Transient Elevation Of Liver Enzymes Research Articles

Efficacy and Safety of Sirolimus for Blue Rubber Bleb Nevus Syndrome: A Prospective Study.

Blue rubber bleb nevus syndrome (BRBNS) is a rare systemic venous malformation (VM) disease. The characteristic gastrointestinal (GI) bleeding from multiple VM lesions causes severe chronic anemia which renders most patients depend on lifelong blood transfusion and frequent endoscopic treatment with dismayed outcomes. Although recent case reports suggest that oral sirolimus (rapamycin) is effective, a comprehensive evaluation of its efficacy and safety is in need. A prospective study was conducted for both pediatric and adult BRBNS patients with administration of sirolimus at the dose of 1.0 mg/m2 to maintain a trough concentration of 3-10 ng/mL. Laboratory tests including complete blood count, biochemical profile, D-dimer, and whole-body magnetic resonance imaging were performed at baseline and 3, 6, and 12 months after treatment. Clinical indicators such as hemoglobin level, lesion size, and transfusion need were evaluated. Adverse effects were recorded regularly. A total of 11 patients (4 males and 7 females) with median age of 14 (range, 5-49) years were recruited. The average lesion size was reduced by 7.4% (P < 0.001), 9.3% (P < 0.001), and 13.0% (P < 0.05) at 3, 6, and 12 months of sirolimus treatment, respectively. Hemoglobin increased significantly after 6- and 12-month treatment (P = 0.006 and 0.019, respectively). Only 1 patient received blood transfusion once during the study. Patients' quality of life and coagulation function were improved. Grade 1-2 adverse effects including oral ulcers (81.8%), acne (27.3%), transient elevation of liver enzymes (18.2%), and hair loss (9.1%) were observed. Sirolimus reduces the size of VMs, alleviates GI bleeding, and eliminates transfusion dependence of patients with BRBNS. The drug-related adverse effects are mild and mostly self-limited. These findings support sirolimus as a first-line treatment for GI and cutaneous VMs of BRBNS (see Visual abstract, Supplementary Digital Content, http://links.lww.com/AJG/B819).

SURG-10. SPECTROSCOPIC MEASUREMENT OF 5-ALA-INDUCED INTRACELLULAR PROTOPORPHYRIN IX IN PEDIATRIC BRAIN TUMORS

OBJECTIVE5-ALA guided resection of glioma in adults enables better delineation between tumor and normal brain, allowing improved resection and improved patients’ outcome. Recently, several reports were published regarding 5-ALA for resection of pediatric brain tumors. The aim of the study was to determine the intracellular fluorescence of PPIX in pediatric brain tumors by hyperspectral imaging and to compare it with visually observed intraoperative fluorescence.METHODS5-ALA was administered orally four hours prior to surgery. During tumor resection the surgeon assessed the fluorescence signal to be strong, weak or absent. Subsequently, fluorescence intensity of samples was measured via spectroscopy. In addition, clinical data, imaging and laboratory data were analyzed.RESULTSEleven children (1–16 years) were operated. Tumor entities included: three medulloblastomas, two pilocytic astrocytomas (PA), two anaplastic ependymomas and one diffuse astrocytoma, anaplastic astrocytoma, pilomyxoid astrocytoma and anaplastic pleomorphic xanthoastrocytoma. Strong fluorescence was visible in all anaplastic tumors and one PA; one PA demonstrated weak fluorescence. Visible fluorescence was strongly associated with intracellular fluorescence intensity and PPIX concentration (P<0.05). Within all tumors with visible fluorescence the intracellular PPIX concentration was greater than 4 µg/ml. Except for moderate and transient elevation of liver enzymes, no 5-ALA related adverse events were reported.CONCLUSIONWe demonstrate a strong association between intraoperative observations and spectrometric measurements of PPIX fluorescence in tumor tissue. As in former studies, fluorescence signal was more commonly observed in malignant glial tumors. Further prospective controlled trials should be conducted to investigate the feasibility of 5-ALA guided resection of pediatric brain tumors.

