Sequence variation of the Epstein-Barr virus nuclear antigen 1 (EBNA1) gene in chronic lymphocytic leukemia and healthy volunteer subjects.

Epstein-Barr virus-related malignancies have been linked to variations in the sequences of EBV genes, notably EBNA1. Therefore, the purpose of this study was to examine the DBD/DD domain and USP7 binding domain sequences at the C-terminus of the EBNA1 gene in patients with chronic lymphocytic leukemia (CLL). This study included 40 CLL patients and 21 healthy volunteers. Using commercial kits, total DNA was extracted from buffy coat samples, and each sample was tested for the presence of the EBV genome. The C-terminus of EBNA1 was then amplified from positive samples, using nested PCR. Sanger sequencing was used to identify mutations in the PCR products, and the results were analyzed using MEGA11 software. The mean ages of CLL patients and healthy individuals were 61.07 ± 10.2 and 59.08 ± 10.3, respectively. In the EBNA-1 amplicons from CLL patients and healthy individuals, 38.5% and 16.7%, respectively, harbored mutations in the DBD/DD domain of the C-terminal region of the EBNA1 gene (P = 0.378). The mutation frequency at locus 97,320 was significantly higher in CLL patients than in healthy individuals (P = 0.039). Three EBV subtypes based on residue 487 were detected. The frequency of alanine, threonine, and valine in both groups was 88, 8, and 4 percent, respectively (P = 0.207). Moreover, all of the isolates from healthy donors had alanine at this position. The findings indicated that the presence of threonine or valine at residue 487 as well as a synonymous substitution at residue 553 in the C-terminal region of EBNA1 might be involved in the pathogenesis of EBV in CLL patients.

Effects of Panax Ginseng on Health-Related Quality of Life in Patients with Non-Metastatic Breast Cancer: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial Ginseng for HRQOL in Breast Cancer.

Being diagnosed with cancer and chemotherapy impose distressing symptoms on patients' Health-Related Quality of Life (HRQOL). This study evaluated ginseng efficacy on improving multiple aspects of HRQOL in breast cancer patients. Forty women with non-metastatic early breast cancer were enrolled in the study. Participants received ginseng (1 g/day) or placebo with standard chemotherapy. HRQOL was evaluated via in-person interviews at baseline, two weeks after the second and last chemotherapy cycles. The FACT-B, a 37-item questionnaire composed of five subscales including physical well-being (PWB), social well-being (SWB), emotional well-being (EWB), functional well-being (FWB), and Breast Cancer Subscale (BCS) was employed to assess HRQOL. A considerable decreasing trend in the mean scores of all subscales, as well as the total score, was observed in the placebo group; nevertheless, the ginseng group experienced a slight decrease in the PWB subscale and a constant or even increasing trend in other subscales and total score. The differences in the mean change of scores during the study period were statistically significant in all domains between the two groups (all p-values < 0.001). Regular ginseng supplementation may provide beneficial effects on enhancing different aspects of HRQOL including PWB, SWB, EWB, FWB, and BCS in breast cancer patients.This study was registered in the Iranian Registry of Clinical Trials (IRCT, IRCT20141227020441N7) in Jan 2020.

Long-term follow-up of patients with hairy cell leukemia in the south of Iran.

BACKGROUND: Hairy cell leukemia (HCL) is an indolent chronic lymphoproliferative disorder and first-line treatment with either intravenous or subcutaneous cladribine generally leads to long-lasting remissions. METHOD: All 131 patients with hairy-cell leukemia (HCL) were analyzed, with a median follow-up of 91 months. Data is from 2007 to 2020. We evaluated the response rate to cladribine as the first line and the response rate to cladribine with or without rituximab in relapsed patients. Further, we assessed relapse-free survival, complications, and secondary malignancy. RESULTS: After a median follow-up of 91 months, the recurrence rate was 24%. The 5-year and 10-year RFS rates were 85% and 66%, respectively. Adding rituximab to 2-CDA leads to a better response rate than just cladribine (90% vs. 27.3%, p-value = 0.002) in the relapsed patients. CONCLUSION: HCL patients have long-term survival when cladribine is the first line of treatment. Furthermore, adding rituximab to cladribine leads to a higher response rate.

