Letteratura scientifica selezionata sul tema "Therater – history"

Incisional hernia repairisone of themostfrequentsurgicalprocedures in General Surgerydue to thehighprevalence of thispathology Thesurgicaltechniqueinvolvesthe use ornot of prostheticmesh, depending onthesurgeon, however, anothercommonproblemistherecurrence of the hernia after a plasty, due to multiplefactorsthatwerestudied in thisresearch, beingnecessary to haveknownthefollow-up of thesepatients in theirpostoperativeperiod and whatcommoncharacteristicstheypresentedthatconditionedthepatients to presentthesepostoperativecomplications and evensurgicalreoperations. Itiswidelydemonstratedthattherecurrence of incisional hernia plastyis a conditionthat can be prevented, knowingtheconditioningriskfactors. Itisimperative to knowtheway in whichpatientshavebeenapproached, theirfollow-up and theirtherapy, determine whichriskfactorswererelevantaccording to thepathology to be studied and thusproposeanalternativesolution, thusreducingmorbidity and mortality. In ourpatients, thesurgicalreoperationsthatnotonlyaffectthequality of life of thepatientsbutalsothegreaterconsumption of material and economicresources in theInstitution. Objective: to determine themostfrequentriskfactorsassociatedwithrecurrence in patientswith a history of incisional hernia plasty at the Naval Medical Center. Material And Methods: 48 electronic records of patientswith a history of abdominal wall hernia plastywereanalyzed. Descriptive and inferentialanalysiswascarriedout in order to associateriskfactorswithrecurrence of incisional hernia. Results: No statisticallysignificantresultswerefoundfortheassociation of obesity, surgicalsiteinfection and smoking withrecurrence of incisional hernia. However, in oursampleobesitywaspresent in 54% of thepatients and 25% overweight. Conclusions: In Naval Medical Center, therate of patientswithincisional hernia plastyislimited, however, overweight andobesityis a characteristicthatourpopulationpresents in common and thatclearly determines multiplecomplications, such as recurrence in this case, requiring a narrowapproach to thiscondition.

Picking winners in electoral contests is a popular sport in Germany,as in many places elsewhere. During the 2002 campaign for theBundestag, pre-election polls tracked the horse race of party supportalmost daily. Election junkies were invited to enter online sweepstakes.They could also bet real money, albeit in limited quantity, onthe parties’ fortunes on WAHL$TREET, a mock stock market runby Die Zeit and other media. As usual, election night witnessed therace of the networks to project the winner the second the pollswhere voters had cast their ballots closed. But in 2002, there wasalso one newcomer in the business of electoral prophecy: a statisticalforecast based on insights from electoral research.

BackgroundFarber disease is frequently misdiagnosed as polyarticular juvenile idiopathic arthritis or seronegative rheumatoid arthritis which leads to a delay in diagnosis for many patients. Farber disease is an ultra-rare lysosomal storage disease caused by mutations in the ASAH1 gene. The resulting deficiency of the acid ceramidase enzyme leads to accumulation of the pro-inflammatory and pro-apoptotic sphingolipid ceramide. Accumulation of ceramide throughout the body leads to the symptoms of Farber disease. Cardinal symptoms include joint disease (polyarticular arthritis and contractures), subcutaneous nodules, and a hoarse or weak voice due to laryngeal nodules. The phenotypic spectrum of Farber disease ranges from rapidly progressive disease causing death in infancy to moderate or slowly progressive disease with survival into late adulthood. Symptoms may vary in severity across patients and phenotypes.ObjectivesTo further define the symptoms of Farber disease, including joint disease, subcutaneous