Conversion to resection post radioembolization in patients with HCC: recommendations from a multidisciplinary working group.

BACKGROUND: Transarterial radioembolization (TARE) with yttrium-90 (90Y) glass microspheres is an efficacious option for converting appropriately selected patients with borderline-resectable hepatocellular carcinoma (HCC) to surgical candidacy. METHODS: In 2018 and 2019, a diverse multidisciplinary group of surgical and interventional experts with experience using 90Y for downstaging and bridging to liver transplant convened to review peer-reviewed literature and personal experience in the use of 90Y to convert borderline resectable liver cancer patients to surgical candidacy. The working group included surgical oncologists specializing in liver cancer, liver transplant surgeons with experience in complex hepatobiliary surgery, and interventional radiologists with experience using 90Y. RESULTS: This document presents expert recommendations based upon the group's experience and consensus. CONCLUSIONS: By combining related evidence from the literature with expert experiences with TARE in surgical candidates, these recommendations aim to demonstrate the safety, efficacy, and feasibility of TARE in converting borderline-resectable patients to surgical options. The document also addresses the concerns about potential complications associated with TARE during the surgical intervention.

Impact of resection margin on outcomes in high-grade soft tissue sarcomas of the extremity-A USSC analysis.

BACKGROUND: The optimal margin of resection for high-grade extremity sarcomas and its impact on survival has long been questioned in the setting of adjuvant radiotherapy. The objective of this study was to investigate the impact of resection status on recurrence and survival. METHODS: All patients with primary, nonmetastatic, high-grade extremity sarcomas that underwent surgical resection from January 2000 to April 2016 in the U.S. Sarcoma Collaborative (USSC) were retrospectively reviewed. Recurrence patterns, recurrence-free survival (RFS), and overall survival (OS) were examined in multivariate analyses (MVA). RESULTS: A cohort of 959 patients was identified with a median follow-up of 34.7 months from diagnosis. R0 resection was achieved in 86.7% (831) while R1 resection in 13.3% (128). Locoregional recurrence for R0 and R1 groups occurred in 9.1% (76) versus 14.8% (19; p = .05) while distant recurrence occurred in 24.7% (205) versus 26.6% (34; p = .65), respectively. Median RFS was 171.2 versus 48.5 (p = .01) while median OS was 149.8 versus 71.5 months (p = .02) for the R0 versus R1 group, respectively. On MVA, female gender (hazard ratio [HR] = 0.69, p = .007) and adjuvant radiotherapy (0.7, p = .04) were associated with improved OS, whereas older age (HR = 1.03, p < .001) and tumor size (HR = 1.01, p < .001) were associated with worse OS. R0 resection status was associated with improved locoregional RFS (HR = 0.56, p = .03) but not with distant RFS (HR = 0.84, p = .4) or OS (HR = 0.7, p = .052). CONCLUSIONS: In high-grade extremity sarcomas, tumor size and gender are predictive of OS while R0 resection status is associated with improved locoregional recurrence rate without a significant impact on distant RFS or OS.

Recurrence patterns after resection of retroperitoneal sarcomas: An eight-institution study from the US Sarcoma Collaborative.

BACKGROUND AND OBJECTIVES: Resection of primary retroperitoneal sarcomas (RPS) has a high incidence of recurrence. This study aims to identify patterns of recurrence and its impact on overall survival. METHODS: Adult patients with primary retroperitoneal soft tissue sarcomas who underwent resection in 2000-2016 at eight institutions of the US Sarcoma Collaborative were evaluated. RESULTS: Four hundred and ninety-eight patients were analyzed, with 56.2% (280 of 498) having recurrences. There were 433 recurrences (1-8) in 280 patients with 126 (25.3%) being locoregional, 82 (16.5%) distant, and 72 (14.5%) both locoregional and distant. Multivariate analyses revealed the following: Patient age P = .0002), tumor grade (P = .02), local recurrence (P = .0003) and distant recurrence (P < .0001) were predictors of disease-specific survival. The 1-, 3-, and 5-year survival rate for patients who recurred vs not was 89.6% (standard error [SE] 1.9) vs 93.5% (1.8), 66.0% (3.2) vs 88.4% (2.6), and 51.8% (3.6) vs 83.9% (3.3), respectively, P < .0001. Median survival was 5.3 years for the recurrence vs 11.3+ years for the no recurrence group (P < .0001). Median survival from the time of recurrence was 2.5 years. CONCLUSIONS: Recurrence after resection of RPS occurs in more than half of patients independently of resection status or perioperative chemotherapy and is equally distributed between locoregional and distant sites. Recurrence is primarily related to tumor biology and is associated with a significant decrease in overall survival.

RAS Mutation Status Confers Prognostic Relevance in Patients Treated With Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Colorectal Cancer.

