Isospin Pomeranchuk effect in twisted bilayer graphene.

In condensed-matter systems, higher temperatures typically disfavour ordered phases, leading to an upper critical temperature for magnetism, superconductivity and other phenomena. An exception is the Pomeranchuk effect in 3He, in which the liquid ground state freezes upon increasing the temperature1, owing to the large entropy of the paramagnetic solid phase. Here we show that a similar mechanism describes the finite-temperature dynamics of spin and valley isospins in magic-angle twisted bilayer graphene2. Notably, a resistivity peak appears at high temperatures near a superlattice filling factor of -1, despite no signs of a commensurate correlated phase appearing in the low-temperature limit. Tilted-field magnetotransport and thermodynamic measurements of the in-plane magnetic moment show that the resistivity peak is connected to a finite-field magnetic phase transition3 at which the system develops finite isospin polarization. These data are suggestive of a Pomeranchuk-type mechanism, in which the entropy of disordered isospin moments in the ferromagnetic phase stabilizes the phase relative to an isospin-unpolarized Fermi liquid phase at higher temperatures. We find the entropy, in units of Boltzmann's constant, to be of the order of unity per unit cell area, with a measurable fraction that is suppressed by an in-plane magnetic field consistent with a contribution from disordered spins. In contrast to 3He, however, no discontinuities are observed in the thermodynamic quantities across this transition. Our findings imply a small isospin stiffness4,5, with implications for the nature of finite-temperature electron transport6-8, as well as for the mechanisms underlying isospin ordering and superconductivity9,10 in twisted bilayer graphene and related systems.

A Unique Monitoring Method for Fecal and Sewage-Derived Chemical Pollution Utilizing International Pellet Watch Approach.

This study established a unique approach to assess fecal contamination by measuring fecal sterols, especially coprostanol (5ß-cholestanol-3ß-ol, 5ß) and cholestanol (5α-cholestan-3ß-ol, 5α) and their ratio 5ß/(5ß + 5α) alongside triclosan (TCS) and methyl-triclosan (MTC) in beached plastic pellets across 40 countries. Coprostanol concentrations ranged from 3.6 to 8190 ng/g pellet with extremely high levels in densely populated areas in African countries. The 5ß/(5ß + 5α) ratio was not affected by the difference in residence time of pellets in aquatic environments, and their spatial pattern showed a positive correlation with that of sedimentary sterols, demonstrating its reliability as an indicator of fecal contamination. Pellets from populated areas of economically developing countries, i.e., Africa and Asia, with lower coverage of wastewater treatment exhibited higher 5ß/(5ß + 5α) ratios (∼0.7) corresponding to ∼1% sewage in seawater, while pellets from developed countries, i.e., the USA, Canada, Japan, and Europe, with higher coverage of modern wastewater treatment displayed lower ratios (∼0.5), corresponding to the first contact limit. Triclosan levels were higher in developing countries (0.4-1298 ng/g pellet), whereas developed countries showed higher methyl-triclosan levels (0.5-70 ng/g pellet) due to TCS conversion during secondary treatment. However, some samples from Japan and Europe displayed higher TCS levels, suggesting contributions from combined sewage overflow (CSO). Combination of 5ß/(5ß + 5α) and MTC/TCS ratios revealed extreme fecal contamination from direct input of raw sewage due to inadequate treatment facilities in some African and South and Southeast Asian countries.

An exosome-based liquid biopsy signature for pre-operative identification of lymph node metastasis in patients with pathological high-risk T1 colorectal cancer.

