The BTLA-HVEM axis restricts CAR T cell efficacy in cancer.

The efficacy of T cell-based immunotherapies is limited by immunosuppressive pressures in the tumor microenvironment. Here we show a predominant role for the interaction between BTLA on effector T cells and HVEM (TNFRSF14) on immunosuppressive tumor microenvironment cells, namely regulatory T cells. High BTLA expression in chimeric antigen receptor (CAR) T cells correlated with poor clinical response to treatment. Therefore, we deleted BTLA in CAR T cells and show improved tumor control and persistence in models of lymphoma and solid malignancies. Mechanistically, BTLA inhibits CAR T cells via recruitment of tyrosine phosphatases SHP-1 and SHP-2, upon trans engagement with HVEM. BTLA knockout thus promotes CAR signaling and subsequently enhances effector function. Overall, these data indicate that the BTLA-HVEM axis is a crucial immune checkpoint in CAR T cell immunotherapy and warrants the use of strategies to overcome this barrier.

Safety and efficacy of a novel anti-CD19 chimeric antigen receptor T cell product targeting a membrane-proximal domain of CD19 with fast on- and off-rates against non-Hodgkin lymphoma: a first-in-human study.

BACKGROUND: Commercial anti-CD19 chimeric antigen receptor T-cell therapies (CART19) are efficacious against advanced B-cell non-Hodgkin lymphoma (NHL); however, most patients ultimately relapse. Several mechanisms contribute to this failure, including CD19-negative escape and CAR T dysfunction. All four commercial CART19 products utilize the FMC63 single-chain variable fragment (scFv) specific to a CD19 membrane-distal epitope and characterized by slow association (on) and dissociation (off) rates. We hypothesized that a novel anti-CD19 scFv that engages an alternative CD19 membrane-proximal epitope independent of FMC63 and that is characterized by faster on- and off-rates could mitigate CART19 failure and improve clinical efficacy. METHODS: We developed an autologous CART19 product with 4-1BB co-stimulation using a novel humanized chicken antibody (h1218). This antibody is specific to a membrane-proximal CD19 epitope and harbors faster on/off rates compared to FMC63. We tested h1218-CART19 in vitro and in vivo using FMC63-CART19-resistant models. We conducted a first-in-human multi-center phase I clinical trial to test AT101 (clinical-grade h1218-CART19) in patients with relapsed or refractory (r/r) NHL. RESULTS: Preclinically, h1218- but not FMC63-CART19 were able to effectively eradicate lymphomas expressing CD19 point mutations (L174V and R163L) or co-expressing FMC63-CAR19 as found in patients relapsing after FMC63-CART19. Furthermore, h1218-CART19 exhibited enhanced killing of B-cell malignancies in vitro and in vivo compared with FMC63-CART19. Mechanistically, we found that h1218-CART19 had reduced activation-induced cell death (AICD) and enhanced expansion compared to FMC63-CART19 owing to faster on- and off-rates. Based on these preclinical results, we performed a phase I dose-escalation trial, testing three dose levels (DL) of AT101 (the GMP version of h1218) using a 3 + 3 design. In 12 treated patients (7 DLBCL, 3 FL, 1 MCL, and 1 MZL), AT101 showed a promising safety profile with 8.3% grade 3 CRS (n = 1) and 8.3% grade 4 ICANS (n = 1). In the whole cohort, the overall response rate was 91.7%, with a complete response rate of 75.0%, which improved to 100% in DL-2 and -3. AT101 expansion correlates with CR and B-cell aplasia. CONCLUSIONS: We developed a novel, safe, and potent CART19 product that recognizes a membrane-proximal domain of CD19 with fast on- and off-rates and showed significant efficacy and promising safety in patients with relapsed B-cell NHL. TRIAL REGISTRATION: NCT05338931; Date: 2022-04-01.

