Coli Sepsis Research Articles

Relapse Hodgkin lymphoma autologous stem cell transplant long term follow up.

e19031 Background: Autologous Stem Cell Transplantation (ABMT) is a standard treatment approach for patients with relapsed Hodgkin’s Lymphoma (HL). We wish to report long term (>10 year) outcomes for patient’s with HL treated with ABMT at our institution. Methods: We treated 35 patients over a 30 year time period (1992-2022). Of these 35 patients, there were 19 males and 16 females with a median age of 41 years (range 21-70 years) and a median performance status of 1 (0-1). The preparative regimen was carmustine, etoposide, and melphalam (CEM, 1992-2005) and BCNU, etoposide, cytarabine and melphalan (BEAM, 2006 to present). Bretuximab was added to BEAM in 2018 as post-transplant consolidation therapy in 13 patients. All patients underwent mobilized peripheral blood stem collections with high dose filgrastim, and starting in 2008 were mobilized with both filgrastim and plexiform. The required stem cell product was at a minimum of 2 million CD34+ cells per kilogram of body weight. Results: Fifteen patients received CEEM and 9/15 (60%) achieved a complete response (CR). Twenty patients received BEAM and 16/20 (80%) achieved a CR, p=0.27 (Fisher’s exact test). The median time to hematological recovery was 12 days (range 8-21). Treatment related complications included: S. epidermis sepsis (3 patients), E. coli sepsis (3 patients), and esophageal perforation that lead to death in 1 patient. With a median follow up 13 years (range 1-23 years), the actual 10 year disease free survival (DFS) is 52% and overall survival (OS) is 64%. The actuarial DFS and OS at 15 years are 52% and 64% respectively. Six patients are in continuous CR for greater than 20 years. Long term complications at greater than 15 years include: cardiomyopathy (5 patients), breast cancer (1 patient), and liposarcoma (1 patient). Conclusions: Patients with relapsed HL can achieve long term curative outcomes when treated with ABMT with most frequent long term complication being cardiomyopathy.

Clinical, laboratory profile and molecular characterization of Orientia tsutsugamushi among fatal scrub typhus patients from Karnataka, India

Background Scrub typhus is a vector-borne infection caused by the obligate intracellular organism Orientia tsutsugamushi. In some cases, scrub typhus can result in severe complications, multiorgan failure and death. Objective To study the clinical and laboratory profiles of patients who succumbed to scrub typhus. Methods A prospective cohort study was conducted from August 2019 through April 2023 on scrub typhus patients admitted to our hospital. Clinical and laboratory parameters of all the patients were recorded, and blood samples were drawn. To confirm scrub typhus, a nested polymerase chain reaction (nPCR) was performed in collected samples. Viable amplicons were sequenced, and phylogenetic analyses were performed to identify infecting genotypes. Results A total of 261 patients were enrolled. Of these, nine (3.45%) patients succumbed at a median (Interquartile Range) duration of 5 (1.5, 10.5) days after admission. Sepsis with septic shock (9, 100%) and acute kidney injury (AKI) (6, 66%) were noted among the succumbed patients. All the succumbed patients (100%) required intensive care admission, inotropic and ventilatory support. While 5 (55%) patients required dialysis, two (22%) required blood transfusion. Three (33%) patient samples were co-positive for Leptospira IgM, and four (44%) patients had superinfection with Candida tropicalis, multi-drug-resistant (MDR) E. Coli sepsis, pan drug-resistant (PDR) Acinetobacter Baumanii, and Klebsiella pneumoniae. Phylogenetic analysis revealed Orientia tsutsugamushi Japanese Gilliam-variant (JG-v) like (50%), Karp-like (37.5%), and Japanese Gilliam (JG) like (12.5%) strains among succumbed patients. Conclusion Delay in scrub typhus diagnosis can result in severe complications, septic shock, and multisystem organ failure, culminating in death.

Long Term Disease Free Survival and Survival of Patients with Relapsed Hodgkin's Lymphoma Treated with Autologous Stem Cell Transplantation

CONCLUSION Autologous Stem Cell Transplantation (ABMT) is a standard treatment approach for patients with relapsed Hodgkin's Lymphoma (HL). We wish to report long term (>10 year) outcomes for patient's with HL treated with ABMT at our institution. We treated 35 patients over a 30 year time period (1992-2022) Of these 35 patients, there were 19 males and 16 females with a median age of 41 years (range 21-70 years) and a median performance status of 1 (0-1). The preparative regimen was carmustine, etoposide, and melphalan (CEM,1992-2005) and BCNU, etoposide, cytarabine, and melphalan (BEAM, 2006 to present). Brentuximab was added was added to BEAM in 2018 as post-transplant consolidation therapy in 13 patients. All patients underwent mobilized peripheral blood stem cell collections with high dose filgrastim and since 2008 filgrastim and plexiform. The required stem cell product was at a minimum 2 million CD34+ cells per kilogram of body weight. Fifteen patients received CEM and 9/15 (60%) achieved a complete response (CR). Twenty patients received BEAM and 16/20 (80%) achieved a CR, p=0.27 (Fisher's exact test). The median time to hematologic recovery was 12 days (range 8-21). Treatment related complications included: S. Epidermis sepsis (3 patients), E. coli sepsis (3 patients) and esophageal perforation that lead to death (1 patient). With a median follow up of 13 years (range 1-23 years).The actual 10 year disease free survival (DFS) is 52% and overall survival (OS) is 64%. The actuarial DFS and OS at 15 years are 52% and 64% respectively. Six patients are in continuous CR for greater than 20 years. Long term complications at greater than 15 years include: cardiomyopathy (5 patients), breast cancer (1 patient), liposarcoma (1patient). Patients with relapsed HL can achieve long term curative outcomes when treated with ABMT. The most frequent long term complication is cardiomyopathy.

