Clinical and serological insights into paraneoplastic brachial amyotrophic diplegia.

BACKGROUND: Brachial amyotrophic diplegia (BAD) is typically linked to a neurodegenerative etiology such as amyotrophic lateral sclerosis (ALS). Clinical and serological characterizations of paraneoplastic neurologic syndromes resembling BAD are limited. METHODS: A retrospective chart review of patients with BAD-like presentations was conducted. Clinical/paraclinical features of paraneoplastic BAD and neurodegenerative BAD cases were compared. RESULTS: Between 2017 and 2023, 13 cases of BAD were identified, of these 10 were neurodegenerative BAD (ALS variant), and 3 cases associated with paraneoplastic autoimmunity. An additional paraneoplastic BAD case diagnosed in 2005 was included. LUZP4-IgG was detected in all four paraneoplastic cases, with coexisting KLHL11-IgG in three cases and ANNA1 (anti-Hu)-IgG in one case. Out of the four paraneoplastic cases, two patients had seminoma, while the remaining two had limited cancer investigation. Three patients exhibited bi-brachial weakness as the initial symptom before the onset of brainstem symptoms or seizures. Compared to BAD patients with a neurodegenerative etiology, a higher proportion of paraneoplastic cases had ataxia (75% vs 0%, p = 0.011). Other clinical features only detected in the paraneoplastic BAD group were vertigo (n = 2), hearing loss (n = 2) and ophthalmoplegia (n = 2). Electrodiagnostic studies in these patients revealed cervical myotome involvement, supportive of motor neuronopathy. All paraneoplastic cases but none of the neurodegenerative BAD cases exhibited inflammatory cerebrospinal fluid (CSF) findings (lymphocytic pleocytosis and/or supernumerary oligoclonal bands; p = 0.067). Despite the administration of immunotherapy and/or cancer treatment, none of the paraneoplastic patients reported clinical improvement. DISCUSSION: BAD or bi-brachial neurogenic weakness is a rare phenotypic presentation associated with paraneoplastic autoimmunity. Co-existing features of brainstem dysfunction or cerebellar ataxia should prompt further paraneoplastic evaluation. Common serological and cancer associations among these cases include LUZP4-IgG and KLHL11-IgG, along with testicular germ cell tumors, respectively.

Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD.

Functional loss of TDP-43, an RNA binding protein genetically and pathologically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leads to the inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote the degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. Here, we show that mRNA transcripts harboring cryptic exons generated de novo proteins in TDP-43-depleted human iPSC-derived neurons in vitro, and de novo peptides were found in cerebrospinal fluid (CSF) samples from patients with ALS or FTD. Using coordinated transcriptomic and proteomic studies of TDP-43-depleted human iPSC-derived neurons, we identified 65 peptides that mapped to 12 cryptic exons. Cryptic exons identified in TDP-43-depleted human iPSC-derived neurons were predictive of cryptic exons expressed in postmortem brain tissue from patients with TDP-43 proteinopathy. These cryptic exons produced transcript variants that generated de novo proteins. We found that the inclusion of cryptic peptide sequences in proteins altered their interactions with other proteins, thereby likely altering their function. Last, we showed that 18 de novo peptides across 13 genes were present in CSF samples from patients with ALS/FTD spectrum disorders. The demonstration of cryptic exon translation suggests new mechanisms for ALS/FTD pathophysiology downstream of TDP-43 dysfunction and may provide a potential strategy to assay TDP-43 function in patient CSF.

Considerations for establishing and maintaining international research collaboration: the example of chemotherapy-induced peripheral neurotoxicity (CIPN)-a white paper.

