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Prognosis for advanced oral carcinoma remains poor. Oncolytic virotherapy uses replication-competent viruses to infect and kill only the tumor cells. However, it has been difficult to investigate the oncolytic activity of viruses against oral carcinomas in mouse models. This study established a mouse model of oral cancer and investigated the in vitro and in vivo anti-tumor effects of HF10, a highly attenuated, replication-competent herpes simplex virus (HSV)-1. Mouse tongue cancer was induced by injecting 4-nitroquinoline 1-oxide into the mouse tongue. The murine oral cancer cell line isolated from this tumor, named NMOC1, formed invasive carcinoma within a week when injected into mouse tongue. HF10 successfully infected, replicated, and spread in the cancer cells in vitro. HF10 was able to kill cancer cells isolated from human or mouse tongue tumor. HF10 injection into tongue carcinomas prolonged mouse survival without any side effects or weight loss. Intertumoral injection of GFP-expressing HF10 confirmed that viral spread was confined within the tumors. Immunohistochemical staining showed that HF10 induced infiltration of CD8-positive T cells around HSV-infected cells in the tumor mass, implying increased anti-tumor immunity. We successfully established an oral cancer cell line and showed that HF10 is a promising therapeutic agent for oral cancer.
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Oncolytic viruses (OVs) remodel the tumor microenvironment by switching a "cold" tumor into a "hot" tumor with high CD8+ T-cell infiltration. CD8+ T-cell activity plays an essential role in the antitumor efficacy of OVs. However, the activity of T cells is impaired by the programmed cell death protein-1/programmed cell death-ligand 1 (PD-1/PD-L1) interaction. To date, it remains unclear why OVs alone have a significant antitumor activity even when PD-L1 expression persists on tumor or immune cells. In this study, we found that canerpaturev (C-REV) treatment significantly suppressed tumor growth, even though it induced a significant increase in PD-L1 expression in tumors in vivo as well as persistence of high PD-L1 expression on antigen-presenting cells (macrophage and dendritic cells [DCs]). Surprisingly, we observed that C-REV treatment increased the abundance of activated CD8+ PD-1- tumor-infiltrating lymphocytes (TILs) in the tumor on both the injected and contralateral sides, although infiltration of CD8+ PD-1high TILs into the tumor was observed in the control group. Moreover, the difference in PD-1 expression was observed only in tumors after treatment with C-REV, whereas most CD8+ T cells in the spleen, tumor-draining lymph nodes and blood were PD-1-negative, and this did not change after C-REV treatment. In addition, changes in expression of T-cell immunoglobulin and mucin-domain containing-3 and T-cell immune-receptor with Ig and ITIM domains were not observed on CD8+ TILs after C-REV treatment. Taken together, our findings may reveal mechanisms that allow OVs to trigger an antitumor immune response, irrespective of a PD-L1-enriched tumor microenvironment, by recruitment of CD8+ PD-1- TILs.
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Antígeno B7-H1/metabolismo , Linfocitos T CD8-positivos/inmunología , Carcinoma de Células Escamosas/inmunología , Herpes Simple/inmunología , Neoplasias Pancreáticas/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Microambiente Tumoral/inmunología , Animales , Antígeno B7-H1/inmunología , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Femenino , Herpes Simple/virología , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Receptor de Muerte Celular Programada 1/inmunología , Simplexvirus/fisiologíaRESUMEN
OBJECTIVE: Ten kilohertz spinal cord stimulation (SCS) is usually initiated in a single-bipolar configuration over the radiological reference point T9/T10 intervertebral disc space for neuropathic back and leg pain. Cascade is a duty-cycled, multi-bipolar contact configuration across an entire eight-contact lead. Potential advantages by using a broader area of SCS coverage include mitigation against minor lead migration and a reduction in the need for reprogramming. We report here the results of a retrospective case series of 114 patients using Cascade. MATERIALS AND METHODS: Retrospective data were collected over two years. We selected patients with neuropathic back with or without/leg pain who had a trial of SCS. Pain assessments using Numerical Rating Scales (NRS) and Patient Global Impression of Change (PGIC) scores were collected at baseline, six months, and last follow-up beyond 12 months (mean 15.1 months). Patients were programmed with 10 kHz SCS using Cascade during the trial, which was continued unless reporting inadequate pain relief. Morbidity and deviations from Cascade programming were also obtained. RESULTS: At six months, 87 of 97 (90.6%) patients with active devices were using Cascade and 58 of 72 (81%) patients at the last follow-up >12 months. There was a significant reduction in back NRS (8.3 vs. 3.9 [p < 0.0001], N = 97) and leg pain (7.53 vs. 3.83 [p < 0.0001], N = 77) at 6 months and last follow-up >12 months back (8.3 vs. 3.95 [p < 0.0001] N = 72), leg (7.53 vs. 3.534 [p < 0.0001], N = 58). The PGIC score was 6 of 7 or all of 7 in 72% of patients (70/97) at six months and in 68% (49/72) of patients at the last follow-up beyond 12 months. CONCLUSION: Cascade is an effective programming methodology that may have benefits over a single-bipole configuration for 10 kHz SCS, particularly during a trial of stimulation. Results from this study suggest it is a durable program for patients with neuropathic back and leg pain.
