Citations

AbstractWe examined the chronic lymphocytic leukemia (CLL) cells of 2457 patients evaluated by the CLL Research Consortium (CRC) and found that 63 (2.6%) expressed immunoglobulin (Ig) encoded by the Ig heavy-chain-variable-region gene (IGHV), IGHV3-21. We identified the amino acid sequence DANGMDV (motif-1) or DPSFYSSSWTLFDY (motif-2) in the Ig heavy-chain (IgH) third complementarity-determining region (HCDR3) of IgH, respectively, used by 25 or 3 cases. The IgH with HCDR3 motif-1 or motif-2, respectively, was paired with Ig light chains (IgL) encoded by IGLV3-21 or IGKV3-20, suggesting that these Ig had been selected for binding to conventional antigen(s). Cases that had HCDR3 motif-1 had a median time from diagnosis to initial therapy comparable with that of cases without a defined HCDR3 motif, as did cases that used mutated IGHV3-21 (n = 27) versus unmutated IGHV3-21 (n = 30). Of 7 examined cases that used Ig encoded by IGHV3-21/IGLV3-21, we found that 5 had a functionally rearranged IGKV allele that apparently had incurred antigendriven somatic mutations and subsequent rearrangement with KDE. This study reveals that CLL cells expressing IGHV3-21/IGLV3-21 most likely were derived from B cells that had experienced somatic mutation and germinal-center maturation in an apparent antigen-driven immune response before undergoing Ig-receptor editing and after germinal-center leukemogenic selection.

Background Although the use of rotator interval closure is frequently advocated as a useful supplement to shoulder instability repairs, the addition of a rotator interval closure after arthroscopic instability repair has not been fully investigated. Purpose The objective of this study was to investigate whether a rotator interval closure improves glenohumeral stability in an anterior and posterior instability shoulder model. Study Design Controlled laboratory study. Methods Fourteen fresh-frozen cadaveric shoulder specimens were dissected free of soft tissues, leaving the rotator cuff intact with simulated cuff loading. All specimens were mounted in a custom testing apparatus using infrared sensors to document glenohumeral translation and rotation. The specimens were then tested for stability in the following order: vented/subluxated state, after arthroscopic anterior (Group 1; 7 specimens) or posterior (Group 2; 7 specimens) instability repair with suture anchors, and then after rotator interval closure. For each of the 3 testing conditions, the following were measured: (1) external and internal rotation at neutral, (2) external and internal rotation at 90° of abduction, (3) posterior and anterior translation at neutral rotation (15 N and 25 N), (4) anterior translation at 90° of abduction and external rotation (Group 1; 15 N and 25 N), (5) posterior translation at 90° of flexion and internal rotation (Group 2; 15 N and 25 N), and (6) sulcus testing in neutral (7.5 N). Results Posterior stability was only improved after anchor capsulolabral repair (8.0 to 5.0 mm; P = .017, 25 N), but there was no improvement after rotator interval closure (5.0 to 4.6 mm; P = .453). However, anterior stability was improved after capsulolabral repair (8.6 to 4.0 mm; P = .016, 25 N) and also improved further by rotator interval closure (4.0 to 2.4 mm; P = .007). The mean loss of external rotation was significantly increased by the addition of the rotator interval closure in both neutral and abducted glenohumeral positions, with a mean external rotation loss of 28° in neutral ( P = .013). The addition of a rotator interval closure did not improve sulcus stability ( P = .4). Conclusion The addition of an arthroscopic rotator interval closure after posterior capsulolabral repair did not improve posterior stability; however, anterior stability was improved further after a rotator interval closure. Inferior stability was not improved. Arthroscopic rotator interval closure significantly decreased external rotation at both neutral and abducted arm positions. Clinical Relevance Arthroscopic closure may be beneficial in certain cases of anterior shoulder instability; however, posterior instability was not improved. Predictable losses of external rotation after rotator interval closure are of concern.

