Tumor histopathology predicts outcomes after resection of colorectal cancer liver metastases treated with and without pre-operative chemotherapy.

BACKGROUND AND OBJECTIVES: Study objectives, included determination of: (i) associations between radiologic and pathologic responses of colorectal cancer liver metastases (CRCLM) to chemotherapy; and (ii) whether CRCLM histopathology is associated with recurrence free survival (RFS) after resection among patients not treated with pre-operative chemotherapy (untreated). METHODS: Demographics, clinicopathologic characteristics, and outcomes among patients who underwent CRCLM resection from 2007 to 2014 were reviewed. Tumor regression grade (TRG) of 1-2 and 4-5 depict low and high proportions of viable tumor relative to fibrosis, respectively. RESULTS: Of 138 patients, 84 (60.9%) were treated with pre-operative chemotherapy. In these patients, there was no difference in proportions with TRG 1-2 among those with verses without radiologic response (26.9% vs. 18.8%, P = 0.393). TRG 1-2 was associated with superior RFS on univariable (median 15 vs. 6 months, P < 0.001) and multivariable (P = 0.005) analyses. Radiologic response was not associated with RFS. Among untreated patients (n = 54), TRG 4-5 was associated with poor RFS on univariable (median 44 vs. 15 months, P = 0.011) and multivariable (P = 0.012) analyses. CONCLUSIONS: High proportions of CRCLM fibrosis occur in 20% of patients without radiologic response to chemotherapy. Among untreated patients, high proportion of viable tumor relative to fibrosis is associated with poor RFS after resection. J. Surg. Oncol. 2016;113:456-462. © 2016 Wiley Periodicals, Inc.

Robotic versus laparoscopic hepatectomy: a matched comparison.

OBJECTIVE: To perform a matched comparison of surgical and postsurgical outcomes between our robotic and laparoscopic hepatic resection experience. BACKGROUND: The application of robotic technology and technique to liver surgery has grown. Robotic methods may have the potential to overcome certain laparoscopic disadvantages, but few studies have drawn a matched comparison of outcomes between robotic and laparoscopic liver resections. METHODS: Demographics, intraoperative variables, and postoperative outcomes among patients undergoing robotic (n = 57) and laparoscopic (n = 114) hepatic resections between November 2007 and December 2011 were reviewed. A 1:2 matched analysis was performed by individually matching patients in the robotic cohort to patients in the laparoscopic cohort based on demographics, comorbidities, performance status, and extent of liver resection. RESULTS: Matched patients undergoing robotic and laparoscopic liver resections displayed no significant differences in operative and postoperative outcomes as measured by blood loss, transfusion rate, R0 negative margin rate, postoperative peak bilirubin, postoperative intensive care unit admission rate, length of stay, and 90-day mortality. Patients undergoing robotic liver surgery had significantly longer operative times (median: 253 vs 199 minutes) and overall room times (median: 342 vs 262 minutes) compared with their laparoscopic counterparts. However, the robotic approach allowed for an increased percentage of major hepatectomies to be performed in a purely minimally invasive fashion (81% vs 7.1%, P < 0.05). CONCLUSIONS: This is the largest series comparing robotic to laparoscopic liver resections. Robotic and laparoscopic liver resection display similar safety and feasibility for hepatectomies. Although a greater proportion of robotic cases were completed in a totally minimally invasive manner, there were no significant benefits over laparoscopic techniques in operative outcomes.

Underlying steatohepatitis, but not simple hepatic steatosis, increases morbidity after liver resection: a case-control study.

