Quadruplet Therapy in De Novo High-Volume Mixed Neuroendocrine Prostate Cancer Using 177Lu-PSMA: A Case Report.

ABSTRACT: We present a case of de novo high-volume metastatic prostate cancer with high PSMA expression, partially PSMA-negative, using quadruplet therapy (PROMISE ver. 2 miTNM; miT4N2M1aM1b(dmi) PRIMARY score: 5, PSMA-expression score: 0-3). Because of our patient's partial PSMA negativity and after a multidisciplinary tumor board discussion, we decided to use a modified protocol involving doublet hormonal therapy along with 177Lu-PSMA and radiation therapy to address the PSMA-negative disease. The patient responded well to this treatment, but recurrence was ultimately inevitable. This case represents a typical example of mixed neuroendocrine prostate carcinoma and highlights its resistant phenotype in response to quadruplet therapy.

Female case with misdiagnosis of hemophilia A who underwent total knee arthroplasty: A case report.

A female was diagnosed with hemophilia A. She had undergone bilateral total knee arthroplasty. She had a history of numerous hemorrhages including hemarthrosis. After further investigations, the diagnosis of von Willebrand disease type 2N was confirmed. The differential diagnoses for hemophilia A include von Willebrand disease, rare bleeding disorders, and severe platelet disorders.

Association of SMAD7 genetic markers and haplotypes with colorectal cancer risk.

PURPOSE: Colorectal cancer (CRC) is one of the common cancers with a high mortality rate worldwide. In Iran, there has been a trend of increased incidence of colorectal cancer in the last three decades that necessitates the early diagnosis. Genetic factors have an influential role in its etiology along with the conventional risk factors such as age, diet, and lifestyle. Results from GWAS have shown significant associations between SMAD7 gene variants and risk of CRC. This study aimed to assess the association of certain polymorphisms as well as haplotypes of this gene and risk of colorectal cancer. METHODS AND MATERIALS: This study was designed as a case-control association study. After obtaining ethical approval and informed consent, blood samples from 209 patients with colorectal cancer were collected and DNA was extracted. Four variants: rs4939827, rs34007497, rs8085824 and rs8088297 were genotyped using ARMS-PCR method. RESULTS: SMAD7 rs4939827 in the recessive and co-dominant models was associated with colorectal cancer risk [TT/CT + CC: OR = 2.90, 95%CI (1.38-6.09), p = 0.005; CC + TT/CT: OR = 1.66, 95%CI (1.00-2.75), p = 0.01]. Haplotype analysis indicated that some SNP combinations including two for-SNPs haplotypes of T-T-C-C and T-C-C-A were significantly associated with CRC risk. CONCLUSION: Based on the identified association of SMAD7 gene variations and haplotypes with colorectal cancer risk in our population, genetic variations in this gene region may have a role in CRC development. This data may shed light on the genetic predisposition of CRC which involves different pathways including TGF-ß.

Investigating the association between rs6983267 polymorphism and susceptibility to gastrointestinal cancers in Iranian population.

Genome-wide association studies have revealed that some single nucleotide polymorphisms at 8q24, such as rs6983267, might be effective in susceptibility to various cancers in different populations. Therefore, rs6983267 might be useful as a marker for multiple cancers. In this study, we considered a population, including 478 gastrointestinal cancer cases from the Iranian population, to investigate the association between rs6983267 and susceptibility to gastrointestinal cancers. The samples were genotyped using the TaqMan real-time PCR method while 10% of them were also confirmed by sequencing. Higher frequency of G allele was associated with higher grades of tumors in esophageal cancer and the tumors located in the lower portion of the esophagus (OR 3.56; 95% CI 1.13-11.24; P = 0.03) and cardia (OR 5.24; 95% CI 1.26-21.83; P = 0.02), which both locations are involved in esophageal adenocarcinomas with poor prognosis. The results indicated that in the male subgroup, the rs6983267 GG genotype significantly enhanced the gastric cancer susceptibility (OR 4.76; 95% CI 1.57-14.45; P = 0.01). GG genotype also increased the risk of intestinal-type gastric cancer, located in non-cardia (OR 4.62; 95% CI 1.25-17.04; P = 0.02). Moreover, gastric cancer cases and controls with a family history of gastrointestinal tumors were mostly genotyped with the G allele (OR 3.61; 95% CI = 1.09-12.01; P = 0.04). There were no remarkable associations between rs6983267 and susceptibility to esophageal and colon cancers in the Iranian population. However, different genotypes of rs6983267 had significant correlations with tumor grade, cancer type, and family history of gastrointestinal cancers. Further investigations in a larger population and other ethnicities are required to confirm these results.

