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Abstract Risk of progression of monoclonal gammopathy of undetermined significance (MGUS) into multiple myeloma and related plasma cell disorders can be determined by three major risk stratification models, namely Mayo2005, Sweden2014, and NCI2019. This retrospective study of 427 patients with MGUS diagnosed according to the 2014 International Myeloma Working Group criteria aimed to describe and analyze the longitudinal applicability of these risk models. In all three models, the majority of patients remained at their baseline risk group, whereas small numbers of patients migrated to a different risk group. Proportions of patients among risk groups remained stable over time (e.g. Mayo2005 model, low-risk group, at baseline: 43%, after 1, 2, 3, 4, 5, and 8 years: 40%, 37%, 37%, 43%, 44%, and 43%). All three risk models reliably distinguished risk of progression at baseline, upon yearly reassessment (e.g. 1 year from diagnosis) and in time-dependent analyses. Upstaging to a high-risk category was associated with an increased risk of progression in all three models (Mayo2005: hazard ratio [HR] = 5.43, 95% confidence interval [95% CI] 1.21–24.39, p = 0.027; Sweden2014: HR = 13.02, 95% CI 5.25–32.28, p

Background Chimeric antigen receptor (CAR) T-cell therapy has demonstrated significant benefits in the treatment of relapsed/refractory multiple myeloma (RRMM). However, these outcomes can be compromised by severe complications, including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome (ICANS) and immune effector cell-associated hematotoxicity (ICAHT), predisposing for life-threatening infections.Methods This retrospective observational study examined a total of 129 patients with RRMM who had received idecabtagene vicleucel (ide-cel) at two major myeloma centers in Germany and one center in the USA to assess the Endothelial Activation and Stress Index (EASIX) as a risk marker for an unfavorable clinical course and outcome after CAR T-cell therapy. EASIX is calculated by lactate dehydrogenase (U/L) × creatinine (mg/dL) / platelets (109 cells/L) and was determined before lymphodepletion (baseline) and at the day of CAR T-cell infusion (day 0). The analysis was extended to EASIX derivatives and the CAR-HEMATOTOX score.Results An elevated baseline EASIX (>median) was identified as a risk marker for severe late ICAHT, manifesting with an impaired hematopoietic reconstitution and pronounced cytopenias during the late post-CAR-T period. Patients with high EASIX levels (>upper quartile) were particularly at risk, as evidenced by an increased rate of an aplastic phenotype of neutrophil recovery, severe late-onset infections and ICANS. Finally, we found associations between baseline EASIX and an inferior progression-free and overall survival. Moreover, the EASIX at day 0 also demonstrated potential to serve as a risk marker for post-CAR-T complications and adverse outcomes.Conclusions In conclusion, EASIX aids in risk stratification at clinically relevant time points prior to CAR T-cell therapy with ide-cel. Increased EASIX levels might help clinicians to identify vulnerable patients to adapt peri-CAR-T management at an early stage.