Bispecific Antibody Molecule Inhibits Tumor Cell Proliferation More Efficiently Than the Two-Molecule Combination.

BACKGROUND: Monoclonal antibodies (mAbs) have proved to be a valuable tool for the treatment of different cancer types. However, clinical use of an increasing number of mAbs, have also highlighted limitations with monotherapy for cancers, in particular for such with more complex mechanisms, requiring action on additional molecules or pathways, or for cancers quickly acquiring resistance following monotherapy. An example for the latter is the mAb trastuzumab, FDA approved for treatment of metastatic gastric carcinoma. To circumvent this, researchers have reported synergistic, anti-proliferative effects by combination targeting of HER2 and EGFR by trastuzumab and the EGFR-targeting mAb Cetuximab overcoming trastuzumab resistance. METHODS: Maintaining the proven functionality of trastuzumab, we have designed bi-specific antibody molecules, called AffiMabs, by fusing an EGFR-targeting Affibody molecule to trastuzumab's heavy or light chains. Having confirmed binding to EGFR and Her2 and cytotoxicity of our AffiMabs, we analyzed apoptosis rate, receptor surface levels, phosphorylation levels of receptors and associated signaling pathways as well as differentially expressed genes on transcriptome level with the aim to elucidate the mode of action of our AffiMabs. RESULTS: The AffiMabs are able to simultaneously bind HER2 and EGFR and show increased cytotoxic effect compared to the original trastuzumab therapeutic molecule and, more importantly, even to the combination of trastuzumab and EGFR-targeting Affibody molecule. Analyzing the mode of action, we could show that bi-specific AffiMabs lead to reduced surface receptor levels and a downregulation of cell cycle associated genes on transcriptome level. CONCLUSION: Our study shows that transcriptome analysis can be used to validate the choice of receptor targets and guide the design of novel multi-specific molecules. The inherent modularity of the AffiMab format renders it readily applicable to other receptor targets.

Establishment of a Patient-derived Xenograft for Development of Personalized HER2-targeting Therapy in Gastric Cancer.

BACKGROUND/AIM: To maximize success rate for development of HER2-targeted therapeutics, patient-derived xenograft (PDX) models reflecting HER2-positive gastric cancer (HER2+ GC) patients were established. MATERIALS AND METHODS: GC tissues obtained from surgery of GC patients were implanted into immune-deficient mice, and tumor tissue of HER2+ PDXs were verified of the patient-mimic HER2 expression by immunohistochemistry and explored for the feasibility by testing with Herceptin, the approved therapeutics and novel HER2 antibody therapeutics being developed. RESULTS: We obtained 5 cases of HER2+ GC PDX models reflecting patient's GC tumor, consisting of 2 cases of HER2 3+ and 2 cases of HER2 2+. Novel HER2 antibody displayed significantly improved anti-cancer efficacy in combination with Herceptin. CONCLUSION: The HER2+ GC PDX models were successfully established to be utilized for preclinical evaluation of HER2-targeting drugs and combined therapies for GC treatment, as an ideal platform of personalized tools for precision therapy.

The Clinical Analysis of the Nasal Septal Cartilage by Measurement Using Computed Tomography.

BACKGROUND: The nasal septal cartilage is often used as a donor graft in rhinoplasty operations but can vary widely in size across the patient population. As such, preoperative estimation of the cartilaginous area is important for patient counseling as well as operating planning. We aim to estimate septal cartilage area by using facial computed tomography (CT) studies. METHODS: The study was performed using facial CT images taken from 200 patients between January 2012 to July 2015. Using the mid-sagittal image, the boundary of cartilaginous septum was delineated from soft tissue using the mean difference in signal intensity (or brightness). The area within this boundary was calculated. The calculated area for septal cartilage was then compared across age groups and sexes. RESULTS: Overall, the mean area of nasal septal cartilage was 8.18 cm2 with the maximum of 12.42 cm2 and the minimum of 4.89 cm2. The cartilage areas were measured to be larger in men than in women (p<0.05). The area decreased with advancing age (p<0.05). CONCLUSION: Measuring the size of septal cartilage using brightness difference is more precise and reliable than previously reported methods. This method can be utilized as the standard for prevention of postoperative complication.

