Integrated analyses of the genetic and clinicopathological features of cholangiolocarcinoma: cholangiolocarcinoma may be characterized by mismatch-repair deficiency.

Cholangiolocarcinoma (CLC) is a primary liver carcinoma that resembles the canals of Hering and that has been reported to be associated with stem cell features. Due to its rarity, the nature of CLC remains unclear, and its pathological classification remains controversial. To clarify the positioning of CLC in primary liver cancers and identify characteristics that could distinguish CLC from other liver cancers, we performed integrated analyses using whole-exome sequencing (WES), immunohistochemistry, and a retrospective review of clinical information on eight CLC cases and two cases of recurrent CLC. WES demonstrated that CLC includes IDH1 and BAP1 mutations, which are characteristic of intrahepatic cholangiocarcinoma (iCCA). A mutational signature analysis showed a pattern similar to that of iCCA, which was different from that of hepatocellular carcinoma (HCC). CLC cells, including CK7, CK19, and EpCAM, were positive for cholangiocytic differentiation markers. However, the hepatocytic differentiation marker AFP and stem cell marker SALL4 were completely negative. The immunostaining patterns of CLC with CD56 and epithelial membrane antigen were similar to those of the noncancerous bile ductules. In contrast, mutational signature cluster analyses revealed that CLC formed a cluster associated with mismatch-repair deficiency (dMMR), which was separate from iCCA. Therefore, to evaluate MMR status, we performed immunostaining of four MMR proteins (PMS2, MSH6, MLH1, and MSH2) and detected dMMR in almost all CLCs. In conclusion, CLC had highly similar characteristics to iCCA but not to HCC. CLC can be categorized as a subtype of iCCA. In contrast, CLC has characteristics of dMMR tumors that are not found in iCCA, suggesting that it should be treated distinctly from iCCA. © 2024 The Pathological Society of Great Britain and Ireland.

Identification of gravity-responsive serum proteins in spaceflight mice using a quantitative proteomic approach with data-independent acquisition mass spectrometry.

Physical inactivity associated with gravity unloading, such as microgravity during spaceflight and hindlimb unloading (HU), can cause various physiological changes. In this study, we attempted to identify serum proteins whose levels fluctuated in response to gravity unloading. First, we quantitatively assessed changes in the serum proteome profiles of spaceflight mice using mass spectrometry with data-independent acquisition. The serum levels of several proteins involved in the responses to estrogen and glucocorticoid, blood vessel maturation, osteoblast differentiation, and ossification were changed by microgravity exposure. Furthermore, a collective evaluation of serum proteomic data from spaceflight and HU mice identified 30 serum proteins, including Mmp2, Igfbp2, Tnc, Cdh5, and Pmel, whose levels varied to a similar extent in both gravity unloading models. These changes in serum levels could be involved in the physiological changes induced by gravity unloading. A collective evaluation of serum, femur, and soleus muscle proteome data of spaceflight mice also showed 24 serum proteins, including Igfbp5, Igfbp3, and Postn, whose levels could be associated with biological changes induced by microgravity. This study examined serum proteome profiles in response to gravity unloading, and may help deepen our understanding of microgravity adaptation mechanisms during prolonged spaceflight missions.

Changes in the astronaut serum proteome during prolonged spaceflight.

The molecular mechanisms associated with spaceflight-induced biological adaptations that may affect many healthy tissue functions remain poorly understood. In this study, we analyzed temporal changes in the serum proteome of six astronauts during prolonged spaceflight missions using quantitative comprehensive proteome analysis performed with the data-independent acquisition method of mass spectrometry (DIA-MS). All six astronauts participated in a spaceflight mission for approximately 6 months and showed a decreasing trend in T-scores at almost all sites where dual-energy X-ray absorptiometry scans were performed. DIA-MS successfully identified 624 nonredundant proteins in sera and further quantitative analysis for each sampling point provided information on serum protein profiles closely related to several time points before (pre-), during (in-), and after (post-) spaceflight. Changes in serum protein levels between spaceflight and on the ground suggest that abnormalities in bone metabolism are induced in astronauts during spaceflight. Furthermore, changes in the proteomic profile occurring during spaceflight suggest that serum levels of bone metabolism-related proteins, namely ALPL, COL1A1, SPP1, and POSTN, could serve as highly responsive indicators of bone metabolism status in spaceflight missions. This study will allow us to accelerate research to improve our understanding of the molecular mechanisms of biological adaptations associated with prolonged spaceflight.

