The pervasive crisis of diminishing radiation therapy access for vulnerable populations in the United States—part 3: Hispanic-American patients

Purpose: Health disparities have profoundly affected underrepresented minorities throughout the United States, particularly with regard to access to evidence-based interventions such as surgery or medication. The degree of disparity in access to radiation therapy (RT) for Hispanic-American patients with cancer has not been previously examined in an extensive manner. Methods and materials: An extensive literature search was performed using the PubMed database to examine studies investigating disparities in RT access for Hispanic-Americans. Results: A total of 34 studies were found, spanning 10 organ systems. Disparities in access to RT for Hispanic-Americans were most prominently studied in cancers of the breast (15 studies), prostate (4 studies), head and neck (4 studies), and gynecologic system (3 studies). Disparities in RT access for Hispanic-Americans were prevalent regardless of the organ system studied and were compounded by limited English proficiency and/or birth outside of the United States. A total of 26 of 34 studies (77%) involved analysis of a population-based database, such as Surveillance, Epidemiology and End Result (15 studies); Surveillance, Epidemiology and End Result-Medicare (4 studies); National Cancer Database (3 studies); or a state tumor registry (4 studies). Conclusions: Hispanic-Americans in the United States have diminished RT access compared with Caucasian patients but are less likely to experience concomitant disparities in mortality than other underrepresented minorities that experience similar disparities (ie, African-Americans). Hispanic-Americans who are born outside of the United States and/or have limited English proficiency may be more likely to experience substandard RT access. These results underscore the importance of finding nationwide solutions to address such inequalities that hinder Hispanic-Americans and other underrepresented minorities throughout the United States

Authors: Motor Neuron Inhibition-Based Gene Therapy for Spasticity REVIEW & ANALYSIS MECHANISM OF SPASTICITY