Clinical Analysis of Lobular Keloid after Ear Piercing.

BACKGROUND: Lobular keloid appears to be a consequence of hypertrophic inflammation secondary to ear piercings performed under unsterile conditions. We wish to understand the pathogenesis of lobular keloids and report operative outcomes with a literature review. METHODS: A retrospective review identified 40 cases of lobular keloids between January, 2005 and December, 2010. Patient records were reviewed for preclinical factors such as presence of inflammation after ear piercing prior to keloid development, surgical management, and histopathologic correlation to recurrence. RESULTS: The operation had been performed by surgical core extirpation or simple excision, postoperative lobular compression, and scar ointments. Perivascular infiltration was noted in intra- and extra-keloid tissue in 70% of patients. The postoperative recurrence rate was 10%, and most of the patients satisfied with treatment outcomes. CONCLUSION: Histological perivascular inflammation is a prominent feature of lobular keloids. Proper surgical treatment, adjuvant treatments, and persistent follow-up observation were sufficient in maintaining a relatively low rates of recurrence.

Reduction of Nasal Bone Fracture using Ultrasound Imaging during Surgery.

BACKGROUND: Most nasal bone fractures are corrected using non-invasive methods. Often, patients are dissatisfied with surgical outcomes following such closed approach. In this study, we compare surgical outcomes following blind closed reduction to that of ultrasound-guided reduction. METHODS: A single-institutional prospective study was performed for all nasal fracture patients (n=28) presenting between May 2013 and November 2013. Upon research consent, patients were randomly assigned to either the control group (n=14, blind reduction) or the experimental group (n=14, ultrasound-guided reduction). Surgical outcomes were evaluated using preoperative and 3-month postoperative X-ray images by two independent surgeons. Patient satisfaction was evaluated using a questionnaire survey. RESULTS: The experimental group consisted of 4 patients with Plane I fracture and 10 patients with Plane II fracture. The control group consisted of 3 patients with Plane I fracture and 11 patients with Plane II fracture. The mean surgical outcomes score and the mean patient dissatisfaction score were found not to differ between the experimental and the control group in Plane I fracture (p=0.755, 0.578, respectively). In a subgroup analysis consisting of Plane II fractures only, surgeons graded outcomes for ultrasound-guided reduction higher than that for the control group (p=0.007). Likewise, among the Plane II fracture patients, those who underwent ultrasound-guided reduction were less dissatisfied than those who underwent blind reduction (p=0.043). CONCLUSION: Our study result suggests that ultrasound-guided closed reduction is superior to blind closed reduction in those patients with Plane II nasal fractures.

Improvement of Infraorbital Rim contour Using Medpor.

BACKGROUND: Asymmetry of the infraorbital rim can be caused by trauma, congenital or acquired disease, or insufficient reduction during a previous operation. Such asymmetry needs to be corrected because the shape of the infraorbital rim or midfacial skeleton defines the overall midfacial contour. METHODS: The study included 5 cases of retruded infraorbital rim. All of the patient underwent restoration of the deficient volume using polyethylene implants between June 2005 and June 2011. The infraorbital rim was accessed through a subciliary approach, and the implants were placed in subperiosteal space. Surgical outcomes were evaluated using preoperative and postoperative computed tomography studies. RESULTS: Implant based augmentation was associated with a mean projection of 4.6 mm enhancement. No postoperative complications were noted during the 30-month follow-up period. CONCLUSION: Because of the safeness, short recovery time, effectiveness, reliability, and potential application to a wide range of facial disproportion problems, this surgical technique can be applied to midfacial retrusion from a variety of etiologies, such as fracture involving infraorbital rim, congenital midfacial hypoplasia, lid malposition after blepharoplasty, and skeletal changes due to aging.

