Development of Neuropathy in Patients With Myeloma Treated With Thalidomide: Patterns of Occurrence and the Role of Electrophysiologic Monitoring

2006 ◽  
Vol 24 (27) ◽  
pp. 4507-4514 ◽  
Author(s):  
Linda Mileshkin ◽  
Richard Stark ◽  
Bruce Day ◽  
John F. Seymour ◽  
Jerome B. Zeldis ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Time Course ◽  
Dose Intensity ◽  
Multicenter Trial ◽  
Duration Of Treatment ◽  
Related Factors ◽  
Prior Therapy ◽  
Length Of Treatment ◽  
Electrophysiological Studies ◽  
Clinically Significant

Purpose Peripheral neuropathy frequently limits the duration of treatment with thalidomide for patients with multiple myeloma. We assessed the time course of occurrence, possible predictive factors, and the utility of serial nerve electrophysiological studies (NES) for detecting onset of neuropathy. Patients and Methods Seventy-five patients with relapsed/refractory myeloma were enrolled onto a multicenter trial of dose-escalating thalidomide with or without interferon. Patients underwent clinical assessment plus NES at baseline and every 3 months. Time to development of neuropathy according to clinical or NES criteria was compared. Patient and treatment-related factors were compared as predictors of neuropathy. Results Thirty-nine percent had some NES abnormalities at baseline. Patients received thalidomide at a median dose-intensity of 373 mg/d. Thirty-one of 75 patients (41%) developed neuropathy during thalidomide treatment; 11 patients (15%) discontinued treatment with thalidomide due to neuropathy. The actuarial incidence of neuropathy increased from 38% at 6 months to 73% at 12 months, with 81% of responding patients developing this complication. Serial NES did not reliably predict the imminent development of clinical neuropathy requiring thalidomide cessation, nor were patient age, sex, or prior therapy predictive. Patients who developed neuropathy had a longer duration of thalidomide exposure (median, 268 v 89 days; P = .0001). Cumulative dose or dose-intensity received was not predictive. Conclusion The majority of patients will develop peripheral neuropathy given sufficient length of treatment with thalidomide. To minimize the risk of neurotoxicity, therapy should be limited to less than 6 months. Electrophysiologic monitoring provides no clear benefit versus careful clinical evaluation for the development of clinically significant neuropathy.

Development of neuropathy in patients (pts) with multiple myeloma (MM) treated with thalidomide (thal)—Patterns of occurrence and the role of electrophysiologic monitoring

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7618-7618 ◽  
Author(s):  
L. R. Mileshkin ◽  
R. Stark ◽  
B. Day ◽  
J. F. Seymour ◽  
J. B. Zeldis ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Time Course ◽  
Treatment Options ◽  
Dose Intensity ◽  
Duration Of Treatment ◽  
Exact Test ◽  
Prior Therapy ◽  
Kaplan Meier ◽  
Clinically Significant ◽  
New Treatment

7618 Background: Given new treatment options for pts with MM, physicians are faced with the dilemma of how best to sequence these drugs in order to optimize efficacy and toxicity. Peripheral neuropathy frequently limits the duration of treatment (Rx) with thal. In this study we assessed the utility of serial nerve electrophysiological studies (NES) to detect the onset of neuropathy, and assessed the time course of occurrence and possible clinical and Rx-related predictive factors. Methods: 75 pts with relapsed/refractory MM were enrolled in a multi-centre trial of thal. In addition to clinical assessment, pts underwent sensory and motor NES at baseline and every 3 months in order to identify neuropathy. We examined the value of baseline and serial NES for development of neuropathy, with time to development of neuropathy according to clinical or NES criteria compared using Kaplan-Meier analysis. Differences between pt and Rx-related variables were compared using a Mann-Whitney U-test or a Fisher’s exact test. Results: Thirty nine percent had some NES abnormalities at baseline. Pts were treated with thal at a median dose intensity of 373 mg/day and followed for a median of 18 months (range 6–26). Thirty-one of the 75 pts (41%) developed neuropathy during thal Rx, with 11 (15%) ceasing thal due to neuropathy. The actuarial incidence of any neuropathy increased from 38% at 6 months to 73% at 12 months with 81% of responding pts developing this complication. The use of NES did not reliably predict the imminent development of clinical neuropathy requiring cessation of thal. Nor were pt age, gender or type of prior therapy (ie vincristine) predictive. Development of neuropathy was related to duration of thal exposure with a median time of 268 days thal in those who developed neuropathy compared to 89 days in those who did not (p = 0.0001). Cumulative dose or dose intensity received were not predictive. Conclusions: The majority of pts will develop peripheral neuropathy given sufficient length of thal Rx and to minimize the risk of neurotoxicity, therapy should be limited to less than six months. NES monitoring provides no clear benefit over careful clinical evaluation for the development of clinically significant neuropathy. [Table: see text]

