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BackgroundSchizophrenia is a heterogeneous neuropsychiatric disorder, categorized by positive, negative, and cognitive symptoms. In trying to improve diagnosis and treatment of schizophrenia researchers have turn to “dual hit” models of schizophrenia that are able to reproduce all symptoms of the disorder. The main objective of this protocol is to present a transparent process on how we plan to review the existing international literature on effectiveness of “dual hit” models used to induce schizophrenia on rodents. MethodsLiterature search strategies will be developed using medical search headings (MeSH). The MEDLINE (PubMed), EMBASE, and Google Scholar databases will be used to search for published studies electronically. We will search for studies involving inducing schizophrenic symptoms using “dual hit” rodent model (post-weaning social isolation and NMDA receptor antagonist). Studies will be screened by titles, abstracts, keywords, and synonyms followed by identifying the full-text articles. All studies that will pass the quality assessment will be included. Data will be extracted by two authors independently and in duplicate, from each eligible study in ensuring that there is consistency between reviews. If the design and comparator are sufficiently homogenous for all studies, meta-analysis will be conducted using a random-effect model.DiscussionThe results of this review will contribute in the development of new “dual hit” models that will be able to characterize schizophrenia symptoms better. It will also shed light to researchers on new developments that need to be made in improving animal models of schizophrenia.Systematic reviews registrationPROSPERO CRD42021247585

We retrospectively studied the impact of cytogenetic abnormalities in 328 consecutive newly diagnosed multiple myeloma (MM) patients. High-risk cytogenetic abnormalities (HRCAs) included del (17p), amp/gain (1q21), t(4;14), and t(14;16). We defined a standard-risk group by the absence of HRCA, an intermediate-risk group with one HRCA, and a high-risk (HiR) group with at least two HRCAs. The HiR group constituted 14.3% of patients and was associated with a median overall survival (OS) of 28.6 months and progression-free survival (PFS) of 14.0 months. Moreover, the HiR group predicted poor outcomes for OS and PFS in multivariate analyses, and bortezomib prolongation to nine cycles could not bring additional benefit to this entity, suggesting the necessity of more effective therapies for these patients. Furthermore, we confirmed the independent prognostic impact of amp 1q21 in this real-world study.

Congenital long QT syndrome [LQTS] is a channelopathy characterized by QT prolongation and polymorphic VT. LQTS however need not be a purely electrical disease. Defects in ion channels may cause myocardial architectural disruption leading to ventricular non compaction [VNC]. It is defined as the presence of prominent ventricular trabeculations and deep intertrabecular recesses within the endomyocardium. We describe the in-utero management of a foetus who was later found to have LQTS with VNC. The detection of ventricular tachycardia and complete heart block in utero should arouse the suspicion of LQTS. It would be wise to avoid QT prolonging antiarrhythmics in this subset of patients.

The Chinese centre for disease control and prevention detected a novel severe acute respiratory syndrome - coronavirus 2 (SARS - CoV2) from a nasopharyngeal swab in a patient with atypical pneumonia in Wuhan, Hubei province, China on January, 2020.1 Corona virus disease-19 (COVID-19) has a high mortality rate in critically ill patients. Acute heart injury, acute kidney injury and sudden thromboembolic events are becoming more common and they can occur regardless of pulmonary or respiratory symptoms.1-5 COVID-19 has been shown to have the ability to create a hypercoagulable state in recent studies.2,3,6,7 Viral infections can cause endothelial cell dysfunction, resulting in excessive throbbing production and fibrinolysis inhibition.8- 10 Hypoxia is also linked to an increase in blood viscosity and the activation of hypoxia-related genes that regulate coagulation and fibrinolysis making thrombotic events more likely.11,12 This septic-like coagulopathy can also lead to venous thrombosis, pulmonary embolism, and, in the worst-case scenario, disseminated intravascular coagulation.3,4 Cerebral venous thrombosis, in particular, can manifest itself in a wide range of neurologic signs and symptoms.13,14 and had consistently fatal results.

