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.

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.

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.

Shelf acetabuloplasty may inhibit range of motion: A computer simulation analysis.

Shelf acetabuloplasty has been performed in patients with developmental dysplasia of the hip (DDH); however, the appropriate position of the shelf has not been determined, particularly with respect to avoiding range of motion (ROM) loss. The aim of this study was to investigate the frequency of ROM inhibition and the influence of 3D position of the shelf following actual shelf acetabuloplasty and virtual surgery using computer simulation analysis. Computed tomography data from 15 patients with DDH who underwent shelf acetabuloplasty were collected between August 2019 and February 2022. The three-dimensional models of a hip joint were constructed using Zed Hip®. Maximal internal rotation (MIR) at 45° and 90° flexion was measured in each patient. The frequency and position of ROM inhibition was determined in a real postoperative model virtually. In addition, a second analysis using virtual acetabuloplasty was performed. Upon placing the shelf, three patterns were provided for the following four parameters: height, coronal inclination, center-edge angle (CEA), and anteroposterior position. The predictors for ROM inhibition were analyzed using a logistic regression model. In the actual postoperative model, a limitation of MIR at 90° and 45° of flexion occurred in 60% and 66.7% of patients, respectively. A higher CEA and anterior position are major factors limiting MIR. The analysis of the virtual shelf acetabuloplasty model revealed that anterior position and CEA were significant factors causing ROM inhibition. As for clinical significance, the results of the current study indicated the optimal location of the shelf to avoid iatrogenic impingement after shelf acetabuloplasty.

Bevacizumab promotes tenogenic differentiation and maturation of rat tendon-derived cells in vitro.

Previous work suggested that tenogenic differentiation of tendon stem/progenitor cells (TSPCs) was suppressed by upregulated expression of the angiogenic marker vascular endothelial growth factor (VEGF). The purpose of this study was to test the hypothesis that anti-VEGF antibody, bevacizumab, promotes in vitro tenogenic differentiation and maturation of two distinct types of TSPCs, tendon proper-derived cells (TDCs), and paratenon-derived cells (PDCs) originating from rat Achilles tendon. TDCs and PDCs were isolated from the tendon proper and the paratenon of rat Achilles tendons. TDCs and PDCs were cultured for 3 days on plates with or without VEGF. TDCs and PDCs were also cultured in collagen gel matrix, and the blocking effect of VEGF was examined by the addition of 100 ng/mL of bevacizumab. Effects of bevacizumab on tenogenic differentiation were assessed using real-time PCR, immunofluorescent staining, and western blotting. VEGF significantly attenuated expression of the Tnmd gene in both PDCs and TDCs (P<0.05). Expressions of the Scx, Tnmd, and Col1a1 genes were significantly upregulated by the addition of bevacizumab (P<0.05). Immunofluorescent staining showed that the percentage of tenomodulin-positive PDCs and TDCs was significantly higher with bevacizumab treatment than in control cultures (P<0.05). Western blotting showed that bevacizumab suppressed pVEGFR-2 protein expression in both PDCs and TDCs. Bevacizumab promoted the in vitro tenogenic differentiation and maturation of two distinct TSPCs derived from rat Achilles tendon. Since the previous studies demonstrated that TSPCs have a potential to contribute to tendon repair, attenuating VEGF levels in TSPCs by administration of bevacizumab is a novel candidate therapeutic option for promoting tendon repair.

Radiologic simulation of leg length change after double level osteotomy in preoperative surgical planning.

