Permanent longitudinal strain damage of cardiotoxic drugs in childhood cancer: What is the safe level?

Objective: Anthracycline administration in children is associated with cardiac dysfunction. Speckle-tracking echocardiography (STE) can detect subclinical cardiac damage that may go undetected by conventional two-dimensional (2D) echocardiography. This study aims to investigate medium-term anthracycline cardiotoxicity using STE and determine a safer administrable level of anthracyclines (ACs). Methods: This observational case-control study enrolled 37 healthy controls and 78 pediatric cancer survivors who received chemotherapy. The patients were divided into two groups: cardiotoxic received (CR) and cardiotoxic free (CF). Data on segmental longitudinal strain (LS), global LS (GLS), and 2D echocardiographic parameters were collected after a drug-free period of at least one year. Results: A total of 115 children with a mean age of 108 ± 55 months, of whom 66% were males, were included in the study. Both the groups of cancer survivors exhibited significantly reduced GLS compared to healthy controls (CR vs. controls, P = 0.001; CF vs. controls, P = 0.013), but no significant difference in left ventricular ejection fraction (LVEF) was observed (P = 0.75). Overall, cancer survivors treated with ACs demonstrated a significant reduction in strain in 10 left ventricular segments, particularly in the basal segments (P < 0.05). Among CR patients, those with impaired GLS (n = 43, GLS worse than -21.9) had significantly higher mean age and cumulative anthracycline dose compared to CR patients with normal GLS (age, P = 0.024; anthracycline dosage, P = 0.036). Using an anthracycline cutoff of 223 mg/m2 resulted in a higher detection rate (49% vs. 25%) and fewer missed cases (51% vs. 74%) compared to the 360 mg/m2 anthracycline cutoff. Conclusion: Childhood cancer survivors demonstrate significantly reduced GLS while preserving a normal LVEF, which does not differ significantly from reference values of healthy children. The reduction in strain appears to be associated with higher anthracycline doses and older age. Lowering the anthracycline threshold to 223 mg/m2 may improve the predictability of a decline in cardiac function using strain imaging at medium-term follow-up.

Philadelphia Chromosome Positive Chronic Myelogenous Leukemia Blastic Crisis in A Patient with Unusual Primary Myelofibrosis Characteristics; A Case Report.

INTRODUCTION: Myeloproliferative neoplasms (MPNs) are divided into BCR-ABL positive Chronic myeloid leukemia (CML) and BCR-ABL negative MPNs including Polycythemia vera (PV), Essential Thrombocythemia (ET) and Primary myelofibrosis (PMF). Evaluation of the Philadelphia chromosome in MPNs is a diagnostic requirement for classic CML. CASE REPORT: In 2020, a 37-year-old woman with negative cytogenetic testing for Janus kinase2 (JAK2), Calreticulin (CALR), myeloproliferative leukemia virus oncogene (MPL), and positive for BCR-ABL1 mutation with reticular fibrosis in bone marrow was diagnosed as CML. Some years ago, the patient had been diagnosed with PMF with evidence of histiocytic necrotizing lymphadenitis or Kikuchi-Fujimoto disease (KFD). The BCR-ABL fusion gene was initially evaluated which was negative. Then, Cutaneous squamous cell carcinoma (cSCC) was confirmed by Dermatopathologist with palpable splenomegaly and high white blood cell (WBC) count with basophilia. Finally, BCR-ABL was detected positive by the fluorescence in situ hybridization (FISH) and quantitative real-time polymerase chain reaction (qRT-PCR). In fact, the co-occurrence of PMF with CML was identified. CONCLUSION: This case study highlighted the importance of some cytogenetic methods in the detection and classification of MPNs. It is recommended that physicians pay more attention to it and be aware of the planning treatment.

The mRNA Expression of PTEN, LEF1, JAK3, LC3 and p62/SQSTM1 Genes in Patients with Chronic Myeloid Leukemia.

