Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Patients with acute myeloid leukaemia (AML) positive for internal tandem duplication (ITD) mutations of FLT3 have poor outcomes. Quizartinib, an oral, highly potent, selective, type 2 FLT3 inhibitor, plus chemotherapy showed antitumour activity with an acceptable safety profile in patients with FLT3-ITD-positive newly diagnosed AML. The aim of the study was to compare the effect of quizartinib versus placebo on overall survival in patients with FLT3-ITD-positive newly diagnosed AML aged 18-75 years. METHODS: We conducted a randomised, double-blind, placebo-controlled, phase 3 trial comparing quizartinib and placebo in combination with chemotherapy in induction and consolidation, followed by quizartinib or placebo single-agent continuation, in patients with FLT3-ITD-positive newly diagnosed AML at 193 hospitals and clinics in 26 countries in Europe; North America; and Asia, Australia, and South America. Patients aged 18-75 years were eligible. Patients were randomly assigned (1:1) to the quizartinib group or the placebo group by an independent biostatistician through an interactive web and voice response system, stratified by region, age, and white blood cell count at diagnosis. Patients, investigators, funders, and contract research organisations were masked to treatments assigned. Induction therapy comprised a standard 7 + 3 induction regimen of cytarabine 100 mg/m2 per day (or 200 mg/m2 per day allowed if institutional or local standard) by continuous intravenous infusion from day 1 to day 7 and anthracycline (daunorubicin 60 mg/m2 per day or idarubicin 12 mg/m2 per day) by intravenous infusion on days 1, 2, and 3, then quizartinib 40 mg orally or placebo once per day, starting on day 8, for 14 days. Patients with complete remission or complete remission with incomplete neutrophil or platelet recovery received standard consolidation with high-dose cytarabine plus quizartinib (40 mg per day orally) or placebo, allogeneic haematopoietic cell transplantation (allo-HCT), or both as consolidation therapy, followed by continuation of single-agent quizartinib or placebo for up to 3 years. The primary outcome was overall survival, defined as time from randomisation until death from any cause and assessed in the intention-to-treat population. Safety was evaluated in all patients who received at least one dose of quizartinib or placebo. This study is registered with ClinicalTrials.gov (NCT02668653). FINDINGS: Between Sept 27, 2016, and Aug 14, 2019, 3468 patients with AML were screened and 539 patients (294 [55%] male patients and 245 [45%] female patients) with FLT3-ITD-positive AML were included and randomly assigned to the quizartinib group (n=268) or placebo group (n=271). 148 (55%) of 268 patients in the quizartinib group and 168 (62%) of 271 patients in the placebo group discontinued the study, primarily because of death (133 [90%] of 148 in the quizartinib group vs 158 [94%] of 168 in the placebo group) or withdrawal of consent (13 [9%] of 148 in the quizartinib group vs 9 [5%] of 168 in the placebo group). Median age was 56 years (range 20-75, IQR 46·0-65·0). At a median follow-up of 39·2 months (IQR 31·9-45·8), median overall survival was 31·9 months (95% CI 21·0-not estimable) for quizartinib versus 15·1 months (13·2-26·2) for placebo (hazard ratio 0·78, 95% CI 0·62-0·98, p=0·032). Similar proportions of patients in the quizartinib and placebo groups had at least one adverse event (264 [100%] of 265 in the quizartinib group and 265 [99%] of 268 in the placebo group) and one grade 3 or higher adverse event (244 [92%] of 265 in the quizartinib group and 240 [90%] of 268 in the placebo group). The most common grade 3 or 4 adverse events were febrile neutropenia, hypokalaemia, and pneumonia in both groups and neutropenia in the quizartinib group. INTERPRETATION: The addition of quizartinib to standard chemotherapy with or without allo-HCT, followed by continuation monotherapy for up to 3 years, resulted in improved overall survival in adults aged 18-75 years with FLT3-ITD-positive newly diagnosed AML. Based on the results from the QuANTUM-First trial, quizartinib provides a new, effective, and generally well tolerated treatment option for adult patients with FLT3-ITD-positive newly diagnosed AML. FUNDING: Daiichi Sankyo.

Characteristics and outcomes of elderly patients with acute myeloid leukemia who receive no treatment in the Surveillance, Epidemiology and End Results-Medicare database.