BACKGROUND: To evaluate the expected postoperative total leg length change using preoperative radiographs during surgical planning of four different methods of double level osteotomy (DLO). METHODS: This study included 34 patients (44 knees) who underwent DLO for varus knee osteoarthritis. Surgical planning was performed so that the postoperative weight bearing line ratio was 62.5%. In DLO, lateral closed or medial open wedge distal femoral osteotomy (LCWDFO, MOWDFO) was performed so that the postoperative mechanical lateral distal femoral angle was 85°, and residual deformity was corrected with medial open or lateral closed wedge high tibial osteotomy (MOWHTO, LCWHTO). Pre- and surgical planning X-rays in the one-leg standing position were compared to assess the change in leg length, and the factors affecting it, in the various surgical groups. The proportion of cases in which Δ total leg length was greater than 6 mm (symptomatic change) was investigated. RESULTS: The mean postoperative total leg length increased significantly with LCWDFO + MOWHTO, MOWDFO + MOWHTO, and MOWDFO + LCWHTO, while it decreased with LCWDFO + LCWHTO. The proportion of cases with a postoperative total leg length change > 6 mm was 72.7%, 2.3%, 100%, and 6.8% in LCWDFO + MOWHTO, LCWDFO + LCWHTO, MOWDFO + MOWHTO, and MOWDFO + LCWHTO, respectively. In addition, the preoperative hip-knee-ankle angle correlated negatively with the postoperative total leg length change in LCWDFO + MOWHTO, MOWDFO + MOWHTO, and MOWDFO + LCWHTO, but not in LCWDFO + LCWHTO. CONCLUSIONS: MOWDFO + MOWHTO had the largest postoperative leg length change and MOWDFO + LCWHTO had the smallest. Symptomatic leg length change (> 6 mm) should be considered in MOWDFO + MOWHTO and LCWDFO + MOWHTO.

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.

Targeting of Periprosthetic Muscles for the Ultrasonographic Screening of Hip Abnormalities in Hip Resurfacing Arthroplasty Patients.

BACKGROUND: Hip resurfacing arthroplasty (HRA) patients require subsequent annual screening for postoperative complications. Ultrasonography may be useful for this purpose but lacks a screening protocol for hips. The purpose of this study was to evaluate the accuracy of ultrasonography for detecting postoperative complications in HRA patients using a screening protocol that specifically targets periprosthetic muscles. METHODS: We enrolled 45 hips from 40 HRA patients with a mean follow-up period of 8.2 years. MRI and ultrasonography scans were simultaneously conducted at follow-up. The ultrasonography assessments were conducted on the anterior part of the hip that targets iliopsoas, sartorius, rectus femoris, lateral with anterior superior and inferior iliac spine (ASIS and AIIS) as bony landmarks, and the lateral and posterior parts that target fascia tensor, short rotators, and gluteus minimus, medius, and maximus with greater trochanter and ischial tuberosity as bony landmarks. The accuracy of diagnosing postoperative abnormalities and the visibility of periprosthetic muscles were compared between these two modalities. RESULTS: Both MRI and ultrasonography detected an abnormal region in eight cases comprising two infections, two pseudotumors, and four patients with greater trochanteric bursitis. Among these cases, four hips required implant removal. The increase in anterior space, measured as the distance between the iliopsoas and resurfacing head, was a good indicator for the abnormal mass in these four HRA cases. In the assessment of periprosthetic muscles, MRI showed a much lower visibility than ultrasonography in the iliopsoas (6.7% vs. 100%), gluteus minimus (6.7% vs. 88.9%), and short rotators (8.8% vs. 71.4%) due to implant halation. CONCLUSIONS: By targeting periprosthetic muscles, ultrasonography can detect postoperative complications as effectively as MRI assessments in HRA patients. Ultrasonography has superior visibility in the periprosthetic muscles of HRA patients, indicating its utility for the screening of small legions in these cases which may not be visible by MRI.

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.

Bevacizumab suppressed degenerative changes in articular cartilage explants from patients with osteoarthritis of the knee.