Abstract Background While quadruplet induction therapies deepen responses in newly diagnosed multiple myeloma patients, their impact on peripheral blood stem cell (PBSC) collection remains incompletely understood. This analysis aims to evaluate the effects of prolonged lenalidomide induction and isatuximab- or elotuzumab-containing quadruplet induction therapies on PBSC mobilization and collection. Methods A total of 179 transplant-eligible patients with newly diagnosed MM treated at a single academic center were included. The patients were evaluated based on PBSC mobilization and collection parameters, including overall collection results, CD34+ cell levels in peripheral blood, leukapheresis (LP) delays, overall number of LP sessions, and the rate of rescue mobilization with plerixafor. The patients underwent four different induction regimens: Lenalidomide, bortezomib, and dexamethasone (RVd, six 21-day cycles, n = 44), isatuximab-RVd (six 21-day cycles, n = 35), RVd (four 21-day cycles, n = 51), or elotuzumab-RVd (four 21-day cycles, n = 49). Results The patients' characteristics were well balanced across the different groups. Collection failures, defined as the inability to collect three sufficient PBSC transplants, were rare (n = 3, 2%), with no occurrences in the isatuximab-RVd and elotuzumab-RVd groups. Intensified induction with six 21-day cycles of RVd did not negatively impact the overall number of collected PBSCs (9.7 × 106/kg bw versus 10.5 × 106/kg bw, p = 0.331) compared to four 21-day cycles of RVd. Plerixafor usage was more common after six cycles of RVd compared to four cycles (16% versus 8%). Addition of elotuzumab to RVd did not adversely affect overall PBSC collection (10.9 × 106/kg bw versus 10.5 × 106/kg bw, p = 0.915). Patients treated with isatuximab-RVd (six cycles) had lower numbers of collected stem cells compared to those receiving RVd (six cycles) induction (8.8 × 106/kg bw versus 9.7 × 106/kg bw, p = 0.801), without experiencing significant delays in LP or increased numbers of LP sessions in a multivariable logistic regression analysis. Plerixafor usage was more common after isatuximab plus RVd compared to RVd alone (34% versus 16%). Conclusions This study demonstrates that stem cell collection is feasible after prolonged induction with isatuximab-RVd without collection failures and might be further explored as induction therapy. Trial registration Patients were treated within the randomized phase III clinical trials GMMG-HD6 (NCT02495922, 24/06/2015) and GMMG-HD7 (NCT03617731, 24/07/2018). However, during stem cell mobilization and -collection, no study-specific therapeutic intervention was performed.

Abstract Mass spectrometry (MS) is a promising tool for monitoring monoclonal protein in plasma cell dyscrasias. We included 480 transplant-eligible newly-diagnosed multiple myeloma (MM) patients from the GMMG-MM5 trial (EudraCT No. 2010-019173-16) and performed a retrospective MS analysis at baseline (480 patients) and at the pre-defined, consecutive time points after induction (444 patients), prior to maintenance (305 patients) and after one year of maintenance (227 patients). We found that MS negativity was significantly associated with improved progression-free survival (PFS) even in patients with complete response (CR) at all investigated follow-up time points. The prognostic impact was independent of established risk factors, such as the revised International Staging System. Combining MS and baseline cytogenetics improved the prediction of outcome: MS-positive patients with high-risk cytogenetics had a dismal PFS of 1.9 years (95% confidence interval [CI]: 1.6–2.3 years) from the start of maintenance. Testing the value of sequential MS prior to and after one year of maintenance, patients converting from MS positivity to negativity had an excellent PFS (median not reached) while patients converting from MS negativity to positivity progressed early (median 0.6 years, 95% CI: 0.3-not reached). Among patients with sustained MS positivity, the baseline high-risk cytogenetic status had a significant impact and defined a group with poor PFS. Combining minimal residual disease (MRD) in the bone marrow and MS allowed the identification of double negative patients with a favorable PFS (median 3.33 years, 95% CI: 3.08-not reached) and no overall survival events. Our study provides strong evidence that MS is superior to conventional response monitoring, highlighting the potential of MS to become a new standard. Our data indicate that MS should be performed sequentially and combined with baseline disease features and MRD to improve its clinical value. Clinical Trials Register: EudraCT No. 2010-019173-16

IntroductionInfections are a leading cause of morbidity and mortality in patients with multiple myeloma (MM). MethodsTo examine the effects of modern second-generation novel agent therapy on immune cell subsets, in particular CD4+-T-cells, and infectious complications in patients with relapsed/refractory MM (RRMM), we conducted a prospective cohort study in 112 RRMM patients. ResultsSubstantially decreased CD4+-T-cells