On the origin of gastric tumours: analysis of a case with intramucosal gastric carcinoma and oxyntic gland adenoma.

Most gastric cancers develop in inflamed gastric mucosa due to Helicobacter pylori infection, typically with metaplastic changes. However, the origins of gastric cancer remain unknown. Here, we present a case of intramucosal gastric carcinoma (IGC) and oxyntic gland adenoma (OGA) derived from spasmolytic polypeptide-expressing metaplasia (SPEM). Early gastric cancer adjacent to a polyp was found in the upper corpus of a 71-year-old woman without H. pylori infection and was endoscopically resected. Histological examination showed IGC and OGA, both of which had predominant MUC6 expression. Interestingly, gastric glands with enriched MUC6-positive mucous cells, referred to as SPEM, expanded between them. Whole-exome sequencing analysis revealed a truncating KRAS(G12D) mutation in IGC, OGA, and SPEM. In addition, TP53 and CDKN2A mutations and a loss of chromosome 17p were found in the IGC, whereas a GNAS mutation was observed in the OGA. These results indicated that IGC and OGA originated from the KRAS-mutated SPEM. © 2023 The Pathological Society of Great Britain and Ireland.

Comprehensive analyses of the clinicopathological features and genomic mutations of combined hepatocellular-cholangiocarcinoma.

AIM: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer that has two different tumor phenotypes in a single tumor nodule. The relationship between genetic mutations and clinicopathological features of cHCC-CCA remains to be elucidated. METHODS: Whole-exome sequencing analyses were carried out in 13 primary and 2 recurrent cHCC-CCAs. The whole-exome analyses and clinicopathological information were integrated. RESULTS: TP53 was the most frequently mutated gene in this cohort, followed by BAP1, IDH1/2, and NFE2L2 mutations in multiple cases. All tumors with diameters <3 cm had TP53 mutations. In contrast, six of seven tumors with diameters ≥3 cm did not have TP53 mutations, but all seven tumors had mutations in genes associated with various pathways, including Wnt, RAS/PI3K, and epigenetic modulators. In the signature analysis, the pattern of mutations shown in the TP53 mutation group tended to be more similar to HCC than the TP53 nonmutation group. Mutations in recurrent cHCC-CCA tumors were frequently identical to those in the primary tumor, suggesting that those tumors originated from identical clones of the primary cHCC-CCA tumors. Recurrent and co-occurrent HCC tumors in the same patients with cHCC-CCA had either common or different mutation patterns from the primary cHCC-CCA tumors in each case. CONCLUSIONS: The study suggested that there were two subtypes of cHCC-CCA, one involving TP53 mutations in the early stage of the carcinogenic process and the other not involving such mutations. The comparison of the variants between primary and recurrent tumors suggested that cHCC-CCA was derived from an identical clone.

Physical Therapy May Not Be Successful for Patients With Cam-Type Femoroacetabular Impingement Syndrome and May Result in Insufficient Hip Range of Motion When Femoral Anteversion Is Less Than 16° and α-Angle Is Greater Than 65°.

