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Tumor stiffness measurement using magnetic resonance elastography can assess tumor mechanical properties and predict hepatocellular carcinoma recurrence. This study aimed to investigate preoperative tumor stiffness on magnetic resonance elastography as a predictor of overall survival and recurrence-free survival in patients with solitary nodular hepatocellular carcinoma who underwent curative resection.Seventy-eight patients with solitary nodular hepatocellular carcinoma who underwent preoperative magnetic resonance elastography and curative resection were retrospectively analyzed. Potential associations of tumor stiffness and other clinicopathological variables with overall survival and recurrence-free survival were analyzed in both univariate and multivariate Cox proportional hazards analyses. The optimal tumor stiffness cutoff value was determined using the minimal P value approach.In multivariate analysis, tumor stiffness (hazard ratio 1.31; 95% confidence interval, 1.07-1.59; P = .008) and vascular invasion (hazard ratio 2.62; 95% confidence interval, 1.27-5.17; P = .010) were independent predictors of recurrence-free survival. For overall survival, tumor stiffness (hazard ratio, 1.33; 95% confidence interval, 1.02-1.76; P = .037) was the only independent predictor. The optimal tumor stiffness cutoff value was 5.81 kPa for both overall survival and recurrence-free survival. Patients with tumor stiffness ≥5.81 kPa had a significantly greater risk of death (hazard ratio 6.10; 95% confidence interval, 2.11-21.90; P.001) than those with tumor stiffness5.81 kPa.Preoperative tumor stiffness as measured by magnetic resonance elastography was a predictor of overall survival and recurrence-free survival in hepatocellular carcinoma patients who underwent curative resection. Higher tumor stiffness was associated with higher risk of recurrence and death.

OBJECTIVE Monitoring the intraoperative motor evoked potentials (MEPs) in pediatric craniotomy is challenging because of its low detection rate, which makes it unreliable. Tetanic stimulation of the peripheral nerves of the extremities and pudendal nerves prior to transcranial electrical stimulation (TES) or direct cortical stimulation (DCS) amplifies the MEPs. The authors investigated the effects of MEP amplification following tetanic stimulation of the median and tibial nerve or the pudendal nerve in pediatric patients undergoing craniotomy. METHODS This prospective observational study included 15 patients ≤ 15 years of age (mean age 8.9 ± 4.9 years) undergoing craniotomy. MEPs were obtained with TES (15 cases) or DCS (8 cases)—conventional MEP without tetanic stimulation (c-MEP) and MEP following tetanic stimulation of the unilateral median and tibial nerves (mt-MEP) or following tetanic stimulation of the pudendal nerve (p-MEP) were used. Compound muscle action potentials were elicited from the abductor pollicis brevis, gastrocnemius, tibialis anterior, and abductor hallucis longus muscles. The authors compared the identification rate and the rate of amplitude increase of each MEP. RESULTS For both TES and DCS, the identification and amplitude increase rates were significantly higher in cases without preoperative hemiparesis for p-MEPs than in those for c-MEPs and mt-MEPs. In comparison to patients with preoperative hemiparesis, p-MEPs displayed a higher identification rate, with fewer false negatives in DCS cases. CONCLUSIONS In pediatric craniotomy, the authors observed the amplification effect of MEPs with pudendal nerve tetanic stimulation and the amplification effect of DCS on MEPs without increasing false negatives. These findings suggested the likelihood of more reliable intraoperative MEP monitoring in pediatric cases.

Rituximab, high-dose methotrexate (HD-MTX), procarbazine and vincristine (R-MPV), has significantly prolonged the survival of patients with primary central nervous system lymphoma (PCNSL), but predictive factors for response to R-MPV have not yet been investigated. Herein, we investigated the correlation of MYD88 L265P and CD79B Y196 mutations, which are the most frequently found molecular alterations in PCNSL, with prognosis of patients with PCNSL treated with R-MPV.We investigated the long-term clinical course and status of MYD88 and CD79B genes in 85 patients with PCNSL treated with R-MPV or HD-MTX treatment, and the correlation of these genetic mutations with prognosis.R-MPV achieved an excellent tumor control rate (61.6% and 69.9% of 5-year progression-free and overall survival rates, respectively). While MYD88 L265P mutation had no significant effect on survival, patients with CD79B Y196 mutations exhibited prolonged survival (p 0.05). However, the association of CD79B Y196 mutation with a better prognosis was not observed in the HD-MTX cohort, which indicated that CD79B Y196 mutation was a predictive marker for a favorable response to R-MPV. Furthermore, we established an all-in-one rapid genotyping system for these genetic mutations.In conclusion, CD79B Y196 mutation is a potent predictive marker for favorable response to R-MPV in PCNSL. The rapid identification of MYD88 L265P and CD79B Y196 mutations can be helpful not only for the accurate molecular diagnosis of PCNSL but also for the prediction of response to R-MPV.

