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Metastasis remains the leading cause of cancer deaths worldwide and lung cancer, known for its highly metastatic progression, remains among the most lethal of malignancies. Lung cancer metastasis can selectively spread to multiple different organs, however the genetic and molecular drivers for this process are still poorly understood. Understanding the heterogeneous genomic profile of lung cancer metastases is considered key in identifying therapeutic targets that prevent its spread. Research has identified the key source for metastasis being clusters of cells rather than individual cancer cells. These clusters, known as metastatic cancer cell clusters (MCCCs) have been shown to be 100-fold more tumorigenic than individual cancer cells. Unfortunately, access to these primary drivers of metastases remains difficult and has limited our understanding of their molecular and genomic profiles. Strong evidence in the literature suggests that differentially regulated biological pathways in MCCCs can provide new therapeutic drug targets to help combat cancer metastases. In order to expand research into MCCCs and their role in metastasis, we demonstrate a novel, proof of principle technology, to capture MCCCs directly from patients' whole blood. Our platform can be readily tuned for different solid tumor types by combining a biomimicry-based margination effect coupled with immunoaffinity to isolate MCCCs. Adopting a selective capture approach based on overexpressed CD44 in MCCCs provides a methodology that preferentially isolates them from whole blood. Furthermore, we demonstrate a high capture efficiency of more than 90% when spiking MCCC-like model cell clusters into whole blood. Characterization of the captured MCCCs from lung cancer patients by immunofluorescence staining and genomic analyses, suggests highly differential morphologies and genomic profiles. This study lays the foundation to identify potential drug targets thus unlocking a new area of anti-metastatic therapeutics.
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Neoplasias Pulmonares , Metástasis de la Neoplasia , Células Neoplásicas Circulantes , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/secundario , Células Neoplásicas Circulantes/patología , Células Neoplásicas Circulantes/metabolismo , Prueba de Estudio Conceptual , Genómica , Femenino , MasculinoRESUMEN
PURPOSE OF REVIEW: There is no diagnostic biomarker that can reliably detect Guillain-Barré syndrome (GBS) or chronic inflammatory demyelinating polyneuropathy (CIDP). Diagnosis relies upon integrating key clinical characteristics and relevant supportive data. Consequently, misdiagnosis and delayed diagnosis are common. Diagnostic criteria have proven valuable resources to improve diagnosis, but are underutilized during routine clinical care. RECENT FINDINGS: In 2021, the EAN/PNS CIDP criteria was published, and were followed by the EAN/PNS GBS criteria in 2023. Both guidelines utilized GRADE methodology to formulate evidence-based recommendations that are intended to be used by adult and paediatric clinicians across diverse care settings to optimize diagnostic accuracy and improve patient outcomes during routine clinical care. SUMMARY: The EAN/PNS GBS and CIDP criteria detail specific clinical, electrophysiological, and laboratory features that raise diagnostic confidence, and call attention to diagnostic mimics. The sensitivity of EAN/PNS and other modern criteria to detect GBS and CIDP is high, but utilization during clinical practice is low. Complexity is one factor limiting widespread application. Strategies are needed to optimize criteria adoption during routine clinical care such that GBS and CIDP diagnosis can be achieved with greater speed and accuracy.
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Síndrome de Guillain-Barré , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante , Guías de Práctica Clínica como Asunto , Humanos , Síndrome de Guillain-Barré/diagnóstico , Síndrome de Guillain-Barré/terapia , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/diagnóstico , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/terapia , Guías de Práctica Clínica como Asunto/normasRESUMEN
Background: Patients with relapsed intracranial germinoma can achieve durable remission with standard chemotherapy regimens and/or reirradiation; however, innovative therapies are required for patients with relapsed and/or refractory intracranial nongerminomatous germ cell tumors (NGGCTs) due to their poor prognosis. Improved outcomes have been reported using reinduction chemotherapy to achieve minimal residual disease, followed by marrow-ablative chemotherapy (HDCx) with autologous hematopoietic progenitor cell rescue (AuHPCR). We conducted a phase II trial evaluating the response and toxicity of a 3-drug combination developed for recurrent intracranial germ cell tumors consisting of gemcitabine, paclitaxel, and oxaliplatin (GemPOx). Methods: A total of 9 patients with confirmed relapsed or refractory intracranial GCT were enrolled after signing informed consent, and received at least 2 cycles of GemPOx, of which all but 1 had relapsed or refractory NGGCTs. One patient with progressive disease was found to have pathologically confirmed malignant transformation to pure embryonal rhabdomyosarcoma (without GCT elements), hence was ineligible and not included in the analysis. Patients who experienced sufficient responses proceeded to receive HDCx with AuHPCR. Treatment response was determined based on radiographic tumor assessments and tumor markers. Results: A total of 7 patients achieved sufficient response and proceeded with HDCx and AuHPCR, and 5 subsequently received additional radiotherapy. A total of 2 patients developed progressive disease while receiving GemPOx. Myelosuppression and transaminitis were the most common treatment-related adverse events. With a mean follow-up of 44 months, 4 patients (3 NGGCTs, 1 germinoma) are alive without evidence of disease. Conclusions: GemPOx demonstrates efficacy in facilitating stem cell mobilization, thus facilitating the feasibility of both HDCx and radiotherapy.
