Optimization of Radium-223 Treatment of Castration-resistant Prostate Cancer Based on the Burden of Skeletal Metastasis and Clinical Parameters.

BACKGROUND: Radium-223 dichloride (Ra-223) is now frequently used to treat prostate cancer that has metastasized to bone, although patient selection continues to be suboptimal for determining who will benefit most from this novel treatment modality. MATERIALS AND METHODS: Seventy-nine patients with metastatic castration-resistant prostate cancer (mCRPC) were treated with Ra-223 from 2012 to 2016. The burden of skeletal metastasis was determined for each using the Bone Scan Index (BSI) as a ratio of diseased to normal bone. Clinical, laboratory, and survival data were collected and examined for associations with BSI, and treatment tolerability was assessed. RESULTS: Chemotherapy-naïve patients were significantly more likely to complete the full course of treatment. Median follow-up was 31 months (range 0.7-38.8 months) and median overall survival was 15.4 months (range 9.5-20.6 months). Overall survival was significantly associated with findings on bone scans (P < .05). Patients with higher BSI tended toward poorer outcomes. Nearly half the patients with low baseline BSI survived 3 years or more following Ra-223 treatment. By contrast, only 20% of the patients with high baseline BSI lived for 1 year, and none lived for an additional 3. Baseline BSI was significantly associated with decreased hemoglobin, higher serum PSA and alkaline phosphatase levels, and treatment-associated reductions in platelet and absolute neutrophil counts. CONCLUSION: Our results suggest better outcomes to Ra-223 therapy for patients who are chemotherapy-naïve and who undergo treatment earlier in the course of their disease as reflected by low BSI and concordant laboratory parameters.

Tumor matrix stiffness provides fertile soil for cancer stem cells.

Matrix stiffness is a mechanical characteristic of the extracellular matrix (ECM) that increases from the tumor core to the tumor periphery in a gradient pattern in a variety of solid tumors and can promote proliferation, invasion, metastasis, drug resistance, and recurrence. Cancer stem cells (CSCs) are a rare subpopulation of tumor cells with self-renewal, asymmetric cell division, and differentiation capabilities. CSCs are thought to be responsible for metastasis, tumor recurrence, chemotherapy resistance, and consequently poor clinical outcomes. Evidence suggests that matrix stiffness can activate receptors and mechanosensor/mechanoregulator proteins such as integrin, FAK, and YAP, modulating the characteristics of tumor cells as well as CSCs through different molecular signaling pathways. A deeper understanding of the effect of matrix stiffness on CSCs characteristics could lead to development of innovative cancer therapies. In this review, we discuss how the stiffness of the ECM is sensed by the cells and how the cells respond to this environmental change as well as the effect of matrix stiffness on CSCs characteristics and also the key malignant processes such as proliferation and EMT. Then, we specifically focus on how increased matrix stiffness affects CSCs in breast, lung, liver, pancreatic, and colorectal cancers. We also discuss how the molecules responsible for increased matrix stiffness and the signaling pathways activated by the enhanced stiffness can be manipulated as a therapeutic strategy for cancer.

Cytoplasmic expression of CD133 stemness marker is associated with tumor aggressiveness in clear cell renal cell carcinoma.

Prominin-1 (CD133) is one of the most commonly used markers for cancer stem cells (CSCs), which are characterized by their ability for self-renewal and tumorigenicity. However, the clinical and prognostic significance of CSCs in renal cell carcinoma (RCC) remains unclear. The aim of this study was to investigate the expression patterns and prognostic significance of the cancer stem cell marker CD133 in different histological subtypes of RCC. CD133 expression was evaluated using immunohistochemistry in 193 well-defined renal tumor samples on tissue microarrays, including 136 (70.5%) clear cell renal cell carcinomas (CCRCCs), 26 (13.5%) papillary RCCs, and 31 (16.1%) chromophobe RCCs. The association between CD133 expression and clinicopathological features as well as the survival outcomes was determined. There was a statistically significant difference between CD133 expression among the different RCC subtypes. In CCRCC, higher cytoplasmic expression of CD133 was significantly associated with increase in grade, stage, microvascular invasion (MVI) and lymph node invasion (LNI), while no association was found with the membranous expression. Moreover, on multivariate analysis, TNM stage and nuclear grade were independent prognostic factors for overall survival (OS) in cytoplasmic expression. We showed that higher cytoplasmic CD133 expression was associated with more aggressive tumor behavior and more advanced disease in CCRCC but not in the other examined subtypes. Our results demonstrated that higher cytoplasmic CD133 expression is clinically significant in CCRCC and is associated with increased tumor aggressiveness and is useful for predicting cancer progression.