Double-hit hot compression tests were carried on medium-carbon low-alloy steels using Gleeble 3800® thermomechanical simulator. The experiments were performed at strain rates of 0.25 and 0.5 s−1 and temperatures of 1150 and 1200 °C with interpass times of 5, 15, and 25 s. The onset of critical stresses for dynamic transformation (DT) for both first and second hit were detected using the double-differentiation method. It was found that the critical stress for DT increased with a decrease in temperature and an increase in strain rate. The presence of dynamically transformed ferrite was observed and quantified using electron-backscatter diffraction, kernal average misorientation, and grain boundary maps. Then, a thermodynamic analysis was carried out using JmatPro software. A method of determining the change in Gibbs energy during DT phenomenon is proposed for double hit deformation.

High-grade B cell lymphomas with rearrangements on C-MYC and BCL2 and/or BCL6 (HGBL with MYC and BCL2 and/or Bcl6 rearrangement) are associated with worse clinical outcomes and thus were introduced as a separate new category in the recently updated WHO classification. From 2012 to 2016, we analyzed a consecutive cohort of large B cell lymphomas (LBCLs) for C-MYC, BCL2, and BCL6 rearrangements and correlated our results with clinical-pathological parameters. Ten of 78 (13%) cases had a C-MYC and BCL2 and/or BCL6 rearrangement, so-called double or triple hit (DH), while double/triple copy number gains (CNGs) were found in eight (10%) patients. Patients with a high-grade lymphoma with DH or CNG progressed significantly more often after first-line chemotherapy (p = 0.005). When treated with standard chemotherapy, patients with a DH or CNG had a significantly worse overall (OS) and recurrence free survival (RFS) compared with all other patients (p = 0.033 and p

The impact on the Indian economy due to novel coronavirus pandemic in 2019-20 has been highly troublesome and disruptive. In spite of all the precautionary measures and numerous restrictions (i.e. ongoing lockdown) taken by the government of India, negative implications have been visualized on the farm economy especially the rabi season crops which are at harvestable stages. It makes the supply of different perishable produce including fruits, vegetables, dairy products, fish etc difficult. It also disturbed the labour availability, market and storage, agri-input system, export-import of agricultural commodities and the complex network of demand-supply chainto a majestic level. Although the entire country facing these challenges, but has double hit the poorest of the poor section of the society. Hence, the priority of the government has to be to protect the lives of every citizen of the country instead of dealing with the economic growth of various departments or fields.

DNase I hypersensitive site (DHS) mapping combined with high-throughput sequencing (DNase-seq) enables the identification of cis-regulatory DNA elements (CREs) genome wide. However, despite the wide applications of DNase-seq in plants, its application to the highly repetitive genomes of plants has lagged. Here, we describe a modified DNase-seq method, making it more practical for application to plants with genomes enriched with repetitive DNA. This approach adopts a double-hit-based strategy, in which small (

In 1980, the 5-year overall survival rate for patients with acute myeloid leukemia (AML) in the United States (US) was a truly dismal 7%. Over 30 years later in 2012, approximately 30% of adult pat...

TO THE EDITOR: Recently, biallelic (“double hit”) TP53 inactivation, occurring in 2% to 4% of newly diagnosed multiple myeloma (MM) patients, was identified as an ultimate high-risk feature of MM, being associated with median survival of

Diffuse large B-cell lymphoma (DLBCL) transformed from follicular lymphoma (FL) (tDLBCL) has been traditionally associated with an aggressive course, but more recent studies have shown longer survivals. The clinical significance of concurrent FL at the time of diagnosis of DLBCL (cDLBCL/FL) is less clear. We compared outcomes of tDLBCL, cDLBCL/FL, and