PURPOSE: To identify factors associated with insufficient range of motion (ROM) improvement after the posterior pelvic tilt change in cam-type femoroacetabular impingement syndrome. METHODS: Preoperative computed tomography images from 71 consecutive patients with femoroacetabular impingement syndrome treated with arthroscopic cam resection were evaluated. Using a dynamic computer simulation program, 3-dimensional models with a 10° posterior pelvic tilt from the supine functional pelvic plane (baseline) were created by computed tomography models. Patients were divided into 2 groups: those who experienced >10° (effective group) and ≤10° (ineffective group) improvements in internal rotation at 90° flexion after a 10° posterior pelvic tilt. Demographic characteristics; preoperative range of internal rotation at 90° flexion; and radiographic parameters, including Tönnis grade, lateral center-edge angle, acetabular roof obliquity angle, central acetabular anteversion, cranial acetabular anteversion, femoral anteversion, and α angle, were compared in the 2 groups. Univariate and multivariable logistic regression analyses were performed to evaluate factors associated with insufficient ROM improvement following a 10° posterior pelvic tilt. RESULTS: The 71 patients included 58 men and 13 women, of mean age 41.4 ± 14.6 years. Posterior pelvic tilt was effective in 13 hips and ineffective in 58. Univariate analysis showed that preoperative range of internal rotation at 90°flexion, femoral anteversion, and α angle differed significantly in the 2 groups. Multivariable analysis showed that femoral anteversion <16° (odds ratio 7.4; 95% confidence interval 1.6-35; P = .012) and α angle >65° (odds ratio 6.7; 95% confidence interval 1.2-37; P = .027) were significant factors associated with insufficient ROM improvement after posterior pelvic tilt. CONCLUSIONS: Physical therapy may not be successful for patients with cam-type femoroacetabular impingement syndrome and may result in insufficient hip ROM when femoral anteversion is less than 16° and α-angle is greater than 65°. CLINICAL RELEVANCE: Patients with a prominent cam-type deformity and lower anterior femoral anteversion are at high risk of clinical failure following improvement in pelvic mobility by conservative treatment alone and are likely to benefit from surgery for cam deformity.

Cartilage Degeneration of the Lateral Compartment of the Knee at Second-Look Arthroscopy Is Associated With Deterioration of 10-Year Clinical Outcomes After Opening-Wedge High Tibial Osteotomy.

PURPOSE: To identify the arthroscopic findings associated with deterioration of 10-year clinical outcomes after opening-wedge high tibial osteotomy (OWHTO) in patients with knee osteoarthritis. METHODS: A total of 114 consecutive knees of 91 patients with knee osteoarthritis who underwent OWHTO between 2007 and 2011 were retrospectively reviewed. Of these patients, those who underwent second-look arthroscopy and were followed up for a minimum of 10 years were enrolled. The Knee Society Score (KSS) and hip-knee-ankle angle were assessed. Cartilage status was graded at the time of osteotomy (first look) and plate removal (second look) according to the International Cartilage Repair Society (ICRS) grading system. The KSS knee subscale score and function subscale score were assessed separately, and on the basis of the changes in each of these scores from 1 to 10 years postoperatively and the minimal clinically important difference (MCID), the patients were divided into 2 groups: deteriorated (deterioration of score ≥ MCID) and non-deteriorated (deterioration of score < MCID). RESULTS: Sixty-nine knees were included in this study. The mean knee score improved continuously from 48.7 ± 11.3 preoperatively to 86.8 ± 10.3 at 1 year (P < .001), 87.5 ± 9.9 at 5 years (P < .001), and 86.5 ± 10.5 at 10 years (P < .001) postoperatively. The mean function score also improved continuously from 62.5 ± 12.1 preoperatively to 90.7 ± 12.9 at 1 year (P < .001), 91.6 ± 12.1 at 5 years (P < .001), and 88.5 ± 13.1 at 10 years (P < .001) postoperatively. Three knees underwent conversion to total knee arthroplasty within 10 years postoperatively. The deteriorated KSS group showed significantly progressed ICRS grades in the lateral compartment compared with the non-deteriorated KSS group. The ICRS grade in the lateral compartment at second-look arthroscopy was identified as the only significant factor associated with both knee score deterioration (odds ratio, 4.89; P = .03) and function score deterioration (odds ratio, 3.91; P = .03) on multivariable logistic regression analysis. CONCLUSIONS: The presence of cartilage degeneration of the lateral compartment of the knee at second-look arthroscopy is associated with deterioration of long-term clinical outcomes after OWHTO. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Tranexamic acid administration for the prevention of periprosthetic joint infection and surgical site infection: a systematic review and meta-analysis.

