Citations

Purpose The goal of this study was to compare open and arthroscopic surgical techniques for “cam‐type” femoroacetabular impingement in terms of feasibility and reliability. Methods We used 5 fresh‐frozen cadaver specimens (10 hips). Anteroposterior and cross‐table radiographs were taken for each. The head‐neck union diameter was measured for each. The amount of bone resection at the anterolateral quadrant of the head‐neck union was planned for each, with specific references to width, length, depth, and position. One side was randomly assigned to the open group and the other to the arthroscopic group. Surgical time, position of the osteotomy, and variation of the length, width, and depth of the final osteotomy with respect to the proposed dimensions were compared. Results In all specimens partial resection of the anterior‐lateral femoral head‐neck junction with improvement of the femoral head‐neck offset was accomplished. A statistically significant difference ( P < .05) was observed for surgical time between the open and arthroscopic groups (shorter in open group). Conclusions When comparing surgical precision, no statistically significant differences were found between the open and arthroscopic procedures in any of the measurements. The depth and width of the osteoplasty were reliably obtained by the arthroscopic technique. However, there was a tendency to underestimate the osteoplasty length with the arthroscopic procedure. Positioning the osteoplasty was also less reliable with the arthroscopic procedure than with the open procedure because of the tendency to place the osteoplasty more posterior and distally than intended. Clinical Relevance Surgical resection of the femoral neck prominence and/or part of the anterolateral neck has been reported to improve femoral head offset and alleviate impingement. This study attempts to document the accuracy of this resection when done arthroscopically compared with an open procedure.

Purpose Acute graft-versus-host disease (GVHD) causes substantial morbidity and mortality after human leukocyte antigen (HLA)-identical sibling transplants. No large registry studies of acute GVHD risk factors have been reported in two decades. Risk factors may have changed in this interval as transplant-related techniques have evolved. Patients and Methods Acute GVHD risk factors were analyzed in 1,960 adults after HLA-identical sibling myeloablative transplant for acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), or chronic myeloid leukemia (CML) reported by 226 centers worldwide to the Center for International Blood and Marrow Transplant Research from 1995 to 2002. Outcome was measured as time from transplant to onset of grade 2 to 4 acute GVHD, with death without acute GVHD as a competing risk. Results Cumulative incidence of grade 2 to 4 acute GVHD was 35% (95% CI, 33% to 37%). In multivariable analyses, factors significantly associated with grade 2 to 4 acute GVHD were cyclophosphamide + total-body irradiation versus busulfan + cyclophosphamide (relative risk [RR] = 1.4; P < .0001), blood cell versus bone marrow grafts in patients age 18 to 39 years (RR = 1.43; P = .0023), recipient age 40 and older versus age 18 to 39 years receiving bone marrow grafts (RR = 1.44; P = .0005), CML versus AML/ALL (RR = 1.35; P = .0003), white/Black versus Asian/Hispanic race (RR = 1.54; P = .0003), Karnofsky performance score less than 90 versus 90 to 100 (RR = 1.27; P = .014), and recipient/donor cytomegalovirus-seronegative versus either positive (RR = 1.20; P = .04). Stratification by disease showed the same significant predictors of grade 2 to 4 acute GVHD for CML; however, KPS and cytomegalovirus serostatus were not significant predictors for AML/ALL. Conclusion This analysis confirmed several previously reported risk factors for grade 2 to 4 acute GVHD. However, several new factors were identified whereas others are no longer significant. These new data may facilitate individualized risk estimates and raise several interesting biologic questions.

The records of patients aged 50 years or over who underwent primary reconstruction of the anterior cruciate ligament between 1990 and 2002 were reviewed. There were 35 knees in 34 patients that met the inclusion criteria. The mean age of the patients was 57 years (50 to 66) and the mean clinical follow-up was for 72 months (25 to 173). A total of 23 knees were reconstructed with patellar tendon allograft, and 12 with patellar tendon autograft. The mean pre-operative knee extension was 1° (−5° to 10°) and flexion was 129° (125° to 150°) and at follow-up these values were 0° (−5° to 5°) and 135° (120° to 150°), respectively. Pre-operatively there were 31 knees (89%) with a Lachman grade 2+ or 3+. Post-operatively, 33 knees (94%) were Lachman grade 0 or 1+. The mean pre- and post-operative International Knee Documentation Committee scores were 39 (23 to 72) and 90 (33 to 100) respectively. The mean pre- and post-operative Lysholm scores were 50 (18 to 68) and 92 (28 to 100) respectively and the mean University of California Los Angeles activity scores were 8.5 before injury (4 to 10), 4.3 (3 to 6) after injury and 8.3 (4 to 10) post-operatively. There were three graft failures (8.6%) requiring revision. We conclude that reconstruction of the anterior cruciate ligament in carefully-selected patients aged 50 years or over can achieve similar results to those in younger patients, with no increased risk of complications.

