Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Concurrent Use of Crocin During Chemoradiation for Esophageal Squamous Cell Carcinoma.

Crocin is the major active carotenoid of saffron (Crocus sativus L.). Its pluripotent effects have led to a growing body of literature investigating its antitumor properties as well as its diverse potentials for mood stabilization, normal tissue protection, and inflammation reduction; However, there is a gap in clinical trials testing this substance in cancer patients. In this randomized, double-blind, placebo-controlled clinical trial, patients with newly diagnosed esophageal squamous cell carcinoma were randomly assigned to either 30 mg/day of crocin or placebo, prescribed during the neoadjuvant chemo-radiotherapy. The primary endpoints were pathological response and toxicity, and secondary endpoints were depression and anxiety levels and survival analysis.

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.

Nanocarrier System for Increasing the Therapeutic Efficacy of Oxaliplatin.

The application of Oxaliplatin (OxPt) in different malignancies is reported to be accompanied by several side effects, including neuropathy, nausea, vomiting, diarrhea, mouth sores, low blood counts, loss of appetite, etc. The passive or active targeting of different tumors can improve OxPt delivery. Considering the demand for novel systems meant to improve the OxPt efficacy and define the shortcomings, we provided an overview of different approaches regarding the delivery of OxPt. There is an extending body of data that exhibits the value of liposomes and polymer- based drug delivery systems as the most successful systems among the OxPt drug delivery procedures. Several clinical trials have been carried out to investigate the side effects and dose-limiting toxicity of liposomal oxaliplatin, such as the assessment on Safety Study of MBP-426 (Liposomal Oxaliplatin Suspension for Injection) to Treat Advanced or Metastatic Solid Tumors. In addition, several studies indicated the biocompatibility and biodegradability of this product, as well as its option for being fictionalized to derive specialized smart nanosystems for the treatment of cancer. The better delivery of OxPt with weaker side effects could be generated by the exertion of Oxaliplatin, which involves the aggregation of new particles and multifaceted nanocarriers to compose a nanocomposite with both inorganic and organic nanoparticles.

Oral silymarin formulation efficacy in management of AC-T protocol induced hepatotoxicity in breast cancer patients: A randomized, triple blind, placebo-controlled clinical trial.

BACKGROUND: Chemotherapeutic agents, with or without other drugs and radiation, may cause indirect or direct hepatotoxicity. Doxorubicin-induced hepatotoxicity (DIH) is a major health concern in cancer patients receiving this cytotoxic drug that is mostly resulted from the production of reactive oxygen species leading to transient or permanent liver damages. Silymarin, a flavonoid extracted from the Silybum marianum, exhibits antioxidant and anti-inflammatory activities. PURPOSE: This study aimed to investigate the clinical efficacy of systemic administration of silymarin in management of chemotherapy induced hepatotoxicity in patients with non-metastatic breast cancer who received doxorubicin/cyclophosphamide-paclitaxel (AC-T) regimen.Material: In this randomized, triple blind, placebo-controlled clinical trial, 30 patients who received AC-T who fulfilled the inclusion criteria were randomly allocated to silymarin (n = 15) or placebo (n = 15) groups to receive oral silymarin 140 mg three times a day or placebo tablets, respectively. Fatty liver severity was assessed by liver ultrasound imaging and FibroScan® and also measurement of liver function tests before and after the intervention. RESULTS: There was a non-significant trend toward more severe liver involvement in placebo group comparing to the silymarin group after intervention based on ultrasonography (p = 0.083). Besides, in silymarin group, hepatic involvement grade based on ultrasonography considerably reduced after intervention (p = 0.012). However, no difference was found between two groups based on FibroScan and liver function tests. CONCLUSION: Oral administration of silymarin could significantly reduce hepatotoxicity severity after 1 month of treatment in non-metastatic breast cancer patients treated with AC-T regimen.

A Systematic Review and Meta-Analysis on the Number of Adjuvant Temozolomide Cycles in Newly Diagnosed Glioblastoma.

BACKGROUND: In newly diagnosed glioblastoma, radiation with concurrent and adjuvant (six cycles) temozolomide (TMZ) is the established standard of postsurgical care. However, the benefit of extending adjuvant TMZ therapy beyond six cycles has remained unknown. METHODS: We searched PubMed, Web of Science, Scopus, and Embase up to October 1, 2021. The search keywords were "glioblastoma," "adjuvant chemotherapy," and their synonyms. The data of randomized clinical trials were extracted and included in this meta-analysis if they had reported patients' median overall survival (OS) or median progression-free survival (PFS). The standard and extended chemotherapy regimens were considered as adjuvant TMZ up to six cycles and beyond six cycles (up to a total of 12 cycles), respectively. The median OS and median PFS were pooled and compared. RESULTS: Four studies consisting of 882 patients (461 patients for the standard chemotherapy group and 421 patients for the extended chemotherapy group) were included in this meta-analysis. The extended TMZ regimen was associated with a nonsignificant improvement in PFS [12.0 months (95% CI 9.0 to 15.0) vs. 10.0 months (95% CI 7.0 to 12.0), P = 0.27] without corresponding improvement in OS [23.0 months (95% CI 19.0 to 27.0) and 24.0 months (95% CI 20.0 to 28.0), P = 0.73]. CONCLUSIONS: In newly diagnosed glioblastoma, continuing adjuvant TMZ beyond six cycles did not shown an increase neither in PFS nor OS.