INTRODUCTION: Chronic myeloid leukemia (CML) is a progressive myeloproliferative disorder resulting from forming a chimeric BCR-ABL gene. The proteins derived from this gene can affect some genes from various signaling pathways such as PI3K/AKT/Wnt/catenin/JAK/Stat involved in proliferation, differentiation, cell death, and genes related to autophagy. Imatinib is the first-line treatment for CML patients, with durable and proper responses in Iranian children and adult CML patients. Hence, we aimed to evaluate the mRNA expression of some selected key genes from those pathways in patients with CML before and under treatment. METHODS: In the case-control study, the mRNA expression of PTEN, LEF1, JAK3, LC3 and p62 genes were measured in 51 CML patients (6 patients before treatment and 45 patients under treatment with imatinib mesylate) and 40 healthy controls using the Real-time PCR method. RESULTS: The mRNA expression of PTEN and P62 were significantly higher in newly diagnosed patients than in controls (P<0.0001 and P = 0.0183, respectively), while the expression of the LC3 gene was significantly lower in the untreated newly diagnosed group than in control subjects (P = 0.0191). The expression level of PTEN, LEF1, JAK3 and P62 genes were significantly decreased in patients under treatment than in the group before treatment (P = 0.0172, P = 0.0002, P = 0.0047 and P = 0.0038, respectively). A positive correlation was seen between the gene expression of P62 and BCR-ABL in the patients under treatment (r 0529, P = 0.016). CONCLUSION: Our findings showed that the changes in expression of these genes were related to the patient's treatment. Due to the key role of these genes in proliferation, differentiation and tumor suppression, it is proposed that these genes may be helpful for follow-up of treatment in CML patients.

Variation in the dynamic of absorption and efficiency of phosphorus use in tomato.

Changes in root growth and metabolism of P in tomato cultivars are necessary in acidic soils in tropical and subtropical regions in response to P deficiency. This increase in the efficiency of phosphorus absorption by tomatoes can significantly reduce the doses of phosphate fertilizers used, as well as, possibly, the more immediate use of P fixed in the soil matrix, with favorable effects on agricultural sustainability, promoting the use of marginal areas in terms of soil fertility, and the national fertilizer economy. The tested hypothesis was that there would be no difference in the uptake and utilization of P by tomato cultivars; therefore, this study investigated the variation in the dynamics of absorption and efficiency of P-use through changes in the root, stem, leaf, gas exchange, and P-use efficiency in tomato cultivars contrasting P-absorption. The experimental design comprised a factorial scheme consisting of two cultivars that were tolerant and sensitive to P deficiency and three P concentrations (control, moderate deficiency, and severe deficiency). P limitation in the tolerant cultivar promoted high dry matter concentration (root, stem, and leaf), leaf area, root volume, nutrient translocation, rate of leaf gas exchange, and efficiency under P-deficiency stress. It was concluded from the research that the variation in the dynamics of absorption and efficiency of P use of the tolerant cultivar increased the production of roots, leaves, and leaf gas exchange under P stress conditions.

Oncogenic and tumor suppressor genes expression in myeloproliferative neoplasms: The hidden side of a complex pathology.

BACKGROUND: The present study aimed to explore the changes in the expressions of six tumor-related genes in myeloproliferative neoplasms (MPNs). The study population included 130 patients with MPNs (52 with chronic myeloid leukemia (CML), 49 with essential thrombocythemia (ET), 20 with polycythemia vera (PV), and 9 with primary myelofibrosis (PMF)) and 51 healthy individuals. METHODS: The expression profiling of six genes (ADAMTS18, CMTM5, CDKN2B, DCC, FHIT, and WNT5B) in the peripheral blood granulocyte cells was explored by real-time quantitative reverse transcription polymerase chain reaction. RESULTS: The patients with MPNs showed significant downregulation of CMTM5 (EFC = 0.66) and DCC (EFC = 0.65) genes in contrast to a non-significant upregulation of ADAMTS18, CDKN2B, FHIT, and WNT5B genes. Downregulation of DCC was consistent in all subtypes of MPN (EFC range: 0.591-0.860). However, CMTM5 had a 1.22-fold upregulation in PMF in contrast to downregulation in other MPN subtypes (EFC range: 0.599-0.775). The results revealed a significant downregulation in CMTM5 and DCC at below 60-years of age. Furthermore, female patients showed a clear-cut downregulation in both CMTM5 and DCC (EFC DCC: 0.436 and CMTM5: 0.570), while male patients presented a less prominent downregulation with a borderline p-value only in DCC (EFC: 0.69; p = 0.05). CONCLUSIONS: Chronic myeloid leukemia cases showed a significant upregulation of WNT5B, as a known oncogenesis gene. Two tumor suppressor genes, namely DCC and CMTM5, were downregulated in the patients with MPNs, especially in females and patients below 60 years of age.