PURPOSE: This white paper provides guidance regarding the process for establishing and maintaining international collaborations to conduct oncology/neurology-focused chemotherapy-induced peripheral neurotoxicity (CIPN) research. METHODS: An international multidisciplinary group of CIPN scientists, clinicians, research administrators, and legal experts have pooled their collective knowledge regarding recommendations for establishing and maintaining international collaboration to foster advancement of CIPN science. RESULTS: Experts provide recommendations in 10 categories: (1) preclinical and (2) clinical research collaboration; (3) collaborators and consortiums; (4) communication; (5) funding; (6) international regulatory standards; (7) staff training; (8) data management, quality control, and data sharing; (9) dissemination across disciplines and countries; and (10) additional recommendations about feasibility, policy, and mentorship. CONCLUSION: Recommendations to establish and maintain international CIPN research collaboration will promote the inclusion of more diverse research participants, increasing consideration of cultural and genetic factors that are essential to inform innovative precision medicine interventions and propel scientific discovery to benefit cancer survivors worldwide. RELEVANCE TO INFORM RESEARCH POLICY: Our suggested guidelines for establishing and maintaining international collaborations to conduct oncology/neurology-focused chemotherapy-induced peripheral neurotoxicity (CIPN) research set forth a challenge to multinational science, clinical, and policy leaders to (1) develop simple, streamlined research designs; (2) address logistical barriers; (3) simplify and standardize regulatory requirements across countries; (4) increase funding to support international collaboration; and (5) foster faculty mentorship.

Radiologically Inserted Gastrostomy Tube Placement Guided by the Assessment and Primary Palliative Care Provided by an Amyotrophic Lateral Sclerosis Multidisciplinary Clinic: A Single-Arm Retrospective Clinical Study.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a median survival of about 3 years. An ALS multidisciplinary team can provide primary palliative care and improve outcomes and quality of life for patients. Feeding tube insertion may be considered for patients with significant weight loss, or respiratory insufficiency. While radiologically inserted gastrostomy (RIG) tube placement may be an option, further studies are required to determine its best timing and appropriateness. This study's objectives were to evaluate the feasibility and outcomes of RIG tube placement in ALS patients over a 90-day follow-up period through the assessment and primary palliative care provided by the multidisciplinary team. This retrospective study reviewed the placement of 16 or 18 French RIG-tube without intubation or endoscopy for 36 ALS patients at a single center between April 2019 and December 2021. Measures included ALS Functional Rating Scale-Revised (ALSFRS-R) scores to determine the ALS stage. Demographic, clinical, procedural, and follow-up data were reviewed. Results showed that the RIG tube placement had a low rate of minor adverse events (11%) and no major procedure-related adverse events. The mean ALSFRS-R score at the time of procedure in subjects who died within 90 days was lower than of those alive beyond 90 days (P = .04). This study found that RIG-tube placement is a safe and effective way to manage dysphagia in ALS patients and highlights the importance of educating members of the multidisciplinary clinic in palliative care principles to determine the appropriateness of RIG tube placement.

Nerve transcriptomes in autoimmune and genetic demyelinating neuropathies: Pathogenic pathway assessment of nerve demyelination.

The pathogenesis of autoimmune demyelinating neuropathies is poorly understood compared to inherited demyelinating forms. We performed whole transcriptome (RNA-Seq) using nerve biopsy tissues of patients with different autoimmune and inherited demyelinating neuropathies (CIDP n = 10, POEMS n = 18, DADS n = 3, CMT1 n = 3) versus healthy controls (n = 6). A limited number of differentially expressed genes compared to healthy controls were identified (POEMS = 125, DADS = 15, CMT = 14, CIDP = 5). Divergent pathogenic pathways including inflammatory, demyelinating and neurite regeneration such as with the triggering receptor expressed on myeloid cells (TREM1) part of the immunoglobulin superfamily and RhoGD1 are found. Shared and discordant pathogenic injury are discovered between autoimmune and inherited forms.

Clinical trials in Charcot-Marie-Tooth disorders: a retrospective and preclinical assessment.

Objective: This study aimed to evaluate the progression of clinical and preclinical trials in Charcot-Marie-Tooth (CMT) disorders. Background: CMT has historically been managed symptomatically and with genetic counseling. The evolution of molecular and pathologic understanding holds a therapeutic promise in gene-targeted therapies. Methods: ClinicalTrials.gov from December 1999 to June 2022 was data extracted for CMT with preclinical animal gene therapy trials also reviewed by PubMed search. Results: The number of active trials was 1 in 1999 and 286 in 2022. Academic settings accounted for 91% and pharmaceutical companies 9%. Of the pharmaceutical and academic trials, 38% and 28%, respectively, were controlled, randomized, and double-blinded. Thirty-two countries participated: the United States accounted for 26% (75/286). In total, 86% of the trials were classified as therapeutic: 50% procedural (21% wrist/elbow surgery; 22% shock wave and hydrodissection therapy), 23% investigational drugs, 15% devices, and 11% physical therapy. Sixty-seven therapeutic trials (49%) were designated phases 1-2 and 51% phases 3-4. The remaining 14% represent non-therapeutic trials: diagnostic testing (3%), functional outcomes (4%), natural history (4%), and standard of care (3%). One-hundred and three (36%) resulted in publications. Phase I human pharmaceutical trials are focusing on the safety of small molecule therapies (n = 8) and AAV and non-viral gene therapy (n = 3). Preclinical animal gene therapy studies include 11 different CMT forms including viral, CRISPR-Cas9, and nanoparticle delivery. Conclusion: Current CMT trials are exploring procedural and molecular therapeutic options with substantial participation of the pharmaceutical industry worldwide. Emerging drug therapies directed at molecular pathogenesis are being advanced in human clinical trials; however, the majority remain within animal investigations.