UNLABELLED: Despite the high prevalence of fatty liver disease, the safety of liver resection in settings of steatohepatitis (SH) or hepatic steatosis is poorly understood. The aim of this study was to determine whether underlying SH or simple hepatic steatosis increases morbidity after liver resection. We compared patients undergoing liver resection with underlying SH or greater than 33% simple hepatic steatosis to controls selected for similar demographics, diagnoses, comorbidities, preoperative chemotherapy treatments, and extent of partial hepatectomy. Primary endpoints included postoperative overall and hepatic-related morbidity. One hundred and two patients with SH and 72 with greater than 33% simple hepatic steatosis who underwent liver resection from 2000 to 2011 were compared to corresponding controls. There were no differences in extent or approach of liver resection, malignant indications, preoperative chemotherapy treatment, elements of metabolic syndrome, alcohol use history, American Society of Anesthesiologists score, age, or gender between patients with SH or simple steatosis and corresponding controls. Ninety-day postoperative overall morbidity (56.9% versus 37.3%; P = 0.008), any hepatic-related morbidity (28.4% versus 15.7%; P = 0.043), surgical hepatic complications (19.6% versus 8.8%; P = 0.046), and hepatic decompensation (16.7% versus 6.9%; P = 0.049) were greater among SH patients, compared to corresponding controls. In contrast, there were no differences in postoperative overall morbidity (34.7% versus 44.4%; P = 0.310), any hepatic-related morbidity (19.4% versus 19.4%; P = 1.000), surgical hepatic complications (13.9% versus 9.7%; P = 0.606), or hepatic decompensation (8.3% versus 9.7%; P = 0.778) between simple hepatic steatosis patients and corresponding controls. Using multivariable logistic regression, SH was independently associated with postoperative overall (odds ratio [OR], 2.316; 95% confidence interval [95% CI]: 1.267-4.241; P = 0.007) and any hepatic-related (OR, 2.722; 95% CI: 1.201-6.168; P = 0.016) morbidity. CONCLUSION: Underlying SH, but not simple hepatic steatosis, increases overall and hepatic-related morbidity after liver resection.

Outcomes of curative treatment for hepatocellular cancer in nonalcoholic steatohepatitis versus hepatitis C and alcoholic liver disease.

UNLABELLED: Concomitant increasing incidences of hepatocellular carcinoma (HCC) and nonalcoholic steatohepatitis (NASH) suggest that a substantial proportion of HCC arises as a result of hepatocellular injury from NASH. The aim of this study was to determine differences in severity of liver dysfunction at HCC diagnosis and long-term survival outcomes between patients undergoing curative therapy for HCC in the background of NASH compared to hepatitis C virus (HCV) and/or alcoholic liver disease (ALD). Patient demographics and comorbidities, clinicopathologic data, and long-term outcomes among patients who underwent liver transplantation, hepatic resection, or radiofrequency ablation for HCC were reviewed. From 2000 to 2010, 303 patients underwent curative treatment of HCC; 52 (17.2%) and 162 (53.5%) patients had NASH and HCV and/or alcoholic liver disease. At HCC diagnosis, NASH patients were older (median age 65 versus 58 years), were more often female (48.1% versus 16.7%), more often had the metabolic syndrome (45.1% versus 14.8%), and had lower model for end-stage liver disease scores (median 9 versus 10) (all P < 0.05). NASH patients were less likely to have hepatic bridging fibrosis or cirrhosis (73.1% versus 93.8%; P < 0.001). After a median follow-up of 50 months after curative treatment, the most frequent cause of death was liver failure. Though there were no differences in recurrence-free survival after curative therapy (median, 60 versus 56 months; P = 0.303), NASH patients had longer overall survival (OS) (median not reached versus 52 months; P = 0.009) independent of other clinicopathologic factors and type of curative treatment. CONCLUSION: Patients with HCC in the setting of NASH have less severe liver dysfunction at HCC diagnosis and better OS after curative treatment compared to counterparts with HCV and/or alcoholic liver disease.

Radiofrequency ablation compared to resection in early-stage hepatocellular carcinoma.