Supplementary Material and Methods

Supplementary Table S1-S4

Isocitrate dehydrogenase-mutant low-grade gliomas (IDHmut-LGG) grow slowly but frequently undergo malignant transformation, which eventually leads to premature death. Chemotherapy and radiotherapy treatments prolong survival, but can also induce genetic (or epigenetic) alterations involved in transformation. Here, we developed a mathematical model of tumor progression based on serial tumor volume data and treatment history of 276 IDHmut-LGGs classified by chromosome 1p/19q codeletion (IDHmut/1p19qcodel and IDHmut/1p19qnoncodel) and performed genome-wide mutational analyses, including targeted sequencing and longitudinal whole-exome sequencing data. These analyses showed that tumor mutational burden correlated positively with malignant transformation rate, and chemotherapy and radiotherapy significantly suppressed tumor growth but increased malignant transformation rate per cell by 1.8 to 2.8 times compared with before treatment. This model revealed that prompt adjuvant chemoradiotherapy prolonged malignant transformation-free survival in small IDHmut-LGGs (≤ 50 cm3). Furthermore, optimal treatment differed according to genetic alterations for large IDHmut-LGGs (> 50 cm3); adjuvant therapies delayed malignant transformation in IDHmut/1p19qnoncodel but often accelerated it in IDHmut/1p19qcodel. Notably, PI3K mutation was not associated with malignant transformation but increased net postoperative proliferation rate and decreased malignant transformation-free survival, prompting the need for adjuvant therapy in IDHmut/1p19qcodel. Overall, this model uncovered therapeutic strategies that could prevent malignant transformation and, consequently, improve overall survival in patients with IDHmut-LGGs.Significance:A mathematical model successfully estimates malignant transformation-free survival and reveals a link between genetic alterations and progression, identifying precision medicine approaches for optimal treatment of IDH-mutant low-grade gliomas.

Supplementary Figures S1-S8

Portal vein thrombosis (PVT) after liver resection is rare but can lead to life-threatening liver failure. This prospective study evaluated patients using contrast-enhanced computed tomography (E-CT) on the first day after liver resection for early PVT detection and management.To evaluate patients by E-CT on the first day after liver resection for early PVT detection and immediate management.Patients who underwent liver resection for primary liver cancer from January 2015 were enrolled. E-CT was performed on the first day after surgery in patients undergoing anatomical resection, multiple resections, or with postoperative bile leakage in the high-risk group for PVT. When PVT was detected, anticoagulant therapy including heparin, warfarin, and edoxaban was administered. E-CT was performed monthly until PVT resolved.The overall incidence of PVT was 1.57% (8/508). E-CT was performed on the first day after surgery in 235 consecutive high-risk patients (165 anatomical resections, 74 multiple resections, and 28 bile leakages), with a PVT incidence of 3.4% (8/235). Symptomatic PVT was not observed in the excluded cohort. Multivariate analyses revealed that sectionectomy was the only independent predictor of PVT [odds ratio (OR) = 12.20; 95% confidence interval (CI): 2.22-115.97;Sectionectomy on the left side should be chosen with caution as it showed the highest risk of PVT. E-CT followed by anticoagulant therapy was effective in managing early-phase PVT for 2 mo without adverse events.

High dorsal resection (HDR) of the liver is a systematic resection technique for hepatocellular carcinoma (HCC) arising in the caudate lobe. HDR is rarely performed, as the procedure requires a high level of operative skill, knowledge of liver anatomy and is performed in patients with limited hepatic function. Between 2002 and 2012, we performed HDR on 9 patients. The median operation time was 534 min (range, 349–903 min), and the median blood loss volume was 430 mL (range, 94–4,530 mL). The severe morbidity rate was 11.1%, but there was no operative mortality, and the median hospitalization was 13 days (range, 8–93 days). The overall survival was 49.7 months (range, 3.1–89.0 months). Despite the hard-to-approach anatomic location, HDR can be carried out safely with good survival compared to other segments.

Background Recent comprehensive studies have revealed several molecular alterations that are frequently found in meningiomas. However, effective treatment reagents targeting specific molecular alterations have not yet been identified because of the limited number of representative research models of meningiomas. Methods We performed organoid cultures using meningioma cells and meningioma tumor tissues. Using immunohistochemistry and molecular analyses consisting of whole-exome sequencing, RNA-seq, and DNA methylation analyses, we compared the histological findings and molecular profiling of organoid models with those of parental tumors. Further, using these organoid models together with a public database of meningiomas, we explored molecular alterations, which are a potent treatment target for meningioma. Results We established 18 organoid models comprising of two malignant meningioma cells (HKBMM and IOMM-Lee), 10 benign meningiomas, four malignant meningiomas, and two solitary fibrous tumors (SFTs). The organoids exhibited consistent histological features and molecular profiles with those of the parental tumors. Using a public database, we identified that upregulated forkhead box M1 (FOXM1) was correlated with increased tumor proliferation. Overexpression of FOXM1 in benign meningioma organoids increased organoid proliferation; depletion of FOXM1 in malignant organoids decreased proliferation. Additionally, thiostrepton, a FOXM1 inhibitor combined with radiation therapy, significantly inhibited the proliferation of malignant meningioma organoid models. Conclusions An organoid model for meningioma enabled us to elucidate the tumor biology of meningioma along with potent treatment targets for meningioma.

Background Surgical indications for liver metastases from pancreatic ductal adenocarcinoma (PDAC) are lacking because outcomes are usually poor. However, liver resection and the recent progress in perioperative chemotherapy have been observed to improve survival. Methods We performed liver resection for liver metastases from PDAC only under the following criteria: (1) liver-only metastasis, (2) up to three tumors, and (3) no increase in the number of metastases during the 3-month observation period. No limitations were placed on the location or size of liver metastasis. In this study, we aimed to validate our surgical criteria and analyze factors affecting survival in patients with PDAC. Results Seventy-nine patients underwent curative resection for PDAC between 2005 and 2015. Seventy-one patients experienced recurrence, with liver-only recurrence in 17 patients. Among these, nine patients underwent liver resection and eight did not. The median survival time was significantly better for patients who underwent liver resection (55 months) than for those with other recurrences (17.5 months, p = 0.016). The median survival after liver recurrence was significantly better in the liver resection group (31 months) than in the non-liver resection group (7 months, p = 0.0008). The median disease-free interval (DFI) after pancreatectomy was significantly longer in the liver resection group (21 months; range, 3–44 months) than in the non-liver resection group (3 months; range, 2–7 months; p = 0.02). Conclusion Good indications for liver metastases from PDAC include solitary metachronous tumors and longer DFIs.