AB0 Blood Groups and Coronary Heart Disease (CHD)

1980 ◽  
Vol 43 (02) ◽  
pp. 137-140 ◽  
Author(s):  
Jan Erikssen ◽  
Erik Thaulow ◽  
Helge Stormorken ◽  
Ole Brendemoen ◽  
Arvid Hellem
Keyword(s):  
Coronary Artery ◽  
Blood Group ◽  
Artery Bypass ◽  
Laboratory Data ◽  
Epidemiological Data ◽  
Consecutive Series ◽  
Related Factors ◽  
Ab0 Blood Groups ◽  
Clinically Significant ◽  
Artery Disease

SummaryThe view based on epidemiological and laboratory data that blood group A subjects (=A) have clinically significant higher thrombotic potential than blood group 0 subjects (= O), is supported by the present finding of a significantly higher platelet retention in A than 0.The completely normal ABO distribution found among 71 cases of proven latent CHD, and the disproportionate excess of 0 vs. A in a consecutive series of 191 coronary artery bypass candidates apparently conflict with epidemiological data indicating a higher risk of achieving CHD in A than 0. The conflict may be solved by suggestinga) that the »thrombotic proneness« in A compared with 0 causes a poorer prognosis in CHD among the former, leaving a disproportionate excess of 0 among longterm CHD survivors, and b) that AB0-related factors have had an insignificant, independent impact on the evolution of preclinical coronary artery disease in our 71 men with latent CHD.

scholarly journals Canine Myocytes Represent a Good Model for Human Ventricular Cells Regarding Their Electrophysiological Properties

2021 ◽  
Vol 14 (8) ◽  
pp. 748
Author(s):  
Péter P. Nánási ◽  
Balázs Horváth ◽  
Fábián Tar ◽  
János Almássy ◽  
Norbert Szentandrássy ◽  
...  
Keyword(s):  
Action Potential ◽  
Time Course ◽  
Laboratory Animals ◽  
Delayed Rectifier ◽  
Ion Currents ◽  
Human Cardiomyocytes ◽  
Ventricular Cells ◽  
Repolarization Reserve ◽  
Electrophysiological Studies ◽  
K Current

Due to the limited availability of healthy human ventricular tissues, the most suitable animal model has to be applied for electrophysiological and pharmacological studies. This can be best identified by studying the properties of ion currents shaping the action potential in the frequently used laboratory animals, such as dogs, rabbits, guinea pigs, or rats, and comparing them to those of human cardiomyocytes. The authors of this article with the experience of three decades of electrophysiological studies, performed in mammalian and human ventricular tissues and isolated cardiomyocytes, summarize their results obtained regarding the major canine and human cardiac ion currents. Accordingly, L-type Ca2+ current (ICa), late Na+ current (INa-late), rapid and slow components of the delayed rectifier K+ current (IKr and IKs, respectively), inward rectifier K+ current (IK1), transient outward K+ current (Ito1), and Na+/Ca2+ exchange current (INCX) were characterized and compared. Importantly, many of these measurements were performed using the action potential voltage clamp technique allowing for visualization of the actual current profiles flowing during the ventricular action potential. Densities and shapes of these ion currents, as well as the action potential configuration, were similar in human and canine ventricular cells, except for the density of IK1 and the recovery kinetics of Ito. IK1 displayed a largely four-fold larger density in canine than human myocytes, and Ito recovery from inactivation displayed a somewhat different time course in the two species. On the basis of these results, it is concluded that canine ventricular cells represent a reasonably good model for human myocytes for electrophysiological studies, however, it must be borne in mind that due to their stronger IK1, the repolarization reserve is more pronounced in canine cells, and moderate differences in the frequency-dependent repolarization patterns can also be anticipated.