BACKGROUND: Metastatic colorectal cancer (mCRC) with peritoneal carcinomatosis is an increasingly prevalent disease that carries significant mortality if left untreated. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) in this patient population is associated with improved outcomes but high morbidity. We sought to study the prognostic significance of the known genomic driver, RAS, in patients with mCRC undergoing CRS/HIPEC to allow for improved assessment of risk-benefit ratio in this patient population. METHODS: Patients undergoing CRS/HIPEC for mCRC between 2010 and 2017 at our institution were identified. Patient demographics, RAS mutation status, perioperative morbidity, overall survival (OS), and relapse-free survival (RFS) were evaluated. RESULTS: Forty-seven patients met inclusion criteria. RAS mutant versus RAS wild-type groups were well matched with no difference in the clinicopathologic factors between groups. RAS mutation was associated with decreased RFS but no difference in OS. CONCLUSIONS: RAS mutation is an independent marker of early recurrence in patients undergoing CRS/HIPEC for mCRC and may identify patients who do not derive benefit from this high-risk procedure.

Stereotactic body radiation therapy for hepatocellular carcinoma: Practice patterns, dose selection and factors impacting survival.

BACKGROUND: Stereotactic body radiation therapy (SBRT) is an emerging option for unresectable hepatocellular carcinoma (HCC) without consensus regarding optimal dose schemas. This analysis identifies practice patterns and factors that influence dose selection and overall survival, with particular emphasis on dose and tumor size. MATERIALS/METHODS: Query of the National Cancer Database (NCDB) identified patients with unresectable, nonmetastatic HCC who received SBRT from 2004 to 2013. Biological Effective Dose (BED) was calculated for each patient in order to uniformly analyze different fractionation regimens. RESULTS: A total of 456 patients met the inclusion criteria. The median BED was 100 Gy (22.5-208.0), which corresponded to the most common dose fractionation (50 Gy in five fractions). Various factors influenced dose selection including tumor size (P < 0.001), tumor stage (P = 0.002), and facility case volume (<0.001). On multivariate analysis, low BED (<75 Gy, HR 2.537, P < 0.001; 75-100 Gy, HR 1.986, P = 0.007), increasing tumor size (HR 1.067, P = 0.032), elevated AFP (HR 1.585, P = 0.019), stage 3 (HR 1.962, P < 0.001), low-volume facilities (1-5 cases HR 1.687, P = 0.006), and a longer time interval from diagnosis to SBRT (>2 to ≤4 months, HR 1.456, P = 0.048; >4 months, HR 2.192, P < 0.001) were associated with worse survival. CONCLUSION: SBRT use is increasing for HCC, and multiple regimens are clinically employed. Although high BED was associated with improved outcomes, multiple factors contributed to the dose selection with favorable patients receiving higher doses. Continued efforts to enhance radiation planning and delivery may help improve utilization, safety, and efficacy.

Outcomes of Elderly Patients Undergoing Curative Resection for Retroperitoneal Sarcomas: Analysis From the US Sarcoma Collaborative.

BACKGROUND: The postoperative outcomes of elderly patients undergoing resection of retroperitoneal sarcomas (RPS) have not been widely studied. METHODS: Patients undergoing surgical resection for primary or recurrent RPS between 2000 and 2015 at participating US Sarcoma Collaborative institutions were identified. Patient demographics, perioperative morbidity, mortality, length of stay, discharge to home, disease-specific survival, and disease-free survival were compared between elderly (≥70 y, n = 171) and nonelderly (<70 y, n = 494) patients. RESULTS: There was no difference in perioperative morbidity (total and major complications elderly versus nonelderly: 39% versus 35%; P = 0.401 and 18% versus 17%; P = 0.646, respectively) or mortality between elderly and nonelderly patients with each group experiencing a 1% 30-d mortality rate. Length of stay and 30-d readmission rates were similar (elderly versus nonelderly; 7 d interquartile range [IQR: 5-9] versus 6 d [IQR: 4-9], P = 0.528 and 11% versus 12%, P = 0.667). Elderly patients were more likely to be discharged to a skilled nursing or rehabilitation facility (elderly versus nonelderly; 19% versus 7%, P < 0.001). There was no difference in 3-y disease-free survival between the elderly and nonelderly patients (41% versus 43%, P = 0.65); however, elderly patients had a lower 3-y disease-specific survival (60% versus 76%, P < 0.001). In elderly patients, the presence of multiple comorbidities and high-grade tumors were most predictive of outcomes. CONCLUSIONS: Advanced age was not associated with an increased risk of perioperative morbidity and mortality following resection of RPS in this multi-institutional review. Although short-term oncologic outcomes were similar in both groups, the risk of death after sarcoma recurrence was higher in elderly patients and may be related to comorbidity burden and tumor histology.

Is long-term survival possible after margin-positive resection of retroperitoneal sarcoma (RPS)?

