Argatroban provides effective alternative anticoagulation in patients with or at risk for HIT during RRT. Argatroban clearance by high-flux membranes during hemodialysis and CVVH is clinically insignificant, necessitating no dose adjustment.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of cytokine-driven immune activation. Cardinal features include fever, hemophagocytosis, hepatosplenomegaly, lymphocytic infiltration, and hypercytokinemia that result in multisystem organ dysfunction and failure. Familial HLH is genetically driven, whereas secondary HLH (SHL) is caused by drugs, autoimmune disease, infection, or cancer. SHL is associated with worse outcomes, with a median overall survival typically of less than 1 year. This reflects difficulty in both diagnostic accuracy and in establishing reliable treatments, especially in cases of malignancyinduced SHL, which have significantly worse outcomes. Malignancy-induced HLH is seen almost exclusively with hematologic malignancies, constituting 97% of cases in the literature over the past 2 years. In these situations, the native immune response driven by CD8 T cells produces an overabundance of T helper 1 cytokines, notably interferon-g, tumor necrosis factor-a, and interleukin-6, which establish a positive feedback loop of inflammation, enhancing replication of hematologic malignancies while leaving the host immune system in disarray. In this paper, we present 2 case studies of secondary HLH driven by HM, followed by a review of the literature discussing the cytokines driving HLH, diagnostic criteria, and current treatments used or undergoing investigation. Case 1A previously healthy 34-year-old male presented with progressive malaise, fevers, and abdominal discomfort. He was found to have massive splenomegaly along with pancytopenia and coagulopathy. Initial laboratory studies showed lactate dehydrogenase (LDH) 470 U/L, ferritin 4450 ng/dL, white blood cell count 1.3 3 10 9 /L, platelets 31 3 10 9 /L, hematocrit 22%, and fibrinogen level 130 mg/dL. A bone marrow (BM) biopsy was performed and showed lymphohistiocytic aggregation without hemophagocytosis. The patient underwent splenectomy; pathology showed splenic red pulp congestion and proliferation of sheets of normal histiocytes with marked erythrophagocytosis. No conclusive evidence of B-or T-cell lymphoma was found at that time, although features suggestive of but not diagnostic for T-cell rich diffuse large B-cell lymphoma (DLBCL) were seen in the spleen. The patient subsequently had a positron emission tomography/computed tomography scan and was found to have small hyperactive para-aortic lymph nodes that were not accessible for biopsy. The patient began therapy for HLH with dexamethasone and etoposide for 6 cycles and tolerated it well, with resolution of his laboratory abnormalities and symptoms.A year and a half after initial diagnosis, he presented to the hospital again with back pain and fevers. A computed tomography scan showed multiple retroperitoneal and periaortic lymph nodes along with liver lesions. He was started on dexamethasone and admitted to the hospital. Multiple lymph node biopsies were performed and were inconclusive, possibly from steroid pretreatment. Further evaluation with bilateral BM biopsies reported T-cell rich ...

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The biodistribution of AAVHSC7, AAVHSC15, and AAVHSC17 following systemic delivery was assessed in cynomolgus macaques (Macaca fascicularis). Animals received a single intravenous (IV) injection of a self-complementary AAVHSC-enhanced green fluorescent protein (eGFP) vector and tissues were harvested at two weeks post-dose for anti-eGFP immunohistochemistry and vector genome analyses. IV delivery of AAVHSC vectors produced widespread distribution of eGFP staining in glial cells throughout the central nervous system, with the highest levels seen in the pons and lateral geniculate nuclei (LGN). eGFP-positive neurons were also observed throughout the central and peripheral nervous systems for all three AAVHSC vectors including brain, spinal cord, and dorsal root ganglia (DRG) with staining evident in neuronal cell bodies, axons and dendritic arborizations. Co-labeling of sections from brain, spinal cord, and DRG with anti-eGFP antibodies and cell-specific markers confirmed eGFP-staining in neurons and glia, including protoplasmic and fibrous astrocytes and oligodendrocytes. For all capsids tested, 50 to 70% of glial cells (S100-β+) and on average 8% of neurons (NeuroTrace+) in the LGN were positive for eGFP expression. In the DRG, 45 to 62% of neurons and 8 to 12% of satellite cells were eGFP-positive for the capsids tested. eGFP staining was also observed in peripheral tissues with abundant staining in hepatocytes, skeletal- and cardio-myocytes and in acinar cells of the pancreas. Biodistribution of AAVHSC vector genomes in the central and peripheral organs generally correlated with eGFP staining and were highest in the liver for all AAVHSC vectors tested. These data demonstrate that AAVHSCs have broad tissue tropism and cross the blood-nerve and blood-brain-barriers following systemic delivery in nonhuman primates, making them suitable gene editing or gene transfer vectors for therapeutic application in human genetic diseases.