Introduction: Identify the non-decoded network in Vascular Parkinsonism (VasP). Objective: To determine what pattern of stroke lesions is responsible for VasP, as compared to those patients who had stroke, gait and balance problems, but absence of a hypokinetic rigid syndrome also called Vascular Pseudo Parkinsonism-V PSeuP. Materials and Methods: Design: prospective cohort study. Participants were consecutively screened for parkinsonian symptoms during a year as according to our previous study. Validated questionnaire (Tanner Questionnaire-TQ) was used, and a new scale operationalizing the criteria for VasP (FMAS score). All participants in the original study had a clinical exam to identify if presence of a hypokinetic rigid syndrome. Lesion patterns were analyzed. Setting: tertiary care stroke prevention clinic at the University of Alberta Hospital. Participants: Eligible participants attained a score of ≥ 4 on the TQ, high risk for parkinsonism. Four groups were considered: V PseuP, VasP (onset of parkinsonism within a year of the stroke -FMAS score of 4), Pseudo Vascular Parkinsonism-PseuVP (hypokinetic rigid syndrome not related to stroke), and Pseudo Vascular Pseudo Parkinsonism-PseuV PseuP (no stroke and no extrapyramidal syndrome), but with gait and balance problems. Baseline demographic information and clinical characteristics were recorded including vascular risk factors, and stroke subtype. All participants had a Holter, CT head and/or brain MRI, and CTA. Medications that produce drug-induced-parkinsonism were recorded for every participant. The primary outcome was to find the pattern of anatomical lesions particularly involved in the VasP subgroup considering the Basal Ganglia Motor Output Circuit-BGMO, the Thalamo Cortical Drive Loop-TCD and connections to frontal cortex. Results: 240 consecutive participants were screened during 12 months. We found 46 patients with potential Parkinsonism (TQ>4). VPseuP was found in 25/46 (54%), VasP in 8/46 (17%), PseuVP in 7/46 (15%), and PseuV PseuP in 6/46 (14%). VasP were older (p

We calculate the production of hypothetical millicharged particles (MCPs) of sub-GeV masses by the J-PARC proton beam in the framework of T2K and future T2HK neutrino oscillation experiments. Concentrating on the region of model parameter space, where an MCP can hit the near neutrino detector twice, we adopt this background-free signature to estimate the sensitivity of T2K and T2HK experiments to MCPs. We find that a previously inaccessible in direct searches region of charges 5$\times$$10^{-4}$-$10^{-2}$ $e$ for MCP masses 0.1-0.5 GeV can be probed., Comment: 15 pages, 8 figures; v2: replaced with published version

BackgroundB-lymphoblastic lymphomas (B-LBLs) with a documented “double-hit” (DH) (IGH/BCL2 and 8q24/MYC rearrangement) are rare and their clinical, cytogenetic and immunophenotypic features have not been well elucidated. Here we describe an unusual case of de novo DH B-LBL.Case presentationA 39-year-old man presented with abdominal distention at admission. Radiological findings revealed a retroperitoneal lump and multiple lymphadenopathy. Histologic examination of the abdominal mass showed a predominant population of neoplastic lymphoblasts with round nuclei, which focally formed single files surrounded by fibrotic septa. These cells have high nuclear to cytoplasmic ratio, fine chromatin, and no inconspicuous nucleoli. Necrosis, apoptotic bodies and mitotic figures were common. Prominent starry-sky appearance was not observed. The typical immunophenotype of malignant cells was positive for TdT, CD99, CD10, PAX-5, Bcl2 (70%), MYC (70%), and negative for CD34,Cyclin-D1, SOX11, CD56, and CD123. The proliferation index was high with Ki-67 of 80%. Fluorescence in situ hybridization (FISH) studies demonstrated 8q24/MYC rearrangement and IGH/BCL2 gene fusion. Subsequent bone marrow biopsy showed no involvement. Normal chromosome karyotype was observed. Finally, the diagnosis of “double-hit” B-LBL was clinically rendered. The patient showed an initial response to six cycles of hyper-CVAD chemotherapy (hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) and was alive at the last follow-up (2020.4.10, six months after the diagnosis).ConclusionsFew guidelines regarding DH B-LBL are available in the literature or in the WHO scheme. The optimal clinical management of such patients has not been fully established attributed to the small number of reported cases. Multicenter data is warranted to better make clinical strategies on patients with DH B-LBL.

Growing evidence indicates a reciprocal relationship between low-grade systemic inflammation and stress exposure towards increased vulnerability to neuropsychiatric disorders, including posttraumatic stress disorder (PTSD). However, the neural correlates of this reciprocity and their influence on the subsequent development of PTSD are largely unknown. Here we investigated alterations in functional connectivity among brain networks related to low-grade inflammation and stress exposure using two large independent data sets. Functional couplings among the higher-order cognitive network system including the salience, default mode, and central executive networks were reduced in association with low-grade inflammation and stress exposure. This reduced functional coupling may also be related to subsequent posttraumatic stress symptom severity. The current findings propose functional couplings among the higher-order cognitive network system as neural correlates of low-grade inflammation and stress exposure, and suggest that low-grade inflammation, alongside with stress, may render individuals more vulnerable to PTSD., Low-grade systemic inflammation and stress increase vulnerability to neuropsychiatric disorders. Here, the authors show that inflammation and stress-induced changes in higher order cognitive networks increase vulnerability to posttraumatic stress disorder.

