Georgios A. Margonis

Association Between Specific Mutations in KRAS Codon 12 and Colorectal Liver Metastasis

IMPORTANCE Currently, one of the most commonly available biomarkers in the treatment of patients with colorectal liver metastases (CRLM) is the Kirsten rat sarcoma viral oncogene homolog (KRAS); however, the prognostic implications of specific mutations of the KRAS gene are still not well defined. OBJECTIVE To investigate the prognostic impact of specific KRAS mutations on patients undergoing liver resection for CRLM. DESIGN, SETTING, AND PARTICIPANTS This retrospective single-center study was conducted from January 1, 2003, to December 31, 2013. Data about specific KRAS mutations for 331 patients who underwent hepatic resection for CRLM at Johns Hopkins Hospital between 2003 and 2013 were analyzed. Clinicopathological characteristics, perioperative details, and outcomes were stratified by specific KRAS mutation at codons 12 and 13. INTERVENTION Resection of CRLM. MAIN OUTCOMES AND MEASURES Overall survival (OS) and recurrence-free survival. RESULTS A mutated KRAS (mtKRAS) was identified in 91 patients (27.5%). At a median follow-up of 27.4 months, recurrence was observed in 48 patients (52.7%) with mtKRAS and 130 patients (54.2%) with wild-type KRAS (wtKRAS) (P = .82). Median and 5-year survival among patients with mtKRAS was 32.4 months and 32.7%, respectively, vs 58.5 months and 46.9%, respectively, for patients with wtKRAS (P = .02). Patients with KRAS codon 12 mutations had worse OS (hazard ratio [HR], 1.54; 95% CI, 1.05-2.27; P = .03) vs those with wtKRAS, whereas a KRAS codon 13 mutation was not associated with prognosis (HR, 1.47; 95% CI, 0.83-2.62; P = .19). Among the 6 most common mutations in codons 12 and 13, only G12V (HR, 1.78; 95% CI, 1.00-3.17; P = .05) and G12S (HR, 3.33; 95% CI, 1.22-9.10; P = .02) were associated with worse OS compared with patients with wtKRAS (both P < .05). Among patients who recurred, G12V (HR, 2.96; 95% CI, 1.32-6.61; P = .01), G12C (HR, 6.74; 95% CI, 2.05-22.2; P = .002), and G12S mutations (HR, 4.91; 95% CI, 1.52-15.8; P = .01) were associated with worse OS (both P < .05). CONCLUSIONS AND RELEVANCE G12V and G12S mutations of codon 12 were independent prognostic factors of worse OS. Among patients who recurred after resection of CRLM, G12V, G12C, and G12S mutations were associated with worse OS. Information on specific KRAS mutations may help individualize therapeutic and surveillance strategies for patients with resected CRLM.

Effect of KRAS Mutation on Long-Term Outcomes of Patients Undergoing Hepatic Resection for Colorectal Liver Metastases

AbstractPurpose To investigate the prognostic value of KRAS in a large cohort of patients undergoing liver resection for colorectal liver metastases (CRLM).MethodsBetween 2003 and 2013, 334 patients underwent hepatic resection for CRLM at Johns Hopkins Hospital and met the inclusion criteria. Clinicopathologic characteristics, perioperative details, and outcomes were stratified by KRAS status—mutant KRAS (mtKRAS) versus wild-type KRAS (wtKRAS)—and analyzed.ResultsmtKRAS was identified in 115 (34.4 %) patients. At a median follow-up of 28.2 months, recurrence was observed in 59 (51.3 %) patients with mtKRAS and 117 (53.4 %) patients with wtKRAS (P = 0.79); there was no difference in the pattern of recurrence (liver: mtKRAS 39.0 % vs. wtKRAS 52.1 %; lung: mtKRAS 55.6 % vs. wtKRAS 64.3 %; both P > 0.05). Although 5-year log-rank overall survival (OS) was comparable among mtKRAS (41.6 %) vs. wtKRAS (48.5 %), on multivariable Cox survival analysis and after adjusting for known predictors of OS mtKRAS was associated with worse OS (hazard ratio 1.65; 95 % confidence interval 1.07–2.54; P = 0.02). Among patients who experienced a recurrence, 5-year OS was worse among those patients who had mtKRAS (mtKRAS 28.1 % vs. wtKRAS 44.5 %; P = 0.004). After controlling for tumor factors and receipt of chemotherapy, mtKRAS status remained independently associated with a worse outcome among patients who experienced recurrence (hazard ratio 2.07; 95 % confidence interval 1.31–3.27; P = 0.002).ConclusionsmtKRAS was noted in one-third of patients with CRLM. Although KRAS status did not affect the pattern of recurrence and recurrence-free survival, mtKRAS was an independent predictor of worse OS. The effect was more pronounced among patients who experienced a recurrence after resection of CRLM.

Clinical and morphometric parameters of frailty for prediction of mortality following hepatopancreaticobiliary surgery in the elderly

Although frailty is a known determinant of poor postoperative outcomes, it can be difficult to identify in patients before surgery. The authors sought to develop a preoperative frailty risk model to predict mortality among patients aged 65 years or more.

