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This article discusses the chronic immune-mediated polyneuropathies, a broad category of acquired polyneuropathies that encompasses chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), the most common immune-mediated neuropathy, the CIDP variants, and the vasculitic neuropathies. Polyneuropathies associated with rheumatological diseases and systemic inflammatory diseases, such as sarcoidosis, will also be briefly covered. These patients' history, examination, serum studies, and electrodiagnostic studies, as well as histopathological findings in the case of vasculitis, confirm the diagnosis and differentiate them from the more common length-dependent polyneuropathies. Prompt identification and initiation of treatment is imperative for these chronic immune-mediated polyneuropathies to prevent disability and even death.

Until postnatal day 12, inner hair cells of the rat cochlea are invested with both afferent and efferent synaptic connections. With the onset of hearing at P12, the efferent synapses disappear, and afferent (ribbon) synapses operate with greater efficiency. This change coincides with increased expression of voltage-gated potassium channels, the loss of calcium-dependent electrogenesis, and the onset of graded receptor potentials driven by sound. The transient efferent synapses include near-membrane postsynaptic cisterns thought to regulate calcium influx through the hair cell9s α9α10-nAChR that activates small conductance Ca 2+ -activated K + (SK) channels. Serial section electron microscopy of inner hair cells from two 9-day-old (male) rat pups revealed many postsynaptic efferent cisterns and presynaptic afferent ribbons whose average minimal separation in 5 cells ranged from 1.1 to 1.7 μm. Efferent synaptic function was studied in rat pups (7-9 days of age) of either sex. The duration of these SK channel mediated inhibitory synaptic currents (IPSCs) was increased by enhanced calcium influx through L-type voltage-gated channels, combined with ryanodine-sensitive release from internal stores — presumably the near-membrane postsynaptic cistern. These data support the possibility that inner hair cell calcium electrogenesis modulates the efficacy of efferent inhibition during the maturation of inner hair cell synapses. SIGNIFICANCE STATEMENT Strict calcium buffering is essential for cellular function. This problem is especially acute for compact hair cells where increasing cytoplasmic calcium promotes the opposing functions of closely adjoining afferent and efferent synapses. The near-membrane postsynaptic cistern at efferent synapses segregates synaptic calcium signals by acting as a dynamic calcium store. The hair cell serves as an informative model for synapses with postsynaptic cisterns (‘C-synapses’) found in central neurons.

Introduction: Sickle cell disease (SCD) is the most prevalent inherited hemoglobinopathy in the United States. While the primary event is polymerization of HbS under deoxygenation in red cells, the contribution of white blood cells and inflammation to SCD pathology has been increasingly recognized. Prior investigations of lymphocytes in SCD revealed varied abnormalities some of which have been shown to be corrected by hydroxyruea (HU) though not uniformly (Nickel 2015, Allali 2019). Alterations in lymphocyte subsets have previously been correlated with survival in elderly populations (Ferguson 1995) and with non-AIDS related mortality in HIV (Helleberg 2014). The aim of this study was to analyze alterations of leukocyte populations in relation to different clinical outcomes in a large set of adult patients with sickle cell disease at steady state. Methods: Patients were consented and data was obtained as part of the INSIGHTS study (NCT02156102). Only patients with HBSS/Sβ0 from whom lymphocyte subset panels had been prospectively collected were included in this analysis. Panels consisted of total CD3+ T cells, CD4+/CD8- (CD4+) and CD8+/CD4- (CD8+) T cells, CD19+ B cells and CD16/56+ NK cells; absolute neutrophil count (ANC), white blood cell count (WBC), CD4/CD8 and ANC/ALC (absolute lymphocyte count) ratios were examined as well. Patients were classified as having cardiovascular events (CVE) if they reported prior stroke, pulmonary embolism, deep vein thrombosis, myocardial infarction, arrhythmia, cardiomyopathy, coronary artery bypass or stent. Ulcer status was defined as history of, or current active cutaneous lower extremity ulcer. Also analyzed were self-reported pulmonary hypertension (pHTN), diabetes mellitus (DM), and a combined End Organ Damage Score (EODS) consisting of one point for each of the following clinical outcomes: CVA, Any Ulcer, pHTN, CAD (MI/CABG/stent), cardiomyopathy, PE/DVT, DM. Multivariate analysis was performed controlling for age, gender and active HU use and Spearman correlation coefficients were calculated using SAS software. Results: 170 patients were included in this analysis, 54.7% female, mean age of 38.7 years, 95.3% HbSS, 64.1% on active HU treatment, and 15.9% chronically transfused. Mean leukocyte counts were within reference ranges except for CD19+ cells (666 c/uL) which were double the upper limit of normal (ULN 321 c/uL) consistent with prior reports. The 40% of patients with a CVE history showed an overall decrease in their lymphocyte populations (CD3+, CD4+, CD8+, CD19+) and WBC compared to those without (Table 1). Patients with a pHTN history (15.3%) had lower total CD3+, CD8+, CD19+, ANC's and WBC's. This resulted, somewhat surprisingly, in a significantly lower ANC/ALC ratio than in those patients without pHTN. No significant correlations with organ damage outcomes were noted for CD4/CD8 ratios or NK cells. Similar to the CVE findings, increased EODS was associated with significantly lower total T lymphocytes, CD4+, CD8+, and CD19+ cells while ANC/ALC ratio was significantly increased (Tables 2 & 3). DM is very rare overall in SCD and was in our adult population (2/170) as well (Morrison 1979). It is notable that these 2 patients had significantly lower overall T and B cells and elevated ANC/ALC ratios. Compared to patients without any history of cutaneous ulcer, those with active ulcers had significantly lower total T cells (CD3+) and CD8+ cells (Table 4) while higher total WBC was seen in patients with a history of but no active ulcer compared to those without an ulcer history. Discussion: Our analysis of a large cohort of adult SCD patients at steady state revealed significant alterations in leukocyte populations in relation to a variety of clinical events. The salient finding was that B and T cell lymphocyte populations were significantly decreased in relation to clinical outcomes such as CVE and pHTN. The potential impact of this finding is highlighted by the adverse survival outcomes associated with lymphopenia seen in studies of general adult populations and in those with other medical problems such as cancer (Zidar 2019, Ray-Coquard 2009). While the interpretation of this study is limited to correlations further follow-up and study of SCD immunophenotypes may reveal important prognostic information that could enhance future care strategies. Disclosures Minniti: Bluebird bio: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CLS Bering: Consultancy; Roche: Consultancy, Research Funding; TauTona: Consultancy, Research Funding; Emmaus: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