In the COVID-19 pandemic caused by SARS-CoV-2, hospitals are stretched beyond capacity. There are widespread reports of dwindling supplies of personal protective equipment (PPE), which are paramount to protect frontline medical/nursing staff and to minimize further spread of the virus. We carried out a rapid review to summarize the existing evidence on SARS-CoV-2 survivorship and methods to disinfect PPE gear, particularly N95 filtering facepiece respirators (FFR). In the absence of data on SARS-CoV-2, we focused on the sister virus SARS-CoV-1. We propose a two-step disinfection process, which is conservative in the absence of robust evidence on SARS-CoV-2. This disinfection protocol is based on an initial storage of PPE for ≥4 days, followed by ultraviolet light (UVC), dry heat treatment, or chemical disinfection. Importantly, each of the two steps is based on independent disinfection mechanisms, so that our proposed protocol is a multiplicative system, maximising the efficacy of our disinfection process. This method could be rapidly implemented in other healthcare settings, while testing of each method is undertaken, increasing the frontline supply of PPE, and avoiding many of the upstream issues of supply chain disruption currently being faced.

Even though non-Hodgkin’s lymphomas were traditionally divided into “low-grade” and “high-grade” lymphomas based on expected indolent and aggressive clinical behavior, respectively, “high-grade B-cell lymphoma (HGBL)” is now a specifically defined category of lymphomas in the 2016 WHO classification. It consists of a group of mature but aggressive B-cell lymphomas that are biologically and clinically distinct and should be classified as a separate category other than diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS) or Burkitt lymphoma (BL). This chapter reviews the two entities under this new category: high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, also called “double-hit” lymphoma (HGBL-DH), and high-grade B-cell lymphoma, not otherwise specified (HGBL, NOS). We shall also discuss in details two other aggressive B-cell lymphomas which have overlapping morphological, immunophenotypic, or genetic features: Burkitt lymphoma (BL) and Burkitt-like lymphoma with 11q aberration. Morphological mimics such as blastoid or other “high-grade” transformations of low-grade B-cell lymphomas will be examined to emphasize their distinguishing features from high-grade B-cell lymphomas mentioned above. Variants and subtypes of DLBCL are discussed in Chap. 6.

Key Clinical Message We describe an High‐grade B‐cell lymphoma case, in which a complex translocation t(3;8;14) with effects on the genes BCL6, MYC, and IGH, was detected. This case could be the first double‐hit lymphoma with a single chromosome rearrangement causing the double effect with three genes involved.

High-grade B-cell lymphomas with MYC, BCL2, and BCL6 rearrangements (triple hit lymphoma) are uncommon. We studied the clinicopathologic features of 40 patients with triple hit lymphoma and compared them to 157 patients with MYC/BCL2 double hit lymphoma and 13 patients with MYC/BCL6 double hit lymphoma. The triple hit lymphoma group included 25 men and 15 women with a median age of 61 years (range, 34−85). Nine patients had a history of B-cell lymphoma. Histologically, 23 (58%) cases were diffuse large B-cell lymphoma and 17 cases had features of B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma. Most cases of triple hit lymphoma were positive for CD10 (100%), BCL2 (95%), BCL6 (82%), MYC (74%), and 71% with MYC and BCL2 coexpression. P53 was overexpressed in 29% of triple hit lymphoma cases. The clinicopathological features of triple hit lymphoma patients were similar to patients with MYC/BCL2 and MYC/BCL6 double hit lymphoma, except that triple hit lymphoma cases were more often CD10 positive compared with MYC/BCL6 double hit lymphoma (p