ObjectStabilization of the atlantoaxial complex has proven to be very challenging. Because of the high mobility of the C1–2 motion segment, fusion rates at this level have been substantially lower than those at the subaxial spine. The set of potential surgical interventions is limited by the anatomy of this region. In 2001 Jürgen Harms described a novel technique for individual fixation of the C-1 lateral mass and the C-2 pedicle by using polyaxial screws and rods. This method has been shown to confer excellent stability in biomechanical studies. Cadaveric and radiographic analyses have indicated that it is safe with respect to osseous and vascular anatomy. Clinical outcome studies and fusion rates have been limited to small case series thus far. The authors reviewed the multicenter experience with 102 patients undergoing C1–2 fusion via the polyaxial screw/rod technique. They also describe a modification to the Harms technique.MethodsOne hundred two patients (60 female and 42 male) with an average age of 62 years were included in this analysis. The average follow-up was 16.4 months. Indications for surgery were instability at the C1–2 level, and a chronic Type II odontoid fracture was the most frequent underlying cause. All patients had evidence of instability on flexion and extension studies. All underwent posterior C-1 lateral mass to C-2 pedicle or pars screw fixation, according to the method of Harms. Thirty-nine patients also underwent distraction and placement of an allograft spacer into the C1–2 joint, the authors' modification of the Harms technique. None of the patients had supplemental sublaminar wiring.ResultsAll but 2 patients with at least a 12-month follow-up had radiographic evidence of fusion or lack of motion on flexion and extension films. All patients with an allograft spacer demonstrated bridging bone across the joint space on plain x-ray films and computed tomography. The C-2 root was sacrificed bilaterally in all patients. A postoperative wound infection developed in 4 patients and was treated conservatively with antibiotics and local wound care. One patient required surgical debridement of the wound. No patient suffered a neurological injury. Unfavorable anatomy precluded the use of C-2 pedicle screws in 23 patients, and thus, they underwent placement of pars screws instead.ConclusionsFusion of C1–2 according to the Harms technique is a safe and effective treatment modality. It is suitable for a wide variety of fracture patterns, congenital abnormalities, or other causes of atlantoaxial instability. Modification of the Harms technique with distraction and placement of an allograft spacer in the joint space may restore C1–2 height and enhance radiographic detection of fusion by demonstrating a graft–bone interface on plain x-ray films, which is easier to visualize than the C1–2 joint.

Alzheimer's Disease (AD) is the most widespread form of dementia during the later stages of life. If improved therapeutics are not developed, the prevalence of AD will drastically increase in the coming years as the world's population ages. By identifying differences in neuronal gene expression profiles between healthy elderly persons and individuals diagnosed with AD, we may be able to better understand the molecular mechanisms that drive AD pathogenesis, including the formation of amyloid plaques and neurofibrillary tangles. In this study, we expression profiled histopathologically normal cortical neurons collected with laser capture microdissection (LCM) from six anatomically and functionally discrete postmortem brain regions in 34 AD-afflicted individuals, using Affymetrix Human Genome U133 Plus 2.0 microarrays. These regions include the entorhinal cortex, hippocampus, middle temporal gyrus, posterior cingulate cortex, superior frontal gyrus, and primary visual cortex. This study is predicated on previous parallel research on the postmortem brains of the same six regions in 14 healthy elderly individuals, for which LCM neurons were similarly processed for expression analysis. We identified significant regional differential expression in AD brains compared with control brains including expression changes of genes previously implicated in AD pathogenesis, particularly with regard to tangle and plaque formation. Pinpointing the expression of factors that may play a role in AD pathogenesis provides a foundation for future identification of new targets for improved AD therapeutics. We provide this carefully phenotyped, laser capture microdissected intraindividual brain region expression data set to the community as a public resource.

Abstract Purpose: To test combination treatment schedules of reovirus and radiation in human and murine tumor cells in vitro and in vivo. Experimental Design: In vitro cytotoxicity and cell cycle effects of reovirus given alone and combined with radiotherapy were assessed by colorimetric, tissue culture infectious dose 50, and fluorescence-activated cell sorting–based assays. Interactions between the agents were evaluated using combination index analysis. The effect of different schedules of reovirus and radiotherapy on viral replication and cytotoxicity was tested in vitro and the combination was assessed in three tumor models in vivo. Results: Characterization of reovirus cytotoxicity in a panel of cell lines yielded a range of sensitivities. Combined reovirus and radiotherapy yielded statistically significantly increased cytotoxicity, particularly in cell lines with moderate susceptibility to reovirus alone. The enhanced cytotoxicity of the combination occurred independently of treatment sequence or schedule. Radiation did not affect viral replication and only reduced reoviral cytotoxicity after clinically irrelevant single doses (>50 Gy). Combination index analysis revealed synergy between radiation (3-10 Gy) and reovirus at multiplicities of infection between 0.001 and 1. Combination treatment significantly increased apoptosis in tumor cells relative to either single-agent treatment. In vivo studies using xenograft and syngeneic tumors showed enhanced activity of the combination relative to reovirus or radiation alone (P < 0.001). Conclusions: Combining reovirus and radiotherapy synergistically enhances cytotoxicity in a variety of tumor cells in vitro and in vivo. These results offer strong support for translational clinical trials of reovirus plus radiotherapy that have been initiated in the clinic.

