Prospective study to assess the clinical efficacy of bone scintigraphy--ROC analysis

The value of preoperative bone scans in patients with primaly breast and prostate cancer was evaluated prospectively. The methodology and some clinical results were described previously. The clinical efficacy of the bone scan was assessed by using ROC analysis and we obtained the following results. 1) Preoperative bone scan of carcinomas of the breast is effective for patients with clinical stage IIIA, IIIB and IV. It is not so effective for patients with clinical stage I and II, but there is no denying the importance of it, because it provides a base-line scan for comparison to subsequent scans obtained in the postoperative period. 2) Preoperative bone scan of prostate carcinomas is effective, especially for clavicle, the ribs and the cervical spine, when compared with bone X-ray. 3) Bone scan is effective means for patients who were diagnosed uncertainly to have bone metastasis.     

Prospective study to assess the clinical efficacy of bone scintigraphy--comparative study of the efficacy in breast carcinoma and prostate carcinoma

Prospective study of bone scintigraphy was performed on 414 patients with breast carcinoma and 88 patients with prostate carcinoma. In 468 of them, confirmative diagnoses of bone, whether metastasis was existent or not, were made after the observations over a year. Finally, the incidences of bone metastasis were 11 percent for breast carcinoma and 54 percent for prostate carcinoma respectively. The efficacy of preoperative bone scintigraphy in breast carcinoma was comparable to that in prostate carcinoma with regard to improvement of predictive probability of bone metastasis: raising up the probability in the positive cases and bringing down in the negative cases.     

Biomonitoring of urinary tamoxifen and its metabolites from breast cancer patients using nonaqueous capillary electrophoresis with electrospray mass spectrometry.

Tamoxifen is an antiestrogen drug used to treat breast cancer. We have extracted tamoxifen and several of its metabolites from urine of patients with both metastatic (stage IV) and locally confined (stages I, II, and III) breast cancer. Analysis of these metabolites was performed by nonaqueous capillary electrophoresis with electrospray-mass spectrometry. Peak heights from extracted ion current electropherograms of the metabolites were used to establish a metabolic profile for each patient. We demonstrate substantial variation among patient profiles, statistically significant differences in the amount of urinary tamoxifen N-oxide found in stages I, II, and III compared to stage IV breast cancer patients, and statistically significant differences in the amount of 3,4-dihydroxytamoxifen found in progressors compared to nonprogressors with metastatic (stage IV) cancer.     

Recent advances in the targeted fluorescent probes for the detection of metastatic bone cancer

Tumors of the breast, prostate, and lung are most likely to metastasize to the bone and typically indicates a poor cure and survival rate in cancer patients. Detection of metastatic bone cancer in early stage would save many lives and greatly improve patients' quality of life. Clinically, bone scintigraphy is often utilized to visualize bone metastases due to its relatively low cost and high sensitivity. Recently, a growth number of analytical researches aimed at developing targeted fluorescent probes to noninvasively image bone metastases with improved spatial resolution and specificity has been reported. In this review, we will summarize and discuss the recent published fluorescent probes on the accurate detection of metastatic bone cancer. First, the design principles of various targeted probes for imaging bone metastases will be presented, highlighting the signal moieties, targeting ligands, and physicochemical properties of the bone-specific probes. Next, the up-to-date bone-targeting fluorescent probes will be summarized and overviewed. Finally, future perspectives and challenges confronting the researchers in this field will be discussed.We believe this review will encourage novel ideas to develop smart targeted molecular probes for bone metastasis imaging,image-guided surgery, and therapeutic imaging materials.     

Recent Advances in Nanomedicine for the Diagnosis and Treatment of Prostate Cancer Bone Metastasis

Patients with advanced prostate cancer can develop painful and debilitating bone metastases. Currently available interventions for prostate cancer bone metastases, including chemotherapy, bisphosphonates, and radiopharmaceuticals, are only palliative. They can relieve pain, reduce complications (e.g., bone fractures), and improve quality of life, but they do not significantly improve survival times. Therefore, additional strategies to enhance the diagnosis and treatment of prostate cancer bone metastases are needed. Nanotechnology is a versatile platform that has been used to increase the specificity and therapeutic efficacy of various treatments for prostate cancer bone metastases. In this review, we summarize preclinical research that utilizes nanotechnology to develop novel diagnostic imaging tools, translational models, and therapies to combat prostate cancer bone metastases.     