S180: RG6234, A NOVEL GPRC5D T-CELL ENGAGING BISPECIFIC ANTIBODY, INDUCES RAPID RESPONSES IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA: PRELIMINARY RESULTS FROM A FIRST-IN-HUMAN TRIAL

Background: Patients (pts) with relapsed/refractory multiple myeloma (RRMM) are in need of effective treatment options. RG6234 is a T-cell engaging bispecific antibody targeting GPRC5D with a novel 2:1 format. NCT04557150 is an ongoing first-in-human Phase 1 trial. We present initial results from the dose-escalation part using intravenous (IV) administration. Aims: To characterize the safety of RG6234 and to identify a recommended Phase 2 dose (RP2D), and to characterize the pharmacokinetics, pharmacodynamics, and preliminary clinical activity. Methods: Eligible pts with RRMM received RG6234 in escalating weekly step-up doses followed by a q2w regimen at a peak ‘target dose’ for up to 1 year. A mCRM model was used for overdose control. Adverse events (AEs) were graded per CTCAE v5.0 and cytokine release syndrome (CRS) per ASTCT criteria (Lee et al. 2019). Response was assessed by the investigator according to IMWG criteria. All pts provided informed consent. Results: As of January 31, 2022, 41 pts had received RG6234 IV (0.006mg to 10mg). Median age was 63 years (range: 27 to 78) and 61% had R-ISS stage II or III at study entry. High-risk cytogenetics (t(4;14), t(14;16), del(17p), 1q21 gain) were present in 17/29 (58%) evaluable cases. Median number of prior therapies was 5 (range: 2 to 15). Pts were triple-class refractory in 67% of cases and penta-class refractory in 36%. Six pts (14.6%) had prior BCMA-directed therapy. CRS occurred in 85.4% of pts (G1 56.1%, G2 24.4%, G3 2.4%). CRS was generally confined to the first cycle, with a median time to onset of 4.2 hours (range: 0 to 64.2), and 14 pts (34%) requiring tocilizumab. Three pts (7.3%) experienced CNS toxicity related to RG6234 (G1 and G3 headache; G1 confusion). G3/4 neutropenia, thrombocytopenia, and anemia occurred in 9.8%, 19.5%, and 12.2% of pts, respectively. Infections were reported in 46.3% of pts (≥G3 14.6%). One patient died of an E. coli sepsis not considered related to RG6234. AEs probably related to target expression included skin-related AEs in 66% of pts (G3 7.3%), dysgeusia/ageusia (36.6%, all G1/2), dry mouth (36.6%, all G1/2), dysphagia (17.1%, all G1/2), and nail changes (12.2%, all G1/2). No discontinuations due to RG6234-related AEs occurred. The maximum tolerated dose (MTD) was not reached. Within the tested target-dose range, RG6234 serum exposure generally showed a dose-proportional increase, with a preliminary IV terminal T½ of ～5 days (mean value, n=22). At the predicted active-dose range (>0.162mg), RG6234 induced profound and rapid reductions in serum free light chains (FLC) and sBCMA. After the first treatment cycle, 93% of evaluable pts (14/15) had <1% of multiple myeloma cells in bone marrow based on flow cytometry. Overall response rate in 34 efficacy evaluable pts across all doses was 68%, and 50% achieved a VGPR or better response, including 2/6 BCMA pre-treated pts. Responses occurred rapidly, with a median time to first response of 1.3 months (95% CI: 1.1, 1.6). Median follow-up was 3.5 months (range: 0.03 to 11.7). Treatment was ongoing for 58.5% of pts at the time of the data cut. Duration of response was not mature. Response was ongoing in 18/23 (78.3%) responding pts, with a longest duration of response of 10 months. Summary/Conclusion: RG6234, a novel T-cell engaging bispecific antibody targeting GPRC5D, demonstrates compelling clinical activity with manageable safety in heavily pretreated pts with RRMM. Dose escalation via IV and subcutaneous routes continues, and data will be updated.

CeNtuRIOn: Rucaparib (R) with nivolumab (N) and ipilimumab (I) in patients (pts) with relapsed ovarian cancer (ROC)—Results of an initial safety cohort.

5577 Background: There is an urgent need to improve outcomes for ROC pts; progression free (PFS)/overall survival (OS) are 4-9 months (mo), 12-20mo respectively. ̃50% ROC pts harbour homologous repair deficiencies (HRD), identified by BRCA mutations (m) &amp; Loss of Heterozygosity (LoH). R, a PARP inhibitor (PARPi) has demonstrated efficacy when used as maintenance after chemotherapy (CT), and is superior to CT if used as treatment for ROC BRCAm pts. However repeating PARPi, even in highly selected BRCAm/HRD pts has limited benefit (1.5-2.5mo extra PFS). Single agent immunotherapy (PD-1/PD-L1/CTLA4 antibodies (Ab)) in ROC pts has been disappointing. Response rate to combined PD-1/CTLA4 Ab in ROC pts is 31.3%. In vitro evidence suggests that combinations of PD-1/CTLA4 Ab /PARPi may be more effective. CeNtuRIOn aims to explore the activity/toxicity of repeat PARPi (R) versus R+I (CTLA4 Ab) versus R+I+N (PD-1 Ab). Here we report safety data from the run-in cohort of 15 ROC pts treated with the triplet combination, RNI. Methods: Eligible pts had received ≥1 and &lt;3 lines CT, were &gt; 3 to &lt;12 months from last platinum CT. Only 1 pt could experience a dose limiting toxicity (DLT) over initial 6 weeks of treatment. Pts received N 240mg q14 days, I 1mg/kg q42 days intravenously for up to 12mo and R orally, 600mg bd continuously. All bar 1 of 7 pts (recruited 06/19–12/19) received N+I to meet DLT evaluability, but 5 of remaining 6 received &lt; 43% R during safety period. 6 further pts were recruited (08/20-06/21), with ≥60% starting dose R in first 6 weeks now required for evaluability. Review of toxicity/tolerability prompted reduction of R starting dose to 400mg bd and ipilimumab limited to 4 cycles for the last 4 pts. Results: Of all 15 recruits, median age was 64. Adverse events (AE)s are detailed in Table. 7 pts were evaluable for safety assessment: n = 4 started on 600mg bd and n = 3 on 400mg bd R. Median R dose intensity in these 7 was 82.5%. There was 1 DLT: G3 nephritis on day 18. 1 pt died of E. Coli sepsis related to colitis. Outcome data will be presented. Conclusions:R (400mg bd)+N+I (4 cycles only) will be taken forward to phase II. Pts will be randomised 1:1:2 to single agent R, R+I or RNI. Pts recruited to R alone are eligible for 2nd randomisation (1:1) to add I or N+I at progression. Clinical trial information: ISRCTN10490346. [Table: see text]