Amelioration of anxiety, depression, and chemotherapy related toxicity after crocin administration during chemotherapy of breast cancer: A double blind, randomized clinical trial.

The effects of saffron (Crocus sativus L.) on mood disorders have already been established. More recently, its anti-neoplastic effects have provoked a great attention. This study aims to assess the effects of crocin administration during doxorubicin-based chemotherapy of breast cancer on anxiety, depression, and chemotherapy toxicity profile. Seventy-two patients with non-metastatic Her2/neu positive or triple negative breast cancer were enrolled and randomly assigned to receive either 30 mg/day of crocin or placebo during chemotherapy [2:2]. Beck's Depression and Anxiety Inventories were used at baseline and end of the trial. In addition, the ECOG Common Toxicity Criteria were applied to assess chemotherapy side-effects. After the intervention, the degree of anxiety and depression decreased significantly in the crocin group (p = .001 for both) and increased significantly in the placebo-group (p = .006 and p = .036, respectively). There were significantly higher grade II-IV leukopenia (47.2% vs. 19.4%, p = .012) in the crocin group, and grade II-IV hypersensitivity-reaction (30.6% vs. 5.6%, p = .006) in addition to neurological disorders (66.7% vs. 41.7%, p = .03) in the placebo-group. The results indicate that using crocin during chemotherapy in patients with breast cancer has ameliorated anxiety and depression. Moreover, leucopenia increased whereas hypersensitivity reaction and neurological disorders decreased in the crocin group. In addition, a trend toward survival improvement was observed, which is going to be investigated on longer follow up.

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.

The Potential Diagnostic and Prognostic Value of Circulating MicroRNAs in the Assessment of Patients With Prostate Cancer: Rational and Progress.

Prostate cancer (P.C.) is one of the most frequent diagnosed cancers among men and the first leading cause of death with an annual incidence of 1.4 million worldwide. Prostate-specific antigen is being used for screening/diagnosis of prostate disease, although it is associated with several limitations. Thus, identification of novel biomarkers is warranted for diagnosis of patients at earlier stages. MicroRNAs (miRNAs) are recently being emerged as potential biomarkers. It has been shown that these small molecules can be circulated in body fluids and prognosticate the risk of developing P.C. Several miRNAs, including MiR-20a, MiR-21, miR-375, miR-378, and miR-141, have been proposed to be expressed in prostate cancer. This review summarizes the current knowledge about possible molecular mechanisms and potential application of tissue specific and circulating microRNAs as diagnosis, prognosis, and therapeutic targets in prostate cancer.

Changes in Cytokeratin 18 during Neoadjuvant Chemotherapy of Breast Cancer: A Prospective Study.

BACKGROUND & OBJECTIVE: Prediction of response to neoadjuvant treatment is an important part of treatment of patients with breast cancer. This study aimed to assess changes in serum levels of Cytokeratin 18 during neoadjuvant chemotherapy in patients with locally advanced breast cancer and its association with neoadjuvant treatments. METHODS: This research was performed on newly diagnosed breast cancer patients referred to Omid Radiotherapy Center and radiotherapy and oncology departments of Emam Reza and Ghaem hospitals, in Mashhad, Iran. Serum levels of M30 and M65 fragments of Cytokeratin 18 were measured before and 24 hours after the first course of neoadjuvant chemotherapy. Changes in serum levels of Cytokeratin 18 and its fragments and their correlation with pathologic response were analyzed. RESULTS: Pre- and post-chemotherapy levels of M30 were respectively 223.9±18.94 and 250.7±23.92 U/L (P=0.24). For M65, these levels were respectively 301.5±313.9 and 330.2±352.2 U/L (P=0.1). Changes in M30 level during chemotherapy in patients with and without pathologic complete response were -20±92.69 and 43.1±106.5, respectively (P=0.1). For M65, these changes were respectively -247±55 and 76±240 (P=0.1). Baseline levels of M30 and M65 had no relation with menopausal status, tumor grade, hormone receptor status, Ki67 expression, molecular subtype, and stage. CONCLUSION: Our findings showed statistically insignificant changes in the level of Caspase-cleaved- (M30) and uncleaved- (M65) cytokeratin 18 fragments (apoptotic and necrotic indicators, respectively) during neoadjuvant chemotherapy in patients with breast cancer. There was no notable relationship between tumor-related factors and either baseline levels or serum changes of CK18 fragments. Also, there was no correlation between M30/M65 level and pathologic response to neoadjuvant chemotherapy.

