Abstract Background The highest mortality rates after liver surgery are reported in patients who undergo resection for hilar cholangiocarcinoma (HCCA). In these patients, postoperative death usually ...follows the development of hepatic insufficiency. We sought to determine the factors associated with postoperative hepatic insufficiency and death due to liver failure in patients undergoing hepatectomy for HCCA. Study Design This study included all consecutive patients who underwent hepatectomy with curative intent for HCCA at two centers from 1996 through 2013. Preoperative clinical and operative data were analyzed to identify independent determinants of i ) hepatic insufficiency and ii ) liver failure–related death. Results The study included 133 patients with right or left major (n=67) or extended (n=66) hepatectomy. Preoperative biliary drainage was performed in 98 patients and was complicated by cholangitis in 40 cases. In all these patients, cholangitis was controlled before surgery. Major (Dindo III-IV) postoperative complications occurred in 73 patients (55%), with 29 suffering from hepatic insufficiency. Fifteen patients (11%) died within 90 days after surgery, 10 of them of liver failure. On multivariate analysis, predictors of postoperative hepatic insufficiency (all p<0.05) were preoperative cholangitis (odds ratio OR=3.2), future liver remnant (FLR) volume <30% (OR=3.5), preoperative total bilirubin level >3 mg/dl (OR=4), and albumin level <3.5 mg/dl (OR=3.3). Only preoperative cholangitis (OR=7.5, p=.016) and FLR volume <30% (OR=7.2, p=.019) predicted postoperative liver failure–related death. Conclusions Preoperative cholangitis and insufficient FLR volume are major determinants of hepatic insufficiency and postoperative liver failure–related death. Given the association between biliary drainage and cholangitis, the preoperative approach to patients with HCCA should be optimized to minimize the risk of cholangitis.
To determine the impact of RAS mutation status on the traditional clinical score (t-CS) to predict survival after resection of colorectal liver metastases (CLM).
The t-CS relies on the following ...factors: primary tumor nodal status, disease-free interval, number and size of CLM, and carcinoembryonic antigen level. We hypothesized that the addition of RAS mutation status could create a modified clinical score (m-CS) that would outperform the t-CS.
Patients who underwent resection of CLM from 2005 through 2013 and had RAS mutation status and t-CS factors available were included. Multivariate analysis was used to identify prognostic factors to include in the m-CS. Log-rank survival analyses were used to compare the t-CS and the m-CS. The m-CS was validated in an international multicenter cohort of 608 patients.
A total of 564 patients were eligible for analysis. RAS mutation was detected in 205 (36.3%) of patients. On multivariate analysis, RAS mutation was associated with poor overall survival, as were positive primary tumor lymph node status and diameter of the largest liver metastasis >50 mm. Each factor was assigned 1 point to produce a m-CS. The m-CS accurately stratified patients by overall and recurrence-free survival in both the initial patient series and validation cohort, whereas the t-CS did not.
Modifying the t-CS by replacing disease-free interval, number of metastases, and CEA level with RAS mutation status produced an m-CS that outperformed the t-CS. The m-CS is therefore a simple validated tool that predicts survival after resection of CLM.
Background
In patients undergoing resection of colorectal liver metastases (CLM), resection margin status is a significant predictor of survival, particularly in patients with suboptimal response to ...preoperative therapy.
RAS
mutations have been linked to more invasive and migratory tumor biology and poor response to modern chemotherapy.
Objective
The aim of this study was to evaluate the relationship between
RAS
mutation and resection margin status in patients undergoing resection of CLM.
Methods
Patients who underwent curative resection of CLM from 2005 to 2013 with known
RAS
mutation status were identified from a prospectively maintained database. A positive margin was defined as tumor cells <1 mm from the parenchymal transection line.
Results
The study included 633 patients, of whom 229 (36.2 %) had mutant
RAS
. The positive margin rate was 11.4 % (26/229) for mutant
RAS
and 5.4 % (22/404) for wild-type
RAS
(
p
= 0.007). In multivariate analysis, the only factors associated with a positive margin were
RAS
mutation (hazard ratio HR 2.439;
p
= 0.005) and carcinoembryonic antigen level 4.5 ng/mL or greater (HR 2.060;
p
= 0.026). Among patients presenting with liver-first recurrence during follow-up, those with mutant
RAS
had narrower margins at initial CLM resection (median 4 mm vs. 7 mm;
p
= 0.031). A positive margin (HR 3.360;
p
< 0.001) and
RAS
mutation (HR 1.629;
p
= 0.044) were independently associated with worse overall survival.
Conclusion
RAS
mutations are associated with positive margins in patients undergoing resection of CLM. Tumors with
RAS
mutation should prompt careful efforts to achieve negative resection margins.
Adequate selection of patients with peritoneal metastasis (PM) for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) remains critical for successful long-term ...outcomes. Factors reflecting tumor biology are currently poorly represented in the selection process. The prognostic relevance of RAS/RAF mutations in patients with PM remains unclear.
Survival data of patients with colorectal PM operated in 6 European tertiary centers were retrospectively collected and predictive factors for survival identified by Cox regression analyses. A simple point-based risk score was developed to allow patient selection and outcome prediction.