Genetic and environmental models of neuropsychiatric disease have grown exponentially over the last 20 years. One measure that is often used to evaluate the translational relevance of these models to human neuropsychiatric disease is prepulse inhibition of startle (PPI), an operational measure of sensorimotor gating. Deficient PPI characterizes several neuropsychiatric disorders but has been most extensively studied in schizophrenia. It has become a useful tool in translational neuropharmacological and molecular genetics studies because it can be measured across species using almost the same experimental parameters. Although initial studies of PPI in rodents were pharmacological because of the robust predictive validity of PPI for antipsychotic efficacy, more recently, PPI has become standard common behavioral measures used in genetic and neurodevelopmental models of schizophrenia. Here we review “two hit” models of schizophrenia and discuss the utility of PPI as a tool in phenotyping these models of relevant risk factors. In the review, we consider approaches to rodent models of genetic and neurodevelopmental risk factors and selectively review “two hit” models of gene × environment and environment × environment interactions in which PPI has been measured.

Inborn errors of metabolism comprise a broad range of genetic diseases of which most are inherited in an autosomal recessive manner. Although being rare, there is a significant increase in their rate especially in countries where consanguineous marriages are performed. Isovaleric aciduria is an organic aciduria characterized by abnormal leucine metabolism resulting from a deficiency in the enzyme isovaleryl-CoA dehydrogenase. Niemann-Pick disease Type C is a rare autosomal recessive inherited disorder involving the intracellular transport of endocytosed cholesterol with sequestration of unesterified cholesterol in lysosomes and late endosomes. Both of these disorders are rarely encountered inborn errors of metabolism. We report a case of a boy with marked jaundice and hapatosplenomegaly, who was later diagnosed as isovaleric aciduria and Niemann-Pick disease Type C concomitantly. The diagnoses were proven by genetic analyses. A novel mutation for Niemann-Pick Type C has also been defined in this case report.

INTRODUCTION mSMART classifies high-risk Multiple Myeloma patients into Double Hit and Triple Hit Myeloma (DH/THM) on the basis of the number of high-risk cytogenetic abnormalities detected. While cytogenetics at diagnosis helps in the decision-making process regarding initial therapy, their role in relapsed MM is not very well studied. We aimed to study the clinical profile and outcomes of patients with DH/THM detected at relapse in a real-world setting. METHODS The case records of all relapsed multiple myeloma patients requiring active therapy between January 2018 and December 2020 were identified. All patients underwent bone marrow examination and repeat FISH cytogenetic analysis. The diagnosis of double hit and triple hit myeloma was based on mSMART classification (Presence of two or more of the following: IgH-FGFR3 translocation, IgH-MAF translocation, TP53 deletion, gain of chromosome 1q). Their case records were retrieved and information regarding baseline characteristics, therapy and outcomes was noted. RESULTS A total of 17 patients were diagnosed with DH/THM at relapse during the study period. Median age of the cohort was 59 years with almost an equal number of male and female patients (M=9; F=8). Renal failure (serum creatinine >2.0mg/dl) was seen in 8 patients (47.1%), while bone lesions, anemia (Hemoglobin 12mg/dl) were seen in 12 (70.6%), 12 (70.6%) and 6 (35.3%) patients respectively. Five patients (29.4%) fulfilled the criteria for plasma cell leukemia. Twelve patients (70.6%) were in first relapse, while 3 patients were diagnosed at second relapse and 1 patient each at 3 rd and 5 th relapse respectively. All but 2 patients had received Bortezomib previously (N=15; 88.2%). Eleven patients (64.7%) had previous exposure to Lenalidomide and 8 patients (47.1%) had previous exposure to Thalidomide. Two patients had previously undergone autologous hematopoietic cell transplant. Median follow-up prior to diagnosing DH/THL was 28 months (Range- 5-89 months). All patients had gain of 1q with at least 3 copies, while 12 patients (70.6%) had 4 or more copies. The most common cytogenetic combination was IgH-FGFR3 translocation with gain of 1q which was seen in 10 patients (58.8%). This was followed by co-occurrence of TP53 deletion with gain of 1q in 5 patients (29.4%). Two patients (11.8%) had triple hit myeloma. Seven patients (41.2%) died within the first month of relapse and a further 3 patients died during the next month. Of the 10 patients who received at-least 1 cycle of therapy, 8 received triplet therapy with the combination of a proteasome inhibitor and an Immunomodulator, one patient received doublet with Lenalidomide and dexamethasone and one patient received Daratumumab based quadruplet therapy. Bortezomib based therapy was used in 5 patients and 4 patients received Carfilzomib based therapy. None of the patients underwent a 2 nd auto transplant. Two patients achieved VGPR or better with therapy. Of the 7 evaluable patients, 5 re-relapsed during follow up. The follow up of entire cohort ranged from 0 to 29 months. Sixteen patients (94.1%) died during follow up. The most common cause of death was progressive/active disease (9 patients, 56.3%) followed by a combination of active disease with sepsis (4 patients, 25%). Median OS was 1 month for the entire cohort. DISCUSSION The outcome of DH/THM at relapse is associated with an aggressive presentation and poor outcomes in the real-world setting. These patients are candidates for early aggressive or novel therapy or clinical trials. Disclosures No relevant conflicts of interest to declare.

