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The effect of bevacizumab plus mFOLFOX6 on downsizing of liver metastases for curative resection has not been well assessed for patients with advanced colorectal liver metastases (CRLMs). This multicenter phase II trial aimed to examine the efficacy and safety of bevacizumab plus mFOLFOX6 for advanced CRLMs harboring mutant-type KRAS.Patients with advanced CRLMs (tumor number of ≥5 and/or technically unresectable) harboring mutant-type KRAS were included. Surgical indication was evaluated every 4 cycles of bevacizumab plus mFOLFOX6. Liver resection was planned if the CRLMs were resectable. The primary endpoint was R0 resection rate. The secondary endpoints included overall survival (OS), recurrence-free survival, progression-free survival, and safety.Between 2013 and 2017, 29 patients from six centers were registered. The rates of complete and partial responses were 0% and 62.1%, respectively. R0 and R1 resections were performed in 19 and 1 patient, respectively (R0 resection rate: 65.5%). No mortality occurred. During the median follow-up of 30.7 months, the 3-year OS rate for all the patients was 64.4% with the median survival of 49.1 months.For advanced CRLMs harboring mutant-type KRAS, bevacizumab plus mFOLFOX6 achieved a high R0 resection rate, leading to favorable survival.

The histological growth pattern of liver metastases (desmoplastic, pushing, and replacement patterns) at the tumor-liver parenchymal interface is a prognostic factor in patients with colorectal cancer. However, data regarding its association with the primary tumor characteristics and molecular alterations are limited. This study evaluated the histological growth pattern in 136 cases of colorectal cancer liver metastases without preoperative treatment, comparing it with the clinicopathological features of the primary tumor. Liver metastasis exhibiting predominantly non-desmoplastic pattern (50%), observed in 74 cases (54%), was associated with hepatic vein invasion (P = 0.025), worse recurrence-free survival (P 0.001) and overall survival (P = 0.008). In multivariate analyses, multiple tumors (P 0.001) and non-desmoplastic patterns (P = 0.009) were associated with worse recurrence-free survival, and tumor size (P = 0.025) and non-desmoplastic pattern (P = 0.025) were associated with worse overall survival. In 88 patients with available primary tumor tissue slides, non-desmoplastic pattern in the liver metastasis was associated with high-grade tumor budding (P = 0.002), high-grade poorly differentiated cluster (P = 0.021), absence of mucinous histology (P = 0.016), and aberrant p53 expression (complete loss or overexpression; P 0.001) of the primary colorectal cancer. In conclusion, the histological growth pattern in liver metastasis was a strong and independent prognostic factor for colorectal cancer. Our observations highlight the significant associations between histological growth patterns in liver metastases and histopathological features of the primary tumor, especially invasive front morphology and p53 aberration.

Micrometastases, defined as microscopic cancer cells spatially separated from the macroscopically evident metastasis, are identified in 24% to 56% of resected colorectal liver metastases (CLMs). Somatic gene mutations have emerged as independent prognostic factors in CLM. This study aimed to determine the prognostic impact and risk factors for the presence of micrometastases, including somatic gene mutations.Prospective evaluation for micrometastases was performed at 2 centers in the US and France from 2015 to 2019. CLM specimens were cut radially from the tumor margin to surrounding grossly normal liver for a distance of 2 cm. Depending on CLM size, 3 to 8 specimens per patient were submitted for microscopic analysis. Somatic gene mutations were detected by next-generation sequencing.Among 140 patients undergoing CLM resection in the US (n = 84) and France (n = 56), 36 (26%) patients were found to have micrometastases. Five-year overall and recurrence-free survival rates with micrometastases were 39% and 0%, respectively, compared with 61% and 20% without micrometastases (both p0.05). In multivariable analyses, the presence of micrometastases was an independent risk factor for worse overall survival (hazard ratio 2.88, 95% CI 1.46 to 5.70, p = 0.002) and recurrence-free survival (hazard ratio 1.56, 95% CI 1.01 to 2.41, p = 0.046). In binary logistic regression analysis, RAS/TP53 co-mutation was found to significantly increase the risk of micrometastases (odds ratio 2.77, 95% CI 1.15 to 6.71, p = 0.024).Micrometastases are associated with significantly worse survival after CLM resection. RAS/TP53 co-mutation correlated with increased risk of micrometastases. Further studies are needed to determine strategies to eradicate micrometastases.

PURPOSE KRAS p.G12C mutations occur in approximately 3% of metastatic colorectal cancers (mCRC). Recently, two allosteric inhibitors of KRAS p.G12C have demonstrated activity in early phase clinical trials. There are no robust studies examining the behavior of this newly targetable population. METHODS We queried the MD Anderson Cancer Center data set for patients with colorectal cancer who harbored KRAS p.G12C mutations between January 2003 and September 2019. Patients were analyzed for clinical characteristics, overall survival (OS), and progression-free survival (PFS) and compared against KRAS nonG12C. Next, we analyzed several internal and external data sets to assess immune signatures, gene expression profiles, hypermethylation, co-occurring mutations, and proteomics. RESULTS Among the 4,632 patients with comprehensive molecular profiling, 134 (2.9%) were found to have KRAS p.G12C mutations. An additional 53 patients with single gene sequencing were included in clinical data but excluded from prevalence analysis allowing for 187 total patients. Sixty-five patients had de novo metastatic disease and received a median of two lines of chemotherapy without surgical intervention. For the first three lines of chemotherapy, the median PFS was 6.4 months (n = 65; 95% CI, 5.0 to 7.4 months), 3.9 months (n = 47; 95% CI, 2.9 to 5.9 months), and 3.0 months (n = 21; 95% CI, 2.0 to 3.4 months), respectively. KRAS p.G12C demonstrated higher rates of basal EGFR activation compared with KRAS nonG12C. When compared with an internal cohort of KRAS nonG12C, KRAS p.G12C patients had worse OS. CONCLUSION PFS is poor for patients with KRAS p.G12C metastatic colorectal cancer. OS was worse in KRAS p.G12C compared with KRAS nonG12C patients. Our data highlight the innate resistance to chemotherapy for KRAS p.G12C patients and serve as a historical comparator for future clinical trials.