Malignant Skin Tumor Misdiagnosed as a Benign Skin Lesion.

Despite the fact that benign skin lesions can undergo malignant transformation, the necessity and timing of the surgical resection have yet to be established. In this study, we analyse three cases of benign-appearing skin lesions, which were found to be carcinomatous on histologic examination and review the literature regarding the importance of prophylactic removal of benign-appearing skin lesion. The first and second cases were female patients wishing for cosmetic surgery. The first patient had a benign-appearing lesion on dorsum nasi, and the second patient had an inconspicuous lesion right along the right nasolabial fold. The third patient was a middle-aged male with a pigmented lesion on the left cheek, who presented to the clinic only after having met the operating surgeon through an acquaintance outside the hospital setting. All of the lesions were suspected to be of benign nature and were excised for cosmesis only. However, histologic examination of these lesions showed that the first two tumors were basal cell carcinoma with the last tumor being squamouse cell carcinoma. Thus, it is considered that removal of benign like skin lesion will result in good prognosis of patients scheduled to undergo other surgery.

Aesthetic Facial Correction of Cleidocranial Dysplasia.

We report two cases of cleidocranial dysplasia, which was managed without significant craniofacial osteotomy. A mother and daughter, both of normal intelligence, presented with central forehead depression, mid-face hypoplasia, and blepharoptosis. The fact that they have an identically deformed face implied a genetic basis. In both patients, radiologic evaluation revealed the underdeveloped maxilla, persistent fontanelle opening, and cleidal aplasia. Clinical findings and radiologic studies were consistent with the diagnosis of cleidocranial dysplasia. Both patients underwent forehead plasty via bicoronal approach, augmentation rhinoplasty using tip plasty, and epicanthoplasty. In addition, the mother underwent malar augmentation using Medpor implantation and reduction genioplasty. The patients did not experience any postoperative complication and remained satisfied with the operation at 6-year follow-up.

Affinity Maturation of Monoclonal Antibody 1E11 by Targeted Randomization in CDR3 Regions Optimizes Therapeutic Antibody Targeting of HER2-Positive Gastric Cancer.

Anti-HER2 murine monoclonal antibody 1E11 has strong and synergistic anti-tumor activity in HER2-overexpressing gastric cancer cells when used in combination with trastuzumab. We presently optimized this antibody for human therapeutics. First, the complementarity determining regions (CDRs) of the murine antibody were grafted onto human germline immunoglobulin variable genes. No difference in affinity and biological activity was observed between chimeric 1E11 (ch1E11) and humanized 1E11 (hz1E11). Next, affinity maturation of hz1E11 was performed by the randomization of CDR-L3 and H3 residues followed by stringent biopanning selection. Milder selection pressure favored the selection of more diverse clones, whereas higher selection stringency resulted in the convergence of the panning output to a smaller number of clones with improved affinity. Clone 1A12 had four amino acid substitutions in CDR-L3, and showed a 10-fold increase in affinity compared to the parental clone and increased potency in an in vitro anti-proliferative activity assay with HER2-overepxressing gastric cancer cells. Clone 1A12 inhibited tumor growth of NCI-N87 xenograft model with similar efficacy to trastuzumab alone, and the combination treatment of 1A12 and trastuzumab completely removed the established tumors. These results suggest that humanized and affinity matured monoclonal antibody 1A12 is a highly optimized molecule for future therapeutic development against HER2-positive tumors.

Comparison of the viability of cryopreserved fat tissue in accordance with the thawing temperature.