Blood loss is associated with the degree of damage in liver stiffness. Severe liver steatosis is a matter of concern in liver surgery, but does not correlate with liver stiffness. This study aimed to assess the relationship between blood perfusion of the liver and blood loss in liver pathologies. Data from elective liver resection for liver cancer were analyzed. All patients underwent preoperative assessments including perfusion CT. Patients were divided into 4 groups in accordance with the pathological background of liver parenchyma. Relationships between portal flow as assessed by perfusion CT and perioperative variables were compared. Factors correlating with blood loss were analyzed. In 166 patients, portal flow from perfusion CT correlated positively with platelet count and negatively with indocyanine green retention rate at 15 min. Background liver pathology was normal liver (NL) in 43 cases, chronic hepatitis (CH) in 56, liver cirrhosis (LC) in 42, and liver steatosis (LS) in 25. Rates of hepatitis viral infection and pathological hepatocellular carcinoma were more frequent in LC and CH groups than in the other groups (p < 0.05). LC and LS showed significantly worse liver function than the NL and CH groups. Portal flow from perfusion CT correlated positively with damage to liver parenchyma and negatively with blood loss at liver transection. Low portal flow on perfusion CT predicts blood loss during liver transection.

Subcuticular sutures reduce wound complication rates only in clean surgeries. Repeat resection is frequently required in liver surgery, due to the high recurrence rate (30–50%) of liver cancers. The aim of this study is to assess that subcuticular sutures is superior to staples in liver surgery. This single-centre, single-blinded, randomised controlled trial was conducted at a university hospital between January 2015 and October 2018. Patients were randomly assigned (1:1) to receive either subcuticular sutures or staples for skin closure. Three risk factors (repeat resection, diabetes mellitus and liver function) were matched preoperatively for equal allocation. The primary endpoint was the wound complication rate, while secondary endpoints were surgical site infection (SSI), duration of postoperative hospitalisation and total medical cost. Subset analyses were performed only for the 3 factors allocated as secondary endpoints. Of the 581 enrolled patients, 281 patients with subcuticular sutures and 283 patients with staples were analysed. As the primary outcome, the wound complication rate with subcuticular sutures (12.5%) did not differ from that with staples [15.9%; odds ratio (OR), 1.33; 95% confidence interval (CI), 0.83–2.15; p = 0.241]. As secondary outcomes, no significant differences were identified between the two procedures in the overall cohort while overall wound complications [7 patients (8.5%) vs. 17 patients (20.0%); OR, 2.68; 95% CI, 1.08–7.29; p = 0.035] with repeat incision were significantly less frequent with subcuticular sutures. Subcuticular sutures were not shown to reduce wound complications compared to staples in open liver resection, but appear beneficial for repeat incisions.

The surgical indications for liver metastasis from bile duct cancer remain contentious, because surgery is generally thought unlikely to improve survival. However, recent reports show that long-term survival has been achieved with liver resection of metastasis from recurrent bile duct cancer in selected patients. Liver resection for liver metastasis from bile duct cancer was proposed only when the following criteria were met: liver-only metastasis, a solitary tumor, and no increase in the number of lesions during 3 months of observation. This study aimed to validate our criteria and to analyze which factors impact on survival. Between 2003 and 2017, 164 patients underwent pathologically curative resection for bile duct cancer. Recurrence developed in 98 of these patients, as liver-only metastasis in 25. Eleven of these 25 patients underwent liver resection (liver resection group), and 14 did not (non-liver resection group). The median overall survival was longer in the liver resection group than in all the patients (44 months vs. 17.8 months, respectively p = 0.040). The median overall survival was better in the liver resection group than in the non-liver resection group (44 months vs. 19.9 months, p = 0.012). The disease-free interval was also significantly longer in the liver resection group than in the non-liver resection group [22 months (range; 4–34 months) vs. 3 months (2–11), p

AIM Platelet count seems to assess liver function and predict liver regeneration, but factors associated with liver regeneration remain unclear. This study analyzed the relationship between platelet recovery and postresection liver regeneration. METHODS Data from 343 candidates from 1245 consecutive patients with liver resection of more than Couinaud's segments were analyzed. Patients were divided into a low-platelet-recovery rate (LPRR) group (lowest 25%) or a control group on the basis of the platelet recovery rate on postoperative day (POD)7. Data were matched before analysis to adjust for operation scale. Trends in liver functional recovery were assessed, and liver volume recovery and remnant ischemic area was calculated using computed tomography volumetry. Factors predicting liver regeneration were analyzed. RESULTS In 78 matched-pair patients, the all-complications rate (42.3% vs. 26.9%, P = 0.002) and infectious complications rate (21.8% vs. 9.0%, P = 0.027) were significantly higher in the LPRR group than in controls. Trends in liver functional recovery did not differ significantly, whereas significant differences remained for platelet recovery. Parenchyma volume recovery was delayed in the LPRR group from POD7 (84.5% vs. 78.1, P

