FOXP1 suppresses immune response signatures and MHC class II expression in activated B-cell-like diffuse large B-cell lymphomas.

The FOXP1 (forkhead box P1) transcription factor is a marker of poor prognosis in diffuse large B-cell lymphoma (DLBCL). Here microarray analysis of FOXP1-silenced DLBCL cell lines identified differential regulation of immune response signatures and major histocompatibility complex class II (MHC II) genes as some of the most significant differences between germinal center B-cell (GCB)-like DLBCL with full-length FOXP1 protein expression versus activated B-cell (ABC)-like DLBCL expressing predominantly short FOXP1 isoforms. In an independent primary DLBCL microarray data set, multiple MHC II genes, including human leukocyte antigen DR alpha chain (HLA-DRA), were inversely correlated with FOXP1 transcript expression (P<0.05). FOXP1 knockdown in ABC-DLBCL cells led to increased cell-surface expression of HLA-DRA and CD74. In R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone)-treated DLBCL patients (n=150), reduced HLA-DRA (<90% frequency) expression correlated with inferior overall survival (P=0.0003) and progression-free survival (P=0.0012) and with non-GCB subtype stratified by the Hans, Choi or Visco-Young algorithms (all P<0.01). In non-GCB DLBCL cases with <90% HLA-DRA, there was an inverse correlation with the frequency (P=0.0456) and intensity (P=0.0349) of FOXP1 expression. We propose that FOXP1 represents a novel regulator of genes targeted by the class II MHC transactivator CIITA (MHC II and CD74) and therapeutically targeting the FOXP1 pathway may improve antigen presentation and immune surveillance in high-risk DLBCL patients.

Reduced expression of TRIM21/Ro52 predicts poor prognosis in diffuse large B-cell lymphoma patients with and without rheumatic disease.

OBJECTIVE: TRIM21 (also known as Ro52) is an autoantigen in rheumatic disease and is predominantly expressed in leucocytes. Overexpression is associated with decreased proliferation, and the TRIM21 gene maps to a tumour suppressor locus. We therefore investigated the expression of TRIM21 in patients with diffuse large B-cell lymphoma (DLBCL) and its potential usefulness as a prognostic biomarker. MATERIALS AND METHODS: TRIM21 expression levels were assessed by immunohistochemistry in lymphoma biopsies from three cohorts of patients with DLBCL: 42 patients with rheumatic disease treated with a cyclophosphamide, vincristine, doxorubicin and prednisone (CHOP)-like regimen, 76 CHOP-treated and 196 rituximab-CHOP-treated nonrheumatic patients. Expression was correlated with clinical and biomedical parameters. TRIM21 expression was assessed in relation to lymphocyte proliferation by quantitative PCR and correlated with (3) H-thymidine incorporation and propidium iodine staining. RESULTS: TRIM21 expression levels differed in the lymphomas compared to normal lymphoid tissue, with reduced expression correlating with shorter overall survival in all three cohorts. In the two larger cohorts, progression-free survival was assessed and was also found to correlate with TRIM21 expression. The association was independent of commonly used clinical prognostic scores, lymphoma subtype and several previously reported prognostic biomarkers. In agreement with this clinical observation, we noted an inverse correlation between TRIM21 expression and proliferation of leucocytes in vitro. CONCLUSIONS: We show that loss of TRIM21 expression is associated with more aggressive lymphoma and increased proliferation, whereas maintenance of TRIM21 expression is associated with better prognosis in patients with DLBCL. Based on our findings, we suggest that TRIM21 should be considered as a novel biomarker for lymphoma characterization and for predicting patient survival.

Reciprocal expression of the endocytic protein HIP1R and its repressor FOXP1 predicts outcome in R-CHOP-treated diffuse large B-cell lymphoma patients.