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Trees with weeping shoot architectures are valued for their beauty and are a resource for understanding how plants regulate posture control. The peach (Prunus persica) weeping phenotype, which has elliptical downward arching branches, is caused by a homozygous mutation in the WEEP gene. Little is known about the function of WEEP despite its high conservation throughout Plantae. Here, we present the results of anatomical, biochemical, biomechanical, physiological, and molecular experiments that provide insight into WEEP function. Our data suggest that weeping peach trees do not have defects in branch structure. Rather, transcriptomes from the adaxial (upper) and abaxial (lower) sides of standard and weeping branch shoot tips revealed flipped expression patterns for genes associated with early auxin response, tissue patterning, cell elongation, and tension wood development. This suggests that WEEP promotes polar auxin transport toward the lower side during shoot gravitropic response, leading to cell elongation and tension wood development. In addition, weeping peach trees exhibited steeper root systems and faster lateral root gravitropic response. This suggests that WEEP moderates root gravitropism and is essential to establishing the set-point angle of lateral roots from the gravity vector. Additionally, size exclusion chromatography indicated that WEEP proteins self-oligomerize, like other proteins with sterile alpha motif domains. Collectively, our results from weeping peach provide insight into polar auxin transport mechanisms associated with gravitropism and lateral shoot and root orientation.
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Gravitropismo , Ácidos Indolacéticos , Proteínas de Plantas , Prunus persica , Ácidos Indolacéticos/metabolismo , Gravitropismo/fisiología , Gravitropismo/genética , Prunus persica/genética , Prunus persica/fisiología , Prunus persica/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Brotes de la Planta/genética , Brotes de la Planta/fisiología , Brotes de la Planta/crecimiento & desarrollo , Regulación de la Expresión Génica de las Plantas , Gravitación , Árboles/fisiología , Árboles/genéticaRESUMEN
BACKGROUND: This study evaluated the safety and pharmacokinetics (PK) of oral ONC201 administered twice-weekly on consecutive days (D1D2) in pediatric patients with newly diagnosed DIPG and/or recurrent/refractory H3 K27M glioma. METHODS: This phase 1 dose-escalation and expansion study included pediatric patients with H3 K27M-mutant glioma and/or DIPG following ≥1 line of therapy (NCT03416530). ONC201 was administered D1D2 at 3 dose levels (DLs; -1, 1, and 2). The actual administered dose within DLs was dependent on weight. Safety was assessed in all DLs; PK analysis was conducted in DL2. Patients receiving once-weekly ONC201 (D1) served as a PK comparator. RESULTS: Twelve patients received D1D2 ONC201 (DL1, nâ =â 3; DL1, nâ =â 3; DL2, nâ =â 6); no dose-limiting toxicities or grade ≥3 treatment-related adverse events occurred. PK analyses at DL2 (D1-250 mg, nâ =â 3; D1-625 mg, nâ =â 3; D1D2-250 mg, nâ =â 2; D1D2-625 mg, nâ =â 2) demonstrated variability in Cmax, AUC0-24, and AUC0-48, with comparable exposures across weight groups. No accumulation occurred with D1D2 dosing; the majority of ONC201 cleared before administration of the second dose. Cmax was variable between groups but did not appear to increase with D1D2 dosing. AUC0-48 was greater with D1D2 than once-weekly. CONCLUSIONS: ONC201 given D1D2 was well tolerated at all DLs and associated with greater AUC0-48.