ABSTRACT Spasticity is a condition resulting from excess motor neuron excitation, leading to involuntary muscle contraction in response to increased velocity of movement, for which there is currently no cure. Existing symptomatic therapies face a variety of limitations. The extent of relief that can be delivered by ablative techniques such as rhizotomy is limited by the potential for sensory denervation. Pharmacological approaches, including intrathecal baclofen, can be undermined by tolerance. One potential new approach to the treatment of spasticity is the control of neuromuscular overactivity through the delivery of genes capable of inducing synaptic inhibition. A variety of experiments in cell culture and animal models have demonstrated the ability of neural gene transfer to inhibit neuronal activity and suppress transmission. Similarly, enthusiasm for the application of gene therapy to neurodegenerative diseases of motor neurons has led to the development of a variety of strategies for motor neuron gene delivery. In this review, we discuss the limitations of existing spasticity therapies, the feasibility of motor neuron inhibition as a gene-based treatment for spasticity, potential inhibitory transgene candidates, strategies for control of transgene expression, and applicable motor neuron gene targeting strategies. Finally, we discuss future directions and the potential for gene-based motor neuron inhibition in therapeutic clinical trials to serve as an effective treatment modality for spasticity, either in conjunction with or as a replacement for presently available therapies. Key Words: Spasticity, Transgene Expression, Motor Neuron, Gene Targeting Spasti city is a condition resulting from excess motor neuron excitation caused by lesions in the upper motor neuron pathway that lead to the absence of inhibition of alpha and/or gamma motor neurons. This loss of inhibition results in involuntary muscle contraction, causing stiffness interfering with movement, speech, and locomotion. 1,2 Affecting more than 12 million people worldwide, spasticity is commonly caused by stroke, multiple sclerosis, cerebral palsy, cerebral infection (encephalitis/meningitis), and/or cerebrospinal trauma. REVIEW & ANALYSIS Spasticity MECHANISM OF SPASTICITY The exact mechanism of spasticity in humans is incompletely understood, primarily because it is multifactorial in nature. It is generally understood that spasticity is caused by pathology involving the stretch reflex, which normally causes a muscle to contract to resist the force that is stretching it. For normal movement to occur, the brain must be able to selectively turn this reflex off, usually via inhibitory signals relayed to the spinal cord via the corticospinal tract. However, damage to this circuit results in disinhibition of the stretch reflex; over time, this reduces the triggering threshold until excessive and complete muscle contraction can occur even at rest, making the limb virtually impossible to move. Specific causes proposed include (a) alpha motor neuron hyperexcitability resulting from an imbalance in excitatory vs. inhibitory alpha motor neurons, and (b) gamma motor neuron hyperactivity manifesting as increased sensitivity of muscle spindle to stretch (fusimotor hyperactivity). 9 Additional causes involve damage to descending tracts that control interneurons responsible for (a) mediating presynaptic inhibition of the Ia terminals on the alpha motor neuron, (b) mediating type II afferents, and (c) reciprocal Ia inhibition. Such damage results in greater afferent stimulus to the alpha motor neuron as a result of stretch, decreased inhibition from type II afferents, and loss of normal inhibition of antagonist muscle during muscle stretch. Finally, a mechanism of decreased recurrent inhibition from Renshaw cells as a consequence of supraspinal damage has also been proposed. Whereas each individual cause contributes to the clinical picture observed in spasticity, it is unlikely that any single hypothesis is sufficient to explain the exact mechanism of spasticity. EXISTING THERAPIES AND LIMITATIONS Medical Therapies Although there are a number of oral medications available to treat spasticity, almost none are effective without significant side effects. The most common medications are diazepam, baclofen, and progabide, all of which are designed to increase presynaptic inhibition of alpha motor neurons by activation of ␥-aminobutyric acid (GABA) receptors. However, these treatments are associated with a high incidence of adverse effects, including sedation, weakness, fever without infection, and elevated liver enzymes. 10,11 Agents affecting ion flux in skeletal muscle, such as dantrolene, lamotrigine, and riluzole, share side effects of muscle weakness, sedation, and idiosyncratic hepatitis. 11,13 These significant toxicities limit the doses of medication that can be employed, thereby limiting efficacy. Furthermore, the issue of tolerance significantly hinders the longterm efficacy of any pharmacologic therapy, particularly for baclofen and diazepam. An alternative medical therapy involves the use of clostridial toxin (i.e., botulinum toxin), which acts by decreasing acetylcholine release at the neuromuscular junction, resulting in a neuromuscular blocking effect. However, the results from this therapy are often transient, with redosing complicated by tachyphylaxis, and increasing dosage complicated by severe muscle weakness. 14 -16 The issue of cost is another consideration. The cost of clostridial toxin treatment might hinder its extensive clinical applications because conventional oral therapies are much less expensive. 17 Surgical Therapies Surgery for spasticity is reserved for cases refractory to medical management or for those that cannot be medically managed because of intolerable side effects. The most common surgical options are generally orthopedic (consisting primarily of tendon-release operations) and neurosurgical. 18,19 Neurosurgical procedures fall into two categories: nonablative and ablative. The most frequently used nonablative procedure is intrathecal baclofen (ITB), which is generally offered for refractory patients with chronic spasticity (Ͼ12 mos). To be considered a candidate, a patient must demonstrate a positive response to ITB at a test dose of less than 100 g, compared with no response to placebo. 