Citations

The treatment of chronic lymphocytic leukemia (CLL) has evolved over the past decade. Our better understanding of disease biology and risk stratification has allowed delivering more effective therapies. In fact, front-line chemoimmunotherapy has demonstrated improvement in overall survival when compared to chemotherapy in randomized studies. Yet, treatment of relapsed CLL remains challenging and few agents are effective in that setting. Ofatumumab (Ofa) is a humanized monoclonal antibody targeted against CD20 with demonstrable activity in rituximab-resistant CLL cell lines. This agent was recently approved for the treatment of relapsed/refractory CLL patients who have failed fludarabine and alemtuzumab. In this review, we provide a historical perspective on approaches to CLL as front-line and in the relapsed setting. We further summarize novel anti-CD20 antibodies with specific emphasis on ofa. We review studies that led to ofatumumab's approval including pre-clinical data, trials using ofa in combination therapies, and adverse events/toxicities reported with this agent.

During physiological spontaneous breathing maneuvers, the diaphragm displaces volume while maintaining curvature. However, with maximal diaphragm activation, curvature decreases sharply. We tested the hypotheses that the relationship between diaphragm muscle shortening and volume displacement (VD) is nonlinear and that curvature is a determinant of such a relationship. Radiopaque markers were surgically placed on three neighboring muscle fibers in the midcostal region of the diaphragm in six dogs. The three-dimensional locations were determined using biplanar fluoroscopy and diaphragm VD, curvature, and muscle shortening were computed in the prone and supine postures during spontaneous breathing (SB), spontaneous inspiration efforts after airway occlusion at lung volumes ranging from functional residual capacity (FRC) to total lung capacity, and during bilateral maximal phrenic nerve stimulation at those same lung volumes. In supine dogs, diaphragm VD was approximately two- to three-fold greater during maximal phrenic nerve stimulation than during SB. The contribution of muscle shortening to VD nonlinearly increases with level of diaphragm activation independent of posture. During submaximal diaphragm activation, the contribution is essentially linear due to constancy of diaphragm curvature in both the prone and supine posture. However, the sudden loss of curvature during maximal bilateral phrenic nerve stimulation at muscle shortening values greater than 40% (ΔL/LFRC) causes a nonlinear increase in the contribution of muscle shortening to diaphragm VD, which is concomitant with a nonlinear change in diaphragm curvature. We conclude that the nonlinear relationship between diaphragm muscle shortening and its VD is, in part, due to a loss of its curvature at extreme muscle shortening.

SUMMARY Lack of activity causes bone loss In most animals. Hibernating bears have physiological processes to prevent cortical and trabecular bone loss associated with reduced physical activity, but different mechanisms of torpor among hibernating species may lead to differences in skeletal responses to hibernation. There are conflicting reports regarding whether small mammals experience bone loss during hibernation. To investigate this phenomenon, we measured cortical and trabecular bone properties in physically active and hibernating juvenile and adult 13-lined ground squirrels (Ictidomys tridecemlineatus, previous genus name Spermophilus). Cortical bone geometry, strength and mineral content were similar in hibernating compared with active squirrels, suggesting that hibernation did not cause macrostructural cortical bone loss. Osteocyte lacunar size increased (linear regression, P=0.001) over the course of hibernation in juvenile squirrels, which may indicate an osteocytic role in mineral homeostasis during hibernation. Osteocyte lacunar density and porosity were greater (+44 and +59%, respectively; P<0.0001) in hibernating compared with active squirrels, which may reflect a decrease in osteoblastic activity (per cell) during hibernation. Trabecular bone volume fraction in the proximal tibia was decreased (–20%; P=0.028) in hibernating compared with physically active adult squirrels, but was not different between hibernating and active juvenile squirrels. Taken together, these data suggest that 13-lined ground squirrels may be unable to prevent microstructural losses of cortical and trabecular bone during hibernation, but importantly may possess a biological mechanism to preserve cortical bone macrostructure and strength during hibernation, thus preventing an increased risk of bone fracture during remobilization in the spring.

When coupled with classical clinical signs and symptoms, magnetic resonance imaging can significantly aid in the diagnosis of multiple sclerosis (MS). However, the differential diagnosis of multiple sclerosis is large and, in the absence of pathognomonic clinical features, can be challenging to diagnose initially. Some conditions, such as primary central nervous system lymphoma (PCNSL) and progressive multifocal leukoencephalopathy (PML), can mimic clinically some of the symptoms prominent in multiple sclerosis. Early treatment with corticosteroids can dramatically improve patient symptoms in MS and PCNSL. We report a case of a man diagnosed with histologically confirmed relapsing remitting multiple sclerosis who subsequently developed histologically confirmed primary central nervous system lymphoma. Immunosuppressant therapy in the treatment of multiple sclerosis may be a potential catalyst in the development of central nervous system lymphoma. The course of his disease and treatment are presented and the current literature reviewed.

Acrocyanosis is symmetric, painless, discoloration of different shades of blue in the distal parts of the body that is marked by symmetry, relative persistence of the skin color changes with aggravation by cold exposure, and frequent association with local hyperhidrosis of hands and feet. Described over a century ago and despite seeming familiarity, it remains a poorly understood condition that shares much in clinical presentation with other conditions characterized by skin color changes in the distal parts of the body. The diagnosis remains mostly clinical, and pathological mechanisms vary suggesting that acrocyanosis may not be a single entity. We performed an extensive literature review to summarize existing knowledge about the demographics, pathology, diagnosis, and treatment of this condition.

Peripheral T-cell lymphomas (PTCL) represent about 12%–15% of non-Hodgkin lymphomas and are characterized for being a molecularly heterogenous group of diseases. The optimal treatment for PTCLs remains to be defined as they are usually refractory to existing therapies and carry a poor prognosis. Pralatrexate (PDX), a rationally designed antifolate drug, was granted FDA approval as a single agent for the treatment of relapsed/refractory PTCL in 2009. Because of its favorable toxicity profile and activity, Pralatrexate has become a major compound for patients with refractory PTCL.