nodules, dysphonia, and osteolysis, which can lead to referral to rheumatology or related specialties. To understand the clinical presentation and broad phenotypic spectrum of this rare disease to aid in clinical diagnosis and reduce diagnostic delay.MethodsThe Observational and Cross-Sectional Cohort Study of the Natural History and Phenotypic Spectrum of Farber Disease (NCT03233841) was the first systematic clinical study of the natural history of Farber disease. The study collected retrospective and prospective data on living and deceased patients, including demographics, clinical presentation, phenotype, diagnostic history, and patient reported outcomes.Results45 patients with Farber disease (27 living, 18 deceased) who had or had not undergone hematopoietic stem cell transplant (HSCT) were enrolled from 16 centers in 9 countries. A cohort of 24 living non-HSCT patients were followed prospectively. The patients represented the broad phenotypic spectrum of Farber disease, from rapidly progressive (severe) to slowly progressive (attenuated). In patients whose data was available for analysis, the average age of patients at enrollment was 7.2 years (range 1 to 28 years). The average age of onset of joint disease (arthritis and/or contractures) was 15 months (range 3 months to 7 years), of subcutaneous nodules was 13 months (range 3 months to 5 years), and of dysphonia was 13 months (range birth to 8 years). The average time from onset of symptoms to Farber disease diagnosis was 2 years (range <1 to 12 years). At baseline, the mean number of joints affected with active arthritis was 11.3 (range 0-36) and the mean number affected with contractures was 18 (range 0-38). 12.5% of patients were reported to have a bone disorder such as osteoporosis or osteolysis. The Child Health Assessment Questionnaire Disability Index (CHAQ) ranging from 0 (no impairment) to 3 (unable to do) was high, with mean scores of 2.62-3.00 across visits.ConclusionData from the Farber disease natural history study further defined the cardinal symptoms, phenotypic spectrum, and high disease-related burden in patients with Farber disease. The large number of joints affected with arthritis or contractures reflects that patients with Farber disease are often referred to rheumatology and can be misdiagnosed with polyarticular juvenile idiopathic arthritis or seronegative rheumatoid arthritis. Demographic information and numbers of patients enrolled indicate that Farber disease is likely not as rare as previously thought. ASAH1 genetic testing for adult and pediatric patients referred to the rheumatology clinic with symptoms including polyarticular arthritis, subcutaneous nodules, dysphonia, or osteolysis, may shorten the time to diagnosis in patients with Farber disease.Disclosure of InterestsLothar Seefried Speakers bureau: Aceragen, Amgen, Alexion, Biomarin, Chiesi, KyowaKirin, Novartis, Theramex, and UCB, Consultant of: Amgen, Alexion, Biomarin, Chiesi, KyowaKirin, Novartis, Theramex, and UCB, Grant/research support from: Alexion, KyowaKirin and Novartis, Kathleen Crosby Employee of: Aceragen, Alexander Solyom Employee of: Aceragen

BackgroundDysmobility Syndrome (DS) is a novel concept to characterize musculoskeletal (MSK) health. DS includes parameters for osteoporosis, sarcopenia and falls[1]. It has been associated with fractures and mortality in community dwelling older adults[2-4]but has never been applied to patients with rheumatic and musculoskeletal diseases (RMD).ObjectivesTo study the prevalence of DS and the association of DS with frailty and major osteoporotic fractures (MOF) in patients with inflammatory and non-inflammatory RMD.MethodsPatients with inflammatory and non-inflammatory RMD aged 65 and older were recruited at a tertiary rheumatology hospital. DS was defined using published cut-offs[1, 2]of the following