Therapeutic potential of targeting the Wnt/ß-catenin pathway in the treatment of pancreatic cancer.

The Wnt/ß-catenin pathway is an important, dysregulated pathway in several tumor types, including pancreatic ductal adenocarcinoma. Although the activation of this pathway is an important component of normal development, its aberrant activation resulting from activating or inactivating mutations in the CTNNB1 gene locus, or in the negative regulators AXIN and APC involving stabilization of ß-catenin, and activation of target genes leads to a more aggressive phenotype, suggesting its potential value as a therapeutic target in the treatment of pancreatic ductal adenocarcinoma. A number of small molecule and biologic agents have now been developed for targeting this pathway. This review summarizes the current knowledge about the therapeutic potential of targeting the Wnt pathway with particular emphasis on preclinical/clinical studies in the treatment of pancreatic ductal adenocarcinoma.

A randomized clinical trial on the antitumoral effects of low molecular weight heparin in the treatment of esophageal cancer.

The current treatment approaches for esophageal cancer are associated with poor survival, and there are ongoing efforts to find new and more effective therapeutic strategies. There are several reports on the antitumoral effects of low-molecular-weight heparins (LMWHs). We have assessed the possible survival benefit of LMWHs in esophageal malignancies. This was a randomized, single-blind, multicenter, Phase II clinical trial on nonmetastatic esophageal cancer candidate for neoadjuvant chemoradiotherapy. Patients were randomly assigned to the chemoradiotherapy-only arm or chemoradiotherapy plus enoxaparin arm using 1:1 allocation. Radiotherapy was delivered in 1.8-Gy daily fractions to a dose of 50.4 Gy in both groups. Paclitaxel 50 mg/m2 and carboplatin (AUC 2) were administered weekly, concurrent with radiotherapy. In the intervention group, patients received enoxaparin (40 mg) and chemoradiation daily. 4-6 weeks after treatment, all patients underwent esophagectomy. After a median follow up of 7 months, estimated 1 year disease-free survival (DFS) in the intervention group was 78.9% and was 70% in the control groups ( p = 0.5). Toxicity from the experimental treatment was minimal, and there were no treatment-related deaths. A pathologically complete response in intervention and control group was 64.8% and 62.5%, respectively ( p = 0.9). There was a nonsignificant trend toward improved survival by the addition of enoxaparin to the concurrent chemoradiotherapy regimen. However, 1 y DFS of both groups were high as expected. A longer follow-up and a larger sample size are required.

Overexpression of cancer-testis antigen melanoma-associated antigen A1 in lung cancer: A novel biomarker for prognosis, and a possible target for immunotherapy.

AIM: We investigated melanoma-associated antigen A1 (MAGE-A1) expression in lung cancer tissues and its correlation with prognostic factors. MATERIALS AND METHODS: In this cross-sectional study, samples from 101 patients with lung cancer were obtained between 2007 and 2014 and stained for MAGE-A1 by immunohistochemistry. Correlation with prognostic factors was assessed by t test, and χ 2 , and Pearson's tests. RESULTS: Eighty non-small-cell lung cancer (NSCLC) and 21 small-cell lung cancer specimens were stained for MAGE-A1. MAGE-A1 was detected more commonly in adenocarcinomas and was expressed more frequently in male and patients >60 years. CONCLUSIONS: MAGE-A1 was found in several lung cancer patients. MAGE-A1 was expressed more commonly in NSCLC, elderly, and men. Further investigations are needed to assess MAGE-A1 as potential cancer biomarkers.

Synergistic effects of Ferula gummosa and radiotherapy on induction of cytotoxicity in HeLa cell line.