Abstract Purpose: Enhancer of zeste homologue 2 (EZH2), a histone methyltransferase, plays a key role in transcriptional repression through chromatin remodeling. Our objectives were to determine the expression pattern of EZH2 and to assess the anticancer effect of EZH2 depletion in pancreatic cancer cells. Experimental Design: Immunohistochemistry and cytosolic/nuclear fractionation were done to determine the expression pattern of EZH2 in normal pancreas and human pancreatic tumors. We used RNA interference, Western blotting, reverse transcription-PCR, and chromatin immunoprecipitation to study the effect of EZH2 depletion on pancreatic cancer cell proliferation and survival. Results: We detected nuclear overexpression of EZH2 in pancreatic cancer cell lines and in 71 of 104 (68%) cases of human pancreatic adenocarcinomas. EZH2 nuclear accumulation was more frequent in poorly differentiated pancreatic adenocarcinomas (31 of 34 cases; P &lt; 0.001). We found that genetic depletion of EZH2 results in reexpression of p27Kip1 and decreased pancreatic cancer cell proliferation. Moreover, we showed that EZH2 depletion sensitized pancreatic cancer cells to doxorubicin and gemcitabine, which leads to a significant induction of apoptosis, suggesting that the combination of EZH2 inhibitors and standard chemotherapy could be a superior potential treatment for pancreatic cancer. Conclusions: Our results show nuclear accumulation of EZH2 as a hallmark of poorly differentiated pancreatic adenocarcinoma; identify the tumor suppressor p27Kip1 as a new target gene of EZH2; show that EZH2 nuclear overexpression contributes to pancreatic cancer cell proliferation; and suggest EZH2 as a potential therapeutic target for the treatment of pancreatic cancer.

Abstract Purpose: To determine the safety and feasibility of daily i.v. administration of wild-type oncolytic reovirus (type 3 Dearing) to patients with advanced cancer, assess viral excretion kinetics and antiviral immune responses, identify tumor localization and replication, and describe antitumor activity. Experimental Design: Patients received escalating doses of reovirus up to 3 × 1010 TCID50 for 5 consecutive days every 4 weeks. Viral excretion was assessed by reverse transcription-PCR and antibody response by cytotoxicity neutralization assay. Pretreatment and post-treatment tumor biopsies were obtained to measure viral uptake and replication. Results: Thirty-three patients received 76 courses of reovirus from 1 × 108 for 1 day up to 3 × 1010 TCID50 for 5 days, repeated every four weeks. Dose-limiting toxicity was not seen. Common grade 1 to 2 toxicities included fever, fatigue, and headache, which were dose and cycle independent. Viral excretion at day 15 was not detected by reverse transcription-PCR at 25 cycles and only in 5 patients at 35 cycles. Neutralizing antibodies were detected in all patients and peaked at 4 weeks. Viral localization and replication in tumor biopsies were confirmed in 3 patients. Antitumor activity was seen by radiologic and tumor marker (carcinoembryonic antigen, CA19.9, and prostate-specific antigen) evaluation. Conclusions: Oncolytic reovirus can be safely and repeatedly administered by i.v. injection at doses up to 3 × 1010 TCID50 for 5 days every 4 weeks without evidence of severe toxicities. Productive reoviral infection of metastatic tumor deposits was confirmed. Reovirus is a safe agent that warrants further evaluation in phase II studies.

