Progressive Sepsis Research Articles

Safety, tolerability and efficacy of 212Pb-DOTAMTATE as a targeted alpha therapy for subjects with unresectable or metastatic somatostatin receptor-expressing gastroenteropancreatic neuroendocrine tumors (SSTR+ GEP-NETs): A phase 2 study.

4020 Background: 212Pb-DOTAMTATE is a Targeted Alpha Therapy (TAT) in clinical development for subjects with SSTR+ neuroendocrine tumors. A phase I dose-escalation study has already been completed (Delpassand et al. J Nucl Med 2022). TAT holds the promise to improve outcomes versus Peptide Receptor Radionuclide Therapy (PRRT) with beta-emitters like 177Lu-DOTATATE, currently considered the standard of care for subjects with GEP-NETs. Methods: ALPHAMEDIX 02 is a Phase II, open-label, multicenter study evaluating the safety, tolerability and efficacy of 212Pb-DOTAMTATE in PRRT-naïve (Cohort 1, N = 36) and PRRT-refractory (Cohort 2, Target N = 30) subjects with histologically confirmed unresectable or metastatic GEP-NETs, positive somatostatin analogue imaging and at least 1 site of measurable disease per RECIST 1.1. 212Pb-DOTAMTATE was administered at 67.6 μCi/kg per cycle, with a maximum activity administered per cycle of 5.5 mCi every 8 weeks, for up to 4 cycles. Primary endpoints include overall response rate (ORR) per RECIST1.1, and incidence and severity of adverse events (AEs). Secondary endpoints include progression free survival, overall survival , and health-related quality of life. Initial results of the already completed cohort 1 are presented. Results: In cohort 1, 17 out of 36 subjects with metastatic SSTR+ GEP-NETs achieved a confirmed response (ORR 47.2% (32.0-63.0%)). In the Phase I trial, five out of eight PRRT- naïve subjects with SSTR+ GEP-NETs treated with the same regimen of 212Pb-DOTAMTATE achieved a response (ORR 62.5% (30.6-86.3%)): the combined ORR from both studies is 50% (22 out of 44, 95%-CI:36% - 64%). Median Duration of Response (DOR) has not been reached in both studies. Four out of five subjects (80%) with confirmed response in Phase I had a DOR of ≥ 12 months. In the ongoing Phase II study the response follow-up for 10 subjects with confirmed response is currently shorter than 6 months: so far 7 out of 17 subjects (41%) with confirmed response had a DOR of ≥ 6 months, and one of these subjects had a DOR of ≥ 12 months. Lymphocytopenia is a lead cause of the 59% grade 3 and 4 AEs reported in subjects in cohort 1. Overall, 4 fatal AEs were reported: death / progressive disease (N = 2), carcinoid syndrome (N = 1) and sepsis (N = 1). Conclusions: In PRRT-naïve subjects with SSTR+ unresectable or metastatic GEP-NETs treatment with up to 4 cycles of ²¹²Pb-DOTAMTATE (67.6 μCi/kg/cycle) was well-tolerated, with a safety profile consistent with the underlying disease and expected toxicities of radioligand therapy, similar to 177Lu-DOTATATE. The ORR of 47.2% in cohort 1 (50% in the pooled dataset) appears to be substantially higher than the ORR previously reported for 177Lu-DOTATATE in the pivotal NETTER-1 study (ORR 18% (10–25%)). Clinical trial information: NCT05153772 .

The Impact of Trainee Involvement on Outcomes in Metabolic and Bariatric Surgery.

The number of bariatric operations performed in the USA rises annually. Trainee exposure to this field is necessary to ensure competency in future surgical generations. However, the safety of trainee involvement of these operations has been called into question. The aim of our study is to describe differences in outcomes between trainees and non-trainees as first assistants (FA) in sleeve gastrectomy (SG). The Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) database METHODS: Patients from the MBSAQIP database who underwent primary SG from 2015 to 2020 were identified. Statistical analysis included two-tailed t-tests and χ2-tests to evaluate the impact of trainees (residents and fellows) compared to non-trainees on post-operative morbidity and operative time. Of the 559,324 cases, 25.8% were performed with trainees as FA. Operative length was 27.9% longer in trainee cases. In the trainee group, there was a higher risk of conversion to open procedure (OR 1.32), readmission (OR 1.19), and specific complications (cardiac arrest, myocardial infarction, progressive renal insufficiency, pulmonary embolism, sepsis, transfusion, intubation, UTI, VTE, ICU admission, and reintervention), though overall rates were < 1% in each group. Non-trainees had a higher rate of septic shock (OR 1.4). No significant difference was seen in all other perioperative outcomes. Trainee involvement in SG leads to longer operative times without a clinically significant increase in morbidity and mortality. Such findings should be used to counsel patients and shape expectations for surgeons and hospitals. A focused bariatric surgery trainee curriculum may lessen this gap.

