Preoperative estimation of future remnant liver function is critical for major hepatic surgery to avoid postoperative morbidity and mortality. Among several liver function tests, the indocyanine ...green (ICG) clearance test is still the most popular dynamic method. The usefulness of ICG clearance test parameters, such as ICGR15, KICG, or PDRICG, has been reported by many investigators. The transcutaneous non-invasive pulse dye densitometry system has made the ICG clearance test more convenient and attractive, even in Western countries. The concept of future remnant KICG (rem KICG), which combines the functional aspect and the volumetric factor of the future remnant liver, seems ideal for determining the maximum extent of major hepatic resection that will not cause postoperative liver failure. For damaged livers with functional heterogeneity among the hepatic segments, fusion images combining technetium-99m-diethylenetriaminepentaacetic acid-galactosyl human serum albumin single photon emission computed tomography (99mTc-GSA SPECT) and X-ray CT are helpful to precisely estimate the functional reserve of the future remnant liver. Another technique for image-based liver function estimation, gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid(Gd-EOB)-enhanced magnetic resonance imaging, may be an ideal candidate for the preoperative determination of future remnant liver function. Using these methods effectively, morbidity and mortality after major hepatic resection could be reduced.
Background/Purpose
There are limitations in obtaining sufficient pancreaticobiliary tumor tissue for genomic profiling of tumors. Herein, we investigated whether archived cytological specimen (ACS) ...is suitable for genomic profiling to identify oncogenic and drug‐matched mutations.
Methods
We constructed a pancreaticobiliary cancer panel for targeted sequencing covering 60 significantly mutated genes (280 220 bp). Eighty DNA samples (19 formalin‐fixed paraffin‐embedded FFPE tissues and 61 ACS) from 44 patients with pancreaticobiliary disease were analyzed. We compared genomic profiles of 19 FFPE and 29 ACS from 19 patients with malignancies (Validation Cohort). We tested 32 ACS from 25 patients (15 malignant and 10 benign) for the ability to discriminate between malignant and benign disorders (Testing Cohort). We explored whether actionable and drug‐matched mutations (Validation and Testing Cohorts) could be identified from ACS.
Results
Oncogenic mutations observed in ACS were identical to those identified in FFPE specimens (76% consistency). Genomic profiling using only ACS discriminated between malignant and benign disorders with 93% accuracy, 91% sensitivity, and 100% specificity. Actionable and drug‐matched mutations were identified in 74% and 32% of ACS, respectively, and in 79% and 21% in FFPE samples, respectively.
Conclusion
Archived cytological specimen may be used to discriminate malignancy and to detect drug‐matched mutations in patients with advanced pancreaticobiliary cancer.
Highlight
There are limitations in obtaining sufficient pancreaticobiliary tumor tissue for genomic profiling. Ohyama and colleagues found that archived cytological specimens were comparable to formalin‐fixed paraffin‐embedded tissues in their ability to discriminate malignancies and detect drug‐matched mutations in advanced pancreaticobiliary cancer, and may help expand the patient population benefiting from targeted drugs.
Background
Obtaining sufficient pancreaticobiliary tumor tissue for genomic profiling has limitations. Liquid biopsies using plasma do not provide sufficient sensitivity. Thus, this study aimed to ...determine the effectiveness of liquid biopsy between bile and plasma for identifying oncogenic and drug‐matched mutations.
Methods
This study created a panel of 60 significantly mutated genes specific to pancreaticobiliary cancer (PBCA) and used it for genomic analysis of 212 deoxyribonucleic acid (DNA) samples (87 bile supernatant, 87 bile precipitate, and 38 plasma) from 87 patients with PBCA. The quantity of extracted DNA from bile and plasma was compared, as were genomic profiles of 38 pairs of bile and plasma from 38 patients with PBCA. Finally, we investigated 87 bile and 38 plasma for the ability to detect druggable mutations.
Results
The amount of DNA was significantly lower in plasma than in bile (p < .001). Oncogenic mutations were identified in 21 of 38 (55%) patients in bile and nine (24%) in plasma samples (p = .005). Bile was significantly more sensitive than plasma in identifying druggable mutations (p = .032). The authors detected 23 drug‐matched mutations in combined bile and plasma, including five ERBB2, four ATM, three BRAF, three BRCA2, three NF1, two PIK3CA, one BRCA1, one IDH1, and one PALB2.
Conclusions
Liquid biopsy using bile may be useful in searching for therapeutic agents, and using the obtained genomic information may improve the prognoses of patients with PBCA.
Plain Language Summary
Genomic profiling of formalin‐fixed paraffin‐embedded tissues may provide actionable targets for molecular and immuno‐oncological treatment.
However, most pancreaticobiliary malignancies are unresectable and formalin‐fixed paraffin‐embedded tissues cannot be obtained.
Although comprehensive genomic profiling tests using plasma have been used in recent years, the utility of those using bile is not clear.
Our study revealed that bile identified more drug‐matched mutations than plasma in advanced pancreaticobiliary cancer patients.