BACKGROUND: According to current guidelines, more than 70% of patients with invasive submucosal colorectal cancer (T1 CRC) undergo a radical operation with lymph node dissection, even though only ~ 10% have lymph node metastasis (LNM). Hence, there is imperative to develop biomarkers that can help robustly identify LNM-positive patients to prevent such overtreatments. Given the emerging interest in exosomal cargo as a source for biomarker development in cancer, we examined the potential of exosomal miRNAs as LNM prediction biomarkers in T1 CRC. METHODS: We analyzed 200 patients with high-risk T1 CRC from two independent cohorts, including a training (n = 58) and a validation cohort (n = 142). Cell-free and exosomal RNAs from pre-operative serum were extracted, followed by quantitative reverse-transcription polymerase chain reactions for a panel of miRNAs. RESULTS: A panel of four miRNAs (miR-181b, miR-193b, miR-195, and miR-411) exhibited robust ability for detecting LNM in the exosomal vs. cell-free component. We subsequently established a cell-free and exosomal combination signature, successfully validated in two independent clinical cohorts (AUC, 0.84; 95% CI 0.70-0.98). Finally, we developed a risk-stratification model by including key pathological features, which reduced the false positive rates for LNM by 76% without missing any true LNM-positive patients. CONCLUSIONS: Our novel exosomal miRNA-based liquid biopsy signature robustly identifies T1 CRC patients at risk of LNM in a preoperative setting. This could be clinically transformative in reducing the significant overtreatment burden of this malignancy.

Association between high expression of intratumoral fibroblast activation protein and survival in patients with intrahepatic cholangiocarcinoma.

BACKGROUND: Cancer-associated fibroblasts (CAFs) have been reported to exhibit protumorigenic effects. Among the well-known CAF markers such as smooth muscle actin (SMA) and fibroblast activation protein (FAP), high expression of SMA in the peritumoral stroma has been reported to be a prognostic factor in various cancers. However, the effect of high FAP expression in intrahepatic cholangiocarcinoma (IHCC) has not been fully clarified. We evaluated the expression of CAF markers, focusing on FAP expression in the peripheral and intratumoral regions, to clarify the association with survival in patients with IHCC. METHODS: The study cohort comprised 37 patients who underwent curative resection for IHCC. The FAP expressions were evaluated in the peripheral and intratumoral regions of the resected tissues. Clinicopathological factors and survival outcomes were investigated between patients with high versus low FAP expression. Uni- and multivariate analyses were performed to identify the prognostic factors for overall survival and relapse-free survival. RESULTS: The median area percentages of FAP expression in the peripheral and intratumoral regions were 15.5% and 17.8%, respectively. High FAP expression in the intratumoral region was significantly associated with worse overall survival and disease-free survival than low FAP expression in the intratumoral region. Multivariate analysis identified high intratumoral FAP expression as a risk factor for worse overall survival (hazard ratio, 2.450; p = 0.049) and relapse-free survival (hazard ratio, 2.743; p = 0.034). CONCLUSIONS: High intratumoral FAP expression was associated with worse survival, suggesting that intratumoral FAP expression represents malignant progression in patients with IHCC.

Multiplication of tumor maximum diameter and number as a new surgical indicator for Barcelona Clinic Liver Cancer intermediate-stage hepatocellular carcinoma.

AIM: Recent advances in treatment modalities have been made, limiting the indication of hepatic resection in the treatment strategy for hepatocellular carcinoma (HCC) patients. This retrospective study investigated the significance of multiplication of tumor maximum diameter and number (MDN) as a surgical indicator for Barcelona Clinic Liver Cancer intermediate-stage HCC. METHODS: A total of 49 patients with Barcelona Clinic Liver Cancer intermediate-stage HCC who underwent curative hepatic resection between 2000 and 2020 were enrolled in this study. Prognostic factors of overall survival and disease-free survival, including the product of MDN, were analyzed. RESULTS: Patients with MDN >12 experienced significantly worse prognosis compared with those with MDN ≤12 (p = 0.0395), and 5-year overall survival rates after hepatic resection were 60.0% and 23.4%, respectively. Furthermore, the disease-free survival rate of patients with MDN >12 was significantly worse compared with those with MDN ≤12 (p = 0.0049), and all patients with MDN >12 experienced recurrence within 3 years after hepatic resection. In the multivariate analysis, MDN >12 was identified as the only independent prognostic factor of both overall survival and disease-free survival. In addition, patients with MDN >12 suffered from uncontrollable recurrence by locoregional treatment, such as more than four intrahepatic and extrahepatic recurrences, after hepatic resection. CONCLUSIONS: MDN index might be a new surgical indicator for Barcelona Clinic Liver Cancer intermediate-stage HCC, and influence clinical decision-making for individual treatment strategies.