BACKGROUND: Adipose tissue damage of cryopreserved fat after autologous fat transfer is inevitable in several processes of re-transplantation. This study aims to compare and analyze the survivability of adipocytes after thawing fat cryopreserved at -20℃ by using thawing methods used in clinics. METHODS: The survival rates of adipocytes in the following thawing groups were measured: natural thawing at 25℃ for 15 minutes; natural thawing at 25℃ for 5 minutes, followed by rapid thawing at 37℃ in a water bath for 5 minutes; and rapid thawing at 37℃ for 10 minutes in a water bath. The survival rates of adipocytes were assessed by measuring the volume of the fat layer in the top layers separated after centrifugation, counting the number of live adipocytes after staining with trypan blue, and measuring the activity of mitochondria in the adipocytes. RESULTS: In the group with rapid thawing for 10 minutes in a water bath, it was observed that the cell count of live adipocytes and the activity of the adipocyte mitochondria were significantly higher than in the other two groups (P<0.05). The volume of the fat layer separated by centrifugation was also measured to be higher, which was, however, not statistically significant. CONCLUSIONS: It was shown that the survival rate of adipocytes was higher when the frozen fat tissue was thawed rapidly at 37℃. It can thus be concluded that if fats thawed with this method are re-transplanted, the survival rate of cryopreserved fats in transplantation will be improved, and thus, the effect of autologous fat transfer will increase.

Combination of novel HER2-targeting antibody 1E11 with trastuzumab shows synergistic antitumor activity in HER2-positive gastric cancer.

The synergistic interaction of two antibodies targeting the same protein could be developed as an effective anti-cancer therapy. Human epidermal growth factor receptor 2 (HER2) is overexpressed in 20-25% of breast and gastric cancer patients, and HER2-targeted antibody therapy using trastuzumab is effective in many of these patients. Nonetheless, improving therapeutic efficacy and patient survival is important, particularly in patients with HER2-positive gastric cancer. Here, we describe the development of 1E11, a HER2-targeted humanized monoclonal antibody showing increased efficacy in a highly synergistic manner in combination with trastuzumab in the HER2-overexpressing gastric cancer cell lines NCI-N87 and OE-19. The two antibodies bind to sub-domain IV of the receptor, but have non-overlapping epitopes, allowing them to simultaneously bind HER2. Treatment with 1E11 alone induced apoptosis in HER2-positive cancer cells, and this effect was enhanced by combination treatment with trastuzumab. Combination treatment with 1E11 and trastuzumab reduced the levels of total HER2 protein and those of aberrant HER2 signaling molecules including phosphorylated HER3 and EGFR. The synergistic antitumor activity of 1E11 in combination with trastuzumab indicates that it could be a novel potent therapeutic antibody for the treatment of HER2-overexpressing gastric cancers.

Transposition of intravascular lipid in experimentally induced fat embolism: a preliminary study.

BACKGROUND: Liposuction is a procedure to reduce the volume of subcutaneous fat by physical force. Intracellular storage fat is composed of triglyceride, whereas circulating fat particles exist as cholesterol or triglycerol bound to carrier proteins. It is unavoidable that the storage form of fat particles enters the circulation system after these particles are physiologically destroyed. To date, however, no studies have clarified the fatal characteristics of fat embolism that occurs after the subclinical phase of free fat particles. METHODS: A mixture of human lipoaspirate and normal saline (1:100, 0.2 mL) was injected into the external jugular vein of rats, weighing 200 g on average. Biopsy specimens of the lung and kidney were examined at 12-hour intervals until postoperative 72 hours. The deposit location and transport of the injected free fat particles were confirmed histologically by an Oil Red O stain. RESULTS: Inconsistent with previous reports, free fat particles were transported from the intravascular space to the parenchyma. At 24 hours after infusion, free fat particles deposited in the vascular lumen were confirmed on the Oil Red O stain. At 72 hours after infusion, free fat particles were accumulated compactly within the parenchymal space near the perivascular area. CONCLUSIONS: Many surgeons are aware of the fatal results and undiscovered pathophysiologic mechanisms of free fat particles. Our results indicate that free fat particles, the storage form of fat that has been degraded through a physiological process, might be removed through a direct transport mechanism and phagocytotic uptake.