INTRODUCTION: Tranexamic acid (TXA) has been widely utilized to reduce blood loss and allogeneic transfusions in patients who undergo lower limb arthroplasty. In recent years, there have been several articles reporting the incidence of periprosthetic joint infection (PJI) as a primary outcome of TXA administration, but no meta-analysis has been conducted to date. The present systematic review and meta-analysis evaluated the efficacy of TXA administration in preventing PJI and surgical site infection (SSI). MATERIALS AND METHODS: Pubmed, CINAHL, and the Cochrane Library bibliographic databases were searched for studies published by May 24, 2022, that evaluated the effects of TXA on PJI and SSI. Two researchers screened the identified studies based on the PRISMA flow diagram. The quality of each randomized clinical trial was assessed using Version 2 of the Cochrane risk-of-bias tool for randomized trials (ROB2.0), and the quality of cohort and case-control studies was assessed by risk of bias for nonrandomized studies (ROBANS-I). RESULTS: Of the 2259 articles identified from the database search, 31 were screened and selected. Treatment with TXA significantly reduced the incidence of overall infection, including PJI, SSI, and other infections (OR 0.55; 95% CI 0.49-0.62) (P < 0.00001), and that of PJI alone (OR 0.53; 95% CI 0.47-0.59) (P < 0.00001). TXA reduced the incidence of overall infection in patients who underwent total hip arthroplasty (THA; OR 0.51; 95% CI: 0.35-0.75) (P = 0.0005) and total knee arthroplasty (TKA; OR 0.55; 95% CI: 0.43-0.71) (P < 0.00001). Intravenous administration of TXA reduced the incidence of overall infection (OR 0.59; 95% CI 0.47-0.75) (P < 0.0001), whereas topical administration did not. CONCLUSIONS: Intravenous administration of TXA reduces the incidence of overall infection in patients undergoing both THA and TKA. LEVEL OF EVIDENCE: Level III.

Gastric Hyperplastic Polyps Can Shrink After Discontinuation of Proton Pump Inhibitors: A Case Series Compared With Continuation of Proton Pump Inhibitors.

GOAL: This study investigated whether gastric hyperplastic polyps (GHPs) shrink after discontinuation of proton pump inhibitor (PPI) alone. BACKGROUND: Long-term use of PPIs has been reported to increase the incidence of GHPs, which sometimes bleed and cause anemia. We experienced a patient whose recurrent hemorrhagic GHPs associated with long-term use of PPIs had disappeared after discontinuation of PPIs. STUDY: This study was conducted retrospectively at Kyoto University Hospital. Patients with histologically confirmed GHPs who had been taking PPIs for >6 months and who had undergone a repeat endoscopy within 2 years were included. Polyp shrinkage was defined as the disappearance of polyps or a reduction of >50% in the long diameter of the largest polyp. RESULTS: Six patients who discontinued PPIs were compared with 17 patients who continued PPIs. Polyp shrinkage was significantly more frequent in the PPI-discontinuation group (5/6, 83%) than in the PPI continuation group (0/17, 0%) (P<0.001). In 2 patients in the PPI-discontinuation group, the polyps completely disappeared finally. CONCLUSION: These findings suggest that discontinuation of PPIs can shrink GHPs in patients using PPIs.

The relationship between the ''Fujisawa point'' and anatomical femorotibial angle following simulated open wedge high tibial osteotomy.

BACKGROUND: We evaluated the relationship between the weight-bearing line (WBL) ratio and anatomical femorotibial angle (FTA) by simulated open wedge high tibial osteotomy (OWHTO). This study evaluated the correlation between the ''Fujisawa point'' and FTA, and identified factors which caused deviations between the two measurement methods. We hypothesized that the Fujisawa point corresponded with 170° of the FTA. METHODS: Preoperative antero-posterior full-length lower limb radiographs of 82 patients were obtained for the OWHTO to place the WBL ratio at a target of 62.5% of the width of the tibial plateau (Fujisawa point). The coronal alignment was measured pre- and post-planning. The patients were divided into two groups by the post-planning FTA: a correspondence group (168.5°â‰¦FTA≦171.5°) and a non-correspondence group (FTA < 168.5°, 171.5° < FTA). The relationship between the Fujisawa point and the FTA was analyzed with multivariate regression analysis. RESULTS: The post-planning FTA was 169.8 ± 1.1° and within 170 ± 1.5° in 69 cases (84.1%) when the WBL ratio was 62.5%. The neck shaft angle was 128.1 ± 5.2° in the correspondence group, and 122.3 ± 6.3° in the non-correspondence group. The multivariate linear regression analysis revealed that the neck shaft angle was the only factor that predicted the correspondence of the Fujisawa point with the FTA at 170° (p = 0.006, odd 1.28). CONCLUSIONS: The post-planning FTA converged at 170° when the WBL ratio passed through the Fujisawa point and the neck shaft angle was the only predictor.