CD14 inhibition improves survival and attenuates thrombo‐inflammation and cardiopulmonary dysfunction in a baboon model of Escherichia coli sepsis

BackgroundDuring sepsis, gram‐negative bacteria induce robust inflammation primarily via lipopolysacharride (LPS) signaling through TLR4, a process that involves the glycosylphosphatidylinositol (GPI)‐anchored receptor CD14 transferring LPS to the Toll‐like receptor 4/myeloid differentiation factor 2 (TLR4/MD‐2) complex. Sepsis also triggers the onset of disseminated intravascular coagulation and consumptive coagulopathy. ObjectivesWe investigated the effect of CD14 blockade on sepsis‐induced coagulopathy, inflammation, organ dysfunction, and mortality. MethodsWe used a baboon model of lethal Escherichia (E) coli sepsis to study two experimental groups (n = 5): (a) E coli challenge; (b) E coli challenge plus anti‐CD14 (23G4) inhibitory antibody administered as an intravenous bolus 30 minutes before the E coli. ResultsFollowing anti‐CD14 treatment, two animals reached the 7‐day end‐point survivor criteria, while three animals had a significantly prolonged survival as compared to the non‐treated animals that developed multiple organ failure and died within 30 hours. Anti‐CD14 reduced the activation of coagulation through inhibition of tissue factor‐dependent pathway, especially in the survivors, and enhanced the fibrinolysis due to strong inhibition of plasminogen activator inhibitor 1. The treatment prevented the robust complement activation induced by E coli, as shown by significantly decreased C3b, C5a, and sC5b‐9. Vital signs, organ function biomarkers, bacteria clearance, and leukocyte and fibrinogen consumption were all improved at varying levels. Anti‐CD14 reduced neutrophil activation, cell death, LPS levels, and pro‐inflammatory cytokines (tumor necrosis factor, interleukin (IL)‐6, IL‐1β, IL‐8, interferon gamma, monocyte chemoattractant protein‐1), more significantly in the survivors than non‐surviving animals. ConclusionsOur results highlight the crosstalk between coagulation/fibrinolysis, inflammation, and complement systems and suggest a protective role of anti‐CD14 treatment in E coli sepsis.

Final Analysis of the Ro-CHOP Phase III Study (Conducted by LYSA): Romidepsin Plus CHOP in Patients with Peripheral T-Cell Lymphoma

Final Analysis of the Ro-CHOP Phase III Study (Conducted by LYSA): Romidepsin Plus CHOP in Patients with Peripheral T-Cell Lymphoma

Results of a Phase 1 Trial of Gda-201, Nicotinamide-Expanded Allogeneic Natural Killer Cells (NAM-NK) in Patients with Refractory Non-Hodgkin Lymphoma (NHL) and Multiple Myeloma (MM)

