Effect of Additional Centralization Procedure on Intraoperative Ultrasound-Assessed Medial Meniscal Extrusion Compared With Medial Meniscal Posterior Root Repair Alone

Abstract

Background:

Medial meniscal extrusion (MME) contributes to knee osteoarthritis and is often caused by a medial meniscal posterior root tear (MMPRT). Although early surgical repair of MMPRT improves outcomes, MME often persists. Centralization techniques aim to reduce meniscal extrusion by anchoring the capsule to the tibial plateau; however, their clinical effectiveness when combined with MMPRT repair remains uncertain.

Purpose:

To evaluate the efficacy of centralization combined with MMPRT repair in reducing MME using intraoperative ultrasound.

Study Design:

Case series; Level of evidence, 4.

Methods:

The study included 26 patients who underwent MMPRT repair with a pullout technique and centralization with three knotless anchors. Of these, 22 patients also underwent additional high tibial osteotomy. Initial tensions of 0 to 40 N were applied to the pullout repair sutures at 60° of knee flexion, and MME was measured by intraoperative ultrasound. MME was also measured at 0°, 30°, 60°, 90°, and 120° of knee flexion, as well as at internally and externally rotated positions (IR and ER) at 30° and 90° of knee flexion, before MMPRT repair, after repair, and after centralization. A total of 22 patients underwent additional high tibial osteotomy after MMPRT repair and centralization.

Results:

When tension of 0 to 40 N was applied to the pullout repair sutures at 60°, the median MME decreased with increasing tension, with a significant reduction observed at 30 and 40 N compared with lower tension levels. Moreover, at tensions ≥30 N, the median MME remained <3 mm after centralization. MME was subsequently measured with 30 N tension applied to the pullout repair sutures. The median MME (mm) before MMPRT repair, after repair, and after centralization ranged from 7.6, 3.9, and 3 at 0° to 4.4, 3.5, and 2.6 at 120°, respectively. At 0°, MME was significantly smaller after centralization than before repair (P < .001) and also smaller than after repair (P < .006). At 120°, MME after centralization was significantly smaller than before repair (P < .001), and the difference among the 3 conditions was also significant (P = .03). Centralization resulted in the smallest MME at both flexion angles. The median MME before MMPRT repair, after repair, and after centralization at 30° were all smaller in the MME in the ER position. Conversely, the ER-IR differences were slight at 90°.

Conclusion:

Intraoperative ultrasound demonstrated that MMPRT repair reduced MME compared with the preoperative condition, and the addition of centralization further enhanced this reduction, yielding greater improvement than MMPRT repair alone.

Keywords

centralization knee medial meniscal extrusion medial meniscal posterior root tear ultrasound

Medial meniscal extrusion (MME) decreases coverage of the medial meniscus of the medial tibial plateau and contributes to the onset and progression of knee osteoarthritis.^25,26,29 MME is diagnosed via magnetic resonance imaging (MRI)^5,10 or ultrasound,^23,27 and it is often seen with a degenerative meniscus, even in the absence of any tears. In particular, however, significant MME can be a sign of a medial meniscal posterior root tear (MMPRT), and these tears often occur in middle-aged and older patients who experience posterior knee pain after minor trauma.^7,9

Surgical repair is recommended as early as possible after diagnosis for MMPRT.^1,16 However, despite second-look arthroscopy confirming satisfactory healing in most cases postoperatively, MRI at a mean follow-up of 36.1 months revealed a reduction in meniscal extrusion in only 56% of cases.⁶ A multicenter study showed significantly improved clinical outcomes—including International Knee Documentation Committee (IKDC) scores, Tegner activity scale, and visual analog scale for pain—at the 2-year follow-up after transtibial root repair. Progressive meniscal extrusion was associated with less improvement in Tegner scores.¹⁹ Another study showed that patients with MMPRTs who undergo pullout fixation generally have positive midterm outcomes, whereas those with reduced meniscal extrusion at 1 year postoperatively show better Lysholm and IKDC scores and radiographic results—including Kellgren–Lawrence grades and joint space widths.⁴ These findings may in part reflect that persistent MME after MMPRT repair could indicate either a failure of the repair itself or a more advanced degenerative condition of the meniscus or knee joint. Nonetheless, minimizing MME remains a critical aspect of treatment, as extrusion has been correlated with inferior clinical and radiographic outcomes. Therefore, addressing MME should remain an essential component in optimizing postoperative outcomes after MMPRT repair.