Skin Extracellular Matrix Breakdown Following Paclitaxel Therapy in Patients with Chemotherapy-Induced Peripheral Neuropathy.

The chemotherapeutic agent paclitaxel causes peripheral neuropathy, a dose-limiting side effect, in up to 68% of cancer patients. In this study, we investigated the impact of paclitaxel therapy on the skin of breast cancer patients with chemotherapy-induced peripheral neuropathy (CIPN), building upon previous findings in zebrafish and rodents. Comprehensive assessments, including neurological examinations and quality of life questionnaires, were conducted, followed by intraepidermal nerve fiber (IENF) density evaluations using skin punch biopsies. Additionally, RNA sequencing, immunostaining for Matrix-Metalloproteinase 13 (MMP-13), and transmission electron microscopy provided insights into molecular and ultrastructural changes in this skin. The results showed no significant difference in IENF density between the control and CIPN patients despite the presence of patient-reported CIPN symptoms. Nevertheless, the RNA sequencing and immunostaining on the skin revealed significantly upregulated MMP-13, which is known to play a key role in CIPN caused by paclitaxel therapy. Additionally, various genes involved in the regulation of the extracellular matrix, microtubules, cell cycle, and nervous system were significantly and differentially expressed. An ultrastructural examination of the skin showed changes in collagen and basement membrane structures. These findings highlight the presence of CIPN in the absence of IENF density changes and support the role of skin remodeling as a major contributor to CIPN.

Clinical, Neurophysiologic, and Pathologic Features in Patients With Early-Onset Postradiation Neuropathy.

OBJECTIVES: The objective of this study was to study early-onset radiation-induced neuropathy reviewing neurologic course, steroid response, and available nerve biopsies. METHODS: Patients coded with radiation-induced neuropathy within 6 months of radiation were reviewed from January 1,1999, to August 31, 2022. Patients had to have electrodiagnostically confirmed neuropathy localized within or distal to radiation fields. Neurologic course and nerve biopsies were reviewed. RESULTS: Twenty-eight patients (16 male and 12 female patients, mean age 63.8 years) were identified. The average radiation dose was 4,659 cGy (range 1,000-7,208). Tumor infiltration was not observed on MRI and PET. Postradiation onsets averaged 2 months (range 0-5). Localizations included brachial (n = 4) plexopathies, lumbosacral (n = 12) plexopathies, radiculopathies (n = 10), and mononeuropathies (n = 2). Neuropathic pain (n = 25) and weakness (n = 25) were typical. The clinical courses were subacute monophasic (n = 14), chronic progressive (n = 8), or static (n = 1), and 5 were without follow-up. Nerve biopsies (n = 8) showed an inflammatory ischemic process with perivascular inflammatory infiltrates (n = 7) or microvasculitis (n = 2). Nine patients, 7 with monophasic courses, received steroid burst therapy with symptom improvement in 8. No patients recovered entirely back to baseline. DISCUSSION: In contrast to chronic radiation-induced neuropathy, early-onset patients most commonly have painful monophasic courses with residual deficits, possibly steroid responsive. An ischemic inflammatory pathogenesis is suggested.

Plexus MRI helps distinguish the immune-mediated neuropathies MADSAM and MMN.