Causes of hospitalization and predictors of in-hospital mortality among people living with HIV in Sicily-Italy between 2010 and 2021

BackgroundDespite the rising number of people living with human immunodeficiency virus (HIV), there is a lack of knowledge about the factors that lead to PLWHs being hospitalized in worldwide literature. Our study aimed to investigate PLWH admissions in Sicily (Italy) between January 2010 and September 2021 and to analyze the characteristics and risk factors for in-hospital mortality and differences between Italians and foreigners. MethodsData from the hospital discharge forms of all people living with HIV (PLWH) hospitalized in Sicilian hospitals were retrospectively collected. Age, sex, nationality, length of stay, acquired immunodeficiency syndrome (AIDS), and non-AIDS-related diseases were evaluated using univariate analysis according to in-hospital mortality rates. The factors associated with mortality were included in the logistic regression model. ResultsIn total, 5281 admissions from 2726 PLWHs occurred, most of which were related to non-AIDS diseases. Approximately 20 % regarded foreign patients, mainly from Africa. Logistic regression analysis revealed an association between in-hospital mortality and some AIDS- and non-AIDS-related diseases (wasting syndrome, lymphomas, Kaposi sarcomas, progressive multifocal leukoencephalopathy, cryptococcosis, abscesses, sepsis, cardiovascular disease, nephropathy, and respiratory diseases). African patient admissions were significantly associated with tuberculosis, toxoplasmosis, Burkitt lymphoma, and hepatitis B diagnoses. ConclusionsOur study showed that most hospitalizations were related to non-AIDS-defining diseases, with differences between Italian and foreign patients, mainly from Africa.

Surgical treatment of chest wall defects after purulent arthritis of the sternoclavicular joint

The frequency of purulent arthritis of the sternoclavicular joint is less than 1 % of all joint infections. As a rule, the cause is the hematogenous spread of a generalized infection or trauma.Material and methods. The result of treatment of 24 patients (18 men, 6 women, mean age 38.4 years) with purulent arthritis of the sternoclavicular joints in the period from January 1, 2012 to December 30, 2022 is presented. The causes, clinical manifestations, options for surgical intervention and treatment outcome.Results. Most patients (20 people) complained of pain and tissue swelling in the area of the affected joint. In 4 patients, the main symptom was pain and limited mobility of the arm on the side of inflammation, while no external manifestations of the infectious process were detected. The main laboratory indicators of the inflammatory process were leukocytosis (mean (12 ± 1.6)·109/l) and an increase in CRP from 4 to 86 mg/l (mean 22 ± 4.2 mg/l). 50 % of patients had type 2 diabetes. In 14 patients, in addition to the destroyed sternoclavicular joint, there was damage to the rib/ribs, sternum. In 5 patients, the infectious process was bilateral. Each patient underwent resection of the clavicle and sternum together with the sternoclavicular joint; if the ribs were affected, they were resected. Intraoperative complication was registered in 1 case – erosive bleeding from the right subclavian vein. All patients were treated in two stages. The main pathogen was Staphilococcus aureus. After cleansing the wound, it was closed with local or displaced tissues. Histological examination of removed macropreparations in 18 patients revealed signs of acute osteomyelitis. 5 patients needed intensive care, of which 4 patients died: from progressive sepsis against the background of multiple organ failure and from progressive heart failure against the background of pulmonary edema. Recurrence of the infectious process in the surgical area occurred in 1 patient.Conclusions. Purulent arthritis of the sternoclavicular joint is not an independent disease. Hematogenous damage to this area is associated with a decrease in immunity and the development of a generalized infection. Treatment should be complex, aimed at surgical removal of pathologically altered structures and tissues, as well as intensive therapy to compensate for organ dysfunctions.