Diffuse midline glioma, H3 K27M-mutant is a lethal brain tumor located in the thalamus, brain stem, or spinal cord. H3 K27M encoded by the mutation of a histone H3 gene such as H3F3A plays a pivotal role in the tumorigenesis of this type of glioma. Although several studies have revealed comprehensive genetic and epigenetic profiling, the prognostic factors of these tumors have not been identified to date. In various cancers, oncogenic driver genes have been found to exhibit characteristic copy number alterations termed mutant allele specific imbalance (MASI). Here, we showed that several diffuse midline glioma, H3 K27M-mutant exhibited high variant allele frequency (VAF) of the mutated H3F3A gene using droplet digital polymerase chain reaction (ddPCR) assays. Whole-genome sequencing (WGS) revealed that these cases had various copy number alterations that affected the mutant and/or wild-type alleles of the H3F3A gene. We also found that these MASI cases showed a significantly higher Ki-67 index and poorer survival compared with those in the lower VAF cases (P H3F3A K27M mutation was associated with the aggressive phenotype of the diffuse midline glioma, H3 K27M-mutant via upregulation of the H3 K27M mutant protein, resulting in downregulation of H3K27me3 modification.

Obturator hernia (OH) is a relatively rare disease and there are various surgical procedures for treating it. We report the case of a patient with an OH who underwent laparoscopic-assisted modified Kugel herniorrhaphy. The patient was a 74-year-old woman admitted to our hospital with nausea and abdominal distension. A diagnosis of intestinal obstruction was made because abdominal computed tomography revealed incarcerated right OH. No apparent strangulation findings were observed, and reduction was performed under ultrasound guidance. Laparoscopic-assisted modified Kugel herniorrhaphy for OH was performed. There were no signs of the bowel necrosis. Pneumoperitoneum was temporarily discontinued, and the OH was repaired by the modified Kugel herniorrhaphy. Laparoscopy confirmed that the direct Kugel patch was placed at the appropriate position. Laparoscopic-assisted modified Kugel herniorrhaphy is considered to be safe and useful for patients with OH and is considered as one of the treatment options.

Engineered cartilage tissue from differentiated mesenchymal stem cells (MSCs) can generate bone in vivo through endochondral ossification (ECO). This ECO-mediated approach has the potential to circumvent the severe problems associated with conventional MSC-based bone tissue engineering techniques that lack mechanisms to induce angiogenesis. Hyaluronic acid (HA) is a key component in the cartilage extracellular matrix. However, the ECO-supporting properties of HA remain largely unclear. This study aimed to compare the ability of HA and collagen hydrogels to support in vitro differentiation of MSC-based hypertrophic cartilage tissues and to promote endochondral bone formation in vivo. Following the chondrogenic and hypertrophic differentiation in vitro, both HA and collagen constructs accumulated sulfated glycosaminoglycan (sGAG) and type 1, type II, and type X collagen. However, HA hydrogels exhibited a more uniform distribution of sGAG, type 1 collagen, type X collagen, and osteocalcin proteins; in addition, the cells embedded in the hydrogels had more rounded cell morphologies than those in the collagen constructs. At week 5 of in vitro culture, two to three constructs were implanted into a subcutaneous pocket in nude mice and harvested after 4 and 8 weeks. Both HA and collagen constructs promoted endochondral bone formation with vascularization and bone marrow development; however, the HA constructs fused to form integrated bone tissues and the bone marrow developed along the space between the two adhered grafts in all implanted pockets (n = 5). In the collagen constructs, the integration was observed in 40% of the pockets (n = 5). Microcomputer CT analysis revealed that the bone volume of HA constructs was larger than that of collagen constructs. In conclusion, compared to collagen hydrogels, HA hydrogels had superior potential to generate integrated bone with vascularization and bone marrow development. This study provides valuable insights for applying ECO-mediated bone tissue engineering approaches for the repair of critical-sized bone defects.

Although high-dose methotrexate (HD-MTX)-based chemotherapy, such as rituximab, HD-MTX, procarbazine and vincristine (R-MPV) regimen, has significantly prolonged the survival of patients with primary central nervous system lymphoma (PCNSL), predictive factors for response to R-MPV have not yet been investigated. Then, we investigated the correlation of MYD88 L265P and CD79B Y196 mutations, which are the most frequently found molecular alterations in PCNSL, with prognosis of patients with PCNSL treated with R-MPV. 47 and 21 patients with PCNSL treated with R-MPV and HD-MTX respectively were included, and correlation of their MYD88 and CD79B status with prognosis was analyzed. R-MPV achieved an excellent tumor control rate (61.6% and 69.9% of 5-year progression-free and overall survival rates, respectively). Among the 47 patients, 36 harbored MYD88 L265P or CD79B Y196 mutations. While the MYD88 L265P mutation had no significant effect on survival, patients with CD79B Y196 mutations exhibited prolonged survival (P < 0.05). However, the association of the CD79B Y196 mutation with a better prognosis was not observed in the HD-MTX cohort, which indicated that the CD79B Y196 mutation was a predictive marker for a favorable response to R-MPV. Furthermore, we established an all-in-one rapid genotyping system for these genetic mutations. This system enabled the detection of these genetic mutations in a small amount of biopsy samples within 90 min. In conclusion, we revealed that the CD79B Y196 mutation is associated with a good response to R-MPV, and the rapid and accurate genotyping system for MYD88 L265P and CD79B Y196 mutations that we developed in this study will enable reliable rapid molecular diagnosis and early prediction of response to R-MPV, which might help to determine the best treatment strategy for PCNSL.