Progress in Targeted Alpha-Particle-Emitting Radiopharmaceuticals as Treatments for Prostate Cancer Patients with Bone Metastases

Bone metastasis remains a major cause of death in cancer patients, and current therapies for bone metastatic disease are mainly palliative. Bone metastases arise after cancer cells have colonized the bone and co-opted the normal bone remodeling process. In addition to bone-targeted therapies (e.g., bisphosphonate and denosumab), hormone therapy, chemotherapy, external beam radiation therapy, and surgical intervention, attempts have been made to use systemic radiotherapy as a means of delivering cytocidal radiation to every bone metastatic lesion. Initially, several bone-seeking beta-minus-particle-emitting radiopharmaceuticals were incorporated into the treatment for bone metastases, but they failed to extend the overall survival in patients. However, recent clinical trials indicate that radium-223 dichloride (²²³RaCl₂), an alpha-particle-emitting radiopharmaceutical, improves the overall survival of prostate cancer patients with bone metastases. This success has renewed interest in targeted alpha-particle therapy development for visceral and bone metastasis. This review will discuss (i) the biology of bone metastasis, especially focusing on the vicious cycle of bone metastasis, (ii) how bone remodeling has been exploited to administer systemic radiotherapies, and (iii) targeted radiotherapy development and progress in the development of targeted alpha-particle therapy for the treatment of prostate cancer bone metastasis.     

Alpha 1-antitrypsin: a novel tumor-associated antigen identified in patients with early-stage breast cancer

Several studies have demonstrated that sera from patients with cancer contain antibodies that recognize a unique group of autologous antigens called tumor-associated antigens (TAA). In the current study, we employed an immunoproteomic approach, combining 2DE, Western blot, and MALDI-MS to identify TAA in the sera of patients diagnosed with infiltrating ductal or in situ carcinoma breast cancer. Sera obtained from 25 newly diagnosed patients with stage II breast cancer and 20 healthy volunteers was evaluated for the presence of novel TAA. Alpha 1-antitrypsin (A1AT) antibodies were detected in 24 of 25 patients with breast cancer (96%) and in 2 of 20 controls (10%). Sensitivity of detection of autoantibodies against A1AT in patients with breast cancer was 96%. Our preliminary results suggest that A1AT and autoantibodies against alpha 1 antitrypsin may be useful serum biomarkers for early-stage breast cancer screening and diagnosis.     

The use of radioiodine in the management of the differentiated tyroid cancer

The use of radioactive iodine (¹³¹I) has substantially improved the prognosis of the differentiated thyroid cancer (DTC); however, its use can be effective only if it is planned with a precise strategy. A “radical” protocol of treatment is described, involving surgical “near total” thyroidectomy, followed by an “ablative” treatment with radioiodine. A total body (TB) scan is performed just after the treatment and, if it is negative, is repeated later with a tracer dose, in order to detect functioning distant metastases, if any, suitable for¹³¹I therapy. Out of a series of 202 patients affected by DTC, several cases (from 9 to 37%, depending on initial stage), who were apparently free of metastases on clinical and radiological basis, resulted positive for functioning metastases not known before, involving lungs, or lymph-nodes, or bones. Patients whose metastases had been discovered only by scan were successfully cured in larger numbers and with lesser amount of radioiodine, compared with others whose metastases were already known on clinical or radiological grounds. Side effects of the treatment were minimal, and not disproportionate to the disease. Patients administered with radioiodine in therapeutic dosage were admitted to the hospital in a special restricted area. Waste handling facilities are described.     

毛萼乙素及其一类物的化学选择性合成

本文首次报道从冬凌草甲素(3)经6步或7步反应改造成毛萼乙素(1)和脱氢毛萼甲素(2), 总产率分别为11和10%, 经4步或5步反应改造成新化合物14-羟基毛萼乙素(4)和14-羟基脱氢毛萼甲素(5), 总产率分别为57和49%。     

Glycoprotein synthesis as a function of epithelial cell arrangement: biosynthesis and release of glycoproteins by human breast and prostate cells in organ culture.