A case report of fatal COVID-19 complicated by rapidly progressive sepsis caused by Klebsiella variicola

BackgroundThere is a growing interest in Klebsiella variicola as a causative pathogen in humans, though its clinical features and the impact of co-infection or secondary infection with COVID-19 remain unknown.Case presentationA 71-year-old man presented with fever, altered mental status and generalized weakness and was admitted to ICU due to severe COVID-19 pneumonia. He was newly diagnosed with type II diabetes mellitus upon admission. On hospital day 3, his respiratory status deteriorated, requiring invasive mechanical ventilation. On hospital day 10, superimposed bacterial pneumonia was suspected and subsequently, broad-spectrum antibiotics were administered for the associated bloodstream infection. On hospital day 13, despite administration of active antibiotics and appropriate source control, he decompensated and died.The causative organism isolated from blood cultures was initially reported as K. pneumoniae, but it was identified as K. variicola by a genetic analysis. A representative isolate (FUJ01370) had a novel multilocus sequence typing allelic profile (gapA-infB-mdh-pgi-phoE-rpoB-tonB: 16-24-21-27-52-17-152), to which sequence type 5794 was assigned (GenBank assembly accession: GCA_019042755.1).ConclusionsWe report a fatal case of respiratory and bloodstream infection due to K. variicola complicating severe COVID-19. Co-infection or secondary infection of K. variicola in COVID-19 is likely under-recognized and can be fulminant as in this case.

Outcomes and Management of Sars-CoV2 Omicron Variant in Recipients of Hematopoietic Cell Transplantation (HCT) and CAR-T Therapy

HCT or CAR-T therapy recipients who develop COVID-19 have decreased overall survival (68% Sharma et al. Lancet Haematol. 2021), likely due to disease-inherent and therapy-related immunodeficiency. The development of specific COVID therapies and vaccination during the pandemic has changed the prevention and management of COVID-19 infection. Nevertheless, with the appearance of new SARS-CoV2 variants and omicron, in particular, questions about the severity of disease in high-risk patients are yet to be defined. Methods We included retrospectively 218 adult HCT/CAR-T recipients diagnosed with presumed COVID-19 omicron variant at Memorial Sloan Kettering Cancer Center (MSK), New York, between December 2021 and February 2022. Data were analyzed using SPSS version 26 (IBM, Armonk, NY). Results Among 218 patients, 107 received an autologous HCT, 92 allogeneic HCT, and 19 CAR-T. The median age was 58 years (range, 21 to 87), and 56% were male. The median time from HCT/CAR-T to SARS-CoV2 infection was 44 months (range, 0.1 to 272 months), and 27 patients (12%) acquired SARS-CoV2 within the first 100 days post-HCT/CAR-T. The primary hematologic diagnoses were plasma cell (37%), myeloid (37%), and lymphoid (26%) malignancies. Myeloablative conditioning was performed in 90 patients (41%). In the alloHCT recipients, 17 donors (18%) were matched related, 51 (55%) matched unrelated, 19 (21%) umbilical cord blood, and 5 (6%) haploidentical. 31% patients had 2 or more comorbidities and 9% received IVIG for hypogammaglobulinemia within the prior month. Of note, 40% of the patients were on active cancer therapy (maintenance or treatment) at the time of COVID-19 infection, and 47% of the alloHCT recipients were on GVHD immunosuppressive treatment. Characteristics of COVID-19 omicron variant infection are shown in Table1. Specific COVID-19 treatment was administered in 111 patients (51%) and included MoAbs in 63 patients (56.7%), sotrovimab being the most frequently used (n=55, 87 %), remdesivir (n= 23, 21%), and other antivirals (n= 15, 14%). Risk factors for admission were presence of > 3 comorbidities (HR, 6.2; 95% CI 2.3-16.3, p= 0.000), progression of disease (POD) (HR, 3.8; 95% CI 1.6-8.9, p= 0.002,) and CAR-T therapy (HR 4.5; 95% CI 1.4-14.1p= 0.008). Regarding vaccination status, 84% (n= 183) of the cohort was vaccinated with mRNA Covid-19 vaccines, with 42% of patients having 1 booster before COVID19 infection. Interestingly, only 15/35 (42%) of the booster patients with measured serologic response showed SARS-CoV-19 Antibodies value> 2500 BAU/I. Nineteen patients showed low titer COVID-19 antibodies (<2500 BAU/I) testing after COVID-19 infection: 3 patients died (2 for POD, 1 for COVID), 3 were not vaccinated, 1 patient had to be revaccinated after HCT, and 6 patients were administered tixagevimab/cilgavimab for future prophylaxis. Persistent/Long COVID were present in 8 (3.5%) patients, showing fatigue and URI symptoms 5/8 (62%) had a previous admission for COVID-19 infection and 5/8 (62%) had a negative spike antibody titer before infection. The median duration of viral shedding (positive SARS-CoV-2 PCR) was 11 weeks (range, 3.2 to 19.1 weeks). After a median follow up of 4 months (range, 0 to 8 months), 21 patients (9.6%) had recurrent COVID infection, and two of them died. The overall mortality rate was 10% in all patients (22/218 patients), with 2.5% (6/22) attributable to COVID. Other causes of death were progressive disease (n=13), sepsis (n=1), and hepatic VOD (n=1). Comparing our omicron cohort with the initial 77 HCT & CAR-T patients infected with first wave COVID-19 in March 2020 at our institution, overall survival at 30 days was 94% vs 78% (p=0.010) (Figure 1). Conclusions In our cohort, mortality attributable to the COVID-19 omicron variant was low (2.5%), and only 19% required admission. Risk factors for admission were presence of 3 or more comorbidities, POD at time of COVID infection, and CAR-T therapy. Altogether our date confirms enhanced overall survival (94%) in HCT, and CART recipients infected with the omicron variant of SARS-CoV2 as compared to prior waves of the COVID-19 pandemic. Access to SARS-COV-2 specific treatments and the higher incidence of vaccination in this cohort appear to be key factors to successfully managing patients in order to reduce COVID-19 mortality. Pre-exposure prophylaxis became available later and is also likely important. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Defibrillation Threshold Testing and Long-term Follow-up in Chagas Disease.

