infect and destroy adjacent cancer cells. This strategy requires regulation of the viral life cycle to obtain robust replication in neoplastic cells and minimize replication in nonneoplastic cells., Methods: Promoters for the human carcinoembryonic antigen (CEA) and MUC1/DF3 tumor-associated antigens were characterized and cloned into HSV-1 mutants as heterologous promoters regulating expression of two different HSV-1 genes. Viral replication in tumor cells and cytotoxicity was quantified with in vitro assays. Antineoplastic efficacy was characterized in a flank tumor xenograft model., Results: Several CEA promoters were cloned and characterized using luciferase reporter assays. The most specific promoter was used to construct and isolate two different HSV-1 mutants in which critical genes are regulated by this promoter (ICP4 and gamma(1) 34.5). Similarly, the promoter for the DF3/MUC1 tumor-associated antigen was cloned into a third HSV-1 mutant such that it regulates expression of gamma(1) 34.5. Regulation of ICP4 expression by the CEA promoter during HSV-1 infection overly attenuates viral replication. Regulation of gamma(1) 34.5 expression by either the CEA promoter or the MUC1/DF3 promoter during HSV-1 infection modulates viral replication, with preferential replication in cells that overexpress the corresponding tumor-associated antigen. A single intratumoral inoculation of an HSV-1 mutant with the MUC1/DF3 promoter regulating gamma(1) 34.5 expression results in significant antineoplastic activity in MUC1-positive pancreatic carcinoma xenografts as compared to mock inoculation., Conclusions: Promoters for tumor-associated antigens may be incorporated into the HSV-1 genome to regulate HSV-1 replication. The choices of HSV-1 gene and tumor-associated promoter are important determinants of success of this strategy. Because of its preferential replication in MUC1-positive tumors, an HSV-1 mutant with the MUC1/DF3 promoter regulating gamma(1) 34.5 expression will undergo further examination as a novel cancer therapy agent.

Background: Herpes simplex virus 1 (HSV-1) infection of cancer cells results in viral replication with cell destruction and liberation of progeny virion that infect adjacent tumor cells. rRp450 is a novel replication-conditional HSV-1 mutant that expresses both the endogenous herpes viral thymidine kinase gene and the rat p450 CYP2B1 transgene; p450 bioactivates such cancer prodrugs as cyclophosphamide., Methods: Viral cytotoxicity and replication assays were performed in colon carcinoma cells as well as primary human hepatocytes. For in vivo studies, diffuse liver metastases were generated by inoculating MC26 cells into the portal system of BALB/c mice. Mice were treated with control media, rRp450, or rRp450 plus cyclophosphamide., Results: Cytopathic effects induced by rRp450 replication in colon carcinoma cells were equivalent to those induced by wild type HSV-1 in vitro. Assays developed to separate cytotoxicity mediated by viral replication from cytotoxicity mediated by chemotherapy confirmed that HSV-1 thymidine kinase bioactivates ganciclovir and CYP2B1 bioactivates cyclophosphamide in rRp450-infected cells. rRp450 mediated cytotoxicity in the presence of cyclophosphamide was increased by 21% to 30% above that achieved by viral replication alone. Cyclophosphamide bioactivation produced bystander killing of colon carcinoma cells but not hepatocytes. In contrast to these effects of cyclophosphamide, rRp450 mediated cytotoxicity was reduced in the presence of ganciclovir. These findings are explained by further experiments showing that bioactivation of cyclophosphamide only minimally affected HSV-1 replication in colon carcinoma cells, whereas bioactivation of ganciclovir markedly attenuated HSV-1 replication. In vivo studies revealed a substantial decrease in hepatic tumor burden in all rRp450-treated animals compared to controls. The addition of cyclophosphamide augmented rRp450's in vivo anti-neoplastic effect., Conclusions: The rRp450 mutant HSV-1 is highly oncolytic against colon carcinoma cells both in vitro and in vivo. rRp450 displays preferential replication in colon carcinoma cells compared to normal hepatocytes. Activation of cyclophosphamide by the p450 transgene augmented the anti-neoplastic effects of rRp450 without simultaneously decreasing viral replication. Oncolysis induced by HSV-1 replication combined with cyclophosphamide prodrug activation warrants further investigation as a potential therapy for colon carcinoma liver metastases., (Copyright 2002 American Cancer Society.)