OBJECTIVES: This study aimed to compare survival outcomes after hepatic resection (HR) and radiofrequency ablation (RFA) in early-stage hepatocellular carcinoma (HCC) at a Western hepatobiliary centre. METHODS: Demographic details, clinicopathologic tumour characteristics and survival outcomes were compared among non-transplant candidate patients undergoing HR (n= 50) and RFA (n= 60) for early-stage HCC during 2001-2011. RESULTS: Patients who underwent HR had larger tumours, a longer length of stay and a higher rate of postoperative complications. After a median follow-up of 29 months, there were no significant differences between the treatment groups in 1-, 3- and 5-year overall survival (OS) [RFA group: 86%, 50%, 35%, respectively; HR group: 88%, 68%, 47%, respectively (P= 0.222)] or disease-free survival (DFS) [RFA group: 68%, 42%, 28%, respectively; HR group: 66%, 42%, 34%, respectively (P= 0.823)]. The 58 patients who underwent RFA demonstrated ablation success on follow-up computed tomography at 3 months. Of these, 96.5% of patients showed sustained ablation success over the entire follow-up period. In a subgroup analysis of patients with tumours measuring 2-5 cm, no differences in OS or DFS emerged between the HR and RFA groups. Similarly, no significant differences in outcomes in patients with Child-Pugh class A cirrhosis were seen between the RFA and HR groups. CONCLUSIONS: Radiofrequency ablation is comparable with HR in terms of OS and DFS. It is a reasonable alternative as a first-line treatment for HCC in well-selected patients who are not candidates for transplant.

Hepatic resection for metastatic gastrointestinal stromal tumors in the tyrosine kinase inhibitor era.

BACKGROUND: Before the advent of tyrosine kinase inhibitors (TKIs), surgical resection was the primary treatment for hepatic gastrointestinal stromal tumor (GIST) metastases. Although TKIs have improved survival in the metastatic setting, outcomes after multimodal therapy comprised of hepatectomy and TKIs for GIST are unknown. The objective of this study was to determine whether combination therapy for hepatic GIST metastases is associated with improved overall survival compared with reported outcomes from surgery or TKI therapy alone. METHODS: Demographics, clinicopathologic tumor characteristics, treatments, and outcomes of patients who underwent hepatic resection at 3 high-volume centers from 1995 to 2010 were reviewed. RESULTS: In total, 39 patients underwent hepatectomy for metastatic GISTs, and 27 patients received postoperative TKI therapy. At a median follow-up of 39.7 months, 23 patients (59%) experienced recurrence at a median of 18 months. The 1-year, 2-year, and 3-year overall survival rates were 96.7%, 76.8%, and 67.9%, respectively. Median survival was not reached at 5 years. The rates of severe complication and mortality were 10.2% (4 patients) and 2.5% (1 patient), respectively. When controlling for confounders, postoperative TKI therapy was associated with improved survival (hazard ratio, 0.04; 95% confidence interval, 0.01-0.50; P = .006), and extrahepatic disease was associated with worse survival (hazard ratio, 9.51; 95% confidence interval, 1.63-55.7; P = .012). CONCLUSIONS: Overall survival after combination therapy exceeded previous reports for the treatment of metastatic GIST with hepatic resection or TKI therapy alone and was significantly enhanced by postoperative TKI therapy. The results from this study support findings that combination therapy for GIST liver metastases comprised of surgical resection and TKI therapy is more effective than surgery or TKI therapy alone.

Does neoadjuvant chemotherapy reveal disease precluding surgical treatment of initially resectable colorectal cancer liver metastases?