Background: Without treatment, acute myeloid leukemia (AML) is rapidly fatal. Nevertheless, a large proportion of elderly AML patients do not receive any treatment. Aim: To characterize the demographics, comorbidities, survival and prognostic factors of elderly AML patients who do not receive any AML treatment or supportive care (SC). Methods: A retrospective cohort analysis of the Surveillance, Epidemiology and End Results-Medicare database (2008-2015). Results: Of 7665 AML patients, 2373 (31%) did not receive any AML treatment or SC. The mean age was 80.4 years, 52.8% were males and 79.7% and 95.3% died within the first 60 and 180 days, respectively; 2.1% survived >12 months and only 5.5% of patients had remission or relapse codes populated. Conclusion: Older age, male gender, concurrent depression, ischemic heart disease, chronic kidney disease and benign prostatic hyperplasia were associated with a decreased likelihood of survival. Multiple factors contribute to the complex clinical status of these patients preventing intensive chemotherapy; they should still ideally be treated, at least with the best SC.

An analysis of the data collected in the Surveillance, Epidemiology and End Results-Medicare database from 2008 to 2015 was performed. This database includes data collected by a national cancer registry on people diagnosed with cancer in the United States and those who enroll in Medicare. This study focused on acute myeloid leukemia (AML) patients who did not receive any AML treatment or supportive care (SC). Of 7665 patients with AML, 2373 (31%) did not receive any AML treatment or SC. At the time the data was indexed for each patient in the database, their mean age was 80.4 years and around 53% were males. Within the first 60 days, around 80% of these patients died; over 95% died within the first 180 days. Only 2% of patients survived more than a year without treatment; these patients were likely in remission. Without treatment, AML patients who were older, were male or who also had depression, ischemic heart disease, chronic kidney disease or benign prostatic hyperplasia had a higher chance of dying early. There could be many reasons why these patients are not treated. The main reasons are their poor health condition and the presence of two or more health conditions in a patient at the same time (comorbidities). However, they should still ideally be treated, at least with the best SC. Additional treatment options are urgently needed for elderly AML patients who have comorbidities and are in poor general health.

Elderly patients with acute myeloid leukemia who only receive supportive care in the Surveillance, Epidemiology and End Results-Medicare database: demographics, treatment patterns and outcomes.

Aim: Elderly acute myeloid leukemia (AML) patients are often not treated with antileukemic therapy due to their poor overall health condition, leaving supportive care as the sole treatment option. Objective: To evaluate patient characteristics, treatment patterns and outcomes of elderly patients with AML who are treated with supportive care only. Methods: A retrospective analysis of elderly AML patients included in the Surveillance, Epidemiology and End Results-Medicare database from 2008 to 2015. Results: Of elderly patients with AML (n = 7665), 3209 (41.9%) received supportive care only. Their mean age was 79 years, 50.5% were males; 48.2% died during the first 3 months and 67.3% died during the first 6 months. 82.2% died within the first year; only 13.2% survived >12 months. 77.9% patients died due to leukemia. Conclusion: In elderly AML patients treated with supportive care only, older age, concurrent hypertension, chronic obstructive pulmonary disease, chronic kidney disease and acute myocardial infarction were identified as prognostic factors associated with decreased likelihood of survival. Ideally, these patients should be treated with antileukemic therapy in addition to supportive care, as most of them die from disease progression.

This study analyzed data on elderly patients with acute myeloid leukemia (AML) who were only treated with supportive care. The source of this data was the Surveillance, Epidemiology and End Results (SEER)-Medicare database. Of the 7665 patients diagnosed with AML during 2008­2015, 3209 (41.9%) received supportive care only. Their mean age at index date was 79 years; slightly more than half of these were males (50.5%). Almost half of these patients (48.2%) died within the first 3 months and approximately two-thirds (67.3%) died within the first 6 months. Only a small proportion (13%) of these patients were alive after 1 year. These patients who were alive after one were likely to be in remission (there was decrease in the signs and symptoms of AML). The results of this study showed that elderly AML patients who only received supportive care were more likely to die early if they also had chronic kidney disease, chronic obstructive pulmonary disease, history of acute myocardial infarction or hypertension. As elderly AML patients may be in poor general health and have other diseases (comorbidities), this could be the reason why they may not be treated with antileukemic therapy. Instead of treatment with supportive care only, these patients should ideally receive antileukemic therapy in addition to supportive care. More research should be done to find alternate treatments for these elderly AML patients.

In vitro evaluation of methicillin-resistant and methicillin-sensitive Staphylococcus aureus susceptibility to Saudi honeys.