S2408 Sunitinib-Induced Acute Liver Failure: A Case Presentation

INTRODUCTION: Drug-induced liver injury is an uncommon but a life-threatening entity. Sunitinib, a tyrosine kinase inhibitor (TKI), is used for advanced and imatinib-refractory gastrointestinal stromal tumors. It causes a transient elevation of liver enzymes in about 39% of patients while grade 3 and 4 hepatotoxicities in 3 % of patients. The incidence of fatal acute liver failure is rare. The incidence of acute cardiomyopathy is seen in 10% of patients. We present a case of fatal acute liver failure and cardiomyopathy within two weeks of sunitinib therapy initiation for advanced pancreatic neuroendocrine carcinoma. CASE DESCRIPTION/METHODS: A 64-year-old male with stage IV high grade pancreatic neuroendocrine carcinoma with metastasis to the liver, spleen, and left adrenal gland, presented with right upper quadrant abdominal pain, nausea, and lethargy. The patient was started on Sunitinib, a month prior to presentation. It was discontinued two weeks before admission due to severe fatigue, decreased oral intake, and dehydration. Physical exam was positive for jaundice, disorientation to time, place, and person and asterixis. The trend of liver function tests during the course of hospitalization is presented in Table 1. The workup to determine other causes of acute liver failure was unremarkable. The patient was started on N-acetylcysteine protocol for acute liver failure and lactulose and rifaximin for suspected hepatic encephalopathy. The patient was not a candidate for a transplant due to stage IV cancer. Transthoracic echocardiography showed new-onset severe acute cardiomyopathy with an ejection fraction of 20–25%. The patient's mental status did not improve despite 3–4 bowel movements per day. Despite aggressive supportive care, his liver failure was irreversible and the patient passed away on day 5 of hospitalization. DISCUSSION: Sunitinib causes time and concentration-dependent cellular injury. The pattern of liver injury is typically hepatocellular. Definitive management of organ dysfunction includes withholding of sunitinib along with supportive care. This case emphasizes that overt liver failure and systolic cardiac dysfunction are infrequent but possibly fatal complications of Sunitinib therapy. We recommend periodic monitoring of baseline liver function and cardiac function status for patients on Sunitinib therapy, especially within the first year of treatment.Table 1.: The trend of liver function tests during the course of hospitalization.

Gene Therapy for Hemophilia: Facts and Quandaries in the 21st Century.

Therapy for hemophilia has evolved in the last 40 years from plasma-based concentrates to recombinant proteins and, more recently, to non-factor therapeutics. Along this same timeline, research in adeno-associated viral (AAV) based gene therapy vectors has provided the framework for early phase clinical trials initially for hemophilia B (HB) and now for hemophilia A. Successive lessons learned from early HB trials have paved the way for current advanced phase trials. Nevertheless, questions linger regarding 1) the optimal balance of vector dose to transgene expression, 2) amount and durability of transgene expression required, and 3) long-term safety. Some trials have demonstrated unique findings not seen previously regarding transient elevation of liver enzymes, immunogenicity of the vector capsid, and loss of transgene expression. This review will provide an update on the clinical AAV gene therapy trials in hemophilia and address the questions above. A thoughtful and rationally approached expansion of gene therapy to the clinics would certainly be a welcome addition to the arsenal of options for hemophilia therapy. Further, the global impact of gene therapy could be vastly improved by expanding eligibility to different patient populations and to developing nations. With the advances made to date, it is possible to envision a shift from the early goal of simply increasing life expectancy to a significant improvement in quality of life by reduction in spontaneous bleeding episodes and disease complications.

Effectiveness of Transarterial Embolization in Treatment of Symptomatic Hepatic Hemangiomas: Systematic Review and Meta-analysis.

To evaluate the current evidence for the effectiveness of transarterial embolization (TAE) in treatment of symptomatic hepatic hemangiomas. A systematic literature review was conducted in PubMed, CINAHL and Scopus databases to identify studies of hepatic hemangiomas treated with transarterial embolization. Main outcome was defined as the mean difference between pre- and post-TAE hemangioma diameters. Treatment agents were categorized as Lipiodol based [bleomycin (L + BE), pingyangmycin (L + PYG) or ethanol (L + ethanol)] and non-Lipiodol based (polyvinyl-alcohol-only). Conventional random-effect meta-analysis technique was applied to analyze data. Of 3080 initially inspected publications, 21 studies were included in the meta-analysis comprising of 1450 patients with total of 1871 hemangiomas (36.2% male, mean age: 46.3 ± 3.6years). One hundred and twenty-six, 1666, 41 and 38 lesions were treated with L + BE, L + PYG, L + ethanol and PVA, respectively. Median follow-up time after embolization was 12months. Lipiodol-based treatments showed significant effect in reducing hemangioma size after TAE compared to PVA (P < 0.001). Pooled diameter reduction (cm) (95% confidence interval) was - 4.37( - 5.32, - 3.42), - 4.70( - 5.70, - 3.71), - 0.93( - 2.02, 0.16) for overall TAE treatment, Lipiodol-based and non-Lipiodol-based treatments, respectively. Main complications included post-embolization syndrome and transient liver enzyme elevation (pooled incidence for Lipiodol-based and non-Lipiodol-based techniques: 36% and 33%; and 37% and 0, respectively). No fatal complications were reported. Symptomatic improvement was reported in 63.3%-100% of the cases with majority of studies (15/21) reporting improvement in all cases (pooled response rate: 98%). Transarterial embolization with bleomycin, pingyangmycin or ethanol in combination with Lipiodol is safe and associated with reduced size of hemangiomas resulting in symptoms alleviation.

Efficacy and safety of octreotide treatment for diazoxide-unresponsive congenital hyperinsulinism in China.