One of the protocols first developed for the treatment of lateral meniscal extrusion is arthroscopic centralization of the extruded meniscus.¹³ In this procedure, the capsule attached to the meniscus is anchored with sutures to the edge of the tibial plateau to centralize the extruded meniscus. The sutures from the anchors pass through the capsule beside the meniscus. The biomechanical effects of the centralization procedure have been confirmed to include restoration of the load-bearing function of the meniscus,^20,24 with satisfactory clinical results and improvement of the meniscal extrusion on MRI observed at the 2-year follow-up.¹²

For the MME caused by MMPRT, centralization is also useful when combined with MMPRT repair.^15,17,22 The latest development in centralization techniques involves the use of 3 knotless anchors. Meniscal extrusion at the posteromedial part is reduced by inserting the anchor through the low posteromedial portal under the meniscus, and the use of knotless soft anchors with the suture-bridge technique then increases the pressurized contact area between the meniscotibial capsule and the edge of the medial tibial plateau to provide a better reduction of the MME.¹⁴ However, the effectiveness of centralization with MMPRT repair to reduce the MME has not been investigated in clinical settings.

This study aimed to investigate the efficacy of centralization combined with MMPRT repair in reducing MME, as assessed using intraoperative ultrasound. The outcomes of combined centralization and repair were compared with repair alone in patients with MMPRT. The hypothesis was that the addition of centralization would further reduce the MME beyond that obtainable by MMPRT repair alone.

Methods

Patients

This study was approved by our institution's internal review board, and informed consent was obtained from all patients. This study included 26 patients who underwent MMPRT repair with a pullout technique and centralization with 3 knotless anchors between May 2023 and May 2024. Centralization with MMPRT repair was indicated for patients who had symptomatic knee issues (such as pain, swelling, and/or catching) and had a preoperative diagnosis of MMPRT based on coronal and sagittal MRI views. In cases with varus alignment with a weightbearing line ratio of <40%, high tibial osteotomy was added after centralization with MMPRT repair. Patients with a history of previous surgery, instability due to ligament injuries, or severe varus alignment requiring double-level osteotomy were excluded.

Surgical Technique

The MMPRT repair was performed using the pullout technique and centralization with 3 knotless anchors, as previously reported,^14,15 and is briefly described here. Arthroscopy confirmed the torn edge of the MMPRT (Figure 1A) and MME (Figure 1B).

Using an MMPRT guide (Arthrex), a 6-mm diameter bone tunnel was created. A vertical mattress suture with a 2-0 FiberWire (Arthrex) and 2 racking hitch knot sutures with SutureTapes (Arthrex) were placed on the torn edge of the medial meniscus (MM), passed through the tunnel (Figure 1C), and set on the TensionLoc (Arthrex) tensioning device for measurements of meniscal extrusion.

For centralization, a mid-medial portal is made with an arthroscopic view from the anterolateral portal, 1 cm proximal to the MM and just anterior to the medial femoral condyle. The meniscotibial ligament was released to enhance the mobilization of the medial meniscus using an arthroscopic rasp through the mid-medial portal (Figure 1D), facilitating the reduction of the meniscal extrusion. If present, osteophytes at the medial tibial plateau that contained a cartilaginous component and contributed to meniscal extrusion were resected using an osteotome through the mid-medial portal. Then, three 1.8-mm Knotless FiberTak soft anchors (Arthrex) were inserted sequentially at the edge of the medial tibial plateau from the posterior to anterior—specifically, the most posterior anchor was inserted via the low posteromedial portal, while the remaining 2 were inserted via the mid-medial portal. Sutures were passed through the capsule at the meniscocapsular junction using a Knee Scorpion Suture Passer (Arthrex) and a Micro Suture Lasso (Arthrex) to approximate the capsule to the tibial plateau. The repair sutures were then passed through the anchors using shuttling suture loops and sequentially tensioned from posterior to anterior to centralize the extruded medial meniscus (Figure 1, E and F). A schematic illustration of the procedure is shown in Figure 2. Upon completion of all measurements, the pullout repair sutures were finally fixed using the TensionLoc at 60° of knee flexion.