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Neoplasias Encefálicas , Glioma , Mutación , Humanos , Masculino , Femenino , Niño , Adolescente , Glioma/tratamiento farmacológico , Glioma/genética , Glioma/patología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Preescolar , Histonas , Antineoplásicos/farmacocinética , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Pirimidinas/farmacocinética , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Esquema de Medicación , Dosis Máxima Tolerada , Relación Dosis-Respuesta a Droga , Pronóstico , Estudios de SeguimientoRESUMEN
Chimerism testing supports the study of engraftment and measurable residual disease (MRD) in patients after allogeneic hematopoietic stem cell transplant. In chimerism MRD, relapse can be predicted by increasing mixed chimerism (IMC), recipient increase ≥0.1% in peripheral blood, and proliferating recipient cells as a surrogate of tumor activity. Conventionally, the combination of short-tandem repeat (STR) and quantitative PCR (qPCR) was needed to ensure assay sensitivity and accuracy in all chimerism status. We evaluated the use of next-generation sequencing (NGS) as an alternate technique. The median numbers of informative markers in unrelated/related cases were 124/82 (NGS; from 202 single-nucleotide polymorphism), 5/3 (qPCR), and 17/10 (STR). Assay sensitivity was 0.22% (NGS), 0.1% (qPCR), and 1% (STR). NGS batch (4 to 48 samples) required 19.60 to 24.80 hours and 1.52 to 2.42 hours of hands-on time (comparable to STR/qPCR). NGS assay cost/sample was $91 to $151, similar to qPCR ($99) but higher than STR ($27). Using 56 serial DNAs from six post-transplant patients monitored by the qPCR/STR, the correlation with NGS was strong for percentage recipient (y = 1.102x + 0.010; R2 = 0.968) and percentage recipient change (y = 0.892x + 0.041; R2 = 0.945). NGS identified all 17 IMC events detected by qPCR (100% sensitivity). The NGS chimerism provides sufficient sensitivity, accuracy, and economical/logistical feasibility in supporting engraftment and MRD monitoring.
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Quimerismo , Trasplante de Células Madre Hematopoyéticas , Humanos , Recurrencia Local de Neoplasia , Repeticiones de Microsatélite , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Reacción en Cadena de la Polimerasa/métodos , Secuenciación de Nucleótidos de Alto RendimientoRESUMEN
Multifocal motor neuropathy (MMN) is a rare immune-mediated motor neuropathy characterized by asymmetric weakness that preferentially affects distal upper limb muscles. The clinical features of MMN may be difficult to differentiate from motor neuron disease. Other conditions that may be mistaken for MMN include inclusion body myositis, chronic inflammatory demyelinating polyradiculoneuropathy, hereditary neuropathy with liability to pressure palsy, focal neuropathies, and radiculopathies. A key distinguishing electrophysiologic feature of MMN is the motor nerve conduction block located at noncompressible sites. MMN is a treatable neuropathy; therefore it is important that primary care physicians are aware of the features of the disease to identify potential patients and make referrals to a neuromuscular specialist in a timely manner. This review provides an overview of the disease, highlights key differential diagnoses, and describes available treatment options for patients with MMN.
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DNA methylation is an essential molecular assay for central nervous system (CNS) tumor diagnostics. While some fusions define specific brain tumors, others occur across many different diagnoses. We performed a retrospective analysis of 219 primary CNS tumors with whole genome DNA methylation and RNA next-generation sequencing. DNA methylation profiling results were compared with RNAseq detected gene fusions. We detected 105 rare fusions involving 31 driver genes, including 23 fusions previously not implicated in brain tumors. In addition, we identified 6 multi-fusion tumors. Rare fusions and multi-fusion events can impact the diagnostic accuracy of DNA methylation by decreasing confidence in the result, such as BRAF, RAF, or FGFR1 fusions, or result in a complete mismatch, such as NTRK, EWSR1, FGFR, and ALK fusions. IMPLICATIONS: DNA methylation signatures need to be interpreted in the context of pathology and discordant results warrant testing for novel and rare gene fusions.