Surgical planning of osteotomies around the knee differs between preoperative standing and supine radiographs in nearly half of cases.

BACKGROUND: To evaluate the difference in surgical planning of osteotomies around the knee between preoperative standing and supine radiographs and to identify risk factors for discrepancies in surgical planning. METHODS: This study included 117 knees of 100 patients who underwent osteotomies around the knee for knee osteoarthritis with genu varum. Surgical planning was performed so that the target point of the postoperative weight-bearing line (WBL) ratio was 62.5% in preoperative standing and supine radiographs. If the opening gap would be > 13 mm in open-wedge high tibial osteotomy (OWHTO), closed-wedge HTO (CWHTO) was planned. If the postoperative mMPTA would be > 95° in isolated HTO, double-level osteotomy (DLO) was planned. In DLO, lateral closed-wedge distal femoral osteotomy was performed so that the postoperative mechanical lateral distal femoral angle (mLDFA) was 85°, and any residual varus deformity was corrected with HTO. RESULTS: Surgical planning differed between standing and supine radiographs in 43.6% of cases. In all knees for which surgical planning differed between standing and supine radiographs, a more invasive type of osteotomy was suggested by standing radiographs than by supine radiographs. The risk factors for discrepancies in surgical planning were a lower WBL ratio in standing radiographs and a lower joint line convergence angle in supine radiographs. CONCLUSIONS: Surgical planning of DLO, CWHTO and OWHTO, in standing radiographs differed from that in supine radiographs in nearly half of the cases. Surgical planning based on standing radiographs leads to more invasive surgical procedures compared to supine radiographs.

The range of the required anterolateral cortex osteotomy distance varied widely in biplanar open wedge high tibial osteotomy.

BACKGROUND: To evaluate the anterolateral cortex distance between the lateral edge of the flange and hinge point in surgical simulations of biplanar open wedge high tibial osteotomy (OWHTO) using computed tomography (CT) images. METHODS: A total of 110 knees treated with OWHTO for medial knee osteoarthritis with varus malalignment were enrolled. Surgical simulations of biplanar OWHTO, including the transverse and ascending cuts, were performed in the standard manner using preoperative CT images. The distance between the lateral edge of the flange and the hinge point was measured. In addition, another plane of the ascending cut was defined through the hinge point. The angle between these two planes of the ascending cut was measured in the axial plane. RESULTS: The mean anterolateral cortex distance was 9.4 ± 4.6 mm (range, - 1.5 mm - 20.3 mm). In 3 knees, osteotomy of the anterolateral cortex was not needed. The mean value of the angle between the two ascending cut planes was 8.4 ± 3.6° (range, - 2.1° - 14.8°), which meant that osteotomy of anterolateral cortex was not needed when the ascending cut was performed at this angle. Moreover, these two values increased when the flange thickness was changed from one-third to one-fourth of the anteroposterior tibial diameter or the angle between the transverse and ascending cuts was changed from 110° to 120°. CONCLUSIONS: In biplanar OWHTO, anterolateral cortex osteotomy would be required. However, the range of the required anterolateral cortex osteotomy distance varied widely and the required anterolateral cortex osteotomy distance depended on the flange thickness and the angle between the transverse and ascending cuts. In addition, change of the ascending cut plane can change the necessity of anterolateral cortex osteotomy.

Potential anatomic risk factors resulting oversized postoperative medial proximal tibial angle after double level osteotomy.