BACKGROUND: The objective of this study is to determine whether neoadjuvant chemotherapy reveals occult disease precluding surgical extirpation of initially resectable colorectal cancer liver metastases (CRCLM). METHODS: Demographics, clinicopathologic tumor characteristics, treatments, and post-operative outcomes of patients aged 18-80 years, with one to four initially resectable CRCLM, and without concurrent extra-hepatic (EHMD) or previous metastatic disease were reviewed. RESULTS: Two hundred and two patients evaluated from 2000 to 2010 met study criteria; 88 (43.6%) were given neoadjuvant chemotherapy. Patients treated with neoadjuvant chemotherapy were younger (median 58 years vs. 65 years, P = 0.0096), had shorter disease free interval from resection of primary tumor to CRCLM diagnosis (median 0 months vs. 12 months, P < 0.0001), and had more CRCLM (median 1 [1-3] vs. 1 [1-2], P = 0.0096) compared to untreated counterparts. There were no differences in rates of concurrent EHMD noted intra-operatively and not on pre-operative imaging (4.5% vs. 3.5%, P = 0.7290), greater intra-operatively observed CRCLM compared to pre-operative imaging (25.3% vs. 17.5%, P = 0.2449), hepatic resection and/or ablation (97.7% vs. 100.0%, P = 0.9853), or 6-month disease recurrence after surgical treatment (25.6% vs. 14.9%, P = 0.0882). Only two (2.3%) patients treated with neoadjuvant chemotherapy had disease progression precluding surgical extirpation. CONCLUSIONS: Neoadjuvant chemotherapy for initially resectable CRCLM does not reveal occult disease precluding surgical treatment.

Surgery versus intra-arterial therapy for neuroendocrine liver metastasis: a multicenter international analysis.

BACKGROUND: Management of patients with neuroendocrine liver metastasis (NELM) remains controversial. We sought to examine the relative efficacy of surgical management versus intra-arterial therapy (IAT) for NELM and determine factors predictive of survival. METHODS: A total of 753 patients who had surgery (n = 339) or IAT (n = 414) for NELM from 1985 to 2010 were identified from nine hepatobiliary centers. Clinicopathologic data were assessed with regression modeling and propensity score matching. RESULTS: Most patients had a pancreatic (32%) or a small bowel (27%) primary tumor; 47% had a hormonally active tumor. There were statistically significant differences in characteristics between surgery versus IAT groups (hormonally active tumors: 28 vs. 48%; hepatic tumor burden >25%: 52% vs. 76%) (all P < 0.001). Among surgical patients, most underwent hepatic resection alone without ablation (78%). The median number of IAT treatments was 1 (range, 1-4). Median and 5-year survival of patients treated with surgery was 123 months and 74% vs. 34 months and 30% for IAT (P < 0.001). In the propensity-adjusted multivariate Cox model, asymptomatic disease (hazard ratio 2.6) was strongly associated with worse outcome (P = 0.001). Although surgical management provided a survival benefit over IAT among symptomatic patients with >25% hepatic tumor involvement, there was no difference in long-term outcome after surgery versus IAT among asymptomatic patients (P = 0.78). CONCLUSIONS: Asymptomatic patients with a large (>25%) burden of liver disease benefited least from surgical management and IAT may be a more appropriate treatment strategy. Surgical management of NELM should be reserved for patients with low-volume disease or for those patients with symptomatic high-volume disease.

Laparoscopic liver resection.

More than 3,000 laparoscopic liver resections (LLR) are performed worldwide for benign disease, malignancy, and living donor hepatectomy. Minimally invasive hepatic resection approaches include pure laparoscopic, hand-assisted laparoscopic, and a laparoscopic-assisted open "hybrid" approach, where the operation is started laparoscopically to mobilize the liver and begin the dissection, followed by a small laparotomy for completion of the parenchymal transection. Surgeons should have an advanced understanding of hepatic anatomy, extensive experience in open liver surgery, and technical skill to control major vascular and biliary structures laparoscopically before embarking on LLR. Although there is no absolute size criterion, smaller, peripheral lesions (<5 cm) that lie far from major vessels and anticipated transection planes are most amenable to LLR. Although the majority of reported LLR are non-anatomic resections or segmentectomies, several surgical groups are now performing laparoscopic major hepatic resections with excellent safety profiles. Patient benefits from LLR include less operative blood loss, less postoperative pain and narcotic requirement, and a shorter length of hospital stay, with comparable postoperative morbidity and mortality to open liver resection. Comparison studies between LLR and open resection have revealed no differences in width of resection margins for malignant lesions or overall survival after resection for hepatocellular cancer or colorectal cancer liver metastases. Advantages of LLR for HCC in particular include avoidance of collateral vessel ligation, decreased postoperative hepatic insufficiency, and fewer postoperative adhesions, all of which are features that enhance subsequent liver transplantation.

