Primary Tumor Foci Research Articles

Cisplatin-induced potentiation of the antitumor effect of photodynamic therapy

The effect of cisplatin on the effectiveness of photodynamic therapy (PDT) was experimentally studied using leukemia P-388 as a tumor growth model. Treatment was initiated in the presence of a disseminated tumor process. Photosens was administered once in dose of 5 mg/kg on day 5 of tumor growth; PDT was made 24 hours after administration of the sensitizer. Cisplatin was given once in a dose of 7 mg/kg 48, 24, 2, and 0.25 hours before PDT concurrently with the start of radiation or 0.25, 2 or 24 hours after it. A local antitumor effect was judged from the suppression of growth in a primary (irradiated) tumor focus; a systemic effect was from the increased lifespan of mice. The local effect of combination treatment during its all used regimens was higher than that of PDT or chemotherapy (CT) alone. The efficiency of systemic CT in during combination treatment versus its individual components was increased only when the cytostatic was injected prior to PDT.

The relationship of TMPRSS2-ERG gene fusion between primary and metastatic prostate cancers

Recent studies have revealed the presence of TMPRSS2-ERG gene fusion in both primary and metastatic prostate cancers. However, the relationship between primary and corresponding metastatic prostate cancers with respect to the status of this gene fusion remains unclear. Using fluorescence in situ hybridization, we evaluated the rearrangement of the ERG gene in the radical prostatectomy specimens and corresponding lymph node metastases from 19 patients with prostate cancer. The mean age of the patients was 61 years, and the median Gleason score in the radical prostatectomy specimens was 7 (4 + 3). Prostate cancer was unifocal in 6 cases and multifocal in 13 cases, including 10 with 2 foci and 3 with 3 foci. In the primary prostate cancers, rearrangement of the ERG gene was observed in 13 cases and associated with deletion of the 5' ERG gene in 8 cases. In the metastases, the ERG rearrangement was present in 10 cases and associated with deletion of the 5' ERG gene in 6 cases. In unifocal prostate cancers, the status of the ERG rearrangement was concordant between the primary prostate cancer and metastasis in 5 of 6 cases. In multifocal prostate cancer, despite a significant interfocal discordance, the status of the ERG rearrangement was concordant between the index (largest) primary tumor focus and metastasis in all 13 cases. Our study demonstrates a close relationship of the TMPRSS2-ERG gene fusion status between primary and metastatic prostate cancer. The concordance of the ERG gene rearrangement status between the index primary tumor focus and metastasis suggests that metastasis most likely arises from the index tumor focus in multifocal prostate cancer.

Expression of Sodium–Iodide Symporter and TSH Receptor in Subclinical Metastatic Lymph Nodes of Papillary Thyroid Microcarcinoma

The clinical significance of the subclinical lymph node (LN) metastasis in clinically node-negative (cN0) papillary thyroid microcarcinoma (PTMC) has been debated. We investigated the expression of sodium-iodide symporter (NIS) and thyroid-stimulating hormone receptor (TSHR) in the subclinical metastatic LNs of PTMC, which are crucial prerequisites for the response to radioactive iodine treatment. Among 149 consecutive patients who received total thyroidectomy in conjunction with prophylactic central neck dissection for cN0 PTMC from October 2005 to December 2007, 20 who had single PTMC and subclinical LN metastasis (cN0, pN1, single PTMC) were included. Immunohistochemical staining was performed with anti-human NIS antibody and anti-human TSHR antibody in 20 primary tumors and 52 metastatic LNs. NIS and TSHR expression was detected in 19 (95%) and 18 (90%) of 20 PTMCs, respectively. NIS and TSHR expression were also detected in 50 (96.2%) and 39 (75%) of 52 metastatic LNs, respectively. In 85% of patients, the presence of NIS expression in primary PTMCs was concordant with that in corresponding metastatic LNs. Intensities of NIS and TSHR expression were diverse. In 6 of 12 cases of multiple metastatic LNs, the metastatic LNs showed heterogeneous intensities of NIS expression. The presence of NIS and TSHR expression was observed with high frequency in both PTMCs and corresponding subclinical metastatic LNs. However, the intensity of NIS and TSHR expression was diverse. Multiple metastatic LNs from single primary tumor focus could have heterogeneous intensity of NIS expression.

