Introduction Hepatitis B virus (HBV) infection remains a global public health threat, with approximately 257 million people suffering from chronic HBV infection worldwide in 2015. HBV reactivation is a known complication of immunosuppressive therapy in people suffering with chronic HBV. Medications commonly associated with HBV reactivation include B-cell depleting agents and anthracycline derivatives. There have been very few documented cases of chemoradiation inducing HBV reactivation among scientific literature. Case report A 44-year-old woman with chronic HBV infection and [FIGO] stage IIIB cervical cancer developed marked transaminitis and increased HBV viral load after receiving treatment with three doses of cisplatin and one dose of carboplatin with concurrent radiation for cervical cancer. Management and outcome: The patient was admitted for acute liver failure and quickly developed encephalopathy, with treatment complicated by coagulopathy, hypoglycemia, and metabolic acidosis. The patient remained unresponsive to maximal therapeutic efforts and was mechanically ventilated for airway protection. She subsequently died after experiencing ventricular tachycardia followed by asystole. Discussion There are currently no standardized guidelines for the screening of HBV infection or prophylaxis treatment algorithm for patients undergoing chemoradiation. When initiating treatment with immunosuppressive therapy, it is important to screen all patients for chronic HBV infection and to work with an interdisciplinary team of oncologists, hepatologists, and pharmacists to initiate prophylactic antiviral therapy and closely monitor to minimize the risk of HBV reactivation.

Key Clinical MessageWe present a case of isolated congenital hyposplenism that was discovered after the peripheral smear revealed Howell-Jolly bodies. This case serves as the basis for a review of hyposplenism for the general practitioner.

One of the most prominent features of multiple myeloma (MM) has been immune deficiency which predisposes patients to infectious complications and suppresses development of anti-MM immune responses. We and others have previously described the T cell dysfunction in Th1, Treg and Th17 cells, plasmacytoid dendritic cells and myeloid-derived suppressor cells (MDSC). However, the most fundamental and long identified deficiency is in the humoral immune response. Suppression of uninvolved immunoglobulins (UIgs) have been well described (i.e. suppression of serum IgA and IgM in IgG myeloma); and antibody responses to vaccination have been inadequate. However, very limited information is available regarding B cell function and how UIgs are suppressed in myeloma. We have now evaluated six different B cell subsets (B1a, B1b, B2, Breg, IRA-B, and MZ) in peripheral blood (PBMC) and bone marrow (BM) to understand alterations in B cell immune function in MM. We have observed significantly lower ratio of B2 (normal B cell-subset) and B1a (natural antibody-producing cells) subsets (10±4 vs 57±17; p < 0.05) and B2 and Breg (regulatory B cell-subset) subsets (14±4 vs 45±13; p< 0.05) in PBMC from MM patients (N=19) compared with healthy donor (N=33) respectively. Similar results were observed in BM samples from MM patients (N=18) compared with healthy donors (N=12); B2/B1a subset (2.4±0.6 vs 8±1.3; p < 0.05) and B2/Breg subset (8±1.4 vs 43.7±8.4; p< 0.05) respectively. To understand whether MM cells directly or indirectly alter B cell-subsets, we incubated myeloma cells (N=4) with healthy donor PBMCs, and analyzed B cell subsets after 3 days. We observed significant elevation in B1 subset (2.5 fold of control) and reduced B2 subset (89±3% of control). When we incubated PBMCs with IL-17A over-expressing MM cells (N=3), we observed further significant reduction in B2 subset (74% of control). When normal PBMCs are cultured in IL-17A (N=4) we observed significantly increased IL-10-producing Breg subset (28% of control). Similarly, co-culture of healthy B cells with MDSC led to significant increase (3.8 times) in Breg cell- population (N=3) compared with control group. To study the impact of B cell dysfunction on T cell function in MM, we activated normal PBMC via anti-CD3 antibody, in the presence or absence of B cells, and measured intra-cellular IFN-γ levels in CD69+ cells. We observed that the absence of B cells significantly inhibited interferon-producing T cells compared to control (by 43%; p<0.05). Importantly, following removal of CD25+ cells (Tregs and activated memory T cells), with or without B cells, we did not observe any difference in the inhibition of IFN-γ, indicating that B cells influence memory T cells rather than naïve T cells for the production of IFN-γ. To evaluate impact of lenalidomide on this interaction, we stimulated purified normal donor CD45RO memory T cells with Th1 polarizing cocktail in the presence or absence of purified normal B cells or B cells from MM patient (MM-B) in presence of lenalidomide and observed thatlenalidomide significantly improved MM-B cell-mediated IFN-γ-producing Th1 responses (by 32%, p<0.05) compared to normal B cell-mediated Th1 responses. In an effort to evaluate whether any therapy may improve the B cell function, we cultured normal PBMCs in the presence of lenalidomide (N=9) and observed reduction in Breg subset by 40% of control. To evaluate the effect of therapy on B cell-subsets in MM, we analyzed B cell subsets in PBMC from newly-diagnosed and lenalidomide-treated MM patients and observed that lenalidomide-treated group showed significant (p<0.05) improvement in B cell subsets (increased B2 and lower B1 cells) even before clinical response. These results suggest that immunomodulatory agents may be able to re-program humoral immunity in these patients. In summary, we report that the myeloma cell driven skewed B cell subset distribution with consequent B cell dysfunction drives the observed abnormalities in humoral/cell mediated immunity. The current therapeutic interventions, besides providing deep clinical responses, may also improve B cell function with impact on long term outcome. Disclosures No relevant conflicts of interest to declare.