KCNJ11 -encoded Kir6.2 assembles with ATP-binding cassette sulphonylurea receptors to generate ATP-sensitive K + (K ATP ) channel complexes. Expressed in tissues with dynamic metabolic flux, these evolutionarily conserved yet structurally and functionally unique heteromultimers serve as high-fidelity rheostats that adjust membrane potential-dependent cell functions to match energetic demand. Genetic defects in channel subunits disrupt the cellular homeostatic response to environmental stress, compromising organ tolerance in the adult. As maladaptation characterizes malignant K ATP channelopathies, establishment of platforms to examine progression of K ATP channel-dependent adaptive behaviour is warranted. Chimeras provide a powerful tool to assay the contribution of genetic variance to stress intolerance during prenatal or post-natal development. Here, KCNJ11 K ATP channel gene knockout↔wild-type chimeras were engineered through diploid aggregation. Integration of wild-type embryonic stem cells into zona pellucida-denuded morula derived from knockout embryos achieved varying degrees of incorporation of stress-tolerant tissue within the K ATP channel-deficient background. Despite the stress-vulnerable phenotype of the knockout, ex vivo derived mosaic blastocysts tolerated intrauterine transfer and implantation, followed by full-term embryonic development in pseudopregnant surrogates to produce live chimeric offspring. The development of adult chimerism from the knockout↔wild-type mosaic embryo offers thereby a new paradigm to probe the ecogenetic control of the K ATP channel-dependent stress response.

Object In 1998, the Radiation Therapy Oncology Group initiated a Phase II study of observation for adults < 40 years old with cerebral low-grade glioma who underwent a neurosurgeon-determined gross-total resection (GTR). Methods Patient eligibility criteria included the presence of a World Health Organization Grade II astrocytoma, oligodendroglioma, or mixed oligoastrocytoma confirmed histologically; age 18–39 years; Karnofsky Performance Scale score ≥ 60; Neurologic Function Scale score ≤ 3; supratentorial tumor location; neurosurgeon-determined GTR; and pre- and postoperative MR imaging with contrast enhancement available for central review by the principal investigator. Patients were observed following GTR and underwent MR imaging every 6 months. Prognostic factors analyzed for their contribution to patient overall survival, progression-free survival (PFS), and tumor recurrence included age, sex, Karnofsky Performance Scale score, Neurologic Function Scale score, histological type, contrast enhancement on preoperative MR imaging, preoperative tumor diameter, residual disease based on postoperative MR imaging, and baseline Mini-Mental State Examination score. Results Between 1998 and 2002, 111 eligible patients were entered into the study. In these 111 patients, the overall survival rates at 2 and 5 years were 99 and 93%, respectively. The PFS rates in these 111 patients at 2 and 5 years were 82 and 48%, respectively. Three prognostic factors predicted significantly poorer PFS in univariate and multivariate analyses: 1) preoperative tumor diameter ≥ 4 cm; 2) astrocytoma/oligoastrocytoma histological type; and 3) residual tumor ≥ 1 cm according to MR imaging. Review of the postoperative MR imaging results revealed that 59% of patients had < 1 cm residual disease (with a subsequent 26% recurrence rate), 32% had 1–2 cm residual disease (with a subsequent 68% recurrence rate), and 9% had > 2 cm residual disease (with a subsequent 89% recurrence rate). Conclusions These data suggest that young adult patients with low-grade glioma who undergo a neurosurgeondetermined GTR have a > 50% risk of tumor progression 5-years postoperatively, warranting close follow-up and consideration for adjuvant treatment.

OBJECTIVE. We investigated the prevalence and types of psychiatric disorders diagnosed by early adulthood among patients who had common forms of strabismus as children. METHODS. The medical records of children (&lt;19 years) who were diagnosed as having esotropia (N = 266) or exotropia (N = 141) while residents of Olmsted County, Minnesota, between January 1, 1985, and December 31, 1994, were reviewed retrospectively for psychiatric disease diagnoses. Each case subject was compared with a randomly selected, individually birth- and gender-matched, control subject from the same population. RESULTS. A mental health disorder was diagnosed for 168 (41.3%) of the 407 patients with a history of childhood strabismus, who were monitored to a mean age of 17.4 years, compared with 125 control subjects (30.7%). Children with exotropia were 3.1 times more likely to develop a psychiatric disorder than were control subjects when monitored to a mean age of 20.3 years. Children with esotropia were no more likely to develop mental illness than were control subjects when monitored for similar periods. Patients with intermittent exotropia also were significantly more likely to have greater numbers of mental health disorders, mental health emergency department visits, and mental health hospitalizations and to have suicidal or homicidal ideation. CONCLUSIONS. Children diagnosed as having strabismus in this population, especially those with exotropia, were at increased risk for developing mental illness by early adulthood. Patients with intermittent exotropia seemed to be particularly prone to developing significant psychiatric diseases by the third decade of life.