Background It is currently unknown whether 6 months of supervised treadmill exercise has a durable benefit on 6‐minute walk performance, even after exercise is completed, in people with peripheral artery disease. Methods and Results A total of 156 participants with peripheral artery disease were randomized to 1 of 3 groups: supervised treadmill exercise, supervised resistance training, or attention control. Participants received supervised sessions during months 1 to 6 and telephone contact during months 6 to 12. Primary outcomes were change in 6‐minute walk distance and short physical performance battery at 6‐month follow‐up and have been reported previously. Secondary outcomes were change in 6‐minute walk and short physical performance battery at 12‐month follow‐up and are reported here. A group of 134 participants (86%) completed the 12‐month follow‐up. At 6‐month follow‐up, compared with control, 6‐minute walk distance improved in the treadmill exercise group (+36.1 m, 95% CI =13.9‐58.3, P =0.001). Between 6‐ and 12‐month follow‐up, 6‐minute walk distance significantly declined (−28.6 m, 95% CI=−52.6 to −4.5, P =0.020) and physical activity declined −272 activity units (95% CI =−546 to +2, P =0.052) in the treadmill exercise group compared with controls. At 12‐month follow‐up, 6 months after completing supervised treadmill exercise, change in 6‐minute walk distance was not different between the treadmill exercise and control groups (+7.5, 95% CI =−17.5 to +32.6, P =0.56). There were no differences in short physical performance battery change between either exercise group and control at 6‐month or 12‐month follow‐up. Conclusions A 6‐month supervised treadmill exercise intervention that improved 6‐minute walk distance at 6‐month follow‐up did not have persistent benefit at 12‐month follow‐up. These results do not support a durable benefit of supervised treadmill exercise in peripheral artery disease. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Identifier: NCT 00106327.

The most common type of non-Hodgkin lymphoma in adults is diffuse large B-cell (DLBCL). There is a historical unmet need for more effective therapies in the 2nd and 3rd line setting. Emerging immunochemotherapies have shown activity in small studies of heavily pre-treated patients with prolonged remissions achieved in some patients. Anti-CD19 CAR (chimeric antigen receptor) T cells are potentially curative in the 3rd line and beyond setting and are under investigation in earlier lines of therapy. Antibody-drug conjugates (ADC’s) such as polatuzumab vedotin targeting the pan-B-cell marker CD79b has proven effectiveness in multiply-relapsed DLBCL patients. Tafasitamab (MOR208) is an anti-CD19 monoclonal antibody producing prolonged remissions when combined with Lenalidomide (LEN) in patients who were not candidates for salvage chemotherapy or autologous stem cell transplant. Selinexor, an oral, small-molecule selective inhibitor of XPO1-mediated nuclear export (SINE), demonstrated prolonged activity against heavily-pretreated DLBCL without cumulative toxicity and is being investigated as part of an oral, chemotherapy-free regimen for relapsed aggressive lymphoma. This article reviews current strategies and novel therapies for relapsed/refractory DLBCL.

Small cell carcinoma of the breast is a rare, aggressive form of breast cancer that is associated with extremely poor outcomes [1]. In an effort to identify possible targets for treatment, we utilized comprehensive genomic profiling in small cell carcinoma of the breast. Under an IRB approved protocol, we identified patients with small cell carcinoma of the breast and small cell carcinoma of the lung profiled by Caris Life Sciences between 2007 and 2015. Tumors were assessed with up to 25 immunohistochemical stains, in situ hybridization of cMET, EGFR, HER2, PIK3CA, and TOP2A, and next generation sequencing as well as Sanger sequencing of 47 genes. 19 patients with small cell carcinoma of the breast were identified, median age was 58 years (range 37-79) and 42 % had metastatic disease at presentation; for comparison, 58 patients with small cell carcinoma of the lung were identified (66 [36-86], 65 % metastatic). By immunohistochemistry, 31 % of small cell carcinoma of the breast patients expressed ER, 13 % expressed PR, and 16 % expressed AR; small cell carcinoma of the lung patients expressed ER 0 %, PR 2 %, and AR 6 %. Small cell carcinoma of the breast and small cell carcinoma of the lung patients had similar patterns of other immunohistochemical expression (0 v 0 % PDL1, 50 v 42 % PD1, and 77 v 95 % TOP2A, respectively). All small carcinoma of the breast and small cell carcinoma of the lung patients were negative for HER2 and cMET amplification by in situ hybridization. Next generation sequencing revealed TP53 mutations in 75 % of patients both with small cell carcinoma of the breast and small cell carcinoma of the lung and PIK3CA mutations in 33 % of small cell carcinoma of the breast patients but no small cell carcinoma of the lung patients (Fisher's exact test p = 0.005, OR 0.02 [0.00-0.52]). No other mutations were found in small cell carcinoma of the breast patients and no other mutation occurred in over 10 % of small cell carcinoma of the lung patients except RB1 in 19 % (p = 0.31). Small cell carcinoma of the breast is an aggressive tumor with few therapeutic options. Molecular profiling suggests many similarities between small cell carcinoma of the breast and small cell carcinoma of the lung with the exception an increased incidence of PIK3CA mutations in small cell carcinoma of the breast, which may have therapeutic implications.