Two-staged pancreatoduodenectomy with exteriorization of pancreatic juice is a safe procedure for high-risk patients. However, two-staged pancreatoduodenectomy requires complex re-laparotomy and adhesion removal. We analyzed whether using hyaluronate carboxymethylcellulose-based bioresorbable membrane (HCM) reduced the time required for the second operation and facilitated good fistula formation in two-staged pancreatoduodenectomy. Between April 2011 and December 2018, data were collected from 206 consecutive patients who underwent two-staged pancreatoduodenectomy. HCM has been used for all patients since 2015. Patients for whom HCM was used (HCM group; n = 61) were compared to historical controls (before 2015) without HCM (control group; n = 145) in terms of feasibility of the second operation (operation time, adhesion grade, and complications) and optimal granulation around the external tube at the second laparotomy. The HCM group showed significantly shorter median operation time [105 min (30–228 min) vs. 151 min (30–331 min); p

Despite curative resection, hepatocellular carcinoma (HCC) has a high probability of recurrence. We validated the potential role of liver resection (LR) for recurrent HCC. Patients with intrahepatic recurrence with up to three lesions were included. We compared survival times of patients undergoing their first LR to those of patients undergoing repeated LR. Then, survival times of the patients who had undergone LR and transcatheter chemoembolization (TACE) for recurrent HCC after propensity score matching were compared. After a median follow-up period of 3.1 years (range, 0.2–16.3), median overall survival times were 6.5 years (95% CI 6.0–7.0), 5.7 years (5.2–6.2), and 5.1 years (4.9–7.3) for the first LR (n = 1234), second LR (n = 273), and third LR (n = 90) groups, respectively. Severe complications frequently occurred in the first LR group (p = 0.059). Operative times were significantly longer for the third LR group (p = 0.012). After the first recurrence, median survival times after one-to-one pair matching were 5.7 years (95% CI 4.5–6.5) and 3.1 years (2.1–3.8) for the second LR group (n = 146) and TACE group (n = 146), respectively (p

Combined hepatocellular‐cholangiocarcinoma (cHCC‐CC) and intrahepatic cholangiocarcinoma (ICC) are classified into one category, but comparison of prognosis of the two carcinomas remains controversial. The aim of the current study was to investigate surgical outcomes for patients with ICC or cHCC‐CC who underwent resection in order to elucidate whether the classification of ICC and cHCC‐CC is justified. Subjects were 61 patients with ICC and 29 patients with cHCC‐CC who underwent liver resection from 2001 to 2017. Clinic‐pathological data from the two groups were compared. Tumor number and vascular invasion were independent risk factors for recurrence‐free survival (RFS) in both groups (P 5 cm vs ≤5 cm, 0.5 years vs 4.0 years, P = .003). For patients with cHCC‐CC, tumor cut‐off size of 2 cm showed statistical significance in median RFS (>2 cm vs ≤2 cm, 0.6 years vs 2.6 years, P = .038). The median RFS of patients with cHCC‐CC was 0.9 years (95% confidence interval: 0.3‐1.6), which was poorer than that of patients with ICC (1.3 years, 0.5‐2.1) (P = .028); the rate of RFS at 5 years was 0% and 37.7% respectively. Our study supports the concept of classifying ICC and cHCC‐CC into different categories because of a significant difference in RFS between the two., Our study supports the concept of classifying ICC and cHCC‐CC into different categories because of a significant difference in RFS between the two.

Liver resection is one of the main treatment strategies for liver malignancies. Mortality and morbidity of liver surgery has improved significantly with progress in selection criteria, development of operative procedures and improvements in perioperative management. Safe liver resection has thus become more available worldwide. We have identified four current topics related to liver resection (anatomical liver resection, laparoscopic liver resection, staged liver resection and chemotherapy‐induced liver injury). The balance between treatment effect and patient safety needs to be considered when planning liver resection. Progress in this area has been rapid thanks to the efforts of many surgeons, and outcomes have improved significantly as a result. These topics remain to be solved and more robust evidence is needed. Precise selection of the optimal procedure and risk evaluation should be standardized with further development of each topic. The present article reviews these four current topics with a focus on safety and efficacy in recent series.

Aim Although radiofrequency ablation (RFA) is an effective local treatment of hepatocellular carcinoma (HCC), local recurrence is relatively frequent. We aimed to elucidate the validity of salvage liver resection for recurrent HCC after RFA. Methods Patients who underwent liver resection for recurrent HCC after RFA (LR after RFA) and those who underwent second liver resection for recurrent HCC (second LR) were included. The short-term outcomes were compared between the two groups. The survival rates between the two groups were compared after propensity-score matching to adjust for the variables, including patient background, liver function, and tumor status. Results Major resection was frequently carried out in the LR after RFA group, but there was no significant difference both in operative data and complication rate between LR after RFA (n = 54) and second LR (n = 266) groups. After a median follow-up period of 1.8 years (range, 0.2-10.5), the median overall survival was 4.4 years (95% confidence interval [CI], 2.2 - not applicable) and 5.6 years (95% CI, 4.5-7.3; P = 0.023) in the LR after RFA group (n = 54) and second LR group (n = 54), respectively, and recurrence-free survival was 1.3 years (0.4-2.2) and 1.2 years (0.5-1.8, P = 0.469), respectively. The only independent factor for overall survival of the LR after RFA group was local recurrence (hazard ratio, 2.73; 1.06-9.00). Conclusions Salvage liver resection of recurrent HCC after RFA could be recommended due to the safety of the procedure, especially in patients without local tumor progression after RFA.