Cancer stem cell research in Iran: potentials and challenges.

Treatment modalities can reduce cancer-related mortality; however, a majority of patients develop drug resistance, metastasis and relapse. It has been proposed that tumorigenic characteristics of tumors are related to a proportion of cancer cells, termed cancer stem cells (CSCs). Following the first evidence regarding the existence of CSC population in acute myeloid leukemia in 1997, publications in CSCs field showed an explosive trend in all cancer types around the world. First research paper in the field of CSCs in Iran was published in 2004 on prostate cancer. Subsequently, an annual number of publications in the field of CSCs displayed a rapidly growing trend. Therefore, in the current review, we have presented a comprehensive evaluation of the CSCs research in Iran.

Evidence for embryonic stem-like signature and epithelial-mesenchymal transition features in the spheroid cells derived from lung adenocarcinoma.

Identification of the cellular and molecular aspects of lung cancer stem cells (LCSCs) that are suggested to be the main culprit of tumor initiation, maintenance, drug resistance, and relapse is a prerequisite for targeted therapy of lung cancer. In the current study, LCSCs subpopulation of A549 cells was enriched, and after characterization of the spheroid cells, complementary DNA (cDNA) microarray analysis was applied to identify differentially expressed genes (DEGs) between the spheroid and parental cells. Microarray results were validated using quantitative real-time reverse transcription-PCR (qRT-PCR), flow cytometry, and western blotting. Our results showed that spheroid cells had higher clonogenic potential, up-regulation of stemness gene Sox2, loss of CD44 expression, and gain of CD24 expression compared to parental cells. Among a total of 160 genes that were differentially expressed between the spheroid cells and the parental cells, 104 genes were up-regulated and 56 genes were down-regulated. Analysis of cDNA microarray revealed an embryonic stem cell-like signature and over-expression of epithelial-mesenchymal transition (EMT)-associated genes in the spheroid cells. cDNA microarray results were validated at the gene expression level using qRT-PCR, and further validation was performed at the protein level by flow cytometry and western blotting. The embryonic stem cell-like signature in the spheroid cells supports two important notions: maintenance of CSCs phenotype by dedifferentiating mechanisms activated through oncogenic pathways and the origination of CSCs from embryonic stem cells (ESCs). PI3/AKT3, as the most common up-regulated pathway, and other pathways related to aggressive tumor behavior and EMT process can confer to the spheroid cells' high potential for metastasis and distant seeding.

Differential Expression of Cancer Stem Cell Markers ALDH1 and CD133 in Various Lung Cancer Subtypes.

Cancer stem cells (CSCs) are hypothesized to be the main culprit of lung cancer progression. Clinicopathological significance of stem cell markers CD133 and ALDH1 in a large group of lung cancer patients was evaluated. ALDH1 and CD133 had higher expression levels in the NSCLC compared to the SCLC. Over-expression of both ALDH1 and CD133 markers was exclusively found in SCC and ADC. Low level of ALDH1 expression was strongly correlated with poor differentiation in ADC cases. Thus, ALDH1(high)/CD133(high) phenotype can be considered as a CSC marker in some lung cancer subtypes.

Comparative gene-expression profiling of CD133(+) and CD133(-) D10 melanoma cells.