Background: NK cells have the capacity to kill tumor targets, representing a novel immunotherapeutic approach to cancer. We have shown promising clinical activity in AML with a previous NK cell preparation. Limitations of NK therapies have included specificity, persistence after infusion, and potential for maximal activity of NK cells in vivo. GDA-201 is a cellular product composed of natural killer (NK) cells from healthy donors expanded ex vivo with nicotinamide (NAM) and IL-15; this is a unique ex vivo activation strategy to induce persistence of potent anti-tumor activity. Prior in vitro studies and pre-clinical models demonstrated that NAM-exposed NK cells exhibited augmented resistance against exhaustion and improved killing function, proliferation, and organ retention. We now report safety and efficacy from a phase 1 clinical trial of GDA-201 in patients (pts) with relapsed or refractory (R/R) NHL or MM. Methods: Following donor apheresis, CD3-depleted mononuclear cells were cultured for 14-16 days with NAM (5mM) and IL-15 (20ng/ml), resulting in a 40-fold increase in NK cells and increased expression of CD62L from 2.9% to 21%. GDA-201 contained ~98% NK cells, and CD3 content was maintained at &amp;lt;0.5% (&amp;lt;5x105/kg/dose). Pts with R/R CD 20-positive NHL or refractory MM received cyclophosphamide (400mg/m2 IV x 3d) and fludarabine (30 mg/m2 /d IV x 3d), followed by two doses of GDA-201 (Days 0 and 2) and low-dose IL-2 (6 million units sc). Pts with NHL or MM received rituximab (375 mg/m2 x 4 weekly or elotuzumab (10 mg/kg x 3 weekly), respectively, to enhance NK cell targeting through antibody-dependent cellular cytotoxicity (ADCC). Results: 20 pts were enrolled: 7 with NHL (4 follicular, 2 transformed, 1 diffuse large cell lymphoma) and 13 with MM, in 3 cohorts of escalating GDA-201 dose; 11 pts received the maximum target dose (median 1.7 x 108 cells/kg, range 1.6-2.0 x 108 cells/kg). There were no dose limiting toxicities. The most common grade 3/4 adverse events were neutropenia and thrombocytopenia, febrile neutropenia (n=2), increased creatinine, hyponatremia, pulmonary edema; all events were transient. One pt had grade 2 cytokine release syndrome at day 18, presenting with fever, hypoxemia and hypotension, responding to tocilizumab; pt later died of E Coli sepsis. There were no neurotoxic events, GVHD or marrow aplasia. Among 7 NHL pts, there were 3 CR and 2 PR with overall response rate of 71%. Median duration of response was 12 months (CR patients) and 5 months (PR patients). Figure 1A illustrates a 57-year-old man with history of CLL and Richter's transformation (large cell lymphoma), pre- GDA-201 and 6 months post therapy; the pt had continued response with 80% tumor shrinkage at 6 months. In MM patients, 1 patient with extramedullary disease had CR and 4 had SD with median duration 2.5 months. In our previous study using overnight-activated NK cells, persistence 7 days after adoptive transfer was limited. Using GDA-201, flow cytometry confirmed persistence of donor NAM-NK in peripheral blood up to day 7-10 (day 7 range 2-55% donor NK cells; Figure 1B), as well as enhanced in vivo proliferation (median Ki67 99%). Conclusions: Cellular therapy using GDA-201 with monoclonal antibodies was safe, and demonstrated early evidence of clinical activity in heavily pre-treated pts with advanced NHL and MM. The recommended dose of GDA-201 for phase 2 is 2.0 x 108 cells/kg. The clinical responses showed that NK cell targeting through ADCC can be efficacious and increase response. Laboratory studies showed that GDA-201 had better persistence than observed in our previous studies using overnight activated cytokine alone stimulated NK cells. This study demonstrated that GDA-201 has an efficacy signal, and larger phase II studies are warranted. Disclosures Bachanova: Incyte: Research Funding; Gamida Cell: Research Funding; Novartis: Research Funding; GT Biopharma: Research Funding; Celgene: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. McKenna:Fate Therapeutics: Research Funding; Magenta Therapeutics: Research Funding; CIBMTR BMT CTN (NIH): Other: Medical Monitor; Icahn School of Medicine, New York, New York: Consultancy; National Eye Institute (NIH): Other: DSMB (2); Gamida: Research Funding; NMDP: Other: Donor and Patient Safety Monitoring Advisory Group; Intima: Patents &amp; Royalties: Royalities, Research Funding. Brachya:Gamida Cell: Employment, Equity Ownership. Peled:Gamida Cell: Employment, Equity Ownership. Miller:GT BioPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CytoSen: Membership on an entity's Board of Directors or advisory committees; Dr. Reddys Laboratory: Membership on an entity's Board of Directors or advisory committees; Moderna: Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics, Inc: Consultancy, Research Funding; OnKImmune: Membership on an entity's Board of Directors or advisory committees.

Modulation of mRNA Expression in Peripheral Tissue in a Rodent E. coli Sepsis Model

The endogenous cannabinoid system (ECS) regulates cytokine production and mitigates pathophysiology in many pro‐inflammatory conditions, such as irritable bowel diseases, atherosclerosis and acute lung injury. Sepsis, a highly morbid condition, results from a dysregulated host response to infection. Despite extensive study the transcriptional regulation of cytokines and the ECS during sepsis remains to be established. We hypothesized that cannabinoid receptor (Cnr1 &amp; 2) mRNA expression increases with systemic infection and these increases coincide with increases in pro‐inflammatory cytokines. We implanted a fibrin clot that contained either 25×106 or 0 E. coli in the peritoneal cavity of adult, male rats (n=8). Rats were euthanized at 3, 6, 12 or 24 h following the implant; lung, liver and serum were harvested. Total RNA was extracted using Trizol reagent, and cDNA was synthesized using reverse transcription PCR. Quantitative real‐time PCR was performed in duplicate for each sample using TaqMan Gene® Expression Assays specific for 18S ribosomal RNA (18S), Cnr1 &amp; 2, interleukin (IL) IL‐4 &amp; IL‐6 and tumor necrosis factor – alpha (TNF‐α). Each target gene was normalized to 18 S content, and relative quantitation of gene expression levels were performed using the comparative CT method (2−ΔΔCT method) with the 0 E. coli fibrin clot at each time point as the comparative control. The time course of cytokine expression depended on the cytokine and the tissue compartment. In liver, IL‐6 peaked at 3h (1086 ± 59% vs 0.36 ± 0.1%, p&lt;0.01). In serum, IL‐4 peaked at 6h (168 ± 34% vs 86 ± 5%). In lung, both IL‐6 and TNF‐α expression levels peaked at 3h (IL‐6: 755 ± 33% vs 8 ± 0.5%, p&lt;0.01; TNF‐a: 496 ± 230% vs 8 ± 0.2%); whereas, IL‐4 levels peaked at 24h (291 ± 31% vs 3 ± 2%, p&lt;0.05). Interestingly, at 24h Cnr2 mRNA increased concomitantly with IL‐4 in the lung (360.0 ± 10% vs 30 ± 5%, p&lt;0.01), whereas the expression levels of Cnr1 mRNA did not increase above sham surgical levels during the time course of this study. These preliminary data and analyses support our hypothesis that induction of ECS, as characterized by the increased transcription of Cnr2 mRNA, is associated with upregulation of mRNA of pro‐inflammatory cytokines.Support or Funding InformationNIH 5T32HL007913‐18, NIH U01 EB021960, VA Research Service I01BX004197This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Hepatocellular Carcinoma Presenting as Hemobilia: A Case Report