Radiological Evaluation of Knee Alignment

Radiological evaluation of knee alignment was performed on a weightbearing long-leg radiograph using digital planning software (mediCAD). The following alignment parameters were analyzed: weightbearing line ratio, the ratio of the width of the tibial plateau from medial to lateral where the weightbearing line passes through; joint-line convergence angle, the angle between the line connecting the lowest points of the medial and lateral femoral condyles and the line connecting the points of medial and lateral tibial plateau; medial proximal tibial angle, the angle between the tibial mechanical axis and the line connecting the medial and lateral tibial plateau; and mechanical lateral distal femoral angle, the angle between the femoral mechanical axis and the line connecting the lowest points of the medial and lateral femoral condyles.

Measurement of MME on MRI

MRI was performed at 3.0 T (Achieva 3.0TX; Philips) with 16-channel coils, with the knee positioned at approximately 20° of flexion, 2 months before the surgery. Ultrasound evaluations—including MME measurements—were conducted by an experienced orthopaedic surgeon (N.O.) with >20 years of expertise in the field, who also serves as the senior ultrasound instructor at our institution. MME width was measured from the most peripheral aspect of the meniscus to the border of the tibia, excluding osteophytes on the mid-coronal slice, in fat-suppressed spoiled gradient echo sequence images.

MME Measurements by Ultrasound

Technical Protocol for Ultrasound Evaluation

MME was measured using ultrasound (11 MHz linear probe, SONIMAGE MX1, Konica Minolta, Inc) with a sleeve-covered probe, while the patient's legs remained flexed and resting on a table. Ultrasound images were obtained in longitudinal sections parallel to the medial collateral ligament, where the medial collateral ligament is best delineated.¹¹ The MME was measured from the most peripheral aspect of the meniscus to the border of the tibia, excluding osteophytes, as observed on the ultrasonography screen.^23,27

Testing of Different Initial Tensions

Initial tensions of 0, 10, 20, 30, and 40 N were applied to the pullout repair sutures using the TensionLoc device with knee flexion at 60°. MME was measured both after the MMPRT repair and after centralization. As there is no definitive evidence regarding the optimal fixation strength for pullout repair in MMPRT, this testing was designed to identify the minimum required tension when the measured MME was reduced to <3 mm.

MM Measurement at Different Knee Flexion Angles

MME was measured at knee flexions of 0°, 30°, 60°, 90°, and 120°, as well as at the manual maximum internally rotated (IR) and externally rotated (ER) positions at knee flexions of 30° and 90°. All measurements were evaluated before, after, and after centralization of the MMPRT repair. The surgeries were performed by 5 surgeons, each with over 15 years of experience, and MME was evaluated using ultrasound by 2 of them (N.O., M.A.). MME at a flexion angle of 0° was evaluated twice before MMPRT repair, after MMPRT repair, and after centralization, to assess intraobserver reliability, yielding intraclass correlation coefficients (ICCs) of 0.97 (95% CI, 0.92-0.99), 0.97 (95% CI, 0.93-0.99), and 0.95 (95% CI, 0.87-0.98), respectively. The ICCs were 0.98 (95% CI, 0.96-0.99), 0.95 (95% CI, 0.95-0.99), and 0.95 (95% CI, 0.83-0.99), respectively. The standard errors of measurement were 0.26, 0.26, and 0.20 after centralization, respectively.

Statistical Analysis

The MME across the 3 time points was compared at each knee flexion angle, and the Friedman test with Scheffé was conducted as a post hoc test using BellCurve software for Excel (Social Survey Research Information Co). The MME was also analyzed at different angles in each group. MMEs were analyzed across 3 groups (neutral, IR, and ER) and 3 time points (rotated position) using the Friedman test with the Scheffé post hoc analysis. P < .05 was considered statistically significant. MME measured by MRI and ultrasound at 30° were compared using the Mann-Whitney U test, and the correlation between them was analyzed using the Pearson correlation. Intraclass and interclass correlation coefficients were also analyzed using the same software. A power analysis was performed with statistical software (G*Power, Version 3.1.9.7; Heinrich Heine Universität Düsseldorf) before the investigation. A sample size of 22 patients was needed for an alpha of .05, a 1-β of 0.8, an effect size²⁸ of 0.4, and a power of 0.95, based on MME measurements at 3 time points: before surgery, after MMPRT repair, and after centralization with MMPRT repair. The sample size of 26 used in the present study showed a power of 0.88.