parameters: Osteoporosis (DXA T-score ≤ -2.5), obesity (DXA % body fat > 30% in men; > 40% in women), low appendicular lean mass (ALM/height2<7.26 kg/m2in men; < 5.45 kg/m2in women), low grip strength (< 30kg in men; < 20kg in women), slow gait speed (< 1.0 m/s) and falls (history of one or more falls within last year). A score of ≥ 3 was defined as having DS. The FRAIL-scale5was used to quantify frailty. Historical data on MOF as defined by FRAX (https://frax.shef.ac.uk/frax/) was collected.Results141 patients (103 women/38 men) were included in the analysis. Mean age was 73 years. Of the total population, 80% had an inflammatory RMD (of those 45% had Rheumatoid Arthritis) as their primary diagnosis. Patients with non-inflammatory diseases had either degenerative spine and/or joint disease and/or fibromyalgia. Mean disease duration was 5 years. Mean DS score was 2.8 (for more demographic data see Table 1). 81/141 (57.5%) participants met DS criteria. DS was more common in women compared to men (63.1 vs. 42.1%, p= 0.0252) and in inflammatory RMD compared to non-inflammatory (61,1 vs. 42.9%, p=0.0811). Patients with DS reported fractures twice as often as those without DS (33,3 vs. 16.6%, p=0.0261). The frequency of individuals with a history of MOF increased with DS score (see Figure 1). Additionally, there was a significant association between DS and FRAIL scores in a univariate linear regression analysis (R2=0,22, p<0.001).ConclusionThis primary study to explore the prevalence of DS in patients with RMD showed that more than half of participants met DS criteria. Similar to studies of community dwelling older adults, fractures were more common in patients with DS. Importantly, a positive association of frailty and DS was seen. Further studies are needed to examine whether DS can be used clinically to better characterize overall MSK health in patients with RMD and whether a standardized management of DS will improve outcomes in these patients.References[1]Binkley N. Osteoporos Int. 2013;24(12):2955-9.[2]Buehring B. J Bone Miner Res. 2018;33(9):1622-9.[3]Hong N. Arch Osteoporos. 2018;13(1):86.[4]Looker AC. Osteoporos Int. 2015;26(1):93-102.[5]Morley JE. J Nutr Health Aging. 2012;16(7):601-8.Table 1.Study demographicsVariableTotaln = 141Femalesn = 103Malesn = 38p-value% Inflammatory RMD80.177.786.80.226Age [years] (SD)72.9(5.2)73.0(5.1)72.7(5.6)0.737Height [cm] (SD)165.3(9.0)161.5(6.2)175.6(6.9)< 0.001Weight [kg] (SD)77.9(15.1)76.1(15.5)82.8(12.9)0.019ALM/height2[kg/m2](SD)6.99(1.17)6.79(1.07)7.51(1.28)0.001Body fat [%] (SD)41.5(7.91)44.7(6.40)33.0(4.72)< 0.001Lowest BMD T-score (SD)-1.6(1.16)-1.7(1.21)-1.4(1.01)0.227Grip strength [kg] (SD)19.0(10.2)14.8(6.79)30.3(9.38)< 0.001Gait speed [m/s] (SD)0.95(0.31)0.89(0.27)1.110.36< 0.001Dysmobility Score (SD)2.8(1.30)2.9(1.30)2.5(1.25)0.054Simple Frail Score (SD)2.6(1.35)2.7(1.28)2.3(1.49)0.085Figure 1.Frequency of individuals with history of MOF by Dysmobility Syndrome (DS) Score. The frequency of individuals with a history of MOF increased with the DS Score (p=0.0509). Note: Only 3 individuals had a DS score of 0 and only 2 had a DS score of 6.AcknowledgementsThe OsteoSys Study was funded by grants EFRE.NRW.(EFRE-0800411, EFRE-0800427, LS-1-1-019c) and noChro.(13GW0338B) - PI Prof. Nina Babel.Disclosure of InterestsBjoern Buehring Speakers bureau: Alexion, Biogen, Boehringer-Ingelheim, Gilead/ Galapagos, MSD,Sanofi Genzyme, UCB, Consultant of: Amgen, Gilead/ Galapagos, Theramex, UCB, Roshnak Parvaee: None declared, Celina Mueller: None declared, Ioana Andreica: None declared, David Kiefer: None declared, Uta Kiltz: None declared, Styliani Tsiami: None declared, Maryam Pourhassan: None declared, Timm Westhoff: None declared, Rainer Wirth: None declared, Xenofon Baraliakos: None declared, Nina Babel: None declared, Juergen Braun: None declared.