There are no accurate mass screening methods for early detection of central nervous system (CNS) tumors. Recently, liquid biopsy has received a lot of attention for less-invasive cancer screening. Unlike other cancers, CNS tumors require efforts to find biomarkers due to the blood–brain barrier, which restricts molecular exchange between the parenchyma and blood. Additionally, because a satisfactory way to collect urinary biomarkers is lacking, urine-based liquid biopsy has not been fully investigated despite the fact that it has some advantages compared to blood or cerebrospinal fluid-based biopsy. Here, we have developed a mass-producible and sterilizable nanowire-based device that can extract urinary microRNAs efficiently. Urinary microRNAs from patients with CNS tumors (n = 119) and noncancer individuals (n = 100) were analyzed using a microarray to yield comprehensive microRNA expression profiles. To clarify the origin of urinary microRNAs of patients with CNS tumors, glioblastoma organoids were generated. Glioblastoma organoid-derived differentially expressed microRNAs (DEMs) included 73.4% of the DEMs in urine of patients with parental tumors but included only 3.9% of those in urine of noncancer individuals, which suggested that many CNS tumor-derived microRNAs could be identified in urine directly. We constructed the diagnostic model based on the expression of the selected microRNAs and found that it was able to differentiate patients and noncancer individuals at a sensitivity and specificity of 100 and 97%, respectively, in an independent dataset. Our findings demonstrate that urinary microRNAs extracted with the nanowire device offer a well-fitted strategy for mass screening of CNS tumors.

Isocitrate dehydrogenase-mutant low-grade gliomas (IDHmut-LGG) grow slowly but frequently undergo malignant transformation, which eventually leads to premature death. Chemotherapy and radiotherapy treatments prolong survival, but can also induce genetic (or epigenetic) alterations involved in transformation. Here, we developed a mathematical model of tumor progression based on serial tumor volume data and treatment history of 276 IDHmut-LGGs classified by chromosome 1p/19q codeletion (IDHmut/1p19qcodel and IDHmut/1p19qnoncodel) and performed genome-wide mutational analyses, including targeted sequencing and longitudinal whole-exome sequencing data. These analyses showed that tumor mutational burden correlated positively with malignant transformation rate, and chemotherapy and radiotherapy significantly suppressed tumor growth but increased malignant transformation rate per cell by 1.8 to 2.8 times compared with before treatment. This model revealed that prompt adjuvant chemoradiotherapy prolonged malignant transformation-free survival in small IDHmut-LGGs (≤ 50 cm3). Furthermore, optimal treatment differed according to genetic alterations for large IDHmut-LGGs (> 50 cm3); adjuvant therapies delayed malignant transformation in IDHmut/1p19qnoncodel but often accelerated it in IDHmut/1p19qcodel. Notably, PI3K mutation was not associated with malignant transformation but increased net postoperative proliferation rate and decreased malignant transformation-free survival, prompting the need for adjuvant therapy in IDHmut/1p19qcodel. Overall, this model uncovered therapeutic strategies that could prevent malignant transformation and, consequently, improve overall survival in patients with IDHmut-LGGs. Significance: A mathematical model successfully estimates malignant transformation-free survival and reveals a link between genetic alterations and progression, identifying precision medicine approaches for optimal treatment of IDH-mutant low-grade gliomas.

Aim Hepatocellular adenoma (HCA) has a lower prevalence in Japan than in Western countries and HCA subtypes have been reported for only a few Japanese patients. We analyzed HCA subtype data 38 patients from 23 hospitals in Japan in order to examine character and difference between Western countries. Methods To confirm HCA and to analyze subtypes, we performed immunohistochemical examinations. Results Thirty-eight cases were found to have HCA without cirrhosis. The male/female ratio was 18/20. Ages ranged from 15 to 79 (average, 43.2) years. Male and elder patients are not rare, furthermore, most of elder patients are male. Glycogen storage disease, past history of medicament use, hepatitis B virus surface antigen-positivity, antihepatitis C virus -positivity, diabetes mellitus, obesity, lipid metabolism disorder and alcoholism were present in of 6, 8, 1, 1, 6, 6, 4, and 6 cases, respectively. As to HCA subtypes, HNF1alpha-inactivated HCA, beta-catenin activated HCA (b-HCA), inflammatory HCA (IHCA) and unclassified HCA (U-HCA) accounted for nine (23.7%), four (10.5%), 17 (44.7%) and eight (21.1%) cases, respectively. Two cases showed coexistence of HCA and hepatocellular carcinoma (HCC) at surgery, and another had HCC which had been detected 23 years after HCA diagnosis. The HCA subtype of one of the former cases was U-HCA, while the remaining two had b-HCA and U-HCA. Conclusions In Japanese HCA cases, the proportions of U-HCA, male and elder cases were slightly higher than in Western countries, and most of elder patients were male. IHCA was however common regardless of race, and was assumed to be the predominant subtype of HCA.

