Discovery medicine
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Historically patients with advanced basal cell carcinoma have been subjected to large surgical resections for the treatment of their disease. However, with the development of vismodegib, a first in class molecule that acts to inhibit the hedgehog pathway, patients with advanced and metastatic basal cell carcinoma may have renewed hope in limiting the morbidity involved with surgery. ⋯ Current progress on utilization of vismodegib for the treatment of advanced basal cell carcinoma is reviewed in this article. Only literature with objective clinical evidence was included in this review.
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Review
Strategies for protecting oligodendrocytes and enhancing remyelination in multiple sclerosis.
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) characterized by encephalitogenic leukocyte infiltration and multifocal plaques of demyelination. Patients present with debilitating clinical sequelae including motor, sensory, and cognitive deficits. For the past 30 years, immune modulating treatments have entered the marketplace and continue to improve in limiting the frequency and severity of relapses, but no cure has been found and no drug has successfully stopped chronic progressive disease. ⋯ From this a number of promising molecular targets have been identified to protect oligodendrocytes and promote remyelination. Combining immunomodulatory therapy with strategies to protect oligodendrocytes from further degeneration and enhance remyelination presents a very real means to improve clinical outcome for chronic progressive patients in the near future. Here we lay out a combination therapy approach to treating MS and survey the current literature on promising drug candidates potentially capable of mediating oligodendrocyte protection and enhancing remyelination.
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Antitumor immunotherapy for colorectal cancer has been studied at the bench and bedside for decades. Some clinical trials of cancer immunotherapy have demonstrated a potential benefit for patients with colorectal cancer, yet immunotherapy remains only an experimental option for this disease. ⋯ Weakness and advantages of each strategy and progress in clinical trials will be described. Examination of previous and ongoing research in colorectal cancer therapy should define a path towards identification, approval, and mainstream adoption of colorectal cancer immunotherapeutics.
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Invasive neurostimulation therapies may be proposed to patients with neuropathic pain refractory to conventional medical management, in order to improve pain relief, functional capacity, and quality of life. In this review, the respective mechanisms of action and efficacy of peripheral nerve stimulation (PNS), nerve root stimulation (NRS), spinal cord stimulation (SCS), deep brain stimulation (DBS), and motor cortex stimulation (MCS) are discussed. PNS appears to be useful in various refractory neuropathic pain indications (as long as there is some preservation of sensation in the painful area), such as intractable chronic headache, pelvic and perineal pain, and low back pain, but evidence for its efficacy is not strongly conclusive, and large-scale randomized controlled studies are necessary to confirm the efficacy in the long term. ⋯ Controlled trials, with the stimulator switched ON or OFF in a double-blind procedure, have demonstrated the efficacy of MCS in the treatment of peripheral and central neuropathic pain, although these trials included a limited number of patients and need to be confirmed by large, controlled, multicenter studies. Despite technical progress in neurosurgical navigation, guided by neuroimaging and intraoperative electrophysiology to optimize electrode positioning, MCS results are still variable, and validated criteria for selecting good candidates for implantation are lacking, except clinical response to preoperative rTMS, which showed correlations with a good response to MCS-induced analgesia. However, the evidence in favor of this technique is sufficient to include it in the range of treatment options for refractory neuropathic pain.
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Drug-refractory pain is an indication for neurostimulation therapy, which can be either non-invasive [mainly transcutaneous electrical nerve stimulation (TENS), repetitive Transcranial Magnetic Stimulation (rTMS), and transcranial direct current stimulation (tDCS)] or invasive which requires the intervention of a surgeon to implant electrodes and a pulse generator [peripheral nerve stimulation (PNS), nerve root stimulation (NRS), spinal cord stimulation (SCS), deep brain stimulation (DBS), and motor cortex stimulation (MCS)]. In this review, the respective mechanisms of action and efficacy of TENS, rTMS, and tDCS are discussed. The advantages of TENS include non-invasiveness and ease to use, so that the technique can be operated by the patient. ⋯ With regard to rTMS, published randomized controlled studies in chronic neuropathic and non-neuropathic pain (fibromyalgia) reached a sufficient level of evidence to recommend this technique for the indication of implanted motor cortex stimulation for the treatment of refractory neuropathic pain or as a long-term treatment for pain syndromes, in which surgery is not indicated, such as fibromyalgia. Other indications, concerning either chronic or acute pain syndromes, such as postoperative pain, should be developed in parallel with the optimization of stimulation parameters. This also includes the availability of new coils and magnetic field waveforms and progress in neuronavigation techniques, especially by the integration of functional imaging and high-resolution EEG data.