ABSTRACTImportanceOctreotide is an off‐label medicine for congenital hyperinsulinism (CHI), but is currently widely used for treatment of patients with CHI. Thus far, variable efficacy and adverse effects have been reported for octreotide.ObjectiveThe present study evaluated the efficacy and safety of a subcutaneous octreotide injection for treatment of diazoxide‐unresponsive CHI in China.MethodsThis study was a retrospective review of children with diazoxide‐unresponsive CHI who were treated with a subcutaneous octreotide injection. The efficacy and side effects of the treatment were assessed.ResultsTwenty‐five Chinese children (15 boys) were involved in the study. Their median age at diagnosis was 8 weeks (range, 1–24 weeks) and median age at the final follow‐up was 1.8 years (range, 0.3–3.3 years). Octreotide therapy effectively increased blood glucose levels in all patients. The intravenous glucose infusion rate was reduced in all patients. Twenty‐one patients gradually discontinued the intravenous glucose infusion while receiving octreotide combined with frequent carbohydrate/glucose‐rich feeding. Among patients with a monoallelic ATP‐sensitive potassium (KATP) channel mutation, 50.0% showed gradual remission during follow up, indicating that the octreotide treatment may be a feasible alternative to surgery, especially for patients with monoallelic KATP‐channel mutations. Transient elevation of liver enzymes occurred in 20.0% of patients, while asymptomatic gallbladder pathology occurred in one patient. The growth rates of these patients were normal (height standard deviation score was 0.3 ± 1.5 at the final follow‐up).InterpretationOctreotide was a well‐tolerated, effective therapy for most children with diazoxide‐unresponsive CHI.

Effect of laparoscopy on liver enzymes

Background: Laparoscopic procedures have gained popularity in recent days because of advantages like small incision, less postoperative pain and discomfort, short hospital stay, early ambulation and early discharge. Very few studies are available to correlate Laparoscopic Surgeries and liver enzyme elevation. This effect may be due to either CO2 pneumoperitoneum, diathermy extruding liver, injury to branch of the hepatic artery or general anesthesia. This study was done to evaluate the changes in liver enzymes pre-operatively and post-operatively following laparoscopy.Methods: This prospective study included 103 patients who underwent various laparoscopic surgeries over a period of 2 years in Bharati Hospital &amp; Research Centre, Pune, India. Serum AST, ALT and bilirubin levels were measured preoperatively and on post-operative day 1 and post-operative day 3. Patients with coexisting liver disease, Patients on long term use of hepatotoxic drugs, patients who developed complications such as CBD injury, obstruction, infection, leakage and high grade fever during surgery and in the post-operative period were excluded.Results: All laparoscopic procedures cause a transient elevation of serum bilirubin and liver enzymes. Elevation in the liver enzymes correlated directly with the duration of pneumoperitoneum. Elevation in the serum bilirubin but doesn’t correlates with the duration of pneumoperitoneum. These elevations do not have clinical significance in patients with normal hepatic function preoperatively.Conclusions: Duration of laparoscopic procedure should be kept to minimum and undue prolongation should be avoided. Decision to convert the operation to open surgery from a laparoscopic surgery should be prompt.

The outcomes of transient elevation of maternal liver enzymes preceding laser treatment for twin-twin transfusion syndrome

BackgroundA proportion of twin-twin transfusion syndrome (TTTS) patients may have elevated liver enzymes (ELEzs) before fetoscopic laser therapy, but the incidence of ELEzs before laser therapy and the association with the perinatal outcomes after laser therapy remain unclear. MethodsFrom October 2008 to April 2015, 93 patients with TTTS who received fetoscopic laser therapy at our hospital were included in this study, and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were measured within 24 h before therapy. If ELEzs (AST > 34 U/L or ALT > 36 U/L) were observed before therapy, the AST and ALT levels were evaluated within 24 h after therapy. The pre-operative characteristics and post-therapy outcomes were compared between patients with and without ELEzs. ResultsAmong 93 TTTS patients before laser operation, 18 patients (were found with ELEzs (19.4%) before laser therapy. In 17 (94.4%) of the 18 cases, their liver enzymes values dropped after laser surgery. Maternal body mass index, age, gestational age of laser therapy, hemoglobin level before laser therapy and survival rates after laser therapy were not significantly different between TTTS with and without ELEzs. The maternal hemoglobin dropped significantly from 10.8 [1.6] g/dL before surgery to 9.6 [1.5] g/dL after laser therapy in TTTS with ELEzs (p < 0.001). ConclusionAn elevated liver enzyme was not associated with poor perinatal outcomes in patients with TTTS after laser therapy. The authors suspected that the reduced liver enzymes values after laser therapy could partly arise from the hemo-dilution effect.

Spectroscopic measurement of 5-ALA-induced intracellular protoporphyrin IX in pediatric brain tumors.