We previously identified autoantibodies to the endocytic-associated protein Huntingtin-interacting protein 1-related (HIP1R) in diffuse large B-cell lymphoma (DLBCL) patients. HIP1R regulates internalization of cell surface receptors via endocytosis, a process relevant to many therapeutic strategies including CD20 targeting with rituximab. In this study, we characterized HIP1R expression patterns, investigated a mechanism of transcriptional regulation and its clinical relevance in DLBCL patients treated with immunochemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone, R-CHOP). HIP1R was preferentially expressed in germinal center B-cell-like DLBCL (P<0.0001) and inversely correlated with the activated B-cell-like DLBCL (ABC-DLBCL) associated transcription factor, Forkhead box P1 (FOXP1). HIP1R was confirmed as a direct FOXP1 target gene in ABC-DLBCL by FOXP1-targeted silencing and chromatin immunoprecipitation. Lower HIP1R protein expression (≤ 10% tumoral positivity) significantly correlated with inferior overall survival (OS, P=0.0003) and progression-free survival (PFS, P=0.0148) in R-CHOP-treated DLBCL patients (n=157). Reciprocal expression with ≥ 70% FOXP1 positivity defined FOXP1(hi)/HIP1R(lo) patients with particularly poor outcome (OS, P=0.0001; PFS, P=0.0016). In an independent R-CHOP-treated DLBCL (n=233) microarray data set, patients with transcript expression in lower quartile HIP1R and FOXP1(hi)/HIP1R(lo) subgroups exhibited worse OS, P=0.0044 and P=0.0004, respectively. HIP1R repression by FOXP1 is strongly associated with poor outcome, thus further understanding of FOXP1-HIP1R and/or endocytic signaling pathways might give rise to novel therapeutic options for DLBCL.

Comprehensive gene expression profiling and immunohistochemical studies support application of immunophenotypic algorithm for molecular subtype classification in diffuse large B-cell lymphoma: a report from the International DLBCL Rituximab-CHOP Consortium Program Study.

Gene expression profiling (GEP) has stratified diffuse large B-cell lymphoma (DLBCL) into molecular subgroups that correspond to different stages of lymphocyte development-namely germinal center B-cell like and activated B-cell like. This classification has prognostic significance, but GEP is expensive and not readily applicable into daily practice, which has lead to immunohistochemical algorithms proposed as a surrogate for GEP analysis. We assembled tissue microarrays from 475 de novo DLBCL patients who were treated with rituximab-CHOP chemotherapy. All cases were successfully profiled by GEP on formalin-fixed, paraffin-embedded tissue samples. Sections were stained with antibodies reactive with CD10, GCET1, FOXP1, MUM1 and BCL6 and cases were classified following a rationale of sequential steps of differentiation of B cells. Cutoffs for each marker were obtained using receiver-operating characteristic curves, obviating the need for any arbitrary method. An algorithm based on the expression of CD10, FOXP1 and BCL6 was developed that had a simpler structure than other recently proposed algorithms and 92.6% concordance with GEP. In multivariate analysis, both the International Prognostic Index and our proposed algorithm were significant independent predictors of progression-free and overall survival. In conclusion, this algorithm effectively predicts prognosis of DLBCL patients matching GEP subgroups in the era of rituximab therapy.

Patterns among sexual assault victims seeking treatment services.

The validity and reliability of research on the nature and extent of sexual assault tends to be affected by different definitions, methodologies, and measurements. As a result, two important aspects of sexual assault associated with patterns of symptom expression and therapeutic interventions are not often reflected in the research; the severity of the assault, including the duration of the abuse, and the age at the time of the assault and the gender of the victim. This research is based on intake forms from Hawai;i's only statewide provider of services to the victims of sexual assault. The analyses reveal that significant differences exist between male and female victims, by age and by assault characteristics, including the type of sexual assault, use of force and injury, length of assault, and the relationship between victim and offender.

High-dose-rate brachytherapy for primary carcinomas of the oral cavity and oropharynx.