External validation of a pre-operative nomogram predicting peri-operative mortality risk after liver resections for malignancy.

AIM: A pre-operative nomogram using a population-based database to predict peri-operative mortality risk after liver resections for malignancy has recently been developed. The aim of the present study was to perform an external validation of the nomogram using data from a high volume institution. METHODS: The National Inpatient Sample (NIS) database (2000-2004) was used initially to construct the nomogram. The dataset for external validation was obtained from a high volume centre specializing in hepatobiliary surgery. Validation was performed using calibration plots and concordance index. RESULTS: A total of 794 patients who underwent liver resection from the years 2000-2010 at the external institute were included in the validation set with an observed mortality rate of 1.6%. The mean total points for this sample of patients was 124.9 [standard error (SE) 1.8, range 0-383] which translates to a nomogram predicted mortality rate of 1.5%, similar to the actual observed overall mortality rate. The nomogram concordance index was 0.65 [95% confidence interval (CI) 0.46-0.82] and calibration plots stratified by quartiles revealed good agreement between the predicted and observed mortality rates. CONCLUSIONS: The present study provides an external validation of the pre-operative nomogram to predict the risk of peri-operative mortality after liver resection for malignancy.

A standard definition of major hepatectomy: resection of four or more liver segments.

BACKGROUND: While commonly used to describe liver resections at risk for post-operative complications, no standard definition of 'major hepatectomy' exists. The objective of the present retrospective study is to specify the extent of hepatic resection that should describe a major hepatectomy. METHODS: Demographics, diagnoses, surgical treatments and outcomes from patients who underwent a liver resection at two high-volume centres were reviewed. RESULTS: From 2002 to 2009, 1670 patients underwent a hepatic resection. Post-operative mortality and severe, overall and hepatic-related morbidity occurred in 4.4%, 29.7%, 41.6% and 19.3% of all patients. Mortality (7.4% vs. 2.7% vs. 2.6%) and severe (36.7% vs. 24.7% vs. 24.1%), overall (49.3% vs. 40.6% vs. 35.9%) and hepatic-related (25.6% vs. 16.4% vs. 15.2%) morbidity were more common after resection of four or more liver segments compared with after three or after two or fewer segments (all P < 0.001). There were no significant differences in any post-operative outcome after resection of three and two or fewer segments (all P > 0.05). On multivariable analysis, resection of four or more liver segments was independently associated with post-operative mortality and severe, overall, and hepatic-related morbidity (all P < 0.01). CONCLUSIONS: A major hepatectomy should be defined as resection of four or more liver segments.

Surgical management of hepatic neuroendocrine tumor metastasis: results from an international multi-institutional analysis.