BACKGROUND: Double level osteotomy (DLO) has been introduced to prevent increased postoperative joint line obliquity. However, although DLO is planned, knees with postoperative medial proximal tibial angle (MPTA) > 95° in preoperative surgical planning are present. This retrospective study aimed to evaluate risk factors for an MPTA > 95° in preoperative surgical planning for DLO in patients with varus knee osteoarthritis (OA). METHODS: A total of 168 knees that underwent osteotomies around the knee for varus knee OA were enrolled. The hip-knee-ankle angle (HKA), weight-bearing line (WBL) ratio, mechanical lateral distal femoral angle (mLDFA), joint line convergence angle (JLCA) and mechanical medial proximal tibial angle (mMPTA) were measured on preoperative radiographs. The postoperative WBL ratio was planned to be 62.5%. When the postoperative mMPTA was more than 95° in isolated high tibial osteotomy (HTO), (DLO) was planned so that the postoperative mLDFA was 85°, and residual deformity was corrected by HTO. Knees with postoperative mMPTA ≤ 95° and > 95° were classified into the correctable group and uncorrectable group, respectively. RESULTS: DLO was required in 101 knees (60.1%). Among them, 41 knees (40.6%) were classified into the uncorrectable group. Binomial logistic regression analysis showed that preoperative JLCA and mMPTA were independent predictors in the uncorrectable group. CONCLUSIONS: Even with DLO, postoperative mMPTA was more than 95° in approximately 40% of cases. Preoperative increased JLCA and decreased mMPTA were risk factors for a postoperative mMPTA of > 95° after DLO.

Deformity analysis of the lower limb on the coronal plane in patients with rheumatoid arthritis and osteoarthritis.

OBJECTIVES: To evaluate joint orientation angles of the coronal plane in patients with rheumatoid arthritis (RA) in comparison with osteoarthritis (OA). METHODS: In total, 72 patients with RA (90 knees) and 76 patients with OA (90 knees) who underwent total knee arthroplasty were enrolled. The hip-knee-ankle (HKA) angle, mechanical lateral distal femoral angle (mLDFA), mechanical medial proximal tibial angle (mMPTA), and joint line convergence angle (JLCA) were measured on preoperative long-leg radiographs in the standing position. Student's t-test was used to assess differences in radiographic data between patients with RA and OA. RESULTS: In knees with RA and OA, the mean HKA was -3.4 ± 9.4° and -10.6 ± 8.0°, the mean mLDFA was 86.6 ± 3.7° and 88.2 ± 2.7°, the mean mMPTA was 85.9 ± 4.0° and 84.3 ± 3.7°, and the mean JLCA was 2.7 ± 4.2° and 6.8 ± 4.1°. All parameters in the knees with RA were more valgus than those with OA. CONCLUSIONS: Knees with RA had a great variability in joint orientation angles on the coronal plane; the whole lower limb alignment and the femur, tibia, and joint were more valgus in knees with RA than with OA.

Oncogenic transcriptomic profile is sustained in the liver after the eradication of the hepatitis C virus.

Hepatocellular carcinoma (HCC) developing after hepatitis C virus (HCV) eradication is a serious clinical concern. However, molecular basis for the hepatocarcinogenesis after sustained virologic response (SVR) remains unclear. In this study, we aimed to unveil the transcriptomic profile of post-SVR liver tissues and explore the molecules associated with post-SVR carcinogenesis. We analysed 90 RNA sequencing datasets, consisting of non-cancerous liver tissues including 20 post-SVR, 40 HCV-positive and 7 normal livers, along with Huh7 cell line specimens before and after HCV infection and eradication. Comparative analysis demonstrated that cell cycle- and mitochondrial function-associated pathways were altered only in HCV-positive non-cancerous liver tissues, whereas some cancer-related pathways were up-regulated in the non-cancerous liver tissues of both post-SVR and HCV-positive cases. The persistent up-regulation of carcinogenesis-associated gene clusters after viral clearance was reconfirmed through in vitro experiments, of which, CYR61, associated with liver fibrosis and carcinogenesis in several cancer types, was the top enriched gene and co-expressed with cell proliferation-associated gene modules. To evaluate whether this molecule could be a predictor of hepatocarcinogenesis after cure of HCV infection, we also examined 127 sera from independent HCV-positive cohorts treated with direct-acting antivirals (DAAs), including 60 post-SVR-HCC patients, and found that the elevated serum Cyr61 was significantly associated with early carcinogenesis after receiving DAA therapy. In conclusion, some oncogenic transcriptomic profiles are sustained in liver tissues after HCV eradication, which might be a molecular basis for the liver cancer development even after viral clearance. Among them, up-regulated CYR61 could be a possible biomarker for post-SVR-HCC.

Multiregional whole-genome sequencing of hepatocellular carcinoma with nodule-in-nodule appearance reveals stepwise cancer evolution.

