Unusual Clinical Features Research Articles

Emergent high fatality lung disease in systemic juvenile arthritis

ObjectiveTo investigate the characteristics and risk factors of a novel parenchymal lung disease (LD), increasingly detected in systemic juvenile idiopathic arthritis (sJIA).MethodsIn a multicentre retrospective study, 61 cases were investigated...

A case report of unusual clinical features of a spontaneous coronary artery rupture: pathologic findings in the rupture site.

BackgroundSpontaneous coronary artery rupture (SCAR) is an extremely rare but life-threatening state. The aetiology and the pathologic findings remain to be fully elucidated.Case summaryA 62-year-old woman, who had been on haemodialysis for 27 years, presented with chest discomfort worsening on deep inspiration that had been ongoing for the past 2 weeks. An echocardiogram and computed tomography showed diffuse pericardial fluid. ST elevation in the broad leads, especially in leads I, II, and aVF, and increased C-reactive peptide and Troponin I levels suggested pericarditis. The patient initially had a stable course with no medications. The chest symptoms disappeared and her vital signs were stable. On Day 13 after admission, however, she had a sudden cardiopulmonary arrest due to a cardiac tamponade. An emergency coronary angiography showed extravasation of the contrast into the epicardium from the branch of the circumflex artery. She was diagnosed with SCAR and underwent a successful coil embolization. However, she went into an irreversible coma due to the cerebral hypoxia. On Day 33, she died of pneumonia. An autopsy showed a rupture of the internal elastic layer of the coronary artery. However, no specific findings, such as aneurysm and dissection, were evident. The common atherosclerotic changes were observed.DiscussionThe stable condition lasting for over 2 weeks was a rare clinical course for SCAR. Long-term hypertension and dialysis would have caused the rupture of the coronary artery with common atherosclerotic changes. We should consider SCAR as one of the differential diagnoses when we observe pericardial fluid.

Clinicopathologic correlations in a family with a TBK1 mutation presenting as primary progressive aphasia and primary lateral sclerosis

Mutations in the TANK binding kinase 1 gene (TBK1) are associated with amyotrophic lateral sclerosis and/or frontotemporal dementia; however, the range of clinical phenotypes and neuropathological changes associated with these mutations have not yet been completely elucidated. We present the detailed clinical, neuroimaging, and neuropathological features of two brothers carrying the TBK1 p.Gly272_Thr331del mutation. Both presented with very similar and unusual clinical features including primary progressive aphasia and asymmetric-onset primary lateral sclerosis (PLS). Repeated electrophysiological studies failed to reveal any lower motor neuron involvement. Neuropathological evaluation of both cases revealed frontotemporal lobar degeneration with TDP-43 proteinopathy type B and selective involvement of upper motor neurons with TDP-43 inclusions. The stereotypical clinical presentation and neuropathological findings in these cases widen the phenotypic spectrum of TBK1 mutations and provide insights into the pathogenesis of PLS.

Infarto bitalámico por trombosis venosa cerebral profunda hallazgos clínicos y radiológicos

La enfermedad cerebrovascular es un problema de salud pública mundial, considerada dentro de las primeras causas de mortalidad. La trombosis venosa cerebral (TVC) es una de sus patologías, que a pesar de ser infrecuente puede llevar a severas complicaciones en el paciente. Es por eso que se presentan dos casos de infartos bitalámicos secundarios a trombosis venosa cerebral profunda, con hallazgos clínicos e imagenológicos inusuales que hicieron aún más difícil su diagnóstico. Debido a las diferentes funciones que posee el tálamo además de la infrecuencia de la trombosis venosa cerebral profunda, la presentación clínica sigue siendo atípica y es usual que se consideren otros diagnósticos al inicio del evento, por lo tanto, consideramos importante proyectar estudios con muestras de mayor tamaño para definir con claridad la clínica y los hallazgos radiológicos de esta patología.

A novel SLC12A1 mutation in Bedouin kindred with antenatal Bartter syndrome type I.