The prognostic implications of primary colorectal tumor location on recurrence and overall survival in patients undergoing resection for colorectal liver metastasis

The prognostic impact of primary colorectal cancer (CRC) location following resection of colorectal liver metastasis (CRLM) remains largely unknown. We sought to characterize the prognostic implications of primary tumor location among patients who underwent curative‐intent hepatectomy for CRLM.

Codon 13 KRAS mutation predicts patterns of recurrence in patients undergoing hepatectomy for colorectal liver metastases.

Investigations regarding the impact of tumor biology after surgical management of colorectal liver metastasis have focused largely on overall survival. We investigated the impact of codon‐specific KRAS mutations on the rates and patterns of recurrence in patients after surgery for colorectal liver metastasis (CRLM).

The Tumor Burden Score: A New “Metro-ticket” Prognostic Tool For Colorectal Liver Metastases Based on Tumor Size and Number of Tumors

Objective: To apply the principles of the Metro-ticket paradigm to develop a prognostic model for patients undergoing hepatic resection of colorectal liver metastasis (CRLM). Background: Whereas the hepatocellular “Metro-ticket” prognostic tool utilizes a continuum of tumor size and number, a similar concept of a CRLM Metro-ticket paradigm has not been investigated. Methods: Tumor Burden Score (TBS) was defined using distance from the origin on a Cartesian plane incorporating maximum tumor size (x-axis) and number of lesions (y-axis). The discriminatory power [area under the curve (AUC)] and goodness-of-fit (Akaike information criteria) of the TBS model versus standard tumor morphology categorization were assessed. The TBS model was validated using 2 external cohorts from Asia and Europe. Results: TBS (AUC 0.669) out-performed both maximum tumor size (AUC 0.619) and number of tumors (AUC 0.595) in predicting overall survival (OS) (P < 0.05). As TBS increased, survival incrementally worsened (5-year OS: zone 1, zone 2, and zone 3—68.9%, 49.4%, and 25.5%; P < 0.05). The stratification of survival based on traditional tumor size and number cut-off criteria was poor. Specifically, 5-year survival for patients in category 1, category 2, and category 3 was 58.3%, 45.5%, and 50.6%, respectively (P > 0.05). The corrected Akaike score information criteria value of the TBS model (2865) was lower than the traditional tumor morphologic categorization model (2905). Survival analysis revealed excellent prognostic discrimination for the TBS model among patients in both external cohorts (P< 0.05). Conclusions: An externally validated “Metro-ticket” TBS model had excellent prognostic discriminatory power. TBS may be an accurate tool to account for the impact of tumor morphology on long-term survival among patients undergoing resection of CRLM.

Effect of Background Liver Cirrhosis on Outcomes of Hepatectomy for Hepatocellular Carcinoma

Importance Background hepatocarcinogenesis is considered a major cause of postoperative recurrence of de novo hepatocellular carcinoma (HCC) in patients with liver cirrhosis (LC). The degree of underlying liver injury has reportedly correlated with surgical outcomes of HCC. However, the pattern and annual rate of recurrence of postoperative de novo HCC are still unclear. Objective To clarify the pattern and rate of recurrence of de novo HCC in patients with LC. Design, Setting, and Participants Data from 799 patients who underwent curative hepatectomy for HCC at Toranomon Hospital and The Johns Hopkins Hospital between January 1, 1995, and December 31, 2014, were retrospectively collected and analyzed. Of the patients who underwent curative hepatectomy for HCC, 424 met inclusion criteria: 73 with normal liver (NL) and 351 with LC. Sixty-four patients who had histologically proven NL parenchyma were matched with an equal number of patients who had established LC, and postoperative outcomes were compared. Interventions Hepatectomy in patients with HCC. Main Outcomes and Measures Patterns of recurrence of HCC and chronological changes in recurrence rates. Results Among 128 matched patients in the study (mean [SD] age, 64.0 [12.7] years; 93 men and 35 women) 1-, 3-, and 5-year cumulative recurrence was 17.2%, 23.0%, and 37.5%, respectively, in the NL group vs 25.0%, 55.5%, and 72.1%, respectively, in the LC group (P = .001). The 3- and 5-year disease-specific survival was 85.7% and 75.4%, respectively, in the NL group vs 74.9% and 59.1%, respectively, in the LC group (P = .04). The median annual incidence of postoperative recurrence of HCC within 5 years after surgery was lower in the NL group (5.9%) compared with the LC group (12.7%) (P = .003). Assessment of recurrence patterns revealed that multiple recurrences near the resection margin or at extrahepatic sites were more frequent in the NL group (9 [50.0%] vs 6 [15.4%]; P = .01), whereas solitary recurrence at a distant site was more common in the LC group (21 [53.8%] vs 1 [5.6%]; P < .001). Conclusions and Relevance Comparison of the patterns and annual incidence of recurrence of HCC demonstrated that the poorer prognosis in the LC group was likely owing to a higher hepatocarcinogenic potential among patients with cirrhosis. Annual recurrence rates in the 2 groups indicate that de novo recurrence may continuously occur from the early postoperative period until the late period after resection of HCC.