Introduction Hemobilia from hepatocellular carcinoma (HCC) is rare and is usually noted in established cases of HCC after an invasive procedure. We describe an unusual case of hemobilia causing obstructive jaundice, cholangitis and pancreatitis with subsequent work up revealing HCC. Case report A 61 yr old Hispanic M presented with one day of abdominal pain, N/V, subjective fevers. His PMH was significant for recent right portal vein thrombosis (PVT) and E coli sepsis for which he was on anticoagulation and oral antibiotics. His vitals were stable. Labs were significant for WBC 15 k/μL, Total bilirubin 15.2 mg/dL (direct bilirubin 12 mg/dl), ALP 704 U/L, lipase 3463 U/L, INR 2.7 and Hgb 11.8 g/dL. CT revealed persistence of right PVT, peripancreatic edema and fluid, and intra and extrahepatic biliary dilation with CBD measuring 17mm with hyperdense material within it suspicious for blood (Fig. 1). ERCP with biliary sphincterotomy was performed due to obstructive jaundice and suspected cholangitis. A large and long organized clot was swept from the CBD confirming hemobilia. A 10 mm x 8 cm covered metal stent was placed in the CBD for tamponade effect and to relieve obstruction. A CT angiogram showed a focus of hypervascularity measuring 19 mm on arterial phase within hepatic segment 5 suspicious for a pseudoaneurysm. A subsequent arteriogram showed the right hepatic lesion to be a hypervascular lesion concerning for HCC with no apparent pseudoaneurysm or active extravasation (Fig. 2). Serum AFP level was elevated at 653 ng/ml. Patient was diagnosed with HCC, which likely was the cause of his right PVT and subsequent hemobilia in the setting of anticoagulation. Patient's hospital course was otherwise unremarkable. During subsequent follow up, he has continued to do well. He has declined liver transplant evaluation and is being evaluated for either transarterial chemoembolization or radiofrequency ablation.2271_A Figure 1. Computerized tomography showing hyperdense material within dilated CBD2271_B Figure 2. A hypervascular lesion right hepatic lobe on arteriogramDiscussion HCC related hemobilia is rare and is usually reported in established HCC patients undergoing hepatobiliary procedures. In our case, patient presented with complication related to hemobilia with subsequent diagnosis of HCC. Bleeding usually stops with supportive therapy alone but in persistent or severe bleeding arterial embolization may be needed. ERCP is warranted when biliary obstruction and its complications are evident. Fully covered metal stents can be effective in achieving hemostasis and relieving obstruction.

Detecting Released Peptidoglycan Associated Lipoprotein (Pal) from Escherichia coli

Gram‐negative sepsis can result from a bacterial infection, such as Escherichia coli (E. coli), which leads to an over‐exuberant inflammatory response in humans. During E. coli sepsis, a bacterial lipoprotein, Pal (peptidoglycan associated lipoprotein), has been shown to be released from the outer membrane of E. coli and is thought to contribute to an inflammatory response in human cells. In E. coli, Pal has two subpopulations: periplasmic Pal, which is bound to peptidoglycan, and surface‐exposed Pal. A biotinylation technique was used to roughly quantify the amount of each Pal subpopulation that was released from E. coli in vitro. Several different antibiotics were tested for their effect on Pal release; ultracentrifugation was also employed to quantify the amount of Pal released in outer membrane vesicles. Preliminary results suggest that both subpopulations of Pal are capable of release from E. coli, and that the majority of Pal is released from E. coli in outer membrane vesicles.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Mini BEAM with Full-Dose of Melphalan (beaM) As a Conditioning Regimen for High Risk Patients with NHL Undergoing Autologous SCT

When considering ASCT for high risk NHL patients with dose-related toxicity concerns, choosing an appropriate conditioning chemotherapy regimen that is both safe and effective presents a challenge. ASCT in elderly population is a feasible and safe procedure, but characterized by higher transplant related mortality compared to younger population. Reports on ASCT in patients with PTLD are rare and limited to case reports without clear understanding of the impact ASCT has on the function of the transplanted organ. Initial outcomes of patients with amyloidosis undergoing ASCT have been marred by significant toxicity, particularly driven by cardiac damage due to amyloid.As such we sought to improve the overall outcomes of our select patients by allowing them to proceed with ASCT, while attempting to reduce toxicity of the conditioning regimen. We used a modified mini-BEAM as conditioning regimen with full dose of melphalan (140mg/m2). This dose was also used due to its efficacy as conditioning regimen in patients with multiple myeloma undergoing ASCT who are elderly or have kidney impairment.6 patients treated at our center received mini BEAM with full dose melphalan (beaM) as conditioning regimen before ASCT. Patients’ characteristics are summarized in Table 1. Two had relapsed PTLD post cardiac transplant (including one with multiply relapsed PTCL), two had Waldenström macroglobulinemia and kidney amyloidosis, one had relapsed DLBCL and one had ALK- ALCL. Treatment prior to ASCT is also listed in Table 1. Conditioning regimen was as follows: carmustine 60mg/m2 on day -6, etoposide 75mg/m2 on days -5 to -2, cytarabine 100mg/m2 on days -5 to -2 and melphalan 140 mg/m2 on day -1. Stem cell infusion was performed on day 0.Stem cell mobilization was performed with filgrastim and plerixafor and was successful in all 6 patients with a median of 1.5 apheresis sessions (range 1-3). Median number of stem cells collected was 6.2 x106/kg (range 3.12 - 12.51 x106/kg).Post ASCT complications included one septic shock with lethal outcome for patient 6 due to MDR E. coli infection. Other side effects (≥grade 3) were: febrile neutropenia (n=2), non-infectious diarrhea (n=3), mucositis (n=1), cellulitis (n=1), seizure in a patient with previous seizure disorder (n=1), C. difficile infection (n=1), pneumonia (n=1), acute kidney injury (n=1), transaminitis (n=1), urinary tract infection (n=1) and HHV6 infection (n=1). Median time to neutrophil engraftment was 12 days (range 9-18) and median time to platelet engraftment was 20.5 days (18-23).Outcomes of patients before and after ASCT are summarized in Table 1. Both patients with PTLD achieved CR to pralatrexate and R-EPOCH respectively and are in remission 499 and 531 days following transplant. WM/amyloidosis patients achieved VGPR for their amyloidosis and one is in CR with respect to his lymphoma. Their last follow up was 399 and 308 days following transplant. Patient with DLBCL relapsed 364 days after transplantation and patient with ALCL died from MDR E. Coli sepsis 10 days following transplant.Mini-BEAM with full-dose of melphalan (beaM) is a safe and efficacious regimen that can be used in select lymphoma patients, particularly those with relapsed PTLD, and patients who are elderly or have impaired organ function. [Display omitted] DisclosuresAmengual:Bristol-Myers Squibb: Research Funding; Acetylon Pharmaceuticals: Research Funding. Lentzsch:BMS: Consultancy; Foundation One: Consultancy; Celgene: Consultancy, Honoraria. O'Connor:Seattle Genetics: Research Funding; Spectrum: Research Funding; Spectrum: Research Funding; Seattle Genetics: Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Research Funding; TG Therapeutics: Research Funding; Bristol Myers Squibb: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Celgene: Research Funding.

