FAPI Uptake in Gallbladder Is It Normal Biodistribution?

ABSTRACT: Radiolabeled fibroblast activation protein inhibitors (FAPIs) have been extensively used in different types of cancers, although not yet FDA approved. Normal patterns of FAPI biodistribution have been investigated, and it is known that FAPI is expressed in nonmalignant pathophysiological lesions, characterized by tissue remodeling such as atherosclerosis, arthritis, and scar/fibrotic tissues. In this interesting image, we are presenting the accumulation of 68 Ga-FAPI in the gallbladder. This finding could be related to a normal distribution of the radiotracer as a physiologic finding. This is a potentially important finding as FAPI may be used as theragnostic agent in the future.

Alvopem® (pemetrexed) safety assessment in patients with non-small cell lung cancer or malignant pleural mesothelioma: a post-marketing surveillance.

BACKGROUND: Lung cancer is the leading cause of cancer deaths worldwide in both men and women, and non-small cell lung cancer (NSCLC) accounts for the majority (~ 85%) of lung cancers. This post-marketing surveillance (PMS) study aimed to evaluate the safety of Pemetrexed (Alvopem®, NanoAlvand, Iran) in Iranian patients with lung cancer or mesothelioma. METHODS: The present study is an observational, single-center, open-label, and post-authorization study. All eligible non-squamous NSCLC and malignant pleural mesothelioma (MPM) patients who received pemetrexed based on the physicians' decision, were enrolled. RESULTS: A total of 199 patients with non-squamous NSCLC [186 patients (93.47%) or MPM (12 patients (6.03%)] were enrolled from March 2016 to February 2020. The most common reported adverse event (AE) was anemia (89.39%), followed by neutropenia (28.79%) and leukopenia (24.75%). The most important grade 3 AEs were anemia and neutropenia, with the incidence rate of 3.54% and 7.58%, respectively. No grade 4 AEs were reported. Moreover, the results of our study showed negative statistically significant correlations between patients' age and mean neutrophil count (r = - 0.17; P = 0.0156) and hemoglobin (r = - 0.16; P = 0.0201) in all six visits. CONCLUSIONS: The results of this open-label, observational PMS showed that Pemetrexed (Alvopem®) is safe in patients with non-squamous NSCLC patients receiving pemetrexed-containing regimens. TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov (NCT04843007) in April 13th, 2021.

The miR-196a SNP Rs11614913 but not the miR-499 rs37464444 SNP is a Risk Factor for Non-small Cell Lung Cancer in an Iranian Population.

Background: Globally, lung cancer represents a major cause of cancer-related deaths. The regulation of gene expression is modulated by small noncoding RNAs called miRNAs that can act as both tumor suppressors and oncogenes. The maturation, expression and binding to target mRNAs is affected by single nucleotide polymorphisms (SNPs) in miRNA genomic regions thereby contributing to cancer susceptibility. SNPs Rs11614913 in miR196a and Rs3746444 in miR-499 are implicated in the development of cancers such as non-small cell lung cancer (NSCLC) in non-Arabic subjects. Materials and Methods: A small cohort of 204 participants including 104 lung cancer patients and 100 non-cancer controls subjects were enrolled into the study. The allele frequencies were determined by Polymerase Chain Reaction- Restriction Fragment Length Polymorphism (PCR-RFLP) and their correlation with lung cancer risk was determined. Results: The miR-196a rs11614913 polymorphism increased the risk of NSCLC (CC vs. TT+TC: OR= 2.26, 95%CI= 1.28 - 3.98, P= 0.0046) in a dominant genetic model. No statistically significant association was found between the miR-499 rs37464444 polymorphism and NSCLC. Conclusion: The rs11614913 polymorphism in miR-196a, but not the miR-499 rs37464444 polymorphism, increased the risk of NSCLC. Further studies with larger sample sizes in correlation with functional outcomes at the cellular level should be undertaken.

Evaluating the safety and effectiveness of PegaGen® (pegfilgrastim) for the prevention of chemotherapy-induced febrile neutropenia: a post-marketing surveillance study.