BACKGROUND We evaluated the associations of surgical margin status and somatic mutations with the incidence of local recurrence (LR) and oncologic outcomes in patients undergoing R0-intent (microscopically negative margin) resection of colorectal liver metastases (CLM). METHODS Patients with CLM who underwent initial R0-intent resection and analysis of tumor tissue using next-generation sequencing during 2001-2018 were analyzed. Recurrences were classified as LR (at the resection margin), other intrahepatic recurrence, or extrahepatic recurrence. Predictors and survival effect of LR were evaluated using univariate and multivariate analysis. RESULTS Of 552 patients analyzed, 415 (75%) had R0 resection (margin width ≥ 1.0 mm), and 38 (7%) had LR. LR incidence was not affected by surgical margin width. RAS/TP53 co-mutation was associated with increased risk of intrahepatic recurrence (67% vs. 49%; p 8 cycles of preoperative chemotherapy (HR, 1.98; p = 0.033), tumor viability ≥ 50% (HR, 1.55; p = 0.007), RAS/TP53 co-mutation (HR, 1.69; p = 0.001), and SMAD4 mutation (HR, 2.44; p

Noninvasive intraductal papillary mucinous neoplasms (IPMNs) theoretically do not metastasize. The purpose of this study is to preoperatively distinguish invasive carcinomas associated with IPMN from noninvasive IPMN.A total of 131 patients who underwent surgical resection for IPMN were retrospectively analyzed to identify the predictors of invasive carcinoma, based on the International Association of Pancreatology Consensus Guidelines.Of the 131 patients, 29 (22%) had invasive carcinomas and 102 (78%) had noninvasive IPMN. An enhancing mural nodule (MN) greater than or equal to 5 mm, obstructive jaundice, an abrupt change in the caliber of the pancreatic duct (PD) with distal pancreatic atrophy, and lymphadenopathy were the significant predictors of invasive carcinoma in univariate analysis. The optimal cutoff value for the size of the enhancing MN to differentiate invasive carcinoma was 13 mm. In multivariate analysis, enhancing MN greater than or equal to 13 mm, obstructive jaundice, and an abrupt change in the PD caliber were the independent predictors. When all these factors were absent, only 17% were invasive carcinomas.Enhancing MN greater than or equal to 13 mm, obstructive jaundice, and an abrupt change in the PD caliber were predictive factors for invasive carcinoma. Systematic lymph node dissection may be omitted when a high-risk patient has none of these factors.

The aim of this prospective study was to analyze the impact of abdominal incision type on postoperative pain and quality of life (QOL) in hepatectomy. In patients undergoing hepatectomy by open, hybrid, or pure laparoscopic approaches, we classified abdominal incisions as: pure laparoscopic (LAP), midline (MID), J-shaped (J), and J-shaped incision plus thoracotomy (TRC). Postoperative pain was measured on postoperative day (POD) 3, 7, 30, and 90 using a visual analog scale (VAS). QOL was evaluated using the short-form-36 questionnaire preoperatively and on POD 30 and 90. We categorized 165 patients into LAP (n = 9, 5%), MID (n = 21, 13%), J (n = 95, 58%), and TRC (n = 40, 24%) groups. Median VAS scores on PODs 3/7/30/90 were: LAP, 27.5/7.5/10/10; MID, 30/10/15/5; J, 50/27.5/20/10, and TRC, 50/30/30/19. The J and TRC groups had significantly higher VAS scores vs. MID on PODs 3 and 7; the LAP and MID groups did not differ significantly. No significant positive correlations were observed between incision length and postoperative VAS, when we stratified patients into two groups according to the presence or absence of a transverse incision. Physical QOL summary scores did not return to preoperative levels even on POD 90, in patients with an additional transverse incision. Mental QOL summary scores worsened with postoperative complications rather than with abdominal incision type. Transverse incisions, rather than incision length, led to worse midline incision pain and poorer QOL recovery post-hepatectomy. A hybrid approach may be a considerable option when pure laparoscopic hepatectomy is technically difficult. This study was registered in the UMIN Clinical Trials Registry (registration number: UMIN000017467; http://www.umin.ac.jp/ctr/index.htm )

Background The therapeutic effect of portal vein (PV) stenting for PV stenosis following nontransplant hepato-pancreato-biliary (HPB) surgery has not been fully investigated. Methods Changes in portal venous pressure (PVP) gradient before and after stenting, complications, symptomatic improvement, and stent patency were evaluated. Results We identified 14 consecutive patients undergoing PV stenting for malignant (n = 8) and benign (n = 6) PV stenosis. Signs of PV stenosis were composed of refractory ascites in 6 patients, varices with hemorrhagic tendencies in 5, and abnormal liver function in 5. The median PVP gradient after PV stenting was 3.0 cm H2O (range, 1.5–3.0), which was significantly smaller than that before PV stenting (median, 15 cm H2O [range, 2.5–25]; P Conclusions Based on durable effect on patency, we deemed PV stenting for PV stenosis after HPB surgery to be safe and beneficial for improving symptoms.