Abstract Purpose: The purpose of the present study was to investigate whether it is possible to achieve truly systemic delivery of oncolytic reovirus, in immunocompetent hosts, using cyclophosphamide to overcome some of the barriers to effective intratumoral delivery and replication of i.v. injected virus. Experimental Design: I.v. delivery of reovirus was combined with different regimens of i.p. administered cyclophosphamide in C57Bl/6 mice bearing established s.c. B16 tumors. Intratumoral viral replication, tumor size, and survival were measured along with levels of neutralizing antibody (NAb) in the blood. Finally, differential toxicities of the virus/cyclophosphamide regimens were monitored through viral replication in systemic organs, survival, and cardiac damage. Results: Repeated i.v. injection of reovirus was poorly effective at seeding intratumoral viral replication/oncolysis. However, by combining i.v. virus with cyclophosphamide, viral titers of between 107 and 108 plaque-forming units per milligram were recovered from regressing tumors. Doses of cyclophosphamide that ablated NAb were associated with severe toxicities, characterized by viral replication in systemic organs—toxicities that are mirrored by repeated reovirus injections into B-cell knockout mice. Next, we restructured the dosing of cyclophosphamide and i.v. virus such that a dose of 3 mg cyclophosphamide was administered 24 h before reovirus injection, and this schedule was repeated every 6 days. Using this protocol, high levels of intratumoral viral access and replication (∼107 plaque-forming units per milligram tumor) were maintained along with systemically protective levels of NAb and only very mild, non–life-threatening toxicity. Conclusion: NAb to oncolytic viruses play a dual role in the context of systemic viral delivery; on one hand, they hinder repeated administration of virus but on the other, they provide an important safety mechanism by which virus released from vigorous intratumoral replication is neutralized before it can disseminate and cause toxicity. These data support the use of cyclophosphamide to modulate, but not ablate, patient NAb, in development of carefully controlled clinical trials of the systemic administration of oncolytic viruses.

Abstract Context: The process of epiphyseal fusion during puberty is regulated by estrogen, even in males. Objective: Our objective was to investigate whether anastrozole, a potent aromatase inhibitor, could delay bone age acceleration and increase predicted adult height in adolescent boys with GH deficiency. Methods: Fifty-two adolescent males with GH deficiency treated with GH were randomized to cotreatment with anastrozole or placebo daily for up to 36 months. Results: Fifty subjects completed 12 months, 41 completed 24 months, and 28 completed 36 months. Linear growth was comparable between groups; however, there was a significantly slower increase in bone age advancement from baseline in the anastrozole group vs. placebo group after 2 yr (+1.8 ± 0.1 vs. +2.7 ± 0.1 yr, P < 0.0001) and after 3 yr (+2.5 ± 0.2 vs. +4.1 ± 0.1 yr, P < 0.0001). This resulted in a net increase in predicted adult height of +4.5 ± 1.2 cm in the anastrozole group at 24 months and +6.7 ± 1.4 cm at 36 months as compared with a 1-cm gain at both time points in the placebo group. Estradiol and estrone concentrations increased less in the anastrozole group compared with placebo group. All boys on the aromatase inhibitor had normal tempo of virilization. Safety data, including glucose, and plasma lipid concentrations were comparable between groups. Conclusions: Anastrozole increases adult height potential of adolescent boys on GH therapy while maintaining normal pubertal progression after 2–3 yr. This treatment offers an alternative in promoting growth in GH-deficient boys in puberty. Long-term follow up is needed to elucidate fully the safety and efficacy of this approach.

Purpose The traditional end point for assessing efficacy of first-line chemotherapies for advanced cancer is overall survival (OS), but this end point requires prolonged follow-up and is potentially confounded by the effects of second-line therapies. We investigated whether progression-free survival (PFS) could be considered a valid surrogate for OS in advanced colorectal cancer. Patients and Methods Individual patient data were available from 10 historical trials comparing fluouracil (FU) + leucovorin with either FU alone (1,744 patients) or with raltitrexed (1,345 patients) and from three validation trials comparing FU + leucovorin with or without irinotecan or oxaliplatin (1,263 patients). Correlation coefficients were estimated in historical trials between the end points of PFS and OS, and between the treatment effects on these end points. Treatment effects on OS were predicted in validation trials, and compared with the observed effects. Results In historical trials, 1,760 patients (57%) had progressed or died at 6 months, and 1,622 (52%) had died at 12 months. The rank correlation coefficient between PFS and OS was equal to 0.82 (95% CI, 0.82 to 0.83). The correlation coefficient between treatment effects on PFS and on OS ranged from 0.99 (95% CI, 0.94 to 1.04) when all trials were considered to 0.74 (95% CI, 0.44 to 1.04) after exclusion of one highly influential trial. In the validation trials, the observed OS hazard ratios were within the 95% prediction intervals. A hazard ratio of 0.77 or lower in terms of PFS would predict a benefit in terms of OS. Conclusion PFS is an acceptable surrogate for OS in advanced colorectal cancer.