Z-lengthening of the Achilles tendon with transverse skin incision.

BACKGROUND: The risk of various complications after Achilles tendon lengthening is mainly related to the length of surgical exposure and the lengthening method. A comprehensive technique to minimize the complications is required. METHODS: The treatment of Achilles tendon tightness in 57 patients (95 ankles) were performed by using a short transverse incision on a skin crease of the heel and by Z-lengthening of the tendon. In the severe cases, two or three transverse incisions were required for greater lengthening of the tendon, and a serial cast or Ilizarov apparatus was applied for the gradual correction. The results of these 95 ankles were compared to those of 18 ankles, which underwent percutaneous sliding lengthening, and to the 19 ankles, which received Z-lengthening with a medial longitudinal incision. RESULTS: The functional and cosmetic satisfaction was achieved among those who underwent the tendon lengthening with the new technique. The mean American Orthopaedic Foot & Ankle Society (AOFAS) score improved from 56.1 to 81.8. The second operations to correct recurrence were performed in the two cerebral palsy patients. CONCLUSIONS: The new technique has a low rate of complications such as scarring, adhesion, total transection, excessive lengthening, and recurrence of shortening. The excellent cosmesis and the short operation time are the additional advantages.

Clinical Characteristics of the Forehead Lipoma.

BACKGROUND: Lipomas can be categorized into deep and superficial lipomas according to anatomical depth. Many cases of forehead lipomas are reported to be deep to the muscle layer. We analyze ultrasound in delineating depth of forehead lipomas. METHODS: A retrospective review was performed for all patients who underwent excision of forehead lipomas between January 2008 and March 2013 and for whom preoperative ultrasound study was available. Sensitivity and specificity of ultrasound imaging was evalauted against depth finding at the time of surgical excision. RESULTS: The review identified 42 patients who met the inclusion criteria. Preoperative ultrasound reading was 18 as deep lipomas and 24 as superficial. However, intraoperative finding revealed 2 of the 18 deep lipomas to be superficial and 13 of the 24 superficial lipomas to be deep lipomas. Overall, ultrasonography turned out to be 69% (29/42) accurate in correctly delineating superficial versus deep lipomas. CONCLUSION: Lipomas of the forehead tend to be located in deeper tissue plane compared to lipomas found elsewhere in the body. Preoperative ultrasonography of lipomas can be helpful, but was not accurate in identifying the depth of forehead lipomas in our patient population. Even if a forehead lipoma is found to be superficial on ultrasound, operative planning should include the possibility of deep lipomas.

Does valgus femoral osteotomy improve femoral head roundness in severe Legg-Calvé-Perthes disease?

BACKGROUND: Many surgeons perform a varus femoral or Salter pelvic osteotomy in patients with Legg-Calvé-Perthes (LCP) disease. However, more severely deformed femoral heads show greater congruency in adduction rather than in abduction. Therefore, a valgus-(flexion) femoral osteotomy (VFO) seems preferable rather than a varus femoral or Salter pelvic osteotomy. QUESTIONS/PURPOSES: We evaluated whether the VFO improves (1) femoral head roundness, (2) radiographic parameters reflecting hip subluxation, and (3) function. METHODS: We treated 25 patients (25 hips; 18 lateral pillar C and seven B) in the late fragmentation stage by VFO. Seven patients had additional pelvic procedures. VFO was performed at a mean age of 9.8 years. Three hips were Stulberg Class II, 20 were Class III, and two were Class IV. The following components of femoral head roundness were calculated from preoperative MRI and final radiographs: lateral and medial head roundness (LHR and MHR); anterior and posterior head roundness (AHR and PHR); central head height; and the ratios MHR/LHR and PHR/AHR. Continuity of Shenton's line, medial gap ratio were evaluated. Function was determined with the Iowa hip score. Minimum followup was 3.1 years (mean, 6.3 years; range, 3.1-11.2 years). RESULTS: All femoral head roundness measurements improved, with greatest improvement in the lateral and anterior head. Pillar C hips showed greater relative improvement than pillar B hips. The continuity of Shenton's line improved and the mean medial gap ratio decreased. Mean Iowa hip score improved from 71 before surgery to 90 at the last followup. CONCLUSIONS: VFO appears to help the deformed femoral head in the fragmentation stage to remodel to fit the acetabulum. LEVEL OF EVIDENCE: Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Early results of one-stage correction for hip instability in cerebral palsy.