Circulating tumor DNA (ctDNA) is a promising biomarker for patients undergoing hepatectomy for colorectal liver metastases (CLM). We hypothesized that post-hepatectomy ctDNA detection would identify patients at highest risk for early recurrence of CLM.Patients with CLM who underwent curative-intent hepatectomy with ctDNA analysis within 180 days postoperatively (1/2013 and 6/2020) were included. Tissue somatic mutations and ctDNA analyses were performed by next-generation sequencing panels. Survival analyses determined factors associated with clinical recurrence 1 year or earlier after hepatectomy. Patients with primary tumors in situ and without 1-year follow-up were excluded. Median follow-up was 28.3 months.Of 105 patients, 32 (30%) were ctDNA positive (ctDNA+) after curative-intent hepatectomy. Compared with ctDNA-negative patients, ctDNA+ patients had multiple CLM (84% vs 55%, p = 0.002) and co-mutated RAS/TP53 (47% vs 23%, p = 0.018). Multiple CLM (odds ration (OR), 5.43; p = 0.005) and co-mutated RAS/TP53 (OR, 3.30; p = 0.019) were independently associated with post-hepatectomy ctDNA. Although perioperative carcinoembryonic antigen levels were not prognostic, postoperative ctDNA+ (hazard ratio (HR), 2.04; p = 0.011) and extrahepatic disease (HR, 2.45, p = 0.004) were independently associated with worse recurrence-free survival. After adjusting for extrahepatic disease, preoperative chemotherapy, multiple CLM, tumor viability of 50% or greater, and co-mutated RAS/TP53, ctDNA+ within 180 days was the only independent risk factor for recurrence 1 year or earlier after hepatectomy (94% vs 49%; HR, 11.8; p = 0.003).Postoperative ctDNA detection is associated with early recurrence 1 year or earlier after curative-intent hepatectomy for CLM, and RAS/TP53 co-mutations result in a more than 3-fold increased risk for postoperative ctDNA positivity. This highlights the complementary effect of tumor tissue and circulating mutational profiling for patients with CLM.

We assessed whether or not covalently closed circular DNA (cccDNA) levels in the background liver influence the recurrence of hepatocellular carcinoma (HCC) in patients with resolved hepatitis B virus (HBV) infection.Among 425 patients who underwent initial hepatectomy for HCC between 2010 and 2018, a retrospective review was performed in 44 with resolved HBV infection. The clinicopathologic characteristics were analyzed for correlation with tumor recurrence. The HBV cccDNA levels were tested via a droplet digital polymerase chain reaction assay.HBV cccDNA was detected in 27 of 44 patients (61%), and the median level was 1.0 copies/1000 ng (range, 0-931.3 copies/1000 ng). Anti-HBc ≥8.9 S/CO was associated with cccDNA detection (odds ratio, 11.08; 95% confidence interval [95% CI], 2.48-49.46; P = 0.002). Twenty-eight patients (64%) developed HCC recurrence after hepatectomy. The overall 3- and 5-year recurrence-free survival rates were 45.7% and 34.3%, respectively.19 HBV cccDNA levels was not significantly associated with HCC recurrence, while the presence of multiple tumors was an independent risk fact or (hazard ratio, 6.53; 95% CI, 2.48-17.19; P0.001.HBV cccDNA levels did not influence HCC recurrence after hepatectomy. Anti-HBc levels may be used as a surrogate marker for cccDNA.

Multidisciplinary treatment for colorectal liver metastases (CLMs) often includes major hepatectomy for preoperative chemotherapy-related hepatic injury, although the safety limit for resection extent is unclear. We investigated this parameter using the estimated indocyanine green clearance rate (ICG-K) of liver remnants, focusing on postoperative subclinical hepatic insufficiency (PHI).Altogether, 225 patients who underwent resection of CLMs were studied. The predictive power of estimated ICG-K of liver remnant (ICG-Krem) for subclinical PHI (peak bilirubin ≥3 mg/dL or refractory ascites) was compared with those of other potential predictors. The suggested safety limit of ICG-Krem ≥0.05 was also assessed.Receiver-operating curve analysis revealed that ICG-Krem [area under the curve (AUC) 0.752, cutoff 0.102] was the best predictor of subclinical PHI (AUC range for others was 0.632-0.668). Makuuchi's criteria corresponded to ICG-Krem 0.10. Subclinical PHI incidence was significantly elevated at ICG-Krem0.10 (26% vs 8%, p = 0.002), while potentially fatal PHI (peak bilirubin7 mg/dL) was not observed until down to ICG-Krem of 0.05.ICG-Krem sensitively predicts subclinical PHI. Liver failure-related death could be avoided so long as ICG-Krem remains at ≥0.05. However, patients with ICG-Krem 0.05-0.10 are at high risk of subclinical PHI and require intensive care postoperatively.