scholarly journals Acupuncture in diabetic peripheral neuropathy—protocol for the randomized, multicenter ACUDPN trial

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
J. Dietzel ◽  
S. Hörder ◽  
I. V. Habermann ◽  
G. Meyer-Hamme ◽  
K. Hahn ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Peripheral Neuropathy ◽  
Nerve Conduction ◽  
Diabetic Peripheral Neuropathy ◽  
Clinical Symptoms ◽  
Multicenter Trial ◽  
Routine Care ◽  
Open Label ◽  
Diabetes Type Ii ◽  
Parallel Group

Abstract Background Acupuncture is used to treat patients with diabetic peripheral neuropathy; however, the evidence is unclear. We present the design and methodology of the ACUDPN (ACUpuncture in Diabetic Peripheral Neuropathy) trial, which investigates the effectiveness of acupuncture for the treatment of diabetic peripheral neuropathy (DPN) symptoms. The aim of this study is to investigate whether acupuncture is effective for the treatment of DPN symptoms. Methods This study is a two-armed, randomized, controlled, parallel group, open-label, confirmatory, multicenter trial (8-week intervention period plus 16 weeks of follow-up). Physicians in outpatient units in Germany who specialize in acupuncture treatment will treat 110 diabetes type II patients with clinical symptoms of peripheral neuropathy in the feet and legs with signs of neuropathy according to nerve conduction testing. The patients will be randomized in a 1:1 ratio to one of the following two groups: (a) semi-standardized acupuncture plus routine care or (b) routine care alone. Acupuncture will consist of 12 treatments per patient over 8 weeks. The primary outcome will be the overall DPN-related complaints in the extremities after 8 weeks as measured by the Visual Analog Scale (VAS). Further outcome measures will include DPN-related pain, the Neuropathic Pain Symptom Inventory (NPSI), Diabetic Peripheral Neuropathic Pain Impact (DPNPI) scores, and nerve conduction parameters of the sural nerve at weeks 8, 16, and 24. Discussion The results of this trial will be available in 2021 and will help clarify whether acupuncture can be considered effective for the treatment of DPN with regard to the subdimensions of the neuropathic clinical picture. Trial registration ClinicalTrials.gov NCT03755960. Registered on 11 August 2018.

Modulation of medial temporal lobe activity in epilepsy patients with hippocampal sclerosis during verbal working memory

2009 ◽  
Vol 15 (4) ◽  
pp. 536-546 ◽  
Author(s):  
PABLO CAMPO ◽  
FERNANDO MAESTÚ ◽  
IRENE GARCÍA-MORALES ◽  
ANTONIO GIL-NAGEL ◽  
BRYAN STRANGE ◽  
...  
Keyword(s):  
Working Memory ◽  
Episodic Memory ◽  
Temporal Lobe ◽  
Medial Temporal Lobe ◽  
Time Course ◽  
Hippocampal Sclerosis ◽  
Stimulus Presentation ◽  
Verbal Working Memory ◽  
Compelling Evidence ◽  
Electrophysiological Studies

AbstractIt has been traditionally assumed that medial temporal lobe (MTL) is not required for working memory (WM). However, animal lesion and electrophysiological studies and human neuropsychological and neuroimaging studies have provided increasing evidences of a critical involvement of MTL in WM. Based on previous findings, the central aim of this study was to investigate the contribution of the MTL to verbal WM encoding. Here, we used magnetoencephalography (MEG) to compare the patterns of MTL activation of 9 epilepsy patients suffering from left hippocampal sclerosis with those of 10 healthy matched controls while they performed a verbal WM task. MEG recordings allow detailed tracking of the time course of MTL activation. We observed impaired WM performance associated with changes in the dynamics of MTL activity in epilepsy patients. Specifically, whereas patients showed decreased activity in damaged MTL, activity in the contralateral MTL was enhanced, an effect that became significant in the 600- to 700-ms interval after stimulus presentation. These findings strongly support the crucial contribution of MTL to verbal WM encoding and provide compelling evidence for the proposal that MTL contributes to both episodic memory and WM. Whether this pattern is signaling reorganization or a normal use of a damaged structure is discussed. (JINS, 2009, 15, 536–546.)