Data of 524 patients with a median age of 59 years and a median peritoneal cancer index of 7 (interquartile range: 3-12) were collected. A complete resection was possible in 505 patients; overall morbidity and 90-day mortality were 50.9% and 2.1%, respectively. PCI hazard ratio (HR): 1.08, N1 stage (HR: 2.15), N2 stage (HR: 2.57), G3 stage (HR: 1.80) as well as KRAS (HR: 1.46) and BRAF (HR: 3.97) mutations were found to significantly impair survival after CRS/HIPEC on multivariate analyses. Mutations of RAS/RAF impaired survival independently of targeted treatment against EGFR. Consequently, a simple point-based risk score termed BIOSCOPE (BIOlogical Score of COlorectal PEritoneal metastasis) based on PCI, N-, G-, and RAS/RAF status was developed, which showed good discrimination development area under the curve (AUC) = 0.72, validation AUC = 0.70, calibration (P = 0.401) and allowed categorization of patients into 4 groups with strongly divergent survival outcomes.
RAS/RAF mutations impair survival after CRS/HIPEC. The novel BIOSCOPE score reflects tumor biology, adequately stratifies long-term outcomes, and improves patient assessment and selection.
The aim of this study was to determine the prognostic value of embryonic origin in patients undergoing resection after chemotherapy for colon cancer liver metastases (CCLM).
We identified 725 ...patients with primary colon cancer and known RAS mutation status who underwent hepatic resection after preoperative chemotherapy for CCLM (1990 to 2015). Survival after resection of CCLM from midgut origin (n = 238) and hindgut origin (n = 487) was analyzed. Predictors of pathologic response and survival were determined. Prognostic value of embryonic origin was validated with a separate cohort of 252 patients with primary colon cancer who underwent resection of CCLM without preoperative chemotherapy.
Recurrence-free survival (RFS) and overall survival (OS) after hepatic resection were worse in patients with midgut origin tumors (RFS rate at 3 years: 15% vs 27%, P < 0.001; OS rate at 3 years: 46% vs 68%, P < 0.001). Independent factors associated with minor pathologic response were midgut embryonic origin odds ratio (OR) 1.55, P = 0.010, absence of bevacizumab (OR 1.42, P = 0.034), and mutant RAS (OR 1.41, P = 0.043). Independent factors associated with worse OS were midgut embryonic origin hazard ratio (HR) 2.04, P < 0.001, carcinoembryonic antigen value ≥5 ng/mL at hepatic resection (HR 1.46, P = 0.0021), synchronous CCLM (HR 1.45, P = 0.012), and mutant RAS (HR 1.43, P = 0.0040). In the validation cohort, patients with CCLM of midgut origin had a worse 3-year OS rate (55% vs 78%, P = 0.003).
Compared with CCLM from hindgut origin, CCLM from midgut origin are associated with worse pathologic response to chemotherapy and worse survival after resection. This effect appears to be independent of RAS mutation status.
Background
Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) provide long-term survival for low-grade pseudomyxoma peritonei (PMP) and multicystic peritoneal ...mesothelioma (MM). Feasibility of laparoscopic CRS-HIPEC has been reported for selected patients but data regarding long-term outcomes are missing to assess the oncological interest. This study aimed to report long-term outcomes for low-grade PMP and MM treated by laparoscopic approach.
Methods
From a prospectively maintained CRS-HIPEC database, all patients who underwent laparoscopic CRS-HIPEC with curative intent were analyzed. Selection criteria for laparoscopic approach were low-grade PMP or MM, with pathological confirmation prior to CRS-HIPEC, ASA 2, age < 75 years, no extrap-eritoneal disease, Peritoneal Cancer Index (PCI) < 10, and a limited history of abdominal surgery.
Results
Between March 2009 and June 2017, 43 patients were scheduled for laparoscopic CRS and HIPEC. Laparoscopic CRS and HIPEC was completed (LSC) in 32 patients and 11 patients were converted to open surgery (CONV). Median age was 44.5 years (17.13–71.4) in the LSC group and 54.9 years (22.5–70.5) in the CONV group (
p
= 0.086). Median BMI was not different between groups, 21.2 and 23.9 for LSC and CONV groups, respectively (
p
= 0.267). There were 21 and 11 patients in the LSC group, and 8 and 3 in the CONV group, with PMP and MM, respectively (
p
= 0.794). Median PCI was 2.5 (0–9) and 7 (1–15) in the LSC and CONV groups, respectively (
p
= 0.004). There was no difference in the completeness of cytoreduction score (
p
= 0.256). After a median follow-up of 31.6 months (95% CI 19.3–36.4), 2 patients in the LSC group and 2 patients in the CONV group presented with peritoneal recurrence.
Conclusion
For selected patients with low aggressive peritoneal disease, laparoscopic CRS-HIPEC provides interesting long-term outcomes.