Livedo Reticularis: A Presenting Sign of Escherichia Coli Sepsis in a Newborn

Livedo reticularis is a red cutaneous netlike pattern that is caused by abnormalities of the microvascularization and can be associated with many other potential systemic etiologies. We describe a case of a newborn that presented with livedo reticularis on his first day of life without any obvious systemic signs. The livedo reticularis was associated with Escherichia Coli K1 meningitis as revealed by laboratory tests. Clinical infectious signs developed a few hours later. Despite appropriate antibiotics therapy, he died on his second day because of sepsis and disseminated intravascular coagulation. Cerebrospinal fluid culture, blood culture, and culture of samples from trachea showed the presence of Escherichia Coli serotype K1 with many virulence determinants. Conclusion: In newborn, livedo reticularis must not be considered as physiological, but as a potential sign of unknown severe bacterial infection. Thus, the presence of livedo reticularis must require urgent laboratory tests.

Immunodeficiency and disseminated mycobacterial infection associated with homozygous nonsense mutation of IKKβ

A, Genealogical tree for the kindred. Arrow highlights index case. Asterisks denote family members who died within the first 2 months of life with febrile illnesses. B, Histology showing granuloma in skin by hematoxylin and eosin staining.

An Occurrence of Sepsis During Inpatient Fecal Disimpaction

Functional constipation is a common pediatric problem that is often treated through well-established algorithms. Fecal disimpaction is the initial therapeutic step, and severe cases require hospitalization for intensive therapies. We describe a significant unexpected complication of this common clinical situation. An 8-year-old boy with suspected chronic functional constipation was hospitalized for disimpaction by continuous nasogastric administration of polyethylene glycol electrolyte (PEG-E) solution. On the sixth day of disimpaction, the patient abruptly developed fever, tachycardia, and tachypnea. Evaluation included blood culture, which grew Escherichia coli, and treatment with a course of appropriate antibiotics was provided. The safety of PEG-E solutions has been shown in studies of children with constipation, which made this patient's illness surprising. Several potential etiologies of his infection were considered, including bacterial translocation (BT). BT is defined as the passage of live microbes and microbial products from the gastrointestinal tract to extraintestinal sites, such as the bloodstream. It has been shown to occur in a variety of clinical conditions but is of unclear clinical significance. In this case, physical damage to the intestinal mucosa was thought to contribute to the potential occurrence of BT, and prolonged disimpaction was considered as a risk factor. E coli sepsis in a child undergoing inpatient nasogastric fecal disimpaction with PEG-E represents a clinical problem never before reported in the literature and should increase clinicians' indices of suspicion for uncommon complications of common procedures.

High-Dose Gemcitabine Combined With Busulfan and Melphalan (Gem/Bu/Mel) With Autologous Stem-Cell Transplant (ASCT) In Refractory and Relapsed Myeloma