BACKGROUND: Honey has been increasingly recognized as a potential therapeutic agent for treatment of wound infections. There is an urgent need for assessment and evaluation of the antibacterial properties against wound pathogens of honeys that have not yet been tested. METHODS: Ten Saudi honeys collected from different geographical locations were screened initially for their antibacterial potential against methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive Staphylococcus aureus (MSSA) by the agar well diffusion method. Manuka honey (UMF-12) was used for comparison. Of the tested honeys, the honey that exhibited the greatest antibacterial activity in the agar well diffusion assay was further evaluated for its minimum inhibitory concentration (MIC) against ten MRSA clinical isolates and three American Type Culture Collection (ATCC) reference strains by the microbroth dilution method. RESULTS: Locally produced honeys exhibited variable antibacterial activity against the tested isolates in the agar well diffusion assay. They were unable to exhibit antibacterial activity against MSSA and MRSA at 25% dilutions (w/v) in catalase solution. However, Sumra and Talha honeys showed a zone of inhibition at 50% dilutions (w/v) in catalase solution. This finding means that both honeys possess weak non-peroxide-based antibacterial activity. Moreover, Sumra honey showed a larger inhibition zone at 50 and 25% dilutions (w/v) in distilled water than Manuka honey against both MSSA and MRSA. This result demonstrates that Sumra honey has more hydrogen peroxide-related antibacterial activity or total antibacterial activity than Manuka honey. In addition, MIC results obtained through a microbroth dilution assay showed that Sumra honey inhibited the growth of all MRSA clinical isolates (n = 10) and reference strains [MRSA (ATCC 43300) and MSSA (ATCC 29213)] at lower concentrations (12.0% v/v) than those required for Manuka honey-mediated inhibition (14.0% v/v). This result means that Sumra honey has more peroxide or synergistic antibacterial activity than Manuka honey. An equivalent MIC (15.0% v/v) was observed for E. coli (ATCC 25922) between Manuka honey and Sumra honey. CONCLUSIONS: Sumra honey may be used as an alternative therapeutic agent for infected wounds and burns, where additional hydrogen peroxide-related antibacterial activity is needed. In the future, the physiochemical characteristics of Sumra honey may be evaluated and standardized.

Mean Platelet Volume, Red Cell Distribution Width to Platelet Count Ratio, Globulin Platelet Index, and 16 Other Indirect Noninvasive Fibrosis Scores: How Much Do Routine Blood Tests Tell About Liver Fibrosis in Chronic Hepatitis C?

BACKGROUND AND AIM: Many indirect noninvasive scores to predict liver fibrosis are calculated from routine blood investigations. Only limited studies have compared their efficacy head to head. We aimed to compare these scores with liver biopsy fibrosis stages in patients with chronic hepatitis C. MATERIALS AND METHODS: From blood investigations of 1602 patients with chronic hepatitis C who underwent a liver biopsy before initiation of antiviral treatment, 19 simple noninvasive scores were calculated. The area under the receiver operating characteristic curves and diagnostic accuracy of each of these scores were calculated (with reference to the Scheuer staging) and compared. RESULTS: The mean age of the patients was 41.8±9.6 years (1365 men). The most common genotype was genotype 4 (65.6%). Significant fibrosis, advanced fibrosis, and cirrhosis were seen in 65.1%, 25.6, and 6.6% of patients, respectively. All the scores except the aspartate transaminase (AST) alanine transaminase ratio, Pohl score, mean platelet volume, fibro-alpha, and red cell distribution width to platelet count ratio index showed high predictive accuracy for the stages of fibrosis. King's score (cutoff, 17.5) showed the highest predictive accuracy for significant and advanced fibrosis. King's score, Göteborg university cirrhosis index, APRI (the AST/platelet count ratio index), and Fibrosis-4 (FIB-4) had the highest predictive accuracy for cirrhosis, with the APRI (cutoff, 2) and FIB-4 (cutoff, 3.25) showing the highest diagnostic accuracy.We derived the study score 8.5 - 0.2(albumin, g/dL) +0.01(AST, IU/L) -0.02(platelet count, 10(9)/L), which at a cutoff of >4.7 had a predictive accuracy of 0.868 (95% confidence interval, 0.833-0.904) for cirrhosis. CONCLUSIONS: King's score for significant and advanced fibrosis and the APRI or FIB-4 score for cirrhosis could be the best simple indirect noninvasive scores.

Eltrombopag increases platelet numbers in thrombocytopenic patients with HCV infection and cirrhosis, allowing for effective antiviral therapy.