Four affected individuals of consanguineous kindred presented at infancy with an apparently autosomal recessive syndrome of polyuria and hypokalemic metabolic alkalosis, following maternal polyhydramnios and premature delivery, culminating in severe failure to thrive. Hypercalciuria, nephrocalcinosis, and hyperaldosteronism were further apparent as well as an unusual finding of intermittent hypernatremia. Additionally, all patients demonstrated variable micrognathia with upper respiratory airway abnormalities. As neither postnatal hyperkalemia nor permanent hearing deficits were shown, clinical assessment was consistent with antenatal Bartter syndrome (ABS) type I, which was never described before in the Israeli Bedouin population. Through genome-wide linkage analysis, we identified a single ∼3.3Mbp disease-associated locus on chromosome 15q21.1, segregating within the pedigree. Whole-exome sequencing revealed a single novel homozygous missense mutation within this locus, in SLC12A1, encoding the Na-K-Cl cotransporter, NKCC2, in accordance with the clinical diagnosis. In this concise study, we report a novel missense mutation within the SLC12A1 gene, causing a severe form of ABS type I, the first to be described in Israeli Bedouins, with unusual clinical features of hypernatremia caused by nephrogenic diabetes insipidus and putatively related micrognathia with upper airway abnormalities .

Phenotypic plasticity of metastatic melanoma

Introduction. Metastatic melanoma is characterized by clinical and morphological heterogeneity and plasticity. Rare cases of metastatic melanoma are known, that have no visual expression of melanocytic markers. Contradictory histology of such melanomas requires a differential diagnosis from morphologically similar non- melanocytic tumors, sarcoma or lymphoma. objective is to describe the extraordinary cases of metastatic melanomas with low expression of differentiation markers. material and methods. 15 melanoma cases with unusual clinical and morphological characteristics were included in the study. These tumors were examined by pathologist and cytologist, by immunohistochemical and FISH analyses, mutations in BRAF, NRAS and KIT genes were detected by PCR. results. Some primary tumors were amelanotic, therefore, they were difficult for differential tumor diagnosis. Most frequently, primary tumors were located on the back, shin or head. In 4 patients the primary focuses were not detected. Metastatic lesions were as large nodular tumors in soft tissues of the back or lower limb. Most tumors belong to mixed or spindle-cell histological types. Spindle-shaped cells were also revealed by cytological analysis. BRAF gene mutations were identified by genetic analysis in 27 % of tumors, NRAS and KIT gene mutations were not detected. In 4 cases FISH analysis was performed to detect EWSR1 gene rearrangements, but it did not confirm the diagnosis of sarcoma. conclusion. The results indicate the presence of a heterogeneous group of melanoma cases, which have a number of morphological and molecular features that bring them closer to sarcomas.

440. The Masqueraders Presenting a Multisystem Disease: Unusual and Atypical Clinical Features of Scrub Typhus in Fukushima, Japan

BackgroundScrub typhus (ST) is endemic in Fukushima, where the highest number has been reported from 2006 to 2011 in Japan. Atypical clinical presentation of ST makes the diagnosis difficult followed by treatment delay. Despite fatal but treatable disease with early recognition, the myriad clinical features of ST have been underreported.MethodsWe reviewed the clinical features of adult patients diagnosed as ST from 2008 to 2017 at Ohta Nishinouchi General Hospital, a major teaching hospital in Fukushima, Japan.ResultsTotal 55 cases (serotype Karp 24, Irie/Kawasaki 21, Hirano/Kuroki 10) of ST were confirmed by elevated specific IgM and IgG in the paired sera and real-time PCR analysis of eschars. Unusual presentations as the main clinical features of ST are found in 7/55 (13%; Karp 4 and Irie/Kawasaki 3), including cardiovascular (3 cases of paroxysmal atrial fibrillation), neurological (2 cases of syncope and one case of encephalitis) and metabolic/electrolyte disorder (one case of hyponatremia). In terms of atypical clinical features, the cases without triad (fever ≥38.0℃, rash and eschar) were found in 14/55 (25%). The cases of “eschar negative scrub typhus” were found in 6/55 (11%; Karp 1, Irie/Kawasaki 2, Hirano/Kuroki 3). The cases without fever and rash were also found in 6/55 (11%; Karp 2, Irie/Kawasaki 3, Hirano/Kuroki 1) and 4/55 (7%; Karp 2, Irie/Kawasaki 1, Hirano/Kuroki 1), respectively. Severe cases (4/55, 7%) were found with shock and disseminated intravascular coagulation including one fatal case (1/55, 1.8%; Hirano/Kuroki). Besides more than the half of ST cases with triad (30/55; 55%), unusual and atypical presentations were found in 38% (21/55) of the total number of cases.ConclusionThe diagnosis of ST is a clinical challenge without typical features. In endemic area, unusual and atypical presentation of ST involving multi-system should be noted as the odds-on favorite differential diagnosis.Disclosures All authors: No reported disclosures.