Results

Patient Characteristics

Patient characteristics are shown in Table 1. The mean age was 61 years (range, 50-76 years), and the cohort included 20 women and 6 men. Twenty patients experienced a distinct injury event, such as a popping sensation while descending stairs, stumbling, or similar events. The median time from injury to surgery was 5 months (range, 3-11 months). The Kellgren–Lawrence (KL) grading distribution was as follows: KL0 = 3, KL1 = 4, KL2 = 8, and KL3 = 11. The median (range) values for weightbearing line ratio, joint-line convergence angle, medial proximal tibial angle, and mechanical lateral distal femoral angle were 38.3% (12.6-53), 1.4° (0.1-3.9), 85.4° (81.8-88.8), and 86.8° (82-91.9), respectively. A total of 22 patients underwent additional high tibial osteotomy after MMPRT repair and centralization. Fifteen patients underwent osteophyte resection during the preparation for centralization.

Table 1

Patient Characteristics ^a

Age, years	61 (50-76)
Sex
Male	6
Female	20
Height, cm	158.7 (146.5-174)
BW, kg	61.9 (48.1-101)
BMI, kg/m²	24.5 (19.2-35.9)
Laterality
Right	9
Left	17
Time to surgery, month, n = 20	5 (3-11)
KL grade
0	3
1	4
2	8
3	11
4	0
WBLR, %	38.3 (12.6-53)
JLCA, deg	1.4 (0.1-3.9)
MPTA, deg	85.4 (81.8-88.8)
mLDFA, deg	86.8 (82-91.9)

The values are presented as number or the median (minimum-maximum). BMI, body mass index; BW, body weight; JLCA, joint line convergence angle; KL, Kellgren–Lawrence; mLDFA, mechanical lateral distal femoral angle; MPTA, medial proximal tibial angle; WBLR, weightbearing line ratio.

MME Assessment Using MRI and Ultrasound

Both MRI and ultrasound successfully depicted MME (Figure 3, A and B). Although MRI was not performed at the same knee flexion angle, the ultrasound evaluation at 30° most closely approximated it. The median MME (IQR) was 4.5 mm (3.5-5.4) on MRI and 5 mm (4.4-5.8) on ultrasound, with no significant difference between the 2 modalities (Figure 3C). There was a significant correlation between MRI and ultrasound measurements (P < .001; r = 0.86), indicating strong agreement between the 2 modalities (Figure 3D).

Applied Tension to Sutures of MMPRT Pullout Repair

With tensions of 0, 10, 20, 30, and 40 N were applied to the suture for pullout repair with the knee at 60° flexion, the median (IQR) MME was 4.8 (4.1-5.6) mm, 4.5 (4.1-5.4) mm, 4.5 (3.9-4.8) mm, 3.9 (3.4-4.6) mm, and 3.7 (3.2-4.6) mm after MMPRT repair and 3.5 (3.2-4.3) mm, 3.4 (3-3.7) mm, 3 (2.8-3.6) mm, 2.9 (2.4-3.2) mm, and 2.6 (2.4-2.9) mm after centralization, respectively. The MME decreased as tension increased, with a significant reduction observed at 30 and 40 N compared with the lower tension levels. Moreover, at tensions ≥30 N, the median MME remained <3 mm, indicating a threshold effect in which higher tension effectively minimizes meniscal extrusion. All subsequent evaluations were performed by applying 30 N tension to the MMPRT repair sutures, as ≥30 N tension reduced the MME after centralization to <3 mm (Figure 4).

Intraoperative Ultrasound Assessment of MME

Ultrasound images showed a reduction in MME after MMPRT repair and a further decrease after centralization (Figure 5). The median (interquartile range [IQR]) MMEs before MMPRT repair, after repair, and after centralization were 7.6 (5.6-9.8) mm, 3.9 (3.2-4.5) mm, and 3 (2.6-3.3) mm at 0°; 5 (4.4-5.8) mm, 4 (3.3-4.4) mm, and 2.9 (2.6-3.4) mm at 30°; 5 (3.9-6) mm, 3.7 (3.2-4.6) mm, and 2.8 (2.3-3.3) mm at 60°; 4.8 (3.9-5.7) mm, 3.6 (2.8-4.8) mm, and 2.8 (2.3-3.1) mm at 90°; and 4.4 (3.6-5.6) mm, 3.5 (2.8-5.1) mm, and 2.6 (2-3.4) mm at 120°, respectively. For all knee flexion angles, a significant reduction of MME was observed after MMPRT repair. Further reduction was observed after centralization (Figure 6).