BACKGROUND: Management of neuroendocrine tumor liver metastasis (NELM) remains controversial, with some advocating an aggressive surgical approach while others have adopted a more conservative strategy. We sought to define the efficacy of the surgical management of NELM in a large multicenter international cohort of patients. METHODS: We identified 339 patients who underwent surgical management for NELM from 1985 to 2009 from an international database of eight major hepatobiliary centers. Relevant clinicopathologic data were assessed using Kaplan-Meier and Cox regression models. RESULTS: Most patients had a pancreatic (40%) or small bowel (25%) neuroendocrine tumor (NET) primary. The majority of patients (60%) had bilateral liver disease. At surgery, 78% of patients underwent hepatic resection, 3% ablation alone, and 19% resection + ablation. Major hepatectomy was performed in 45% of patients, and 14% underwent a second liver operation. Carcinoid was the most common NET histological subtype (53%). Median survival was 125 months, with overall 5- and 10-year survival of 74%, and 51%, respectively. Disease recurred in 94% of patients at 5 years. Patients with hormonally functional NET who had R0/R1 resection benefited the most from surgery (P = 0.01). On multivariate analyses, synchronous disease [hazard ratio (HR) = 1.9], nonfunctional NET hormonal status (HR = 2.0), and extrahepatic disease (HR = 3.0) remained predictive of worse survival (all P < 0.05). CONCLUSIONS: Liver-directed surgery for NELM is associated with prolonged survival; however, the majority of patients will develop recurrent disease. Patients with hormonally functional hepatic metastasis without prior extrahepatic or synchronous disease derive the greatest survival benefit from surgical management.

Liver transplantation for glycogen storage disease type Ia.

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) most often occurs within hepatocellular adenomas (HCAs) in glycogen storage disease Ia (GSD Ia) patients. The objective of this retrospective study is to assess outcomes after liver transplantation (LT) for GSD Ia where the principal indication for transplantation was prevention of HCC. METHODS: Petitions to the United Network for Organ Sharing region 11 review board for additional model for end-stage liver disease listing points were made on behalf of GSD Ia patients. Demographics, pre-operative comorbidity, and outcomes for GSD Ia patients who underwent LT were reviewed. RESULTS: Between 2004 and 2006, five GSD Ia patients underwent LT. Multiple HCAs with focal hemorrhage and/or necrosis but without histological evidence of malignancy were identified in all explanted specimens. Four of five patients had complications after LT, including cytomegalovirus (CMV) infections and steroid responsive allograft rejection. Hemoglobin levels and serum triglyceride, total cholesterol, blood glucose, and lactic acid concentrations improved in all patients after LT. Corn starch feeding was not required in any patient after LT. Renal function worsened in three patients despite modifications to primary immunosuppressive medications. All patients are alive at last follow-up (range 25-48 months) and all post-transplant complications have resolved. CONCLUSIONS: By removing all possible adenomatous tissue and reversing the underlying hepatic enzymatic deficiency, LT provides definitive prevention against HCC and correction of most metabolic derangements in GSD Ia patients. Renal dysfunction secondary to GSD Ia persists--underscoring the need for further studies to better understand the mechanisms of renal dysfunction in these patients.

Synchronous colorectal liver metastases: is it time to reconsider traditional paradigms of management?

BACKGROUND: Patients with synchronous colorectal liver metastases (CLM) are typically treated with initial colorectal resection followed by arbitrary and prolonged courses of chemotherapy. Partial hepatectomy is considered only for patients without interval disease progression. This review describes the rationale for this treatment approach and the recent developments suggesting that this management paradigm should be reconsidered. RESULTS: Because asymptomatic colorectal cancer often does not lead to complications, and given the potential benefit of chemotherapy in downsizing unresectable to resectable liver disease, most patients with asymptomatic primary tumors and unresectable synchronous CLM should be first treated with chemotherapy. In contrast, initial hepatic resection should be considered for resectable synchronous CLM. Survival benefits from prehepatectomy chemotherapy have not been established. Several reports demonstrate morbidity after hepatic resection from extended durations of irinotecan- and/or oxaliplatin-based prehepatectomy chemotherapy. Although shorter treatment periods may not have these deleterious effects on subsequent hepatic resection, prospective studies reveal that most patients with supposedly aggressive disease with short treatment durations will not be identified. Moreover, a complete radiologic response to prehepatectomy chemotherapy is not only rare but also does not equate with a complete pathological response. Finally, several studies suggest that simultaneous colorectal and minor hepatic resections can performed safely with benefits in total morbidity when compared with traditional staged procedures. CONCLUSIONS: The traditional treatment paradigm centering on the utility of prehepatectomy chemotherapy for resectable synchronous CLM should be reconsidered. Recent developments underscore the need for prospective randomized controlled trials evaluating the optimal timing of hepatectomy relative to chemotherapy.