BACKGROUND: This study was designed to test the hypothesis that blockade of vascular endothelial growth factor (VEGF) suppresses degenerative changes in articular cartilage from patients with osteoarthritis (OA). METHODS: Articular cartilage from eight OA patients was subjected to explant culture for 2 days in the presence or absence of 10 ng/ml recombinant interleukin (IL)-1ß. The blocking effect of VEGF was examined by the addition of 10 or 100 ng/ml of bevacizumab. The culture media were harvested, and markers for cartilage degradation were measured by sandwich enzyme-linked immunoassay. Total RNA was isolated from cartilage tissues, and gene expressions associated with the anabolic response were examined by the quantitative real-time polymerase chain reaction. RESULTS: Bevacizumab significantly reduced concentrations of matrix metalloproteinase (MMP)-2, MMP-3, and cartilage oligomeric matrix protein in the culture media with and without IL-1ß. Significant suppressive effects of bevacizumab on MMP-9 and MMP-13 were shown only in the presence of IL-1ß. Gene expression of Col2a1 was significantly increased by the addition of bevacizumab in the absence of IL-1ß. CONCLUSION: Bevacizumab inhibits catabolic reactions and stimulates anabolic function in articular cartilage derived from OA patients directly, suggesting a protective effect on articular cartilage from OA progression.

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.

Patient-specific instrumentation for total knee arthroplasty improves reproducibility in the planned rotational positioning of the tibial component.

BACKGROUND: The purpose of this study was to evaluate the reproducibility of planned component positioning including tibial rotational alignment in patient-specific instrumentation (PSI) for total knee arthroplasty (TKA). METHODS: A total of 100 knees of 100 patients underwent TKA using PSI (n = 50) or the conventional method (n = 50). Full-length anteroposterior radiographs of the lower limb were taken in the standing position, and the coronal alignments of the femoral and tibial components were measured. Computed tomography (CT) images of the lower limb were obtained preoperatively and postoperatively, and the rotational alignments of the femoral and tibial components were measured. The difference from the preoperative planning in tibial rotational alignment was measured using three-dimensionally merged pre- and postoperative images. The mean values and rates of outliers in each measurement were compared between the PSI group and the conventional group. RESULTS: There were no significant differences in coronal alignment of the femoral and tibial components and rotational alignment of the femoral component between the two groups. With respect to rotational alignment of the tibial component from the preoperatively planned reference axis, the PSI group showed a lower rate of outliers (internal rotation > 10°) than the conventional group (p < 0.05). CONCLUSIONS: This study demonstrated that the difference from the preoperative planning in tibial rotational positioning was accurately evaluated using novel three-dimensional measurement method, and PSI could reduce outliers in rotational alignment of the tibial component (internal rotation > 10°). PSI is a useful technique for improving the reproducibility of the planned tibial rotational positioning in TKA.

Minimum 5-Year Outcomes of Osteochondral Autograft Transplantation with a Concomitant High Tibial Osteotomy for Spontaneous Osteonecrosis of the Knee with a Large Lesion.

OBJECTIVE: The purpose of this study was to evaluate the mid-term clinical outcomes of osteochondral autograft transplantation (OAT) with concomitant high tibial osteotomy (HTO) in spontaneous osteonecrosis of the knee (SONK) with a large lesion. DESIGN: A total of 48 knees of 48 consecutive patients with SONK (lesion size ≥4 cm2, no age criteria) who underwent opening wedge HTO and concomitant OAT were retrospectively investigated, and those who were followed up postoperatively for at least 5 years were included in this case series study. Clinical outcomes were evaluated using knee and function scores of Knee Society Score, radiographic outcomes were evaluated using the anatomical femorotibial angle (FTA), and these outcomes were compared between patients aged ≥70 years and <70 years. RESULTS: Of the 48 cases, a total of 43 cases were available for review at a minimum of 5 years, and 5 cases were excluded from the analysis. Overall, the mean knee score improved from preoperative 48.8 ± 13.3 to postoperative 87.9 ± 8.6 at 1 year (P < 0.05) and 85.0 ± 10.4 at final follow-up (P < 0.05 vs. preop., N.S. vs. 1 year). The mean function score also improved from preoperative 60.1 ± 10.9 to postoperative 87.3 ± 12.2 at 1 year (P < 0.05) and 84.2 ± 12.4 at final follow-up (P < 0.05 vs. preop., N.S. vs. 1 year). The mean standing FTA was corrected significantly from 181.1° ± 2.7° preoperatively to 169.7° ± 2.4° at 1 year (P < 0.05) and 169.4° ± 3.1° at final follow-up (P < 0.05 vs. preop., N.S. vs. 1 year). There were no significant differences in clinical and radiographic outcomes between patients aged ≥70 years and <70 years. There were 4 cases of lateral hinge fracture around the osteotomy site and 1 case of delayed union. None of the patients underwent revision surgery during the follow-up period (survival rate of 100%). CONCLUSIONS: Mid-term clinical outcomes of patients with SONK who underwent HTO and OAT with a relatively large lesion were good.