IntroductionMore active high-dose (HD) regimens are needed for refractory myeloma, where single-agent melphalan offers poor outcomes. Registry data suggest that busulfan/melphalan might be superior to melphalan in 1st-line treatment of chemosensitive patients. While gemcitabine has potent activity in vitro against resistant myeloma cell lines, this drug has shown little activity in patients with resistant myeloma when tested in short 30-min infusions. Gemcitabine cytotoxicity correlates with the intracellular accumulation of its active triphosphate metabolite, which is optimized when infused at a fixed dose rate (FDR) of 10 mg/m2/min. We previously developed a HD regimen of Gem/Bu/Mel, infusing gemcitabine at FDR and exploiting its inhibition of DNA damage repair, with a manageable toxicity profile. In its phase 1 trial (Nieto, BBMT 2012) Gem/Bu/Mel showed some encouraging signs of activity in patients with refractory myeloma. Thus, we wished to study Gem/Bu/Mel in refractory myeloma patients who either had an estimated CR likelihood <15% with high-dose melphalan or had disease that previously failed HD Mel, whose median PFS after a 2nd ASCT is typically ≤1 year (Qazilbash, Cancer 2006; Michaelis, BBMT 2013). MethodsPatients ages 18-70, with myeloma treated in 1st-line therapy with lenalidomide, bortezomib or thalidomide, plus ≥1 of the following 3 criteria: no response to 1st-line therapy, relapse after 1st-line therapy, or relapse after prior ASCT, along with adequate end-organ function, were eligible for this phase 2 study. Gemcitabine was given on days -8 and -3 as a loading dose of 75 mg/m2 followed by FDR infusion of 1,800 mg/m2. Busulfan was given on days -8 to -5 targeting AUC 4,000/day x 4. Melphalan was given at 60 mg/m2/day x 2 (days -3 and -2). The primary study endpoint was CR rate (determined by day 100 before starting maintenance treatment); secondary endpoints were CR+VGPR, RR, PFS and OS. This trial was sized with >85% power to detect a CR rate ≥20%, which was considered clinically significant. ResultsBetween 11/10 and 6/13, 60 patients were enrolled, all of whom had failed at least 1 line of therapy (Table).Age57 (39-65)ISS stage at diagnosis124 (40%)218 (30%)318 (30%)Median # prior lines of treatment (range)3 (2-10)Primary refractory (IMWG criteria: never achieved a minimal response or better with any therapy)9 (15%)Relapsed and refractory (IMWG criteria: nonresponsive while on salvage therapy or progressive within 60 days of last therapy)24 (40%)High-risk cytogeneticsOverall20 (33%)17p-9 (15%)t(4;14) or t(14;16)4 (7%)1q+6 (10%)Cytogenetic 13q-6 (10%)Extramedullary disease5 (8%)Renal failure at diagnosis15 (25%)Hypercalcemia at diagnosis10 (17%)Prior ASCT25 (42%)Status at HDC (CR / PR / no response)9 / 30 / 21PD at HDC14 (23%)Neutrophils and platelets engrafted on d+10 (8-13) and d+11 (9-16), respectively. There were 3 treatment-related deaths (4.9% TRM: 1 pneumonia, 1 cardiac arrest with unrevealing autopsy, 1 E coli sepsis). Toxicities: mucositis (50% G2, 18% G3), rash (20% G2, 6% G3), asymptomatic transaminase elevation (17% G2, 8% G3) and bilirubin elevation (3% G2, 10% G3) (no cases of VOD), with no renal, cardiac, neurological or pulmonary toxicity. Among 49 patients with measurable disease at transplant and evaluable for response, the CR rate was 24.5% (95% CI, 16-32.5%), 42% CR/VGPR rate (36-50%), and 77.5% RR (71-83%). Posttransplant maintenance was given to 38 patients, using lenalidomide (N=23), bortezomib (N=11), thalidomide (N=3) and bendamustine (N=1). At median f/u of 16 months (range, 2-31), the PFS and OS rates are 55% (median 15 months) and 77% (median not reached), respectively (Figure). In the subset of 25 patients receiving Gem/Bu/Mel as a 2nd salvage ASCT, there were 1 CR, 2 VGPR and 7 PR for a CR+VGPR of 19%, RR 62.5%, with 52% PFS (median 15 months) and 68% OS (median NR). In the subset of 20 patients with high-risk cytogenetics (N=20), there were 28% CR, 56% CR+VGPR and 83% RR, with 55% PFS (median 14 months) and 80% OS (median NR). [Display omitted] ConclusionsGem/Bu/Mel is a safe and highly active HD regimen in refractory myeloma and warrants its further study in earlier stages of this disease. Disclosures:Nieto:Otsuka Pharmaceuticals: Research Funding. Off Label Use: Gemcitabine not approved for myeloma. Qazilbash:Otsuka Pharmaceuticals: Research Funding.

Escherichia coli - Marauding masquerading microbe.

Escherichia coli is a rare cause of monoarticular septic arthritis, but is an even rarer cause of polyarticular septic arthritis. We report an unusual case of polyarticular septic arthritis with an atypical presentation caused by E. coli, the source of which was a left pyelonephritis. Our patient developed E coli sepsis resulting in polyarticular septic arthritis (PASA) in the absence of typical risk factors except for pre-existing osteoarthritis. The joints involved were the hip, ankle, sternoclavicular and L5/S1 joints. Of interest, ankle pain was not reported or evident until correlated with nuclear medicine scans. Furthermore, sternoclavicular joint involvement presented as left shoulder pain, resulting in an initial misdiagnosis of left shoulder septic arthritis. The patient was treated with surgical washout and antibiotic therapy. He was subsequently discharged from rehabilitation having returned to his baseline level of mobility. Future consideration will be given to total hip arthroplasty. There are no reported cases of E. coli PASA involving more than three joints in the absence of any recognized risk factors for septic arthritis. Asymptomatic involvement of joints can occur in polyarticular septic arthritis and should be considered in all cases of monoarticular septic arthritis (MASA). We believe that clinical suspicion is the key to early and comprehensive diagnosis of polyarticular septic arthritis particularly when presenting in an atypical fashion with an atypical pathogen. Strong consideration should be given to performing nuclear imaging in cases of monoarticular septic arthritis where polyarticular involvement cannot be definitively ruled out.