AIMS: The present study aimed to compare the gene-expression profiling of CD133(+) and CD133(-) D10 cells. MATERIALS & METHODS: Cancer stem cell-like properties and gene-expression profiling of CD133(+) D10 cells versus CD133(-) cells were evaluated. RESULTS: The CD133(+) D10 cells showed significantly higher clonogenic and spheroid forming potential, also higher expression of stemness genes NANOG and OCT4A compared with the CD133(-) cells. Gene-expression profiling of CD133(+) versus CD133(-) D10 cells revealed that 130 genes including ABC transporter superfamily (ABCC1, ABCG2 and ABCC6) were upregulated, while 61 genes including apoptosis modifying genes (CASP8 and TNFRSF4) were downregulated. CONCLUSION: We conclude that many genes involved in drug resistance and tumor aggressiveness are upregulated in CD133(+) D10 cells and targeting them might be an efficient strategy for treatment of melanoma.

Incidental Finding of Synchronous, Benign, Metastasizing Leiomyoma with Distinct Cytogenetics in the Lung and Uterus.

This paper will present a case of benign metastasizing leiomyoma, incidentally found during the preoperative evaluation for acute cholecystitis. The preoperative chest X-ray revealed diffuse bilateral lung nodules suspicious for hematogenous metastasis and the densities measured 1-1.5 cm. A pelvis computed tomography (CT) scan showed in-homogeneous uterine mass with unusual vascular supply raising concern for leiomyosarcoma. Open lung biopsy revealed benign-appearing smooth-muscle neoplasm suggestive of metastatic leiomyoma. The patient was then treated with total abdominal hysterectomy with bilateral salpingo-oopherectomy which had identical pathology to the lung. As there were innumerable pulmonary metastases where complete resection was impossible, surgical castration appeared to be effective in reducing tumor size. The patient was also started on an aromatase inhibitor that subsequently improved her clinical outcome. Management strategies, cytogenetics, and histological diagnosis are discussed.

Human C1 inhibitor attenuates liver ischemia-reperfusion injury and promotes liver regeneration.

Liver ischemia-reperfusion injury (IRI) is a well-known cause of morbidity and mortality after liver transplantation (LT). Activation of the complement system contributes to the pathogenesis of IRI. Effective treatment strategies aimed at reducing hepatic IRI and accelerating liver regeneration could offer major benefits in LT. Herein, we investigated the effect of C1-esterase inhibitor (human) [C1-INH] on IRI and liver regeneration. Mice were subjected to 60-min partial IRI, with or without 70% partial hepatectomy, or CCl4-induced acute liver failure. Before liver injury, the animals were pretreated with intravenous C1-INH or normal saline. Liver IRI was evaluated using serum levels of alanine aminotransferase, serum interleukin-6, and histopathology. Liver samples were stained for specific markers of regeneration (5-bromo-2'-deoxyuridine [BrdU] staining and proliferating cell nuclear antigen [PCNA]). Histology, serum interleukin-6, and alanine aminotransferase release revealed that C1-INH treatment attenuated liver injury compared with controls. Improved animal survival and increased number of BrdU- and PCNA-positive cells were observed in C1-INH-treated animals which underwent IRI + partial hepatectomy or CCl4 injection compared with control group. These data indicate that complement plays a key role in IRI and liver regeneration. C1-INH represents a potential therapeutic strategy to reduce IRI and promote regeneration in LT.

Dural involvement in central nervous system langerhans cells histiocytosis (LCH) on FDG PET/CT: Case report and review of CNS manifestations of LCH on PET/CT.

We report a case of multisystem Langerhans cell histiocytosis in a pediatric patient with central nervous system involvement, highlighting F-18(FDG) uptake characteristics of dural sites of disease. We also highlight the advantages of functional data offered by FDG-PET as a useful follow-up tool to assess viability and, therefore, treatment response of previously known central nervous system lesions. The utility of recognizing characteristic patterns of FDG uptake in dural disease is also applicable in cases of diagnostic uncertainty, such as when evaluating isolated dural lesions or when distinguishing between Langerhans cell histiocytosis and similar appearing lesions such as meningiomas.

Reduced expression of NGEP is associated with high-grade prostate cancers: a tissue microarray analysis.