Liver cell adenoma: a multicenter analysis of risk factors for rupture and malignancy.

BACKGROUND: Liver cell adenoma (LCA) is a benign hepatic tumor with poorly characterized risk for spontaneous rupture and malignant transformation. METHODS: Records from five tertiary hepatobiliary centers were reviewed for all patients treated for LCA from 1997 to 2006. Clinicopathological data were collected and analyzed, and factors that were associated with rupture and/or malignant transformation were assessed by using multivariable logistic regression. RESULTS: A total of 124 patients were analyzed, of which 8 (6.5%) were men; 119 patients underwent resection, and 5 patients had embolic therapy only. Mean patient age was 39+/-11 years, and 55% had history of hormone use. Rupture occurred in 31 (25%) cases. Ruptured tumors were larger (10.5+/-4.5 cm vs. 7.2+/-4.8 cm; p=0.001), and no tumor <5 cm ruptured. Patients with ruptured LCAs were more likely to require preoperative blood transfusion (32% vs. 9%, p=0.006), preoperative embolization (16% vs. 1%, p=0.021), and major (>or=3 segments) hepatic resection (65% vs. 32%, p=0.003). By multivariate analysis, increasing tumor size (odds ratio (OR), 7.8; 95% confidence interval (CI), 2.2-26.3; p<0.01) and recent (within 6 months) hormone use (OR, 4.5; 95% CI, 1.5-13.3; p<0.01) remained independently associated with risk of rupture. Five cases (4%) had evidence of underlying malignancy, but none had LCA <8 cm in diameter. CONCLUSION: In this multicenter analysis of patients with LCAs, risk of rupture correlated with increasing tumor size and recent hormone use. Rupture is associated with greater need for preoperative blood transfusion and major hepatic resection. These data suggest that patients with asymptomatic LCAs approaching 4 cm and those requiring hormonal therapy should undergo surgical therapy.

Timing of multimodality therapy for resectable synchronous colorectal liver metastases: a retrospective multi-institutional analysis.

The optimal timing of chemotherapy relative to resection of synchronous colorectal liver metastases (SCRLM) is not known. The objective of this retrospective multi-institutional study was to assess the influence of chemotherapy administered before and after hepatic resection on long-term outcomes among patients with initially resectable SCRLM treated from 1995 to 2005. Clinicopathologic data, treatments, and long-term outcomes from patients with initially resectable SCRLM who underwent partial hepatectomy at three hepatobiliary centers were reviewed. Four hundred ninety-nine consecutive patients underwent resection; 297 (59.5%) and 264 (52.9%) were treated with chemotherapy before and after resection. Chemotherapy strategies included pre-hepatectomy alone (n = 148, 24.7%), post-hepatectomy alone (n = 115, 23.0%), perioperative (n = 149, 29.0%), and no chemotherapy (n = 87, 17.4%). Male gender (p = 0.0029, HR = 1.41 [1.12-1.77]), node-positive primary tumor (p = 0.0046, HR = 1.40 [1.11-1.77]), four or more SCRLM (p = 0.0005, HR = 1.65 [1.24-2.18]), and post-hepatectomy chemotherapy treatment for 6 months or longer (p = 0.039, HR = 0.75 [0.57-0.99]) were associated with recurrence-free survival after discovery of SCRLM. Carcinoembryonic antigen >200 ng/ml (p = 0.0003, HR = 2.33 [1.48-3.69]), extrahepatic metastatic disease (p = 0.0025, HR = 2.34 [1.35-4.05]), four or more SCRLM (p = 0.033, HR = 1.43 [1.03-2.00]), and post-hepatectomy chemotherapy treatment for 2 months or longer (p < 0.0001, HR = 0.59 [0.45-0.76]) were associated with overall survival. Pre-hepatectomy chemotherapy was not associated with recurrence-free or overall survival. Patients treated with perioperative chemotherapy had similar outcomes as patients treated with post-hepatectomy chemotherapy only. We conclude that chemotherapy administered after but not before resection of SCRLM was associated with improved recurrence-free and overall survival. However, prospective randomized trials are needed to determine the optimal timing of chemotherapy.