INTRODUCTION: Cancer pathogenesis is usually characterized by a long evolutionary process where genomic driver events accumulate over time, conferring advantage to distinct subclones, allowing their expansion and progression. METHODS: To investigate the multiple myeloma (MM) evolutionary history, we characterized the mutational processes' landscape and activity over time utilizing a large cohort of 89 whole genomes and 973 exomes. To improve the accuracy of mutational signatures analysis, we analyzed both the 3' and 5' nucleotide context of each mutation and we developed the novel fitting algorithm mmSig, which fits the entire mutational catalogue of each patient with the mutational signatures involved in MM pathogenesis. The contribution of each mutational signature was then corrected based on the cosine similarity between the original 96-mutational profile and the reconstructed profile generated without that signature. To reconstruct the genetic evolutionary history of each patient's cancer, we integrated two approaches. First dividing all mutations into clonal (early) or subclonal (late), then subdivided the clonal mutations into duplicated mutations (present on two alleles and therefore acquired before the duplication) or non-duplicated mutations (detected on a single allele), reflecting either pre-gain and post-gain mutations on the minor allele, or post-gain mutations acquired on one of the duplicated alleles. RESULTS Eight mutational signatures were identified, seven of which showed significant similarity with the most recent mutational signature catalogue (i.e SBS1, SBS2, SBS5, SBS8, SBS9, SBS13 and SBS18). The new mutational signature (named SBS-MM1) was observed only among relapsed patients exposed to alkylating agents (i.e melphalan). The etiology of this specific signature was further confirmed by analyzing recent whole genomes public data from human-induced pluripotent stem cells exposed to melphalan (Kucab et al, Cell 2019). Reconstructing the chronological activity of each mutational signature, we identified four different routes to acquire the full mutational spectrum in MM based on the differential temporal activity of AID (SBS9) and APOBEC (SBS2 and SBS13). Our data indicate that AID activity is not limited to the first contact with the GC, but persists in the majority of patients, behaving similarly to a B-memory cells, capable of re-entering the germinal center upon antigen stimulation to undergo clonal expansion several times before MM diagnosis. Next, we confirmed the clock-like nature (i.e constant mutation rate) of SBS5 in MM and other post-germinal center disorders such as chronic lymphocytic leukemia and B-cell lymphomas. Based on the SBS5 mutation rates and the corrected ratio between duplicated and non-duplicated mutations within large chromosomal gains, we could time the acquisition of the first copy number gain during the life history of each MM patient. Intriguingly, the first MM chromosomal duplication was acquired on average 38 years (ranges 11-64) before sample collection. In 23/27 (85%) cases the first multi gain event occurred before 30 years of age, and in 13/27 (48%) before 20 years reflecting a long and slow process potentially influenced and accelerated by extrinsic and intrinsic factors. DISCUSSION Our analysis provides a glimpse into the early stages of myelomagenesis, where acquisition of the first key drivers precedes cancer diagnosis by decades. Defining the time window when transformation occurs opens up for new avenues of research: to identify causal mechanisms of disease initiation and evolution, to better define the optimal time to start therapy, and ultimately develop early prevention strategies. Disclosures Bolli: CELGENE: Honoraria; JANSSEN: Honoraria; GILEAD: Other: Travel expenses. Corradini:Janssen: Honoraria, Other: Travel Costs; Jazz Pharmaceutics: Honoraria; KiowaKirin: Honoraria; Servier: Honoraria; Takeda: Honoraria, Other: Travel Costs; Kite: Honoraria; Novartis: Honoraria, Other: Travel Costs; Gilead: Honoraria, Other: Travel Costs; Roche: Honoraria; Sanofi: Honoraria; BMS: Other: Travel Costs. Anderson:Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Other: Scientific Founder; Oncopep: Other: Scientific Founder; Amgen: Consultancy, Speakers Bureau; Sanofi-Aventis: Other: Advisory Board. Moreau:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Papaemmanuil:Celgene: Research Funding. Avet-Loiseau:takeda: Consultancy, Other: travel fees, lecture fees, Research