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Dolor Crónico , Estimulación de la Médula Espinal , Humanos , Pierna , Estudios Retrospectivos , Médula Espinal , Resultado del TratamientoRESUMEN
OBJECTIVES: Early clinical trials suggest that deep brain stimulation at kilohertz frequencies (10 kHz-DBS) may be effective in improving motor symptoms in patients with movement disorders. The 10 kHz-DBS can deliver significantly more power in tissue compared to conventional frequency DBS, reflecting increased pulse compression (duty cycle). We hypothesize that 10 kHz-DBS modulates neuronal function through moderate local tissue heating, analogous to kilohertz spinal cord stimulation (10 kHz-SCS). To establish the role of tissue heating in 10 kHz-DBS (30 µs, 10 kHz, at intensities of 3-7 mApeak ), a decisive first step is to characterize the range of temperature changes during clinical kHz-DBS protocols. MATERIALS AND METHODS: We developed a high-resolution magnetic resonance imaging-derived DBS model incorporating joule-heat coupled bio-heat multi-physics to establish the role of tissue heating. Volume of tissue activated (VTA) under assumptions of activating function (for 130 Hz) or heating (for 10 kHz) based neuromodulation are contrasted. RESULTS: DBS waveform power (waveform RMS) determined joule heating at the deep brain tissues. Peak heating was supralinearly dependent on stimulation RMS. The 10 kHz-DBS stimulation with 2.3 to 5.4 mARMS (corresponding to 3 to 7 mApeak ) produced 0.10 to 1.38°C heating at the subthalamic nucleus (STN) target under standard tissue parameters. Maximum temperature increases were predicted inside the electrode encapsulation layer (enCAP) with 2.3 to 5.4 mARMS producing 0.13 to 1.87°C under standard tissue parameters. Tissue parameter analysis predicted STN heating was especially sensitive (ranging from 0.44 to 1.35°C at 3.8 mARMS ) to decreasing enCAP electrical conductivity and decreasing STN thermal conductivity. CONCLUSIONS: Subject to validation with in vivo measurements, neuromodulation through a heating mechanism of action by 10 kHz-DBS can indicate novel therapeutic pathways and strategies for dose optimization.
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Encéfalo , Estimulación Encefálica Profunda/métodos , Análisis de Elementos Finitos , Modelos Neurológicos , Temperatura Corporal , HumanosRESUMEN
The naturally occurring oncolytic herpes simplex virus canerpaturev (C-REV), formerly HF10, proved its therapeutic efficacy and safety in multiple clinical trials against melanoma, pancreatic, breast, and head and neck cancers. Meanwhile, patients with colorectal cancer, which has increased in prevalence in recent decades, continue to have poor prognosis and morbidity. Combination therapy has better response rates than monotherapy. Hence, we investigated the antitumor efficacy of cetuximab, a widely used anti-epidermal growth factor receptor (EGFR) monoclonal antibody, and C-REV, either alone or in combination, in vitro and in an in vivo human colorectal xenograft model. In human colorectal cancer cell lines with different levels of EGFR expression (HT-29, WiDr, and CW2), C-REV exhibited cytotoxic effects in a time- and dose-dependent manner, irrespective of EGFR expression. Moreover, cetuximab had no effect on viral replication in vitro. Combining cetuximab and C-REV induced a synergistic antitumor effect in HT-29 tumor xenograft models by promoting the distribution of C-REV throughout the tumor and suppressing angiogenesis. Application of cetuximab prior to C-REV yielded better tumor regression than administration of the drug after the virus. Thus, cetuximab represents an ideal virus-associated agent for antitumor therapy, and combination therapy represents a promising antitumor strategy for human colorectal cancer.