Background: TP53 is altered in ~50% of human cancers. Alterations mainly include mutations and/or deletions, but also copy-neutral loss of heterozygosity (CN-LOH) was reported. Frequently, both TP53 alleles are altered (by mutation + deletion, mutation + CN-LOH or ≥2 mutations), leading to a "double hit" event. Aim: Analysis of TP53 aberrations using WGS in 4646 cases with 29 different hematological malignancies, comparing (1) the frequencies of TP53 alterations, (2) occurrence of single hit vs. double hit, (3) correlation with complex karyotype and (4) impact on survival. Methods: Whole-genome sequencing (WGS) was performed for all 4,646 patients (median coverage 100x). 151bp paired-end reads were generated on NovaSeq 6000 and HiSeqX machines (Illumina, San Diego, CA). As no sample specific normal tissue was available, a so-called Tumor/Unmatched normal (TUN) workflow was used to reduce technical artefacts and germline calls. All reported p-values are two-sided and were considered significant at p Results: In the total cohort of 4,646 cases, in 582 (13%) at least one alteration (alt) involving TP53 was detected (comprising mutations (mut), deletions (del) and CN-LOH (LOH); Fig 1A,B). Cases were categorized as follows: cases with (1) 1 TP53 mut only (n=166), (2) del only (n=100), (3) LOH only (n=15), constituting the single hit events. Further, (4) cases with mut+del (might include 1 or more mut, n=211), cases with mut+LOH (≥1 mut, n=41), cases with ≥2 mut only (without del or LOH, n=49), resulting in double hit events (Fig 1B). Regarding the respective entities, high frequencies of TP53 alt were mainly detected in lymphoid malignancies (e.g. HGBL, MPAL, vHZL, MZL, MCL), whereas they were infrequent or absent in many myeloid malignancies (e.g. aCML, MPN, CMML, CML, MLN_eo; Fig 1A). For further analysis, only entities in which >10 cases showed TP53 alt events were used. Comparison of single hit vs. double hit revealed that T-NHL, MM, MPN and MDS predominantly showed a single hit, whereas the double hit was frequent in MPAL, MZL, MDS/MPN-U, CLL and MCL cases (Fig 1A). However, the type of double hit differed between myeloid and lymphoid malignancies, as myeloid neoplasms showed a high frequency of cases with ≥2 mut only, whereas in many lymphoid malignancies the double hit was predominantly generated by mut+del (Fig 1A,C). All TP53-associated events (mut, del, LOH and the respective combinations) were found to be associated with a complex karyotype in the total cohort (LOH: 14% complex karyotype in cases without TP53 alt vs. 59% in cases with TP53 alt, p Conclusions: (1) Frequency of TP53 alterations and of double hit vs. single hit differs markedly between entities. (2) The kind of TP53 complexity differs between both lineages (double hit in myeloid neoplasms: often ≥2 mut only; in lymphoid malignancies: predominantly mut+del). (3) In 7% (41/582) of cases with TP53 alt, CN-LOH transforms a single hit into a double hit. (4) In the total cohort and in the majority of selected entities (except MZL and T-NHL), TP53 alt are associated with complex karyotype. (5) In the total cohort, all events involving TP53 impact on OS; cases with double hit show an inferior outcome compared to single hit. (6) Regarding OS, the selected entities can be divided into three categories: (i) no influence of TP53 alt (HGBL, MZL, T-NHL); (ii) double hit required for impact on OS (MCL, MPAL); (iii) influence of both single hit and double hit with inferior outcome of double hit (all other). Figure 1 Figure 1. Disclosures Kern: MLL Munich Leukemia Laboratory: Other: Part ownership. Haferlach: MLL Munich Leukemia Laboratory: Other: Part ownership. Haferlach: MLL Munich Leukemia Laboratory: Other: Part ownership.