BACKGROUND & AIMS: Thrombocytopenia is common among patients with hepatitis C virus (HCV) infection and advanced fibrosis or cirrhosis, limiting initiation and dose of peginterferon-alfa (PEG) and ribavirin (RBV) therapy. The phase 3 randomized, controlled studies, Eltrombopag to Initiate and Maintain Interferon Antiviral Treatment to Benefit Subjects with Hepatitis C-Related Liver Disease (ENABLE)-1 and ENABLE-2, investigated the ability of eltrombopag to increase the number of platelets in patients, thereby allowing them to receive initiation or maintenance therapy with PEG and RBV. METHODS: Patients with HCV infection and thrombocytopenia (platelet count <75,000/µL) who participated in ENABLE-1 (n = 715) or ENABLE-2 (n = 805), from approximately 150 centers in 23 countries, received open-label eltrombopag (25-100 mg/day) for 9 weeks or fewer. Patients whose platelet counts reached the predefined minimal threshold for the initiation of PEG and RBV therapy (95% from ENABLE-1 and 94% from ENABLE-2) entered the antiviral treatment phase, and were assigned randomly (2:1) to groups that received eltrombopag or placebo along with antiviral therapy (24 or 48 weeks, depending on HCV genotype). The primary end point was sustained virologic response (SVR) 24 weeks after completion of antiviral therapy. RESULTS: More patients who received eltrombopag than placebo achieved SVRs (ENABLE-1: eltrombopag, 23%; placebo, 14%; P = .0064; ENABLE-2: eltrombopag, 19%; placebo, 13%; P = .0202). PEG was administered at higher doses, with fewer dose reductions, in the eltrombopag groups of each study compared with the placebo groups. More patients who received eltrombopag than placebo maintained platelet counts of 50,000/µL or higher throughout antiviral treatment (ENABLE-1, 69% vs 15%; ENABLE-2, 81% vs 23%). Adverse events were similar between groups, with the exception of hepatic decompensation (both studies: eltrombopag, 10%; placebo, 5%) and thromboembolic events, which were more common in the eltrombopag group of ENABLE-2. CONCLUSIONS: Eltrombopag increases platelet numbers in thrombocytopenic patients with HCV and advanced fibrosis and cirrhosis, allowing otherwise ineligible or marginal patients to begin and maintain antiviral therapy, leading to significantly increased rates of SVR. Clinical trial no: NCT00516321, NCT00529568.

Results of a phase I dose escalation study of eltrombopag in patients with advanced soft tissue sarcoma receiving doxorubicin and ifosfamide.

BACKGROUND: The objective of this Phase I dose escalation study was to explore the safety and tolerability of eltrombopag, an oral, nonpeptide, thrombopoietin receptor agonist, in patients with advanced soft tissue sarcoma (STS) and thrombocytopenia due to treatment with doxorubicin and ifosfamide (AI) combination chemotherapy. METHODS: Patients aged 18 or older with histologically confirmed, locally advanced or metastatic STS were treated with 1 cycle of AI followed by AI with eltrombopag starting at Cycle 2, using 2 different dosing schedules. The study design included an eltrombopag dose escalation phase starting at 75 mg daily to determine the optimal biological dose (OBD). RESULTS: Eighteen patients were enrolled and 15 received at least 1 dose of chemotherapy; 3 patients withdrew prior to receiving eltrombopag. Seven, 4, and 1 patients received 75 mg, 100 mg, and 150 mg eltrombopag daily, respectively. No dose-limiting toxicities were reported. Due to slow recruitment, the study was closed prior to identifying an OBD. The most common hematologic adverse events (AEs) were thrombocytopenia (80%), neutropenia (73%), and anemia (67%). The most common nonhematologic AEs were fatigue (53%), alanine aminotransferase increased, constipation, and nausea (47% each). Eleven of 12 patients who received eltrombopag completed at least 2 chemotherapy cycles; all had increased platelet counts on Day 1 of Cycle 2 (cycle with eltrombopag) compared to Day 1 of Cycle 1 (cycle without eltrombopag). CONCLUSIONS: Although data are limited, safety data were consistent with the known toxicities of AI combination chemotherapy or the side effect profile of eltrombopag seen in other studies. Available data suggest a potential pre- and post-chemotherapy dosing scheme for eltrombopag when administered with AI chemotherapy, and support further investigation of eltrombopag treatment in patients with chemotherapy-induced thrombocytopenia.

CAR-T: What Is Next?

The year 2017 was marked by the Food and Drug Administration (FDA) approval of the first two chimeric antigen receptor-T (CAR-T) therapies. The approved indications were for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and for the treatment of patients up to 25 years of age with acute lymphoblastic leukemia (ALL) that is refractory or in a second or later relapse. Since then, extensive research activities have been ongoing globally on different hematologic and solid tumors to assess the safety and efficacy of CAR-T therapy for these diseases. Limitations to CAR-T therapy became apparent from, e.g., the relapse in up to 60% of patients and certain side effects such as cytokine release syndrome (CRS). This led to extensive clinical activities aimed at overcoming these obstacles, so that the use of CAR-T therapy can be expanded. Attempts to improve on efficacy and safety include changing the CAR-T administration schedule, combining it with chemotherapy, and the development of next-generation CAR-T therapies, e.g., through the use of CAR-natural killer (CAR-NK) and CAR macrophages (CAR-Ms). This review will focus on new CAR-T treatment strategies in hematologic malignancies, clinical trials aimed at improving efficacy and addressing side effects, the challenges that CAR-T therapy faces in solid tumors, and the ongoing research aimed at overcoming these challenges.

Low or undetectable TPO receptor expression in malignant tissue and cell lines derived from breast, lung, and ovarian tumors.