5-Aminolevulinic acid (5-ALA)-guided resection of gliomas in adults enables better delineation between tumor and normal brain, allowing improved resection and improved patients' outcome. Recently, several reports were published regarding 5-ALA for resection of pediatric brain tumors. The aim of the study was to determine the intracellular fluorescence of protoporphyrin IX (PPIX) in pediatric brain tumors by hyperspectral imaging and to compare it with visually observed intraoperative fluorescence. 5-ALA was administered orally 4h prior to surgery. During tumor resection, the surgeon assessed the fluorescence signal to be strong, weak, or absent. Subsequently, fluorescence intensity of tumor samples was measured via spectroscopy. In addition, clinical data, imaging, and laboratory data were analyzed. Eleven children (1-16years) were operated. Tumor entities included three (n = 3) medulloblastomas, two (n = 2) pilocytic astrocytomas (PA), two (n = 2) anaplastic ependymomas and one (n = 1) diffuse astrocytoma, anaplastic astrocytoma (n = 1), pilomyxoid astrocytoma (n = 1) and anaplastic pleomorphic xanthoastrocytoma (n = 1). Strong fluorescence was visible in all anaplastic tumors and one PA; one PA demonstrated weak fluorescence. Visible fluorescence was strongly associated with intracellular fluorescence intensity and PPIX concentration (P < 0.05). Within all tumors with visible fluorescence, the intracellular PPIX concentration was greater than 4μg/ml. Except for moderate and transient elevation of liver enzymes, no 5-ALA related adverse events were reported. We demonstrate a strong association between intraoperative observations and spectrometric measurements of PPIX fluorescence in tumor tissue. As in former studies, fluorescence signal was more commonly observed in malignant glial tumors. Further prospective controlled trials should be conducted to investigate the feasibility of 5-ALA-guided resection of pediatric brain tumors.

Advances and challenges for hemophilia gene therapy.

Hemophilia is an X-linked inherited bleeding disorder, resulting from defects in the F8 (hemophilia A) or F9 (hemophilia B) genes. Persons with hemophilia have bleeding episodes into the soft tissues and joints, which are treated with self-infusion of factor VIII or IX concentrates. Hemophilia provides an attractive target for gene therapy studies, due to the monogenic nature of these disorders and easily measurable endpoints (factor levels and bleed rates). All successful, pre-clinical and clinical studies to date have utilized recombinant adeno-associated viral (AAV) vectors for factor VIII or IX hepatocyte transduction. Recent clinical data have presented normalization of factor levels in some patients with improvements in bleed rate and quality of life. The main toxicity seen within these studies has been early transient elevation in liver enzymes, with variable effect on transgene expression. Although long-term data are awaited, durable expression has been seen within the hemophilia dog model with no late-toxicity or oncogenesis. There are a number of phase III studies currently recruiting; however, there may be some limitations in translating these data to clinical practice, due to inclusion/exclusion criteria. AAV-based gene therapy is one of a number of novel approaches for treatment of hemophilia with other gene therapy (in vivo and ex vivo) and non-replacement therapies progressing through clinical trials. Availability of these high-cost novel therapeutics will require evolution of both clinical and financial healthcare services to allow equitable personalization of care for persons with hemophilia.

The first report of atovaquone/proguanil-induced vanishing bile duct syndrome: Case report and mini-review.

The combination of Atovaquone and Proguanil (Malarone™) has been widely used for treatment and prevention of Plasmodium falciparum malaria. Transient elevation of liver enzymes is a recognized side effect of the medication. The association of Vanishing bile duct syndrome (VBDS) with the use of Atovaqoune/Proguanil was not previously reported. We describe a case of a 62-year-old male with no history of liver disease who presented with painless jaundice after receiving malaria prophylaxis with Atovaquone-proguanil for 25 days. The patient developed severe hepatitis with Vanishing bile duct syndrome. This case highlights a serious side effect of a usually well-tolerated medication.

Comparative study of postoperative hepatic and renal function changes in laparoscopic and open cholecystectomy

Background: It has been shown that there is a transient elevation of serum liver enzymes after laparoscopic surgeries and major causative factor seemed to be the CO2 pneumoperitoneum. In most of the cases, it does not have any clinical significance in the patient with normal preoperative liver function. However, in patients with deranged liver function, these changes can have great significance.Methods: The present study was designed to determine and compare changes in liver function tests and renal function test following laparoscopic cholecystectomy and open cholecystectomy. This study was conducted on 100 patients admitted to Swaroop Rani Nehru Hospital, Allahabad, India from August 2017 to January 2019 who were having symptomatic cholelithiasis with a history of either acute cholecystitis, biliary colic or chronic cholecystitis. All patients were investigated for complete liver function tests and renal function test including serum bilirubin, SGOT, SGPT, alkaline phosphatase, LDH, S. urea, S. creatinine, S. Na+, S. K+, S. Ca+ and urinary sodium (UNa+). The laboratory tests were carried out in the same laboratory using one type of instrument.Results: In open cholecystectomy, bilirubin decreased by 11% (p value equals 0.191) and remained decreased to the preoperative value on day 1 and day 7. While, laparoscopic cholecystectomy at 14 mmHg pressure, mean bilirubin decreases by 14% immediately postoperatively (p value equals 0.1733) and returns to normal level in 7 days. These changes are clinically insignificant and statistically insignificant.Conclusions: Enzyme elevations could mostly be attributed to the adverse effects of the pneumoperitoneum on the hepatic blood flow and renal blood flow and CO2 absorption in the blood. Though, these changes do not seem to be clinically significant, care should be taken before deciding to perform laparoscopic cholecystectomy. This study suggested that laparoscopic cholecystectomy is a safe operative procedure and have added advantages. The disturbances in the function of the kidney after laparoscopic cholecystectomy are self-limited and not associated with any morbidity in patients with a healthy kidney function.