Pathologic response to preoperative chemotherapy predicts survival in patients with colorectal liver metastases (CLMs) who undergo hepatectomy. In multiple CLMs, mixed pathologic response, wherein tumors exhibit different degrees of treatment response, is possible. We sought to evaluate survival outcomes of mixed response in patients with multiple CLMs.We conducted a retrospective cohort study using a single-institution database of patients with two or more CLMs who underwent preoperative chemotherapy and hepatectomy (2010-2018). Pathologic response of each tumor was measured on pathology. Patients were stratified by pathologic response as complete (pCR) = 0-1% viability; major (pMajR) = 2-49% viability; minor (pMinR) = 50-99% viability; or mixed (pMixR) = at least one pCR/MajR tumor and one pMinR. Recurrence-free survival (RFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and adjusted risk of death was evaluated using Cox regression.Among 444 patients, 6% had pCR, 34% had pMajR, 36% had pMinR, and 24% had pMixR. Median and 5-year RFS for patients with pMixR was 10.4 months and 16%, respectively, compared with pMajR (11.3 months and 18%, respectively), pMinR (7.7 months and 13%, respectively), and pCR (23.1 months and 38%, respectively) [log-rank p 0.001]. Median and 5-year OS for patients with pMixR was 77.4 months and 60%, respectively, compared with pMajR (80.5 months and 63%, respectively), pMinR (49.9 months and 39%, respectively), and pCR (median OS not reached; median follow-up of 37.1 months and 5-year OS of 65%) [log-rank p = 0.002]. pMixR was associated with a 52% risk of death reduction (hazard ratio 0.48, 95% confidence interval 0.30-0.78 vs. pMinR).One-quarter of patients with multiple CLMs have pMixR following preoperative chemotherapy and hepatectomy. OS and RFS for patients with pMixR mirror those of pMajR rather than pMinR, suggesting the greatest response achieved in any metastasis best predicts survival.

Objectives In two-stage hepatectomy for bilateral liver metastases, patient dropout between stages is a major issue. We recently proposed a novel approach of fast-track two-staged hepatectomy (FT-TSH), in which patients undergo concurrent first-stage hepatectomy (FSH) with portal vein embolization (PVE) in a hybrid interventional radiology surgical suite. However, its efficacy remains unclear. Methods Patients with bilateral liver metastases scheduled for FT-TSH at MD Anderson Cancer Center between October 2017 and December 2020 were included on a prospective registry. The effectiveness and feasibility were evaluated. Results Nineteen patients were scheduled for FT-TSH. Primary site of tumor was colon/rectum in 18 patients and ovary in one patient. Median number of tumors was 10 and median size of largest tumor before surgery was 2.4 cm. Two (11%) patients did not undergo PVE and seventeen patients (89%) completed FSH + PVE. None of the patients had a major complication (Clavien-Dindo grade ≥ III) after FSH + PVE. Median kinetic growth rate after FSH + PVE was 2.9%/week (range 0.8–5.6). Twelve patients (71%) among the seventeen who underwent FSH + PVE proceeded to second-stage hepatectomy, and ten patients (59%) finally completed second-stage hepatectomy. Median interval between stages was 5.6 weeks (4.0–20.1). One patient (10%) had a major morbidity after SSH, and there was no 90-day mortality. Conclusions FT-TSH is safe and allows for short intervals between hepatectomy stages while achieving favorable liver hypertrophy. Further investigation is needed to evaluate the true efficacy of FT-TSH.

We evaluated the associations of surgical margin status and somatic mutations with the incidence of local recurrence (LR) and oncologic outcomes in patients undergoing R0-intent (microscopically negative margin) resection of colorectal liver metastases (CLM).Patients with CLM who underwent initial R0-intent resection and analysis of tumor tissue using next-generation sequencing during 2001-2018 were analyzed. Recurrences were classified as LR (at the resection margin), other intrahepatic recurrence, or extrahepatic recurrence. Predictors and survival effect of LR were evaluated using univariate and multivariate analysis.Of 552 patients analyzed, 415 (75%) had R0 resection (margin width ≥ 1.0 mm), and 38 (7%) had LR. LR incidence was not affected by surgical margin width. RAS/TP53 co-mutation was associated with increased risk of intrahepatic recurrence (67% vs. 49%; p 0.001) and overall recurrence (p 0.001). However, incidence of LR did not differ significantly by RAS/TP53, BRAF, SMAD4, or FBXW7 mutation. Extrahepatic disease (hazard ratio [HR], 1.47; p = 0.034), 8 cycles of preoperative chemotherapy (HR, 1.98; p = 0.033), tumor viability ≥ 50% (HR, 1.55; p = 0.007), RAS/TP53 co-mutation (HR, 1.69; p = 0.001), and SMAD4 mutation (HR, 2.44; p 0.001) were independently associated with poor overall survival, but surgical margin status was not.Although somatic mutations were associated with overall recurrence, neither surgical margin width nor somatic mutations affected LR risk after R0-intent hepatectomy for CLM. LR and prognosis were likely driven by individual tumor biology rather than surgical margins.

In the pandemic of severe acute respiratory syndrome due to coronavirus-2 (SARS-CoV-2), United States (U.S.) also experienced the spread of coronavirus disease 2019 (COVID-19). Here, we report the current status of Houston, Texas and the response to COVID-19 at MD Anderson Cancer Center (MDACC) and in the Department of Surgical Oncology. MDACC has taken the institutional measures in order to prevent its employees and patients from COVID-19. Furthermore, surgeons have also responded aggressively in the outpatient setting, operating room and inpatient care. The predicted peak in Texas is on April 29 and our mitigation measures appear to be effective at the time of writing, however there still remain a lot of unknowns about SARS-CoV-2 and the performance of cancer operations remains an ongoing and delicate issue. In order to minimize the risks to patients, our healthcare system, and our community, MDACC has navigated the countering pressures through honest and open communication with patients, judicious use of alternative treatment strategies, and thoughtful selection of surgical cases.