Background
Patients undergoing cytoreductive surgery for colorectal peritoneal metastases who have a pathologic complete response (pCR) to neoadjuvant chemotherapy experience a significantly longer ...survival than those with residual disease. This response is known only after surgery. This study aimed to examine clinical and radiologic predictors of a pCR.
Methods
From July 2018 to December 2019, the study prospectively enrolled 120 patients. The clinical and radiologic findings were compared between patients with and without a pCR. A protocol for pathologic evaluation was followed.
Results
A pCR was observed in 34 patients (28.3%). Receiver operating characteristic (ROC) curves showed that patients with a surgical Peritoneal Cancer Index (sPCI) of 3 or lower had an 80% probability of experiencing a pCR, and that patients with a radiologic PCI (rPCI) of 2 or lower had a 70% probability of experiencing a pCR. A pCR was correctly predicted for 47% of the patients by imaging and for 44.4% of the patients by surgical evaluation. The site of primary tumor, the timing of peritoneal metastasis (PM), histology, tumor marker positivity, and mutations in known poor prognostic genes (
KRAS
) did not differ between the patients with and those without pCR. The primary tumor showed residual disease in 23.5% and regional nodes in 26.4% of the patients with pCR.
Conclusions
The rPCI and sPCI concurred with a pCR in less than 50% of the patients. The patients with a lower PCI had greater concordance. An sPCI of 3 or lower was predictive of a pCR in 80% of the patients. The impact of
KRAS
mutations on pCR should be evaluated in a larger series. The predictors of pCR and response to systemic chemotherapy should be incorporated in prognostic scores used to select patients for surgery.
Background
Gastric pneumatosis (GP) is a rare radiologic finding with an unpredictable prognosis. The aim of this study was to identify mortality risk factors from patients presenting with GP on ...computed tomography (CT), and to develop a model which would allow us to predict which patients would benefit most from operative management.
Methods
Between 2010 and 2020, all CT-scan reports in four tertiary centers were searched for the following terms: “gastric pneumatosis,” “intramural gastric air” or “emphysematous gastritis.” The retrieved CT scans were reviewed by a senior surgeon and a senior radiologist. Relevant clinical and laboratory data for these patients were extracted from the institutions’ medical records.
Results
Among 58 patients with GP, portal venous gas and bowel ischemia were present on CT scan in 52 (90%) and 17 patients (29%), respectively. The 30-day mortality rate was 31%. Univariate analysis identified the following variables as predictive of mortality at the time of the diagnosis of GP: abdominal guarding, hemodynamic instability, arterial lactate level >2 mmol/l, and the absence of gastric dilatation. Multivariable analysis identified the following variables as independent predictors of mortality: arterial lactate level (OR: 1.39, 95% CI: 1.07–1.79) and the absence of gastric dilatation (OR: 0.07, 95% CI: 0.01–0.79). None of the patients presenting with a baseline lactate rate<2 mmol/l died within 30 days following diagnosis, and no more than 17 patients out of 58 had bowel ischemia (29%).
Conclusions
GP could be managed non-operatively, even in the presence of portal venous gas. However, patients with arterial lactate level>2 mmol/l, or the absence of gastric dilation should be surgically explored due to a non-negligible risk of mortality.
Phosphorylation is a major post-translation modification (PTM) of proteins which is finely tuned by the activity of several hundred kinases and phosphatases. It controls most if not all cellular ...pathways including anti-viral responses. Accordingly, viruses often induce important changes in the phosphorylation of host factors that can either promote or counteract viral replication. Among more than 500 kinases constituting the human kinome only few have been described as important for the hepatitis B virus (HBV) infectious cycle, and most of them intervene during early or late infectious steps by phosphorylating the viral Core (HBc) protein. In addition, little is known on the consequences of HBV infection on the activity of cellular kinases. The objective of this study was to investigate the global impact of HBV infection on the cellular phosphorylation landscape early after infection. For this, primary human hepatocytes (PHHs) were challenged or not with HBV, and a mass spectrometry (MS)-based quantitative phosphoproteomic analysis was conducted 2- and 7-days post-infection. The results indicated that while, as expected, HBV infection only minimally modified the cell proteome, significant changes were observed in the phosphorylation state of several host proteins at both time points. Gene enrichment and ontology analyses of up- and down-phosphorylated proteins revealed common and distinct signatures induced by infection. In particular, HBV infection resulted in up-phosphorylation of proteins involved in DNA damage signaling and repair, RNA metabolism, in particular splicing, and cytoplasmic cell-signaling. Down-phosphorylated proteins were mostly involved in cell signaling and communication. Validation studies carried out on selected up-phosphorylated proteins, revealed that HBV infection induced a DNA damage response characterized by the appearance of 53BP1 foci, the inactivation of which by siRNA increased cccDNA levels. In addition, among up-phosphorylated RNA binding proteins (RBPs), SRRM2, a major scaffold of nuclear speckles behaved as an antiviral factor. In accordance with these findings, kinase prediction analysis indicated that HBV infection upregulates the activity of major kinases involved in DNA repair. These results strongly suggest that HBV infection triggers an intrinsic anti-viral response involving DNA repair factors and RBPs that contribute to reduce HBV replication in cell culture models.
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