Sudden cardiac death is the most common cause of death in chronic Chagas cardiomyopathy (CCC). Because most CCC patients who are candidates for implantable cardioverter-defibrillators (ICD) meet criteria for high defibrillation threshold values, a defibrillator threshold test (DTT) is suggested. We investigated the use of DTT in CCC patients, focusing on deaths related to ICD and arrhythmic events, as well as treatment during long-term follow-up. We retrospectively evaluated 133 CCC patients who received an ICD mainly for secondary prevention. Demographic, clinical, laboratory data, Rassi score, and DTT data were collected, with p < 0.05 considered significant. The mean patient age was 61 (SD, 13) years and 72% were men. The baseline left ventricular ejection fraction was 40 (SD, 15%) and the mean Rassi score was 10 (SD, 4). No deaths occurred during DTT and no ICD failures were documented. There was a relationship between higher baseline Rassi scores and higher DTT scores (ANOVA = 0.007). The mean time to first shock was 474 (SD, 628) days, although shock was only necessary for 28 (35%) patients with ventricular tachycardia, since most cases resolved spontaneously or through antitachycardia pacing. After a mean clinical follow-up of 1728 (SD, 1189) days, 43 deaths occurred, mainly related to progressive heart failure and sepsis. A routine DTT may not be necessary for CCC patients who receive an ICD for secondary prevention. High DTT values seem to be unusual and may be related to high Rassi scores.

Caecal volvulus: a rare entity of intestinal obstruction: 2 cases report

Caecal volvulus is a very rare cause of intestinal obstruction. Patients with this condition may present with variable clinical presentation ranging from intermittent, self-limiting abdominal pain to acute abdominal pain associated with progressive intestinal ischemia, sepsis, and death. In this report, we presented two cases of caecal twist which was diagnosed with series of radiological imaging and labs. The first patient, 83 years old male underwent caecopexy, appendicectomy, and the second female who was 36 years old underwent right hemicolectomy with ileocolic anastomosis. We reported our experience in the management of 2 cases of caecal volvulus in our department.

Renal mucormycosis presenting during the COVID-19 pandemic: A series of 11 cases from a tertiary care center in India.

Introduction:Renal mucormycosis has been documented to occur even in apparently immunocompetent individuals. Owing to the rarity of this disease, literature on its management is small. We present our experience of diagnosing and managing 11 cases of primary renal mucormycosis who presented during the second wave of the COVID-19 pandemic in India.Methods:We reviewed the records of all patients presenting to our institute with a diagnosis of acute pyelonephritis from March 2021 to September 2021. All patients with a radiological, microbiological, or histopathological diagnosis of renal mucormycosis were included in the analysis and all demographic and clinical details, including a history of COVID-19 disease and its treatment, were noted. All patients were treated by a combination of intravenous antifungal therapy and aggressive surgical debridement including nephrectomy and multivisceral resection as required. Predictors of mortality were evaluated by statistical analysis.Results:A total of 93 patients presented to our hospital with features of acute pyelonephritis of which 11 patients were suspected to have primary renal mucormycosis based on characteristic imaging features and confirmed on microbiological and histopathological examination. Of these, four patients had a history of COVID-19 infection. Only one patient had diabetes mellitus. Ten patients underwent nephrectomy and seven needed resections of surrounding organs. The colon was the most commonly involved organ. Five patients (45.5%) died of progressive sepsis. None of the predictors of mortality that were analyzed showed statistical significance.Conclusion:A high index of suspicion, early cross-sectional imaging, prompt institution of antifungal therapy, and aggressive surgical extirpation are very important for achieving good outcomes in patients of primary renal mucormycosis.