Efficacy and safety of convalescent plasma therapy in severe COVID-19 patients with acute respiratory distress syndrome.

Since SARS-CoV-2 infection is rapidly spreading all around the world, affecting many people and exhausting health care resources, therapeutic options must be quickly investigated in order to develop a safe and effective treatment. The present study was designed to evaluate the safety and efficacy of convalescent plasma (CP) for treating severe cases of COVID-19 who developed acute respiratory distress syndrome (ARDS). Among 64 confirmed cases of severe COVID-19 with ARDS in this study, 32 patients received CP besides first line treatment. Their clinical response and outcome in regard to disease severity and mortality rate were evaluated and compared with the other 32 patients in the control group who were historically matched while randomly chosen from previous patients with the same conditions except for receiving CP therapy. Analysis of the data was performed using SPSS software. Patients with plasma therapy showed improvements in their clinical outcomes including a reduction in disease severity in terms of SOFA and APACHE II scores, the length of ICU stay, need for noninvasive ventilation and intubation and also showed an increase in oxygenation. They also showed reduction in mortality which was statistically significant in less severe cases with mild or moderate ARDS. Early administration of the convalescent plasma could successfully contribute to the treatment of severe COVID-19 patients with mild or moderate ARDS at risk of progressing to critical state.

Interaction of perforin and granzyme B and HTLV-1 viral factors is associated with Adult T cell Leukemia development.

OBJECTIVES: Human T cell leukaemia virus type 1 (HTLV-1) is associated with adult T cell leukaemia (ATL), a malignant lymphoproliferative disease that infects CD4 T cells. It is not clear why the majority of HTLV-1-infected individuals remain asymptomatic carries (ACs) and a minority develop ATL. Cellular immune response has a critical role in ATL and destroys malignant and HTLV-1-infected cells. Perforin and granzyme have important functional roles in apoptosis and destruction of infected cells. In the present study we examined the role of perforin and granzyme in ATL patients and ACs. MATERIALS AND METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from ATL patients and ACs by using Ficoll-hypaque density centrifugation. RNA was extracted and cDNA was synthesized. A real-time PCR TaqMan method was designed and optimized for evaluation of perforin, granzyme, tax, and HBZ gene expression. HTLV-1 proviral load (PVL) was quantified in patients with ATL and ACs. RESULTS: The mRNA expression of tax and HBZ was significantly higher in ATL patients than ACs (P=0.011 and P=0.0001,respectively). The HTLV-1 PVL was higher in ATL patients compared to with AC group (P=0.015). There was a significant increase in perforin gene expression in ACs compared with ATL patients (P=0.002). Furthermore, the expression of granzyme was also higher in ACs compared with ATL patients, and significant differences were observed between the two groups (P=0.036). CONCLUSION: Low expression of perforin and granzyme in ATL patients seems to influence the efficiency of CTL function and destruction of HTLV-1-infected cells, which might contribute to the disease pathogenesis.

Complete sequence of human T cell leukemia virus type 1 in ATLL patients from Northeast Iran, Mashhad revealed a prematurely terminated protease and an elongated pX open reading frame III.

To gain insight into the origin, evolution, dissemination and viral factors affecting HTLV-1-associated diseases, knowing the complete viral genome sequences is important. So far, no full-length HTLV-1 genome sequence has been reported from Iran. Here we report the complete nucleotide sequence of HTLV-1 viruses isolated from adult T cell leukemia/lymphoma (ATLL) patients from this region. The genome size of HTLV-1-MhD (Mashhad) was found to be 9036 bp and sequence analysis of the LTR region showed that it belongs to cosmopolitan subtype A. Comparing the sequences with isolates from another endemic area (HTLV-1ATK) revealed variations in the U3 region (~3.4%), while there was 99.1% and 97.0% similarity in R and U5 regions, respectively. The nucleotide sequences of HTLV-1 gag, pro and pol genes had a difference of 1.1% compared with HTLV-1 ATK with 16 nucleotides replaced in the gag and 27 in the pol regions. There was no variability in the amino acid sequences in the p24gag, however three residues were different in the p19gag and one in the p15gag. The nucleotide sequence of env showed a divergence of 1.5% compared to ATK with 22-nucleotide variation. The HTLV-1-MhD Tax, p13, p30, and p12 had 99.1, 100, 98.8, and 98%, respectively similarity with the prototype strain. Four amino acid changes were detected in ORF1 and ORF2 products p12 and p30, respectively, while the p13 region showed 100% conservation. The nucleotide identity between the isolates of Mashhad and those isolated from France, Germany, China, Canada and Brazil was 99.1%, 99.2%, 97.9%, 99% and 99.3%, respectively. Four amino acid changes compared with HTLV-1ATK from Japan were detected in ORF1 and ORF2 products p12 and p30, respectively, while the p13 region showed 100% conservation. This data could provide information regarding the evolutionary history, phylogeny, origin of the virus and vaccine design.