Surgical management of gallbladder cancer.

This article describes the epidemiology, risk factors, diagnostic imaging tools, and operative management of gallbladder cancer. The rarity of gallbladder cancer coupled with the prevalence of benign gallbladder disease mean that most patients undergo initial procedures that violate tumor planes, complicating attempts at future oncologic resection. Fortunately, a previous laparoscopic or open cholecystectomy does not lessen survival after definitive surgical extirpation. Large retrospective and underpowered prospective studies have suggested benefit to adjuvant chemotherapy or radiotherapy; however, these results need to be confirmed with large prospective randomized trials.

RNA aptamer-targeted inhibition of NF-kappa B suppresses non-small cell lung cancer resistance to doxorubicin.

Due to the prevalence of tumor chemoresistance, the clinical response of advanced non-small cell lung cancer (NSCLC) to chemotherapy is poor. We suppressed tumor resistance to doxorubicin (Dox) in A549 cells, a human NSCLC cell line, both in vitro and in vivo in a lung tumor xenograft model, using a novel adenoviral expression system to deliver an RNA aptamer (A-p50) that specifically inhibits nuclear factor-kappaB (NF-kappaB) activation. By achieving selective, targeted, and early inhibition of NF-kappaB activity, we demonstrate that NF-kappaB plays a critical role in Dox-induced chemoresistance by regulating genes involved in proliferation (Ki-67), response to DNA damage (GADD153), antiapoptosis (Bcl-XL), and pH regulation (CA9). This Dox-induced NF-kappaB activation and subsequent chemoresistance is dependent on expression of p53. We also demonstrate that NF-kappaB promotes angiogenesis in the presence of Dox via the hypoxia-inducible factor-1alpha/vascular endothelial growth factor (HIF-1alpha/VEGF) pathway, revealing a previously unknown mechanism of NSCLC resistance to Dox. These studies provide important insights into the mechanisms of Dox-induced chemoresistance, and they demonstrate a novel, effective, and clinically practical strategy for interfering with these processes.

Evaluation of peri-operative chemotherapy using a prognostic nomogram for survival after resection of colorectal liver metastases.

INTRODUCTION: Nomograms are statistical tools designed to predict outcomes. This study evaluates the effects of peri-operative chemotherapy on the accuracy of a prognostic nomogram for disease-specific survival (DSS) after resection of colorectal liver metastases (CRLM) established at Memorial-Sloan Kettering Cancer Center (MSKCC). METHODS: An external cohort of 203 patients who underwent resection of CRLM between 1996 and 2006 was used to assess the nomogram. RESULTS: After median follow-up of 30.4 months (range 0.33-150), Kaplan-Meier (KM) estimates for 3-, 5- and 8-year post-resection DSS were 56%, 41%, and 32%, respectively; similar to nomogram-predicted probabilities for DSS. The concordance index for the nomogram was higher (0.602) than for the Fong colorectal risk score (CRS; 0.533). KM DSS was longer for patients (n= 50) treated with at least 6 months of peri-operative irinotecan or oxaliplatin compared with all other patients (median 66 vs. 40 months, P= 0.06). KM DSS was greater than nomogram predicted DSS for treated patients and less than nomogram predicted DSS for all other patients. CONCLUSIONS: The CRLM nomogram was validated by an external cohort and more accurately predicted post-resection survival than the commonly used CRS. Differences in observed and nomogram-predicted survival may reflect the effect of treatment factors, such as peri-operative chemotherapy.