INTRODUCTION mSMART classifies high-risk Multiple Myeloma patients into Double Hit and Triple Hit Myeloma (DH/THM) on the basis of the number of high-risk cytogenetic abnormalities detected. The outcome of these patients with the use of proteasome inhibitors and IMiDs with upfront Auto HSCT is not known in the real-world setting. We retrospectively studied the outcome of these patients in a resource constrained setting. METHODS The case records of all newly diagnosed multiple myeloma patients who fulfilled the criteria for active myeloma between January 2018 and December 2020 were identified. The diagnosis of double hit and triple hit myeloma was based on mSMART classification (Presence of two or more of the following: IgH-FGFR3 translocation, IgH-MAF translocation, TP53 deletion, gain of chromosome 1q). Their case records were retrieved and information regarding baseline characteristics, therapy and outcomes was noted. RESULTS A total of 55 patients with newly diagnosed DH/THM were treated at our center during the study period. Median age of the cohort was 60 years with almost an equal number of male and female patients (M= 26; F= 29). Renal failure (serum creatinine >2.0mg/dl) was present in 33 patients (60%) while bone lesions, anemia (Hemoglobin 12mg/dl) were present in 44 (80%), 51 (92.7%) and 24 (43.6%) patients respectively. Six patients (10.9%) fulfilled the criteria for plasma cell leukemia. All but 2 patients had gain of 1q with at least 3 copies. The most common cytogenetic combination was IgH-FGFR3 translocation with gain of 1q, which was seen in 28 patients (50.9%). This was followed by co-occurrence of TP53 deletion with gain of chromosome 1q in 11 patients (20%). Nine patients (16.4%) had triple hit myeloma. Bortezomib was used in the initial therapy of 43 patients (78.2%) and IMiDs (lenalidomide, thalidomide and pomalidomide) were used in the initial therapy of 32 patients (58.2%). Most patients received triplet therapy (N=32; 58.2%) with the most common regimen being RVd. Nine patients (16.4%) died within the first month of diagnosis and another 7 died in next month [15 patients in 2 months (29.1%)]. The most common cause of death within 2 months was progressive disease (N=13; 81.3%). Twenty-two patients (40%) achieved VGPR or better with anti-myeloma therapy and 7 patients (12.7%) underwent autologous HCT. Of the 39 evaluable patients, 21 patients (53.8%) relapsed during follow up with a median EFS of 8 months. Of the 7 patients who underwent transplant, 5 patients have had a follow-up of more than 1 year, of whom 3 have relapsed. One patient with post-transplant relapse died with progressive disease and CMV colitis. Median follow up of the entire cohort was 11 months (Range- 0 to 35 months). After excluding patients who died within the first 2 months of diagnosis, the median follow up was 14 months (Range- 3 to 35 months). Thirty-three patients (60%) patients died during follow-up. The most common cause of death was active or progressive disease (25 patients, 78.1%). Median OS for the cohort was 13 months. On univariate analysis, survival was better for patients without renal injury at presentation (29 months vs 6 months; p=0.007) and patients with 5% circulating plasma cells (Hazard ratio- 3.082; p-0.020) were significantly associated with increased risk of mortality, while achievement of VGPR or better with therapy was associated with longer survival (Hazard ratio- 0.174; p-0.001). DISCUSSION The outcome of DH/THM remains poor in the real-world setting. The outcome was not affected by specific high-risk cytogenetic abnormalities or their combination in our study. Progressive disease within the first two months of diagnosis was the most common cause of death in more than 1/3 rd of the patients. Novel therapies and protocols are required to improve outcomes for this group of multiple myeloma patients. Disclosures No relevant conflicts of interest to declare.