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PURPOSE OF REVIEW: Spinal cord stimulation (SCS), based on the gate theory of nociception, has been shown to be effective in the management of chronic pain conditions. While early-generation technology offered many patients improvement in their pain and symptoms, limitations including paresthesia, dependence on mapping, decreased chronological efficacy, and inadequate coverage left many patients with persistent pain and overt therapeutic failure. RECENT FINDINGS: New advances in neuromodulation technology circumvent many of these previous limitations and offer patients improved pain relief and quality of life. In this review, an update on recent technological developments in the field of SCS and peripheral neuromodulation is presented with discussion on differentiating characteristics which may help guide applicability to individual patient needs.
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Dolor Crónico/terapia , Manejo del Dolor/métodos , Dimensión del Dolor/métodos , Estimulación de la Médula Espinal/métodos , Dolor Crónico/diagnóstico , Ganglios Espinales/patología , Humanos , Manejo del Dolor/tendencias , Dimensión del Dolor/tendencias , Estimulación de la Médula Espinal/tendencias , Tecnología Inalámbrica/tendenciasRESUMEN
BACKGROUND: Current treatment options for bladder disorders of neurogenic etiology often leave unsatisfactory results. Therefore, new and effective treatments must be investigated. High-frequency spinal cord stimulation (HF-SCS) at 10 kHz has proven to be effective in the treatment of refractory chronic back and leg pain. OBJECTIVE: To evaluate the efficacy of HF-SCS at 10 kHz in alleviating lower urinary tract dysfunction and bladder incontinence in 5 patients with underlying neurological disease or spinal cord injury, through retrospective study. METHODS: Urodynamic parameters such as voiding frequency, residual volume, episodes of incontinence, and the patients' subjective impression impairment of life were assessed and compared pre- and postoperatively. Reduction in pain intensity was assessed as change on the Numeric Rating Scale (NRS). RESULTS: All 5 patients had significantly positive outcomes. Episodes of leakage per day improved by 83% on average. Quality of life questionnaires and subjective bother scale revealed an improvement of 36% and 57%, respectively. Individual symptoms among the patient group such as residual volume also responded to the treatment as well. Mean pain NRS of 8.6 cm was reduced to 3.9 cm (55%) at 6 mo follow-up. CONCLUSION: HF-SCS at 10 kHz significantly alleviated symptoms of neurogenic bladder incontinence in patients suffering from neurological disease or spinal cord injury. However, larger and prospective, randomized studies are necessary to make a clear statement regarding the efficacy of this therapy in lower urinary tract dysfunction and bladder incontinence.
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Estimulación de la Médula Espinal/métodos , Vejiga Urinaria Neurogénica/terapia , Incontinencia Urinaria/terapia , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Calidad de Vida , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Oncolytic viruses selectively target and kill cancer cells in an immunogenic fashion, thus supporting the establishment of therapeutically relevant tumor-specific immune responses. In 2015, the US Food and Drug Administration (FDA) approved the oncolytic herpes simplex virus T-VEC for use in advanced melanoma patients. Since then, a plethora of trials has been initiated to assess the safety and efficacy of multiple oncolytic viruses in patients affected with various malignancies. Here, we summarize recent preclinical and clinical progress in the field of oncolytic virotherapy.
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INTRODUCTION: Melanoma treatments have evolved rapidly in the past decade and have included the use of intratumoral injections of engineered oncolytic viruses. One such oncolytic virus is talimogene laherparepvec (T-VEC), which is the first approved therapy of its kind for use in recurrent, unresectable stage IIIB-IVM1a melanoma. Additional oncolytic viruses and their uses in combination with other interventions are currently under investigation. AREAS COVERED: Oncolytic viruses are being evaluated as immunotherapies for a variety of advanced malignancies. In this article, we review T-VEC, the only FDA-approved engineered oncolytic virus, in addition to ongoing research regarding other oncolytic viruses for the treatment of advanced melanomas. Finally, we discuss opportunities to improve these therapies through viral, host, and tumor-related modifications. EXPERT OPINION: Engineered and naturally oncolytic viruses have demonstrable local and systemic efficacy as immunotherapies in cancer. T-VEC leads the way with improved survival outcomes for unresectable, stage IIIB-IVM1a melanoma as a monotherapy, and is demonstrating superior results in combination with systemic checkpoint inhibitors. Additional viral vectors show acceptable safety profiles and varying degrees of efficacy in targeting melanoma. The indications for use of oncolytic viruses will expand as their efficacy and appropriate usage is better understood in coming years.