BACKGROUND: Among immune-mediated neuropathies, clinical-electrophysiological overlap exists between multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) and multifocal motor neuropathy (MMN). Divergent immune pathogenesis, immunotherapy response, and prognosis exist between these two disorders. MRI reports have not shown distinction of these disorders, but biopsy confirmation is lacking in earlier reports. MADSAM nerves are hypertrophic with onion bulbs, inflammation, and edema, whereas MMN findings are limited to multifocal axonal atrophy. OBJECTIVES: To understand if plexus MRI can distinguish MADSAM from MMN among pathologically (nerve biopsy) confirmed cases. METHODS: Retrospective chart review and blinded plexus MRI review of biopsy-confirmed MADSAM and MMN cases at Mayo Clinic. RESULTS: Nine brachial plexuses (MADSAM-5, MMN-4) and 6 lumbosacral plexuses (MADSAM-4, MMN-2) had fascicular biopsies of varied nerves. Median follow-up in MADSAM was 93 months (range: 7-180) and 27 (range: 12-109) in MMN (p = 0.34). MRI hypertrophy occurred solely in MADSAM (89%, 8/9) with T2-hyperintensity in both. There was no correlation between time to imaging for hypertrophy, symptom onset age, or motor neuropathy impairments (mNIS). At last follow-up, on diverse immunotherapies mNIS improved in MADSAM (median - 4, range: -22 to 0), whereas MMN worsened (median 3, range: 0 to 6, p = 0.03) on largely IVIG. CONCLUSION: Nerve hypertrophy on plexus MRI helps distinguish MMN from MADSAM, where better immunotherapy treatment outcomes were observed. These findings are consistent with the immune pathogenesis seen on biopsies. Radiologic distinction is possible independent of time to imaging and extent of motor deficits, suggesting MRI is helpful in patients with uncertain clinical-electrophysiologic diagnosis, especially motor-onset MADSAM.

A randomized placebo-controlled phase 3 study of mesenchymal stem cells induced to secrete high levels of neurotrophic factors in amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative illness with great unmet patient need. We aimed to evaluate whether mesenchymal stem cells induced to secrete high levels of neurotrophic factors (MSC-NTF), a novel autologous cell-therapy capable of targeting multiple pathways, could safely slow ALS disease progression. METHODS: This randomized, double-blind, placebo-controlled study enrolled ALS participants meeting revised El Escorial criteria, revised ALS Functional Rating Scale (ALSFRS-R) ≥25 (screening) and ≥3 ALSFRS-R points decline prior to randomization. Participants received three treatments of MSC-NTF or placebo intrathecally. The primary endpoint evaluated efficacy of MSC-NTF through a responder analysis and safety. A change in disease progression post-treatment of ≥1.25 points/mo defines a clinical response. A pre-specified analysis leveraged baseline ALSFRS-R of 35 as a subgroup threshold. RESULTS: Overall, MSC-NTF treatment was well tolerated; there were no safety concerns. Thirty-three percent of MSC-NTF and 28% of placebo participants met clinical response criteria at 28 wk (odds ratio [OR] = 1.33, P = .45); thus, the primary endpoint was not met. A pre-specified analysis of participants with baseline ALSFRS-R ≥ 35 (n = 58) showed a clinical response rate at 28 wk of 35% MSC-NTF and 16% placebo (OR = 2.6, P = .29). Significant improvements in cerebrospinal biomarkers of neuroinflammation, neurodegeneration, and neurotrophic factor support were observed with MSC-NTF, with placebo unchanged. DISCUSSION: The study did not reach statistical significance on the primary endpoint. However, a pre-specified subgroup suggests that MSC-NTF participants with less severe disease may have retained more function compared to placebo. Given the unmet patient need, the results of this trial warrant further investigation.

Academic Physician Specialists' Approaches to Counseling Patients Interested in Unproven Stem Cell and Regenerative Therapies-A Qualitative Analysis.

OBJECTIVE: To explore the experiences, approaches, and challenges of physicians consulting patients about experimental stem cell and regenerative medicine interventions (SCRIs). PARTICIPANTS AND METHODS: From August 21, 2018, through July 30, 2019, semistructured interviews of 25 specialists in cardiology, ophthalmology, orthopedics, pulmonology, and neurology were conducted and qualitatively analyzed using modified grounded theory. RESULTS: All specialists used informational approaches to counsel patients, especially orthopedists. Informational approaches included explaining stem cell science, sharing risks, and providing principles. Several specialists also used relational counseling approaches including emphasizing that physicians want what is best for patients, acknowledging suffering, reassuring continued care, empathizing with patients and families, and underscoring that patients have the final decision. Many specialists reported being comfortable with the conversation, although some were less comfortable and several noted challenges in the consultation including wanting to support a patient's decision but worrying about harms from unproven SCRIs, navigating family pressure, and addressing stem cell hype and unrealistic expectations. Specialists also desired that additional resources be available for them and patients. CONCLUSION: Physicians relied more heavily on providing patients with information about SCRIs than using relational counseling approaches. Efforts should be directed at helping physicians address the informational and relational needs of patients, including providing tools and resources that inform physicians about the unproven SCRI industry, building skills in empathic communication, and the creation and dissemination of evidence-based resources to offer patients.