20 Although highly effective in improving muscle tone and reducing postoperative spasticity, ITB is fraught with catheter-and wound-related morbidity, both at the time of implantation and throughout the life of the implanted device. 20,21 There are limited data characterizing the problem of tolerance to ITB. [22][23][24][25] In many cases, ITB tolerance is ascribed to progression of the underlying disease (in amyotrophic lateral sclerosis and multiple sclerosis) or to dynamic catheter obstruction (kinking), which is difficult to demonstrate on standard pump contrast injections (pumpograms) or nuclear medicine studies. 23,26 In our practice, we use inpatient externalized catheter ITB trials to address the question of baclofen tolerance. In this context, it is easy to assess the patency of the catheter and document the threshold for response to an intrathecal drug. Outpatient trials of bolus intrathecal injection can be attempted, but these are often misleading because of the inherent differences in the pharmacokinetics of bolus and pump injection. However, the majority of our patients require gradually escalated doses of ITB to maintain adequate control of spasticity. May 2007 Gene Therapy for Spasticity 413 Another nonablative option is spinal cord stimulation, which has been shown to facilitate spasticity control, spasm inhibition, and gait improvement in spastic patients, 27-29 likely by selective modification of segmental spinal reflexes. 33 The most common ablative procedure is selective dorsal rhizotomy, which uses intraoperative electromyography and stimulation to identify the rootlets most responsible for causing severe spasticity. 42-45 POSSIBLE FUTURE THERAPIES Despite the wide range of medical and surgical treatments for spasticity, there is currently no treatment modality that is hardware free, reversible, adjustable, nondestructive, and not subject to tolerance. 2,3,14 -16,46 A potential modality for satisfying these criteria is the use of viral vectors to elicit effects on muscle contraction via gene transfer, because selective control of certain genes has been shown to modulate neuronal activity in multiple applications. POTENTIAL INHIBITORY TRANSGENES One of the most widely studied inhibitory transgenes is the gene encoding glutamate decarboxylase (GAD), the rate-limiting enzyme required to produce the inhibitory neurotransmitter GABA. In vitro and in vivo studies using retroviral vectors and adeno-associated virus (AAV) vectors have suggested that it is feasible to achieve long-term GAD expression in the CNS. 57 GAD was expressed, and the expression of GAD induced production of GABA in these neurons. These findings suggest that AAV-mediated GAD gene transfer might provide a treatment option for overactive diseases such as Parkinson disease. 57,58 These results have led to an ongoing Phase I trial of GAD gene transfer to the human subthalamic nucleus for medically refractory Parkinson disease patients. Tetanus Toxin Light Chain Our laboratory has focused on the gene for the light chain (LC) fragment of clostridial neurotoxin. The expression of this gene in neurons provides inhibition of synaptic function in transgenic mice via reversible suppression of glutamatergic neurotransmission. 59,60 Clostridial intoxication in neurons involves the production of inactive single-chain clostridial neurotoxin polypeptides, which are released after bacterial lysis. This release converts the polypeptide from an inactive single-chain molecule to an active di-chain molecule composed of a heavy chain (HC) and an LC fragment linked by a single disulfide bond. HC binds axon terminals and triggers internalization of the toxin. Once inside the neuron, reduction of the disulfide bond releases the active LC fragment. The activated LC cleaves the soluble N-ethylmaleimide-sensitive factor attachment receptor proteins responsible for synaptic vesicle membrane fusion. 59 Such specific, reversible, effective neuronal inhibition makes LC a viable transgene candidate for exploring gene-based treatment of spasticity. Inwardly Rectifying Potassium Channel Kir2.1 Another gene of interest as a feasible modulator of motor neuron activity is Kir2.1, which encodes inwardly rectifying potassium (Kir) channels in the heart and brain. For inwardly rectifying potassium channels, the inward flow of potassium ions at subthreshold is greater than the outward flow of potassium ions for the opposite driving force. This inward rectification results when intracellular magnesium ions and polyamines enter the ion channel pore from the cytoplasmic side but are unable to pass through it to the extracellular solution. The block is more intense at decreased membrane potentials as the larger depolarization facilitates the movement of magnesium ions and polyamines into the pore. In contrast, as membrane potentials approach the resting membrane potential, the decreasing depolarization hinders magnesium ion movement into the pore. When the membrane potential exceeds the resting membrane potential (hyperpolarization), magnesium ions become prevented from entering the channel. Inwardly rectifying potassium channels prevent the membrane potential from depolarizing by increasing the membrane potassium conductance. This increase in potassium permeability counterbalances the excitatory synaptic potentials that drive the initial membrane depolarization, hence inhibiting the formation of the action potential. In this way, the Kir2.1 contributes to stabilizing the resting potential at a sufficiently negative level to prevent enough sodium channel availability for action potential in the CNS and heart. Kir2.1 has been demonstrated to inhibit both evoked and spontaneous activity of neurons in vitro. STRATEGIES FOR CONTROL OF TRANSGENE EXPRESSION Inducible Gene Expression System Gene therapy will only prove beneficial as a treatment modality for spasticity if it provides advantages over existing pharmacologic and lesionbased modalities. For this to be accomplished, transgene expression must be both adjustable and reversible. One way to control viral vector-mediated transgene expression is to use inducible promoter elements. Several inducible promoter systems have been developed for this purpose, such as tetracycline, RU-486, rapamycin responsive systems, and the chimeric drosophila/bombyx ecdysone receptor system