Bile may help widen the patient population benefiting from targeted drugs.
Bile contained a large amount of tumor‐derived DNA in pancreaticobiliary cancer. Liquid biopsy using bile may be useful in searching for therapeutic agents.
Background/Aims Complete operative resection is the only approach to cure for intrahepatic cholangiocellular carcinoma (ICC), but the disease’s prognosis is notably poor. A novel therapeutic approach ...is urgently required. CXC chemokine receptor 2 (CXCR2) has been associated with tumorigenesis and metastasis in human cancers. In this study, we investigated the suppressive effect of ICC growth by blocking CXCR2. Material and methods The role of CXCR2 was estimated using the human ICC cell lines, RBE and SSP25. CXCR2 small interfering RNA (siRNA) and an antagonist (SB225002) were used to block CXCR2. Proliferation assays, migration assays, and invasion assays were performed to confirm the suppressive effect of blocking CXCR2. Subcutaneous SSP25 tumors were established in athymic nude mice, and the mice were given SB225002. The expression of CXCR2 in ICC was determined by immunohistochemical staining of 34 ICC specimens. We investigated the relationship between CXCR2 expression and prognosis in ICC. Results The prognosis of patients who had higher CXCR2 expression in ICC was significantly poor ( P = .004). CXCR2 siRNA treatment significantly suppressed CXCR2 expression in both RBE and SSP25. Cell proliferation, migration, and invasion were significantly suppressed by both CXCR2 siRNA and SB225002 compared with the control group. SB225002 also suppressed the growth of transplanted subcutaneous tumors ( P = .02) Conclusion Our results demonstrated that blocking CXCR2 clearly suppressed the development of ICC. Blocking CXCR2 may be a promising therapeutic approach for ICC.
To evaluate the effectiveness of radio-frequency (RF) ablation and percutaneous microwave coagulation (PMC) for treatment of hepatocellular carcinoma (HCC).
Seventy-two patients with 94 HCC nodules ...were randomly assigned to RF ablation and PMC groups. Thirty-six patients with 48 nodules were treated with RF ablation, and 36 patients with 46 nodules were treated with PMC. Therapeutic effect, residual foci of untreated disease, and complications of RF ablation and PMC were prospectively evaluated with statistical analyses.
The number of treatment sessions per nodule was significantly lower in the RF ablation group than in the PMC group (1.1 vs 2.4; P <.001). Complete therapeutic effect was achieved in 46 (96%) of 48 nodules treated with RF ablation and in 41 (89%) of 46 nodules treated with PMC (P =.26). Major complications occurred in one patient treated with RF ablation and in four patients treated with PMC (P =.36). During follow-up (range, 6-27 months), residual foci of untreated disease were seen in four of 48 nodules treated with RF ablation and in eight of 46 nodules treated with PMC. No significant difference in rates of residual foci of untreated disease was noted (P =.20, log-rank test).
RF ablation and PMC thus far have had equivalent therapeutic effects, complication rates, and rates of residual foci of untreated disease. However, RF tumor ablation can be achieved with fewer sessions.
Genomic profiling of tumors is available, but whether the small fragment obtained via endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) is sufficient for these examinations is unknown. Here ...we investigated whether EUS-FNB specimens are suitable for genomic profiling to identify oncogenic and drug-matched mutations.
We constructed a pancreatobiliary cancer panel for targeted panel sequencing that covered 60 significantly mutated genes and compared the results with those of whole-exome sequencing (WES). In total, 20 and 53 formalin-fixed paraffin-embedded tissues obtained via surgery and EUS-FNB were analyzed, respectively. First, we examined the DNA quality and genomic profiles of 20 paired samples from 20 malignant lesions obtained via surgery and EUS-FNB. We then tested 33 samples obtained via EUS-FNB from 24 malignant and 9 benign lesions for the discrimination of malignancy. Finally, we explored drug-matched mutations from EUS-FNB specimens.
Although the DNA quantity obtained via surgery was higher than that obtained via EUS-FNB (P = 0.017), the DNA quality and mean depth were equivalent (P = 0.441 and P = 0.251). Panel sequencing of EUS-FNB specimens identified more oncogenic mutations than WES (90 % vs. 50 %). Furthermore, the number of oncogenic mutations did not differ between EUS-FNB and surgically resected specimens. Genomic profiling of EUS-FNB specimens enabled the discrimination of malignancy with 98 % accuracy. Of 44 malignant lesions, drug-matched alterations were identified in 14 % (6/44) of malignant lesions.
EUS-FNB specimens can be widely utilized for diagnostic purposes, discrimination of malignancy, and detection of drug-matched mutations for the treatment of pancreatic cancer.
•Genomic analysis of FFPE tissue obtained via EUS-FNB revealed oncogenic mutations in almost all patients with PC.•Genomic profiles of EUS-FNB specimens could better discriminate malignancies than conventional histological diagnosis.•Actionable mutations were detected in around 90 % of patients with PC.•EUS-FNB specimens have great potential for revealing the genomic profile of primary tumors in the era of precision medicine.