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Neoplasias Encefálicas , Metilación de ADN , Humanos , Metilación de ADN/genética , Estudios Retrospectivos , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Fusión Génica , Proteínas de Fusión Oncogénica/genéticaRESUMEN
OBJECTIVES: To assess the safety, tolerability, and key pharmacodynamic effects of subcutaneous batoclimab, a fully human anti-neonatal Fc receptor monoclonal antibody, in patients with generalized myasthenia gravis and anti-acetylcholine receptor antibodies. METHODS: A Phase 2a, proof-of-concept, randomized, double-blind, placebo-controlled trial is described. Eligible patients were randomized (1:1:1) to receive once-weekly subcutaneous injections of batoclimab 340 mg, batoclimab 680 mg, or matching placebo for 6 weeks. Subsequently, all patients could enter an open-label extension study where they received batoclimab 340 mg once every 2 weeks for 6 weeks. Primary endpoints were safety, tolerability, and change from baseline in total immunoglobulin G, immunoglobulin G subclasses, and anti-acetylcholine receptor antibodies at 6 weeks post-baseline. Secondary endpoints included changes from baseline to 6 weeks post-baseline for Myasthenia Gravis Activities of Daily Living, Quantitative Myasthenia Gravis, Myasthenia Gravis Composite, and revised 15-item Myasthenia Gravis Quality of Life scores. RESULTS: Seventeen patients were randomized to batoclimab 680 mg (n = 6), batoclimab 340 mg (n = 5), or placebo (n = 6). Batoclimab was associated with significantly greater reductions in total immunoglobulin G and anti-acetylcholine receptor antibodies from baseline to 6 weeks post-baseline than placebo. Reductions in immunoglobulin G subclasses were generally consistent with total immunoglobulin G. While clinical measures showed directionally favorable improvements over time, the study was not powered to draw conclusions about therapeutic efficacy. No safety issues were identified. INTERPRETATION: The safety profile, pharmacodynamics, and preliminary clinical benefits observed in this study support further investigation of subcutaneous batoclimab injections as a potential patient-administered therapy for seropositive generalized myasthenia gravis.
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Actividades Cotidianas , Miastenia Gravis , Humanos , Calidad de Vida , Miastenia Gravis/tratamiento farmacológico , Receptores Colinérgicos , Anticuerpos Monoclonales/uso terapéutico , Autoanticuerpos , Inmunoglobulina GRESUMEN
Objective: Understanding the regulation and function of plant genes is essential for addressing the challenges faced by modern agriculture. Plant transformation, in conjunction with fluorescence microscopy, offers a powerful approach to investigate the dynamic behavior of plant genes and the proteins they encode. We previously developed a set of Gateway-compatible tissue-specific plant transformation vectors. In this paper we aim to expand the toolkit of vectors available for Agrobacterium-mediated plant transformation and protoplast transfection. Results: Here, we introduce new Agrobacterium-mediated plant transformation vectors by introducing additional fluorophores to create the pJRA vector series. Additionally, we introduce the pLCS series of vectors, a new set of modular Gateway- and Gibson assembly-compatible vectors designed for protoplast transfection. All described vectors are available from Addgene to serve as a resource for the plant research community.
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Metastasis remains the leading cause of cancer deaths worldwide and lung cancer, known for its highly metastatic progression, remains among the most lethal of malignancies. The heterogeneous genomic profile of lung cancer metastases is often unknown. Since different metastatic events can selectively spread to multiple organs, strongly suggests more studies are needed to understand and target these different pathways. Unfortunately, access to the primary driver of metastases, the metastatic cancer cell clusters (MCCCs), remains difficult and limited. These metastatic clusters have been shown to be 100-fold more tumorigenic than individual cancer cells. Capturing and characterizing MCCCs is a key limiting factor in efforts to help treat and ultimately prevent cancer metastasis. Elucidating differentially regulated biological pathways in MCCCs will help uncover new therapeutic drug targets to help combat cancer metastases. We demonstrate a novel, proof of principle technology, to capture MCCCs directly from patients' whole blood. Our platform can be readily tuned for different solid tumor types by combining a biomimicry-based margination effect coupled with immunoaffinity to isolate MCCCs. Adopting a selective capture approach based on overexpressed CD44 in MCCCs provides a methodology that preferentially isolates them from whole blood. Furthermore, we demonstrate a high capture efficiency of more than 90% when spiking MCCC-like model cell clusters into whole blood. Characterization of the captured MCCCs from lung cancer patients by immunofluorescence staining and genomic analyses, suggests highly differential morphologies and genomic profiles., This study lays the foundation to identify potential drug targets thus unlocking a new area of anti-metastatic therapeutics.