Hematopoietic chimerism and donor-specific skin allograft tolerance after non-genotoxic CD117 antibody-drug-conjugate conditioning in MHC-mismatched allotransplantation

Hematopoietic chimerism after allogeneic bone marrow transplantation may establish a state of donor antigen-specific tolerance. However, current allotransplantation protocols involve genotoxic conditioning which has harmful side-effects and predisposes to infection and cancer. Here we describe a non-genotoxic conditioning protocol for fully MHC-mismatched bone marrow allotransplantation in mice involving transient immunosuppression and selective depletion of recipient hematopoietic stem cells with a CD117-antibody-drug-conjugate (ADC). This protocol resulted in multilineage, high level (up to 50%), durable, donor-derived hematopoietic chimerism after transplantation of 20 million total bone marrow cells, compared with ≤ 2.1% hematopoietic chimerism from 50 million total bone marrow cells without conditioning. Moreover, long-term survival of bone marrow donor-type but not third party skin allografts is achieved in CD117-ADC-conditioned chimeric mice without chronic immunosuppression. The only observed adverse event is transient elevation of liver enzymes in the first week after conditioning. These results provide proof-of-principle for CD117-ADC as a non−genotoxic, highly-targeted conditioning agent in allotransplantation and tolerance protocols.

MP0250 Combined with Bortezomib and Dexamethasone in Multiple Myeloma Patients Previoulsy Exposed to Proteasome Inhibitors and Immunomodulatory Drugs

BackgroundMP0250 is a first-in-class selective tri-specific multi-DARPin® drug candidate neutralizing VEGF-Α and HGF as well as binding to human serum albumin to increase its plasma half-life. Preclinical studies have shown that MP0250 enhances sensitivity of Multiple Myeloma (MM) cells to bortezomib, inhibits tumor growth and reduces bone destruction. In this clinical phase 2 trial (NCT03136653), we are investigating the safety, tolerability and efficacy of the combination of MP0250 plus bortezomib and dexamethasone (dex) in patients (pts) with relapsed/refractory (RR) MM previously exposed to proteasome inhibitors (PI) and immunomodulatory drugs (IMiD).AimsTo study the efficacy and safety of MP0250 in combination with bortezomib and dexamethasone in patients with RRMM.Trial DesignThis trial is recruiting adults ≥18 years of age with RRMM who have progressed after at least two prior treatment regimens including bortezomib and an IMiD. A dose-escalation phase (part 1) consisting of two cohorts will define a safe dose of the combination of MP0250 plus bortezomib + dex followed by a dose-expansion phase (part 2). Patients were enrolled to receive iv MP0250 on day 1 + subcutaneous bortezomib 1.3 mg/m² on days 1, 4, 8, 11, oral dexamethasone (dex) 20 mg on days 1-2, 4-5, 8-9, 11-12 of each 21-day cycle. Up to 40 patients will be enrolled. Patients will receive treatment until there is documented disease progression or unacceptable toxicity.MethodsThe primary endpoint is efficacy in terms of overall response rate (ORR) per International Myeloma Working Group criteria. Secondary endpoints include safety, immunogenicity, progression free survival (PFS) and duration of response (DOR). Exploratory endpoints include overall survival, pharmacokinetics and potential biomarkers that include MM specific markers and cytokines monitoring bone homeostasis. The safety analysis set (SAF) is defined as patients who have received at least 1 dose of the combination of MP0250 plus bortezomib + dex.ResultsData cut off was 21 July 2018. 8 pts have been treated in cohort 1 and 3 pts in cohort 2. Median time from initial diagnosis to first dose was 4.8 years (range, 1-10). Median number of prior therapies was 3 (range, 2-5). All 11 pts had prior exposure to IMiDs and PIs and 4 pts were considered PI refractory. Four patients received PI immediately prior to receive MP250 in combination. The most frequent drug-related grade ≥ 3 AEs: hypertension in 3 pts, thrombocytopenia in 6 pts, proteinuria in 2 pts and transient liver enzyme elevation in 1 patient. One dose-limiting toxicity has been reported in cohort 1 (grade 3 hypertension) and two in cohort 2 (grade 3 epistaxis, grade 3 proteinuria). There were no infusion-related reactions. Best response achieved in the 8 efficacy evaluable pts in cohort 1 was VGPR in 1 and PR in 4 for an overall response rate (ORR, ≥PR) of 62.5%. In cohort 2, 1 patient achieved Minimal Response (MR), 1 patient stable disease and 1 progressive disease. Three of four patients who were coming immediately from a PI based regimen achieved a response. Pharmacokinetics data in cohort 1 show sustained exposure over multiple cycles with a mean half-life of 11 days, and no indication of ADA mediated drug clearance was observed. Data from cohort 1 patients show accumulation of MP0250-HGF complexes over multiple cycles confirming the stable binding of MP0250 to HGF suggesting that all circulating HGF is neutralized.SummaryData from cohort 1 (8 mg/Kg q3w) suggest that MP0250 can be safely combined with bortezomib and dex in patients with relapsed and refractory MM. Durable responses were seen in patients who came from PI based pretreatment suggesting that MP0250 might be capable to reverse PI resistance. DisclosuresKnop:Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Goldschmidt:Sanofi: Consultancy, Research Funding; ArtTempi: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Adaptive Biotechnology: Consultancy; Amgen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding. Raab:BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Dürig:Janssen: Consultancy, Honoraria; Celgene: Honoraria; Roche: Honoraria, Speakers Bureau. Castellano Acosta:Molecular Partners AG: Employment. Lemaillet:Molecular Partners AG: Employment. Cortijo:Molecular Partners AG: Employment. Sudhir:Molecular Partners AG: Employment.