Protective effects of Panax ginseng against doxorubicin-induced cardiac toxicity in patients with non-metastatic breast cancer: A randomized, double-blind, placebo-controlled clinical trial.

INTRODUCTION: Anthracycline-based chemotherapy increases the risk of cancer therapeutics-related cardiac dysfunction. Recently, evidences from in vitro experiments and animal studies have shown that ginsenosides may exert cardiovascular protection against cancer therapeutics-related cardiac dysfunction. Here, we aimed to evaluate this effect in a clinical situation. METHODS: In this randomized, double-blind, placebo-controlled clinical trial, women with non-metastatic breast cancer whose left ventricular ejection fraction was ≥ 50% were randomly assigned in 1:1 ratio to receive ginseng (1 g/day) or placebo besides standard chemotherapy. Echocardiographic measurements were performed at baseline, after the fourth, and eighth chemotherapy cycles. High-sensitive cardiac troponin I was assessed at baseline and after the 4th cycle. The primary endpoint of the study was change in left ventricular ejection fraction. Cancer therapeutics-related cardiac dysfunction was defined as a drop in left ventricular ejection fraction of ≥ 10% from baseline. RESULTS: Results from 30 patients were included in the final analysis (15 patients in each group). In the intervention and control groups, left ventricular ejection fraction was dropped from 62.0 ± 0.9% to 60.7 ± 1.0% (difference = -1.3 ± 1.1%) and from 63.27 ± 1.1% to 58.0 ± 1.3% (difference = -5.27 ± 0.8%), respectively (difference = 3.97%, p = 0.006) at the end of the fourth cycle of chemotherapy. After the eighth cycle of chemotherapy, the mean left ventricular ejection fraction was increased by 0.8 ± 1.3% from baseline in the intervention group, whereas the placebo group experienced a reduction of -7.3 ± 1.4% (difference = 8.1%, p-value < 0.001). None of the patients in the ginseng group in comparison to 1(6.7%, p-value = 0.5) and 5 (33.3%, p-value = 0.02) patients in the placebo group developed cancer therapeutics-related cardiac dysfunction after the fourth and eighth cycles, respectively. High-sensitive cardiac troponin I levels were not significantly different between groups. CONCLUSIONS: Prophylactic ginseng supplementation may protect against doxorubicin-induced early cancer therapeutics-related cardiac dysfunction and early decline in left ventricular ejection fraction in breast cancer patients.

Comparing efficacy and safety of P013, a proposed pertuzumab biosimilar, with the reference product in HER2-positive breast cancer patients: a randomized, phase III, equivalency clinical trial.

BACKGROUND: Breast cancer is the most frequently diagnosed cancer and the leading reason for cancer-related death among women. Neoadjuvant treatment with dual-HER2 (human epidermal growth factor receptor 2) blockade has shown promising effects in this regard. The present study aimed to compare the efficacy and safety of a proposed pertuzumab biosimilar with the reference pertuzumab. METHODS: This randomized, phase III, multicenter, equivalency clinical trial was conducted on chemotherapy-naive women with HER2-positive breast cancer. Patients were randomly assigned (1:1) to receive six cycles of either P013 (CinnaGen, Iran) or the originator product (Perjeta, Roche, Switzerland) along with trastuzumab, carboplatin, and docetaxel every 3 weeks. Patients were stratified by cancer type (operable, locally advanced, inflammatory) and hormone receptor status. The primary endpoint was breast pathologic complete response (bpCR). Secondary endpoints included comparisons of total pCR, overall response rate (ORR), breast-conserving surgery (BCS), safety, and immunogenicity. RESULTS: Two hundred fourteen patients were randomized to treatment groups. bpCR rate in the per-protocol population was 67.62% in the P013 and 71.57% in the reference drug groups. Based on bpCR, P013 was equivalent to the reference pertuzumab with a mean difference of - 0.04 (95% CI: - 0.16, 0.09). Secondary endpoints were also comparable between the two groups. CONCLUSIONS: The proposed biosimilar P013 was equivalent to the reference product in terms of efficacy. The safety of both medications was also comparable.