IntroductionA variety of biomarkers are considered for diagnosis (e.g., β2-microgobulin, albumin, or LDH) and prognosis [e.g., cytogenetic aberrations detected by fluorescence in situ hybridization (FISH)] of multiple myeloma (MM). More recently, clonal evolution has been established as key. Little is known on the clinical implications of clonal evolution.MethodsWe performed in-depth analyses of 25 patients with newly diagnosed MM with respect to detailed clinical information analyzing blood samples collected at several time points during follow-up (median follow-up: 3.26 years since first diagnosis). We split our cohort into two subgroups: with and without new FISH clones developing in the course of disease.ResultsEach subgroup showed a characteristic chromosomal profile. Forty-three percent of patients had evidence of appearing new clones. The patients with new clones showed an increased number of translocations affecting chromosomes 14 (78% vs. 33%; p = 0.0805) and 11, and alterations in chromosome 4 (amplifications and translocations). New clones, on the contrary, were characterized by alterations affecting chromosome 17. Subsequent to the development of the new clone, 6 out of 9 patients experienced disease progression compared to 3 out of 12 for patients without new clones. Duration of the therapy applied for the longest time was significantly shorter within the group of patients developing new clones (median: 273 vs. 406.5 days; p = 0.0465).DiscussionWe demonstrated that the development of new clones, carrying large-scale alterations, was associated with inferior disease course and shorter response to therapy, possibly affecting progression-free survival and overall survival as well. Further studies evaluating larger cohorts are necessary for the validation of our results.

Abstract Lenalidomide (LEN) maintenance (MT) post autologous stem cell transplantation (ASCT) is standard of care in newly diagnosed multiple myeloma (MM) but has not been compared to other agents in clinical trials. We retrospectively compared bortezomib (BTZ; n = 138) or LEN (n = 183) MT from two subsequent GMMG phase III trials. All patients received three cycles of BTZ-based triplet induction and post-ASCT MT. BTZ MT (1.3 mg/m2 i.v.) was administered every 2 weeks for 2 years. LEN MT included two consolidation cycles (25 mg p.o., days 1–21 of 28 day cycles) followed by 10–15 mg/day for 2 years. The BTZ cohort more frequently received tandem ASCT (91% vs. 33%) due to different tandem ASCT strategies. In the LEN and BTZ cohort, 43% and 46% of patients completed 2 years of MT as intended (p = 0.57). Progression-free survival (PFS; HR = 0.83, p = 0.18) and overall survival (OS; HR = 0.70, p = 0.15) did not differ significantly with LEN vs. BTZ MT. Patients with

The outcomes of patients with multiple myeloma (MM) refractory to immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) remain poor. In this study, we performed whole genome and transcriptome sequencing of 39 heavily pretreated relapsed/refractory MM (RRMM) patients to identify mechanisms of resistance and potential therapeutic targets. We observed a high mutational load and indications of increased genomic instability. Recurrently mutated genes in RRMM, which had not been previously reported or only observed at a lower frequency in newly diagnosed MM, included NRAS, BRAF, TP53, SLC4A7, MLLT4, EWSR1, HCFC2, and COPS3. We found multiple genomic regions with bi-allelic events affecting tumor suppressor genes and demonstrated a significant adverse impact of bi-allelic TP53 alterations on survival. With regard to potentially resistance conferring mutations, recurrently mutated gene networks included genes with relevance for PI and IMiD activity; the latter particularly affecting members of the Cereblon and the COP9 signalosome complex. We observed a major impact of signatures associated with exposure to melphalan or impaired DNA double-strand break homologous recombination repair in RRMM. The latter coincided with mutations in genes associated with PARP inhibitor sensitivity in 49% of RRMM patients; a finding with potential therapeutic implications. In conclusion, this comprehensive genomic characterization revealed a complex mutational and structural landscape in RRMM and highlights potential implications for therapeutic strategies.