64 Background: According to recent reports, ~1 in 4 patients with metastatic prostate cancer may harbor alterations in DNA damage repair (DDR) genes. Clinical trial data demonstrates that prostate cancer patients with DDR mutations may respond to poly-ADP ribose polymerase (PARP) inhibitors. Less is known about the mutational profile in minority patients with prostate cancer. We sought to determine the genomic profile of prostate cancer in an ethnically diverse patient population at a single center. Methods: We performed a retrospective review of men with prostate cancer at the Montefiore-Einstein Cancer Center who had next generation sequencing (NGS) with FoundationOne solid tumor testing between 2/2016 - 8/2019. Individual chart review was used to obtain clinical and demographic data including self-reported race/ethnicity. Results: NGS was attempted on archival tissue from 95 patients and results were obtained for 85. Among patients with results, the self-reported race/ethnicity was: Hispanic (H) 37.6%, Non-Hispanic Black (NHB) 52.9%, Non-Hispanic White (NHW) 4.7%, and Other (O) 4.7%. At the time of tissue sampling, 61 patients had metastatic disease and 10 were castration-resistant. 63 samples were from the prostate, 7 from bone, 7 from lymph node, 3 from liver and 5 from other soft tissue sites. The most commonly altered genes included: TP53 (26%), TMPRSS2-ERG fusion (23%), and PTEN (17%). Alterations in the androgen receptor were identified in 5 samples (all with CRPC). 32.8% had alterations in DDR genes including BRCA2 9 (10.6%), ATM 7 (8.2%), ATR 4 (4.7%), BRIP1 2 (2.3%), CDK12 3 (3.5%), FANCA 2 (2.3%), and PALB2 1 (1.2%). Alterations in mismatch repair genes (MSH2, MLH1, MSH6, PMS2) were present in 4 (4.7%) patients (3 of these were MSI-H). In samples where tumor mutational burden (TMB) was reported, 4 (4.7%) were TMB-high (3 MSI-H and 1 with POLE mutation). Conclusions: DDR gene mutations are common in this primarily minority population. As DDR mutations become more common in the CRPC setting, our data may underestimate the frequency of DDR mutations as only 10 patients had CRPC at the time of tissue sampling. Minority men, like all men, with prostate cancer should be considered for genomic analysis as results are likely to guide therapeutic decisions.