PURPOSE: Phase IV clinical trials are required to evaluate the real-world safety and effectiveness of drugs. This study aimed to evaluate the safety and effectiveness of once-per-cycle administration of PegaGen® (pegfilgrastim, CinnaGen, Iran) in cancer patients. METHODS: In this open-label, multicenter, prospective, real-world, post-marketing surveillance study, patients with any type of cancer receiving chemotherapy regimens with a high risk of febrile neutropenia (FN) were included if they were prescribed pegfilgrastim for FN prophylaxis. The primary objective of this study was to assess the safety and the secondary objective was to assess the effectiveness of pegfilgrastim in the prevention of FN in cancer patients. RESULTS: A total of 654 patients (51.73 ± 15.12 years of age) were enrolled and 3615 cycles of pegfilgrastim injections were recorded. The most common malignancies among the study patients were breast cancer (n = 192, 29.36%), lymphoma (n = 131, 20.03%), and gastric cancer (n = 65, 9.94%). The median (Q1, Q3) number of pegfilgrastim cycles per patient was 6 (4, 7). A single 6 mg dose was injected in 99.17% of the cycles. A total number of 816 adverse events (AEs) were reported in 246 patients (37.62%). Bone pain was recorded in 141 patients (21.56%) and in 440 cycles (12.17%). Among all patients, 45 patients (6.88%) experienced FN 51 times, and FN frequency was 1.4% among cycles. Moreover, 14 (2.14%) patients were hospitalized following FN. Antibiotics were administered to 24 patients (3.67%) for FN treatment. CONCLUSION: The results from this post-marketing surveillance study support the safety and effectiveness of PegaGen® used for the prevention of chemotherapy-induced FN in patients with various types of cancer and treatment regimens. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04460079.

The Frequency of Epidermal Growth Factor Receptor (EGFR) Mutation in Patients with Lung Adenocarcinoma Referred to a Lung Diseases Hospital; A Cross-Sectional Study from Iran.

Background & Objective: Various studies showed the use of epidermal growth factor receptors (EGFRs) gene mutations in the therapeutic plan of patients with advanced lung cancer. This study aimed to investigate the frequency and types of EGFR gene mutations among Iranian patients with lung adenocarcinoma referred to a specialized lung diseases hospital from 2014 to 2019. Methods: The data of all patients with lung adenocarcinoma referred to the Molecular Department of Masih Daneshvari Hospital Laboratory (National Research Institute of Tuberculosis and Lung Diseases) from 2014 to 2019 for EGFR mutation tests were collected. Patients' characteristics data and information on the frequency and types of EGFR gene mutations were obtained from the hospital information system (HIS). The collected data were analyzed using SPSS 25. Results: A total of 570 individuals (Mean age of 58.74, 51.6% Male) were included in the study; 113 out of 570 patients (19.8%) were diagnosed with gene mutation. In terms of the type of mutation, 65 participants (57%) showed deletion, 48 patients (42.1%) were diagnosed with replacement, and one (0.9%) case demonstrated both. Notably, the mutation rate detected among the female patients was significantly higher than the male ones (P=0.001); in particular, deletion type of mutation was found more among women, although both genders were the same in terms of the replacement frequency. However, the age had no effect on the mutation in this study (P=0.05). Conclusion: Among Iranian patients with lung adenocarcinoma, 19.8% harbored EGFR gene mutation. This mutation was found in association with lung cancer and could affect the patient's therapeutic plan.

Clinical Effectiveness of Erlova in EGFR-Mutated Non-Small Cell Lung Cancer: An Affordable Price with Clinical Benefit.

BACKGROUND: Thyrosin kinase inhibitors (TKIs) is approved for the first line treatment of non-small cell lung cancer (NSCLC) patients with  epidermal growth factor receptor (EGFR) mutation. This study performed to assess clinical effectiveness and safety of Erlova (generic form of Erlotinib). METHODS: Somatic mutations of EGFR gene were studied in tumor tissue by polymerase chain reaction (PCR) and bi-directional sequencing in 513 chemonaive and histologically verified lung adenocarcinoma Iranian patients. Patients  with EGFR mutation received Erlova at 150 mg/day  as first line treatment. Primary endpoint was progression free survival (PFS). RESULTS: About 21% (n=109) cases had EGFR mutation. Most EGFR mutations were  occurred at exon 19. Among them, sixty nine patients treated with Erlova. Median PFS was 11.4 months and objective response rate (ORR) was about  88%. Most frequent treatment related adverse events was  skin rash. CONCLUSION: Our findings showed Erlova had remarkable effectiveness. In  mutation-positive patients with EGFR, Erlova can be used  safely instead of  other tyrosine-kinase inhibitors.

Inflammatory Potential of Diet and Odds of Lung Cancer: A Case-Control Study.