The use of hepatitis B core antibody (anti-HBc)-positive grafts is one strategy for expanding the donor pool for liver transplantation (LT). The aim of this study was to determine the risk factors associated with hepatitis B virus (HBV) recurrence after living donor LT (LDLT) of anti-HBc-positive grafts. From January 1996 to December 2018, a total of 609 LDLT procedures were performed at our center. A retrospective review was performed for 31 patients (23 males and 8 females; median age = 47 years) who underwent LDLT for HBV-unrelated liver disease from anti-HBc-positive donors. The factors associated with HBV recurrence were evaluated and compared between the HBV recurrence and non-recurrence groups. The median follow-up period after LT was 135 months (range, 6-273 months). Four of 31 patients (12.9%) developed post-LT HBV recurrence. All four cases were HBV-naïve patients (anti-HBc-negative and Hepatitis B surface antibody-negative). The median interval between LDLT and HBV recurrence was 42 months (range, 20-51). The overall actuarial rates of HBV recurrence at 1, 3, 5, 10, and 20 years were 0%, 7.2%, 15.7%, 15.7%, and 15.7%, respectively. Although there were no significant differences between the HBV recurrence and non-recurrence groups, HBV recurrence tended to occur in HBV-naïve recipients (P = 0.093). HBV-naïve status may contribute to HBV recurrence after LDLT for HBV-unrelated liver disease from anti-HBc-positive donors. Careful monitoring for serological HBV markers is needed, particularly in this group.

Benign portal vein stenosis is a rare complication following pancreaticoduodenectomy. Because a direct surgical approach to the portal vein is difficult due to severe adhesions following pancreaticoduodenectomy, portal vein stent placement is considered a good treatment option. Herein, we report 3 cases of severe portal vein stenosis following pancreaticoduodenectomy that were treated with portal venous stent placement in a hybrid operating room, combining a conventional operating room with an angiography suite. High-resolution images on digital subtraction angiography provide better contrast and support accurate stent placement compared to using a mobile C-arm.

The factors associated with hepatitis B virus (HBV) recurrence after living donor liver transplantation (LDLT) have not been fully clarified. The aim of this study was to determine the risk factors associated with HBV recurrence after LDLT. From January 1996 to December 2018, a total of 609 LDLT operations were performed at our center. A retrospective review was performed of 70 patients (male, n = 59; female, n = 11; median age = 54 years) who underwent LDLT for HBV-related liver disease. The virologic and biochemical data, tumor burden, antiviral and immunosuppressive therapy were evaluated and compared between the HBV recurrence and non-recurrence groups. Eleven of 70 patients (16%) developed post-LDLT HBV recurrence. The overall actuarial rates of HBV recurrence at 1, 3, 5, 10, and 20 years were 0%, 13%, 16.7%, 18.8%, and 18.8%, respectively. The median interval between LDLT and HBV recurrence was 57 months (range, 18-124 months). Based on the univariate and multivariate analyses, a serum HBV DNA level of ≥ 4 log copies/mL (hazard ratio [HR], 4.861; 95% confidence interval [95% CI], 1.172-20.165; P = 0.029), and hepatocellular carcinoma (HCC) beyond the Milan criteria (HR, 10.083; 95% CI, 2.749-36.982; P < 0.001) were independent risk factors for HBV recurrence after LDLT. In LDLT patients, high pre-LT HBV DNA levels and HCC beyond the Milan criteria were risk factors for HBV recurrence. With the current expansion of the LT criteria for HCC, we should remain cautious regarding the risk of HBV recurrence, particularly in these groups.

For patients with colorectal liver metastases (CLM), the combination of surgical resection with other therapeutic options is essential. This article shows how recent advances in knowledge of tumor biology, including genetic alterations, affect the choice of therapeutic approach for patients with CLM. We reviewed the literature on recent advances in knowledge about CLM tumor biology including genetic profiles, clinical risk score models for CLM, preoperative therapy for CLM, and liver-directed therapy for CLM. Studies showed that RAS alteration is a negative prognostic factor in addition to traditional clinical risk factors (e.g., larger diameter and higher number of CLM, spread of the primary tumor to regional lymph nodes). Although the response to preoperative chemotherapy is an important predictor of survival, poor response is not a contraindication to surgical resection. The combination of surgical therapy and percutaneous ablation can be considered in marginally resectable cases; however, a wider ablation margin is required for RAS-mutant CLM. More recently, genetic analysis using next-generation sequencing showed the negative prognostic impact of alterations in TP53, SMAD4, FBXW7, and RAS/BRAF in patients with CLM. In RAS-mutant CLM, intensive follow-up is required in patients who remain recurrence free 2 years after surgery. In patients with CLM, RAS mutation status is important in predicting postoperative survival, selecting the treatment approach, and tailoring postoperative follow-up. In addition, more recent genetic analyses of CLM have identified additional predictors of survival.

Background Gadoxetic acid (Gd-EOB-DTPA)-enhanced MRI is superior to CT in the detection of colorectal liver metastases (CRLMs) smaller than 10 mm. However, few studies have used MRI findings to predict patients' long-term prognosis. Purpose To investigate the relationship between Gd-EOB-DTPA-enhanced MRI findings in the liver parenchyma peripheral to CRLM and both pathologic vessel invasion and long-term prognosis. Materials and Methods This retrospective study included patients who underwent Gd-EOB-DTPA-enhanced MRI before curative surgery for CRLM, without neoadjuvant chemotherapy, between July 2008 and June 2015. Early enhancement, reduced Gd-EOB-DTPA uptake, and bile duct dilatation peripheral to the CRLM at MRI were evaluated by three abdominal radiologists. All tumor specimens were reevaluated for the presence or absence of portal vein, hepatic vein, and bile duct invasion. Predictors of recurrence-free survival (RFS) and overall survival (OS) after surgery were identified with Cox proportional hazard model with the Bayesian information criterion. Previously reported prognosticators were selected for multivariable analyses. The median follow-up period was 60 months (range, 9-127 months). Results Overall, 106 patients (mean age, 65 years ± 12 [standard deviation]; 68 men) with 148 CRLMs were evaluated. Bile duct dilatation peripheral to the tumor was associated with pathologic portal vein invasion (sensitivity, 12 of 50 [24%]; specificity, 89 of 98 [91%]; P = .02), bile duct invasion (sensitivity, eight of 19 [42%]; specificity, 116 of 129 [90%]; P = .001), poor RFS (P = .03; hazard ratio [HR] = 2.4 [95% confidence interval {CI}: 1.3, 4.2]), and poor OS (P = .01; HR = 2.4 [95% CI: 1.2, 4.9]). For RFS and OS, early enhancement and reduced Gd-EOB-DTPA uptake peripheral to the CRLM were eliminated by means of variable selection in the multivariable analysis, but the combination of these findings with bile duct dilatation provided a predictor of poor OS (P = .001; HR = 3.3 [95% CI: 1.6, 6.8]). Conclusion MRI signal intensity changes peripheral to the colorectal liver metastasis were predictors of long-term prognosis after curative surgery without neoadjuvant chemotherapy. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Bashir in this issue.