Transanal lateral lymph node dissection with intraoperative hologram support in low rectal cancer.

BACKGROUND: In Japan, the standard treatment for stage II/III advanced low rectal cancer is total mesorectal excision plus lateral lymph node dissection (LLND). There are also recent reports on the use of transanal LLND. However, the transanal anatomy is difficult to understand, and additional support tools are required to improve the surgical safety. The present study examined the utility of holograms with mixed reality as an intraoperative support tool for assessing the complex pelvic anatomy. METHODS: Polygon (stereolithography) files of patients' pelvic organs were created and exported from the SYNAPSE VINCENT imaging system and uploaded into the Holoeyes MD virtual reality software. Three-dimensional images were automatically converted into patient-specific holograms. Each hologram was then installed into a head mount display (HoloLens2), and the surgeons and assistants wore the HoloLens2 when they performed transanal LLND. Twelve digestive surgeons with prior practice in hologram manipulation evaluated the utility of the intraoperative hologram support by means of a questionnaire. RESULTS: Intraoperative hologram support improved the surgical understanding of the lateral lymph node region anatomy. In the questionnaire, 75% of the surgeons answered that the hologram accurately reflected the anatomy, and 92% of the surgeons answered that the anatomy was better understood by simulating the hologram intraoperatively than preoperatively. Moreover, 92% of the surgeons agreed that intraoperative holograms were a useful support tool for improving the surgical safety. CONCLUSIONS: Intraoperative hologram support improved the surgical understanding of the pelvic anatomy for transanal LLND. Intraoperative holograms may represent a next-generation surgical tool for transanal LLND.

Preoperative Weight Loss Program for Hepatocellular Carcinoma Patients with High Body Mass Index in Hepatectomy.

BACKGROUND: This study aimed to investigate the usefulness of a weight-loss program (WLP) in patients with a high body mass index (BMI) prior to liver resection (Hx) for hepatocellular carcinoma (HCC). METHODS: Among 445 patients with HCC who underwent initial Hx between 2000 and 2020, 19 with a high BMI (≥25.0) were enrolled in our WLP since 2014. For calorie restriction, the amount of energy consumed was calculated as the standard body weight (SBW) kg × 20-25 kcal/day. Protein mass was calculated as SBW kg × 1.0-1.2 g/day to maintain skeletal muscle mass. Patients also performed both aerobic and resistance exercises. The before-and-after changes were compared, and the effect of WLP on the short- and long-term results was investigated. RESULTS: The average length of WLP was 21 days, and weight loss was successfully achieved in all patients. Body fat mass was reduced during the program, while skeletal muscle mass was maintained. WLP led to improvements in liver function and fibrotic markers, without tumor progression. There were no postoperative complications (≥Clavien-Dindo [CD] III). A retrospective comparison between with and without WLP using propensity score-matching analysis revealed that WLP group showed better NLR value, however, there were no significant differences in both short and long-term outcomes after Hx based on participation in the WLP. CONCLUSIONS: WLP with multidisciplinary intervention improved immune-nutrition status and liver function of obese patients. WLP had not affected both short and long-term outcomes after Hx.

Impact of apparent diffusion coefficient on prognosis of early hepatocellular carcinoma: a case control study.