OBJECTIVE: Cervical cancer is the second most common type of cancer among women, worldwide; and for treatment of this type of cancer radiotherapy is commonly used. Ferula gummosa Boiss ("Barije" in Persian, from the family Apiaceae), (F. gummosa), is an extremely precious medicinal plant which naturally grows throughout the Mediterranean and Central Asia and is a native plant in Iran. The present study examined the cytotoxic effects of F. gummosa in terms of induction of apoptosis and radiosensitivity in HeLa cells. MATERIALS AND METHODS: In order to determine F. gummosa cytotoxicity in HeLa cells, the cells were incubated with different concentrations of the plant resin (0-1000 µg/ml) for 24, 48 and 72 hr. Cytotoxicity was determined by MTT assay. The role of apoptosis in F. gummosa cytotoxicity was investigated using flow cytometry following propidium iodide (PI) staining of DNA. For radiosensitivity assessment, F. gummosa-treated cells were exposed to 2 Gy γ-rays, and cytotoxicity was determined in irradiated and non-irradiated (control) groups by MTT and the synergism factor was calculated. RESULTS: F. gummosa decreased cell viability in HeLa cells in a concentration- and time-dependent manner. Flow cytometry analysis indicated that apoptosis is involved in F. gummosa-induced cytotoxicity. Co-administration of F. gummosa and radiotherapy, showed that this plant at non-toxic low doses, could result in almost 5-fold increment in sensitization of cells towards radiation-induced toxicity. CONCLUSION: The concurrent use of F. gummosa and radiation increases radiosensitivity and cell death. Therefore, F. gummosa can be considered as a potential radiosensitizer agent against cervical cancer.

The Esophageal Cancer and the PI3K/AKT/mTOR Signaling Regulatory microRNAs: a Novel Marker for Prognosis, and a Possible Target for Immunotherapy.

The Phosphatidylinositol 3-kinase/AKT/Mammalian Target of Rapamycin (PI3K/AKT/mTOR) pathway has a critical regulatory role in cell biology including translation, transcription, and autophagy. Dysregulation of this pathway is involved in the pathogenesis, development, and prognosis of esophageal cancer that has been assessed in the recent years and its potential as a target in therapy. This report summarizes the current knowledge about PI3K/AKT/mTOR pathway and its cross-talk with a focus on the value of targeting this pathway as a potential therapeutic target in the treatment of esophageal cancer.

Evaluation of MAGE-1 Cancer-Testis Antigen Expression in Invasive Breast Cancer and its Correlation with Prognostic Factors.

BACKGROUND: Aberrant expression of cancer-testis antigens (CTA) in breast carcinoma tissue, and its natural expression in the testis, the tissue away from the immune system, makes them good candidates for cancer immunotherapy and vaccines designing. OBJECTIVES: The aim of this study was to assess the expression of a CTA (MAGE-1) in invasive breast cancer and its correlation with prognostic factors. METHODS: Paraffin blocks of breast cancer tissues from 113 patients operated in 2011 - 2013 were stained for MAGE-1expression by immunohistochemistry (IHC). The associations of MAGE-1 expression with known prognostic factors were assessed by statistical analysis using SPSS 16. RESULTS: MAGE-1 expression was found in cancer cell cytoplasms of 30.1% of patients, with different degrees of intensity, (23.9% moderate and 6.2% strong). Nuclear staining turned positive in 31.8%, stratified from moderate in 26.5%to to strong in 5.3%. There was a significant association between the number of lymph nodes involved and both nuclear (P = 0.042) and cytoplasmic (P = 0.003) MAGE-1 expression. There was also a significant correlation between the nuclear expression of MAGE-1 and tumor size (P = 0.018). Cytoplasmic expression of MAGE-1 increased with increasing pathologic grade of tumors although the association was not statistically significant (P = 0.119). CONCLUSIONS: CTA MAGE-1 has significant association with some prognostic factors in breast cancer and may have the role of a prognostic factor.

The effect of surveillance on the outcome of breast cancer patients.

BACKGROUND: The beginning of metastasis poorly affects the prognosis of breastcancer patients. Lung is the most frequent site of visceral metastasis, and the rate of recurrence is 10-30%. We have tried to find out if the routine Chest X Ray (CXR) could play a role for early detection of lung metastasis, during the prognosis of these patients. METHODS: The files of the breast cancer patients between 1996 to 2006 (1739 patients) have reviewed. Clinical characteristics of patients with pulmonary metastasis have recorded. Patients, who lacked imaging files or lacked an appropriate follow-up, have excluded. Data have analyzed by SPSS 11.5. The survival analyses have performed by using the Kaplan-Meier method. RESULTS: Fifty-six patients, median age 46, have entered into this retrospective study. Median tumor size was 4cm; median number of Lymphadenopathy (LAP) was 4. The intermediate grade has detected in 74% of patients. All patients have received adjuvant treatment. Median time from cancer diagnosis to pulmonary metastasis was 22 months. Pulmonary metastasis has detected by control CXR in77.4% and patients' symptoms in 22.6%. Forty eight patients have received chemotherapy in metastatic phase. In 28 patients (50%), other sites of metastasis (bone, liver, and brain) have discovered.The most frequent pattern of lung recurrence was pulmonary nodule (44.6%), followed by pleural effusion (28.6%). Median survival was 27.5; median survival from pulmonary metastasis was 8 m. CONCLUSION: Early detection of pulmonary metastasis by CXR did not affect patients' endpoints. None of the probable prognostic factors have shown a significant effect on patients' outcome. Despite systemic treatment, survival after metastasis is low.