The MMEs before MMPRT repair, after repair, and after centralization were measured at the IR and ER positions at knee flexions of 30° and 90°. At a 30° IR, the median MMEs were 5 (4-6.3) mm, 4 (3.5-4.6) mm, and 3.5 (2.9-4) mm. At a 30° ER, the median MMEs were 4.1 (2.9-5.2) mm, 3.2 (2-3.9) mm, and 2.2 (1.6-2.8) mm, respectively (Figure 7). At 30° in both the IR and ER positions, MME was significantly larger before surgery than after MMPRT repair and centralization combined with MMPRT repair. At 90° IR, the median MMEs were 4.4 (3.5-5.4) mm, 3.7 (2.9-4.5) mm, and 3.2 (2.4-3.4) mm, and at 90° ER, the median MMEs were 4.2 (3-5.2) mm, 3.2 (2.1-4) mm, and 2.3 (1.6-3.2) mm, respectively (Figure 8). At 90° in the IR position, MME was significantly smaller after centralization combined with MMPRT repair, compared with both the presurgery and post-MMPRT repair states. The MMEs at different knee flexion angles were not significantly different in any group.

Discussion

The most important finding of this study was that intraoperative ultrasound showed that MMPRT repair reduced MME, compared with the preoperative condition, with the addition of centralization further enhancing this reduction and achieving the greatest improvement compared with MMPRT repair alone.

We evaluated MME using both MRI and ultrasound. Although the timing of MRI and ultrasound assessments differed and the knee flexion angles were not identical, a significant correlation was observed between the 2 measurements. This finding suggests that ultrasound may be a reliable alternative to MRI for assessing MME, particularly because of its advantages in portability, cost-effectiveness, and real-time intraoperative applicability.

In a report on the cause of MMPRT, Krych et al¹⁸ reported that all patients in a sample of 27 symptomatic knees with serial MRI scans taken both before and after an MMPRT diagnosis demonstrated meniscotibial ligament disruption and associated meniscal extrusion before the development of MMPRT. This suggests that meniscotibial ligament disruption and MME are early and predisposing events that contribute to the occurrence of MMPRT. At that point, MMPRT repair alone may not effectively reposition the extruded meniscus to its normal position, particularly in chronic cases. Additionally, a multicenter study reported that 56% of patients who underwent MMPRT repair experienced increased postoperative meniscal extrusion, which negatively impacted their activity levels. This finding suggests that MMPRT repair alone may be insufficient to fully restore meniscal function and prevent further extrusion.¹⁹ Even after MMPRT repair, meniscotibial ligament disruption, a key factor contributing to MME, remains unaddressed without centralization. Conversely, the centralization procedure releases the meniscotibial ligament for mobilization of the medial meniscus, thereby easing the reduction of the meniscal extrusion. Additionally, if osteophytes are left untreated, another contributing factor to MME persists. The osteophytes at the medial tibial plateau, which include a cartilaginous component, are the cause of the meniscal extrusion.⁸ Therefore, osteophyte resection is an essential part of the centralization preparation process. These preparations for centralization enabled a greater reduction in MME than with MMPRT repair alone.

The definition of what degree of extrusion constitutes a pathologically meaningful meniscal extrusion is not clear. Substantial MME (>3 mm) is associated with severe meniscal degeneration, extensive tears, complex tears, large radial tears, and tears involving the meniscal root.⁵ However, Shimozaki et al²⁷ reported that the MME >2 mm, as measured via ultrasound at a knee flexion angle of 0°, was considered a significant MME, as a previous ultrasound study²⁸ indicated that even healthy adults have an MME of 0.9 ± 0.6 mm at a knee flexion angle of 0°. In the present study, the MME was reduced to <3 mm with the addition of centralization, but the extent to which deviation should be reduced remains unclear. We did not clarify in the present study whether the reduction of medial MME was associated with improved clinical outcomes, nor did we quantify the amount of extrusion reduction. However, a previous study demonstrated that clinical failure after MMPRT repair can occur even in the long term.³ Logistic regression analysis identified a postoperative increase in MM >0.7 mm as an independent predictor of failure. This finding underscores the importance of minimizing MME whenever possible to optimize long-term outcomes.