Early diagnosis of craniofacial necrotising fasciitis: Analysis of clinical risk factors.

Necrotising fasciitis (NF) is a rapidly progressing fatal disease. Craniofacial necrotising fasciitis (CNF) is limited to the region above the mandibular margin, and early diagnosis is particularly difficult in the absence of related studies. Ten‐year data of patients with craniofacial infection were collected from four separate hospitals. Based on the diagnostic criteria, patients were classified into abscess and CNF. The risk factors for early diagnosis were analysed by comparing the two groups. Simple abscess was found in 176 patients, and CNF was detected in 25 patients. The risk factors associated with CNF include old age, presence of odontogenic infection, elevated white blood cell count (WBC), increased C‐reactive protein (CRP), high levels of creatinine (Cr) and glucose (Glu) and low levels of haemoglobin (Hb) and albumin (Alb). In addition, fever above 38°C and sinusitis at the time of admission and progressive sepsis after admission were also risk factors. Among the statistically significant risk factors, low Alb level showed the greatest association with CNF progression. Appropriate management of CNF via early diagnosis and extensive surgical intervention based on identified risk factors can reduce the mortality rate, complications and unnecessary medical expenses. Clinical question/level of evidence: Diagnostic, III.

Randomized experimental study of two novel techniques for transanal repair of dehiscent low rectal anastomosis.

Anastomotic leak after low anterior rectal resection is a dreadful complication. Early diagnosis, prompt management of sepsis followed by closure of anastomotic defect may increase chances of anastomotic salvage. In this randomized experimental study, we evaluated two different methods of trans-anal anastomotic repair. A model of anastomotic leak was created in 42 male pigs. Laparoscopic low anterior resection was performed with anastomosis created using a circular stapler with half of the staples removed. Two days later, animals were randomized into a TAMIS (trans-anal minimally invasive surgery) repair, endoscopic suture (ENDO) or control group with no treatment (CONTROL). Signs of intraabdominal infection (IAI), macroscopic anastomotic healing and burst tests were evaluated to assess closure quality after animals were sacrificed on the ninth postoperative day. Closure was technically feasible in all 28 animals. Two animals had to be euthanized due to progressive sepsis at four and five days after endoscopic closure. Healed anastomosis with no visible defect was observed in 10/14 and 11/14 animals in TAMIS and ENDO groups, respectively, versus 2/14 in CONTROL (p < 0.05). Overall IAI rate was significantly lower in TAMIS (4/14; p = 0.006) and ENDO (5/14; p = 0.018) compared to CONTROL (12/14). Burst tests confirmed sealed closure in healed anastomosis with a median failure pressure of 190 (110-300) mmHg in TAMIS and 200 (100-300) mmHg in ENDO group (p = 0.644). In this randomized experimental study, we found that both evaluated techniques are effective in early repair of dehiscent colorectal anastomosis with a high healing rate.

Circulating mitochondrial DNA-triggered autophagy dysfunction via STING underlies sepsis-related acute lung injury

The STING pathway and its induction of autophagy initiate a potent immune defense response upon the recognition of pathogenic DNA. However, this protective response is minimal, as STING activation worsens organ damage, and abnormal autophagy is observed during progressive sepsis. Whether and how the STING pathway affects autophagic flux during sepsis-induced acute lung injury (sALI) are currently unknown. Here, we demonstrate that the level of circulating mtDNA and degree of STING activation are increased in sALI patients. Furthermore, STING activation was found to play a pivotal role in mtDNA-mediated lung injury by evoking an inflammatory storm and disturbing autophagy. Mechanistically, STING activation interferes with lysosomal acidification in an interferon (IFN)-dependent manner without affecting autophagosome biogenesis or fusion, aggravating sepsis. Induction of autophagy or STING deficiency alleviated lung injury. These findings provide new insights into the role of STING in the regulatory mechanisms behind extrapulmonary sALI.