CD117-Amanitin Antibody Drug Conjugates Effectively Deplete Human and Non-Human Primate HSCs: Proof of Concept As a Targeted Strategy for Conditioning Patients for Bone Marrow Transplant

Background: Genotoxic conditioning prior to allogeneic and autologous bone marrow transplantation (BMT) limits the use of these potentially curative treatments due to risks of regimen-related morbidities and mortality, including risks of organ toxicity, infertility, and secondary malignancies. CD117, which is specifically expressed on hematopoietic stem cells (HSCs) and progenitors is rapidly internalized and is an ideal target for an antibody drug conjugate (ADC) based approach to conditioning. We have previously shown that a single dose of an anti-CD117 ADC depleted >95% of bone marrow HSCs in a humanized mouse model and reduced disease burden while extending survival in an AML tumor model (Hartigan et al., Blood 2017 130:1894). The aim of this translational study was to develop a potent anti-CD117 ADC highly effective in eliminating host HSCs with a short half-life and minimal adverse side effects in a non-human primate (NHP) model.Methods: Three different DNA-damaging cytotoxic payloads and amanitin (AM) were site specifically conjugated to an anti-CD117 antibody. The ADCs were titrated and evaluated for in vitro cytotoxicity using human bone marrow CD34+ cells. The ADCs were administered in ascending doses to humanized NSG mice. HSC depletion and immunophenotype of the human cells in the peripheral blood was determined by flow cytometry. For amanitin conjugates, NHP HSC depletion was evaluated in male cynomolgus monkeys in single ascending doses (3/group). HSC content in the bone marrow was monitored by flow cytometry and colony-forming unit (CFU) analysis on day 7 or 14 and 56 post dosing. Hematology and clinical chemistries were evaluated throughout the two-month study.Results: Of the toxins evaluated, only anti-CD117 conjugated with the RNA polymerase II inhibitor amanitin resulted in >90% depletion of human HSCs in humanized NSG mice at 0.3 mg/kg. The AM-conjugates also demonstrated a broad therapeutic window in this model (therapeutic index of >120). As a proof-of-concept for the depletion of HSCs in large animals, a single i.v. dose escalation study was performed with the cross-reactive anti-CD117-AM in NHP. On-target, dose-dependent decreases in phenotypic HSCs and CFUs were observed in the bone marrow at day 7 post anti-CD117-AM dosing with >95% HSC depletion observed with a single dose of 0.3 mg/kg (Fig. 1). In the periphery, a dose-dependent transient decrease in reticulocytes was observed at day 4 with a neutrophil and monocyte nadir at day 18. The depth and duration of the depletion was also dose-dependent. The anti-CD117-AM induced depletion was on target and amanitin dependent as the unconjugated antibody and isotype-AM had no effect. Notably, white blood cell and lymphocyte counts were stable through day 56, demonstrating that this strategy will spare the adaptive immune system. Thrombocytopenia occurred 4-8 days post infusion and was dose-dependent, transient and reversible. This also occurred with the isotype-AM, suggesting the effect was off-target.Because the half-life of the anti-CD117-AM was 5 days, a second dose escalation study with anti-CD117-AM engineered to have a short half-life (~18 h) was performed in NHPs. The short half-life anti-CD117-AM demonstrated similar potency on all cell parameters at 0.3 mg/kg and was well tolerated at the effective dose. As expected, the short half-life anti-CD117-AM was rapidly cleared with a half-life of 15-18 h. In both studies, a transient dose dependent elevation of liver enzymes was observed in groups treated with the highest doses of isotype-AM, anti-CD117-AM, and the short half-life anti-CD117-AM.Conclusions: Anti-CD117-AM exhibited potent elimination of NHP HSCs and progenitors in vivo. The potency of short half-life anti-CD117-AM was comparable, providing a model for target cell depletion and rapid clearance prior to BMT. Both ADCs were well tolerated at the efficacious doses. This strategy preserves the adaptive immune system with delayed onset of neutrophil nadir (18 days), potentially shortening the period of neutropenia. Targeted depletion of hematopoietic cell subtypes with limited off-target effects could provide a significant improvement in standard-of-care approaches to patient preparation prior to HSC transplant. [Display omitted] DisclosuresPearse:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. McDonough:Magenta Therapeutics: Employment, Equity Ownership. Proctor:Magenta Therapeutics: Employment, Equity Ownership. Panwar:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Sarma:Magenta Therapeutics: Employment, Equity Ownership. McShea:Magenta Therapeutics: Employment, Equity Ownership. Kien:Magenta Therapeutics: Employment, Equity Ownership. Dushime:Magenta Therapeutics: Employment, Equity Ownership. Adams:Magenta Therapeutics: Employment, Equity Ownership. Hyzy:Magenta Therapeutics: Employment, Equity Ownership. Brooks:Magenta Therapeutics: Employment, Equity Ownership. Palchaudhuri:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties; Harvard University: Patents & Royalties. Li:Magenta Therapeutics: Employment, Equity Ownership. Kallen:Magenta Therapeutics: Employment, Equity Ownership. Sawant:Magenta Therapeutics: Employment, Equity Ownership. McDonagh:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Boitano:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Cooke:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties.