Prevalence of Human Papilloma Virus in Sinonasal Papilloma in Southern Iranian Population.

STATEMENT OF THE PROBLEM: Sinonasal papilloma (SNP) is a rare benign lesion characterized by high recurrence rate and malignant transformation. PURPOSE: This study aimed to investigate the prevalence of human papilloma virus (HPV) infection in these lesions in South of Iran. MATERIALS AND METHOD: In this cross sectional retrospective study, a total of 41 patients, 38 SNP and 3 SNP/Squamous cell carcinoma cases, from 2007 to 2014 were studied. Human papilloma virus (HPV) DNA detection was performed by nested PCR method and positive cases were analyzed for high risk HPV-16 and HPV-18. RESULTS: HPV was detected in 31.7%; HPV- 16 in 4.9% and HPV 18 was not detected at all. Dysplastic epithelium was detected in 53% that was not associated with HPV. Three cases were accompanied with malignant transformation that HPV genome was detected in only one case and none of them were positive for HPV16 /18 genomic DNA. CONCLUSION: Current research suggests that HPV may be involved in the development of SNP. But the high risk HPV is not important in malignant transformation. More studies are needed to elucidate the possible etiologic mechanism between HPV, inverted papilloma, and squamous cell carcinoma.

The Prevalence of Human Papilloma Virus in Squamous Cell Carcinoma of Oral Tongue.

BACKGROUND AND OBJECTIVE: Oral tongue Squamous Cell carcinoma (SCC) commonly involves males between the sixth to eighth decades of life. Major risk factors are tobacco usage and alcohol consumption. The increasing number of patients developing oral tongue cancer without these well-known risk factors suggests that a viral infection, such as Human Papillomavirus (HPV), may be responsible for this increase, by acting as an oncogenic agent. This study investigated the prevalence of HPV infection and its clinicopathologic significance in oral tongue SCCs. METHODS: Tissue blocks from a total of 50 cases (patients with oral tongue SCC) and 50 controls (palatine tonsillar tissues with benign diagnosis) were selected. DNA was extracted from tumoral and non-tumoral tissue blocks. Detection of common HPV DNA by nested Polymerase Chain Reaction (PCR), and high-risk genotypes, HPV 16 and HPV 18, by conventional PCR, was achieved and the results correlated with clinicopathological parameters. RESULTS: Of the 50 patients (18 males and 32 females with a mean age of 57.36±12.18 years, and age range of 27 to 86 years), 7 (14%) had HPV positive results. None of the control group subjects had HPV DNA positive results (P-value of 0.012). The HPV genotype 16/18 was not detected in positive cases. No statistically significant association was found between HPV status and gender, age, tumor grade, tumor stage or lymph node involvement. CONCLUSION: Although there was a significantly higher prevalence of HPV in oral tongue SCC, its association with carcinogenesis in this area requires further studies.

Conjunctival Lesions; a Histopathologic Review in Fars Province, Iran.