A randomized, double-blind, phase III, non-inferiority clinical trial comparing the efficacy and safety of TA4415V (a proposed Trastuzumab biosimilar) and Herceptin (Trastuzumab reference product) in HER2-positive early-stage breast Cancer patients.

BACKGROUND: This study compared efficacy and safety of TA4415V, a trastuzumab biosimilar, with reference trastuzumab in patients with human epidermal growth factor receptor 2-positive (HER2-positive) early-stage breast cancer treated in the neoadjuvant setting in Iran. METHODS: Patients were randomly assigned to receive neoadjuvant TA4415V or reference trastuzumab concurrently with docetaxel (TH phase) for 4 cycles after treatment with 4 cycles of doxorubicin and cyclophosphamide (AC phase). Chemotherapy was followed by surgery. The primary endpoint was the comparison of pathologic complete response (pCR) rate in the per-protocol population. Secondary endpoints included comparisons of overall response rate (ORR), breast-conserving surgery (BCS), safety, and immunogenicity. RESULTS: Ninety-two participants were analyzed in the per-protocol population (TA4415V, n = 48; reference trastuzumab, n = 44). The pCR rates were 37.50% and 34.09% with TA4415V and reference drug, respectively. The 95% CI of the estimated treatment outcome difference (- 0·03 [95% CI - 0.23 to 0.16]) was within the non-inferiority margin. No statistically significant difference was observed between the groups for other efficacy variables in the ITT population: ORR (89.13% vs. 83.33%; p = 0.72) and BCS (20.37% vs. 12.96%; p = 0.42) in the TA4415V and reference drug group, respectively. At least one grade 3 or 4 adverse events occurred in 27 (50%) patients in the TA4415V group versus 29 (53.70%) in the reference trastuzumab group (p = 0.70). The decrease in left ventricular ejection fraction (LVEF), as an adverse event of special interest (AESI) for trastuzumab, was compared between treatment groups in TH phase. Results demonstrated an LVEF decrease in 7 (12.96%) and 9 (16.67%) patients in TA4415V and reference trastuzumab groups, respectively (p = 0.59). Anti-drug antibodies (ADA) were not detected in any samples of groups. CONCLUSIONS: Non-inferiority for efficacy was demonstrated between TA4415V and Herceptin based on the ratio of pCR rates in HER2-positive early breast cancer patients. In addition, ORR and BCS, as secondary endpoints, were not significantly different. Safety profile and immunogenicity were also comparable between the two groups.

Sildenafil for Primary Prevention of Anthracycline-Induced Cardiac Toxicity: A Phase I/II Randomized Clinical Trial, SILDAT-TAHA6 Trial.

Background: Previous animal studies have shown a protective effect of 5-phosphodiesterase inhibitors on cancer therapeutics-related cardiac dysfunction (CTRCD) of anthracyclines. Aim: The aim of this study was to evaluate the clinical effect of sildenafil on the primary prevention of CTRCD in human. Materials and Methods: In this randomized double-blind clinical trial, the primary end point was efficacy in preventing the reduction of left ventricular ejection fraction (LVEF). The intervention group patients received sildenafil at a dose of 25 milligrams twice a day before starting the chemotherapeutic regimen, and the control group received placebo. All the patients at baseline and after the 6-month follow-up underwent 4D and speckle-tracking echocardiography and cardiac MRI, accompanied by hs-troponin I and NT-Pro-BNP measurement. Results: Sixty patients were enrolled in this study, and data from 52 patients (24 patients in the intervention group and 28 patients in the control group) were used in the final analysis. Our findings showed that in the intervention and control groups, LVEF was dropped from 61.28 ± 7.36 to 51.57 ± 7.67 (difference (D) = -9.71 ± 11.95, p=0.003) and from 57.9 ± 7.29 to 50.2 ± 7.02% (D = -7.7 ± 5.93; p=0.001), respectively (between-group difference = -2.01%, p=0.26). CTRCD was detected in 11 patients in the control group (42.8%) and 10 in the intervention group (41.6%, p=0.51). Conclusion: Consumption of sildenafil for primary prevention of anthracycline-induced cardiac toxicity seems to be unbeneficial. This trial is registered with IRCT20180506039554N1.