The utilization of an inhibitor of spermidine and spermine synthesis as a tool for the study of the determination of cavitation in the preimplantation mouse embryo

Development ◽  
1979 ◽  
Vol 53 (1) ◽  
pp. 145-162
Author(s):  
H. Alexandre
Keyword(s):  
Biological Clock ◽  
Duration Of Treatment ◽  
Experimental Conditions ◽  
Cell Stage ◽  
Cytoplasmic Factor ◽  
Average Cell ◽  
Length Of Treatment ◽  
Preimplantation Mouse ◽  
The One

The inhibition of spermidine and spermine synthesis by methylglyoxal-Bis(guanylhydrazone) (MeGAG) at concentrations of 5, 10 and 20 µM, induces a reversible metabolic quiescence of mouse embryos, cultured in vitro from the 2-cell stage, at an average of 10·2, 8·5 and 6·9 cell stages respectively. In contrast, the inhibition of putrescine synthesis by α-methylornithine (α-MeOrn) at concentrations up to 10 mM fails to inhibit blastocyst formation, as shown previously. Complete reversibility of this induced arrest of development is observed for treatments up to 31 h with MeGAG at 10 µM. In agreement with the biological clock theory of Smith & MacLaren's hypothesis, the delay in cavitation is proportional to the length of treatment. However, the average cell numbers of the ‘delayed nascent blastocysts’ of all treated embryos (21·8–24·2) are consistently lower than that of control embryos (33·6) irrespective of the duration of treatment. It seems therefore that under some experimental conditions, DNA and chromosome replication on the one hand and cytoplasmic maturation on the other may be desynchronized. This suggests a role for a cytoplasmic factor in the induction of cavitation.

Second-line bosutinib (BOS) for patients (pts) with chronic phase (CP) chronic myeloid leukemia (CML): Final 10-year results of a phase 1/2 study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7009-7009
Author(s):  
Carlo Gambacorti-Passerini ◽  
Tim H. Brümmendorf ◽  
Dong-Wook Kim ◽  
Yeow Tee Goh ◽  
Irina S Dyagil ◽  
...  
Keyword(s):  
Phase 1 ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Dose Intensity ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Second Line ◽  
Prior Therapy ◽  
Kaplan Meier ◽  
Imatinib Resistant

7009 Background: BOS is approved for Philadelphia chromosome (Ph)+ CML resistant/intolerant to prior therapy and newly diagnosed Ph+ CP CML. In a phase 1/2 study, second-line BOS showed durable efficacy and manageable toxicity in pts with imatinib-resistant (IM-R) or -intolerant (IM-I) Ph+ CP CML. Methods: This final efficacy and safety analysis of the phase 1/2 study and extension study was based on ≥10 y of follow-up (FU). Ph+ CP CML pts who received BOS starting at 500 mg/d after prior treatment (Tx) with imatinib only were included. Results: 19% of pts were on BOS at y 10, and 13% were still on BOS at study completion after ≥10 y; 19% completed ≥10 y of FU. Median duration of Tx and FU were 26 and 54 mo, respectively. Median (range) dose intensity was 436 (87–599) mg/d. The most common primary reasons for permanent Tx discontinuation were lack of efficacy (unsatisfactory response or disease progression; 27%) and adverse events (AEs; 26%). In pts with a valid baseline assessment, cumulative complete cytogenetic response (CCyR), major molecular response (MMR) and MR4 rates (95% CI), respectively, were 50% (43–56), 42% (35–49) and 37% (30–44) (IM-R: 48% [41–56], 46% [37–55] and 39% [31–48]; IM-I: 53% [41–64], 36% [25–48] and 33% [22–45]). Responses were durable, with estimated probabilities of maintaining CCyR, MMR and MR4 > 50% after ≥10 y (Table). At 10 y, cumulative incidence of on-Tx progression/death was 24% and Kaplan-Meier (K-M) overall survival 72% (Table); 55 deaths (IM-R: n = 41; IM-I: n = 14) occurred on study, none BOS-related. Any grade Tx-emergent AEs (TEAEs) in ≥40% of pts were diarrhea (86%), nausea (46%) and thrombocytopenia (42%). Pleural effusion, cardiac and vascular TEAEs occurred in 13%, 12% and 11% of pts, respectively. 28% of pts had AEs leading to permanent Tx discontinuation; most common (≥2% of pts) were thrombocytopenia (6%), neutropenia (2%) and alanine aminotransferase increased (2%). Conclusions: These 10-y data are consistent with prior results of durable efficacy and manageable toxicity with second-line BOS and support long-term BOS use in CP CML pts after imatinib failure. Clinical trial information: NCT00261846 and NCT01903733. [Table: see text]