Background Most current models for predicting survival after resection of colorectal liver metastasis include largest diameter and number of colorectal liver metastases as dichotomous variables, resulting in underestimation of the extent of risk variation and substantial loss of statistical power. The aim of this study was to develop and validate a new prognostic model for patients undergoing liver resection including largest diameter and number of colorectal liver metastases as continuous variables. Methods A prognostic model was developed using data from patients who underwent liver resection for colorectal liver metastases at MD Anderson Cancer Center and had RAS mutational data. A Cox proportional hazards model analysis was used to develop a model based on largest colorectal liver metastasis diameter and number of metastases as continuous variables. The model results were shown using contour plots, and validated externally in an international multi-institutional cohort. Results A total of 810 patients met the inclusion criteria. Largest colorectal liver metastasis diameter (hazard ratio (HR) 1.11, 95 per cent confidence interval 1.06 to 1.16; P Conclusion The contour prognostic model, based on diameter and number of lesions considered as continuous variables along with RAS mutation, predicts overall survival after resection of colorectal liver metastasis.

PURPOSE: KRAS p.G12C mutations occur in approximately 3% of metastatic colorectal cancers (mCRC). Recently, two allosteric inhibitors of KRAS p.G12C have demonstrated activity in early phase clinical trials. There are no robust studies examining the behavior of this newly targetable population. METHODS: We queried the MD Anderson Cancer Center data set for patients with colorectal cancer who harbored KRAS p.G12C mutations between January 2003 and September 2019. Patients were analyzed for clinical characteristics, overall survival (OS), and progression-free survival (PFS) and compared against KRAS nonG12C. Next, we analyzed several internal and external data sets to assess immune signatures, gene expression profiles, hypermethylation, co-occurring mutations, and proteomics. RESULTS: Among the 4,632 patients with comprehensive molecular profiling, 134 (2.9%) were found to have KRAS p.G12C mutations. An additional 53 patients with single gene sequencing were included in clinical data but excluded from prevalence analysis allowing for 187 total patients. Sixty-five patients had de novo metastatic disease and received a median of two lines of chemotherapy without surgical intervention. For the first three lines of chemotherapy, the median PFS was 6.4 months (n = 65; 95% CI, 5.0 to 7.4 months), 3.9 months (n = 47; 95% CI, 2.9 to 5.9 months), and 3.0 months (n = 21; 95% CI, 2.0 to 3.4 months), respectively. KRAS p.G12C demonstrated higher rates of basal EGFR activation compared with KRAS nonG12C. When compared with an internal cohort of KRAS nonG12C, KRAS p.G12C patients had worse OS. CONCLUSION: PFS is poor for patients with KRAS p.G12C metastatic colorectal cancer. OS was worse in KRAS p.G12C compared with KRAS nonG12C patients. Our data highlight the innate resistance to chemotherapy for KRAS p.G12C patients and serve as a historical comparator for future clinical trials.

450 Background: The oncological benefit of bevacizumab plus mFOLFOX6 in advanced colorectal liver metastases (CRLMs) in terms of conversion to curative resection remains unknown. This multicenter phase II trial aimed to evaluate the efficacy and safety of bevacizumab plus mFOLFOX6 as induction chemotherapy for advanced CRLMs harboring mutant-type KRAS. Methods: Patients who had advanced CRLMs (tumor number of ≥5 and/or technically unresectable) harboring mutant-type KRAS were included in this study. The induction chemotherapy of bevacizumab plus mFOLFOX6 was administered and assessed for resectability every 4 cycles. If the unresectable CRLMs were converted to be resectable, liver resection was planned after a waiting period of 4–6 weeks and followed by postoperative chemotherapy up to 12 cycles. The primary endpoint was R0 resection rate. The secondary endpoints were safety, recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS). The trial was conducted following approval from the Institutional Ethics Review Board of all institutions and registered in the University Hospital Medical Information Network Clinical Trials Registry (registration number: UMIN000009530). Results: Between February 2013 and December 2017, 29 patients from six centers were enrolled in this trial. The rates of complete and partial responses were 0% and 62.1%, respectively. R0 and R1 resections were performed in 19 and 1 patient, respectively (R0 resection rate: 65.5%). No mortality after liver resection occurred. During the median follow-up of 30.7 months (range, 7.2–82.6 months), the median OS for the 29 patients was 49.1 months. The 3-year PFS and OS rates were 7.4%, and 64.4%, respectively. The 3-year RFS rate was 10.0% in 20 patients who achieved R0 or R1 resections. Conclusions: Bevacizumab plus mFOLFOX6 achieved a high R0 resection rate with a favorable survival for patients with advanced CRLMs harboring mutant-type KRAS. Clinical trial information: UMIN000009530.