NUT Midline Carcinoma Mimicking Tonsillitis in an Eight-Year-Old Girl

We review a unique case of NUT midline carcinoma that presented in a young girl with an initial diagnosis of tonsillar abscess. We stress the importance of assaying poorly differentiated carcinomas in young patients for the t(15;19) translocation. Our patient presented with tonsillar enlargement and cervical lymphadenopathy mimicking acute tonsillitis. The clinical suspicion for malignancy arose after an aspirate from the tonsil did not yield any pus, and biopsy of a cervical lymph node demonstrated undifferentiated carcinoma. Further analysis by fluorescence in situ hybridization was positive for rearrangements in both BRD4 and NUT genes consistent with NUT carcinoma. In addition, fluorodeoxyglucose-positron emission tomography (FDG-PET) revealed a very high standard uptake value in both the primary tumor and metastatic foci, suggesting that FDG-PET could be a useful tool in the staging and follow-up of NUT midline carcinoma.

A case of primary lung cancer lesion demonstrated by F-18 FDG positron emission tomography/computed tomography (PET/CT) one year after the detection of metastatic brain tumor

Cancer of unknown primary origin (CUP) is an aggressive disease with a poor prognosis. Metastatic brain tumors occur in approximately 15% of all cancer patients. F-18 2'-deoxy-2fluoro-D-glucose (FDG) positron emission tomography (PET) combined with computed tomography (PET/CT) contributes to the evaluation of cancer staging, although the benefits of PET/CT for detection of CUP origins has yet to be determined. In this study, we present a 37-year-old man with a brain tumor detected by magnetic resonance imaging. Surgical biopsy indicated a metastatic undifferentiated carcinoma, while clinical examination and a CT scan did not detect any abnormalities, with the exception of brain metastases. PET/CT did not reveal abnormal FDG uptake. PET/CT revealed abnormal intense FDG uptake in a small nodular lesion in the right lung 1 year following the detection of brain metastasis, and no other abnormal FDG uptake was observed elsewhere in the body. Right upper lobectomy and dissection of mediastinal lymph nodes were performed. The pathological diagnosis was poorly differentiated adenocarcinoma, which was similar to the brain metastatic lesion, and there was no lymph node metastasis. This case revealed an extremely rare lung cancer with primary lesions demonstrated by PET/CT 1 year after the detection of brain metastasis. This case reveals that F-18 FDG PET/CT imaging of CUP origin is capable of positively impacting on the identification of small primary tumor foci.

Sonographic Assessment of Hypopharyngeal Carcinoma

This study investigated the ability of sonography for diagnosis of hypopharyngeal carcinoma. Between November 2008 and January 2010, 34 consecutive patients with hypopharyngeal carcinoma (34 tumors) were examined by sonography. The visualization capability of sonography was evaluated by grading criteria of "excellent," "good," "moderate," and "poor" in comparison with computed tomography (CT). Localization of the primary tumor foci and intrahypopharyngeal and extrahypopharyngeal invasion were initially assessed by sonography and confirmed with surgical and pathologic findings. Laryngeal movement was observed on real-time sonography and compared with endoscopic findings. On sonography, 29 of the 34 lesions (85.3%) were graded excellent, similar to the shapes and dimensions of the tumors on CT. Localization was correctly undertaken in 26 of the 28 foci resected (92.9%), with excellent agreement between sonography and surgical and pathologic findings (κ = 0.823; P < .001). In evaluating intrahypopharyngeal and extrahypopharyngeal invasion with sonography, the sensitivity and specificity were 90.9% and 82.4%, respectively, for intrahypopharyngeal intersubsite spreading, 50.0% and 96.2% for diagnosis of thyroid cartilage destruction, both 100% for evaluation of cervical esophagus, neck soft tissue, and thyroid gland involvement, and 76.9% and 100% for assessment of hemilarynx fixation. Sonography has a similar role in visualization of hypopharyngeal carcinoma as CT and is satisfactory in localization of the primary focus and assessment of tumor extension inside and outside the hypopharynx.