New gene expressed in prostate (NGEP) is a newly diagnosed prostate-specific gene that is expressed only in normal prostate and prostate cancer cells. Discovery of tissue-specific markers may promote the development of novel targets for immunotherapy of prostate cancer. In the present study, the staining pattern and clinical significance of NGEP were evaluated in a series of prostate tissues composed of 123 prostate cancer, 19 high-grade prostatic intraepithelial neoplasia and 44 samples of benign prostate tissue included in tissue microarrays using immunohistochemistry. Our study demonstrated that NGEP localized mainly in the apical and lateral membranes and was also partially distributed in the cytoplasm of epithelial cells of normal prostate tissue. All of the examined prostate tissues expressed NGEP with a variety of intensities; the level of expression was significantly more in the benign prostate tissues compared to malignant prostate samples (P value <0.001). Among prostate adenocarcinoma samples, a significant and inverse correlation was observed between the intensity of NGEP expression and increased Gleason score (P = 0.007). Taken together, we found that NGEP protein is widely expressed in low-grade to high-grade prostate adenocarcinomas as well as benign prostate tissues, and the intensity of expression is inversely proportional to the level of malignancy. NGEP could be an attractive target for immune-based therapy of prostate cancer patients as an alternative to the conventional therapies particularly in indolent patients.

Expression of stem cell markers, CD133 and CD44, in pediatric solid tumors: a study using tissue microarray.

Based on the cancer stem cell (CSC) concept model, a small population of cells with unique self-renewal properties and malignant potential exists in tumors. Immunohistochemistry was performed to detect the expression of CSC markers, CD133 and CD44, in a series of pediatric tumors. The association between expression of these markers and tumor characteristics was then analyzed. In Wilms tumors (WT), a significant positive correlation was found between expression of CD133 and the National Wilms Tumor Stage (NWTS) (p = 0.047). In neuroblastomas (NB), expression of CD133 was positively correlated with the International Neuroblastoma Staging System (INSS) (p-value = 0.012), indicating that the rate of CD133 positivity increased with the stage of these tumors. CD133, as a putative stem cell marker, is associated with more advanced stages of Wilms and NB tumors; therefore, this molecule can be a potential clinical prognostic marker in children suffering from NB or Wilms tumor.

PET/CT Imaging in Treatment Planning and Surveillance of Sinonasal Neoplasms.

Sinonasal cancers are uncommon malignancies with a generally unfavorable prognosis, often presenting at an advanced stage. Their high rate of recurrence supports close imaging surveillance and the utilization of functional imaging techniques. Whole-body 18F-FDG PET/CT has very high sensitivity for the diagnosis of sinonasal malignancies and can also be used as a "metabolic biopsy" in the characterization of some of the more common subgroups of these tumors, though due to overlap in uptake, histological confirmation is still needed. For certain tumor types, radiotracers, such as 11C-choline, and radiolabeled somatostatin analogs, including 68Ga-DOTATATE/DOTATOC, have proven useful in treatment planning and surveillance. Although serial scans for posttreatment surveillance allow the detection of subclinical lesions, the optimal schedule and efficacy in terms of survival are yet to be determined. Pitfalls of 18F-FDG, such as post-surgical and post-radiotherapy crusting and inflammation, may cause false-positive hypermetabolism in the absence of relapse.

Matrix metalloproteinase-9 functional promoter polymorphism 1562C>T increased risk of early-onset coronary artery disease.

The Matrix metalloproteinase-9 functional promoter polymorphism 1562C>T may be considered an important genetic determinant of early-onset coronary artery disease (ECAD). In this study, association between MMP-9 1562C>T allele with plasma MMP-9 activity, homocysteine and lipid-lipoproteins level and ECAD in Iranian subjects was investigated. This case-control study consisted of 53 ECAD patients (age < 55 years) and unrelated late-onsets CAD (age>70 years) who angiographically had at least 50% stenosis. MMP-9 1562C>T polymorphism was detected by PCRRFLP, plasma MMP-9 activity, serum lipid and homocysteine levels were determined by gelatin gel zymography, enzyme assay and by HPLC, respectively. The presence of MMP-9 1562C>T allele was found to be associated with ECAD (OR=3.2, P=0.001). The ECAD patients with MMP-9 1562C>T allele had higher MMP-9 activity (P=0.001), LDL-C (P=0.045), TC (P=0.02) and homocysteine (P=0.01) levels than the LCAD subjects. MMP-9 1562C>T allele is a risk factor for ECAD. The carriers of this allele have high levels of MMP-9 activity, LDL-C, TC and homocysteine (P=0.01), thus, are more likely to develop myocardial infarction and CAD at young age (less than 55 years).