BACKGROUND: We investigated the usefulness of apparent diffusion coefficients (ADC) from diffusion-weighted images (DWI) obtained using magnetic resonance imaging (MRI) for prognosis of early hepatocellular carcinoma (HCC): Barcelona Clinic Liver Cancer (BCLC) stage 0 and A. METHODS: We enrolled 102 patients who had undergone surgical resection for early HCC: BCLC stage 0 and A, and calculated their minimum ADC using DWI-MRI. We divided patients into ADCHigh (n = 72) and ADCLow (n = 30) groups, and compared clinicopathological factors between the two groups. RESULTS: The ADCLow group showed higher protein induced by vitamin K absence-II (PIVKA-II) levels (p = 0.02) compared with the ADCHigh group. In overall survival, the ADCLow group showed significantly worse prognosis than the ADCHigh group (p < 0.01). Univariate analysis identified multiple tumors, infiltrative growth, high PIVKA-II, and low ADC value as prognostic factors. Multivariate analysis identified infiltrative growth and low ADC value as an independent prognostic factor. CONCLUSION: ADC values can be used to estimate the prognosis of early HCC.

Clinical impact of myosteatosis measured by magnetic resonance imaging on long-term outcomes of hepatocellular carcinoma after radical hepatectomy.

AIMS: A variety of factors have been reported to affect long-term outcomes after radical resection of hepatocellular carcinoma (HCC). However, the indicators remain controversial. The purpose of this study was to evaluate the relationship between myosteatosis of the multifidus muscle and long-term outcomes after radical surgery for HCC. METHODS: We retrospectively analyzed clinicopathological data for 187 patients with HCC who underwent radical surgery at Tokushima University between January 2009 and December 2020 and measured the density of fat in the multifidus muscle at L3 on their preoperative magnetic resonance images (MRI). Associations of myosteatosis and clinicopathological factors with long-term outcomes were evaluated. RESULTS: The patients were divided into a myosteatosis-negative group (n = 122) and a myosteatosis-positive group (n = 65). The cancer-specific survival rate after hepatectomy was significantly worse in the myosteatosis-positive group than in the myosteatosis-negative group (p = 0.03). Univariate analysis identified multiple tumors, stage III/IV disease, an alfa-fetoprotein level ≥ 10 ng/ml, PIVKA-II ≥ 400 AU/ml, vp(+) status, and myosteatosis to be prognostic factors for cancer-specific survival. Multivariate analysis revealed multiple tumors, an alfa-fetoprotein level ≥ 10 ng/ml, and myosteatosis to be independent prognostic factors. CONCLUSIONS: Myosteatosis measured by MRI is a simple and useful predictor of the long-term outcome after radical surgery for HCC.

A blood-based noninvasive miRNA signature for predicting survival outcomes in patients with intrahepatic cholangiocarcinoma.

BACKGROUND: The prognosis in patients with intrahepatic cholangiocarcinoma (ICC) is generally poor. To improve treatment selection, we sought to identify microRNA (miRNA) signature associated with survival outcomes in ICC. METHODS: We first analysed the miRNA expression profiles of primary ICC from two public datasets to identify a miRNA panel to detect patients for short-term survival. We then analysed 309 specimens, including 241 FFPE samples from two clinical cohorts (training: n = 177; validation: n = 64) and matched plasma samples (n = 68), and developed a risk-stratification model incorporating the panel and CA 19-9 levels to predict survival outcomes in ICC. RESULTS: We identified a 7-miRNA panel that robustly classified patients with poor outcomes in the discovery cohorts (AUC = 0.80 and 0.88, respectively). We subsequently trained this miRNA panel in a clinical cohort (AUC = 0.83) and evaluated its performance in an independent validation cohort (AUC = 0.82) and plasma samples from the additional validation cohort (AUC = 0.78). Patients in both clinical cohorts who were classified as high-risk had significantly worse prognosis (p < 0.01). The risk-stratification model demonstrated superior performance compared to models (AUC = 0.85). CONCLUSIONS: We established a novel miRNA signature that could robustly predict survival outcomes in resected tissues and liquid biopsies to improve the clinical management of patients with ICC.

A Liquid Biopsy Assay for Noninvasive Identification of Lymph Node Metastases in T1 Colorectal Cancer.