HTLV-1-host interactions on the development of adult T cell leukemia/lymphoma: virus and host gene expressions.

BACKGROUND: Adult T-cell leukemia/lymphoma (ATLL) is a lymphoproliferative disorder of HTLV-1-host interactions in infected TCD4+ cells. In this study, the HTLV-1 proviral load (PVL) and HBZ as viral elements and AKT1, BAD, FOXP3, RORγt and IFNλ3 as the host factors were investigated. METHODS: The study was conducted in ATLLs, HTLV-1-associated myelopathy/tropical spastic paraparesis patients (HAM/TSPs) and HTLV-1-asympthomatic carriers (ACs). The DNA and mRNA from peripheral blood mononuclear cells were extracted for gene expression assessments via qRT-PCR, TaqMan assay, and then confirmed by western blotting. RESULTS: As it was expected, the HTLV-1-PVL were higher in ATLLs than ACs (P = 0.002) and HAM/TSP (P = 0.041). The HBZ expression in ATLL (101.76 ± 61.3) was radically higher than in ACs (0.12 ± 0.05) and HAM/TSP (0.01 ± 0.1) (P = 0.001). Furthermore, the AKT1 expression in ATLLs (13.52 ± 4.78) was higher than ACs (1.17 ± 0.27) (P = 0.05) and HAM/TSPs (0.72 ± 0.49) (P = 0.008). However, BAD expression in ATLL was slightly higher than ACs and HAM/TSPs and not significant. The FOXP3 in ATLLs (41.02 ± 24.2) was more than ACs (1.44 ± 1) (P = 0.007) and HAM/TSP (0.45 ± 0.15) (P = 0.01). However, RORγt in ATLLs (27.43 ± 14.8) was higher than ACs (1.05 ± 0.32) (P = 0.02) but not HAM/TSPs. Finally, the IFNλ3 expression between ATLLs (31.92 ± 26.02) and ACs (1.46 ± 0.63) (P = 0.01) and ACs and HAM/TSPs (680.62 ± 674.6) (P = 0.02) were statistically different, but not between ATLLs and HAM/TSPs. CONCLUSIONS: The present and our previous study demonstrated that HTLV-1-PVL and HBZ and host AKT1 and Rad 51 are novel candidates for molecular targeting therapy of ATLL. However, high level of RORγt may inhibit Th1 response and complicated in ATLL progressions.

Evaluation of the role of TAX, HBZ, and HTLV-1 proviral load on the survival of ATLL patients.

BACKGROUND: Adult T-cell leukemia/lymphoma (ATLL) is an aggressive malignancy with very poor prognosis and short survival, caused by the human T-lymphotropic virus type-1 (HTLV-1). The HTLV-1 biomarkers trans-activator x (TAX) and HTLV-1 basic leucine zipper factor (HBZ) are main oncogenes and life-threatening elements. This study aimed to assess the role of the TAX and HBZ genes and HTLV-1 proviral load (PVL) in the survival of patients with ATLL. METHODS: Forty-three HTLV-1-infected individuals, including 18 asymptomatic carriers (AC) and 25 ATLL patients (ATLL), were evaluated between 2011 and 2015. The mRNA expression of TAX and HBZ and the HTLV-1 PVL were measured by quantitative PCR. RESULTS: Significant differences in the mean expression levels of TAX and HBZ were observed between the two study groups (ATLL and AC, P=0.014 and P=0.000, respectively). In addition, the ATLL group showed a significantly higher PVL than AC (P=0.000). There was a significant negative relationship between PVL and survival among all study groups (P=0.047). CONCLUSION: The HTLV-1 PVL and expression of TAX and HBZ were higher in the ATLL group than in the AC group. Moreover, a higher PVL was associated with shorter survival time among all ATLL subjects. Therefore, measurement of PVL, TAX, and HBZ may be beneficial for monitoring and predicting HTLV-1-infection outcomes, and PVL may be useful for prognosis assessment of ATLL patients. This research demonstrates the possible correlation between these virological markers and survival in ATLL patients.

Screening for Lynch Syndrome in Cases with Colorectal Carcinoma from Mashhad.