Liver stiffness measurement using magnetic resonance elastography can assess the severity of liver fibrosis, which is significantly associated with recurrence after curative resection for hepatocellular carcinoma. The aim of this prospective study was to investigate whether preoperative liver stiffness measurement by magnetic resonance elastograhy can predict recurrence after curative resection for hepatocellular carcinoma.Patients who underwent preoperative liver stiffness measurement and curative resection for hepatocellular carcinoma were enrolled in this study. Potential associations between liver stiffness measurement, along with other clinical and pathologic variables, and intrahepatic hepatocellular carcinoma recurrence were analyzed.In total, 156 patients were included in this study. During a median follow-up period of 25.1 months (range, 6.0-60.5 months), 72 (46.1%) patients with hepatocellular carcinoma had an intrahepatic recurrence. The median disease-free period after resection was 17.9 months (range, 1.0-60.5 months). In the multivariate analysis, liver stiffness measurement (hazard ratio, 1.27; 95% confidence interval, 1.11-1.43; P.001) and vascular invasion (hazard ratio, 1.96; 95% confidence interval, 1.15-3.25; P = .013) were identified as independent predictors of recurrence. When the optimal cutoff point was set at 4.53 kPa using the minimal P value approach, the disease-free period after curative resection in 71 patients with a liver stiffness measurement value ≥4.53 kPa (11.3 months [range, 2.0-60.5 months]) was significantly shorter than that of 85 patients with a liver stiffness measurement value4.53 kPa (22.5 months [range, 1.1-60.5 months]; P.001).Liver stiffness measurement using magnetic resonance elastography is a useful preoperative predictor of intrahepatic recurrence after curative resection for hepatocellular carcinoma.

Liver cancer frequently requires repeated liver resections due to the high recurrence rate. The aim of this study was to clarify whether subcuticular sutures reduce wound complication rates following repeat incisions. Data from 382 repeated liver resections in 1,245 consecutive patients were assessed. Patients were divided into a Subcuticular sutures group and a Skin staples group on the basis of the wound-closure method. To avoid bias in analysing wound complications, data were matched to adjust for patient background and operation variables. After matching, 82 matched, paired patients with subcuticular sutures or skin staples were compared. Total wound complication rate was significantly lower with subcuticular sutures than with skin staples (8.5% vs. 20.7%, p = 0.027). Incisional surgical site infection was also lower with subcuticular sutures than with skin staples (6.1% vs. 17.1, p = 0.028). Univariate analysis revealed 4 factors associated with wound complications: body mass index; serum albumin concentration; wound length; and closure with skin staples. Multivariate analysis revealed closure with skin staples (odds ratio, 2.91; 95% confidence interval, 1.07-7.94; p = 0.037) as the only independent factor negatively associated with wound complications. Subcuticular sutures appear to reduce wound complications compared to skin staples following repeat incision for liver resection.

This paper presents a case of critical anatomic variation in laparoscopic cholecystectomy, as an anterior segmental branch of segment V from the left hepatic artery passing anterior to the fundus of the gallbladder and coursing to the anterior hepatic segment. A 46-year-old man was admitted to our hospital complaining of hypochondralgia attributed to gallbladder stones. An aberrant artery crossed the ventral side of the neck of the gallbladder and ran into the right liver Glissonean sheath of segment V. During laparoscopic cholecystectomy, this artery was taped and exposed from proximal to distal ends, revealing an origin from the left hepatic artery with the vessel acting as the anterior branch of segment V to the liver. The cystic artery branching from the aberrant artery was found on the left side of the gallbladder. Laparoscopic cholecystectomy was performed with no injury to the hepatic arteries and the patient was discharged 3 days postoperatively. In general laparoscopic cholecystectomy, we expose only the area inside Calot’s triangle. With such an approach, this type of aberrant hepatic artery may be injured intraoperatively without consequences. Detailed preoperative evaluation using modalities such as 3-dimensional reconstruction of CT and knowledge of variations in the hepatic artery will help avoid vessel injury.

AIM Repeat resection for intrahepatic recurrent hepatocellular carcinoma (HCC) is effective for the long-term survival of patients; however, little is known about the surgical outcomes of extrahepatic nodules. The aim of this study is to investigate whether resection can contribute to the survival of patients with extrahepatic recurrent HCC. METHODS Under the conditions that intrahepatic recurrent HCC was absent or controlled by locoregional therapies, patients who had resectable extrahepatic recurrent HCC in the lymph nodes, adrenal gland, peritoneum, lung, or brain were included in this study. The survival of patients who did (Surgical group) and did not (Non-surgical group, underwent other therapies) undergo resection for extrahepatic recurrent HCC was compared. RESULTS Thirty-eight and 26 patients were included in the Surgical and Non-surgical groups, respectively. No patient had severe postoperative complications. After a median follow-up of 1.2 (range, 0.2-8.8) years, the median cumulative incidence of extrahepatic recurrent HCC was 1.2 years (95% confidence interval [CI], 0.4-3.5) in the Surgical group. The median overall survival was 5.3 (95% CI, 2.5-8.8) and 1.1 (0.8-2.3) years in the Surgical and Non-surgical groups, respectively (P

Background We have previously shown the value of next-generation des-r-carboxy prothrombin (NX-DCP) for predicting vascular invasion in hepatocellular carcinoma (HCC). Since conventional DCP is inaccurate under some conditions, this study aimed to assess whether NX-DCP immunohistochemical staining was related to vascular invasion in HCC. Methods Fifty-six patients scheduled to undergo resection for single HCC were divided into two groups, with and without pathological portal vein invasion. Immunohistochemical features of HCC and sites of vascular invasion were assessed using alpha-fetoprotein (AFP), conventional DCP, and NX-DCP. Results Pathological portal vein invasion was absent in 43 patients and present in 13 patients. Patient characteristics, pathological background of the liver parenchyma, and tumor-related factors did not differ significantly between the groups. There was no significant difference in the serum AFP level between the groups, whereas levels of conventional DCP (p p = 0.08), but NX-DCP stained significantly more at the sites of vascular invasion (15.4% vs. 46.2%, p = 0.01) than conventional DCP. No vascular invasion was stained by AFP. Conclusions NX-DCP offers better sensitivity for detecting sites of vascular invasion than AFP and conventional DCP.