Lung cancer is one of the common types of malignant disorders and the most prevalent cause of cancer mortality worldwide. Few studies have examined the association of dietary inflammatory index (DII) with lung cancer and findings from these studies are conflicting. Moreover, no study has examined this association in the Middle East. Therefore, the current case-control study was conducted to examine the association between DII and lung cancer among Iranian adults. We recruited 140 pathologically confirmed cases of lung cancer and 140 healthy controls who were matched with cases in terms of age. Dietary intakes were assessed using a 142-item Willett-format dish-based semi-quantitative food frequency questionnaire. DII scores were calculated using the method developed by Shivappa et al. Overall, we found a significant positive association between DII and lung cancer so that after controlling for potential confounders, individuals in the highest tertile of DII scores had 2.03 times more odds of lung cancer compared to those in the lowest tertile (OR: 2.01; 95% CI: 1.02-4.01). This significant positive association was also seen in men, but not in women. In conclusion, adherence to a pro-inflammatory diet was associated with increased odds of lung cancer in adults, particularly in male adults.

Evaluation Expression of miR-146a and miR-155 in Non-Small-Cell Lung Cancer Patients.

BACKGROUND: Non-small-cell lung cancer (NSCLC) is the major type of lung cancer. MicroRNAs (miRNAs) are novel markers and targets in cancer therapy and can act as both tumor suppressors and oncogenes and affect immune function. The aim of this study was to investigate the expression of miR146a and miR155 in linked to blood immune cell phenotypes and serum cytokines in NSCLC patients. METHODS: Thirty-three NSCLC patients and 30 healthy subjects were enrolled in this study. The allele frequencies of potential DNA polymorphisms were studied using polymerase chain reaction (PCR)-restriction fragment length polymorphism (PCR-RFLP) analysis in peripheral blood samples. Quantitative reverse transcription PCR (qRT-PCR) was used to measure the expression of miR-146a and miR-155 in peripheral blood mononuclear cells (PBMCs). Serum cytokine (IL-1ß, IL-6, TNF-α, TGF-ß, IL-4, IFN-γ) levels were determined by ELISA. The frequency of circulating CD3+CTLA-4+ and CD4+CD25+FOXP3+ (T regulatory cells/Treg) expression was measured by flow cytometry. RESULTS: miR-146a was significantly downregulated in PBMC of NSCLC patients (P ≤ 0.001). Moreover, IL-6 and TGF-ß levels were elevated in NSCLC patients (P ≤ 0.001, P ≤ 0.018, respectively). CD3+ CTLA-4+ and Treg cells frequencies were higher in patients than in control subjects (P ≤ 0.0001, P ≤ 0.0001, respectively). There was a positive correlation between miR-155 and IL-1ß levels (r=0.567, p ≤ 0.001) and a negative correlation between miR-146a and TGF-ß levels (r=-0.376, P ≤ 0.031) in NSCLC patients. No significant differences were found in the relative expression of miR-146a and miR-155, cytokine levels or immune cell numbers according to miR-146a and miR-155 (GG/GC/CC, TT/AT/AA) genotypes. However, there was a positive correlation between miR-146a and IL-1ß levels (r=0.74, P ≤ 0.009) in GG subjects and a positive correlation between miR-146a expression and CD3+CTLA4+ cell frequency (r=0.79, P ≤ 0.01) in CC genotyped subjects. Conversely, a negative correlation between miR-146a expression and Treg cell frequency (r=-0.87, P ≤ 0.05) was observed with the GG genotype. A positive correlation between miR-155 and IL-1ß expression (r=0.58, p ≤ 0.009) in the TT genotype and between miR-155 expression and CD3+CTLA-4 cell frequency (r=0.75, P ≤ 0.01) was observed in the AT genotype. CONCLUSIONS: The current data suggest that the miR-146a expression in PBMC and serum TGF-ß and IL-1ß levels may act as blood markers in NSCLC patients. Further study is needed to elucidate the link between immune cells and serum miR146 at early disease stages.

Circulating Levels of Monocytic Myeloid-Derived Suppressor Cells (M-MDSC) and CXCL-8 in Non-Small Cell Lung Cancer (NSCLC).