Age of Transfused Blood Impacts Perioperative Outcomes Among Patients Who Undergo Major Gastrointestinal Surgery.

Objective: To evaluate the impact of transfused packed red blood cell (PRBC) age on perioperative morbidity among patients undergoing major gastrointestinal surgery. Background: Patients undergoing major surgery often receive PRBC transfusions. The effect of PRBC age (ie, storage duration before transfusion) on perioperative surgical outcomes remains poorly defined. Methods: In this study, 1365 patients were identified who underwent a hepato-pancreatic or colorectal resection and received ≥1 unit of PRBCs between 2009 and 2014 at the Johns Hopkins Hospital. Data regarding the storage duration of PRBCs, clinicopathologic characteristics, and perioperative outcomes were obtained and analyzed. Multivariable modified Poisson regression analyses were performed to assess the effect of PRBC age on perioperative morbidity. Results: A total of 5901 PRBC units were transfused for a median of 2 (interquartile range 2–4) units transfused per patient. In all, 936 (68.6%) patients received only units of blood that had been stored for less than 35 days (“fresh” blood), whereas 429 (31.4%) patients received at least 1 unit of PRBC that had been stored for ≥35 days (“older” blood). Overall postoperative morbidity was 32.8%. The incidence of postoperative complications (42.7% vs 28.3%) was higher among patients who received “older” vs “fresh” blood (P < 0.001). After adjusting for confounders on multivariable analysis, transfusion of “older” blood remained independently associated with an increased risk of perioperative morbidity (Relative Risk 1.20, P = 0.03). Conclusions: The use of “older” blood was an independent predictor of postoperative morbidity among patients undergoing hepato-pancreatic or colorectal procedures. Transfusion of “older” blood products may contribute to a higher risk of postoperative complications.

Curative surgical resection of adrenocortical carcinoma: Determining long-term outcome based on conditional disease-free probability

Objective: To evaluate conditional disease-free survival (CDFS) for patients who underwent curative intent surgery for adrenocortical carcinoma (ACC). Background: ACC is a rare but aggressive tumor. Survival estimates are usually reported as survival from the time of surgery. CDFS estimates may be more clinically relevant by accounting for the changing likelihood of disease-free survival (DFS) according to time elapsed after surgery. Methods: CDFS was assessed using a multi-institutional cohort of patients. Cox proportional hazards models were used to evaluate factors associated with DFS. Three-year CDFS (CDFS3) estimates at “x” year after surgery were calculated as follows: CDFS3 = DFS(x+3)/DFS(x). Results: One hundred ninety-two patients were included in the study cohort; median patient age was 52 years. On presentation, 36% of patients had a functional tumor and median size was 11.5 cm. Most patients underwent R0 resection (75%) and 9% had N1 disease. Overall 1-, 3-, and 5-year DFS was 59%, 34%, and 22%, respectively. Using CDFS estimates, the probability of remaining disease free for an additional 3 years given that the patient had survived without disease at 1, 3, and 5 years, was 43%, 53%, and 70%, respectively. Patients with less favorable prognosis at baseline demonstrated the greatest increase in CDFS3 over time (eg, capsular invasion: 28%–88%, &Dgr;60% vs no capsular invasion: 51%–87%, &Dgr;36%). Conclusions: DFS estimates for patients with ACC improved dramatically over time, in particular among patients with initial worse prognoses. CDFS estimates may provide more clinically relevant information about the changing likelihood of DFS over time.

National trends in the use of surgery for benign hepatic tumors in the United States

BACKGROUND The widespread use of diagnostic imaging has led to an increase in the incidence and diagnosis of benign liver tumors. The objective of this study was to define the overall use and temporal trends of operative procedures for benign liver tumors using a nationally representative cohort. METHODS All patients who underwent liver surgery for benign liver tumors between 2000 and 2011 were identified from the Nationwide Inpatient Sample database. Trends in annual volume of liver procedures were analyzed using the average annual percent change (AAPC) assessed by joinpoint analysis. RESULTS There were 2,489 open (94.5%) and 144 (5.5%) minimally invasive surgical (MIS) procedures. Partial hepatectomy accounted for 43.8% of all cases (n = 1,153). Surgery for patients with benign liver tumors increased from 156 in 2000 to 272 in 2011 (AAPC, 5.8%; 95% CI, 3.2-8.6%). There was decline in the relative use of open operative procedures from 98.1% in 2000 to 92.3% in 2011 (AAPC, -0.4%; 95% CI, -0.7 to -0.1%). In contrast, the proportion of MIS procedures increased from 1.9% in 2000 to 7.7% in 2011 (AAPC, 7.4%; 95% CI, 1.9-13.3%). The median duration of stay among all patients was 5 days (interquartile range, 4-7; 5 days [open] vs 3 days [MIS]; P < .001). Inpatient mortality was 0.6% (n = 15 [open] vs n = 0 [MIS]; P = .43) and did not change during the study period (P > .05). CONCLUSION Overall volume of surgical management of benign liver tumors has increased substantially over the past decade. There has been a relative shift away from open procedures toward MIS procedures.