Biological Effects of High Tibial Osteotomy on Spontaneous Osteonecrosis of the Knee.

OBJECTIVE: The purpose of this study was to evaluate the postoperative status of spontaneous osteonecrosis of the knee (SONK) after high tibial osteotomy (HTO) with concomitant bone marrow stimulation (BMS) using synovial fluid (SF) biomarkers. DESIGN: Twenty patients with SONK who underwent opening wedge HTO were enrolled. Paired SF samples from the affected knee were collected at the time of HTO surgery and at the time of plate removal. SF concentrations of interleukin (IL)-6, IL-8, and matrix metalloproteinase (MMP)-13 were measured by enzyme-linked immunosorbent assays. The Knee Society Score (KSS) and hip-knee-ankle (HKA) angle were assessed before and 2 years after HTO. RESULTS: The KSS knee and function scores were significantly improved after HTO (mean changes of 33.8 and 29.4, respectively). The mean HKA angle was changed from mechanical varus (-8.6°) to valgus (5.2°). Concentrations of IL-6, IL-8, and MMP-13 were significantly decreased after HTO (mean changes of -73.7%, -32.4%, and -47.9% from preoperative baseline, respectively). Significant correlations were found between lesion size and concentrations of biomarkers, except for preoperative MMP-13. CONCLUSIONS: SF levels of biomarkers of inflammation and cartilage degradation were reduced after HTO with a concomitant BMS procedure, suggesting a biological improvement in SONK.

Expansion of Gastric Intestinal Metaplasia with Copy Number Aberrations Contributes to Field Cancerization.

Intestinal metaplasia (IM) is a risk factor for gastric cancer following infection with Helicobacter pylori. To explore the susceptibility of pure gastric IM to cancer development, we investigated genetic alterations in single IM gastric glands. We isolated 50 single IM or non-IM glands from the inflamed gastric mucosa of 11 patients with intramucosal gastric carcinoma (IGC) and 4 patients without IGC; 19 single glands in the noninflamed gastric mucosa of 11 individuals from our cohort and previous dataset were also included as controls. Whole-exome sequencing of single glands revealed significantly higher accumulation of somatic mutations in various genes within IM glands compared with non-IM glands. Clonal ordering analysis showed that IM glands expanded to form clusters with shared mutations. In addition, targeted-capture deep sequencing and copy number (CN) analyses were performed in 96 clustered IM or non-IM gastric glands from 26 patients with IGC. CN analyses were also performed on 41 IGC samples and The Cancer Genome Atlas-Stomach Adenocarcinoma datasets. These analyses revealed that polyclonally expanded IM commonly acquired CN aberrations (CNA), including amplification of chromosomes 8, 20, and 2. A large portion of clustered IM glands typically consisted of common CNAs rather than other cancer-related mutations. Moreover, the CNA patterns of clustered IM glands were similar to those of IGC, indicative of precancerous conditions. Taken together, these findings suggest that, in the gastric mucosa inflamed with H. pylori infection, IM glands expand via acquisition of CNAs comparable with those of IGC, contributing to field cancerization. SIGNIFICANCE: This study contributes to our understanding of gastric intestinal metaplasia as a risk factor for gastric adenocarcinoma via their multifocal expansion and acquisition of CNAs and somatic mutations.

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.

Return to sports activity after opening wedge high tibial osteotomy in patients aged 70 years and older.