BACKGROUND & AIMS: We recently reported use of tissue-based transcriptomic biomarkers (microRNA [miRNA] or messenger RNA [mRNA]) for identification of lymph node metastasis (LNM) in patients with invasive submucosal colorectal cancers (T1 CRC). In this study, we translated our tissue-based biomarkers into a blood-based liquid biopsy assay for noninvasive detection of LNM in patients with high-risk T1 CRC. METHODS: We analyzed 330 specimens from patients with high-risk T1 CRC, which included 188 serum samples from 2 clinical cohorts-a training cohort (N = 46) and a validation cohort (N = 142)-and matched formalin-fixed paraffin-embedded samples (N = 142). We performed quantitative reverse-transcription polymerase chain reaction, followed by logistic regression analysis, to develop an integrated transcriptomic panel and establish a risk-stratification model combined with clinical risk factors. RESULTS: We used comprehensive expression profiling of a training cohort of LNM-positive and LMN-negative serum specimens to identify an optimized transcriptomic panel of 4 miRNAs (miR-181b, miR-193b, miR-195, and miR-411) and 5 mRNAs (AMT, forkhead box A1 [FOXA1], polymeric immunoglobulin receptor [PIGR], matrix metalloproteinase 1 [MMP1], and matrix metalloproteinase 9 [MMP9]), which robustly identified patients with LNM (area under the curve [AUC], 0.86; 95% confidence interval [CI], 0.72-0.94). We validated panel performance in an independent validation cohort (AUC, 0.82; 95% CI, 0.74-0.88). Our risk-stratification model was more accurate than the panel and an independent predictor for identification of LNM (AUC, 0.90; univariate: odds ratio [OR], 37.17; 95% CI, 4.48-308.35; P < .001; multivariate: OR, 17.28; 95% CI, 1.82-164.07; P = .013). The model limited potential overtreatment to only 18% of all patients, which is dramatically superior to pathologic features that are currently used (92%). CONCLUSIONS: A novel risk-stratification model for noninvasive identification of T1 CRC has the potential to avoid unnecessary operations for patients classified as high-risk by conventional risk-classification criteria.

A Transcriptomic Signature for Risk-Stratification and Recurrence Prediction in Intrahepatic Cholangiocarcinoma.

BACKGROUND AND AIMS: Tumor recurrence is frequent even in intrahepatic cholangiocarcinoma (ICC), and improved strategies are needed to identify patients at highest risk for such recurrence. We performed genome-wide expression profile analyses to discover and validate a gene signature associated with recurrence in patients with ICC. APPROACH AND RESULTS: For biomarker discovery, we analyzed genome-wide transcriptomic profiling in ICC tumors from two public data sets: The Cancer Genome Atlas (n = 27) and GSE107943 (n = 28). We identified an eight-gene panel (BIRC5 [baculoviral IAP repeat containing 5], CDC20 [cell division cycle 20], CDH2 [cadherin 2], CENPW [centromere protein W], JPH1 [junctophilin 1], MAD2L1 [mitotic arrest deficient 2 like 1], NEIL3 [Nei like DNA glycosylase 3], and POC1A [POC1 centriolar protein A]) that robustly identified patients with recurrence in the discovery (AUC = 0.92) and in silico validation cohorts (AUC = 0.91). We next analyzed 241 specimens from patients with ICC (training cohort, n = 64; validation cohort, n = 177), followed by Cox proportional hazard regression analysis, to develop an integrated transcriptomic panel and establish a risk-stratification model for recurrence in ICC. We subsequently trained this transcriptomic panel in a clinical cohort (AUC = 0.89; 95% confidence interval [CI] = 0.79-0.95), followed by evaluating its performance in an independent validation cohort (AUC = 0.86; 95% CI = 0.80-0.90). By combining our transcriptomic panel with various clinicopathologic features, we established a risk-stratification model that was significantly superior for the identification of recurrence (AUC = 0.89; univariate HR = 6.08, 95% CI = 3.55-10.41, P < 0.01; and multivariate HR = 3.49, 95% CI = 1.81-6.71, P < 0.01). The risk-stratification model identified potential recurrence in 85% of high-risk patients and nonrecurrence in 76% of low-risk patients, which is dramatically superior to currently used pathological features. CONCLUSIONS: We report a transcriptomic signature for risk-stratification and recurrence prediction that is superior to currently used clinicopathological features in patients with ICC.