INTRODUCTION: Lynch Syndrome (LS) is a genetically inherited autosomal disorder that increases the risk of many types of cancer, especially colorectal cancer (CRC). Identifying these subjects improves morbidity and mortality. We aimed to assess the prevalence of LS with both clinical criteria and universal strategy in Mashhad, Iran. METHODS: In this retrospective study, we screened 322 patients with CRC between 2013 and 2016 in Mashhad, Iran. CRCs were screened based on Amsterdam II criteria, revised Bethesda guideline, and universal strategy. Information regarding the clinical criteria was obtained by interviewing the patients or, their families. Tumors were screened by pathologists with IHC staining of four Mismatch repair (MMR) proteins (MLH1, MSH2, MSH6, and PMS2). Tumors with absent IHC staining of MLH1 were tested for BRAF mutations to exclude sporadic CRCs. RESULTS: Of 322 CRCs, 33 cases were found to be deficient-MMR; 22 of these had concurrent loss of MLH1 and PMS2, followed by concurrent loss of MSH2 and MSH6 in 8 CRCs. Twenty-two cases with a loss of MLH1 underwent testing for the BRAF mutation, 4 of which were recognized as a positive BRAF mutation. Finally, 29 CRCs were found as being positive screen for LS. Poor sensitivity (21.74%) was found for the Amsterdam II criteria and a poor positive predictive value (15.39%) for the revised Bethesda. CONCLUSION: Application of clinical criteria may not be effective enough to identify LS and at least 2-antibody panel (PMS2, MSH6) should be conducted for newly diagnosed CRCs.

Assessment of HTLV-1 proviral load, LAT, BIM, c-FOS and RAD51 gene expression in adult T cell leukemia/lymphoma.

Adult T cell leukemia/lymphoma (ATLL) is a life-threatening malignancy of HTLV-1 infected Th lymphocytes. In the present study host-virus interactions were investigated by assessment of HTLV-1 proviral load (PVL) and host gene expression. A cross-sectional study was carried out on 18 ATLL, 10 HAM/TSP patients and 18 HTLV-1 asymptomatic carriers (ACs). DNA and mRNA of the peripheral blood mononuclear cells were extracted for PVL and LAT, BIM, c-FOS and RAD51 gene expression measurement using qRT-PCR. The mean PVL in ATLL patients was 11,430 ± 3770 copies/104 which was statistically higher than ACs, 530 ± 119 copies/104, (p < 0.001). The expression of BIM, and c-FOS in ATLL patients were higher than HTLV-1 ACs; however, there were no statistically significant differences. The expression of RAD51 as an essential player on DNA repair showed around 160 times increase in ATLL group (166 ± 95) compared to ACs (1.04 ± 0.34) which is statistically significant (p < 0.001). Interestingly, there was a positive correlation between RAD51 expression and HTLV-PVL. The expression of LAT as a central adaptor in TCR signaling interestingly was around 36 times higher in ATLL group than ACs (ATLL; 41.33 ± 19.91 vs. ACs; 1.15 ± 0.22, p < 0.001). This finding showed that TCR signaling pathway mainly provides the growth factors for transformed cells. Furthermore, the overexpression of RAD51 which has been induced in HTLV-1 infected cells as a consequence of virus replication is not able to overcome the DNA damage toward cell transformation.

Topical capsaicin therapy for uremic pruritus in patients on hemodialysis.

INTRODUCTION: Pruritus is one of the common problems in patients on hemodialysis. There are several causes for pruritus, and different treatment modalities are applied to control it. The aim of this study was to evaluate the therapeutic effect of capsaicin on pruritus, compared with placebo, in patients on hemodialysis. MATERIALS AND METHODS: This randomized double-blinded cross-over clinical trial was performed on 34 patients on hemodialysis with uremic pruritus. The patients were divided into 2 groups, one group received capsaicin 0.03% and the other, placebo, for 4 weeks. Treatment was stopped for 2 weeks as washout period and continued as a cross-over technique. Pruritus scores were analyzed and compared. RESULTS: Thirty-four patients on long-term hemodialysis, 14 men and 20 women with a mean age of 57.0 +/- 18.6 years were studied. The mean of pruritus score before capsaicin treatment was 15.9 +/- 6.3, which was reduced to 6.4 +/- 3.9, 4.7 +/- 3.1, 3.2 +/- 2.9, and 2.5 +/- 2.5 on weeks 1 to 4, respectively (P < .001). In the placebo group, pruritus score before treatment was 15.0 +/- 6.0 on average, and it was 11.7 +/- 5.8, 9.4 +/- 5.9, 7.9 +/- 5.5, and 7.2 +/- 5.5, respectively, on weeks 1 to 4 (P < .001). There was no significant difference in pruritus scores before the treatment between the two groups, but after each week, the difference was significant (P < .001). Repeated measurement test showed that decreasing in pruritus severity in the capsaicin group was more than that in the placebo group during treatment period (P < .001). CONCLUSIONS: Capsaicin is a new safe and effective topical treatment for hemodialysis-induced pruritus in patients with end-stage renal disease.