BACKGROUND: Numerous efficacious chemotherapy regimens may cause thrombocytopenia. Thrombopoietin receptor (TPO-R) agonists, such as eltrombopag, represent a novel approach for the treatment of chemotherapy-induced thrombocytopenia. The TPO-R MPL is expressed on megakaryocytes and megakaryocyte precursors, although little is known about its expression on other tissues. METHODS: Breast, lung, and ovarian tumor samples were analyzed for MPL expression by microarray and/or quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and for TPO-R protein expression by immunohistochemistry (IHC). Cell line proliferation assays were used to analyze the in vitro effect of eltrombopag on breast, lung, and ovarian tumor cell proliferation. The lung carcinoma cell lines were also analyzed for TPO-R protein expression by Western blot. RESULTS: MPL mRNA was not detectable in 118 breast tumors and was detectable at only very low levels in 48% of 29 lung tumors studied by microarray analysis. By qRT-PCR, low but detectable levels of MPL mRNA were detectable in some normal (14-43%) and malignant (3-17%) breast, lung, and ovarian tissues. A comparison of MPL to EPOR, ERBB2, and IGF1R mRNA demonstrates that MPL mRNA levels were far lower than those of EPOR and ERBB2 mRNA in the same tissues. IHC analysis showed negligible TPO-R protein expression in tumor tissues, confirming mRNA analysis. Culture of breast, lung, and ovarian carcinoma cell lines showed no increase, and in fact, showed a decrease in proliferation following incubation with eltrombopag. Western blot analyses revealed no detectable TPO-R protein expression in the lung carcinoma cell lines. CONCLUSIONS: Multiple analyses of breast, lung, and ovarian tumor samples and/or cell lines show no evidence of MPL mRNA or TPO-R protein expression. Eltrombopag does not stimulate growth of breast, lung, or ovarian tumor cell lines at doses likely to exert their actions on megakaryocytes and megakaryocyte precursors.

Surgical management of biliary complications following living donor liver transplantation.

BACKGROUND: Biliary complications (BC) account for much of the morbidities seen after living donor liver transplantation (LDLT). Surgical reconstruction might be necessary after the failure of endoscopic or percutaneous procedures. METHODS: Between November 2002 and December 2009, a total of 76 LDLTs were performed. Six patients were excluded from statistical analysis because of early graft or patient loss. RESULTS: Of 70, 26 (37.1%) developed BC; 12 (46.2%) were successfully managed by non-surgical procedures, three (11.5%) died from BC-related sepsis, one (3.8%) died from BC-unrelated causes, and 10 (38.5%) underwent surgical reconstruction. Of those 10, four patients had single duct reconstruction, five patients had double ducts reconstruction, and reconstruction was abandoned in one patient because of hepatic artery thrombosis. After a median follow-up period of 4.5 yr (0.1-6), seven (70%) remained well with no recurrent biliary problems, and three (30%) had recurrent BCs that were managed either conservatively or by retransplantation. Patients who underwent surgical reconstruction had significantly fewer hospital admissions, less need for invasive procedures, and shorter cumulative hospital stay (p < 0.05). CONCLUSIONS: In our experience, BCs after LDLT were frequently resistant to non-surgical procedures. Surgical reconstruction is associated with fewer hospital admissions and less need for invasive procedures leading to reduced resources utilization.

CAR-T Therapy, the End of a Chapter or the Beginning of a New One?

Chimeric antigen receptor-T (CAR-T) therapy targeting CD19 has revolutionised the treatment of advanced acute lymphoblastic leukaemia (ALL) and diffuse large B-cell lymphoma (DLBCL). The ability to specifically target the cancer cells has shown high positive results as reported in the registration studies. The success of CAR-T therapy in the first two indications led to the initiation of a large number of studies testing CAR-T therapy in different haematologic tumours such as acute myelogenous leukaemia (AML), Hodgkin's disease (HD), chronic lymphocytic leukaemia (CLL), multiple myeloma (MM), as well as different solid tumours. Unfortunately, relapses occurred in patients treated with CAR-T therapy, calling for the development of effective subsequent therapies. Likewise, this novel mechanism of action was also accompanied by a different toxicity profile, such as cytokine release syndrome (CRS). Patients' access to the treatment is still limited by its cost. Notwithstanding, this did not prohibit further development of this new therapy to treat other malignancies. This research activity of CAR-T therapy moves it from being used as an end-stage treatment for ALL and DLBCL to a new therapeutic option for a wide range of patients with different haematologic and solid tumours.

Digestive system involvement and clinical outcomes among COVID-19 patients: A retrospective cohort study from Qatar.