The pervasive crisis of diminishing radiation therapy access for vulnerable populations in the United States, part 2: American Indian patients

Introduction: American Indian/Alaska Native (AI/AN) patients with cancer disproportionally present with more advanced stages of disease and have the worst cancer-specific survival rates of any racial/ethnic group in the United States. The presence of disparities in radiation therapy (RT) access for AI/AN patients has rarely been examined. Methods and materials: National Cancer Institute (NCI) initiatives toward addressing AI/AN disparities were examined. Additionally, an extensive PubMed literature search for studies investigating RT access disparities in AI/AN patients was performed. Results: Literature describing RT access disparities for the AI/AN patient population is sparse, revealing only 3 studies, each of which described initiatives from the Walking Forward program, the NCI Cancer Disparity Research Partnership initiative to address barriers to cancer screening among AI populations in the Northern Plains region (eg, geographic remoteness and mistrust of health care providers). This program has used patient navigation, community education, and access to clinical trials for more than 4000 AI/AN patients to combat high cancer mortality rates. Over the course of its 15-year existence, the program has resulted in patients presenting with earlier stages of disease and experiencing higher cure rates. Lung cancer, the most common cause of cancer-related mortality in AI/AN patients, is the most recent and ongoing focus of the program. Conclusion: The amount of information regarding RT access in AI/AN patients is limited, with nearly all peer-reviewed published progress in this area being associated with the Walking Forward program. Further initiatives from this program will hopefully inspire similar initiatives throughout the country to reduce the barriers to optimized cancer care that these patients face. Given the similarities with cancer disparities of populations worldwide, the AI/AN experience should be included within the broad issue of a global shortage of cancer care among underserved populations

The pervasive crisis of diminishing radiation therapy access for vulnerable populations in the United States—Part 4: Appalachian patients

Purpose: Compared with the rest of the United States, the population of Appalachia has lower education levels, higher rates of poverty, and limited access to health care. The presence of disparities in radiation therapy (RT) access for Appalachian patients with cancer has rarely been examined. Methods and materials: The National Cancer Institute initiatives toward addressing disparities in treatment access for rural populations were examined. An extensive literature search was undertaken for studies investigating RT access disparities in Appalachian patients, beginning with the most common cancers in these patients (lung, colorectal, and cervical). Results: Although the literature investigating RT access disparities in Appalachia is relatively sparse, studies examining lung, colorectal, cervical, prostate, head and neck, breast, and esophageal cancer, as well as lymphoma, indicate an unfortunate commonality in barriers to optimal RT access for Appalachian patients with cancer. These barriers are predominantly socioeconomic in nature (low income and lack of private insurance) but are exacerbated by paucities in both the number and quality of radiation centers that are accessible to this patient population. Conclusions: Regardless of organ system, there are significant barriers for Appalachian patients with cancer to receive RT. Such diminished access is alarming and warrants resources devoted to addressing these disparities, which often go overlooked because of the assumption that the overall wealth of the United States is tangibly applicable to all of its citizens. Without intelligently targeted investments of time and finances in this arena, there is great risk of exacerbating rather than alleviating the already heavy burden facing Appalachian patients with cancer

The pervasive crisis of diminishing radiation therapy access for vulnerable populations in the United States, part 1: African-American patients

Introduction: African Americans experience the highest burden of cancer incidence and mortality in the United States and have been persistently less likely to receive interventional care, even when such care has been proven superior to conservative management by randomized controlled trials. The presence of disparities in access to radiation therapy (RT) for African American cancer patients has rarely been examined in an expansive fashion. Methods and materials: An extensive literature search was performed using the PubMed database to examine studies investigating disparities in RT access for African Americans. Results: A total of 55 studies were found, spanning 11 organ systems. Disparities in access to RT for African Americans were most prominently study in cancers of the breast (23 studies), prostate (7 studies), gynecologic system (5 studies), and hematologic system (5 studies). Disparities in RT access for African Americans were prevalent regardless of organ system studied and often occurred independently of socioeconomic status. Fifty of 55 studies (91%) involved analysis of a population-based database such as Surveillance, Epidemiology and End Result (SEER; 26 studies), SEER-Medicare (5 studies), National Cancer Database (3 studies), or a state tumor registry (13 studies). Conclusions: African Americans in the United States have diminished access to RT compared with Caucasian patients, independent of but often in concert with low socioeconomic status. These findings underscore the importance of finding systemic and systematic solutions to address these inequalities to reduce the barriers that patient race provides in receipt of optimal cancer care