Alterations of mesenchymal stromal cells in cerebrospinal fluid: insights from transcriptomics and an ALS clinical trial.

BACKGROUND: Mesenchymal stromal cells (MSCs) have been studied with increasing intensity as clinicians and researchers strive to understand the ability of MSCs to modulate disease progression and promote tissue regeneration. As MSCs are used for diverse applications, it is important to appreciate how specific physiological environments may stimulate changes that alter the phenotype of the cells. One need for neuroregenerative applications is to characterize the spectrum of MSC responses to the cerebrospinal fluid (CSF) environment after their injection into the intrathecal space. Mechanistic understanding of cellular biology in response to the CSF environment may predict the ability of MSCs to promote injury repair or provide neuroprotection in neurodegenerative diseases. METHODS: In this study, we characterized changes in morphology, metabolism, and gene expression occurring in human adipose-derived MSCs cultured in human (hCSF) or artificial CSF (aCSF) as well as examined relevant protein levels in the CSF of subjects treated with MSCs for amyotrophic lateral sclerosis (ALS). RESULTS: Our results demonstrated that, under intrathecal-like conditions, MSCs retained their morphology, though they became quiescent. Large-scale transcriptomic analysis of MSCs revealed a distinct gene expression profile for cells cultured in aCSF. The aCSF culture environment induced expression of genes related to angiogenesis and immunomodulation. In addition, MSCs in aCSF expressed genes encoding nutritional growth factors to expression levels at or above those of control cells. Furthermore, we observed a dose-dependent increase in growth factors and immunomodulatory cytokines in CSF from subjects with ALS treated intrathecally with autologous MSCs. CONCLUSIONS: Overall, our results suggest that MSCs injected into the intrathecal space in ongoing clinical trials remain viable and may provide a therapeutic benefit to patients.

Expanded neuromuscular morbidity in Hodgkin lymphoma after radiotherapy.

Our study aims to quantitate neuromuscular morbidity from radiotherapy in Hodgkin lymphoma including: (i) frequency and (ii) time of onsets for neurological localizations; (iii) degree of disabilities and (iv) number of clinical visits compared to cardiopulmonary Hodgkin lymphoma-radiation complications. Medical records from Mayo Health systems were retrieved; identifying neuromuscular radiation treated Hodgkin lymphoma-complications from 1 January 1994 to 31 December 2016. Of an estimated 4100 post-radiotherapy Hodgkin lymphoma patients, 4.6% (189) were identified with complications. Mean latency to physician visit for symptoms was 23.7 years (range: 1-50). Most commonly identified complications included: head drop 10% (19) with or without myopathy, myopathy 39% (73), plexopathy 29% (54), myelopathy 27% (51) and polyradiculopathy 13% (24). Other findings included benign and malignant nerve sheath tumours 5% (9), phrenic and long thoracic mononeuropathies 7% (14) and compressive spinal meningioma 2% (4). Patients frequently had multiple coexisting complications (single = 76% [144], double = 17% [33], triple = 4% [8], quadruple = 2% [4]). Cardiac 28% (53) and pulmonary 15% (29) complications were also seen in these patients. History of Hodgkin lymphoma was initially overlooked by neurologists (14.3%, 48/336 clinical notes). Hospital and outpatient visits for complications were frequent: neuromuscular 19% (77/411) versus cardiopulmonary 30% (125/411). Testing was largely exclusionary, except when imaging identified secondary malignancy. Modified Rankin score at diagnosis varied: 0-1 (55.8%), 2-3 (5.8%) and 4-5 (38.3%). Neuromuscular complications among post-radiation Hodgkin lymphoma are diverse, occurring in ∼1 of 20 having markedly delayed onsets often eluding diagnosis. Frequent care visits and major morbidity are common. Survivorship recommendations should recognize the diverse neurological complications.