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Bioingeniería , Inmunoterapia , Melanoma/terapia , Viroterapia Oncolítica , Virus Oncolíticos/fisiología , Animales , Bioingeniería/métodos , Bioingeniería/tendencias , Vectores Genéticos , Humanos , Inmunoterapia/métodos , Inmunoterapia/tendencias , Melanoma/patología , Viroterapia Oncolítica/métodos , Viroterapia Oncolítica/tendencias , Virus Oncolíticos/genética , Recurrencia , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/terapia , Melanoma Cutáneo MalignoRESUMEN
Oncolytic virotherapy is a kind of antitumor therapy using viruses with natural or engineered tumor-selective replication to intentionally infect and kill tumor cells. An early clinical trial has been performed in the 1950s using wild-type and non-engineered in vitro-passaged virus strains and vaccine strains (first generation oncolytic viruses). Because of the advances in biotechnology and virology, the field of virotherapy has rapidly evolved over the past two decades and innovative recombinant selectivity-enhanced viruses (second generation oncolytic viruses). Nowadays, therapeutic transgene-delivering "armed" oncolytic viruses (third generation oncolytic viruses) have been engineered using many kinds of viruses. In this chapter, the history, mechanisms, rationality, and advantages of oncolytic virotherapy by herpes simplex virus (HSV) are mentioned. Past and ongoing clinical trials by oncolytic HSVs (G207, HSV1716, NV1020, HF10, Talimogene laherparepvec (T-VEC, OncoVEXGM-CSF)) are also summarized. Finally, the way of enhancement of oncolytic virotherapy by gene modification or combination therapy with radiation, chemotherapy, or immune checkpoint inhibitors are discussed.
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Neoplasias/terapia , Viroterapia Oncolítica , Virus Oncolíticos/fisiología , Simplexvirus/fisiología , Animales , Humanos , Viroterapia Oncolítica/métodos , Viroterapia Oncolítica/tendencias , Virus Oncolíticos/genética , Simplexvirus/genéticaRESUMEN
BACKGROUND: Prognosis of pancreatic cancer is poor with a 5-year survival rate of only 7%. Although several new chemotherapy treatments have shown promising results, all patients will eventually progress, and we need to develop newer chemotherapy treatments to improve response rates and overall survival (OS). HF10 is a spontaneously mutated oncolytic virus derived from a herpes simplex virus-1, and it has potential to show strong antitumor effect against malignancies without damaging normal tissue. We aimed to evaluate the safety and anti-tumor effectiveness in phase I dose-escalation trial of direct injection of HF10 into unresectable locally advanced pancreatic cancer under endoscopic ultrasound (EUS)-guidance in combination with erlotinib and gemcitabine administration. The mid-term results have been previously reported and here we report the final results of our study. METHODS: This was a single arm, open-label Phase I trial. HF10 was injected once every 2 weeks and continued up to four times in total unless dose-limiting toxicity (DLT) appears. A total of nine subjects in three Cohorts with dose-escalation were planned to be enrolled in this trial. The primary endpoint was the safety assessment and the secondary endpoint was the efficacy assessment. RESULTS: Twelve patients enrolled in this clinical trial, and ten subjects received this therapy. Five patients showed Grade III myelosuppression and two patients developed serious adverse events (AEs) (perforation of duodenum, hepatic dysfunction). However, all of these events were judged as AEs unrelated to HF10. Tumor responses were three partial responses (PR), four stable diseases (SD), and two progressive diseases (PD) out of nine subjects who completed the treatment. Target lesion responses were three PRs and six SDs. The median progression free survival (PFS) was 6.3 months, whereas the median OS was 15.5 months. Two subjects from Cohort 1 and 2 showed downstaging and finally achieved surgical complete response (CR). CONCLUSIONS: HF10 direct injection under EUS-guidance in combination with erlotinib and gemcitabine was a safe treatment for locally advanced pancreatic cancer. Combination therapy of HF10 and chemotherapy should be explored further in large prospective studies. TRIAL REGISTRATION: This study was prospectively registered in UMIN-CTR (UMIN000010150) on March 4th, 2013.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Herpesvirus Humano 1/genética , Viroterapia Oncolítica/métodos , Virus Oncolíticos/genética , Neoplasias Pancreáticas/terapia , Adulto , Anciano , Terapia Combinada/efectos adversos , Terapia Combinada/métodos , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Endosonografía , Clorhidrato de Erlotinib/uso terapéutico , Femenino , Humanos , Inyecciones Intralesiones/métodos , Masculino , Persona de Mediana Edad , Mutación , Viroterapia Oncolítica/efectos adversos , Páncreas/diagnóstico por imagen , Páncreas/patología , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Supervivencia sin Progresión , Tasa de Supervivencia , Resultado del Tratamiento , Ultrasonografía Intervencional , Adulto Joven , Gemcitabina , Neoplasias PancreáticasRESUMEN
OBJECTIVES AND METHODS: A few published reports describe successful clinical use of low-frequency spinal cord stimulation (SCS) in the cervical spine resulting in bilateral upper and lower extremity pain relief. A major side-effect when using this modality of SCS is the uneven intensity of paresthesias, which are frequently excessive in upper extremities while attempting to achieve optimal paresthesia coverage in all 4 extremities. RESULTS AND CONCLUSIONS: Here we describe a successful case of high-frequency SCS at 10 kHz where profound control of neuropathic pain of all 4 extremities was achieved without the complication of paresthesias. Discussed are future implications of such therapy.