Although the concept of using viruses as antineoplastic agents dates back nearly a century, recent advances in the fields of molecular biology, genetics, and virology have enabled investigators to engineer viruses with greater potency and tumor specificity. Further enhancements involve arming these viruses with therapeutic transgenes, and combining the traditional modalities of chemotherapy and radiation therapy with oncolytic viral therapy in hopes of reducing the chance of developing resistant tumor cell clones. Another means of augmenting the antineoplastic effect of these viruses involves modulating the immune response to minimize antiviral immunity, while at the same time maximizing antitumor immunity. A better understanding of mechanisms that viruses use to overcome cellular defenses to achieve robust replication within the cell will lead to development of oncolytic viruses with better tumor specificity and reduced toxicity. Initial clinical studies have shown that oncolytic viral therapy for metastatic disease is safe and well tolerated. In addition, using similar genetic modification strategies, these viruses have demonstrated antineoplastic effects in humans similar to those seen in preclinical animal models.

Myb34.5 is a herpes simplex virus 1 (HSV-1) mutant deleted in the gene for ribonucleotide reductase (ICP6). It also carries a version of gamma(1)34.5 (a viral gene product that promotes the dephosphorylation of eIF-2alpha) that is under control of the E2F-responsive cellular B-myb promoter, rather than of its endogenous promoter. Myb34.5 replication in tumor cells results in their destruction (oncolysis). gamma(1)34.5 expression by HSV-1 subverts an important cell defense mechanism against viral replication by preventing shutoff of protein synthesis after viral infection. Infection of colon carcinoma cells with Myb34.5 results in greater eIF-2alpha dephosphorylation and viral replication compared with infection with HSV-1 mutants completely defective in gamma(1)34.5 expression. In contrast, infection of normal hepatocytes with Myb34.5 results in low levels of eIF-2alpha dephosphorylation and viral replication that are similar to those observed with HSV-1 mutants completely defective in gamma(1)34.5 and ICP6. When administered intravascularly into mice with diffuse liver metastases, Myb34.5 has greater antineoplastic activity than HSV-1 mutants with completely defective gamma(1)34.5 expression and more restricted biodistribution compared with HSV-1 mutants with wild-type gamma(1)34.5 expression. Myb34.5 displays reduced virulence and toxicity compared to HSV-1 mutants with wild-type gamma(1)34.5 expression. Portal venous administration of Myb34.5 significantly reduces liver tumor burden in and prolongs the life of mice with diffuse liver metastases. Preexisting Ab's to HSV-1 do not reduce the antitumor efficacy of Myb34.5 in vivo.

The concept of using replicating viruses as anticancer agents is not a new one, but the ability to genetically modify these viruses into increasingly potent and tumor-specific vectors is a recent phenomenon. As more is learned about the functions of viral gene products in controlling the mammalian cell cycle and in disabling cellular defense mechanisms, specific viral functions can be augmented or eliminated to enhance antineoplastic efficacy. In this article, general mechanisms by which oncolytic viruses achieve their antitumor efficacy and specificity are reviewed. The paradoxical roles of the immune response are addressed with respect to oncolytic viral therapy, as it, on one hand, impedes the spread of viral infection, and on the other, augments tumor cell destruction through the recruitment of T cells "vaccinated" against tumor antigens. The most commonly used oncolytic viruses are each reviewed in turn, including adenoviruses, herpes simplex viruses, vaccinia viruses, reoviruses, and Newcastle disease viruses. Special attention is focused on the unique biology of each of these viruses as well as the status of several of these mutants in clinical trials.