BACKGROUND: Myeloid-derived suppressor cells (MDSC) are categorized as granulocytic (G-MDSCs) and monocytic (M-MDSCs) and their expansion play a role in cancer progression. Recruitment to the cancer site depends upon the presence of a chemoattractant. We aimed to investigate the presence of MDSC subtypes and of interleukin-8 (CXCL-8) in the peripheral blood in lung cancer subtypes including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) patients. MATERIALS AND METHODS: Peripheral blood samples of 26 NSCLC patients, 18 SCLC patients, and 8 healthy control donors (HDs) were harvested and the surface expression of CD14, CD15, CD11b, and HLA-DR on MDSCs was measured using flow cytometry. The level of serum CXCL8 was measured by the ELISA method. RESULTS: The frequency of circulating M-MDSCs was significantly higher in patients with NSCLC than in SCLC and HDs. In contrast, there was no statistical difference concerning the frequency of circulating G-MDSCs between the three groups. The concentration of CXCL-8 was significantly higher in the NSCLC and SCLC patients than in HD control with no significant difference between NSCLC and SCLC groups. There was no correlation between serum CXCL8 and G-MDSC levels. CONCLUSION: Our data confirm a higher frequency of circulating M-MDSCs, but not G-MDSCs, in the blood of those suffering from NSCLC but not for SCLC cases. Measuring MDSC subtypes and serum chemotactic factors may have implications for the differential diagnosis of NSCLC.

The miR-146a SNP Rs2910164 and miR-155 SNP rs767649 Are Risk Factors for Non-Small Cell Lung Cancer in the Iranian Population.

Background: Lung cancer is one of the leading causes of death worldwide. MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression and may act as both tumor suppressors and as oncogenes. The presence of single nucleotide polymorphisms (SNPs) inside the miRNA genomic region could affect target miRNA maturation, expression, and binding to its target mRNA and contribute to cancer development. Previous studies on the SNPs Rs2910164 in miR-146a and Rs767649 in miR-155 showed association with non-small cell lung cancer (NSCLC) development. Thus, the aim of this study was to detect any correlation between those SNPs in Iranian NSCLC patients. Methods: In a small cohort study, 165 NSCLC patients and 147 noncancer controls were enrolled between Apr 2015 and Sep 2019 at the Masih Daneshvari Hospital, Tehran, Iran. Allele frequencies from the genomic DNA of blood cells were studied using PCR-RFLP and their association with the risk of lung cancer was evaluated. Results: The rs2910164C allele (OR = 1.56, 95% CI = 1.10-2.21, p = 0.012) and CC genotype (OR = 2.93, 95% CI = 1.07-7.9, p = 0.034, respectively) were associated with a significantly increased risk for lung cancer compared to that for the GG genotype. When patients were stratified according to smoking exposure, no association with rs2910164 variants was found. The AT genotype (OR = 0.57, 95% CI = 0.33-0.99, p = 0.048) and the A allele frequency (OR = 0.58, 95% CI = 0.35-0.98, p = 0.043) in rs767649 were lower in NSCLC patients in comparison with the control group. In addition, the rs767649 AT genotype frequency in smoking controls was higher than in smoking NSCLC patients (OR = 0.44, 95% CI = 0.21-0.90, p = 0.024). No association was found between rs2910164 and rs767649 variants and stage or type of NSCLC. Conclusion: Our finding suggests that miR-146a rs2910164 and miR-155 rs767649 polymorphisms may be considered as genetic risk factors for the susceptibility to NSCLC in the Iranian population. However, a larger multicenter study across Iran is needed to confirm these findings.

Circulating free DNA concentration as a marker of disease recurrence and metastatic potential in lung cancer.

BACKGROUND: Plasma circulating cell-free (cf) DNA is regarded as a source of tumor DNA. Based on availability of blood tissue for the purposes of early detection of cancer and patients' follow-up, several studies have evaluated concentration of cf DNA in cancer patients in association with tumor features. In the present study, we assessed concentration of cf DNA in lung cancer patients with two commercial kits (MN and QIAGEN) to find whether it can be used as a prognostic biomarker. RESULTS: Primary cf DNA concentrations as measured by QIAGEN kit was significantly higher in patients who died in the follow-up period compared with alive patients (P = 0.007). Moreover, the concentrations as measured by both methods were higher in patients who experienced recurrence in the follow-up period compared with patients without recurrence (P = 0.008 and 0.007 for MN and QIAGEN kits respectively). Significant associations were also found between cf DNA concentrations and tumor stage (P = 0.005 and 0.02 for MN and QIAGEN kits respectively). Notably, cf DNA concentration was higher in metastatic tumors compared with non-metastatic tumors in association with number of involved organs. Based on the AUC values, both kits could differentiate metastatic cancers from non-metastatic ones with accuracy of 98%. CONCLUSIONS: The current study highlights the accuracy of cf DNA concentrations for prediction of disease course in lung cancer patients.