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Myelin-associated glycoprotein (MAG) is a transmembrane glycoprotein concentrated in periaxonal Schwann cell and oligodendroglial membranes of myelin sheaths that serves as an antigen for immunoglobulin M (IgM) monoclonal antibodies. Individuals who harbor anti-MAG antibodies classically develop a progressive autoimmune peripheral neuropathy characterized clinically by ataxia, distal sensory loss, and gait instability, and electrophysiologically by distally accentuated conduction velocity slowing. Although off-label immunotherapy is common, there are currently no proven effective disease-modifying therapeutics, and most patients experience slow accumulation of disability over years and decades. The typically slowly progressive nature of this neuropathy presents unique challenges when trying to find effective anti-MAG therapeutic agents. Drug development has also been hampered by the lack of validated outcome measures that can detect clinically meaningful changes in a reasonable amount of time as well as by the lack of disease activity biomarkers. In this invited review, we provide an update on the state of clinicometric outcome measures and disease activity biomarkers in anti-MAG neuropathy. We highlight the insensitivity of widely used existing clinicometric outcome measures such as the Inflammatory Neuropathy Cause and Treatment (INCAT) disability score as well as the INCAT sensory subscore in anti-MAG neuropathy, referencing the two previous negative randomized controlled clinical trials evaluating rituximab. We then discuss newly emerging candidate therapeutic agents, including tyrosine kinase inhibitors and enhanced B-cell-depleting agents, among others. We conclude with a practical approach to the evaluation and management of anti-MAG neuropathy patients.
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Neuritis , Enfermedades del Sistema Nervioso Periférico , Humanos , Glicoproteína Asociada a Mielina , Enfermedades del Sistema Nervioso Periférico/terapia , Rituximab/uso terapéutico , Anticuerpos Monoclonales , Inmunoglobulina M , Autoanticuerpos , Neuritis/tratamiento farmacológico , BiomarcadoresRESUMEN
Trees with weeping shoot architectures are valued for their beauty and serve as tremendous resources for understanding how plants regulate posture control. The Prunus persica (peach) weeping phenotype, which has elliptical downward arching branches, is caused by a homozygous mutation in the WEEP gene. Until now, little was known about the function of WEEP protein despite its high conservation throughout Plantae. Here, we present the results of anatomical, biochemical, biomechanical, physiological, and molecular experiments that provide insight into WEEP function. Our data suggest that weeping peach does not have defects in branch structure. Rather, transcriptomes from the adaxial (upper) and abaxial (lower) sides of standard and weeping branch shoot tips revealed flipped expression patterns for genes associated with early auxin response, tissue patterning, cell elongation, and tension wood development. This suggests that WEEP promotes polar auxin transport toward the lower side during shoot gravitropic response, leading to cell elongation and tension wood development. In addition, weeping peach trees exhibited steeper root systems and faster root gravitropic response, just as barley and wheat with mutations in their WEEP homolog EGT2. This suggests that the role of WEEP in regulating lateral organ angles and orientations during gravitropism may be conserved. Additionally, size-exclusion chromatography indicated that WEEP proteins self-oligomerize, like other SAM-domain proteins. This oligomerization may be required for WEEP to function in formation of protein complexes during auxin transport. Collectively, our results from weeping peach provide new insight into polar auxin transport mechanisms associated with gravitropism and lateral shoot and root orientation.
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BACKGROUND: Prospective data on maintenance therapy with bevacizumab for persons with NF2-related schwannomatosis (NF2-SWN) is lacking. In this prospective multicenter phase II study, we evaluated the efficacy, safety, and tolerability of bevacizumab for maintenance therapy in children and adults with NF2-SWN and hearing loss due to vestibular schwannomas (VS). METHODS: Following induction therapy, participants received bevacizumab 5 mg/kg every 3 weeks for 18 months. Participants were monitored for changes in hearing, tumor size, and quality of life (QOL), and for adverse events. Hearing loss was defined as a statistically significant decline in word recognition score (WRS) or pure-tone average compared to the study baseline; tumor growth was defined as >20% increase in volume compared to baseline. RESULTS: Twenty participants with NF2-SWN (median age 23.5 years; range, 12.5-62.5 years) with hearing loss in the target ear (median WRS 70%, range 2%-94%) received maintenance bevacizumab. Freedom from hearing loss in the target ear was 95% after 48 weeks, 89% after 72 weeks, and 70% after 98 weeks. Freedom from tumor growth in the target VS was 94% after 48 weeks, 89% after 72 weeks, and 89% after 98 weeks. NF2-related QOL remained stable for 98 weeks whereas tinnitus-related distress decreased. Maintenance bevacizumab was well tolerated, with 3 participants (15%) discontinuing treatment due to adverse events. CONCLUSIONS: Maintenance bevacizumab (5 mg/kg every 3 weeks) is associated with high rates of hearing and tumor stability during 18 months of follow-up. No new unexpected adverse events related to bevacizumab were identified in this population.
