Srinevas K. Reddy

Simultaneous resections of colorectal cancer and synchronous liver metastases: A multi-institutional analysis

BackgroundThe safety of simultaneous resections of colorectal cancer and synchronous liver metastases (SCRLM) is not established. This multi-institutional retrospective study compared postoperative outcomes after simultaneous and staged colorectal and hepatic resections.MethodsClinicopathologic data, treatments, and postoperative outcomes from patients who underwent simultaneous or staged colorectal and hepatic resections at three hepatobiliary centers from 1985–2006 were reviewed.Results610 patients underwent simultaneous (n = 135) or staged (n = 475) resections of colorectal cancer and SCRLM. Seventy staged patients underwent colorectal and hepatic resections at the same institution. Simultaneous patients had fewer (median 1 versus 2) and smaller (median 2.5 versus 3.5 cm) metastases and less often underwent major (≥ three segments) hepatectomy (26.7% versus 61.3%, p < 0.05). Combined hospital stay was lower after simultaneous resections (median 8.5 versus 14 days, p < 0.0001). Mortality (1.0% versus 0.5%) and severe morbidity (14.1% versus 12.5%) were similar after simultaneous colorectal resection and minor hepatectomy compared with isolated minor hepatectomy (both p > 0.05). For major hepatectomy, simultaneous colorectal resection increased mortality (8.3% versus 1.4%, p < 0.05) and severe morbidity (36.1% versus 15.1%, p < 0.05). Combined severe morbidity after staged resections was lower compared to simultaneous resections (36.1% versus 17.6%, p = 0.05) for major hepatectomy but similar for minor hepatectomy (14.1% versus 10.5%, p > 0.05). Major hepatectomy independently predicted severe morbidity after simultaneous resections [hazard ratio (HR) = 3.4, p = 0.008].ConclusionsSimultaneous colorectal and minor hepatic resections are safe and should be performed for most patients with SCRLM. Due to increased risk of severe morbidity, caution should be exercised before performing simultaneous colorectal and major hepatic resections.

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.

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

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. (HEPATOLOGY 2012;55:1811–1821)

Hepatectomy for Noncolorectal Non-Neuroendocrine Metastatic Cancer: A Multi-Institutional Analysis

BACKGROUND Although hepatic metastasectomy is well established for colorectal and neuroendocrine cancer, the approach to hepatic metastases from other sites is not well defined. We sought to examine the management of noncolorectal non-neuroendocrine liver metastases. STUDY DESIGN A retrospective review from 4 major liver centers identified patients who underwent liver resection for noncolorectal non-neuroendocrine metastases between 1990 and 2009. The Kaplan-Meier method was used to analyze survival, and Cox regression models were used to examine prognostic variables. RESULTS There were 420 patients available for analysis. Breast cancer (n = 115; 27%) was the most common primary malignancy, followed by sarcoma (n = 98; 23%), and genitourinary cancers (n = 92; 22%). Crude postoperative morbidity and mortality rates were 20% and 2%, respectively. Overall median survival was 49 months, and 1, 3, and 5-year Kaplan-Meier survival rates were 73%, 50%, and 31%. Survival was not significantly different between the various primary tumor types. Recurrent disease was found after hepatectomy in 66% of patients. In multivariable models, lymphovascular invasion (p = 0.05) and metastases ≥5 cm (p = 0.04) were independent predictors of poorer survival. Median survival was shorter for resections performed between 1990 and 1999 (n = 101, 32 months) when compared with resections between 2000 and 2009 (n = 319, 66 months; p = 0.003). CONCLUSIONS Hepatic metastasectomy for noncolorectal non-neuroendocrine cancers is safe and feasible in selected patients. Lymphovascular invasion and metastases ≥5 cm were found to be associated with poorer survival. Patients undergoing metastasectomy in more recent years appear to be surviving longer, however, the reasons for this are not conclusively determined.

Major Liver Resection in Elderly Patients: A Multi-Institutional Analysis

BACKGROUND Because of the aging United States population, increase in overall life expectancy, and rising incidence of hepatobiliary tumors, more elderly patients are considered for hepatic resection. The objective of this study was to assess the influence of age on postoperative outcomes after major hepatectomy among a contemporary cohort from 2 high volume centers. STUDY DESIGN Demographics, diagnoses, surgical treatments, and postoperative outcomes of patients who underwent major hepatic resection were reviewed. RESULTS There were 856 patients who underwent major hepatectomy (resection of 3 or more segments) from 2002 to 2009. Postoperative mortality and morbidity occurred in 53 (6.2%) and 403 (47.1%) patients, respectively. Increasing age was independently associated with postoperative mortality (p = 0.0345). Each 1-year and 10-year increase in age resulted in an odds ratio of mortality after major hepatic resection of 1.036 (95% CI [1.003-1.071]) and 1.426 (95% CI [1.026-1.982]), respectively. This relationship was independent of American Society of Anesthesiology (ASA) score. Increasing age was associated with postoperative sepsis (p = 0.0224, odds ratio for each year 1.025 [range 1.003 to 1.048]) after major hepatic resection, but not overall postoperative morbidity. CONCLUSIONS In the contemporary era, increasing age is independently associated with postoperative mortality after major hepatic resection at high volume academic centers.

RNA Aptamer-targeted Inhibition of NF-κB 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-κB (NF-κB) activation. By achieving selective, targeted, and early inhibition of NF-κB activity, we demonstrate that NF-κB 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-κB activation and subsequent chemoresistance is dependent on expression of p53. We also demonstrate that NF-κB promotes angiogenesis in the presence of Dox via the hypoxia-inducible factor-1α/vascular endothelial growth factor (HIF-1α/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.

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?

BackgroundPatients 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.ResultsBecause 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.

Underlying steatohepatitis, but not simple hepatic steatosis, increases morbidity after liver resection: A case‐control study

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. (HEPATOLOGY 2012)

Liver-Directed Surgery for Metastatic Squamous Cell Carcinoma to the Liver: Results of a Multi-Center Analysis

BackgroundThe role of hepatic resection for metastatic squamous cell carcinoma (SCC) remains unknown. The current study evaluates the role of hepatic resection in patients with metastatic SCC to the liver.MethodsBetween 1988 and 2006, 52 patients underwent hepatic resection of metastatic SCC at eight major cancer centers. Clinicopathologic factors were analyzed with regard to disease-free survival (DFS) and overall survival (OS).ResultsPrimary SCC site was anal (n = 27), head/neck (n = 12), lung (n = 4), esophagus (n = 2), and other (n = 7). Treatment of primary SCC was chemotherapy ± radiotherapy alone (n = 29), chemotherapy ± radiotherapy + surgery (n = 15), or surgery alone (n = 8). Forty-seven patients underwent resection alone, 2 resection + radiofrequency ablation (RFA), and 3 RFA only. At last follow-up, 33 (63.5%) patients had recurred. The median time to recurrence was 9.8 months, and 5-year DFS was 18.6%. Factors associated with reduced DFS were liver tumor size > 5 cm (hazard ratio (HR) = 2.02) and positive surgical margin (HR = 2.33). The overall median survival after hepatic resection was 22.3 months and 5-year actuarial OS was 20.5%. Risk factors associated with worse overall survival included synchronous disease (HR = 4.09), hepatic metastasis > 5 cm (HR = 1.71) and positive surgical resection margin (HR = 1.83).ConclusionsThe majority of patients will recur following hepatic resection of SCC. Long-term survival, however, can be achieved following surgical resection of SCC liver metastasis, especially in patients who present with limited metachronous disease amenable to margin negative resection.