We demonstrate that a technique is available to investigate glycoprotein synthesis in organ cultures of human breast and prostate surgical specimens where the 3-dimensional epithelial cell arrangement remains intact. Malignant breast and prostate epithelium maintained their capacity to synthesize glycoproteins for at least 3 days as followed by the incorporation of [3H]glucosamine into macromolecules. Over 70% of incorporation was by malignant cells as judged by autoradiography. Labeled glycoproteins were released into glandular lumina and consequently into the culture fluid. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed predominantly one group of macrmolecules released with an apparent molecular weight of 48,000 +/- 6,000 daltons. This glycoprotein was found in all of the breast specimens studied, which included 1 medullary, 1 infiltrating lobular, and 8 infiltrating duct carcinomas. The pattern was independent of the availability of estrogen receptors. A similar glycoprotein was also observed in the culture media from a Grade I and a Grade II well-differentiated infiltrating prostate carcinoma. Incorporation was below the level of detection in 4 of 6 cases of benign prostatic hyperplasia. A more complex pattern of labeled glycoproteins was found in the media of a Grade II and a Grade III poorly-differentiated prostate carcinoma. The established human mammary carcinoma cell line MCF-7 synthesized and released a similar 48,000 molecular weight glycoprotein but additional components with larger molecular weights were also released. An intriguing interpretation that 3-dimensional tissue integrity restricts some glycoprotein synthesis is discussed. Cells grown in 2-dimensional monolayers could escape from such a topographic restriction and express additional families of glycoproteins.     

Nuclear annexin II negatively regulates growth of LNCaP cells and substitution of ser 11 and 25 to glu prevents nucleo-cytoplasmic shuttling of annexin II

Background  

Annexin II heavy chain (also called p36, calpactin I) is lost in prostate cancers and in a majority of prostate intraepithelial neoplasia (PIN). Loss of annexin II heavy chain appears to be specific for prostate cancer since overexpression of annexin II is observed in a majority of human cancers, including pancreatic cancer, breast cancer and brain tumors. Annexin II exists as a heterotetramer in complex with a protein ligand p11 (S100A10), and as a monomer. Diverse cellular functions are proposed for the two forms of annexin II. The monomer is involved in DNA synthesis. A leucine-rich nuclear export signal (NES) in the N-terminus of annexin II regulates its nuclear export by the CRM1-mediated nuclear export pathway. Mutation of the NES sequence results in nuclear retention of annexin II.     

Nanoaggregate Probe for Breast Cancer Metastasis through Multispectral Optoacoustic Tomography and Aggregation‐Induced NIR‐I/II Fluorescence Imaging

An activatable nanoprobe for imaging breast cancer metastases through near infrared‐I (NIR‐I)/NIR‐II fluorescence imaging and multispectral optoacoustic tomography (MSOT) imaging was designed. With a dihydroxanthene moiety serving as the electron donor, quinolinium as the electron acceptor and nitrobenzyloxydiphenylamino as the recognition element, the probe can specifically respond to nitroreductase and transform into an activated D‐π‐A structure with a NIR emission band extending beyond 900 nm. The activated nanoprobe exhibits NIR emission enhanced by aggregation‐induced emission (AIE) and produces strong optoacoustic signal. The nanoprobe was used to detect and image metastases from the orthotopic breast tumors to lymph nodes and then to lung in two breast cancer mouse models. Moreover, the nanoprobe can monitor the treatment efficacy during chemotherapeutic course through fluorescence and MSOT imaging.     

Production of Monoclonal antibodies to membrane components of human colorectal cancer HCT-116 cell line for diagnostic purposes

Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. The survival rate of people diagnosed in the early stages of disease is 92 % whereas; less than 11 % of patients survive if reached stage IV. Moreover, only 24 % of cases are diagnosed during stage I. Thus, the early diagnosis of the CRC will save many lives, reduce suffering of patients. Biomarkers that are in use for the diagnosis of CRC such as Carcinoembryonic Antigen (CEA), Carbohydrate Antigen (CA 19–9) suffer from low sensitivity, expressed in other neoplasms, and not expressed in early stages of cancer. This study aims to find a highly sensitive and specific biomarker for early detection of CRC. Hybridoma clones were established by fusing spleen cells from mice hyperimmunized with human cell membrane homogenate of HCT116 with murine myeloma cells X63Ag8. One clone was selected after fusion and designated as D2C5. Isotyping of secretory antibody revealed an IgG1 kappa light chain and was reactive to a protein with molecular weight about 55 kDa using immunoblot. In situ reactivity of the D2C5 showed homogenous and cytoplasmic pattern staining in stage IV and III, discrete and heterogeneous pattern was seen in stage II samples. Moreover, nuclear staining pattern was seen in one slide of stage II samples. In addition, mucinous type was detected. Low peripheral staining was observed in normal colon tissue. These observations suggest the localization of the target protein in the cytoplasm of epithelial cells with high expression in more advanced cases, suggesting a cytokeratin pattern of staining.     

Aptamer based fluorescent probe for serum HER2-ECD detection: The clinical utility in breast cancer

HB5 aptamer-based probe has been developed for serum HER2-ECD test in auxiliary clinical diagnosis and treatment for HER2-positive breast cancer patients.     

Identification of molecular markers for the oncogenic differentiation of hepatocellular carcinoma

The aim of this study was to identify molecular markers associated with oncogenic differentiation in hepatocellular carcinoma (HCC). Using an unsupervised clustering method with a cDNA microarray, HCC (T) gene expression profiles and corresponding non-tumor tissues (NT) from 40 patients were analyzed. Of total 217 genes, 72 were expressed preferentially in HCC tissues. Among 186 differentially regulated genes, there were molecular chaperone and tumor suppressor gene clusters in the Edmondson grades I and II (GI/II) subclass compared with the liver cirrhosis (LC) subclass. The Edmondson grades III and IV (GIII/IV) subclass with a poor survival (P=0.0133) contained 122 differentially regulated genes with a cluster containing various metastasis- and invasion-related genes compared with the GI/II subclass. Immunohistochemical analysis revealed that ANXA2, one of the 72 genes preferentially expressed in HCC, was over-expressed in the sinusoidal endothelium and in malignant hepatocytes in HCC. The genes identified in the HCC subclasses will be useful molecular markers for the genesis and progression of HCC. In addition, ANXA2 might be a novel marker for tumor angiogenesis in HCC.     

Pilot study of capillary electrophoresis coupled to mass spectrometry as a tool to define potential prostate cancer biomarkers in urine

We describe the use of capillary electrophoresis (CE) coupled with mass spectrometry (MS) to identify single polypeptides and patterns of polypeptides specific for prostate cancer (CaP) in human urine. Using improved sample preparation methods that enable enhanced comparability between different samples, we examined samples from 47 patients who underwent prostate biopsy. Of this group, 21 patients had benign pathology and 26 with CaP, and these were used to define potential biomarkers, which allow discrimination between these two states. In addition, CE-MS data from these 47 urine samples were compared to that of 41 young men (control) without known or suspected clinical CaP to further confirm the polypeptides indicative for CaP. Upon crossvalidation of the same samples, several polypeptides were selected that enabled correct classification of the CaP patients with 92% sensitivity and 96% specificity. We then examined an additional 474 samples from patients with renal disease enrolled in other studies and found that 14 (3%) had polypeptides suggestive of CaP possibly indicating that they harbor clinical CaP. In conclusion, this early pilot study suggests that CE-MS of urine warrants further investigation as a tool that can identify putative biomarkers for CaP.     

Photodynamic diagnosis in respiratory tract malignancy using an excimer dye laser system

Equipment has been developed for the early-stage diagnosis and treatment of cancer using an excimer dye laser. The excimer laser beam is obtained by exciting XeCl. A 405 nm beam tuned by DPS dye is used for tumour localization and a 630 nm beam obtained with a rhodamine B dye is used for treatment. The equipment was applied clinically on the basis of extensive experimental research. Effectiveness for cancer localization was examined in 11 cases: four were early stage (three lung cancer and one vocal cord cancer), four were stage I, two were stage III and one was stage IV. All cases were squamous cell carcinoma except for one case of adenocarcinoma. Fluorescence was recognized in all lesions and the equipment was effective for localization.     