Funding; celgene: Consultancy, Other: travel fees, lecture fees, Research Funding. Munshi:Adaptive: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Oncopep: Consultancy; Abbvie: Consultancy. Landgren:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Theradex: Other: IDMC; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract STUDY QUESTION Does the application of reference ranges for sex steroids and the modified Ferriman-Gallwey (mFG) scale established in the community from which the study sample was drawn, combined with the most conservative polycystic ovary morphology (PCOM) criteria to the recognised diagnostic criteria for polycystic ovary syndrome (PCOS) improve the certainty of diagnosis of PCOS in non-healthcare-seeking women? SUMMARY ANSWER Despite application of the stringent definitions of the elements used to diagnose PCOS in a non-healthcare seeking community-based sample, the risk of diagnostic uncertainty remains. WHAT IS KNOWN ALREADY There is heterogeneity in prevalence estimates for PCOS due, in part, to lack of standardisation of the elements comprising the recognised National Institutes of Health (NIH), Rotterdam and Androgen Excess Society (AE-PCOS) diagnostic criteria. The AE-PCOS Society proposed refinements to the definitions of biochemical androgen excess and PCOM that can now be incorporated into these sets of diagnostic criteria to estimate PCOS prevalence. STUDY DESIGN, SIZE, DURATION An Australian cross-sectional study of 168 non-healthcare-seeking women. PARTICIPANTS/MATERIALS, SETTING, METHODS The 168 included women were aged 18–39 years, euthyroid and normoprolactinemic, not recently pregnant, breast feeding or using systemic hormones. Each provided menstrual history and assessment of the mFG, had measurement of sex steroids by liquid chromatography, tandem mass spectrometry, and a pelvic ultrasound. The presence of PCOS was determined using modified (m) NIH, Rotterdam, and AE-PCOS criteria according to AE-PCOS Society recommendations. MAIN RESULTS AND THE ROLE OF CHANCE Overall, 10.1% of the included participants met the mNIH PCOS criteria, which requires the presence of menstrual dysfunction, while 18.5% met the mRotterdam and 17.5% the AE-PCOS criteria, with the latter requiring hyperandrogenism. Eight of the 27 participants with menstrual dysfunction, 10 of 31 women with PCOM, and 39 of 68 women with hyperandrogenism had no other feature of PCOS. Of the 19 participants with hyperandrogenaemia, 10 met the mNIH criteria (52.5%) and 14 met both the mRotterdam and AE-PCOS criteria (78.9%). Women who had the combination of hyperandrogenism and PCOM explained the greatest discrepancy between the mNIH and the other criteria. LIMITATIONS, REASONS FOR CAUTION Clinical androgenisation relied on participant self-assessment, which has been shown to be valid when compared with clinician assessment. The sample size was a function of both the strict inclusion criteria and the requirements of non-healthcare-seeking women having a blood draw and pelvic ultrasound which may have introduced a selection bias. WIDER IMPLICATIONS OF THE FINDINGS Despite applying stringent cut-offs for serum androgens, the mFG scale and the ovarian follicle count, these criteria remain arbitrary. Accordingly, healthy women may be captured by these criteria, and misidentified as having PCOS, while women with the condition may be missed. Consequently, PCOS remains a diagnosis to be made with care. STUDY FUNDING/COMPETING INTEREST(S) The study was supported by the Grollo-Ruzzene Foundation. Dr S.R.D. is an NHMRC Senior Principal Research Fellow (Grant no. 1135843). S.R.D. has been paid for developing and delivering educational presentations for Besins Healthcare, BioFemme and Pfizer Australia, has been on Advisory Boards for Theramex, Abbott Laboratories, Mayne Pharmaceuticals and Roche and a consultant to Lawley Pharmaceuticals and Que Oncology and has received has received institutional grant funding for Que Oncology research; there are no other relationships or activities that could appear to have influenced the submitted work. TRIAL REGISTRATION NUMBER N/A