BACKGROUND: Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 virus most commonly presents with respiratory symptoms. While gastrointestinal (GI) manifestations either at presentation or during hospitalization are also common, their impact on clinical outcomes is controversial. Some studies have described worse outcomes in COVID-19 patients with GI symptoms, while others have shown either no association or a protective effect. There is a need for consistent standards to describe GI symptoms in COVID-19 patients and to assess their effect on clinical outcomes, including mortality and disease severity. AIM: To investigate the prevalence of GI symptoms in hospitalized COVID-19 patients and their correlation with disease severity and clinical outcomes. METHODS: We retrospectively reviewed 601 consecutive adult COVID-19 patients requiring hospitalization between May 1-15, 2020. GI symptoms were recorded at admission and during hospitalization. Demographic, clinical, laboratory, and treatment data were retrieved. Clinical outcomes included all-cause mortality, disease severity at presentation, need for intensive care unit (ICU) admission, development of acute respiratory distress syndrome, and need for mechanical ventilation. Multivariate logistic regression model was used to identify independent predictors of the adverse outcomes. RESULTS: The prevalence of any GI symptom at admission was 27.1% and during hospitalization was 19.8%. The most common symptoms were nausea (98 patients), diarrhea (76 patients), vomiting (73 patients), and epigastric pain or discomfort (69 patients). There was no difference in the mortality between the two groups (6.21% vs 5.5%, P = 0.7). Patients with GI symptoms were more likely to have severe disease at presentation (33.13% vs 22.5%, P < 0.001) and prolonged hospital stay (15 d vs 14 d, P = 0.04). There was no difference in other clinical outcomes, including ICU admission, development of acute respiratory distress syndrome, or need for mechanical ventilation. Drugs associated with the development of GI symptoms during hospitalization were ribavirin (diarrhea 26.37% P < 0.001, anorexia 17.58%, P = 0.02), hydroxychloroquine (vomiting 28.52%, P = 0.009) and lopinavir/ritonavir (nausea 32.65% P = 0.049, vomiting 31.47% P = 0.004, and epigastric pain 12.65% P = 0.048). In the multivariate regression analysis, age > 65 years was associated with increased mortality risk [odds ratio (OR) 7.53, confidence interval (CI): 3.09-18.29, P < 0.001], ICU admission (OR: 1.79, CI: 1.13-2.83, P = 0.012), and need for mechanical ventilation (OR: 1.89, CI:1.94-2.99, P = 0.007). Hypertension was an independent risk factor for ICU admission (OR: 1.82, CI:1.17-2.84, P = 0.008) and need for mechanical ventilation (OR: 1.66, CI: 1.05-2.62, P = 0.028). CONCLUSION: Patients with GI symptoms are more likely to have severe disease at presentation; however, mortality and disease progression is not different between the two groups.

Recurrence of hepatitis C virus genotype-4 infection following orthotopic liver transplantation: natural history and predictors of outcome.

BACKGROUND AND OBJECTIVES: There are few reports on hepatitis C virus genotype 4 (HCV-4) recurrences after orthotopic liver transplantation (OLT). Therefore, we undertook a study to determine the epidemiological, clinical and virological characteristics of patients with biopsy-proven recurrent HCV infection and analyzed the factors that influence recurrent disease severity. We also compared disease recurrence and outcomes between HCV-4 and other genotypes. PATIENTS AND METHODS: All patients who underwent OLT (locally or abroad) for HCV related hepatic cirrrhosis from 1991 to 2006 and had recurrent HCV infection were identified. Clinical, laboratory and pathological data before and after OLT were collected and analyzed. RESULTS: Of 116 patients who underwent OLT for hepatitis C, 46 (39.7%) patients satisfied the criteria of recurrrent hepatitis C. Twenty-nine (63%) patients were infected with HCV genotype 4. Mean (SD) for age was 54.9 (10.9) years. Nineteen of the HCV genotype 4 patients (65.5%) were males, 21 (72.4%) received deceased donor grafts, and 7 (24.1%) developed > or =1 acute rejection episodes. Pathologically, 7 (24.1%) and 4 (13.8%) patients had inflammation grade 3-4 and fibrosis stage 3-4, respectively. Follow-up biopsy in 9 (31%) HCV genotype 4 patients showed stable, worse and improved fibrosis stage in 5, 2 and 2 patients, respectively. Of the 7 patients in the recurrent HCV group who died, 6 were infected with genotype 4 and 4 of them died of HCV-related disease. CONCLUSION: This analysis suggests that HCV recurrence following OLT in HCV-4 patients is not significantly different from its recurrence for other genotypes.

MLL-Rearranged Acute Leukemia with t(4;11)(q21;q23)-Current Treatment Options. Is There a Role for CAR-T Cell Therapy?