Dose-Adjusted Rituximab Mini-CYVE (CYtarabine bolus, VEpeside and dexamethasone) for Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma Not Eligible for High Dose Therapy

Background. There is no current standard of care for the management of patients with relapsed or refractory B-cell non-Hodgkin Lymphoma (R/R B-NHL) ineligible for high-dose therapy. While cytarabine and etoposide are commonly used drugs in salvage regiments for patients eligible for high dose therapy (HDT) and auto-stem cell transplant, data are sparse in the context of ineligibility for high-dose therapy. We designed a dose-adjusted combination of rituximab plus mini-CYVE (CYtarabine bolus, VEpeside and dexamethasone) regimen (R-mini-CYVE), for R/R B-NHL patient's ineligible for HDT.Patients and methods. We retrospectively included patients over 60 years old and ineligible for HDT that received R-mini-CYVE regimen for R/R B-cell NHL between January 2009 and November 2015 at Gustave Roussy, Villejuif, France. Patients must be previously treated with anthracycline-containing chemotherapy regimen. Patients could be included regardless of performance status statement and comorbidity. Treatment consisted of combination of intravenously rituximab mini-CYVE given for six to eight cycles every three weeks. All patients received the same doses of rituximab intravenously 375 mg/m2 at day 1, and oral dexamethasone 40 mg/d at days 1-4. Patients received intravenously cytarabine bolus at days 1 and 2 and vepeside at days 1 to 3. Patients were allocated in four dose levels of chemotherapy (cytarabine bolus and vepeside), according to physician discretion among age and comorbidity. Dose levels of cytarabine/vepeside in mg/m2/d were 500/75 for level 1, 1000/75 for level 2, 1000/100 for level 3 and 1500/100 for level 4. Patients were assessed for response after two cycles and at the end of treatment, by computerized tomography scan according to the international harmonized project Cheson 1999 criteria. Primary endpoints were overall survival, and overall response rate (ORR) at the end of treatment. Toxicity was registered according to the CTCAEv4.03.Results. Thirty-seven patients (21 men and 16 woman) received at least one cycle of rituximab mini-CYVE treatment. Among them, the reasons for no eligibility to HDT were a poor performance status over 2 (n=28), renal impairment with glomerular filtration rate below 60 ml/min (n=7), hearing impairment (n=2). Histological types were diffuse large B-cell lymphoma in 31/37 (84 %) patients and indolent B-cell NHL in 6/37 (16 %) patients. At inclusion, median age was 75 [61-88] years old, median number of prior therapies lines was 1 [1-5], Ann-Arbor stage was 3 or 4 in 28/37 (76%) and serum lactate dehydrogenase was increase in 19/37 (51%) patients. Thirteen, 9, 8 and 7 patients received the dose levels 1, 2, 3 and 4, respectively. Median number of cycles was 4 [1-8]. Hematological adverse events grade 3-5 were experienced in 26/37 (70%) patients, and non-hematological grade 3-4 adverse event in 7/37 (19%) patients. One patient died from febrile neutropenia grade 5 during treatment. Non-hematological grade 3-4 adverse events were sepsis in 6/37 (16%) patients and acute cerebellar syndrome related to aracytine at dose level 2 in 1/37 (3%) of patients. Adverse events led to treatment discontinuation in 4/37 (11 %) of pts. ORR was 43% (16/37 pts) including 35% (13/37 pts) of CR or CRu and 8% (3/37) of PR. Median OS and PFS were 13.2 (95% C.I, 9.8-16.6 months), and 6.4 (95% C.I, 1.2 - 11.5) months. With a median follow-up of 12 [range 1 to 60] months, 25/37 patients (67%) had died from progressive disease (n=21), sepsis (n=3) or pulmonary embolism (n=1).Conclusion. The dose-adjusted rituximab mini-CYVE regimen demonstrated a favorable safety and efficacy profile in R/R B-cell NHL patients not eligible for high-dose chemotherapy. Further studies are warranted to investigate this regimen in this population of patients. DisclosuresRibrag:BMS: Honoraria; Roche: Honoraria; Infinity: Honoraria; MSD: Honoraria; Nanostring: Honoraria; Gilead: Honoraria; Servier: Consultancy, Honoraria; ArgenX: Research Funding; Epizyme: Honoraria.

Updated Safety and Efficacy of Venetoclax with Decitabine or Azacitidine in Treatment-Naive, Elderly Patients with Acute Myeloid Leukemia

Updated Safety and Efficacy of Venetoclax with Decitabine or Azacitidine in Treatment-Naive, Elderly Patients with Acute Myeloid Leukemia

Postmortem whole-genome sequencing on a dried blood spot identifies a novel homozygous SUOX variant causing isolated sulfite oxidase deficiency.