Postsurgical Neuropathy: A Descriptive Review.

Postsurgical neuropathies represent an infrequent but potentially devastating complication of surgery that may result in significant morbidity with medicolegal implications. Elucidation of this phenomenon has evolved over the past few decades, with emerging evidence for not only iatrogenic factors contributing to this process but also inflammatory causes. This distinction can be important; for instance, cases in which inflammatory etiologies are suspected may benefit from further investigations including nerve biopsy and may benefit from treatment in the form of immunotherapy. In contrast, postsurgical neuropathies due to perioperative causes including anesthesia, traction, compression, and transection will not benefit in the same manner. This article summarizes early and current literature surrounding the frequency of new neurologic deficits after various surgical types, potential causes including anatomical and inflammatory considerations, and roles for treatment. To capture the scope of the issue, a literature review was conducted for human studies in English via MEDLINE and EMBASE from January 1, 1988 to March 31, 2018. Search terms included anesthesia and/or surgical procedures, operative, peripheral nervous system diseases, trauma, mononeuropathy, polyneuropathy, peripheral nervous system, nerve compression, neuropathy, plexopathy, postoperative, postsurgical, perioperative, complication. We excluded case series with less than 10 patients and review papers. We then narrowed the studies to those presented highlighting key concepts in postsurgical neuropathy.

Modeling chemotherapy induced peripheral neuropathy (CIPN) in vitro: Prospects and limitations.

Neuronal cell cultures have been used as an essential tool for studying pathomechanisms of toxicity of chemotherapeutic drugs and to develop neuroprotective approaches. They offer the opportunity to dissect disease mechanisms and molecular pathways while allowing precise control of a variety of confounding factors of the physio-chemical environment. As such, a growing number of in vitro studies are published each year to decipher mechanisms of neurotoxicity of taxanes, vinca alcaloids, proteasome inhibitors and platin derivatives and/or to test neuroprotective strategies. Here, we provide a review of cell culture techniques and outcome measures that have been used in the past or are currently employed to model chemotherapy induced neuropathy in vitro. Furthermore, we discuss their advantages as well as their limitations and ways to enhance efficiency and reproducibility of cell culture studies in the field of toxic neuropathy.

Pathogenesis of paclitaxel-induced peripheral neuropathy: A current review of in vitro and in vivo findings using rodent and human model systems.

Paclitaxel (Brand name Taxol) is widely used in the treatment of common cancers like breast, ovarian and lung cancer. Although highly effective in blocking tumor progression, paclitaxel also causes peripheral neuropathy as a side effect in 60-70% of chemotherapy patients. Recent efforts by numerous labs have aimed at defining the underlying mechanisms of paclitaxel-induced peripheral neuropathy (PIPN). In vitro models using rodent dorsal root ganglion neurons, human induced pluripotent stem cells, and rodent in vivo models have revealed a number of molecular pathways affected by paclitaxel within axons of sensory neurons and within other cell types, such as the immune system and peripheral glia, as well skin. These studies revealed that paclitaxel induces altered calcium signaling, neuropeptide and growth factor release, mitochondrial damage and reactive oxygen species formation, and can activate ion channels that mediate responses to extracellular cues. Recent studies also suggest a role for the matrix-metalloproteinase 13 (MMP-13) in mediating neuropathy. These diverse changes may be secondary to paclitaxel-induced microtubule transport impairment. Human genetic studies, although still limited, also highlight the involvement of cytoskeletal changes in PIPN. Newly identified molecular targets resulting from these studies could provide the basis for the development of therapies with which to either prevent or reverse paclitaxel-induced peripheral neuropathy in chemotherapy patients.

Association between ALS and retroviruses: evidence from bioinformatics analysis.