The MLL (mixed-lineage leukemia) gene, located on chromosome 11q23, is involved in chromosomal translocations in a subtype of acute leukemia, which represents approximately 10% of acute lymphoblastic leukemia and 2.8% of acute myeloid leukemia cases. These translocations form fusions with various genes, of which more than 80 partner genes for MLL have been identified. The most recurrent fusion partner in MLL rearrangements (MLL-r) is AF4, mapping at chromosome 4q21, accounting for approximately 36% of MLL-r leukemia and particularly prevalent in MLL-r acute lymphoblastic leukemia (ALL) cases (57%). MLL-r leukemia is associated with a sudden onset, aggressive progression, and notoriously poor prognosis in comparison to non-MLL-r leukemias. Despite modern chemotherapeutic interventions and the use of hematopoietic stem cell transplantations, infants, children, and adults with MLL-r leukemia generally have poor prognosis and response to these treatments. Based on the frequency of patients who relapse, do not achieve complete remission, or have brief event-free survival, there is a clear clinical need for a new effective therapy. In this review, we outline the current therapy options for MLL-r patients and the potential application of CAR-T therapy.

Hepatocellular carcinoma in a rapidly growing community: Epidemiology, clinico-pathology and predictors of extrahepatic metastasis.

BACKGROUND AND STUDY AIMS: Hepatocellular carcinoma (HCC) with extrahepatic metastasis has been studied, however, data from the Middle East remain scarce. In this study, we assess epidemiology of HCC in Qatar, and identify predictors of the metastatic behaviour. PATIENTS AND METHODS: All newly-diagnosed HCC patients on top of liver cirrhosis between 2011 and 2015 were included in the study. RESULTS: A total of 180 patients met our inclusion criteria. The mean age was 58.8 ±â€¯10.5 years with a mean follow-up of 1.0 ±â€¯1.1 years. There were 150 male patients and HCV was the most common cause of liver cirrhosis 108 (60%), and 22 (12.2%) patients were classified as Child-Pugh class C. The overall survival of 51.1%, and 47 (26%) had at least one extrahepatic metastasis at the time of diagnosis. Single site metastasis was diagnosed in 10 patients, whereas 37 patients had multiple sites metastases. We compared patients who had metastases with patients who did not have metastasis at the time of diagnosis of HCC regarding several variables, and analysis revealed that tumour diameter larger than 5 cm (OR = 6.10, 95% CI = 1.85-20.12) (p = 0.003), and bilobar liver involvement (OR = 5.49, 95% CI = 1.10-27.30) (p = 0.037) were independent predictors of metastatic behaviour of HCC. CONCLUSION: The incidence of HCC is rising in our population, extrahepatic metastasis is no longer rare and tumours larger than 5 cm and bilobar involvement are determinants of the extrahepatic metastasis.

Eltrombopag for thrombocytopenia in patients with advanced solid tumors receiving gemcitabine-based chemotherapy: a randomized, placebo-controlled phase 2 study.

In this phase 2 study, patients with solid tumors receiving gemcitabine monotherapy or gemcitabine plus cisplatin/carboplatin were randomized 2:1 to eltrombopag 100 mg (n = 52) or placebo (n = 23) for 5 days before and after chemotherapy was started. The primary endpoint was prechemotherapy (Day 1) platelet count across ≤6 cycles. Prechemotherapy platelet counts were numerically higher with eltrombopag than placebo. Frequencies of grades 3/4 thrombocytopenia were lower with eltrombopag in both the combination therapy (77 vs. 100%) and monotherapy (36 vs. 42%) groups. Proportionately fewer eltrombopag-treated patients had platelet counts <100 × 109/L at nadir. Among patients receiving combination chemotherapy, mean time to recovery from platelet nadir was 8 days with eltrombopag vs. 15 days with placebo. Eltrombopag-treated patients had fewer dose delays/reductions or missed doses due to thrombocytopenia in both the combination therapy (77 vs. 91%) and monotherapy (62 vs. 83%) groups. Adverse events and serious adverse events were less frequent with eltrombopag in both chemotherapy groups, with reduced rates of anemia, neutropenia, and thrombocytopenia in patients receiving combination chemotherapy. In conclusion, eltrombopag treatment shortened the time to recovery from platelet nadir in patients treated with gemcitabine-based chemotherapy and reduced dose delays/reductions due to thrombocytopenia.

Paediatric acute myeloid leukaemia with the t(7;12)(q36;p13) rearrangement: a review of the biological and clinical management aspects.