Usefulness of complementary next-generation sequencing and quantitative immunohistochemistry panels for predicting brain metastases and selecting treatment outcomes of non–small cell lung cancer

To demonstrate the usefulness of complementary next-generation sequencing (NGS) and immunohistochemistry (IHC) counting, we analyzed 196 patients with non-small cell lung cancer who underwent surgical resection and adjuvant chemotherapy. Formalin-fixed, paraffin-embedded samples of adenocarcinoma (ADC), squamous cell carcinoma, and large cell carcinoma were used to prepare tissue microarrays and were examined by protein H-score IHC image analysis and NGS for oncogenes and proto-oncogenes and genes of tumor suppressors, immune checkpoints, epithelial-mesenchymal transition factors, tyrosine kinase receptors, and vascular endothelial growth factors. In patients with brain metastases, primary tumors expressed lower PIK3CA protein levels. Overexpression of p53 and a higher PD-L1 protein H-score were detected in patients who underwent surgical treatment followed by chemotherapy as compared with those who underwent only surgical treatment The absence of brain metastases was associated with wild-type sequences of genes EGFR, CD267, CTLA-4, and ZEB1. The combination of protein overexpression according to IHC and mutation according to NGS was rare (ie, represented by a very low percentage of concordant cases), except for p53 and vascular endothelial growth factor. Our data suggest that protein levels detected by IHC may be a useful complementary tool when mutations are not detected by NGS and also support the idea to expand this approach beyond ADC to include squamous cell carcinoma and even large cell carcinoma, particularly for patients with unusual clinical characteristics. Conversely, well-pronounced immunogenotypic features seemed to predict the clinical outcome after univariate and multivariate analyses. Patients with a solid ADC subtype and mutated genes EGFR, CTLA4, PDCD1LG2, or ZEB1 complemented with PD-L1 or p53 protein lower expression that only underwent surgical treatment who develop brain metastases may have the worst prognosis.

Adams-Oliver syndrome: A case report of unusual clinical features with unique genetic presentation

Adams-Oliver syndrome: A case report of unusual clinical features with unique genetic presentation

Parathyroid immunohistochemistry in a 12-year-old mixed-breed dog with parathyroid adenocarcinoma

SummaryA 12-year-old, female, spayed, mixed-breed dog with acute lethargy, anorexia and weakness and markedly elevated total and ionised calcium concentration showed an enlarged left cranial parathyroid gland on ultrasonography of...

Vegetating erosive cutaneous lesions and pyogenic granuloma in the course of mucous membrane pemphigoid: a case report and review of literature

Mucous membrane pemphigoid (MMP) is a group of chronic autoimmune sub-epithelial blistering disorders, which mostly affect the oral mucosa and the conjunctiva. MMP is very diverse in terms of both the clinical and immunological features (IgG and IgA autoantibodies may react with different antigens). MMP can be induced by infections and medication, including ophthalmologic medication, which may lead to the development of eye lesions. In contrast, a vegetating variant of MMP is extremely rare. Here, we report an MMP case that demonstrated unusual clinical features, that is, pyogenic granulomas on the conjunctivae and extensive vegetating erosions on the skin of intertriginous regions. All these lesions were considered to be induced by unconventional medication containing arsenic.

Analysis of chikungunya outbreak of 2016 in Rajasthan: a clinico-epidemiological study

Background: To describe the diversity of clinical manifestations, laboratory findings and outcome of chikungunya fever in patients attending SMS Hospital, Jaipur during the epidemic of 2016 (September to November).Methods: All cases of febrile illness with polyarthralgia/polyarthritis diagnosed as chikungunya were analyzed. Diagnosis was made by ELISA based IgM serology and RT PCR assay.Results: A total of 200 cases were studied. All of them presented with fever, severe crippling joint pain & tenderness, headache, anorexia and body rash. On examination, there was periarticular edema, erythema, and tenderness in joints with post auricular and cervical lymphadenopathy. Unusual manifestations were hyper pigmentation of face and forehead and scrotal ulcers. On investigations patient had leucopenia with elevated level of SGOT, SGPT with normal bilirubin levels. Other complications observed were encephalopathy, encephalitis, myocarditis and hepatitis. There was no mortality in this group.Conclusions: Chikungunya though prevalent is under-reported. The diagnostic certainty is mandated by presence of febrile transiently crippling polyarthragias / arthritis. On analyzing a large series, unusual clinical features may emerge.