Introduction Multiple myeloma (MM) patients (pts) with high-risk cytogenetic abnormalities (CA) have a shorter survival as compared to the standard-risk ones. In the FORTE study, carfilzomib-lenalidomide-dexamethasone induction/consolidation with ASCT (KRd-ASCT) significantly improved progression-free survival (PFS) vs KRd without ASCT (KRd12) or carfilzomib-cyclophosphamide-dexamethasone (KCd) plus ASCT (KCd-ASCT). KR maintenance also prolonged PFS vs R. The primary aim of this analysis was to evaluate the impact of treatment on PFS and 1-year sustained MRD negativity (1y-MRD neg) rates according to pt cytogenetic risk. Methods Pts were randomized to KRd-ASCT vs KCd-ASCT vs KRd12 and, thereafter, to KR vs R maintenance. High risk (HiR) was defined as the presence of ≥1 HiR CA [del17p, t(4;14), t(14;16), del1p and 1q gain (3 copies) or amp1q (≥4 copies)], double hit (DH) as the presence of ≥2 HiR CA, standard risk (SR) as the absence of all evaluated HiR CA. Results 396 out of 474 enrolled pts with complete fluorescence in situ hybridization (FISH) data were included in the analysis: 243 HiR, 105 DH and 153 SR pts. Among HiR pts, 60 had del17p, 65 t(4;14), 20 t(14;16), 44 del1p, 126 1q gain and 49 amp1q. SR pts benefited from intensification with KRd-ASCT vs KRd12 (HR 0.47, p=0.05) and KCd-ASCT (HR 0.38, p=0.01), with a 4-year PFS of 80%, 67% and 57%, respectively. In HiR pts, KRd-ASCT improved PFS vs KRd12 (HR 0.6, p=0.04) and KCd-ASCT (HR 0.57, p=0.01), with a 4-year PFS of 62%, 45% and 45%, respectively. The advantage with KRd-ASCT vs KRd12 (HR 0.53, p=0.07) and KCd-ASCT (HR 0.49; p=0.03) was also observed in DH pts (4-year PFS 55%, 31% and 33%, respectively). Despite the limited number of patients in each subgroup, a trend towards a PFS benefit from KRd-ASCT vs KRd12 was observed in pts with del17p (HR 0.61, p=0.3), t(4;14) (HR 0.59, p=0.2) and 1q gain (HR 0.45, p=0.02). In pts with del1p, KRd-ASCT (HR 0.24, p=0.06) and KRd12 (HR 0.33, p=0.09) showed superiority over KCd-ASCT, while amp1q pts had the worst outcome regardless of treatment (KRd-ASCT vs KCd-ASCT, HR 1.16, p=0.73; KRd12 vs KCd-ASCT, HR 1.34, p=0.45). KR improved PFS vs R in SR (3-year PFS 90% vs 73%, HR 0.42, p=0.06), HiR (3-year PFS 69% vs 56%, HR 0.6, p=0.04) and DH pts (3-year PFS 67% vs 42%, HR 0.53, p=0.1). Despite the small subgroups, a beneficial trend with KR vs R was observed in pts with del17p (HR 0.59, p=0.37), t(4;14) (HR 0.59, p=0.3), 1q gain (HR 0.54, p=0.07) and del1p (HR 0.23, p=0.08), while amp1q pts showed the worst outcome and no benefit from KR vs R (HR 0.83, p=0.7). Conclusion KRd-ASCT and KR maintenance are highly effective in SR and also in HiR and DH pts, with impressive 4-year PFS from diagnosis (KRd-ASCT: HiR 62%, DH 55%) and 3-year PFS from maintenance (KR: HiR 69%, DH 67%), thus providing an effective option in HiR pts, who still represent an unmet medical need.

We report on a young patient with a bicuspid aortic valve operated on for type A acute aortic dissection because of a blunt thoracic trauma. Aortic root replacement and ascending aortic and total arch repair together with the postoperative course were uneventful. Multigenerational genetic analyses revealed mutations in the NOTCH1 and ACTA2 genes in the patient and his father. The screening of his parents and children revealed no bicuspid aortic valve or aortic root dilation. This exceptionally rare case of double-hit mutations and the presence of blunt trauma reveals the complex etiology of aortic dissection in patients with a bicuspid aortic valve.