The presence of chromosomal abnormalities is one of the most important criteria for leukaemia diagnosis and management. Infant leukaemia is a rare disease that affects children in their first year of life. It has been estimated that approximately one third of infants with acute myeloid leukaemia harbour the t(7;12)(q36;p13) rearrangement in their leukaemic blasts. However, the WHO classification of acute myeloid leukaemia does not yet include the t(7;12) as a separate entity among the different genetic subtypes, although the presence of this chromosomal abnormality has been associated with an extremely poor clinical outcome. Currently, there is no consensus treatment for t(7;12) leukaemia patients. However, with the inferior outcome with the standard induction therapy, stem cell transplantation may offer a better chance for disease control. A better insight into the chromosome biology of this entity might shed some light into the pathogenic mechanisms arising from this chromosomal translocation, that at present are not fully understood. Further work is needed to improve our understanding of the molecular and genetic basis of this disorder. This will hopefully open some grounds for possible tailored treatment for this subset of very young patients with inferior disease outcome. This review aims at highlighting the cytogenetic features that characterise the t(7;12) leukaemias for a better detection of the abnormality in the diagnostic setting. We also review treatment and clinical outcome in the cases reported to date.

Aspartate transaminase to platelet ratio index in hepatitis C virus and Schistosomiasis coinfection.

AIM: To assess the diagnostic accuracy, of aminotransferase-to-platelet ratio index (APRI) alone and with antischistosomal antibody (Ab) in patients with hepatitis C virus (HCV) and schistosomiasis coinfection. METHODS: This retrospective study included medical records of three hundred and eighty three Egyptian men patients who had undergone percutaneous liver biopsy between January 2006 to April 2014 in tertiary care hospital in Qatar for diagnosis or monitoring purpose were selected. Data of patients > 18 years of age were included in the study. The values of HCV RNA titer and antischistosomal antibody titer were also taken into consideration. Patients were excluded from the study if they had any other concomitant chronic liver disease, including; history of previous antiviral or interferon therapy, immunosuppressive, therapy, chronic hepatitis B infection, human immunodeficiency virus co-infection, autoimmune hepatitis, decompensated liver disease, hepatocellular carcinoma, prior liver transplantation, and if no data about the liver biopsy present. RESULTS: Median age of patients was 46 years. About 7.1% had no fibrosis, whereas 30.4%, 37.5%, 20.4%, and 4.6% had fibrosis of stage I, II, III, and IV respectively. In bivariate analysis, APRI score, levels of AST, platelet count and age of patient showed statistically significant association with liver fibrosis (P < 0.0001); whereas antischistosomal antibody titer (P = 0.52) and HCV RNA titer (P = 0.79) failed to show a significant association. The respective AUC values for no fibrosis, significant fibrosis, severe fibrosis and cirrhosis of APRI score were 63%, 73.2%, 81.1% and 88.9% respectively. This showed good sensitivity and specificity of APRI alone for grading of liver fibrosis. But the inclusion of anti-Schistosoma antibody did not improve the prediction of fibrosis stage. CONCLUSION: The study results suggest that noninvasive biochemical markers like APRI are sensitive and specific in diagnosing the degree of fibrosis and cirrhosis in patients with coinfection of HCV and schistosomiasis as compared to biopsy. The addition of antischistosomal Ab to APRI did not improve sensitivity for predicting the degree of cirrhosis.

Eltrombopag with gemcitabine-based chemotherapy in patients with advanced solid tumors: a randomized phase I study.

Preventing chemotherapy-induced thrombocytopenia could avoid chemotherapy dose reductions and delays. The safety and maximum tolerated dose of eltrombopag, an oral thrombopoietin receptor agonist, with gemcitabine-based therapy was evaluated. Patients with advanced solid tumors and platelets ≤300 × 10(9) /L receiving gemcitabine plus cisplatin or carboplatin (Group A) or gemcitabine monotherapy (Group B) were randomized 3:1 to receive eltrombopag or placebo at a starting dose of 100 mg daily administered on days -5 to -1 and days 2-6 starting from cycle 2 of treatment. Nineteen patients (Group A, n = 9; Group B, n = 10) received eltrombopag 100 mg and seven (Group A, n = 3; Group B, n = 4) received matching placebo. Nine eltrombopag patients in Group A and eight in Group B had 38 and 54 occurrences of platelet counts ≥400 × 10(9) /L, respectively. Mean platelet nadirs across cycles 2-6 were 115 × 10(9) /L and 143 × 10(9) /L for eltrombopag-treated patients versus 53 × 10(9) /L and 103 × 10(9) /L for placebo-treated patients in Groups A and B, respectively. No dose-limiting toxicities were reported for eltrombopag; however, due to several occurrences of thrombocytosis, a decision was made not to dose-escalate eltrombopag to >100 mg daily. In Groups A and B, 14% of eltrombopag versus 50% of placebo patients required chemotherapy dose reductions and/or delays for any reason across cycles 3-6. Eltrombopag 100 mg once daily administered 5 days before and after day 1 of chemotherapy was well tolerated with an acceptable safety profile, and will be further tested in a phase II trial. Fewer patients receiving eltrombopag required chemotherapy dose delays and/or reductions compared with those receiving placebo.