Thymoma Recurrence and its Predisposing Factors in Iranian Population: a Single Center Study.

BACKGROUND: Thymoma is relatively rare tumor. Prognosis and patients' outcome vary across different studies. We aimed to study the predisposing factors causing tumor recurrence in thymoma patients. MATERIALS AND METHODS: A total of 43 thymoma or thymic carcinoma patients treated at the National Institute of Tuberculosis and Lung Disease (NRITLD), Masih Daneshvari Hospital from September 2005 to January 2017 were evaluated. The primary endpoint was the progression free survival (PFS). The relation of predisposing factors to PFS was studied. RESULTS: Median age was 55 years old. The mean of follow-up duration was 22.9 months. The most prevalent pathology was thymoma unspecified. Pure red cell aplasia (n=3, 6.9%) was the most prevalent Para neoplastic syndrome. Most of the patients (n=23, 54%) were in stage III and IV Masaoka-Koga staging system. Disease progression was observed in 17 patients (39. 5%). Most recurrences occurred locally. None of demographic characteristics differed between patients who experienced disease recurrence and those who did not. After univariate and multivariate analysis, predisposing factor for disease progression was only Masaoka-Koga stage (P-value=0.015 and 0.031 respectively). CONCLUSION: In this study, among different probable predisposing factors, only Masaoka-Koga stage had significant effect on disease recurrence. Large case-control studies may be required for better evaluation of risk factors.

A Phase IV Efficacy Study of Formeta Plus Carboplatin as First-Line Treatment of Advanced Non-Squamous, Non-Small Cell Lung Cancer in Iran: An Affordable Price with Clinical Benefit

Background: This study performed to assess the efficacy and safety of Formeta (generic form of Pemetrexed) plus Carboplatin as first-line chemotherapy in advanced stage, non- squamous, non small cell lung cancer ( NSCLC) in Iran. Methods: This was a post marketing single-arm phase IV efficacy study of Formeta (manufactured by Oncomed.,Czech Republic ) and Carboplatin in chemo-naive advanced non-squamous NSCLC Iranian patients. Patients received up to six cycles of Formeta (500 mg/m2) combined with Carboplatin (area under the curve: AUC 5) every 3 weeks. The primary endpoint was the progression free survival (PFS) and secondary endpoints were safety and overall survival (OS). Results: Fifty-two patients were enrolled between June 2014 to January 2016, and 44 patients were evaluable for both safety and efficacy. Partial and complete responses were achieved in 19 (36.5 %) and 2 (3.8%) patients, respectively as well as stable disease in 8 patients (15.3 %). Median of PFS and OS were 7.9 ± 1.1 months and 12.43±0.6 months, respectively. Anemia was the most prevalent adverse events of this regimen. Grades 3 or 4 of adverse events were not observed in any patients. Non-hematologic and other grades of hematologic toxicities were generally mild, and there were no treatment-related deaths. Conclusion: The combination of Formeta and Carboplatin was effective in advanced non-squamous NSCLC and can be a suitable candidate as first-line treatment in these patient's population.

Comparison of immortalization assay and polymerase chain reaction detection of Epstein-Barr virus in pediatric transplant recipients and control samples.

The polymerase chain reaction technique (PCR) has become a standard for the detection of Epstein-Barr virus ( EBV). Several studies have shown that solid organ transplant recipients fated to develop post-transplant lymphoproliferative disease (PTLD) have higher mean levels of EB viremia as measured by PCR. We directly compared PCR and immortalization assay (IA) for EBV detection from control cell lines as well as from peripheral blood monouclear cells (PBMC) and saliva samples from 9 pediatric solid organ transplant recipients. Results were expressed as the lowest amount of DNA and/or number of cells detected. All samples negative for EBV by PCR had amplifiable DNA detected using beta-actin primers. When control cell lines were assayed and positive in both assays, PCR was at least 200 times more sensitive than IA, as expected. When PBMC and saliva were compared, 1 patient, with a mononucleosis-like syndrome, was positive for EBV by IA only. When both IA and PCR were positive however, PCR was able to detect 5-500 times less EBV than IA, as expected. The associations of positive test with each assay and the diagnosis of PTLD were similar.