Objectively Measured Intensity-specific Physical Activity and Hippocampal Volume Among Community-dwelling Older Adults.

BACKGROUND: The hippocampus is a brain structure important for memory and cognitive function. Physical activity may help prevent hippocampal atrophy. However, few studies have measured sedentary behavior (SB) and intensity-specific physical activity using an accelerometer. This study aimed to examine the cross-sectional associations of objectively-determined SB, light-intensity physical activity (LPA), and moderate-to-vigorous physical activity (MVPA) measured by an accelerometer with hippocampal volume among community-dwelling older adults using compositional data analysis (CoDa) approach. METHODS: This cross-sectional study was part of the Neuron to Environmental Impact across Generations (NEIGE) study. A randomly recruited sample of 485 Japanese older adults (47% male; aged 65-84 years) wore tri-axial accelerometers (Omron Healthcare) for 7 consecutive days in 2017. Hippocampal volume was measured with magnetic resonance imaging and the left and right hippocampal volumes were automatically segmented using FreeSurfer software. Associations of sedentary and physically active behaviors with hippocampal volume were examined with compositional linear regression analysis based on isometric log-ratio transformations of time use adjusted for potential confounding factors. RESULTS: The relative proportion of time spent in MVPA, compared to the other two activities, was significantly positively associated with right hippocampal volume (ß: 57.1, P-value = 0.027). However, no association existed between higher proportions of MVPA and left hippocampal volume, or between proportions of SB or LPA with either left or right hippocampal volumes. CONCLUSION: The proportion of time spent in MVPA, relative to the other two activities, was significantly positively associated with right hippocampal volume. MVPA may be beneficial for maintaining hippocampal volume.

Intraoperative support with three-dimensional holographic cholangiography in hepatobiliary surgery.

PURPOSE: This study was performed to investigate the potential of intraoperative three-dimensional (3D) holographic cholangiography, which provides a computer graphics model of the biliary tract, with mixed reality techniques. METHODS: Two patients with intraductal papillary neoplasm of the bile duct were enrolled in the study. Intraoperative 3D cholangiography was performed in a hybrid operating room. Three-dimensional polygon data using the acquired cholangiography data were installed into a head mount display (HoloLens; Microsoft Corporation, Redmond, WA, USA). RESULTS: Upon completion of intraoperative 3D cholangiography, a hologram was immediately and successfully made in the operating room using the acquired cholangiography data, and several surgeons wearing the HoloLens succeeded in sharing the same hologram. Compared with usual two-dimensional cholangiography, this 3D holographic cholangiography technique contributed to more accurate reappearance of the bile ducts, especially the B1 origination site, and moving the hologram from the respective operators' angles by means of easy gesture-handling without any monitors. CONCLUSION: Intraoperative 3D holographic cholangiography might be a new next-generation operation-support tool in terms of immediacy, accurate anatomical reappearance, and ease of handling.

Intraoperative holographic image-guided surgery in a transanal approach for rectal cancer.

PURPOSE: Urethral injury is one of the most important complications in transanal total mesorectal excision (TaTME) in male patients with rectal cancer. The purpose of this study was to investigate holographic image-guided surgery in TaTME. METHODS: Polygon (stereolithography) files were created and exported from SYNAPSE VINCENT, and then uploaded into the Holoeyes MD system (Holoeyes Inc., Tokyo, Japan). After uploading the data, the three-dimensional image was automatically converted into a case-specific hologram. The hologram was then installed into the head mount display, HoloLens (Microsoft Corporation, Redmond, WA). The surgeons and assistants wore the HoloLens when they performed TaTME. RESULTS: In a Wi-Fi-enabled operating room, each surgeon, wearing a HoloLens, shared the same hologram and succeeded in adjusting the hologram by making simple hand gestures from their respective angles. The hologram contributed to better comprehension of the positional relationships between the urethra and the surrounding pelvic organs during surgery. All surgeons were able to properly determine the dissection line. CONCLUSIONS: This first experience suggests that intraoperative holograms contributed to reducing the risk of urethral injury and understanding transanal anatomy. Intraoperative holograms have the potential to become a new next-generation surgical support tool for use in spatial awareness and the sharing of information between surgeons.