BACKGROUND: The purpose of this study was to evaluate return to sports (RTS) after opening wedge high tibial osteotomy (OWHTO) in elderly patients and associated factors affecting RTS. METHODS: Seventy-four patients (mean age 68 years) who underwent OWHTO were enrolled. Clinical outcomes were evaluated using the Knee Society Score (KSS). Patients were asked regarding types of sports activities and their levels of participation within preoperative 1 year and postoperative 1 year. Levels of participation in sports and recreational activities were examined using the Tegner activity scale. The outcomes were compared between two age groups (≥ 70 years vs. < 70 years). RESULTS: Of the 74 patients overall, 59 participated in at least one sport preoperatively, and 55 returned to sports postoperatively (RTS 93%). The KSS knee score and function score were significantly improved after surgery in both age groups (P < 0.05), but no significant differences were found between the age groups. The Tegner activity scales for ≥ 70 years and < 70 years were 2.9 ± 1.1 and 4.0 ± 1.9 preoperatively (P < 0.01) and 2.7 ± 1.2 and 3.3 ± 1.4 postoperatively (P = 0.16), respectively. RTS was reported by 24 of 25 (96.0%) in the age < 70 years group and 31 of 34 (91.2%) in the age ≥ 70 years group. Majority of age ≥ 70 years participated in low-impact sports preoperatively and returned to the same impact level postoperatively. CONCLUSIONS: The rate of RTS after OWHTO was high in patients aged 70 years and older with low-impact level. OWHTO is a preferred surgical option for elderly patients who desire RTS.

Compromised anti-tumor-immune features of myeloid cell components in chronic myeloid leukemia patients.

Chronic myeloid leukemia (CML) is a form of myeloproliferative neoplasm caused by the oncogenic tyrosine kinase BCR-ABL. Although tyrosine kinase inhibitors have dramatically improved the prognosis of patients with CML, several problems such as resistance and recurrence still exist. Immunological control may contribute to solving these problems, and it is important to understand why CML patients fail to spontaneously develop anti-tumor immunity. Here, we show that differentiation of conventional dendritic cells (cDCs), which are vital for anti-tumor immunity, is restricted from an early stage of hematopoiesis in CML. In addition, we found that monocytes and basophils, which are increased in CML patients, express high levels of PD-L1, an immune checkpoint molecule that inhibits T cell responses. Moreover, RNA-sequencing analysis revealed that basophils express genes related to poor prognosis in CML. Our data suggest that BCR-ABL not only disrupts the "accelerator" (i.e., cDCs) but also applies the "brake" (i.e., monocytes and basophils) of anti-tumor immunity, compromising the defense against CML cells.

No differences in clinical outcomes and cartilage repair between opening wedge and closed wedge high tibial osteotomies at short-term follow-up: A retrospective case series analysis.

PURPOSE: The aim of this study was to assess differences in clinical outcomes and postoperative cartilage repair between opening wedge high tibial osteotomy (OWHTO) and closed wedge HTO (CWHTO) for medial osteoarthritis (OA) of the knee. METHODS: A total of 90 knees of 76 patients who underwent OWHTO (45 knees of 40 patients) and CWHTO (45 knees of 36 patients) was followed-up for 2 years. Cartilage repair at the medial compartment was arthroscopically classified into the following stages: Stage 1 (no reparative change); Stage 2 (partial coverage with white cartilaginous tissue); and Stage 3 (full coverage with white cartilaginous tissue). Clinical outcomes were assessed using Knee Society scores, and radiographic assessment was carried out by anatomical femorotibial angle (aFTA). RESULTS: Regarding preoperative OA grade, varus alignment, and function score, CWHTO patients showed more advanced OA status than OWHTO patients. Knee scores and function scores were significantly improved after surgery with both HTO procedures (P < 0.05), with no significant difference between the two procedures. Cartilage repair of stage 2 or 3 was found in more than 80% of the subjects in the medial femoral condyle and more than 60% in the medial tibial condyle. However, there were no significant differences between the two HTO procedures. Multivariate logistic regression analysis showed that preoperative International Cartilage Repair Society (ICRS) grade was the only factor affecting cartilage repair. CONCLUSIONS: CWHTO improved clinical outcomes and cartilage status as much as OWHTO. Although the effects of cartilage repair on clinical outcomes are unknown, HTO is an effective treatment option even for severe medial OA of the knee.