The gyri and sulci of the human brain were defined by pioneers such as Louis-Pierre Gratiolet and Alexander Ecker, and extensified by, among others, Dejerine (1895) and von Economo and Koskinas (1925). Extensive discussions of the cerebral sulci and their variations were presented by Ono et al. (1990), Duvernoy (1992), Tamraz and Comair (2000), and Rhoton (2007). An anatomical parcellation of the spatially normalized single high resolution T1 volume provided by the Montreal Neurological Institute (MNI; Collins, 1994; Collins et al., 1998) was used for the macroscopical labeling of functional studies (Tzourio-Mazoyer et al., 2002; Rolls et al., 2015). In the standard atlas of the human brain by Mai et al. (2016), the terminology from Mai and Paxinos (2012) is used. It contains an extensively analyzed individual brain hemisphere in the MNI-space. A recent revision of the terminology on the central nervous system in the Terminologia Anatomica (TA, 1998) was made by the Working Group Neuroanatomy of the Federative International Programme for Anatomical Terminology (FIPAT) of the International Federation of Associations of Anatomists (IFAA), and posted online as the Terminologia Neuroanatomica (TNA, 2017: http://FIPAT.library.dal.ca) as the official FIPAT terminology. This review deals with the various terminologies for the cerebral gyri and sulci, aiming for a common terminology.

To investigate cytogenetic evolution after upfront autologous stem cell transplantation for newly diagnosed myeloma we retrospectively analyzed fluorescence in situ hybridization results of 128 patients with paired bone marrow samples from the time of primary diagnosis and at relapse. High-risk cytogenetic abnormalities (deletion 17p and/or gain 1q21) occurred more frequently after relapse (odds ratio: 6.33; 95% confidence interval: 1.86–33.42; P

We investigated the impact of subcutaneous versus intravenous bortezomib in the MM5 trial of the German-Speaking Myeloma Multicenter Group which compared bortezomib, doxorubicin, and dexamethasone with bortezomib, cyclophosphamide, and dexamethasone induction therapy in newly diagnosed multiple myeloma. Based on data from relapsed myeloma, the route of administration for bortezomib was changed from intravenous to subcutaneous after 314 of 604 patients had been enrolled. We analyzed 598 patients who received at least one dose of trial medication. Adverse events were reported more frequently in patients treated with intravenous bortezomib (intravenous=65%; subcutaneous=56%, P=0.02). Rates of grade 2 or more peripheral neuropathy were higher in patients treated with intravenous bortezomib during the third cycle (intravenous=8%; subcutaneous=2%, P=0.001). Overall response rates were similar in patients treated intravenously or subcutaneously. The presence of International Staging System stage III disease, renal impairment or adverse cytogenetic abnormalities did not have a negative impact on overall response rates in either group. To our knowledge this is the largest study to present data comparing subcutaneous with intravenous bortezomib in newly diagnosed myeloma. We show better tolerance and similar overall response rates for subcutaneous compared to intravenous bortezomib. The clinical trial is registered at eudract.ema.europa.eu as n. 2010-019173-16.

Diffuse and focal bone marrow infiltration patterns detected by magnetic resonance imaging have been shown to be of prognostic significance in all stages of monoclonal plasma cell disorders and have, therefore, been incorporated into the definition of the disease. The aim of this retrospective analysis was to develop a rapidly evaluable prognostic scoring system, incorporating the most significant information acquired from magnetic resonance imaging. Therefore, the impact of bone marrow infiltration patterns on progression-free and overall survival in 161 transplant-eligible myeloma patients was evaluated. Compared to salt and pepper/minimal diffuse infiltration, moderate/severe diffuse infiltration had a negative prognostic impact on both progression-free survival (P

We treated a thirteen year old boy for life-threatening self-injurious behavior (SIB) and severe Kanner’s autism with Deep Brain Stimulation (DBS) in the amygdaloid complex as well as in the supra-amygdaloid projection system. Two DBS-electrodes were placed in both structures of each hemisphere. The stimulation contacts targeted the paralaminar, the basolateral, the central amygdala as well as the supra-amygdaloid projection system. DBS was applied to each of these structures, but only stimulation of the baso-lateral part proved effective in improving SIB and core symptoms of the autism spectrum in the emotional, social and even cognitive domains over a follow up of now 24 months. These results, which have been gained for the first time in a patient, support hypotheses, according to which the amygdala may be pivotal in the pathogeneses of autism and point to the special relevance of the baso-lateral part.