Idiopathic renal replacement lipomatosis: A diagnostic and therapeutic challenge.

Renal replacement lipomatosis is a rare benign renal disorder where the renal parenchyma is replaced by mature fatty tissue. It poses a diagnostic challenge to the clinicians due to an unusual presentation and clinical features. The disease usually presents in middle age with vague pain in the affected flank and variable urological symptoms. Although the condition is preceded by calculus disease or chronic inflammation, as an extremely rare occurrence, it can occur without any pre-existing condition, as in our case. Increasing awareness among the surgeons about the existence of such a condition will help the surgical fraternity to diagnose and manage such cases properly.

Asthma Mimickers: Approach to Differential Diagnosis.

The airway of a child can be easily obstructed because of its small size and there are myriad conditions that may obstruct it. Though asthma is the most common condition causing reversible obstruction of the airway; there are a large number of conditions which can obstruct the airway both reversibly and irreversibly. These asthma mimics can present as clinical problems from the neonatal period through adolescence. This article presents an overview of the clinical situations that must be kept in mind when the child presents with subtly unusual clinical features or a deviant course. This is followed by a brief description of the common mimickers along with clinical clues to their diagnosis. Clinicians will need a high index of suspicion for diagnosing these conditions. Prompt recognition and optimal case management and referral will ensure the best outcomes in these children.

Homozygous GRID2 missense mutation predicts a shift in the D-serine binding domain of GluD2 in a case with generalized brain atrophy and unusual clinical features

BackgroundSpinocerebellar ataxias comprise a large and heterogeneous group of disorders that may present with isolated ataxia, or ataxia in combination with other neurologic or non-neurologic symptoms. Monoallelic or biallelic GRID2 mutations were recently reported in rare cases with cerebellar syndrome and variable degree of ataxia, ocular symptoms, hypotonia and developmental delay.Case presentationWe report on a consanguineous family with autosomal recessive childhood onset of slowly progressive cerebellar ataxia and delayed psychomotor development in three siblings. MRI of an adult and affected family member revealed slightly widened cerebral and cerebellar sulci, suggesting generalized brain atrophy, and mild cerebellar atrophy. Using whole exome sequencing we identified a novel homozygous missense variant [c.2128C > T, p.(Arg710Trp)] in GRID2 that segregates with the disease. The missense variant is located in a conserved region encoding the extracellular serine-binding domain of the GluD2 protein and predicts a change in conformation of the protein.ConclusionThe widespread supratentorial brain abnormalities, absence of oculomotor symptoms, increased peripheral muscle tone and the novel missense mutation add to the clinical and genetic variability in GRID2 associated cerebellar syndrome. The neuroradiological findings in our family indicate a generalized neurodegenerative process to be taken into account in other families segregating complex clinical features and GRID2 mutations.

Severe episodic memory impairment after strategic infarct: A case report

ABSTRACT.Brain infarcts located in strategic regions often result in cognitive impairment. Based on a case study, this paper describes unusual and specific clinical and neuropsychological features of a strategic ischemic lesion in the left medial temporal lobe (MTL) structures. Taken together with the literature data, the case illustrates that a unilateral strategic infarct in MTL structures may result in severe impairment of episodic memory (EM), which refers to the ability to encode and retrieve personal experiences, including information about the time and place of an event and detailed description of the event itself. The preservation of other cognitive functions, the severe functional impairment, and the type of visual-verbal deficit in a left-sided lesion were identified as singular features of the case. The current case supports the critical role of the MTL structures in EM formation.

Upregulated miR-9-3p Promotes Cell Growth and Inhibits Apoptosis in Medullary Thyroid Carcinoma by Targeting BLCAP.