BACKGROUND/OBJECTIVES: For various reasons, some patients undergo a gross margin positive resection (R2) leading to a dilemma in care. We hypothesized that there is a subset of patients who have long-term survival (LTS, ≥5 years) after R2 resection for retroperitoneal sarcoma (RPS). METHODS: National Cancer Database data from 1998 to 2011 were reviewed to identify patients with RPS who had R2 resections. Logistic and Cox regression models were used to compare LTS with short-term survival. RESULTS: Of 12,028 patients, R2 resection rate was 3.28% (4.9% in 1998; 2.5% in 2011). Median survival for RPS with R2 resection was 21 months versus 69 months for those with R0/R1 resections (P < 0.001). Of 272 patients with available survival, 24% (n = 64) survived ≥5 years with 64% alive at follow-up. LTS was most often seen in younger patients (<65 years) with well-differentiated liposarcoma. Chemotherapy appeared to improve survival in the first 3 postoperative years, but paradoxical effects were seen in LTS (Hazards Ratio [HR] 0.69, 95%CI: 0.50-0.95, P = 0.024) in first 3 years versus (HR 2.15, 95%CI: 1.21-3.81, P = 0.009). CONCLUSION: Long-term survival is possible for a subset of patients after an R2 resection for RPS, especially with favorable histology characteristics. Benefits of chemotherapy in margin positive settings need to be investigated. J. Surg. Oncol. 2016;113:823-827. © 2016 Wiley Periodicals, Inc.

Role of Akt inhibition on Notch1 expression in hepatocellular carcinoma: potential role for dual targeted therapy.

BACKGROUND: We have shown that an Akt inhibitor, MK2206, reduces hepatocellular carcinoma (HCC) proliferation. To further delineate MK2206, we sought to investigate the Notch1 pathway and hypothesize that MK2206 treatment will result in Notch1 inhibition with either subsequent or parallel Akt suppression. METHODS: HCC cell lines were treated with various concentrations of MK2206. Cell proliferation was determined via real-time live cell imaging. Knockdown of Notch1 was used to observe interaction between Notch1 and pAkt. Cell lysates were analyzed via Western blotting for Notch and Akt pathway targets. RESULTS: After treatment with MK2206 (up to 2 µM), there was a 60% reduction in cell viability at 48 hours with a concomitant reduction in Notch1 expression. Knockdown of Notch1 in HCC cell lines correlated with reduction in Akt phosphorylation. CONCLUSIONS: MK2206 inhibits both the PI3-K/Akt and Notch1 pathways. Therefore, further characterization of MK2206 comparing the 2 pathways is warranted and the effect of dual targeting in HCC.

Laparoscopic Simultaneous Resection of Colorectal Primary Tumor and Liver Metastases: Results of a Multicenter International Study.

BACKGROUND: With the advance of modern laparoscopic technology, laparoscopic colorectal surgery and laparoscopic liver surgery are both worldwide accepted. Preliminary brief series have shown the feasibility of combined laparoscopic resection of colorectal cancer (CRC) and synchronous colorectal liver metastases (SCRLM). We aim to report a large International multicenter series of laparoscopic simultaneous resection of CRC and SCRLM. METHODS: Between 1997 and 2013, 142 laparoscopic liver resections were performed with simultaneous colorectal surgery for SCRLM. The surgical and postoperative variables evaluated were the duration of the intervention, blood loss, transfusion rate, conversion rate, resection margin, specific and overall morbidity, perioperative mortality, length of hospital stay, and survival. Univariate and multivariate analyses were performed examining postoperative morbidity in the all cohort of patients. RESULTS: The median number of liver lesions was 1 (1-9) and the median larger diameter at diagnosis was 28 (2-100) mm. The median operative time was 360 (120-690) min. Seven patients (4.9%) required conversion. The global morbidity was 31.0% and the mortality was 2.1%. After a median follow-up of 29 (1-108) months, 40 patients (28.2%) developed tumor recurrence. Curative treatment of recurrence was possible in 17 patients (12.0%), including a second liver resection in 13 patients (9.1%), which was performed by laparoscopy in 7 patients (4.9%). Overall 1-, 3-, and 5-year survivals were 98.8, 82.1, and 71.9%, respectively. By multivariate analysis, ASA score≥3 [OR 13.6 (1.8-99.6); P=0.01] and operative time [OR 1.008 (1.001-1.016); P=0.03] were independent predictors of postoperative morbidity. CONCLUSIONS: Our combined data show that in experienced centers, simultaneous laparoscopic approach is technically feasible, safe, and associated with good oncological outcomes.

Effect of the experience of surgical chairpersons on departmental National Institutes of Health funding.