BACKGROUND: Emerging evidence suggests retroviruses play a role in the pathophysiology of amyotrophic lateral sclerosis (ALS). Specifically, activation of ancient viral genes embedded in the human genome is theorized to lead to motor neuron degeneration. We explore whether connections exist between ALS and retroviruses through protein interaction networks (PIN) and pathway analysis, and consider the potential roles in drug target discovery. Protein database and pathway/network analytical software including Ingenuity Pathway BioProfiler, STRING, and CytoScape were utilized to identify overlapping protein interaction networks and extract core cluster (s) of retroviruses and ALS. RESULTS: Topological and statistical analysis of the ALS-PIN and retrovirus-PIN identified a shared, essential protein network and a core cluster with significant connections with both networks. The identified core cluster has three interleukin molecules IL10, Il-6 and IL-1B, a central apoptosis regulator TP53, and several major transcription regulators including MAPK1, ANXA5, SQSTM1, SREBF2, and FADD. Pathway enrichment analysis showed that this core cluster is associated with the glucocorticoid receptor singling and neuroinflammation signaling pathways. For confirmation purposes, we applied the same methodology to the West Nile and Polio virus, which demonstrated trivial connectivity with ALS, supporting the unique connection between ALS and retroviruses. CONCLUSIONS: Bioinformatics analysis provides evidence to support pathological links between ALS and retroviral activation. The neuroinflammation and apoptotic regulation pathways are specifically implicated. The continuation and further analysis of large scale genome studies may prove useful in exploring genes important in retroviral activation and ALS, which may help discover new drug targets.

NurOwn, phase 2, randomized, clinical trial in patients with ALS: Safety, clinical, and biomarker results.

OBJECTIVE: To determine the safety and efficacy of mesenchymal stem cell (MSC)-neurotrophic factor (NTF) cells (NurOwn®, autologous bone marrow-derived MSCs, induced to secrete NTFs) delivered by combined intrathecal and intramuscular administration to participants with amyotrophic lateral sclerosis (ALS) in a phase 2 randomized controlled trial. METHODS: The study enrolled 48 participants randomized 3:1 (treatment: placebo). After a 3-month pretransplant period, participants received 1 dose of MSC-NTF cells (n = 36) or placebo (n = 12) and were followed for 6 months. CSF was collected before and 2 weeks after transplantation. RESULTS: The study met its primary safety endpoint. The rate of disease progression (Revised ALS Functional Rating Scale [ALSFRS-R] slope change) in the overall study population was similar in treated and placebo participants. In a prespecified rapid progressor subgroup (n = 21), rate of disease progression was improved at early time points (p < 0.05). To address heterogeneity, a responder analysis showed that a higher proportion of treated participants experienced ≥1.5 points/month ALSFRS-R slope improvement compared to placebo at all time points, and was significant in rapid progressors at 4 and 12 weeks (p = 0.004 and 0.046, respectively). CSF neurotrophic factors increased and CSF inflammatory biomarkers decreased in treated participants (p < 0.05) post-transplantation. CSF monocyte chemoattractant protein-1 levels correlated with ALSFRS-R slope improvement up to 24 weeks (p < 0.05). CONCLUSION: A single-dose transplantation of MSC-NTF cells is safe and demonstrated early promising signs of efficacy. This establishes a clear path forward for a multidose randomized clinical trial of intrathecal autologous MSC-NTF cell transplantation in ALS. CLASSIFICATION OF EVIDENCE: This phase II study provides Class I evidence.

Platinum-induced peripheral neurotoxicity: From pathogenesis to treatment.

Platinum-induced peripheral neurotoxicity (PIPN) is a common side effect of platinum-based chemotherapy that may cause dose reduction and discontinuation, with oxaliplatin being more neurotoxic. PIPN includes acute neurotoxicity restricted to oxaliplatin, and chronic non-length-dependent sensory neuronopathy with positive and negative sensory symptoms and neuropathic pain in both upper and lower limbs. Chronic sensory axonal neuropathy manifesting as stocking-and-glove distribution is also frequent. Worsening of neuropathic symptoms after completing the last chemotherapy course may occur. Motor and autonomic involvement is uncommon. Ototoxicity is frequent in children and more commonly to cisplatin. Platinum-based compounds result in more prolonged neuropathic symptoms in comparison to other chemotherapy agents. Patient reported outcomes questionnaires, clinical evaluation and instrumental tools offer complementary information in PIPN. Electrodiagnostic features include diffusely reduced/abolished sensory action potentials, in keeping with a sensory neuronopathy. PIPN is dependent on cumulative dose but there is a large variability in its occurrence. The search for additional risk factors for PIPN has thus far yielded no consistent findings. There are currently no neuroprotective strategies to reduce the risk of PIPN, and symptomatic treatment is limited to duloxetine that was found effective in a single phase III intervention study. This review critically examines the pathogenesis, incidence, risk factors (both clinical and pharmacogenetic), clinical phenotype and management of PIPN.