Rapid whole-genome sequencing (rWGS) has shown that genetic diseases are a common cause of infant mortality in neonatal intensive care units. Dried blood spots collected for newborn screening allow investigation of causes of infant mortality that were not diagnosed during life. Here, we present a neonate who developed seizures and encephalopathy on the third day of life that was refractory to antiepileptic medications. The patient died on day of life 16 after progressive respiratory failure and sepsis. The parents had lost two prior children after similar presentations, neither of whom had a definitive diagnosis. Postmortem rWGS of a dried blood spot identified a pathogenic homozygous frameshift variant in the SUOX gene associated with isolated sulfite oxidase deficiency (c.1390_1391del, p.Leu464GlyfsTer10). This case highlights that early, accurate molecular diagnosis has the potential to influence prenatal counseling and guide management in rare, genetic disorders and has added importance in cases of a strong family history and risk factors such as consanguinity.

Guillain-Barré Syndrome after Lung Transplantation in the Immediate Postoperative Period

A 58-year-old man, incapable of maintaining oxygen saturation with mechanical ventilation, was admitted to our hospital for veno-venous extracorporeal membrane oxygenation (ECMO) treatment. He was diagnosed with acute respiratory distress syndrome (ARDS) due to influenza A pneumonia. His condition stabilized with antibiotics and steroid administration, but weaning from ECMO failed due to post-infectious pulmonary sequelae. On day 84 after admission, he underwent bilateral lung transplantation. In the postoperative phase, he did not regain consciousness even after discontinuation of sedatives for 3 days. However, spontaneous pupillary reflex and eye movements were preserved, while communication and upper and lower limb movements were affected. The nerve conduction study was diagnostic of Guillain-Barre syndrome. He was managed with intravenous immunoglobulins and plasmapheresis. Mild recovery of the facial muscles was seen, but he died 24 days post-surgery due to progressive ARDS and sepsis.

A Mouse Model of Candidiasis.

The intravenous challenge model of Candida albicans infection in mice is a well-established procedure that mirrors disseminated candidiasis in humans. In this model, in which the fungus is delivered into the bloodstream causing a systemic infection, the kidneys are the primary target organs. Mice develop renal failure and septic shock that recapitulates the progressive sepsis seen in humans during severe clinical cases. This model is used to study inflammation and the host immune response against fungal infection. This chapter describes the intravenous candidiasis infection protocol, detailing different steps from the preparation of the inoculum, injection of Candida, monitoring of animals, collection of tissue from infected mice, sample preparation and analysis of several parameters related to infection and the inflammatory response.

Evaluation of Mesenchymal Stem Cell Therapy for Sepsis: A Randomized Controlled Porcine Study.

Background: Treatment with mesenchymal stem cells (MSCs) has elicited considerable interest as an adjunctive therapy in sepsis. However, the encouraging effects of experiments with MSC in rodents have not been adequately studied in large-animal models with better relevance to human sepsis.Objectives: Here, we aimed to assess safety and efficacy of bone marrow-derived MSCs in a clinically relevant porcine model of progressive peritonitis-induced sepsis.Methods: Thirty-two anesthetized, mechanically ventilated, and instrumented pigs were randomly assigned into four groups (n = 8 per group): (1) sham-operated group (CONTROL); (2) sham-operated group treated with MSCs (MSC-CONTROL); (3) sepsis group with standard supportive care (SEPSIS); and (4) sepsis group treated with MSCs (MSC-SEPSIS). Peritoneal sepsis was induced by inoculating cultivated autologous feces. MSCs (1 × 106/kg) were administered intravenously at 6 h after sepsis induction.Results: Before, 12, 18, and 24 h after the induction of peritonitis, we measured systemic, regional, and microvascular hemodynamics, multiple-organ functions, mitochondrial energy metabolism, systemic immune-inflammatory response, and oxidative stress. Administration of MSCs in the MSC-CONTROL group did not elicit any measurable acute effects. Treatment of septic animals with MSCs failed to mitigate sepsis-induced hemodynamic alterations or the gradual rise in Sepsis-related organ failure assessment scores. MSCs did not confer any protection against sepsis-mediated cellular myocardial depression and mitochondrial dysfunction. MSCs also failed to modulate the deregulated immune-inflammatory response.Conclusion: Intravenous administration of bone marrow-derived MSCs to healthy animals was well-tolerated. However, in this large-animal, clinically relevant peritonitis-induced sepsis model, MSCs were not capable of reversing any of the sepsis-induced disturbances in multiple biological, organ, and cellular systems.