Successful treatment of acute promyelocytic leukemia in a patient with prosthetic heart valves: a case report and review of the literature.

BACKGROUND: Although life-threatening hemorrhage is a usual manifestation of acute promyelocytic leukemia (APL), thrombotic events seem to be more common in APL compared to other subtypes of acute leukemia. The treatment and prophylaxis of thrombosis are controversial due to the high risk of bleeding caused by disseminated intravascular coagulation (DIC) and thrombocytopenia. To the best of our knowledge we report the first case of APL in a patient with prosthetic heart valves successfully treated with a combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). We hope this case report helps clinicians to manage different spectra of coagulopathy in APL successfully. CASE PRESENTATION: A 38-year-old Asian man presented with diagnosis of APL confirmed by bone marrow biopsy. He was on warfarin due to prosthetic mitral and aortic valves. He was at risk of both hemorrhagic events due to DIC and life-threatening valve thrombosis. Our management regimen included unfractionated heparin adjusted according to the platelet count to prevent both valve thrombosis and bleeding events. The patient tolerated treatment well without any hemorrhagic or thrombotic events, and complete molecular remission was achieved by ATRA and ATO without the need for chemotherapeutic agents. CONCLUSION: Although this case is exceptional, a precise evaluation may be needed to select the appropriate dose and type of anticoagulant to treat a patient with APL.

Combination of Low-Dose, Short-Course Mycophenolate Mofetil With Cyclosporine and Methotrexate for Graft-Versus-Host Disease Prophylaxis in Allogeneic Stem Cell Transplant.

OBJECTIVES: With the standard regimen for graft-versushost disease prophylaxis in allogeneic stem cell transplant with human leukocyte antigen-matched donor, grade II-IV acute graft-versus-host disease occurs in 30% to 50% of sibling and up to 80% of unrelated recipients. Studies with limited patient numbers have shown efficacy and safety of mycophenolate mofetil for graft-versus-host disease prophylaxis. We investigated the effect of low-dose mycophenolate mofetil added to a standardized prophylaxis regimen for graft-versus-host disease in related human leukocyte antigen-matched allogeneic stem cell transplant. MATERIALS AND METHODS: In this prospective randomized clinical trial, we compared cyclosporine and methotrexate versus the combination of cyclosporine, methotrexate, and mycophenolate mofetil in all patients who underwent human leukocyte antigencompatible related donor allogeneic stem cell transplant for acute leukemia during 3 years at the Bone Marrow Transplant Unit at Namazi Hospital, Shiraz University of Medical Sciences (Shiraz, Iran). RESULTS: All 134 patients in both groups underwent successful engraftment. Recovery times for neutrophils and platelets were not significantly different between groups (P < .05). Incidence of acute graft-versus-host disease in the cyclosporine, methotrexate, and mycophenolate mofetil group was less than in the cyclosporine and methotrexate group (21.6% vs 40.9%; P = .041). Incidence of grade II-IV acute graftversus-host disease in the mycophenolate mofetil group was 15.2% versus the control group at 33% (P = .045). CONCLUSIONS: Our single-center study suggests the combination of mycophenolate mofetil, cyclosporine, and methotrexate is superior to the standard regimen of cyclosporine and methotrexate for graft-versushost disease prophylaxis after human leukocyte antigen-matched related donor allogeneic stem cell transplant.