In this series, we performed high tibial osteotomy for medial meniscal root tears with <40% of the weightbearing axis. When centralization was performed on varus knee joints without this, the reduction in MME could be obtained. However, a previous study revealed that poor clinical outcomes after medial meniscal root repairs were attributable to residual MME and varus alignment.³ Therefore, we believe that both the centralization and correction of alignment are critical for better clinical outcomes in varus alignment.

Ultrasound can evaluate meniscal extrusion at different flexion angles of the knee joint, while MRI can only evaluate meniscal deviation at a given angle. Shimozaki et al²⁷ evaluated MME using ultrasonography and classified patients with abnormal MME into 2 groups: the decreased group and the nondecreased group during knee flexion. The reduced group was defined as cases in which MME decreased by >1 mm at 90° of knee flexion compared with 0° of knee flexion. Most cases in the nondecreased group had MMPRT or radial tears and showed no decrease in MME for knee flexions from 0° to 90°, indicating a loss of meniscal hoop function. In the present study, no significant reduction in meniscal extrusion was observed under any of the 3 conditions during knee flexion. This discrepancy may be due to differences in patient characteristics: our study included patients with MMPRT, whereas that study focused on patients with early-stage osteoarthritis.

Meniscal extrusion decreased during IR at a knee flexion of 30° compared with neutral or IR. This is likely due to increases in tension in the meniscotibial ligament and the capsule, which then reduce meniscal extrusion. At a knee flexion of 90°, the tension did not change, possibly because the capsule became looser than at 30°. We did not determine whether MMPRT repair should be fixed at the ER position. However, because we fixed the pullout sutures at the flexed position, the effect of rotation must have been minimal. Further study is necessary to confirm the optimal rotation angle for fixing the MMPRT repair.

Our study has several limitations. First, it was conducted at time zero during surgery; therefore, whether the results will be maintained long term is unclear. Second, all subsequent evaluations were performed by applying 30 N of tension to the MMPRT repair sutures, as using 30 N or more reduced MME to <3 mm after centralization. However, there remains no definitive evidence regarding the optimal fixation strength. Comparisons between single- and double-transtibial tunnels have shown that both configurations result in similar displacement and ultimate failure loads, with only a slight, nonsignificant advantage observed in the 2-tunnel technique.²¹ Analyses of repair construct displacement under cyclic loading have revealed that the meniscus-suture interface is the primary contributor to overall displacement, while the button-bone interface and suture elongation have relatively minor effects.² Despite these comprehensive biomechanical assessments, there remains no conclusive evidence regarding the optimal fixation strength for MMPRT repair, emphasizing the need for further research to establish standardized fixation parameters. Third, ultrasound evaluations were performed after arthroscopy under all three conditions; however, it remains possible that arthroscopic fluid might have affected meniscal extrusion. However, as the MMPRT repair was performed first, followed by centralization, the total arthroscopic duration was longest in the centralization group. If arthroscopic fluid were to influence the position of the medial meniscus, it would likely push the MME outward, rather than reduce it. However, the centralization group exhibited the greatest reduction in MME. With this in mind, we believe that the effect of arthroscopic fluid on this study is minimal. Fourth, we did not evaluate the impact of centralization under weightbearing conditions. Given that meniscal load increases during walking, future studies should examine outcomes under weightbearing conditions. A previous study assessed MME under loading conditions using ultrasonography and MRI in patients with early knee osteoarthritis and reported that 75% of patients exhibited MME >2 mm in the supine position at full extension. Further research is needed to clarify the effect of MMPRT repair and MMPRT repair combined with centralization in standing and walking conditions. Lastly, whether reducing MME will preserve cartilage condition remains unclear. Long-term follow-up is necessary to confirm these findings.

Conclusion

Intraoperative ultrasound demonstrated that MMPRT repair reduced MME, compared with the preoperative condition, and the addition of centralization further enhanced this reduction, achieving the greatest improvement compared with MMPRT repair alone.

Footnotes

Acknowledgements

The authors thank Ms Hisako Katano and Ms Chiaki Okumura for managing our laboratory.

Submitted March 25, 2025; accepted November 6, 2025.

One or more of the authors has declared the following potential conflict of interest or source of funding: This study was funded by Nobutake Ozeki and the Japan Society for the Promotion of Science (22K09301). AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto. This study was approved by the internal review board of the Institute of Science Tokyo, and informed consent was obtained from all patients.

ORCID iDs

Nobutake Ozeki

Yusuke Nakagawa

Takashi Hoshino

Ichiro Sekiya

Hideyuki Koga

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