Recent genetic analyses revealed genetic heterogeneity in hepatocellular carcinoma (HCC), although it remains unclear how genetic alterations contribute to the multistage progression of HCC, especially the early step from hypovascular liver nodules to hypervascular HCC. We conducted multiregional whole-genome sequencing on HCCs with a nodule-in-nodule appearance, consisting of inner hypervascular HCC surrounded by hypovascular HCC arising from a common origin, and identified point mutations, structural variations, and copy-number variations in each specimen. According to the genetic landscape of the inner and outer regions, together with the pathological and radiological findings, we examined the stepwise evolution of cancer cells from slow-growing HCC to rapid-growing HCC. We first demonstrated that most tumor cells consisting of hypovascular well-differentiated HCCs already harbored thousands of point mutations and even several structural variations, including chromosomal translocations and chromothripsis, as the trunk events. Telomerase reverse transcriptase (TERT)-associated aberrations, including promoter mutations, chromosomal translocation, and hepatitis B virus DNA integration, as well as abnormal methylation status, were commonly detected as the trunk aberrations, while various liver cancer-related genes, which differed in each case, had additionally accumulated in the inner dedifferentiated nodules. Further, differences in the trunk and branch mutational signatures suggested a multistep contribution to the mutagenesis in each case. In conclusion, genomic alterations associated with the TERT gene could be the key driver events to form the hypovascular HCC, and additional case-specific driver mutations accumulate during the progression phase, forming intra- and inter-tumoral heterogeneity, confirming the importance of genetic testing before targeting therapy. These data shed light on the process of multistep hepatocarcinogenesis and will be helpful toward investigating new therapeutic strategies for HCC. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Increased contact area of flange and decreased wedge volume of osteotomy site by open wedge distal tibial tuberosity arc osteotomy compared to the conventional technique.

PURPOSE: The purpose of this study was to evaluate the area of the osteotomy surface, including the flange and wedge volume, in open wedge high tibial osteotomy (OWHTO), distal tibial tuberosity osteotomy (DTO), and distal tibial tuberosity arc osteotomy (DTAO) using tibial sawbones. It was hypothesized that the area of the osteotomy surface, including the flange, in DTAO was larger than that in OWHTO and DTO and that the wedge volume in DTAO was smaller than that in OWHTO and DTO. METHODS: Fifteen tibial sawbones were divided equally into three groups: OWHTO, DTO, and DTAO. The total area of the osteotomy surface in OWHTO, DTO, and DTAO was compared using image analysis software. The contact area of the flange and the wedge volume at wedge heights of 5, 10, and 15 mm were compared among osteotomy types. One-way repeated-measures analysis of variance was used to compare the total area of the osteotomy surface, the contact area of the flange, and the wedge volume at 5, 10, and 15 mm in OWHTO, DTO, and DTAO. RESULTS: The total area of the osteotomy surface in DTO and DTAO was significantly larger than that in OWHTO (P < 0.05). The contact area of the flange in DTAO was significantly larger than that in OWHTO at each wedge height (P < 0.05). In addition, the contact area of the flange in DTAO was significantly larger than that in DTO at wedge heights of 5 and 15 mm (P < 0.05). The wedge volume in DTAO was significantly smaller than that in DTO at each wedge height (P < 0.05). CONCLUSIONS: This study demonstrated that an increase in the flange contact area and a decrease in the wedge volume in the opening gap were found in DTAO compared to DTO. This would be an advantage for anteroposterior screw insertion from the flange to the distal tibial fragment and bone union at the osteotomy site.

Varus inclination of the tibia is related to patellofemoral osteoarthritis in Japanese female patients with moderate knee osteoarthritis.