PB2000 OUTCOME OF PEDIATRIC NODULAR LYMPHOCYTE PREDOMINANT HODGKIN LYMPHOMA, IS ABVD THE BEST REGIMEN? 10 YEARS SINGLE CENTER EXPERIENCE, REPORT FROM CHILDREN CANCER HOSPITAL, EGYPT.

Background:Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is an uncommon subtype of Hodgkin lymphoma (HL) in children and accounts for 5–10% of all pediatric HL.Aims:The aim of the study to analyze the clinical characteristics and treatment outcome of Pediatric NLPHL.Methods:Retrospective study including all newly diagnosed patients less than 18 years old with NLPHL and treated in children cancer hospital Egypt CCHE between 2007 and 2017.Results:Among 43 pediatric NLPHL patients, 29 had early stage (18 with stage I, 11 with stage II). Fourteen patients had advanced stage (7 with stage III &amp; 7 with stage IV). Eleven patients had a mediastinal disease, 8 patients had splenic involvement, 2 patient had bulky disease and 10 patient had B symptoms at diagnosis.28 Patients with Early‐stage disease treatment; surgery and observation 6 patients, Chemotherapy 6 patients and Combined modality 17 patients. Relapse was seen in 7(25%) patients, 1 observation arm, 3 from chemotherapy arm (ABVD) and 3 from the combined arm (ABVD+IFRTH). 14 advanced stage patients received treatment; Chemotherapy (ABVD) 6 patients, Combined (ABVD+IFRTH) 8 patients, Relapse in 7 (50%) patients (all stage 4 disease), 6 from chemotherapy arm and 1 from the combined arm. 2 patients died (stage IV) from progressive disease and sepsis. B symptoms, mediastinal and splenic involvement had a significant impact on DFS on univariate analysis while combined treatment modality (Chemotherapy and Radiotherapy) had an impact on the outcome of both univariate and multivariate analysis.5 Years DFS, OS for whole group was 64% and 94% respectively, while 5y DFS for early stage 83% and advanced stage 45% (p‐value = .01) and 5 Years OS for early stage was 100% and advanced stage 87 % (p‐value = .08).Summary/Conclusion:Early stage NLPHL had a better outcome but unexpected higher relapse in chemotherapy treatment arm raising a question about the role of radiotherapy while advanced stage disease had poor outcome rising a question of what should be the best chemotherapy regimen for pediatric NLPHL patients.

Vagus Nerve Stimulation Attenuates Multiple Organ Dysfunction in Resuscitated Porcine Progressive Sepsis.

To investigate the potential benefits of vagus nerve stimulation in a clinically-relevant large animal model of progressive sepsis. Prospective, controlled, randomized trial. University animal research laboratory. Twenty-five domestic pigs were divided into three groups: 1) sepsis group (eight pigs), 2) sepsis + vagus nerve stimulation group (nine pigs), and 3) control sham group (eight pigs). Sepsis was induced by cultivated autologous feces inoculation in anesthetized, mechanically ventilated, and surgically instrumented pigs and followed for 24 hours. Electrical stimulation of the cervical vagus nerve was initiated 6 hours after the induction of peritonitis and maintained throughout the experiment. Measurements of hemodynamics, electrocardiography, biochemistry, blood gases, cytokines, and blood cells were collected at baseline (just before peritonitis induction) and at the end of the in vivo experiment (24 hr after peritonitis induction). Subsequent in vitro analyses addressed cardiac contractility and calcium handling in isolated tissues and myocytes and analyzed mitochondrial function by ultrasensitive oxygraphy. Vagus nerve stimulation partially or completely prevented the development of hyperlactatemia, hyperdynamic circulation, cellular myocardial depression, shift in sympathovagal balance toward sympathetic dominance, and cardiac mitochondrial dysfunction, and reduced the number of activated monocytes. Sequential Organ Failure Assessment scores and vasopressor requirements significantly decreased after vagus nerve stimulation. In a clinically-relevant large animal model of progressive sepsis, vagus nerve stimulation was associated with a number of beneficial effects that resulted in significantly attenuated multiple organ dysfunction and reduced vasopressor and fluid resuscitation requirements. This suggests that vagus nerve stimulation might provide a significant therapeutic potential that warrants further thorough investigation.