OBJECTIVE: Local control for patients treated with primary radiation therapy for tumors of the oral cavity is improved using low-dose-rate brachytherapy. Oropharyngeal carcinomas have also been treated with brachytherapy. The few reports in the literature regarding high-dose-rate brachytherapy (HDRBT) for head and neck cancer involve small numbers of patients and often contain a mix of palliative and curative cases. The purpose of this study is to evaluate the feasibility of HDRBT in the largest reported cohort of primary head and neck cancer patients treated with primary radiation therapy. STUDY DESIGN: This is a prospective nonrandomized study. METHODS: Fifty-five patients with primary untreated squamous cell carcinomas of the oral cavity and oropharynx were analyzed. There were 16 patients with T1, 26 with T2, 8 with T3, and 5 with T4 tumors. All patients received external-beam radiotherapy (EBRT) followed by HDRBT. Thirty-eight patients received hyperfractionated (twice daily) EBRT followed by HDRBT two or three times daily. Patients with cervical adenopathy also received hyperthermia and an electron boost to the site(s) of positive nodes. Median follow-up was 2.7 years. Toxicity and local control were analyzed. Data were analyzed by the Kaplan-Meier life-table method with statistical significance determined by the X2 and log-rank tests. RESULTS: High-dose-rate brachytherapy was extremely well tolerated. Only 9 patients (16%) developed a complication. Four patients developed osteoradionecrosis, and five developed soft tissue necrosis, all of which healed with conservative medical management. No complication required surgical intervention or hospitalization. Actuarial 2-year local control for the entire cohort was 79%. Local control was 87% for patients with T1 (15/16) and T2 (22/26) tumors versus 47% for T3 (5/8) and T4 (2/5) tumors (P < .01). CONCLUSIONS: High-dose-rate brachytherapy is feasible as a boost for patients with primary squamous cell carcinomas of the oral cavity and oropharynx. Patients with T1 and T2 tumors fared exceptionally well; those with advanced tumors may require more aggressive treatment, such as higher radiation doses, surgical resection, or systemic chemotherapy. The use of HDRBT both shortens the overall treatment time and limits the volume of tissue exposed to high doses of radiation therapy. In the future, as more patients treated with HDRBT are evaluable, we hope to identify potential factors that predict for local control so that we may select patients optimally for this treatment.

Spontaneous resolution of soft-tissue interposition after closed reduction of hip endoprosthesis dislocation.

Over a 5-year period at a single institution, 164 endoprostheses were used for the treatment of displaced femoral neck fractures. Soft-tissue restraint preservation and repair (hip capsule and labrum) is recommended to enhance stability after endoprosthesis placement. When dislocation does occur, however, this soft tissue may become interposed after closed reduction. This occurred in 2 of the dislocations reported here. In these 2 dislocations, despite the widened joint space, the range of motion was stable. Neither of these cases had a subsequent dislocation, and after 1 month, both had spontaneously narrowed their joint space back to the immediate postoperative state.

Uncemented total hip arthroplasty using the CLS stem: a titanium alloy implant with a corundum blast finish. Results at a mean 6 years in a prospective study.

An uncemented titanium alloy stem with a corundum blast finish and an uncemented titanium fibermetal mesh socket were implanted in a series of 57 hips. These prostheses were selected for use in the youngest, most active, and/or heaviest candidates for total hip arthroplasty. Fifty hips were available for study at a minimum 60 months. At a mean 6 years, 92% of the hips were rated good or excellent. The mean Harris hip score was 92. One patient experienced mild thigh pain. The corundum blast finish was associated with reliable implant stability. Survival analysis predicted a 96% rate of implant survival at 92 months. Loss of bone density was rated mild, minimal, or none in 88% of the hips. Three hips developed severe bone loss due to systemic disease. Polyethylene wear was measurable in 86% of the hips. Twenty hips developed focal proximal femoral bone erosions. One hip had endosteal cavitation distal to zone 7. The presence of proximal femoral erosions or endosteal cavitation correlated positively with the presence of measurable polyethylene wear. The limited and proximal distribution of femoral bone erosion despite evidence of extensive polyethylene wear suggested that bone apposition to the corundum blast finish resulted in a barrier to migration of wear debris.

Hip arthroplasty using the cementless CLS stem. A 2--4-year experience.

