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.

A Post-Marketing Surveillance Study to Evaluate the Safety Profile of AlvotereⓇ (Docetaxel) in Iranian Patients Diagnosed with Different Types of Cancers Receiving Chemotherapy.

BACKGROUND: Docetaxel is a clinically well established antimitotic chemotherapy medication. Labeled docetaxel indications are breast cancer, gastric cancer, head and neck cancer, non-small cell lung cancer, and prostate cancer. OBJECTIVE: This is a Phase IV study to evaluate the safety profile of docetaxel (Alvotere; NanoAlvand, Iran) in Iranian patients diagnosed with different types of cancers receiving chemotherapy regimens with docetaxel. METHODS: Patients who received Alvotere as a part of their chemotherapy regimen were enrolled in this Phase IV, observational, multicenter, open-label study. Alvotere was administrated as a single agent or in combination with other chemotherapy agents. Safety parameters in each cycle were assessed, and the related data were recorded in booklets. FINDINGS: A total of 411 patients with different types of cancers were enrolled from 25 centers in Iran. The most common malignancies among participants were breast cancer (49.88%), followed by gastric cancer (22.63%). Participants' mean age was 53.33 years, and the mean total dose used in each cycle was 132 mg. According to the results, 341 patients experienced at least 1 adverse event, that the most common was alopecia (41.12%). In total, 92 (22.38%) patients had at least 1 adverse event of grade 3 or 4, and 25 (6.08%) patients showed 54 serious adverse events, which the causality assessment for all was possibly related to Alvotere. There was a significant difference between men and women in the incidence of skin and subcutaneous tissue disorders (55.63% in women vs 41.73% in men; P = 0.009). Also, the incidence of gastrointestinal disorders, nervous system disorders, skin and subcutaneous tissue disorders, hepatic enzymes increase, and fluid retention was significantly higher (P < 0.05) in patients receiving anthracyclines in their chemotherapy regimens. CONCLUSIONS: The findings of this open-label, observational, multicenter, postmarketing surveillance showed that Alvotere appears to have an acceptable safety profile in Iranian cancer patients receiving chemotherapeutic regimens. (Curr Ther Res Clin Exp. 2022; 82:XXX-XXX) © 2022 Elsevier HS Journals, Inc.

Coexistence of p190 BCR/ABL Transcript and CALR 52-bp Deletion in Chronic Myeloid Leukemia Blast Crisis: A Case Report.

We introduce a 78-year-old woman presented with thrombocytosis and high blast count who had a history of splenectomy. Her cytogenetic analysis revealed aberrant chromosomal rearrangements in different clonal populations harboring 46XX karyotype with t(9;22) (q34;q11). RT-PCR assay detected the e1a2 BCR-ABL translocation resulting from rearrangement of the minor breakpoint cluster region (m-bcr) in BCR gene. Subsequent evaluation of the disease showed calreticulin (CALR) 52-bp deletion as well as the absence of JAK2 (V617F) heterozygous mutation in granulocyte population of peripheral blood using allele-specific PCR and bi-directional DNA sequencing. To our knowledge, this is the first case of a patient initially diagnosed as p190 BCR-ABL transcript positive CML in blast crisis characterized by a 52-bp deletion in CALR gene.

Hepatic metastatic niche: from normal to pre-metastatic and metastatic niche.

Liver is the organ responsible for hematopoiesis during fetal life, which is also a target organ of metastasis for several cancers. In order to recognize the hepatic metastatic changes, obtain a better grasp of cancer prevention, treatment, and inhibition mode of hepatic metastasis progression, we investigate the changes and transformation of normal hepatic niche cells to metastatic niche ones in this review. On the other hand, since metastatic diseases alter the liver function, the changes in a number of cancers that metastasize to the liver have also been reviewed. Relevant English-language literature was searched and retrieved from PubMed (1994-2014) using the following keywords: hepatic stem cell niche, hepatic metastatic niche, chemokine, and microRNAs (miRNAs). Also, over 86 published studies were investigated, and bioinformatics analysis of differentially expressed miRNAs in hepatic cancer and metastasis was performed. Metastasis is developed in several stages with specific changes and mechanisms in each stage. Recognition of these changes would lead to detection of new biomarkers and clinical targets involved in specific stages of liver metastasis. Investigation of the hepatic stem cell niche, development of metastasis in liver tissue, as well as changes in chemokines and miRNAs in metastatic hepatic niche can significantly contribute to faster detection of liver metastasis progression.