The purpose of anatomic resection of the liver is to systemically eliminate malignant tumors that spread via the portal vein. Moreover, it results in reducing bleeding and bile leakage from the cut ...surface of the liver because Glisson's pedicle resection leads to parenchyma transection. Anatomical resection includes hemi‐hepatectomy, sectionectomy, and segmentectomy. Recently, it has been noticed that this concept is not always appropriate for the liver resection including the right paramedian sector. It can be divided vertically into the ventral and the dorsal area according to the ramification of the third order of the portal veins. In the present study, we focused on the right paramedian sector and described techniques of surgical procedures of hepatectomy including resection of the ventral or dorsal areas.
Background Recent studies of hepatic regeneration have mainly focused on the growth of parenchymal cells. However, remodeling of liver vessels seems to be crucial during hepatic regeneration. In this ...study, we investigated the influence of antiangiogenesis on hepatic regeneration using sFlt-1, a soluble receptor for vascular endothelial growth factor that acts as a dominant negative receptor, and the hepatocyte growth factor antagonist NK4. Methods A sFlt-1–expressing adenoviral vector, an NK4-expressing adenoviral vector, or both combined were infected into C57BL6 mice via the tail vein. A 70% partial hepatectomy was performed on all of the mice 48 hours after infection. The remnants of the liver were removed after the partial hepatectomy, and hepatic regeneration was assessed by measuring the remnant liver weight and hepatocyte mitosis, bromodeoxyuridine staining, immunohistochemical staining with anti–platelet endothelial cell adhesion molecule-1 antibodies, and real-time polymerase chain reaction studies for angiogenic factors. Results The immunohistochemical staining for CD31 showed suppression of sinusoidal endothelial cells growth in sFlt-1–expressing adenoviral vector–and NK4-expressing adenoviral vector–infected mice. Increases in the remnant hepatic weight were significantly lower in the sFlt-1–expressing adenoviral vector–infected mice. The bromodeoxyuridine index and mitotic cell results revealed a significant decrease in hepatic regeneration in the sFlt-1–expressing adenoviral vector–and NK4-expressing adenoviral vector–infected mice. The suppressive effects on hepatic regeneration were significantly enhanced by combined sFlt-1–expressing adenoviral vector and NK4-expressing adenoviral vector infection. Real-time polymerase chain reaction results revealed the significant suppression of angiogenic growth factor receptors Tie-1 and Tie-2. Conclusion The angiogenesis inhibitor significantly suppressed hepatic regeneration. These results suggest that hepatic regeneration after hepatectomy closely correlates with angiogenesis.
While hepatocytes rarely undergo proliferation in normal livers, they quickly induce proliferation in response to loss of liver mass by toxin or inflammation-induced hepatocyte injury, trauma, or ...surgical resection, leading to a restoration of liver mass to its original size. Recent studies suggest that Toll-like receptor (TLR) signaling participates in this regenerative response. Myeloid differentiation factor (MyD88), a common adaptor molecule in the TLR, IL-1 and IL-18 receptor signaling, plays a key role, at least, in the early phase of liver regeneration. Currently, definite ligands which bind to TLRs and initiate this process are still unclear. TLRs stimulated by their corresponding ligands, as well as tumor necrosis factor (TNF) receptors (TNFRs), can activate downstream signal molecules, including transcription factor nuclear factor (NF)-κB and c-Jun N-terminal kinase (JNK). Previous studies have revealed the important role of TNF receptor signaling, NF-κB, and JNK in liver regeneration by using hepatocyte-specific gene-modified animals. This review will summarize the current knowledge of TLR signaling and their related molecules in liver regeneration. We will also discuss whether modulating these factors may become new therapeutic strategies to promote liver regeneration in various clinical situations.
Hepatectomy is a complicated operative procedure because of its anatomical complexity, vascular variability, and impaired hepatic function due to associated hepatitis or cirrhosis. Thus preoperative ...detailed topography and precise liver resection volume measurements should be obtained for a curative hepatectomy. The aim of this study was to assess the feasibility and accuracy of a novel three-dimensional (3D) virtual hepatectomy simulation software in patients who underwent liver resection or living donor liver transplantation. We developed the hepatectomy simulation software, which was programmed to analyze detailed 3D vascular structure and to predict liver resection volume and margins. In 72 patients receiving hepatectomy, the predicted liver resection volumes and margins revealed a significant correlation with the actual value with a mean difference of 9.3 mL (P < .0001) and 1.6 mm (P < .01), respectively. The drainage area by hepatic veins was quantified to achieve reconstruction of the corresponding venous branch. In conclusion, this hepatectomy simulation software reliably predicted an accurate liver resection volume, the cancer-free margin, and the drainage volume of hepatic vein branches. This software may promote curative hepatectomy and may be used for other interventional therapies in the treatment of liver disease.
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