Fifty-one Cementless Spotorno (CLS, Protek A. G. Berne) stems were implanted in 43 patients with either a Harris Galante (Zimmer, Warsaw, IN) socket or bipolar head. Patients were evaluated at a mean of 31 months. Eighty percent of the hips were in patients who were less than 50 years of age or weighed more than 80 kg. The CLS stem achieved initial stability by wedging a proximally fluted, straight stem into a retained bed of femoral trabecular and cortical bone. Distal canal fill was avoided. The postoperative mean Harris hip score was 95. Eighty percent of the hips were rated excellent, 16% good, 2% fair, and 2% poor. No stem required revision. Six percent had slight, occasional thigh pain. No patient had mild, moderate, or severe thigh pain. Six percent had a limp related to the operated hip. Fifty-three percent of the hips developed a radiographic appearance of bone apposition at the stem tip. Fifty-five percent of the hips had some reduction in proximal bone density. These changes suggested that as bone remodeling occurred, the initial proximal load transfer situation expected from the CLS stem design changed to include some distal load transfer resulting in proximal stress shielding. Ninety-four percent of the hips had either no change in femoral bone density or only patchy loss of density isolated to zone 7. A high dislocation rate was attributed to an unfavorable head-to-neck diameter ratio, a valgus neck shaft angle, and a patient population capable of excellent hip motion.

Early femoral component loosening in DF-80 total hip arthroplasty.

Forty-seven DF-80 total hip arthroplasties performed in 40 patients were evaluated to determine the incidence and causes of early femoral component loosening. With an average 37.1-month follow-up period, 48.9% of the femoral components developed bone cement-bone radiolucent lines worrisome for stem loosening. Twenty-three percent of the stems had subsided and 4.3% had been revised. Radiolucent lines were apparent very early (average, 8.8 months). Statistical analysis revealed positive correlations between the use of the larger (45-mm) offset stem and both the appearance of radiolucent lines and stem loosening. Being male and tall also were associated with stem loosening. The causes for early DF-80 femoral component loosening could not be defined with certainty. The results of this study and a review of the literature suggest that failure may be a result of early biologic weakening of the proximal cement-bone interface combined with a stem design that maintains proximal bone loading. Metal debris did not appear to be a factor in loosening of this titanium alloy stem.

Internal fixation of fractures and non-unions of the humeral shaft. Indications and results in a multi-center study.

We performed ninety-six internal-fixation procedures for fracture or non-union of the humeral shaft in eighty-four patients, with a mean follow-up of 32.6 months (range, three months to fourteen years). The primary indications for operative intervention included humeral shaft fracture in a patient with multiple trauma, non-union, inadequate reduction of a humeral shaft fracture by closed methods, pathological humeral-shaft fracture, and progressive radial-nerve palsy. Methods of internal fixation included compression plates and screws and intramedullary Küntscher nails or Rush rods. The use of an AO/ASIF compression plate or interfragmentary lag screws with an AO/ASIF neutralization plate in twenty-seven multiply-injured patients resulted in a union rate of 100 per cent and generally good motion of the shoulder and elbow. Five multiply-injured patients also obtained good results through fixation by a modified Hackethal technique using two Rush rods. The use of intramedullary Küntscher nails resulted in a rate of union of 91 per cent in eleven multiply injured patients. Ten patients with non-union of a humeral shaft fracture had an 80 per cent rate of union with the use of an AO/ASIF compression plate. The use of a Küntscher nail in eleven patients with non-union resulted in a rate of union of only 73 per cent and frequently caused subacromial impingement. Fractures of the humeral shaft that had had an inadequate reduction by closed means or were associated with progressive radial-nerve palsy were best managed by a compression plate or the modified Hackethal technique.(ABSTRACT TRUNCATED AT 250 WORDS)

Menarcheal status and parent-child relations in families of seventh-grade girls.

The associations between menarcheal status and several child-rearing and outcome variables were examined for mother-daughter and father-daughter dyads. All variables were assessed with questionnaires as an extension of earlier observational studies. Analyses were conducted via multiple regression analyses wherein menarcheal status was treated as a continuous variable and was entered into the regression equation as a set of power polynomial terms. The results indicated that most of the significant relations occurred for the mother-daughter dyad, and most of these relations were curvilinear. When menarche occurs at or around the modal time, changes in parent-child relations may be best thought of as temporary perturbations, but when menarche occurs early the effects may persist.