Medullary thyroid carcinoma (MTC) is a neuroendocrine cancer derived from parafollicular C cells in the thyroid gland. It has great interest as a research focus because of its unusual genetic, clinical, and prognostic characteristics. However, the pathogenesis in MTC is not completely clear. We investigated the role of miR-9-3p and bladder cancer-associated protein (BLCAP) in MTC TT cells. First, miR-9-3p expression was upregulated in human MTC tissues and TT cells and compared to the control by RT-PCR. Flow cytometric analysis indicated that the cell cycle progression in TT cells was significantly inhibited by the miR-9-3p inhibitor but was increased by the miR-9-3p mimic. On the contrary, the apoptosis of TT cells was significantly increased by the miR-9-3p inhibitor and suppressed by the miR-9-3p mimic. A similar change pattern was observed in the expression of apoptosis-regulated protein caspase 3 induced by the miR-9-3p mimic or inhibitor in TT cells. We then identified that BLCAP is a target of miR-9-3p by bioinformatic prediction and luciferase reporter assay. The expression of BLCAP was also significantly downregulated by the miR-9-3p mimic while being upregulated by the miR-9-3p inhibitor in TT cells. Furthermore, we confirmed that the inhibited apoptosis of TT cells induced by the miR-9-3p mimic was enhanced by BLCAP overexpression. The levels of apoptosis were strongly decreased by BLCAP silencing in TT cells, which were not further influenced by the miR-9-3p inhibitor. In summary, upregulated miR-9-3p has a positive role in human MTC progression by regulating the growth and apoptosis of cancer cells via targeting BLCAP. This might represent a possible diagnosis or therapeutic target for MTC.

The clinicopathologic spectrum of mature aggressive B cell lymphomas.

Our understanding of mature aggressive B cell lymphomas has evolved significantly in the last years as reflected in the 2016 update of the WHO lymphoma classification. A main topic of the 2016 European Association for Haematopathology/Society of Hematopathology lymphoma workshop in Basel therefore was the clinicopathological spectrum of mature aggressive B cell lymphomas with the exception of conventional diffuse large B cell lymphoma. In this review, we summarize two sessions dedicated to "high-grade B cell lymphomas, with MYC and BCL2 and/or BCL6 rearrangements (so-called double/triple-hit lymphomas)" and "high-grade B cell lymphomas, NOS" as defined in the 2016 update of the WHO lymphoma classification, Burkitt lymphoma and related neoplasms, and terminally differentiated aggressive B cell lymphomas. One focus was on cases of Burkitt lymphoma with unusual clinical features such as spontaneous regression or association with immunosuppression, and the new provisional category of Burkitt-like lymphoma with 11q aberration. The large numbers of cases submitted for the new high-grade categories with or without genetic "double/triple hit" demonstrated the broad clinical and pathological spectrum of this group and gave ample opportunity for discussion. In this review, current definitions and our understanding of the main high-grade categories, potential problem areas, and suggestions for the immunophenotypic and genetic work-up of these neoplasms are discussed and illustrated by many interesting and challenging cases submitted to the workshop.

Animal Models of Zika Virus Infection, Pathogenesis, and Immunity.

Zika virus (ZIKV) is an emerging mosquito-transmitted flavivirus that now causes epidemics affecting millions of people on multiple continents. The virus has received global attention because of some of its unusual epidemiological and clinical features, including persistent infection in the male reproductive tract and sexual transmission, an ability to cross the placenta during pregnancy and infect the developing fetus to cause congenital malformations, and its association with Guillain-Barré syndrome in adults. This past year has witnessed an intensive effort by the global scientific community to understand the biology of ZIKV and to develop pathogenesis models for the rapid testing of possible countermeasures. Here, we review the recent advances in and utility and limitations of newly developed mouse and nonhuman primate models of ZIKV infection and pathogenesis.