PURPOSE: To determine the prevalence of various types of conjunctival lesions, at a tertiary ophthalmic center in Fars Province, South of Iran. METHODS: Histopathologic slides and medical records of conjunctival lesions submitted to the pathology department of Khalili Hospital, Shiraz, Iran were reviewed from April, 2009 to July, 2013. The histopathologic diagnoses were categorized into benign, pre-malignant, and malignant lesions. The prevalence of various types of conjunctival lesions was calculated. RESULTS: Histologic sections of 631 conjunctival lesions were reviewed. Benign lesions were most prevalent (81.8%), followed by premalignant (10.8%) and malignant (7.4%) lesions. Pterygia were the most common benign lesions (69.2%), intraepithelial dysplasia constituted most cases of premalignant lesions (94.1%), and squamous cell carcinoma was the most frequent malignant lesion (93.6%). Benign lesions were the most common type of lesions in all age groups, however the prevalence of malignant lesions increased significantly with age (P < 0.001). CONCLUSION: Benign lesions were the most common conjunctival lesions with pterygia on top of the list, while intraepithelial neoplasia and squamous cell carcinoma were the most common premalignant and malignant lesions, respectively. Conjunctival malignant lesions were more prevalent with older age.

The small round blue cell tumors of the sinonasal area: histological and immunohistochemical findings.

BACKGROUND: Primary Small round blue cell tumors (SRBCT) in sinonasal comprise histogenetically diverse entities with overlapping morphologic features. Because of the limited initial biopsy tissue materials, differential diagnostic difficulties may arise, and as they have different management, exact diagnosis and classification are very important. OBJECTIVES: In this study, we analyzed the immunohistochemical expression of a panel of markers in the classification and diagnosis of sinonasal SRBCTs. MATERIAL AND METHODS: This cross sectional study was performed on 36 paraffin embedded tissue samples. Histologic and immunohistochemical slides from 36 patients with SRBCT were analyzed retrospectively. The patients were admitted in Khalili hospital, Shiraz from 1383 to 1388. RESULTS: There were 13 women and 23 men with the mean age of 53 ±12.1. There were 9 malignant melanoma, seven poorly differentiated SCC; six lymphoma (DLBL); 4 SCNEC; three SNUC; two ON; two Ewing/PNET; two embryonal rhabdomyosarcoma, and one plasmacytoma. Pan-cytokeratin was strongly expressed poorly differentiated SCC and all cases of SNUC. Coexpression of desmin and nuclear myoD1 was only detected in rhabdomyosarcoma. HMB45 was only expressed in sinonasal melanoma. CD99 expression was identified only in Ewing/PNET. FLI-1 was detected in 50% of PNET. P63 was expressed in poorly differentiated SCC (2/7) and SNUC (1/3). CONCLUSIONS: The results of our study indicate that the integration of histopathologic findings with application of limited but highly specific markers led to the separation of carcinomas, lymphoma and melanomas from other small cell tumors. Using a panel of keratin, LCA, desmin, and HMB45 is the most practical and economic approach to accurately classify these tumors.

Extramedullary plasmacytoma of the nasal cavity report of three cases with review of the literature.

Extramedullary plasmacytoma is a rare neoplasm characterized by monoclonal proliferation of plasma cells. Most lesions occur in the head and neck, primarily in the upper aerodigestive tract. The nasal cavity and nasal septum are the most common sites of occurrence. In this report, three patients admitted in our clinic with history of nasal obstruction and/or epistaxis. Patients were diagnosed with extramedullary plasmacytoma and mass were completely excised. This entity usually occurred in 5th-6th decade of life. One of our patients, a young man, was completely asymptomatic and following a paroxysm of coughing, a polypoid mass was expectorated. The clinical and histopathologic findings of plasmacytoma are discussed. In order to exclude systemic involvement, systematic approach using clinical, laboratory, and radiologic investigations was performed. Extramedullary plasmacytoma of the nasal cavity is rare and should be considered in the differential diagnosis of nasal cavity masses especially in young age group.

Comparison between presence of epstein barr virus in nodal and extra nodal diffuse large B cell lymphoma of head and neck, an Iranian experience.