The BAFF/NFκB axis is crucial to interactions between sorafenib-resistant HCC cells and cancer-associated fibroblasts.

The tumor microenvironment affects malignancy in hepatocellular carcinoma (HCC) cells, and cancer-associated fibroblasts (CAFs) play an important role in the microenvironment. As recent studies indicated a difference between CAFs isolated from chemoresistant and non-resistant cancer tissues, therefore we investigated the intracellular mechanism in resistant HCC co-cultured CAFs and interactions between these CAFs with cancer cells. We established a sorafenib-resistant (SR) Huh7 (human HCC) cell line, and characterized it with cytokine assays, then developed CAFs by co-culturing human hepatic stellate cells with resistant or parental Huh7 cells. The 2 types of CAFs were co-cultured with parental Huh7 cells, thereafter the cell viability of these Huh7 cells was checked under sorafenib treatment. The SR Huh7 (Huh7SR ) cells expressed increased B-cell activating factor (BAFF), which promoted high expression of CAF-specific markers in Huh7SR -co-cultured CAFs, showed activated BAFF, BAFF-R, and downstream of the NFκB-Nrf2 pathway, and aggravated invasion, migration, and drug resistance in co-cultured Huh7 cells. When we knocked down BAFF expression in Huh7SR cells, the previously increased malignancy and BAFF/NFκB axis in Huh7SR -co-cultured CAFs reversed, and enhanced chemoresistance in co-cultured Huh7 cells returned as well. In conclusion, the BAFF/NFκB pathway was activated in CAFs co-cultured with cell-culture medium from resistant Huh7, which promoted chemoresistance, and increased the malignancy in co-cultured non-resistant Huh7 cells. This suggests that the BAFF/NFκB axis in CAFs might be a potential therapeutic target in chemoresistance of HCC.

Significance of Frailty in Prognosis After Hepatectomy for Elderly Patients with Hepatocellular Carcinoma.

BACKGROUND: The concept of frailty becomes important for patients who undergo surgery in this recent aging society. The aim of this study is to investigate the frailty as a prognostic factor in elderly patients with hepatocellular carcinoma (HCC) who underwent hepatectomy. PATIENTS AND METHODS: A total of 92 patients over 75 years old who underwent hepatectomy were enrolled in this study. Frailty was defined as clinical frailty scale (CFS) ≥ 4. Patients were divided into two groups, i.e., frailty group (n = 21) and no-frailty group (n = 71), and clinicopathological features were compared between them. RESULTS: The frailty group showed significant higher PIVKA-II level and larger tumor diameter (p < 0.05). CRP level and modified Glasgow prognostic score were significantly higher in the frailty group (p < 0.05). The frailty group showed higher rate of postoperative complications of Clavien-Dindo III (p = 0.06) and longer postoperative stay (p = 0.08). Cancer-specific, overall, and disease-free survival rates were significantly worse in the frailty group (p < 0.05). Frailty was detected as an independent prognostic factor on multivariate analysis of cancer-specific survival. CONCLUSION: Frailty can estimate the prognosis of HCC patients who underwent hepatectomy.