Background High risk smoldering multiple myeloma (HRSMM), defined as having immunoparesis and at least 95% abnormal plasma cells/all plasma cells by advanced flow cytometry, has a risk of progression to multiple myeloma of about 75% after 5 years of diagnosis. These patient have no symptoms and current standard is to follow them without treatment. Isatuximab is an IgG1 monoclonal antibody that binds to CD38 highly expressed in myeloma cells. Isatuximab has activity as monotherapy (overall response rate (ORR) 35%), with lenalidomide/dexamethasone (ORR 56%) and pomalidomide/dexamethasone (ORR 62%) in relapsed MM. We designed a phase II study to test the efficacy of isatuximab in high risk smoldering myeloma. Our study is registered in clinicaltrials.gov as NCT02960555. Methods The primary endpoint of the study is the ORR of isatuximab 20 mg/kg IV days 1, 8, 15, 22 cycle 1; days 1, 15 cycles 2-6 and day 1 cycles 7-30 in high risk smoldering myeloma. 24 patients were accrued in the first stage (of maximum 61 patients). Secondary endpoints are PFS, OS, clinical benefit rate (CBR). Exploratory endpoints are quality of life analysis (QoL), MRD, molecular/immune characterization using DNA/RNA sequencing of myeloma cells and the microenvironment before and after treatment. Results 24 patients with HRSMM were accrued from 02/08/2017 until 12/21/2018 (Table 1). All patients are evaluable for response. Best responses: ORR (≥PR) 15(62.5%), CR MRD- flow at 10-5 1 (5%), VGPR 4 (17%), PR 10 (42%), minor response (MR) 4 (18%), stable disease 5 (21%); CBR (≥MR) 79%. Median number of cycles received were 11.5 (range 6-30). Five patients have stopped treatment (one has completed the study, one with heavy history of smoking was diagnosed with squamous cell cancer of the tongue, one could no longer travel to treatments due to relocation, two progressed to active multiple myeloma after 16 and 6 cycles of treatment, respectively). There have been no deaths. DNA/RNA seq is ongoing for biomarkers of response. There were 5 grade 3 severe treatment-related adverse events (RAE) which resolved to baseline: dyspnea -related to infusion reaction (n=2), headache (n=1), ANC decrease (n=1), urinary tract infection (n=1). Most common grade 1-2 related adverse events (n): nausea (7), vomit (5), WBC decrease (3), diarrhea (3), fatigue (6), headache (4), mucositis (4), myalgia (4) and infusion reaction (3). In patients with available QoL functional scores (n=9 at baseline and n=7 after 6 months of therapy), isatuximab was effective in reducing their anxiety and worry of progression to multiple myeloma. Isatuximab also improved general QoL scores by the end of cycle 6 of treatment which were now comparable to those in the general population (Figure 1). Conclusion Isatuximab is very well tolerated, results in high response rates in HRSMM and has the potential to change the natural history of this disease. In ongoing QoL analysis, initial data shows improvement in QoL and decreased cancer worry after isatuximab treatment. Immune-genomic analysis is ongoing and may identify patients that benefit the most from treatment. Disclosures Manasanch: celgene: Honoraria; merck: Research Funding; quest diagnostics: Research Funding; sanofi: Research Funding; BMS: Honoraria; Sanofi: Honoraria. Jagannath:Multiple Myeloma Research Foundation: Speakers Bureau; BMS: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Medicom: Speakers Bureau; Merck: Consultancy. Lee:Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; GlaxoSmithKline plc: Research Funding; Sanofi: Consultancy; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Patel:Poseida Therapeutics, Cellectis, Abbvie: Research Funding; Oncopeptides, Nektar, Precision Biosciences, BMS: Consultancy; Takeda, Celgene, Janssen: Consultancy, Research Funding. Kaufman:Janssen: Other: travel/lodging, Research Funding. Thomas:Xencor: Research Funding; BMS: Research Funding; Celgene: Research Funding; Amgen: Research Funding. Mailankody:Takeda Oncology: Research Funding; Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; CME activity by Physician Education Resource: Honoraria. Lendvai:Janssen: Employment. Neelapu:Acerta: Research Funding; Celgene: Consultancy, Research Funding; BMS: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Incyte: Consultancy; Merck: Consultancy, Research Funding; Allogene: Consultancy; Cellectis: Research Funding; Poseida: Research Funding; Karus: Research Funding; Pfizer: Consultancy; Unum Therapeutics: Consultancy, Research Funding; Novartis: Consultancy; Precision Biosciences: Consultancy; Cell Medica: Consultancy. Orlowski:Poseida Therapeutics, Inc.: Research Funding. Landgren:Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Theradex: Other: IDMC; Abbvie: Membership on an entity's Board of Directors or advisory committees; Merck: Other: IDMC. OffLabel Disclosure: Isatuximab for the treatment of smoldering myeloma