Photodynamic therapy of vertebral metastases: evaluating tumor-to-neural tissue uptake of BPD-MA and ALA-PpIX in a murine model of metastatic human breast carcinoma

Photodynamic therapy has been successfully applied to numerous cancers. Its potential to treat cancer metastases in the spine has been demonstrated previously in a preclinical animal model. The aim of this study was to test two photosensitizers, benzoporphyrin-derivative monoacid ring A (BPD-MA) and by 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX), for their potential use to treat bony metastases. The difference in photosensitizer concentration in the spinal cord and the surrounding tumor-bearing vertebrae was of particular interest to assess the risk of potential collateral damage to the spinal cord. Vertebral metastases in a rat model were generated by intracardiac injection of human breast cancer cells. When tumor growth was confirmed, photosensitizers were injected systemically and the animals were euthanized at different time points. The following tissues were harvested: liver, kidney, ovaries, appendicular bone, spinal cord and lumbar vertebrae. Photosensitizer tissue concentration of BPD-MA or PpIX was determined by fluorescence spectrophotometry. In contrast to BPD-MA, ALA-PpIX did not demonstrate an appreciable difference in the uptake ratio in tumor-bearing vertebrae compared to spinal cord. The highest ratio for BPD-MA concentration was found 15 min after injection, which can be recommended for therapy in this model.     

Differential scanning calorimetry (DSC) of blood serum in chronic obstructive pulmonary disease (COPD)

Chronic obstructive pulmonary disease (COPD) is a major global health challenge with a gloom perspective of being one of the big three cause of death by 2020. No reliable/reproducible biomarker has been identified so far to match the clinically-based staging system (GOLD). Blood samples of 30 subjects divided into 6 groups (no-COPD/-smoker, no-COPD/non-smoker, COPD I, COPD II, COPD III, COPD IV) with 5 patients in each were tested by differential scanning calorimetry. There is a clear 15.4 % difference between the heat flow maxima measured when no-COPD subjects were compared in accordance to their smoking/non-smoking status. Odds ratio of different heat flow in actively smoking COPD patients in stage IV and stage I was 1.61. A reverse tendency is detected in the relevant non-smoking COPD groups. The differences are inconsistent in intermediate stages (COPD II and III). DSC seems to be an applicable and objective method for monitoring nicotine abuse. There is a chance to detect specific typology of thermokinetic patterns in the two extremes of COPD (I vs. IV). Further studies with increased sample size are needed to allow calculations on specificity/sensitivity/positive and negative predictive value of enthalpies and heat flow maximums. The first clinically relevant blood-based COPD marker on the intravascular side of the alveo-capillary screen is demonstrated by our pilot study.     

Phytochemical studies and cytotoxicity evaluations of Colchicum tunicatum Feinbr and Colchicum hierosolymitanum Feinbr (Colchicaceae): two native Jordanian meadow saffrons

As a part of our continuing investigation of Jordanian Colchicum species, the biologically active components of Colchicum hierosolymitanum Feinbr and Colchicum tunicatum Feinbr (Colchicaceae) were pursued. The brine shrimp lethality test (BSLT) was used to direct the fractionation and isolation of active components. Five and four known colchicinoids were isolated and characterized from C. tunicatum and C. hierosolymitanum, respectively. The known colchicinoids, reported for the first time from these two species are: (-)-colchicine (I), 3-demethyl-(-)-colchicine (II), (-)-cornigerine (III), beta-lumicolchicine (IV), and (-)-androbiphenyline (V) from C. tunicatum, and (-)-colchicine (I), 2-demethyl-(-)-colchicine (VI), (-)-cornigerine (III), and beta-lumicolchicine (IV) from C. hierosolymitanum. The chemical structures of the isolated compounds have been elucidated using a series of spectroscopic and spectrometric techniques principally; 1D-NMR (1H and 13C) and low resolution EI-MS and APCIMS. All pure compounds were evaluated for cytotoxicity against three human cancer cell lines; MCF-7 human breast carcinoma, NCI-H460 human large cell lung carcinoma, and SF-268 human astrocytoma. (-)-Colchicine (I) and (-)-cornigerine (III) were found to be the most bioactive of the identified compounds with EC50 values in the range of 0.016-0.097 microM.