Stromal tumor-infiltrating lymphocytes level as a prognostic factor for resected intrahepatic cholangiocarcinoma and its prediction by apparent diffusion coefficient.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) are a prognostic factor or an indicator of chemotherapy response for various malignancies. The aim of this study was to investigate the prognostic impact of TILs in resected intrahepatic cholangiocarcinoma (IHCC). We also investigated the usefulness of the apparent diffusion coefficient (ADC) in diffusion-weighted magnetic resonance imaging (DW-MRI) to predict TILs. METHODS: We enrolled 23 patients with IHCC who underwent initial hepatic resection in Tokushima University Hospital from 2006 to 2017. We evaluated stromal TILs in the tumor marginal area and central area in surgical specimens. Patients were divided into low vs high stromal TILs groups. We analyzed the patients' clinicopathological factors, including prognosis, according to the degree of stromal TILs. We also analyzed the correlation between stromal TILs and the minimum ADC value. RESULTS: Stromal TILs in the marginal area reflected overall survival more accurately than that in the central area. Additionally, marginal low TILs was significantly associated with lymph node metastasis and portal vein invasion. Both overall- and disease-free survival rates in the marginal low TILs group were significantly worse than those in the marginal high TILs group (P < 0.05). In the multivariate analysis, marginal low TILs were an independent prognostic factor for both overall- and disease-free survival (P < 0.05), and marginal low TILs were significantly associated with lower minimum ADC values (P < 0.02). CONCLUSIONS: Stromal TILs, especially in the marginal area, might demonstrate prognostic impact in patients with IHCC. Moreover, the ADC values from MRI may predict TILs in IHCC tumor tissue.

Significance of frailty in prognosis after surgery in patients with pancreatic ductal adenocarcinoma.

BACKGROUND: Frailty is an important consideration for older patients undergoing surgery. We aimed to investigate whether frailty could be a prognostic factor in patients with pancreatic ductal adenocarcinoma who underwent pancreatic resection. METHODS: One hundred and twenty patients who underwent pancreatic resection for pancreatic ductal adenocarcinoma were enrolled. Frailty was defined as a clinical frailty scale score ≥4. Patients were divided into frailty (n = 29) and non-frailty (n=91) groups, and clinicopathological factors were compared between the two groups. RESULTS: The frailty group showed an older age, lower serum albumin concentration, lower prognostic nutritional index, larger tumor diameter, and higher rate of lymph node metastasis than the non-frailty group (p < 0.05). Neutrophil-lymphocyte ratio and modified Glasgow prognostic score tended to be higher in the frailty group. Cancer-specific and disease-free survival rates were significantly poor in the frailty group (p < 0.05). With a multivariate analysis, frailty was an independent prognostic factor of cancer-specific survival. CONCLUSIONS: Frailty can predict the prognosis of patients with pancreatic ductal adenocarcinoma who undergo pancreatic resection.

A new pathological classification of intrahepatic cholangiocarcinoma according to protein expression of SSTR2 and Bcl2.

BACKGROUND: No universal classification method for intrahepatic cholangiocarcinoma (IHCC) has been reported based on the embryological origin of biliary epithelial cells. The aim of this study was to classify IHCC according to protein expression levels of somatostatin receptor 2 (SSTR2) and b-cell leukemia/lymphoma 2 (Bcl2) and to elucidate the clinicopathological features of each group. METHODS: Fifty-two IHCC patients who underwent hepatic resection were enrolled in this study. Protein expression levels of SSTR2 and Bcl2 were examined using immunohistochemistry. Clinicopathological factors were compared between the three groups and prognostic factors were investigated. RESULTS: The patients were divided into three groups: SSTR2 positive and Bcl2 negative (p-Group H, n = 21), SSTR2 negative and Bcl2 positive (p-Group P, n = 14), and the indeterminate group (p-Group U, n = 17) for cases where SSTR2 and Bcl2 were both positive or both negative. All p-Group P cases displayed curability A or B. The 5-year survival rates of p-Group H and U patients were worse than those in p-Group P. p-Group H had higher T-factor, clinical stage, and incidence of periductal infiltration than p-Group P. CONCLUSIONS: This method could be used to classify IHCC into peripheral and perihilar type by embryological expression patterns of SSTR2 and Bcl2.