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Neuralgia/terapia , Estimulación de la Médula Espinal/métodos , Adulto , Humanos , Masculino , Neuralgia/etiología , Parestesia/etiología , Traumatismos de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/terapia , Estimulación de la Médula Espinal/efectos adversos , Estimulación de la Médula Espinal/instrumentación , Resultado del TratamientoRESUMEN
Advanced melanoma has long been treated with chemotherapy using cytotoxic agents like dacarbazine (DTIC), but overall survival rates with these drugs have been generally low. Recently, immunoregulatory monoclonal antibodies and molecularly targeted therapy with a BRAF inhibitor and/or a MEK inhibitor, have been used to treat malignant melanoma and have improved the survival rate of patients with advanced melanoma. However, high prices of these drugs are problematic. In this study, we evaluated the oncolytic efficacy of HF10, an attenuated, replication-competent HSV, with DTIC in immunocompetent mice model of malignant melanoma. For in vitro studies, cytotoxicity assays were conducted in clone M3 mouse melanoma cells. For the in vivo studies, subcutaneous melanoma models were prepared in DBA/2 mice with clone M3 cells, and then HF10 was intratumorally inoculated with/without intraperitoneal DTIC injection. The efficacy of the therapies was evaluated by survival, growth of subcutaneous tumor, and histopathological and immunological analyses. Both HF10 infection and DTIC treatment showed cytotoxic effects in melanoma cells, but combination treatment with HF10 and DTIC showed a rapid and strong cytotoxic effect compared with monotherapy. In the subcutaneous melanoma model, intratumoral HF10 inoculation significantly inhibited tumor growth. HF10 also inhibited the growth of non-inoculated contralateral tumors when it was injected into the ipsilateral tumors of mice. In histologic and immunohistochemical analysis, tumor lysis and inflammatory cell infiltration were observed after intratumoral HF10 inoculation. When mice were treated with HF10 and DTIC, the combination therapy induced a robust systemic anti-tumor immune response and prolonged survival. IFN-γ secretion from splenocytes of the HF10-DTIC combination therapy group showed more IFN-γ secretion than did the other groups. These data showed the efficacy of HF10 and DTIC combination therapy in a mouse melanoma model.
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Oncolytic viruses (OVs) are opening new possibilities in cancer therapy with their unique mechanism of selective replication within tumor cells and triggering of antitumor immune responses. HF10 is an oncolytic herpes simplex virus-1 with a unique genomic structure that has non-engineered deletions and insertions accompanied by frame-shift mutations, in contrast to the majority of engineered OVs. At the genetic level, HF10 naturally lacks the expression of UL43, UL49.5, UL55, UL56, and latency-associated transcripts, and overexpresses UL53 and UL54. In preclinical studies, HF10 replicated efficiently within tumor cells with extensive cytolytic effects and induced increased numbers of activated CD4+ and CD8+ T cells and natural killer cells within the tumor, leading to a significant reduction in tumor growth and prolonged survival rates. Investigator-initiated clinical studies of HF10 have been completed in recurrent breast carcinoma, head and neck cancer, and unresectable pancreatic cancer in Japan. Phase I trials were subsequently completed in refractory superficial cancers and melanoma in the United States. HF10 has been demonstrated to have a high safety margin with low frequency of adverse effects in all treated patients. Interestingly, HF10 antigens were detected in pancreatic carcinoma over 300 days after treatment with infiltration of CD4+ and CD8+ T cells, which enhanced the immune response. To date, preliminary results from a Phase II trial have indicated that HF10 in combination with ipilimumab (anti-CTLA-4) is safe and well tolerated, with high antitumor efficacy. Improvement of the effect of ipilimumab was observed in patients with stage IIIb, IIIc, or IV unresectable or metastatic melanoma. This review provides a concise description of the genomic functional organization of HF10 compared with talimogene laherparepvec. Furthermore, this review focuses on HF10 in cancer treatment as monotherapy as well as in combination therapy through a concise description of all preclinical and clinical data. In addition, we will address approaches for future directions in HF10 studies as cancer therapy.