BACKGROUND: We evaluated the clinical and radiological results of one-stage correction for cerebral palsy patients. METHODS: We reviewed clinical outcomes and radiologic indices of 32 dysplastic hips in 23 children with cerebral palsy (13 males, 10 females; mean age, 8.6 years). Ten hips had dislocation, while 22 had subluxation. Preoperative Gross Motor Function Classification System (GMFCS) scores of the patients were as follows; level V (13 patients), level IV (9), and level III (1). Acetabular deficiency was anterior in 5 hips, superolateral in 7, posterior in 11 and mixed in 9, according to 3 dimensional computed tomography. The combined surgery included open reduction of the femoral head, release of contracted muscles, femoral shortening varus derotation osteotomy and the modified Dega osteotomy. Hip range of motion, GMFCS level, acetabular index, center-edge angle and migration percentage were measured before and after surgery. The mean follow-up period was 28.1 months. RESULTS: Hip abduction (median, 40°), sitting comfort and GMFCS level were improved after surgery, and pain was decreased. There were two cases of femoral head avascular necrosis, but no infection, nonunion, resubluxation or redislocation. All radiologic indices showed improvement after surgery. CONCLUSIONS: A single event multilevel surgery including soft tissue, pelvic and femoral side correction is effective in treating spastic dislocation of the hip in cerebral palsy.

MR-based parameters as a supplement to radiographs in managing developmental hip dysplasia.

BACKGROUND: Some dysplastic hips with favorable radiographic parameters fail to develop normally, suggesting that we should consider cartilaginous or soft tissue structures for further information regarding the condition of the hip. The purpose of this study was to provide a clear definition of concentric reduction in developmental dysplasia of the hip (DDH) based on magnetic resonance imaging (MRI), and to determine how radiographic and MR-based parameters could be used together to treat dysplastic hips. METHODS: We studied range of motion (ROM)-MRI of 25 patients with unilateral hip dysplasia (mean age at the time of MR imaging, 44.1 months). Each ROM-MRI consisted of a set of bilateral hip scans in the following positions: neutral; abduction; abduction- internal rotation; abduction-internal rotation-flexion; and adduction. Before MR scanning, the 25 patients received the following primary treatments: closed reduction (n = 15; at a mean age of 14.5 months); and open reduction (n = 10; at a mean age of 10.0 months). The following new parameters appear to be useful in treating DDH: 1) the labral angle, the angle the labrum makes with the acetabulum; 2) the uncorrected labral deformity (ULD), the "residual deformity" (deflection of the labrum) when the affected labrum is freed from pressure in abduction; and 3) the zone of compressive force (ZCF), the region of the acetabulum through which the body weight acts on the femoral head. RESULTS: A concentrically-reduced hip is one in which the labrum points downward in the neutral position, at the same angle as that of the normal side; and in which the ZCF is zone 3, the inner acetabular zone as defined herein. The ULD and the ZCF may be determined precisely as we have done, or the physician may simply observe the changes in the orientation of the labrum and compare the changes qualitatively to the unaffected side, and likewise for the medial joint space. CONCLUSIONS: Detailed analysis of the labrum as permitted by ROM-MRI, together with acetabular index and other parameters measured from radiographs, provides important information for physicians treating childhood hip dysplasia.