Outcome of Very Young (≤ 40 Years) Patients with Immunoglobulin Light Chain Amyloidosis (AL): A Case Control Study

BACKGROUND Light-chain amyloidosis (AL) is the most common form of systemic amyloidosis, with an incidence of approximately 1 case/100,000 person-years. Clinically relevant data with regard to the very young (≤ 40 years) patients (pts) are scant. We present a case-control study of very young pts with AL seen at a single institution. METHODS We reviewed the medical records of all pts with AL who were consecutively evaluated at Mayo Clinic, Rochester, MN between 01/01/1995 and 12/31/2015. The clinical characteristics and survival outcomes of very young pts at the time of AL diagnosis (cases) were compared to a 2:1 matched cohort of pts (controls) with AL who were 65 years or older and matched by the time of diagnosis. Upfront autologous stem cell transplantation (ASCT) was defined as transplantation within 6 months of the diagnosis of AL. The Kaplan-Meier method was used to all time-to-event analyses. The average years of life lost was computed by subtracting the mean survival from diagnosis observed in the cohort from the mean survival expected in the population based on life-tables. RESULTS Of 3433 pts with AL, 50 (1.5%) pts were ≤ 40 years of age at diagnosis (cases). Fatigue, peripheral edema, dyspnea and bleeding were less common at presentation in cases compared to controls (table A). The cases were also more likely to have liver or GI involvement (OR= 3.45, 95% CI: 1.6-7.2). Unusual initial clinical features in the cases included unprovoked splenic rupture (2%) and erectile dysfunction (4%) observed 6-15 months prior to the diagnosis of AL in cases; no such features were observed in the control group. The median time between the onset of symptoms and definitive diagnosis was 0.4 years (95% CI: 0.3-0.7) for the cases and 1 year (95% CI: 0.8-1.2) for controls (p 10% BMPCs without active myeloma (AL-PCMM) (p=0.16). Monoclonal light chain involvement without involvement of heavy chain was seen in 23 cases (50%) and 31 controls (32%), (OR= 2.1, 95% CI: 1.04-4.37). The median follow-up was similar for cases and controls, [10.9 years (95% CI: 7.6-12) vs 9.9 years (95% CI 8-14)], respectively. The estimated average years-of-life lost was 8.6 years over 20 years of follow-up in cases, (Figure 1a). In cases, 1 and 10-year overall survival (OS) from diagnosis was 73% and 51%, respectively (median OS 12.7 years; 95% CI: 4.0-NR) while, in controls, 1 year and 10 year OS was 62% and 15% respectively (median OS 2.1 years; 95% CI (1.0-3.6), p<0.001), (Figure 1b). Cardiac involvement was associated with a worse OS in both cohorts, (cases: median OS was 3.2 years with cardiac involvement (95% CI: 0.6-8.7) vs NR (95% CI: 8.0-NR) in those without; p=0.003; controls: median OS was 1.1 years with cardiac involvement (95% CI: 0.53-1.6) vs 4.8 years (95% CI: 3.7-8.1) in those without; p=0.02. Thirty one of 47 (66%) cases were eligible and 20 of 79 (25%) controls were eligible for upfront ASCT. In cases, upfront ASCT was associated with a longer OS. Median OS was NR (95% CI: NR-NR) in pts who underwent upfront ASCT (n=25) vs 4.0 years (95% CI: 0.5-8) in pts who did not, p≤0.0001. For controls, the median OS was 9 years (95% CI: 0.5-11) for pts who underwent upfront ASCT (n=7) vs 1.6 years (95% CI: 1.0-2.8) for pts who did not (n=93), p=0.26. In cases, six (12%) pts underwent solid organ transplantation (kidney 5, heart 1) and none in the control arm. CONCLUSIONS AL amyloidosis is infrequently encountered at the age of ≤40 years, but the loss of productive years of life and the disease burden are substantial in this cohort. A substantial delay in diagnosis from the onset of symptoms was noted in our study in the control population. Cardiac involvement remains a primary determinant of prognosis irrespective to age. Although over one-half of young pts are alive 10 years after the diagnosis (contrast ≈15% ≥ 65 years), early mortality remains substantial irrespective of age. An ASCT-based approach is associated with superior outcome in the young. A greater proportion of the young pts is fitter and ASCT-eligible at diagnosis, and should therefore be offered this approach. ![Figure][1] ![Figure][1] ![Figure][1] Disclosures Dispenzieri: Jannsen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; pfizer: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding. Kumar: Array BioPharma: Consultancy, Research Funding; Kesios: Consultancy; Onyx: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; AbbVie: Research Funding; Glycomimetics: Consultancy; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; BMS: Consultancy; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kapoor: Amgen: Research Funding; Takeda: Research Funding; Celgene: Research Funding. [1]: pending:yes