Evaluation of Reversed Administration Order of Busulfan (BU) and Cyclophosphamide (CY) as Conditioning on Liver Toxicity in Allogenic Hematopoietic Stem Cell Transplantation (ALL-HSCT).

Background: Busulfan (BU) in combination with cyclophosphamide (CY) is used as an effective conditioning regimen in hematopoietic SCT. Busulfan, depletes glutathione level in liver and causes elevated levels of CY metabolites. Cyclophosphamide metabolites are highly toxic for sinusoidal endothelial cells and cause VOD/ SOS with high mortality rate. Materials and Methods: Between September 2013 and September 2015, all adult patients with acute leukemia who were candidates for myeloablative allogenic SCT and were admitted to Stem Cell Transplantation center were enrolled in this prospective randomized clinical trial. We tested the hypothesis that reverse administration from BU-CY (n=28) to CY-BU group (n=27) would reduce liver toxicity. Results: Liver function tests were significantly higher in the BU-CY group between day -1 and +4 (p<0.05), but VOD/SOS was not diagnosed in both groups. The incidence and severity of acute GVHD was higher in the BU-CY group, but not statistically significant. Engraftment and mortality rate were not different. Conclusion: These data support the concept that CY-BU is associated with less liver toxicity, suggesting CY-BU is superior to BU-CY as conditioning.

Glucocorticoid induced diabetes and lipid profiles disorders amongst lymphoid malignancy survivors.

BACKGROUND AND AIMS: Hyperglycemia and glucose test abnormalities are problems during the treatment of patients with lymphoid malignancy, caused by corticosteroid therapy. However, its long-term complications or risk of developing diabetes are not available. METHODS: Two hundred patients with lymphoid hematologic malignancy were recruited and followed up for median of 47 months. The underlying hematologic malignancy includes Hodgkin's disease (HD), Non-Hodgkin's Lymphoma (NHL), Chronic Lymphocytic Leukemia(CLL), Multiple Myeloma (MM) and Acute Lymphocytic Leukemia (ALL). Fasting blood sugar, glucose tolerance test and lipid profiles were measured before each chemotherapy cycle and every 3 months after. This study was designed to evaluate patients for long-term follow up of glucose tests abnormalities. RESULTS: The mean age of the non-diabetic patients was significantly lower than that of diabetics and patients with fasting glucose disorder (p < 0.001). The prevalence of diabetes and impaired FBS and GTT was higher in NHL (9%), CLL (6.5%) and MM (1.5%), respectively. For lipid profiles, the highest levels of cholesterol and triglycerides were observed in multiple myeloma and the lowest in Hodgkin's lymphoma (P:0.004). CONCLUSIONS: The most important factor for steroid-induced diabetes is age, which was more prevalent with age increase (P < 0.001). Glucocorticoid-induced diabetes is common in multiple myeloma and then in chronic lymphocytic leukemia and non-Hodgkin's lymphoma in comparison with Hodgkin's lymphoma and acute lymphoblastic leukemia.

Stem Cell Transplant in Severe Glanzmann Thrombasthenia in an Adult Patient.

Glanzmann thrombasthenia is an inherited auto-somal recessive disorder characterized by normal platelet count but lack of platelet aggregation due to absence of platelet glycoprotein IIb/IIIa. The disease usually is associated with mild bleeding, but severe fatal hemorrhage may occur. Allogeneic stem cell transplant is the only curative method of treatment. A literature search showed 18 previously reported cases of Glanzmann thrombasthenia treated with allogeneic hematopoietic stem cell transplant. We report an 18-year-old woman with severe Glanzmann thrombasthenia who was treated with allogeneic hematopoietic stem cell transplant from her sister. After 24-month follow-up, the patient was well, had no bleeding tendency, and had mild chronic skin graft-versus-host disease.