Legal Briefs: Devastating Consequences From Prolonged Use of an Umbilical Arterial Catheter

A 960-g, 26-3/7 weeks’ gestation male twin B was delivered by normal vaginal spontaneous delivery in the breech position to 31-year-old, healthy, gravida 3 para 1 mother whose pregnancy was complicated by preterm labor and diamniotic dichorionic twins. The mother received antibiotics, a partial course of betamethasone, and magnesium sulfate for tocolysis. At delivery, the infant had a heart rate (HR) less than 100 beats per minute, no respiratory effort, and was blue. The infant was intubated and required resuscitation, including chest compressions for 15 seconds, and 2 doses of epinephrine via an endotracheal tube (ETT). Apgar scores were 2 at 1 minute, 4 at 5 minutes, and 7 at 10 minutes. The infant was then admitted to the NICU, where an umbilical venous catheter (UVC) and an umbilical arterial catheter (UAC) were placed. The UVC was placed in the right atrium, where it remained until its removal several days later, and his UAC was placed appropriately at the seventh thoracic vertebrae and removed on day 13. The infant’s vital signs and blood pressure were normal. He had respiratory distress syndrome, for which he was given 3 doses of surfactant. Initially, the infant required 100% oxygen, but after several hours, the inspired oxygen was weaned to 30%, and the ventilator settings were low. His initial complete blood cell count revealed a white blood cell count (WBC) of 3.1 × 103/uL, a platelet count of 185 × 103/uL, and a hematocrit reading of 51% (0.51). The infant was given ampicillin and gentamicin after blood culture results were obtained, and he was started on low-dose indomethacin for intraventricular hemorrhage prophylaxis. On day 1, the fraction of inspired oxygen (Fio2) and ventilatory settings were low. The blood gas values were normal, with some permissive hypercarbia in the …

To Drain or Not Drain: PleurX Indwelling Drainage Catheters for Non-Malignant Refractory Ascites or Hepatic Hydrothorax

Purpose: The insertion of chronic indwelling drainage catheters for treatment of refractory ascites or hepatic hydrothorax in cirrhotic patients is controversial due to concerns related to infectious complications. PleurX drainage catheters are reported to have low infection rates due to their design and polyester cuff that promotes tissue ingrowth. The aim of the current study was to determine the 30 and 90-day mortality in cirrhotic patients with refractory non-malignant ascites or hepatic hydrothorax after placement of PleurX catheter. Methods: An interventional radiology database was queried for patients who underwent a PleurX catheter for indication of non-malignant refractory ascites or hepatic hydrothorax between the dates of January 1st, 2005 to January 1st, 2011 at a single transplant center. Medical records including the transplant database were reviewed by two of the study investigators. Demographics, laboratories, catheter related infectious morbidity, and mortality were collected. Results: A total of 26 patients with non-malignant ascites (n=16) and hepatic hydrothorax (n=10) underwent PleurX catheter insertion during the study period. The mean age was 57.1 ± 7.5 years and 61.5% were male. The mean MELD score was 21.7 ± 7.7 with majority of patients belonging to Child's - Pugh class C (69%). Follow up data was available for all the patients. The 30 and 90-day mortality in the study cohort was 30.8% and 61.5%, respectively. Two catheter related infections (8%) occurred within 30 days of insertion (Candida glabrata peritonitis and E. Coli sepsis). 69% (n=18) of the patients in the study cohort were transplant eligible and were being followed in the pretransplant clinic. The 30 and 90-day mortality in the study cohort was 27.8% and 66.7%, respectively. 11.1% of the patients were transplanted after insertion with an time to transplant of 107 ± 79.2 days. The two above-mentioned infections were within this group. In the remaining transplant non-eligible patients (n=8), PleurX was performed for palliation. The 30 and 90-day mortality was 37.5% and 50.0%, respectively. No catheter related infections were found in this subgroup. 4 patients survived to the end of the study period with average length of follow-up of 607 ± 128 days. Conclusion: Patients undergoing PleurX catheter drainage placement for refractory ascites and hepatic hydrothorax have high 30 day and 90-day mortality presumably from underlying liver disease. Due to low incidence of infectious complications, PleurX catheter could be an option when serial large volume paracentesis or transjugular intrahepatic shunts are not an option.

Characteristics of early-onset neonatal sepsis caused by Escherichia coli

ObjectiveThis study was conducted to document the perinatal risk factors associated with early-onset neonatal Escherichia coli sepsis and adverse neonatal outcomes. Materials and MethodsA case-control study of early-onset E coli sepsis compared with that of non-E coli sepsis was conducted by a retrospective data review of all infants with a diagnosis of sepsis during the first 7 days of life from the pediatric unit of Mackay Memorial Hospital from January 2004 to October 2008. After adjustment for gestational age, each patient with E coli early-onset sepsis was further compared with two gestational age-matched uninfected controls. ResultsCompared with infants with non-E coli sepsis (n = 27), infants with E coli sepsis (n = 19) were more likely to have preterm birth, especially at less than 30 weeks of gestation (47% vs. 4%, p < 0.01), very low birth weights (<1500 g; 47% vs. 4%, p < 0.01), intrapartum fever (26% vs. 4%, p = 0.036), preterm premature rupture of membranes (PPROM; 74% vs. 11%, p < 0.01), prolonged rupture of membranes (>24 hours; 47% vs. 0%, p < 0.01), antibiotic use (63% vs. 15%, p < 0.01), and sepsis onset on the first day of life (63% vs. 15%, p < 0.01). After adjusting for gestational age, intrapartum fever (26% vs. 5%, p = 0.035) and PPROM (74% vs. 39%, p = 0.015) were more common in infants with E coli sepsis. Fifteen of the 19 E coli isolates (79%) were ampicillin-resistant, and three (16%) were gentamicin-resistant. Antepartum and intrapartum antibiotic exposure was associated with ampicillin-resistant E coli sepsis (100% vs. 43%, p < 0.01). ConclusionEarly-onset E coli sepsis is more common in premature and very low birth weight infants and is more likely associated with intrapartum fever, PPROM, and sepsis onset on the first day of life than non-E coli sepsis. Broad-spectrum, multiple antibiotics or longer duration of antibiotic exposure may be associated with antibiotic-resistant pathogen infection.