Molecular basis of chronic lymphocytic leukemia diagnosis and prognosis.

BACKGROUNDS: Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults and is characterized by a clonal accumulation of mature apoptosis-resistant neoplastic cells. It is also a heterogeneous disease with a variable clinical outcome. Here, we present a review of currently known (epi)genetic alterations that are related to the etiology, progression and chemo-refractoriness of CLL. Relevant literature was identified through a PubMed search (1994-2014) of English-language papers using the terms CLL, signaling pathway, cytogenetic abnormality, somatic mutation, epigenetic alteration and micro-RNA. RESULTS: CLL is characterized by the presence of gross chromosomal abnormalities, epigenetic alterations, micro-RNA expression alterations, immunoglobulin heavy chain gene mutations and other genetic lesions. The expression of unmutated immunoglobulin heavy chain variable region (IGHV) genes, ZAP-70 and CD38 proteins, the occurrence of chromosomal abnormalities such as 17p and 11q deletions and mutations of the NOTCH1, SF3B1 and BIRC3 genes have been associated with a poor prognosis. In addition, mutations in tumor suppressor genes, such as TP53 and ATM, have been associated with refractoriness to conventional chemotherapeutic agents. Micro-RNA expression alterations and aberrant methylation patterns in genes that are specifically deregulated in CLL, including the BCL-2, TCL1 and ZAP-70 genes, have also been encountered and linked to distinct clinical parameters. CONCLUSIONS: Specific chromosomal abnormalities and gene mutations may serve as diagnostic and prognostic indicators for disease progression and survival. The identification of these anomalies by state-of-the-art molecular (cyto)genetic techniques such as fluorescence in situ hybridization (FISH), comparative genomic hybridization (CGH), single nucleotide polymorphism (SNP) microarray-based genomic profiling and next-generation sequencing (NGS) can be of paramount help for the clinical management of these patients, including optimal treatment design. The efficacy of novel therapeutics should to be tested according to the presence of these molecular lesions in CLL patients.

Rare Cytogenetic Abnormalities and Alteration of microRNAs in Acute Myeloid Leukemia and Response to Therapy.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults, which is heterogeneous in terms of morphological, cytogenetic and clinical features. Cytogenetic abnormalities, including karyotype aberrations, gene mutations and gene expression abnormalities are the most important diagnostic tools in diagnosis, classification and prognosis in acute myeloid leukemias. Based on World Health Organization (WHO) classification, acute myeloid leukemias can be divided to four groups. Due to the heterogeneous nature of AML and since most therapeutic protocols in AML are based on genetic alterations, gathering further information in the field of rare disorders as well as common cytogenetic abnormalities would be helpful in determining the prognosis and treatment in this group of diseases. Recently, the role of microRNAs (miRNAs) in both normal hematopoiesis and myeloid leukemic cell differentiation in myeloid lineage has been specified. miRNAs can be used instead of genes for AML diagnosis and classification in the future, and can also play a decisive role in the evaluation of relapse as well as response to treatment in the patients. Therefore, their use in clinical trials can affect treatment protocols and play a role in therapeutic strategies for these patients. In this review, we have examined rare cytogenetic abnormalities in different groups of acute myeloid leukemias according to WHO classification, and the role of miRNA expression in classification, diagnosis and response to treatment of these disorders has also been dealt with.

Evaluating the Survival Rate and the Secondary Malignancies after Treating Hodgkin's Lymphoma Patients with Chemotherapy Regimens.

In this study we surveyed the average survival time of the treated Hodgkin's lymphoma patients and also the side effects and malignancies occurring secondary to the treatment. This is a retrospective study of patients referring to Ahwaz's Shafa hospital in a period of 10 years diagnosed with Hodgkin's lymphoma without any age restriction. After gathering all their data, we calculated their survival rate and the chance for a relapse and the secondary malignancies. 389 patients were included in the study with an average age of 27.5 years old and they had received only chemotherapy regimens. 87.9% of them had been treated by ABVD and 12.1 % by Stanford V regimen. 23.1% of them experienced a relapse and 13.1% of all patients, passed away during the study. Secondary malignancies were observed in 11 cases. An overall mean survival time of 295.31 months was resulted. The secondary malignancies after treating Hodgkin's lymphoma patients are different between chemotherapy regimens and chemotherapy - radiotherapy.