BACKGROUND: Experience and application of recruitment packages can be critical in leadership efforts of surgical chairpersons in promoting research, although attrition of these efforts can happen over time due to lack of new resources. We aimed to examine the impact of experience of surgical chairpersons on departmental National Institutes of Health (NIH) funding. METHODS: Experience as a chairperson defined as the number of years spent as an interim or permanent chair was abstracted from the department Web site (US medical schools only). The NIH funding (US dollars) of the departments were obtained from the Blue Ridge Medical Institute (www.brimr.org). The change in NIH funding from the immediate previous financial year (2010-2009 and 2011-2010) was used to classify chairpersons into four groups: group 1 (-/-), group 2 (-/+), group 3 (+/+), and group 4 (+/-) for analysis. RESULTS: Median NIH funding were $1.9 (0.7-6) million, $1.8 (0.6-5) million, and $1.7 (0.7-5) million for 2009, 2010, and 2011, respectively, and the median experience as a surgical chairperson was 6 y (3-10). Recent chairpersons (<1 y) inherited departments that usually lost NIH funding (62%) and were frequently unable to develop a positive trend for growth over the next fiscal year ([-/-] n = 4 and [+/-] n = 2, 75%). Chairpersons who held their positions for 4-6 y were most likely to be associated with trends of positive funding growth, whereas chairpersons >10 y were most likely to have lost funding (66%, P = 0.07). CONCLUSIONS: Provision of new development dollars later in their tenure and retention of chairpersons might lead to more positive trends in increase in NIH funding.

Microwave ablation for hepatic malignancies: a call for standard reporting and outcomes.

BACKGROUND: Clinical standards of reporting microwave ablation outcomes have not been defined with regard to ablation success, 90-day morbidity, local recurrence after ablation, and nonablation hepatic recurrence. We propose recommendations for microwave ablation reporting and quality standards. METHODS: Literature review of clinical studies focusing on microwave ablation of primary and metastatic hepatic tumors was reported. RESULTS: Ablation success remains the highest quality reporting standard with variations in nomenclature, but with a universal agreement of complete destruction of the target lesion within 1 month after initial microwave ablation. Local recurrence after ablation remains highly variable, with reports as low as 2.2% to as high as 22%; standards lack a common, clearly defined distance from the initial target ablated lesion and the requirement that the target lesion be defined as an ablation success before it can be called a recurrence. Nonablation hepatic recurrence, nonhepatic recurrence, and 90-day morbidity and mortality remain limited in the current literature. CONCLUSIONS: Standardization of hepatic microwave ablation reporting standards are proposed. Current reporting standards in microwave ablation of hepatic malignancies are suboptimal and lack standardization for comparison across institutions.

Mitochondria-targeted antioxidant and glycolysis inhibition: synergistic therapy in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Mito-carboxy proxyl (Mito-CP), a lipophilic cationic nitroxide, accumulates in the mitochondria because of the large negative transmembrane potential. Studies have shown that these agents act by disrupting the energy-producing mechanism, inducing mitochondrial-mediated apoptosis, and also enhancing the action of other chemotherapeutic agents in cancer cells. We hypothesized that the combination of Mito-CP and glycolysis inhibitor, 2-deoxyglucose (2-DG), would synergistically inhibit HCC in vitro. HepG2 cells and primary hepatocytes were treated with various combinations of Mito-CP and 2-DG. Cell cytotoxicity was measured using the methylthiazolyldiphenyl-tetrazolium bromide assay and ATP bioluminescence assay. In addition, caspase 3/7 enzymatic activity was examined after treatment. Mito-CP and 2-DG induced synergistic cytotoxicity in HepG2 cells in a dose-dependent and time-dependent manner, whereas primary cells remained viable and unaffected after treatment. The intracellular ATP levels of HepG2 cells were suppressed within 6 h of combination treatment, whereas primary cells maintained higher levels of ATP. Dose-dependent increases in caspase 3/7 activity occurred in HepG2 cells in a time-dependent manner, showing the initiation of cell death through the apoptotic pathway. These findings indicate that a combination of Mito-CP and 2-DG effectively inhibits HCC growth in vitro. The increase in caspase 3/7 activity supports the occurrence of 2-DG-induced and Mito-CP-induced apoptotic death in HCC. The inability of the compounds to induce cytotoxicity or suppress the production of ATP in primary hepatocytes provides a selective and synergistic approach for the treatment of HCC.

Biliary inflammatory pseudotumor: imaging features in seven patients.

OBJECTIVE: Hepatic biliary pseudotumor is a benign, rare, and poorly understood tumor that is typically diagnosed after aggressive surgical intervention. The purpose of this report is to describe the clinical and imaging features of this tumor in seven patients. CONCLUSION: Although secondary clinical features may rarely suggest inflammatory pseudotumor, the typical presenting symptom--painless obstructive jaundice--is indicative of malignancy. The imaging appearance of hepatic hilar biliary pseudotumor is also indistinguishable from that of cholangiocarcinoma.