The objective of this study was to investigate the incidence and clinical significance of intratumoral fat deposition in colorectal liver metastases (CLMs) after preoperative chemotherapy using dual-echo gradient-recalled echo MRI.Our institutional review board approved this retrospective radiographic study and waived the requirement for informed patient consent. Fifty-nine patients (33 men, 26 women; median age, 62 years old) who underwent preoperative MRI and curative hepatic resection for colorectal liver metastases after chemotherapy were selected. Twenty patients also underwent MRI before chemotherapy. On dual-echo gradient-recalled echo MR images, intratumoral fat deposition and fat signal fraction at the densest areas of fat deposition in colorectal liver metastases were evaluated. Predictors of overall survival and intratumoral fat deposition after chemotherapy were identified by multivariate analyses.Before and after chemotherapy, 0 (0%) and 32 (54%) of the patients exhibited intratumoral fat deposition, respectively. Independent predictors of poor overall survival were presence of five or more CLMs (p0.001), fat signal fraction of 12% or more (p = 0.01), age of 65 years or older (p = 0.02), and tumor response classified as progressive or stable disease by the Response Evaluation Criteria in Solid Tumors 1.1 (p = 0.049). Predictors of tumor fat signal fraction being 12% or greater after chemotherapy were largest tumor size of 5 cm or more (p = 0.005), tumor calcification (p = 0.008), and history of cetuximab or panitumumab administration (p = 0.04).CLMs after preoperative chemotherapy frequently exhibit intratumoral fat deposition.

Systematic resection of the tumor-bearing portal territory is reportedly correlated with an improved survival of patients with liver tumors, especially in hepatocellular carcinoma. Despite advances in surgical management, however, anatomic resection of deeply/centrally located tumors remains a challenging procedure not only with technical difficulty but also because of decreased hepatic functional reserve frequently observed due to underlying liver disease. In this report, we have reported a novel technique that allows a promising approach for deeply/centrally located tumors with maximizing both the surgical and oncological safety. Bilateral anatomic resection of the ventral parts of the paramedian sectors (BVPM) offers a sufficient surgical window for safe access to the perihilar region. This technique is based on Hjortsjo's theory for liver anatomy and enables systematic removal of the 3rd-order portal territories. In addition, the current technique is advantageous in minimizing the loss of the normal liver parenchyma without leaving ischemia or congestion in the future liver remnant. Of the seven consecutive patients who were treated with this procedure, all the patients achieved R0 resection with acceptable rate of major morbidity (1/7, 14%). The BVPM may offer a safe and maximized chance of curative resection for deeply/centrally located liver tumors.

A potentially favorable effect of chemotherapy on the incidence of micrometastases has been reported in patients with colorectal liver metastases (CLMs); however, the actual influence of chemotherapy on the distribution of micrometastases and surgical curability remains unclear.The clinical impact of preoperative chemotherapy on the incidence and distribution of micrometastases was assessed in 191 patients with 357 CLM nodules. Potential radiologic measures for predicting the extent of microscopic cancer spread and surgical curability were then sought among the size-based and non-size-based radiologic response criteria.Multivariate analysis estimated a reduced incidence of micrometastases in patients receiving preoperative chemotherapy (odds ratio [OR] 0.45, 95% confidence interval [CI] 0.26-0.76, p = 0.003). Furthermore, the addition of biologic agents to the preoperative chemotherapy regimen was correlated with a reduced incidence of microscopic cancer spread beyond a width of 1 mm from the margin of the main tumor (OR 0.28, 95% CI 0.11-0.74, p = 0.010 for bevacizumab; and OR 0.29, 95% CI 0.09-0.99, p = 0.048 for anti-epidermal growth factor receptor antibody). Receiver operating characteristic analyses revealed that the computed tomography (CT) morphologic response showed a moderate predictive power for the distribution of micrometastases, with an area under the curve of 0.687, while size-based response criteria were not reliable for estimating the extent of microscopic cancer spread.Notwithstanding the potential selection of patients after preoperative chemotherapy, the incidence and distribution of micrometastases may be reduced by preoperative chemotherapy. CT morphologic response may be a reliable predictor of both the degree of microscopic cancer spread and the curability of surgery.

The value of repeat hepatectomy for intrahepatic recurrence after curative resection of neuroendocrine liver metastasis (NELM) remains unclear. The aim of this retrospective cohort study was to determine the significance of repeat hepatectomy for recurrent NELM.Patients who underwent hepatectomy for NELM between 1994 and 2016 were identified. The indications for a first hepatectomy were adequate liver remnant volume and no extrahepatic metastasis. The diagnosis of recurrent NELM was based on radiographic examinations. The indications for a repeat hepatectomy were the same as those for the first hepatectomy. Clinicopathologic factors, short-term survival, and long-term survival were investigated using clinical records.Forty-four patients enrolled in this study. Thirty-three patients among them underwent a curative hepatectomy, and 28 of them developed recurrence. Of them, 16 patients underwent a repeat hepatectomy. The overall survival of the repeat hepatectomy cohort (n = 16) was significantly better than that of the no repeat hepatectomy cohort (n = 12) (P.001). The progression free survival after the first hepatectomy (n = 44) and that after repeat hepatectomy (n = 16) were similar (P = .546). No significant difference was seen between the frequency of major complications (Clavien-Dindo score ≥ 3a) after the first and repeat hepatectomy (P = .279). No repeat hepatectomy (hazard ratio [HR] 5.0, P = .036) was identified as an independent predictive factor of a poor outcome among the recurrent cohort, along with the presence of multiple nodules (HR 26.2, P = .008) and a CA19-9 level ≥40 U/mL (HR 11.2, P = .012).A repeat hepatectomy is feasible in selected patients with recurrent NELM.