The trypanosome genome is characterized by RNA polymerase II-driven polycistronic transcription of protein-coding genes. Ten to hundreds of genes are co-transcribed from a single promoter; thus, selective regulation of individual genes via initiation is impossible. However, selective responses to external stimuli occur and post-transcriptional mechanisms are thought to account for all temporal gene expression patterns. We show that genes encoding mRNAs that are differentially regulated during the heat-shock response are selectively positioned in polycistronic transcription units; downregulated genes are close to transcription initiation sites and upregulated genes are distant. We demonstrate that the position of a reporter gene within a transcription unit is sufficient to reproduce this effect. Analysis of gene ontology annotations reveals that positional bias is not restricted to stress–response genes and that there is a genome-wide organization based on proximity to transcription initiation sites. Furthermore, we show that the relative abundance of mRNAs at different time points in the cell division cycle is dependent on the location of the corresponding genes to transcription initiation sites. This work provides evidence that the genome in trypanosomes is organized to facilitate co-coordinated temporal control of gene expression in the absence of selective promoters.

The wealth of competing parcellations with limited cross-correspondence between atlases of the human thalamus raises problems in a time when the usefulness of neuroanatomical methods is increasingly appreciated for modern computational analyses of the brain. An unequivocal nomenclature is, however, compulsory for the understanding of the organization of the thalamus. This situation cannot be improved by renewed discussion but with implementation of neuroinformatics tools. We adopted a new volumetric approach to characterize the significant subdivisions and determined the relationships between the parcellation schemes of nine most influential atlases of the human thalamus. The volumes of each atlas were 3d-reconstructed and spatially registered to the standard MNI/ICBM2009b reference volume of the Human Brain Atlas in the MNI (Montreal Neurological Institute) space (Mai and Majtanik, 2017). This normalization of the individual thalamus shapes allowed for the comparison of the nuclear regions delineated by the different authors. Quantitative cross-comparisons revealed the extent of predictability of territorial borders for 11 area clusters. In case of discordant parcellations we re-analyzed the underlying histological features and the original descriptions. The final scheme of the spatial organization provided the frame for the selected terms for the subdivisions of the human thalamus using on the (modified) terminology of the Federative International Programme for Anatomical Terminology (FIPAT). Waiving of exact individual definition of regional boundaries in favor of the statistical representation within the open MNI platform provides the common and objective (standardized) ground to achieve concordance between results from different sources (microscopy, imaging etc.).

Introduction: Male orgasmic disorder is common, with few treatment options. Cabergoline is a dopamine agonist that acts centrally to normalize serum prolactin that could improve orgasmic dysfunction. Aims: To determine whether cabergoline increases the potential for orgasm in men with orgasmic disorder. Methods: A retrospective chart review of men treated in a single andrology clinic for delayed orgasm or anorgasmia in a pilot study using cabergoline 0.5 mg twice weekly was performed. Duration of treatment and response were noted. Medical records were examined for other factors including history of prostatectomy and concomitant androgen supplementation. Main Outcome Measures: Subjective improvement in orgasmic function resulting from cabergoline treatment. Results: Of 131 men treated with cabergoline for orgasmic disorder, 87 (66.4%) reported subjective improvement in orgasm and 44 (33.6%) reported no change in orgasm. Duration of therapy (P = .03) and concomitant testosterone therapy (P = .02) were associated with a significant positive response to cabergoline treatment. No differences were found between injectable and non-injectable testosterone formulations (P = .90), and neither age (P = .90) nor prior prostatectomy (P = .41) influenced the outcome of cabergoline treatment. Serum testosterone levels before (P = .26) and after (P = .81) treatment were not significantly different in responders vs non-responders. Conclusion: Cabergoline is a potentially effective and easy-to-administer treatment for male orgasmic disorder, the efficacy of which appears to be independent of patient age or orgasmic disorder etiology. Prospective randomized trials are needed to determine the true role of cabergoline in the treatment of this disorder.