Mizoribine is as Effective as Methotrexate for the Treatment of Polymyalgia Rheumatica: A Retrospective Case Series Analysis.

This study aims to evaluate the efficacy and safety of mizoribine (MZR) as a steroid-sparing agent compared to methotrexate (MTX) in the treatment of polymyalgia rheumatica in elderly patients. Twenty-four patients (9 males, 15 females; mean age 71.7 years; range 50 to 86 years) diagnosed with polymyalgia rheumatica between April 1998 and August 2014, who received prednisone in combination with either MTX or MZR, were included. We collected the data on the cumulative prednisone dose that patients received within 48 weeks after MTX or MZR and its side effect profile. There were 10 patients in the MTX group and 14 in the MZR group. The cumulative prednisone dose over 0-48 weeks was 2272±396 mg in the MTX group and 1907±241 mg in the MZR group, which was not significantly different (p=0.41). In terms of side effects, in the MTX group, three patients experienced a transient elevation in liver enzymes, and one patient developed gastrointestinal symptoms that led to MTX withdrawal. In the MZR group, one patient was hospitalized due to pneumonia that led to MZR withdrawal. Mizoribine was non-inferior to MTX in terms of steroid-sparing effects on polymyalgia rheumatica. Also, MZR tended to have fewer side effects than MTX.

Liver stereotactic radiotherapy (SRT) with functional treatment planning for patients with intermediate stage hepatocellular carcinoma (HCC)

The objective of this study was to analyze hepatic failure progression and survival in patients with Barcelona Clinic Liver Cancer (BCLC) A3-B hepatocellular carcinoma (HCC) after stereotactic radiotherapy (SRT) with functional treatment planning. Liver SPECT was co-registered to 4DCT for avoidance of functional liver during SRT planning. Liver dose constraints/fractionation was based on functional liver volume. Concurrent capecitabine was administered for fraction size ≤ 4 Gy. Hepatic function, toxicity, and radiographic response were documented q4–6 months following radiotherapy. Twenty-two patients (14 Child-Pugh A, 8 Child-Pugh B Cirrhosis) with 39 lesions were analyzed. Fourteen patients received SBRT (mean dose 44.7 Gy, 5–6 fractions). Eight patients received SRT and concurrent capecitabine (mean dose 40.7 Gy, 14–18 fractions). Mean follow-up was 20 months. Nine patients developed grade ≤ 2 transient elevation of liver enzymes. At 24 months, Child-Pugh class was stable in 59% patients and MELD progression free survival was 76%. No RILD or accelerated hepatic failure was observed. In-field local control was 97.4% and overall survival was 59% at 2 years. Liver SRT with functional treatment planning is safe in intermediate hepatocellular carcinoma. Liver failure is not hastened despite the inclusion of 36% Child-Pugh B patients.

Recombinant Adeno-Associated Viral Integration and Genotoxicity: Insights from Animal Models.

Currently, clinical gene therapy is experiencing a renaissance, with new products for clinical use approved in Europe and clinical trials for multiple diseases reporting positive results, especially those using recombinant adeno-associated viral (rAAV) vectors. Amid this new success, it is prudent to recall that the field of gene therapy experienced tragic setbacks in 1999 and 2002 because of the serious adverse events related to retroviral and adenoviral gene delivery in two clinical trials that resulted in the death of two patients. In both cases, the toxicity observed in humans had been documented to occur in animal models. However, these toxicities were either undetected or underappreciated before they arose in humans. rAAVs have been tested extensively in animals and animal models of disease, largely without adverse events, except for transient elevation in liver enzymes in some patients. However, a small but growing number of murine studies have documented that adeno-associated viral gene delivery can result in insertional mutagenesis. Herein, the aggregate data are reviewed from multiple murine studies where genotoxicity associated with rAAV treatment has been observed. The data emphasize the need for a proactive position to evaluate the potential risks and possible solutions associated with AAV-mediated gene therapy.

Antibiotic treatment for Clostridium difficile-associated diarrhoea in adults.