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OBJECTIVE: Spinal cord stimulation (SCS) treats neuropathic pain through retrograde stimulation of dorsal column axons and their inhibitory effects on wide dynamic range (WDR) neurons. Typical SCS uses frequencies from 50-100 Hz. Newer stimulation paradigms use high-frequency stimulation (HFS) up to 10 kHz and produce pain relief but without paresthesia. Our hypothesis is that HFS preferentially blocks larger diameter axons (12-15 µm) based on dynamics of ion channel gates and the electric potential gradient seen along the axon, resulting in inhibition of WDR cells without paresthesia. METHODS: We input field potential values from a finite element model of SCS into an active axon model with ion channel subcomponents for fiber diameters 1-20 µm and simulated dynamics on a 0.001 msec time scale. RESULTS: Assuming some degree of wave rectification seen at the axon, action potential (AP) blockade occurs as hypothesized, preferentially in larger over smaller diameters with blockade in most medium and large diameters occurring between 4.5 and 10 kHz. Simulations show both ion channel gate and virtual anode dynamics are necessary. CONCLUSION: At clinical HFS frequencies and pulse widths, HFS preferentially blocks larger-diameter fibers and concomitantly recruits medium and smaller fibers. These effects are a result of interaction between ion gate dynamics and the "activating function" (AF) deriving from current distribution over the axon. The larger fibers that cause paresthesia in low-frequency simulation are blocked, while medium and smaller fibers are recruited, leading to paresthesia-free neuropathic pain relief by inhibiting WDR cells.
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Axones/fisiología , Modelos Biológicos , Neuralgia/terapia , Estimulación de la Médula Espinal/métodos , Médula Espinal/fisiología , Potenciales de Acción/fisiología , Fenómenos Biofísicos , Simulación por Computador , Humanos , Neuralgia/etiología , Dimensión del Dolor , Parestesia/complicacionesRESUMEN
OBJECTIVE: Chronic pain remains a serious public health problem worldwide. A spinal cord stimulation (SCS) therapy called HF10 SCS uses 10-kHz high-frequency stimulation to provide pain relief without paresthesia. In this article, we describe the therapy, device, and the methods of implant and then review the safety and effectiveness data for this therapy. RESULTS: HF10 SCS uses a charge-balanced stimulation waveform that has been shown to be safe in both animal and human studies. Data from a multicenter, prospective clinical trial shows that the therapy provides substantial back and leg pain relief. Numerous additional reports suggest improved pain relief in other body areas and for complex pain patterns, even for patients who have previously failed other neuromodulation therapies. CONCLUSIONS: The clinical experience reported in this article supports the efficacy and pain relief provided by HF10 SCS therapy. Clinical studies have also concluded that HF10 SCS does not generate paresthesia nor was it necessary to provide adequate coverage for pain relief. As clinical evidence accumulates and technological innovation improves patient outcomes, neuromodulatory techniques will be sought earlier in the treatment continuum to reduce the suffering for the many with otherwise intractable chronic pain.
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Dolor Crónico/terapia , Manejo del Dolor/métodos , Estimulación de la Médula Espinal/métodos , Animales , HumanosRESUMEN
Breast cancer is one of the most common and feared cancers faced by women. The prognosis of patients with advanced or recurrent breast cancer remains poor despite refinements in multimodality therapies involving chemotherapeutic and hormonal agents. Multimodal therapy with more specific and effective strategy is urgently needed. The oncolytic herpes simplex virus (HSV) has potential to become a new effective treatment option because of its broad host range and tumor selective viral distribution. Bevacizumab is a monoclonal antibody against VEGFA, which inhibits angiogenesis and therefore tumor growth. Our approach to enhance the antitumor effect of the oncolytic HSV is to combine oncolytic HSV HF10 and bevacizumab in the treatment of breast cancer. Our results showed that bevacizumab enhanced viral distribution as well as tumor hypoxia and expanded the population of apoptotic cells and therefore induced a synergistic antitumor effect. HF10 is expected to be a promising agent in combination with bevacizumab in the anticancer treatment.