Background The development of laparoscopic liver resection has led to the hypothesis that intraoperative blood loss may be a key indicator of surgical care quality. This study assessed short- and long-term results of patients according to three levels of intraoperative blood loss during laparoscopic liver resection for colorectal liver metastasis. Methods All patients who underwent laparoscopic liver resection for colorectal liver metastasis between 2000 and 2018 were included. Difficulty of laparoscopic liver resection was defined according to the Institut Mutualiste Montsouris classification. Three levels of the extent of intraoperative blood loss were defined: massive (≥1,000 mL), substantial (≥75th percentile of intraoperative blood loss within each grade of difficulty), and normal intraoperative blood loss. Results During study period, 317 patients underwent laparoscopic liver resection for colorectal liver metastasis. Among them, 213 (67.2%), 80 (25.2%), and 24 (7.6%) patients had normal, substantial, and massive intraoperative blood loss, respectively. Twenty-six patients (8.2%) required transfusion. Massive intraoperative blood loss came from a major hepatic vein in 54% of cases and were managed by laparoscopy in 83% of the cases. Laparoscopic liver resection difficulty grade (odds ratio = 3.15; P = .053) and number of colorectal liver metastasis (odds ratio = 1.24; P = .020) were independently associated with massive intraoperative blood loss. Risks factors for substantial intraoperative blood loss were bi-lobar colorectal liver metastasis (odds ratio = 3.12; P = .033) and sinusoidal obstruction syndrome (odds ratio = 3.27; P = .004). The level of intraoperative blood loss was not associated with severe complications nor overall and disease-free survival. Requirement of transfusion was associated with severe complications (odds ratio = 7.27; P = .002) and decreased 1-, 3-, and 5-year overall survival (87%, 68%, and 61% vs 95%, 88%, and 79%; P = .042). Conclusion The extent of intraoperative blood loss did not affect short- and long-term results of laparoscopic liver resection for colorectal liver metastasis. Massive intraoperative blood loss was often incidental and, 83% of the time, manageable by laparoscopy. Rather than intraoperative blood loss, transfusion is a better relevant indicator of laparoscopic liver resection surgical quality.

Background Surgical treatment for hepatocellular carcinoma (HCC) is advancing, but a robust prediction model for survival after resection is not available. The aim of this study was to propose a prognostic grading system for resection of HCC. Methods This was a retrospective, multicentre study of patients who underwent first resection of HCC with curative intent between 2000 and 2007. Patients were divided randomly by a cross-validation method into training and validation sets. Prognostic factors were identified using a Cox proportional hazards model. The predictive model was built by decision-tree analysis to define the resection grades, and subsequently validated. Results A total of 16 931 patients from 795 hospitals were included. In the training set (8465 patients), four surgical grades were classified based on prognosis: grade A1 (1236 patients, 14.6 per cent; single tumour 3 cm or smaller and anatomical R0 resection); grade A2 (3614, 42.7 per cent; single tumour larger than 3 cm, or non-anatomical R0 resection); grade B (2277, 26.9 per cent; multiple tumours, or vascular invasion, and R0 resection); and grade C (1338, 15.8 per cent; multiple tumours with vascular invasion and R0 resection, or R1 resection). Five-year survival rates were 73.9 per cent (hazard ratio (HR) 1.00), 64.7 per cent (HR 1.51, 95 per cent c.i. 1.29 to 1.78), 50.6 per cent (HR 2.53, 2.15 to 2.98), and 34.8 per cent (HR 4.60, 3.90 to 5.42) for grades A1, A2, B, and C respectively. In the validation set (8466 patients), the grades had equivalent reproducibility for both overall and recurrence-free survival (all P Conclusion This grade is used to predict prognosis of patients undergoing resection of HCC.

Biliary intraepithelial neoplasia (BilIN) was newly defined by the WHO in 2010 and is characterized by biliary cell atypia with an intraductal papillary lesion. It is always found in the major bile duct, but not in liver parenchyma. A 50-mm irregular tumor was detected in the paracaval portion of the hepatic caudate lobe of a 61-year-old man. He had undergone total gastrectomy for advanced gastric cancer 2 years earlier. The tumor had increased from 20 to 50 mm in the last 6 months. Abdominal CT showed an irregular hypo-enhanced tumor, with a honeycomb appearance inside the tumor. Diffusion-weighted MRI and PET showed that the tumor had malignant features, though no tumor markers were elevated. The tumor seemed to invade into the inferior vena cava (IVC) and hepatic veins. At operation, under side clamping of the IVC, a total of 10 cm of ventral side IVC was resected with the left liver. Pathologically, the tumor was an inflammatory pseudo-tumor that contained intermediate-grade BilIN of persistent liver parenchyma in the tumor. The honeycomb appearance within the tumor showed a causal relationship between the pathological and etiological representations of BilIN. Considering BilIN avoids an unnecessary operation when we encounter atypical imaging findings of liver tumors.