The KRAS mutation status is reportedly correlated with poor survival outcome in patients with colorectal liver metastases (CLM); however, its true prognostic impact and the reason for the poor prognosis remain unclear. Data on 163 patients with a known KRAS mutation status who underwent curative resection for CLM were retrospectively reviewed. The long-term survival and site-specific incidence of recurrence were then compared between patients with a KRAS mutation (mtKRAS) and those without a mutation (wtKRAS). The mtKRAS group had a poorer 3-year disease-specific survival (DSS) rate (59.8 vs. 83.6 %, p = 0.016), 3-year recurrence-free survival (RFS) rate (0 vs. 20.2 %, p = 0.069), and median time to surgical failure (TSF) [18.8 vs. 39.7 months, p = 0.001] than the wtKRAS group. The cumulative incidences of liver recurrence and lung recurrence at 3 years were also higher in the mtKRAS group (76.2 vs. 54.7 %, p = 0.060; and 71.9 vs. 37.3 %, p

Background Recent advances in liver surgery have dramatically improved the safety of hepatectomy for hepatocellular carcinoma (HCC). The aim of this study was to compare outcomes for patients fulfilling an extended criteria vs. those fulfilling the conventional criteria based on the bilirubin and indocyanine green (ICG) clearance (Makuuchi's criteria). Methods The short term outcomes of patients undergoing hepatectomy for HCC and who fulfilled the expanded criteria (ICG clearance of future remnant liver [ICG-Krem] ≥ 0.05 estimated using 3-D volumetry) were retrospectively reviewed and were compared between those fulfilling the conventional criteria. Postoperative hepatic insufficiency (PHI) was defined as peak total bilirubin >7 mg/dL. Results A total of 323 patients undergoing resection of whom 269 (83%) met conventional criteria (In-M) and 54 (17%) extended criteria (Ex-M). The overall morbidity rates were not significantly different. The incidence of PHI was 0.37% in In-M and 3.7% in Ex-M (P = 0.074), with no liver-related deaths. When the ICG-Krem ≥ 0.05 criterion was included, major hepatectomy was performed in 24 patients (41%) in Ex-M with no significant increase in major morbidity (13%), PHI(3.3%), or liver-related death (0%) compared with minor hepatectomy (n = 30) in Ex-M(10%, 4% and 0%, respectively). Conclusions Objective criteria using ICG clearance rate and 3-D volumetry may offer opportunities for safe surgical resection in selected patients exceeding the conventional criteria.

Background: Understanding the genetic background of a tumor is important to better stratify patient prognosis and select optimal treatment. For colorectal liver metastases (CLM), however, clinically available biomarkers remain limited. Methods: After a comprehensive sequencing of 578 cancer-related genes in 10 patients exhibiting very good/poor responses to chemotherapy, the A5.1 variant of the MICA gene was selected as a potential biomarker for CLM. The clinical relevance of MICA A5.1 was then investigated in 58 patients who underwent CLM resection after chemotherapy. Results: The A5.1 variant was observed in 16 (27.6%) patients examined using direct DNA sequencing, and a very high concordance rate (56/58, 96.6%) for the MICA variant was confirmed between tumor tissues and normal liver parenchyma. A multivariate analysis of 38 patients with no history of treatment with anti-EGFR antibodies confirmed that MICA A5.1 was significantly correlated with an optimal CT morphologic response (OR 11.67; 95% CI 2.08–65.60; p = 0.005) and tended to be correlated with a tumor viability of < 20% after chemotherapy (OR 5.91; 95% CI 0.97–36.02; p = 0.054). MICA A5.1 was also associated with a decreased risk of progression after CLM resection. Conclusion: The MICA A5.1 polymorphism was associated with a better CT morphologic response to chemotherapy and a reduced risk of relapse after CLM resection. Given the high concordance rate in MICA variants between normal liver tissue and CLM, the genetic background of the host could be a new biomarker for CLM.

The ratio of the bilirubin concentration in abdominal drainage fluid to the serum bilirubin concentration (d-Bil/s-Bil) has been used as a predictor of biliary fistula (BF) formation after hepatobiliary surgery. The d-Bil/s-Bil ratio is highly influenced by the amount of drainage and is not always reliable, especially when the amount of drainage is large. In this study, the usefulness of the d-Bil/s-Bil ratio and total bilirubin amount in the drainage fluid (TBA) (bilirubin concentration in the drainage fluid x the amount of drainage) as predictors of severe BF (sBF) formation was evaluated retrospectively from the data of 306 patients who had undergone hepatobiliary surgery. Of the 306 patients, 201 patients were included in the training set and the remaining 105 in the validation set, to determine the best parameter to predict sBF formation after hepatobiliary surgery. Receiver-operating characteristic curve analysis revealed that the predictive power of TBA was superior to that of the d-Bil/s-Bil ratio throughout the postoperative period, and that the TBA on postoperative day (POD) 1 showed the highest discriminatory power in the training set (area under the curve, 0.789; cutoff value, 470 mg/day). The TBA on POD 1 also showed the highest predictive power for sBF formation in the validation set, with a sensitivity of 100%, specificity of 97.1%, and accuracy of 97.1%. In conclusion, TBA may be a more reliable predictor of sBF than the conventionally used d-Bil/s-Bil ratio. Early prediction of sBF may be useful for early removal of unnecessary prophylactic drainage tubes after hepatobiliary surgery.