Clostridium difficile (C. difficile) is recognized as a frequent cause of antibiotic-associated diarrhoea and colitis. This review is an update of a previously published Cochrane review. The aim of this review is to investigate the efficacy and safety of antibiotic therapy for C. difficile-associated diarrhoea (CDAD), or C. difficile infection (CDI), being synonymous terms. We searched MEDLINE, EMBASE, CENTRAL and the Cochrane IBD Group Specialized Trials Register from inception to 26 January 2017. We also searched clinicaltrials.gov and clinicaltrialsregister.eu for ongoing trials. Only randomised controlled trials assessing antibiotic treatment for CDI were included in the review. Three authors independently assessed abstracts and full text articles for inclusion and extracted data. The risk of bias was independently rated by two authors. For dichotomous outcomes, we calculated the risk ratio (RR) and corresponding 95% confidence interval (95% CI). We pooled data using a fixed-effect model, except where significant heterogeneity was detected, at which time a random-effects model was used. The following outcomes were sought: sustained symptomatic cure (defined as initial symptomatic response and no recurrence of CDI), sustained bacteriologic cure, adverse reactions to the intervention, death and cost. Twenty-two studies (3215 participants) were included. The majority of studies enrolled patients with mild to moderate CDI who could tolerate oral antibiotics. Sixteen of the included studies excluded patients with severe CDI and few patients with severe CDI were included in the other six studies. Twelve different antibiotics were investigated: vancomycin, metronidazole, fusidic acid, nitazoxanide, teicoplanin, rifampin, rifaximin, bacitracin, cadazolid, LFF517, surotomycin and fidaxomicin. Most of the studies were active comparator studies comparing vancomycin with other antibiotics. One small study compared vancomycin to placebo. There were no other studies that compared antibiotic treatment to a placebo or a 'no treatment' control group. The risk of bias was rated as high for 17 of 22 included studies. Vancomycin was found to be more effective than metronidazole for achieving symptomatic cure. Seventy-two per cent (318/444) of metronidazole patients achieved symptomatic cure compared to 79% (339/428) of vancomycin patients (RR 0.90, 95% CI 0.84 to 0.97; moderate quality evidence). Fidaxomicin was found to be more effective than vancomycin for achieving symptomatic cure. Seventy-one per cent (407/572) of fidaxomicin patients achieved symptomatic cure compared to 61% (361/592) of vancomycin patients (RR 1.17, 95% CI 1.04 to 1.31; moderate quality evidence). Teicoplanin may be more effective than vancomycin for achieving a symptomatic cure. Eightly-seven per cent (48/55) of teicoplanin patients achieved symptomatic cure compared to 73% (40/55) of vancomycin patients (RR 1.21, 95% CI 1.00 to 1.46; very low quality evidence). For other comparisons including the one placebo-controlled study the quality of evidence was low or very low due to imprecision and in many cases high risk of bias because of attrition and lack of blinding. One hundred and forty deaths were reported in the studies, all of which were attributed by study authors to the co-morbidities of the participants that lead to acquiring CDI. Although many other adverse events were reported during therapy, these were attributed to the participants' co-morbidities. The only adverse events directly attributed to study medication were rare nausea and transient elevation of liver enzymes. Recent cost data (July 2016) for a 10 day course of treatment shows that metronidazole 500 mg is the least expensive antibiotic with a cost of USD 13 (Health Warehouse). Vancomycin 125 mg costs USD 1779 (Walgreens for 56 tablets) compared to fidaxomicin 200 mg at USD 3453.83 or more (Optimer Pharmaceuticals) and teicoplanin at approximately USD 83.67 (GBP 71.40, British National Formulary). No firm conclusions can be drawn regarding the efficacy of antibiotic treatment in severe CDI as most studies excluded patients with severe disease. The lack of any 'no treatment' control studies does not allow for any conclusions regarding the need for antibiotic treatment in patients with mild CDI beyond withdrawal of the initiating antibiotic. Nonetheless, moderate quality evidence suggests that vancomycin is superior to metronidazole and fidaxomicin is superior to vancomycin. The differences in effectiveness between these antibiotics were not too large and the advantage of metronidazole is its far lower cost compared to the other two antibiotics. The quality of evidence for teicoplanin is very low. Adequately powered studies are needed to determine if teicoplanin performs as well as the other antibiotics. A trial comparing the two cheapest antibiotics, metronidazole and teicoplanin, would be of interest.

Paracetamol in Patent Ductus Arteriosus Treatment: Efficacious and Safe?

In preterm infants, failure or delay in spontaneous closure of Ductus Arteriosus (DA), resulting in the condition of Patent Ductus Arteriosus (PDA), represents a significant issue. A prolonged situation of PDA can be associated with several short- and long-term complications. Despite years of researches and clinical experience on PDA management, unresolved questions about the treatment and heterogeneity of clinical practices in different centers still remain, in particular regarding timing and modality of intervention. Nowadays, the most reasonable strategy seems to be reserving the treatment only to hemodynamically significant PDA. The first-line therapy is medical, and ibuprofen, related to several side effects especially in terms of nephrotoxicity, is the drug of choice. Administration of oral or intravenous paracetamol (acetaminophen) recently gained attention, appearing effective as traditional nonsteroidal anti-inflammatory drugs (NSAIDs) in PDA closure, with lower toxicity. The results of the studies analyzed in this review mostly support paracetamol efficacy in ductal closure, with inconstant low and transient elevation of liver enzymes as reported side effect. However, more studies are needed to confirm if this therapy shows a real safety profile and to evaluate its long-term outcomes, before considering paracetamol as first-choice drug in PDA treatment.