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Pérdida Auditiva , Neurofibromatosis 2 , Neuroma Acústico , Adulto , Niño , Humanos , Adulto Joven , Neuroma Acústico/complicaciones , Neuroma Acústico/tratamiento farmacológico , Neuroma Acústico/patología , Bevacizumab/uso terapéutico , Calidad de Vida , Estudios Prospectivos , Resultado del Tratamiento , Neurofibromatosis 2/complicaciones , Neurofibromatosis 2/tratamiento farmacológico , Pérdida Auditiva/inducido químicamenteRESUMEN
PURPOSE: We tested the feasibility of survivorship care plan (SCP) delivery with/without a lay health educator (LHE) telephone-delivered information session among rural cancer survivors, and their effects on health-related self-efficacy and knowledge of cancer history. METHODS: Randomized trial of cancer survivors from 3 rural oncology clinics featuring either SCP alone (control) or SCP plus LHE-delivered information session (intervention). Participants completed a questionnaire on health-related self-efficacy and knowledge of cancer-specific medical history. Responses were compared to medical records for accuracy. SCPs were then mailed to participants. Approximately 5 months later, participants completed a follow-up questionnaire. A subset of participants took part in subsequent qualitative interviews about their study experience. FINDINGS: Of 301 survivors approached, 72 (23.9%) were randomized (mean age 66.4 years; 3.1 years from diagnosis; 62.5% female), and 65 (90.3%) completed the study. Global mental and physical health or self-efficacy scores did not change significantly from baseline to follow-up for either group. In exploratory analyses, self-efficacy increased in participants with inadequate/marginal health literacy in the intervention arm (+0.7, 95% CI = 0.1-1.2; P = .01). Accuracy of knowledge did not improve but was high at baseline (mean 76.0±14.5%). 60.1% and 48.4% of control and intervention participants, respectively, found SCPs definitely/somewhat useful. Qualitative data (n = 20) suggested that SCPs were helpful to patients when primary and oncology care were less integrated. CONCLUSIONS: An LHE-delivered informational session was feasible but had limited benefit to rural cancer survivors versus delivery of SCP alone but may be of benefit to patients with low health literacy or with less integrated care.
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Supervivientes de Cáncer , Educadores en Salud , Neoplasias , Humanos , Femenino , Anciano , Masculino , Supervivencia , Proyectos Piloto , Estudios de Factibilidad , Planificación de Atención al Paciente , Neoplasias/terapiaRESUMEN
INTRODUCTION/AIMS: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired immune-mediated peripheral nerve disorder with variable prognosis and long-term dependence on immunotherapy. Frequent assessment of grip strength can be a useful tool to identify intravenous immunoglobulin (IVIG) treatment-related fluctuations (TRFs) and optimize IVIG treatment in real-time, but the long-term implications of TRFs are unknown. We aimed to explore the impact that real-time TRFs had on long-term CIDP prognosis, strength impairment, and disability. METHODS: This retrospective observational cohort study analyzed standard of care clinical and treatment outcomes in patients who participated in a published prospective study of intra-IVIG-cycle grip strength quantification. Patients were analyzed based upon the presence or absence of TRFs, as determined in the initial prospective study. RESULTS: Data were available for 23 CIDP patients with a mean follow-up period of 44.7 mo. There were no differences in baseline or follow-up strength, disability, or IVIG usage in patients with a low number of fluctuations compared to those with a high number of fluctuations. In both groups, drug-free remission was achieved in about one-third of patients. DISCUSSION: TRFs are important to identify in order to optimize treatment in real time, but poorly predict long-term disease activity status. The presence of minor TRFs are unlikely to result in substantial accumulation of disability over time. Periodic IVIG optimization trials using objective outcomes are encouraged in all CIDP patients receiving chronic IVIG treatment as a means to identify the lowest effective IVIG dose and frequency.