Introduction Peripheral neuropathy (PN) is a common disorder that can be caused by amyloid light-chain amyloidosis (AL). AL is a rare disorder caused by the deposition of amyloid fibers, originating from malignant plasma cells. Amyloid deposition in peripheral nerves causes PN and is present in 35% of patients with newly diagnosed AL. Diagnosis of AL can be difficult, leading to under-recognition, diagnostic delay, and delayed treatment. Virtually all instances of AL are preceded by monoclonal gammopathy of undetermined significance (MGUS). MGUS is relatively common with a reported prevalence of 4.2% in the general Caucasian population over the age of 50 years. Although MGUS is usually considered asymptomatic, a significant proportion of affected individuals develop PN. However, we are not aware of any studies assessing how PN affects risk of MGUS progression to AL. We were therefore motivated to conduct a large population-based study including 15,351 Swedish individuals with MGUS diagnosed 1986-2013. Methods Participants diagnosed with MGUS between 1986-2013 were recruited from a registry of a nationwide network of hematology- and oncology centers and the Swedish Patient Registry. We then cross-linked data on recorded diagnoses of AL and PN from the Swedish Patient Registry, diagnoses of lymphoproliferative disorders form the Swedish Cancer Registry, and dates of death from the Cause of Death Registry to our study cohort. Individuals with a previous history of other lymphoproliferative disorders were excluded from the study. A multi-state survival model was created. At inclusion, participants started providing person time into the PN or the non-PN states depending on whether they had a previous diagnosis of PN. Those with MGUS who developed PN after inclusion were included into the PN state at the time of PN diagnosis and provided person time in the PN state after that. We then created a Cox proportional hazard regression model with AL as the endpoint. Participants were censored at diagnosis of other lymphoproliferative disorders. We adjusted for sex, age, and year of MGUS diagnosis. Results We included 15,351 participants with MGUS. Of those, 996 participants provided person-time with PN (6.5%). About half of those had PN at MGUS diagnosis (55%). A total of 174 cases of AL were recorded, with AL being more common among those who had PN (2.1% vs 1.0% p=0.002). Those who had PN had a 2.3-fold increased risk of AL as compared to those who did not have PN (hazard ratio (HR): 2.3; 95% confidence interval (95% CI): 1.5-3.7; p<0.001). The results were similar for those who had PN at MGUS diagnosis and those who did not. More than half of AL cases (53%) were diagnosed within one year after MGUS diagnosis. The rate was even higher among those with PN, with 82% of AL cases among those who presented with PN being diagnosed within one year after MGUS diagnosis. In the first year after inclusion, the incidence of AL was 15.2 and 6.1 per 1000 person-years for participants with and without PN respectively (HR: 1.8; 95% CI:1.0-3.4; p=0.04). Participants with PN continued to have an increased risk of progression to AL after the first year with an incidence of AL of 2.6 per 1000 person-years as compared to 1.1 per 1000 person-years among participants who did not have PN (HR:2.4; 95% CI: 1.1-5.0; p=0.02) (Figure). Discussion In this large population-based study, including 15,351 individuals with MGUS, we found that individuals with MGUS who develop PN have an increased risk of progression to AL. In fact, individuals with MGUS who have PN at MGUS diagnosis might already have AL. This risk of AL was highest during the first year after MGUS diagnosis with participants with PN having a higher risk than those who did not have PN. PN continued to be associated with a higher risk of MGUS progression to AL throughout the study period. This is the largest study that we are aware of assessing the association of PN and MGUS progression to AL. Since this is a registry-based study based on recorded diagnoses, some clinical data, including MGUS isotype, is not available. These findings suggest that increased awareness of PN as a feature of MGUS might decrease diagnostic delay and improve outcomes for patients with AL. Figure Disclosures Landgren: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Theradex: Other: IDMC; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Other: IDMC; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.