We have previously demonstrated that Th17 cells, which produce IL-17A, are significantly elevated in peripheral blood and bone marrow (BM) of patients with Multiple Myeloma (MM) and IL-17A promotes MM cell growth and survival, both in vitro and in vivo via IL-17A receptor. We have recently evaluated and observed that anti-IL-17A monoclonal antibody (mAb) significantly inhibited MM cell growth in vitro, while IL-17A induced proliferation of MM cells compared to control. We have also observed significant down-regulation of IL-6 production by anti-IL-17A mAb in MM-BMSC co-culture. Importantly, the administration of anti-IL-17A mAb weekly for 4 weeks in the SCIDhu model of human myeloma, where MM cells grow within the human microenvironment in mice led to a significant inhibition of tumor growth compared to the control mice. This remarkable activity of anti-IL17 mAb raised the question of whether the myeloma cells themselves are a possible source of IL-17. In this study, we used transcriptome sequencing (RNA-Seq) data to evaluate the expression of IL-17A in primary CD138+ myeloma cells (N=17) compared to normal plasma cells (NPC) (N=5). Whereas none of the NPCs expressed IL-17A, it was significantly over-expressed in majority of MM cells. In addition, these data also showed that the expression of other IL-17 family members (IL-7B, C, D, E & F) and Th17-associated pro-inflammatory cytokines (IL-21, IL-22 & IL-23) were not significantly elevated in primary myeloma cells compared to normal donor plasma cells. We further validated these observations by IL-17 immunoblot showing IL17 expression in all MM cell lines and 10 out of 14 primary patient MM cells; confirmed IL-17 expression in MM cells by quantitative RT-PCR, and flow cytometry and by immuno-histochemistry and confocal microscopy. We observed that IL-17 knock down by IL-17-specific siRNA inhibited MM cell growth as well as their ability to induce IL-6 production in co-cultures with BMSC. Finally, expression profile data from 172 uniformly treated patients showed that patients with lower IL-17A expression had superior overall survival compared to those with higher expression. These data confirms that MM cells express IL-17 and targeting it with a mAb will abrogate the autocrine loop making it an attractive therapeutic target. Disclosures: No relevant conflicts of interest to declare.