PURPOSE: The aim of this study was to investigate whether the tibial tuberosity-trochlear groove (TT-TG) distance and lateral patellar tilt, which induce patellofemoral osteoarthritis (OA), are related to the coronal deformity of the lower limb in varus knee OA. It was hypothesized that varus inclination of the tibia was negatively correlated with the TT-TG distance and lateral patellar tilt in Japanese female patients with moderate knee OA. METHODS: A total of 104 female patients (139 knees) scheduled to undergo knee osteotomy for varus knee OA were enrolled. The coronal lower limb alignment was measured on anteroposterior whole-leg radiographs. The TT-TG distance, patellar tilt angle, and the patellofemoral joint space were measured both medially and laterally on computed tomography images. The correlations between coronal lower limb alignment and the TT-TG distance or patellar tilt angle, and the correlations between the TT-TG distance or patellar tilt angle and patellofemoral joint space were evaluated. RESULTS: The medial proximal tibial angle was negatively correlated with the TT-TG distance (r = - 0.383, P < 0.01) and patellar tilt angle (r = - 0.34, P < 0.01). Lateral patellofemoral joint space was negatively correlated with the TT-TG distance (r = - 0.256, P = 0.002) and patellar tilt angle (r = - 0.205, P = 0.016). CONCLUSIONS: Varus inclination of the proximal tibia may induce lateralization of the tibial tuberosity and lateral patellar tilt. The tibial tuberosity lateralization and lateral patellar tilt may induce lateral patellofemoral OA in patients with varus knee OA. LEVEL OF EVIDENCE: III.

Coronal shaft bowing of the femur affects varus inclination of the surgical transepicondylar axis in varus knee osteoarthritis.

PURPOSE: This study investigated the relationship between femoral shaft bowing and the orientation of the surgical transepicondylar axis (TEA) in the coronal plane in varus knee osteoarthritis (OA). METHODS: A total of 82 knees scheduled to undergo total knee arthroplasty (TKA) for the treatment of varus knee OA were enrolled. The hip-knee-ankle angle (HKA) was measured preoperatively on anteroposterior whole-leg standing radiographs. The lateral angle between the TEA and the mechanical axis of the femur (MA-TEA) was measured in the coronal plane from preoperative computed tomography (CT) images. Femoral shaft bowing was measured on CT images. Pearson's correlation coefficient was used to examine the correlation of the MA-TEA with the HKA and femoral shaft bowing. RESULTS: The MA-TEA correlated negatively with the HKA (r = - 0.321, P < 0.01) and positively with femoral shaft bowing (r = 0.415, P < 0.01). CONCLUSIONS: The TEA changed to varus as femoral shaft bowing increased in patients with varus knee OA. This suggests that the TEA is not always the centre of the rotational axis of the femur after TKA. In addition, the TEA may not be useful as a consistent parameter in the coronal plane in patients with increasing femoral shaft bowing. LEVEL OF EVIDENCE: III.

Intraoperatively accurate limb alignment after opening wedge high tibial osteotomy can be lost by large knee joint line convergence angle during surgery.

INTRODUCTION: The purpose of this study was to assess early postoperative loss of achieved correction and associated factors after opening wedge high tibial osteotomy (OWHTO). MATERIALS AND METHODS: OWHTO was performed in 121 patients with osteoarthritis of the knee (mean age 66 years, 154 knees). Anteroposterior radiographs of the knee and full-length leg, and varus and valgus stress radiographs of the knee were taken, and the femorotibial angle (FTA), joint line convergence angle (JLCA), and medial proximal tibial angle (MPTA) were measured. The changes in the FTA, JLCA, and MPTA were defined as ΔFTA, ΔJLCA, and ΔMPTA. RESULTS: The ΔFTA and ΔJLCA at postoperative 0-2 days were - 1.8 ± 1.2° and - 1.9 ± 1.4°, respectively. The ΔFTA, ΔJLCA and ΔMPTA at postoperative 1-12 months were 0.9 ± 1.3°, 0.2 ± 1.2° and - 0.8 ± 0.8°, respectively. A positive correlation was found between ΔFTA and ΔJLCA at postoperative 0-2 days (ρ = 0.642, P < 0.001) and at postoperative 1-12 months (ρ = 0.402, P < 0.001). A negative correlation was found between ΔFTA and ΔMPTA at postoperative 1-12 months (ρ = - 0.534, P < 0.001). A discrepancy in alignment represented by the FTA occurred in the supine radiographs between the day of surgery and postoperative 2 days. Multiple regression analysis suggested that postoperative JLCA on the day of surgery was the factor related to early postoperative change of the FTA. CONCLUSIONS: This study demonstrated the early loss of achieved correction after OWHTO due to change of the JLCA, even if the accurate alignment is obtained intraoperatively.