BACKGROUND: Epstein Barr Virus (EBV) is one of the most common viral infections in human population. EBV has a significant role in pathogenesis of Hodgkin's lymphoma, Burkitt's lymphoma and nasopharyngeal carcinoma. The role of EBV in non-Hodgkin's lymphoma, diffuse large B cell (NHL - DLBL) in the head and neck is controversial. OBJECTIVES: The purpose of this study is to find out the difference between the presence of Epstein Barr virus in nodal and extra nodal lymphoma of head and neck. PATIENTS AND METHODS: A total of 30 cases of DLBL in two separate groups were collected from pathology department. The first group was consisted of 15 patients with DLBL of neck lymph node and the other was consisted of 15 patients with extra nodal DLBL of head and neck mainly in palatine tonsil. Both immune-histo-chemical (IHC) study and polymerase chain reaction (PCR) for detection of late membrane antigen (LMP) were performed on formalin fixed paraffin embedded tissue. RESULTS: All 30 cases were negative for EBV in IHC method. But in PCR method, 10% of patients were positive for LMP gene. There were 2 positive cases in nodal lymphoma and 1 positive case in extra nodal lymphoma group. CONCLUSIONS: Compare with PCR method, it seems that IHC is not a sensitive method for detection of EBV. Overall, the finding of EBV in NHL depends on site, type of lymphoma and the detection method.

Study the polymorphism of CYP3A5 and CYP3A4 loci in Iranian population with laryngeal squamous cell carcinoma.

Cancer reflects a complicated network of interactions between genes and environmental factors. Cytochrome P450 (CYP) is a multi-gene superfamily participating in the metabolism of xenobiotics. The aim of our study was to examine whether polymorphisms in the CYP enzyme genes affect the risk of developing larynx squamous cell carcinoma (SCC). Polymorphism of CYP3A5 and CYP3A4 genes were investigated in 50 patients with laryngeal SCC and 100 control subjects by polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP). In patients the CYP3A5 3/3 and 1/3genotypes were detected in 92% and 8% respectively. There was no relation between genotype, allele frequency and grade/stage of tumor. In control group, the frequency of CYP3A5 3/3 and CYP3A5 1/3 genotype were 98% and 2% respectively. There was no significant difference in genotype and allele frequency of this gene between patient and control group. In respect of CYP3A41A/B, people in both patient and control groups had the same genotype of CYP3A41A/1A. In this study, the CYP gene variants were not associated with increased risk of laryngeal SCC. Study on the other genetic factors which are involved in activation/detoxication of procarcinogenes, such as CYP1A1, CYP1B1, CYP2E1 and gluthation S transferase is recommended.

Molecular diagnosis of nasopharyngeal carcinoma using detection of Epstein-Barr virus latent membrane protein-1 gene in cervical metastatic lymph nodes.

BACKGROUND: Cervical lymphadenopathy could be a manifestation of occult nasopharyngeal carcinoma (NPC). Epstein-Barr virus (EBV) is frequently detected in NPC, and its malignant transformation is associated through the action of the oncoprotein latent membrane protein-1 (LMP-1). PURPOSE: The aim of this study was to investigate whether a primary nasopharyngeal origin could be localized by detection of EBV LMP-1 gene in cervical metastatic lymph nodes. MATERIALS AND METHODS: In this prospective study, 32 paraffin-embedded tissues of various head and neck carcinomas and 20 normal tonsil specimens were examined for the presence of LMP-1 gene, using polymerase chain reaction. RESULTS: Ten of 12 nasopharyngeal biopsies and 8 of 10 metastatic lymph nodes of the same NPC were positive for LMP-1 gene. The LMP-1 gene was detected in metastatic lymph nodes of NPC, with a sensitivity of 80%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 91%. On the contrary, the LMP-1 gene was not detected in any of the samples of other head and neck carcinomas and their metastatic nodes as well as in tonsillar specimens. There was a significant association between the presence of LMP-1 gene and tumor location in the nasopharynx (P < .0001). CONCLUSION: The presence of LMP-1 gene in metastatic cervical lymph nodes is significantly associated with nasopharyngeal origin of the carcinoma. Meanwhile, EBV has no role in the tumorigenesis of carcinomas arising from other head and neck regions.