Multifocal Meningiomas Mimicking Metastasis on 18F-Fluciclovine PET/CT.

A 65-year-old male patient with a past medical history of prostate adenocarcinoma presented with biochemical recurrence (prostate-specific antigen level of 5.91 mg/L). 18F-FACBC PET/CT was acquired to evaluate the disease recurrence and metastasis. Multifocal areas of tracer uptake localized to the dural surface of frontal convexities and cavernous sinuses were seen. Subsequent MRI confirmed lesions to be consistent with multifocal meningiomas. Focal intracranial 18F-fluciclovine radiotracer uptake especially at the skull base may present with a diagnostic challenge, and it may be difficult to differentiate between bone metastasis and meningiomas.

18F-Fluciclovine-Avid Mediastinal Lymph Node Metastasis of Cutaneous Malignant Melanoma.

ABSTRACT: A 63-year-old man with recent diagnosis of high-risk prostate adenocarcinoma was referred to our Nuclear Medicine Department for 18F-fluciclovine PET/CT to rule out metastasis in the setting of elevated serum prostate-specific antigen levels. The patient had previous history of nodular melanoma of the right cheek treated 6 years back with surgery and adjuvant radiation. Surveillance 18F-FDG PET/CT for melanoma 1 month back had revealed enlarged FDG-avid mediastinal para-aortic lymph nodes, which on endoscopic biopsy had revealed melanoma metastasis. On current fluciclovine PET/CT, the same enlarged para-aortic lymph nodes showed fluciclovine uptake, suggesting false-positive uptake.

Common molecular markers between circulating tumor cells and blood exosomes in colorectal cancer: a systematic and analytical review.

Nearly half of patients with colorectal cancer (CRC), the third leading cause of cancer deaths worldwide, are diagnosed in the late stages of the disease. Appropriate treatment is not applied in a timely manner and nearly 90% of the patients who experience metastasis ultimately die. Timely detection of CRC can increase the five-year survival rate of patients. Existing histopathological and molecular classifications are insufficient for prediction of metastasis, which limits approaches to treatment. Detection of reliable cancer-related biomarkers can improve early diagnosis, prognosis, and treatment response prediction and recurrence risk. Circulating tumor cells (CTCs) and exosomes in peripheral blood can be used in a liquid biopsy to assess the status of a tumor. Exosomes are abundant and available in all fluids of the body, have a high half-life and are released by most cells. Tumor-derived exosomes are released from primary tumors or CTCs with selective cargo that represents the overall tumor. The current systematic review highlights new trends and approaches in the detection of CRC biomarkers to determine tumor signatures using CTC and exosomes. When these are combined, they could be used to guide molecular pathology and can revolutionize detection tools. Relevant observational studies published until July 24, 2019 which evaluated the expression of tumor markers in CTCs and exosomes were searched in PubMed, Scopus, Embase, and ISI Web of Science databases. The extracted biomarkers were analyzed using String and EnrichR tools.

Human telomerase reverse transcriptase protein expression predicts tumour aggressiveness and survival in patients with clear cell renal cell carcinoma.