Prior studies have evaluated incidence and survival trends for B-Acute Lymphoblastic Leukemia (B-ALL) in children and adults. However, there have been no recent studies evaluating the difference in survival between different race and ethnicities in the era of tyrosine kinase inhibitors and novel combination therapy. We wanted to determine 5-year observed survival for adult patients with B-ALL diagnosed in recent years and assess for any difference in survival by race-ethnicity. Methods: We used Surveillance Epidemiology End Results (SEER) 18 registry to identify B-ALL patients using ICD-O-3 codes 9811-9818 and 9836. SEER 18 covers ~28% of US population. The year of diagnosis was limited to 2010-2016 in order to capture a patient population most likely treated with modern therapies. We limited our study to adults aged 20 years (yrs) or more, which were then divided into the following age groups: 20-29, 30-39, 40-49, 50-59, 60-69,70-79,80+ yrs of age. Gender, race-ethnicity, median family income and observed overall survival (OS) were obtained from SEER. For multivariate survival analysis, Cox proportional hazard model was used to adjust for clinically important and other relevant variables (age, gender, race-ethnicity, median income). We included median family income, a county level characteristic in our analysis as a surrogate for access to care. We divided these counties into quintiles based on median family income and included that variable in the multivariate model. We did not adjust for genetic risk or patient insurance status, as the information provided in SEER was inadequate and would likely lead to misclassification bias. SEER Stat 8.3.5 and SAS student edition were used for analysis. Results: 4244 cases of B-ALL were identified with an age adjusted incidence rate of 0.92 per 100,000. B-ALL occurred at all ages, but incidence was higher in young adults ( Age adjusted incidence was the highest among Hispanics (1.61{1.53-1.71}), followed by Non-Hispanic Whites (NHW)(0.77{0.73-0.8}, Non-Hispanic Asian Pacific Islander (NHAPI)(0.7{0.63-0.78}) and Non-Hispanic Blacks (NHB)(0.54{0.47-0.61}); this difference was statistically significant (p-value About 52% of population died during the study period from any cause. We limited our survival analysis to patients without second malignancy to avoid the confounding effect of another cancer associated mortality. We evaluated OS differences between race-ethnicity in a multivariate model that adjusted for age, sex and income. We found that when compared to NHW, Hispanics (Hazard Ratio (HR) 1.3{1.16-1.46}; p Conclusion: Our study showed a significant survival disparity in adult B-ALL by race and ethnicity in the modern era. This can partly be attributed to differences in access to care as shown in our study. Interestingly, Hispanic and NHB have a significantly worse overall survival compared to NHW and NHAPI even after accounting for income differences, as a surrogate for access to care. This could be due to other unaccounted measure of health disparity, availability of allogeneic transplantation and/or difference in disease biology. Further studies are needed to evaluate such differences, identify barriers to care in minority populations and characterize potential differences in the genetic make-up of B-ALL in the various ethnic/racial groups. Disclosures Sica: Physician's Education Resources (PER): Honoraria. Verma:Stelexis: Equity Ownership, Honoraria; Acceleron: Honoraria; Celgene: Honoraria; BMS: Research Funding; Janssen: Research Funding.

Hearing loss among the elderly correlates with diminished social, mental, and physical health. Age-related cochlear cell death does occur, but growing anatomical evidence suggests that synaptic rearrangements on sensory hair cells also contribute to auditory functional decline. Here we present voltage-clamp recordings from inner hair cells of the C57BL/6J mouse model of age-related hearing loss, which reveal that cholinergic synaptic inputs re-emerge during aging. These efferents are functionally inhibitory, using the same ionic mechanisms as do efferent contacts present transiently before the developmental onset of hearing. The strength of efferent inhibition of inner hair cells increases with hearing threshold elevation. These data indicate that the aged cochlea regains features of the developing cochlea and that efferent inhibition of the primary receptors of the auditory system re-emerges with hearing impairment. SIGNIFICANCE STATEMENT Synaptic changes in the auditory periphery are increasingly recognized as important factors in hearing loss. To date, anatomical work has described the loss of afferent contacts from cochlear hair cells. However, relatively little is known about the efferent innervation of the cochlea during hearing loss. We performed intracellular recordings from mouse inner hair cells across the lifespan and show that efferent innervation of inner hair cells arises in parallel with the loss of afferent contacts and elevated hearing threshold during aging. These efferent neurons inhibit inner hair cells, raising the possibility that they play a role in the progression of age-related hearing loss.

Cochlear inner hair cells (IHCs) are temporarily innervated by efferent cholinergic fibers prior to the onset of hearing. During low-frequency firing, these efferent synapses have a relatively low probability of transmitter release but facilitate strongly with repetitive stimulation. A retrograde signal from the hair cell to the efferent terminal contributes to this facilitation. When IHCs were treated with the ryanodine receptor agonist, cyclic adenosine phosphoribose (cADPR), release probability of the efferent terminal rose. This effect was quantified by computing the quantum content from a train of 100 suprathreshold stimuli to the efferent fibers. Quantum content was sevenfold higher when IHCs were treated with 100 μM cADPR (applied in the recording pipette). Since cADPR is membrane impermeant, this result implies that an extracellular messenger travels from the hair cell to the efferent terminal. cADPR is presumed to generate this messenger by increasing cytoplasmic calcium. Consistent with this presumption, voltage-gated calcium flux into the IHC also caused retrograde facilitation of efferent transmission. Retrograde facilitation was observed in IHCs of a vesicular glutamate transporter (VGlut3) null mouse and for wild-type rat hair cells subject to wide-spectrum glutamate receptor blockade, demonstrating that glutamate was unlikely to be the extracellular messenger. Rather, bath application of nitric oxide (NO) donors caused an increase in potassium-evoked efferent transmitter release while the NO scavenger carboxy-PTIO was able to prevent retrograde facilitation produced by cADPR or IHC depolarization. Thus, hair cell activity can drive retrograde facilitation of efferent input via calcium-dependent production of NO.