scholarly journals T118M Variant of PMP22 Gene Presents with Painful Peripheral Neuropathy and Varying Charcot-Marie-Tooth Features: A Case Series and Review of the Literature

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Kwo Wei David Ho ◽  
Nivedita U. Jerath
Keyword(s):  
Peripheral Neuropathy ◽  
Autosomal Recessive ◽  
Clinical Effect ◽  
Case Series ◽  
Pmp22 Gene ◽  
Loss Of Function ◽  
Review Of The Literature ◽  
Partial Loss ◽  
Charcot Marie Tooth ◽  
Electrophysiological Studies

The clinical effect of T118M variant of the PMP22 gene has been controversial. Several studies have suggested that it may be autosomal recessive, partial loss of function, or a benign variant. Here we report three cases in further support that the T118M variant of the PMP22 gene is a partial loss of function variant. These three unrelated cases were heterozygotes with the T118M variant of the PMP22 gene. All three cases presented with painful peripheral neuropathy and varying degrees of Charcot-Marie-Tooth exam features. Electrophysiological studies revealed polyneuropathy with axonal and demyelinating features in one case, but there were minimal electrophysiological changes in the other two cases. We propose that the T118M variant can cause painful peripheral neuropathy, which may be an underrecognized feature of this variant.

scholarly journals Sequencing multiple myeloma therapies with and after antibody therapies

Hematology ◽  
2020 ◽  
Vol 2020 (1) ◽  
pp. 248-258
Author(s):  
Niels W. C. J. van de Donk
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitors ◽  
Related Factors ◽  
Prior Therapy ◽  
Choice Of Treatment ◽  
Heavily Pretreated ◽  
First Relapse ◽  
Pretreated Patients ◽  
New Treatment ◽  
Selection Of

Abstract In multiple myeloma (MM), treatment selection and sequencing become increasingly complex with the increasing number of therapeutic options, including antibodies. Choice of treatment is dependent on various factors including patient- and tumor-related features. In addition, treatment-related factors, such as type and response to prior therapy, are also critical in terms of the selection of a new treatment regimen. Furthermore, approval status and reimbursement policies influence treatment choice. At the time of first relapse, patients who received a bortezomib-based regimen can switch to lenalidomide-based treatment, whereas patients who received lenalidomide until progression can switch to a proteasome inhibitor–based therapy. Alternatively, there is increasing evidence that pomalidomide-based triplets are also effective following the development of lenalidomide-refractory disease both in early and later relapse settings. Patients who become refractory to immunomodulatory drugs, proteasome inhibitors, and CD38 antibodies have a poor prognosis. These triple-class refractory patients may benefit from novel, recently approved agents such as XPO1 inhibitors or from participation in a clinical trial. Furthermore, retreatment with agents that were received in previous lines of therapy can also be considered in heavily pretreated patients, for example, in combination with classic cytotoxic drugs. Importantly, with the increasing use of CD38 antibodies in newly diagnosed and early relapsed/refractory MM, more information is needed on the potential value of retreatment with CD38 antibodies. With the introduction of new immunotherapies with novel modes of action, we also need a better understanding of sequencing of immunotherapeutic agents by taking into account the effect of prior therapy on immune function.

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