Human telomerase reverse transcriptase (hTERT) is an active component of telomerase and responsible for its catalytic activity, associated with cell proliferation and differentiation. For the first time, the present study was conducted to evaluate the expression and prognostic significance of hTERT in different histological subtypes of renal cell carcinoma (RCC). Expression of hTERT was examined in 176 well-defined renal tumour samples including clear cell RCCs (ccRCCs), papillary and chromophobe RCCs using immunohistochemistry on tissue microarrays. The association between hTERT expression and clinicopathological parameters as well as survival outcomes were then analysed. There was a statistically significant difference in terms of hTERT expression among various RCC subtypes. In ccRCC, increased expression of hTERT was significantly associated with advanced stage, higher grade, presence of microvascular invasion, lymph node invasion, and metastasis. Moreover, in the multivariate analysis, tumour stage and tumour size were independent predictors of the disease-specific survival (DSS). Additionally, expression of hTERT was found to be a significant predictor of worse DSS (p = 0.012) in the univariate analysis. In papillary carcinoma samples (type I and II), significant association was detected between hTERT expression and the tumour stage (p = 0.010, p = 0.050), respectively. In chromophobe RCC, no significant association was detected between expression of hTERT and clinicopathological parameters and survival data. We showed that hTERT protein expression was associated with more aggressive tumour behaviour and more advanced disease in ccRCC patients. Also, hTERT may be a novel poor prognostic indicator of DSS, if the patients are followed for more prolonged time periods.

Seizure susceptibility alteration following reversible cholestasis in mice: Modulation by opioids and nitric oxide.

There is an increasing body of evidence that the central nervous system is affected by cholestatic liver disorders. Cholestasis has been shown to result in a decreased seizure propensity which is believed to be mediated by an increased opioidergic tone and nitric oxide (NO) signaling pathway. In this study, we used a reversible chemically-induced cholestasis model in mice to investigate the changes in seizure susceptibility. The cholestasis was induced by intragastric administration of alpha-naphthylisothiocyanate (ANIT) (100 mg/kg) or vehicle (corn oil). The threshold to generalized clonic seizures induced by timed intravenous infusion of pentylenetetrazole (PTZ) was used as an index of seizure propensity. The role of opioid receptors and NO pathway in the changes of seizure threshold, and the responsiveness to the anticonvulsant effect of opioid agonist, morphine, during and after the resolution of cholestasis was studied in this reversible paradigm of cholestatic disease. A significant increase in cholestasis-related biochemical markers as well as in clonic seizure threshold was observed; it was maximal at day 3 after cholestasis induction and slowly decreased to normal thereafter. Seizure threshold rise was inhibited by chronic administration of the opioid antagonist naltrexone or acute administration of N-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO production. Co-administration of subeffective doses of L-NAME and naltrexone showed an additive effect. Injection of an anticonvulsant dose of morphine on day 7 after cholestasis induction did not increase seizure threshold, suggestive of a downregulation of receptors even after cholestasis resolution. These data shows that ANIT-induced cholestasis leads to a reversible increased resistance to PTZ-induced seizures through an opioid/NO-mediated pathway, and is probably accompanied by downregulation of opioid receptors.

The effects of N-acetylcysteine on the expression of matrix metalloproteinase-2 and tissue inhibitor of matrix metalloproteinase-2 in hepatic fibrosis in bile duct ligated rats.

AIM: N-acetylcysteine can inhibit the formation of intracellular reactive oxygen intermediates. Cellular redox state plays a role in regulating the secretion of matrix metalloproteinase-2. We investigated the effects of N-acetylcysteine on the expression of matrix metalloproteinase-2 and tissue inhibitor of matrix metalloproteinase-2. METHODS: Bile duct ligated rats were used as a model of hepatic fibrosis. We compared the level of gene expression (using real-time reverse transcription polymerase chain reaction [RT-PCR]), liver function parameters, hepatic reactive oxygen production, lipid peroxidation and glutathione state in experimental groups. RESULTS: N-acetylcysteine treatment significantly improved liver function parameters including the plasma levels of aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase and bilirubin. In addition, significant improvement of glutathione state and reactive oxygen production were observed. Hepatic lipid peroxidation was reversed by N-acetylcysteine treatment. Although N-acetylcysteine treatment did not completely normalize the increased matrix metalloproteinase-2 expression, it significantly decreased its level by 65%. N-acetylcysteine treatment also significantly decreased matrix metalloproteinase-2 activity and normalized tissue inhibitor of matrix metalloproteinase-2 expression. CONCLUSION: Collectively, N-acetylcysteine showed inhibition of matrix metalloproteinase-2 expression and activity. In addition, administration of N-acetylcysteine was associated with downregulation of the expression of tissue inhibitor of matrix metalloproteinase-2 and amelioration of oxidative stress in the liver of bile duct ligated rats.