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Inmunoglobulinas Intravenosas , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/diagnóstico , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/tratamiento farmacológico , Estudios Prospectivos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Background: ONC201, a dopamine receptor D2 (DRD2) antagonist and caseinolytic protease P (ClpP) agonist, has induced durable tumor regressions in adults with recurrent H3 K27M-mutant glioma. We report results from the first phase I pediatric clinical trial of ONC201. Methods: This open-label, multi-center clinical trial (NCT03416530) of ONC201 for pediatric H3 K27M-mutant diffuse midline glioma (DMG) or diffuse intrinsic pontine glioma (DIPG) employed a dose-escalation and dose-expansion design. The primary endpoint was the recommended phase II dose (RP2D). A standard 3â +â 3 dose escalation design was implemented. The target dose was the previously established adult RP2D (625 mg), scaled by body weight. Twenty-two pediatric patients with DMG/DIPG were treated following radiation; prior lines of systemic therapy in addition to radiation were permitted providing sufficient time had elapsed prior to study treatment. Results: The RP2D of orally administered ONC201 in this pediatric population was determined to be the adult RP2D (625 mg), scaled by body weight; no dose-limiting toxicities (DLT) occurred. The most frequent treatment-emergent Grade 1-2 AEs were headache, nausea, vomiting, dizziness and increase in alanine aminotransferase. Pharmacokinetics were determined following the first dose: T 1/2, 8.4 h; T max, 2.1 h; C max, 2.3 µg/mL; AUC0-tlast, 16.4 hµg/mL. Median duration of treatment was 20.6 weeks (range 5.1-129). Five (22.7%) patients, all of whom initiated ONC201 following radiation and prior to recurrence, were alive at 2 years from diagnosis. Conclusions: The adult 625 mg weekly RP2D of ONC201 scaled by body weight was well tolerated. Further investigation of ONC201 for DMG/DIPG is warranted.
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Chronic inflammatory demyelinating polyneuropathy (CIDP) is a chronic immune-mediated peripheral form of polyneuropathy. No reliable diagnostic biomarkers are available by which to make the diagnosis of CIDP. As a result, diagnosis of the condition can be challenging. Many patients are not recognized early in the disease course, and on the other end of the spectrum both establishing early and accurate diagnosis as well as avoiding misdiagnosis and overtreatment. Identification of the hallmark clinical, electrophysiological, and laboratory features of the disease are critical to facilitate rapid diagnosis, while an understanding of diagnostic pitfalls can help prevent misdiagnosis. Since the original description of CIDP in the 1970s, over 15 sets of diagnostic criteria have been proposed. The criteria published in 2021 by the European Academy of Neurology / Peripheral Nerve Society (EAN/PNS) were developed for use during routine clinical care and are available in the public domain. These criteria provide clinicians with an invaluable resource by which the data collected during the evaluation of the patient with possible CIDP can be interpreted. One point of importance that bridges diagnosis to treatment is objectification of the treatment response. Interpretation of how patients respond to treatment drives both long-term treatment paradigms and the diagnosis at which these treatments are aimed. Although no approach is perfect, utilization of strength impairment and disability outcomes in clinical practice can help unravel the difficulties in interpreting response to treatment. Just as improvement in these outcomes is considered diagnostically supportive, the absence of objective benefit argues against it and should prompt reconsideration of a CIDP diagnosis.
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Polineuropatías , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante , Humanos , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/diagnóstico , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/terapia , Nervios Periféricos , Errores Diagnósticos , BiomarcadoresRESUMEN
Diffuse spinal cord gliomas (SCGs) are rare tumors associated with a high morbidity and mortality that affect both pediatric and adult populations. In this retrospective study, we sought to characterize the clinical, pathological, and molecular features of diffuse SCG in 22 patients with histological and molecular analyses. The median age of our cohort was 23.64 years (range 1-82) and the overall median survival was 397 days. K27M mutation was significantly more prevalent in males compared to females. Gross total resection and chemotherapy were associated with improved survival, compared to biopsy and no chemotherapy. While there was no association between tumor grade, K27M status (p = 0.366) or radiation (p = 0.772), and survival, males showed a trend toward shorter survival. K27M mutant tumors showed increased chromosomal instability and a distinct DNA methylation signature.