Occult Squamous Cell Carcinoma of the Uvula Detected by F-18 FDG PET/CT in a Case of Carcinoma of Unknown Primary in the Head and Neck

Incidence of unknown primary head/neck tumors with metastatic cervical lymphadenopathy at time of diagnosis is approximately 2% to 9%. Detecting site of original disease is challenging. We present a 75-year-old woman with bulky unilateral level 2 and 3 lymphadenopathy. Clinical examination and computed tomography (CT) did not reveal detectable abnormalities except neck-node metastases; biopsy indicated metastatic squamous cell carcinoma (SCC). F-18 FDG PET/CT imaging was performed to detect the primary tumor site, which revealed a small metabolically-avid lesion in uvula, biopsy demonstrated SCC, the origin of metastatic disease. F-18 FDG PET/CT imaging of unknown primary head/neck tumors can have positive impact in identifying small occult primary tumor foci.

Conjunctival plasmacytoma

Background Plasmacytomas are plasma cell tumors that may be a primary or secondary tumor focus, the latter of which are associated with multiple myeloma. We present a rare case of a solitary extramedullary plasmacytoma involving the conjunctiva. Case Report A 33-year-old white man presented with the initial complaint of redness in both eyes, more in his right than left eye. A vascularized conjunctival lesion was noted in his right eye. The patient underwent excisional biopsy, which found a conjunctival plasmacytoma. Conclusion Although plasmacytomas of the eye and orbit are rare, it is important to be familiar with these tumors that may be associated with multiple myeloma. Definitive diagnosis is made by biopsy and histopathologic examination of the tissue. Plasmacytomas may be treated with external beam radiation, local excision, or radiotherapy after surgical excision. Long-term follow-up, including periodic systemic evaluation, is required to establish that orbital involvement is not an early manifestation of multiple myeloma.

Implication of Extracapsular Invasion of Sentinel Lymph Nodes in Breast Cancer: Prediction of Nonsentinel Lymph Node Metastasis

Accurate intraoperative diagnosis of sentinel lymph node (SLN) metastases enables the selection of patients who require axillary lymph node dissection (ALND). However, many patients with positive SLN do not show metastasis to other axillary lymph nodes. In this study, we investigated the factors that may determine the likelihood of additional positive nodes in the axilla when metastasis is found in the SLN. SLN biopsy was performed on 276 patients with breast cancer with clinically negative nodes, of which 46 (16.6%) had positive SLNs and underwent ALND. Eleven (23.9%) of these 46 cases had additional metastasis in nonsentinel lymph nodes (NSLN). The clinical and pathological features of these cases were reviewed and statistical analysis was performed. All cases of positive nodes in NSLN in our series had extracapsular invasion (ECI) at the metastatic SLNs. Furthermore, the absence of ECI of SLN was significantly associated with the absence of metastasis in the NSLN (P < 0.001). As contributing factors, the absence of lymphatic invasion at the primary tumor, primary tumor size (<2 cm) and foci size in the metastatic SLN fell short of reaching statistical significance. Other factors, including histological type, pathological grade, estrogen receptor status, HER2 status, and age, were not significantly associated with metastatic involvement of NSLN. Our results suggest that the presence of ECI at metastatic SLNs is a strong predictor for residual disease in the axilla. These findings imply the possibility that ALND might be foregone in the treatment of patients with breast cancer without ECI at metastatic SLNs.

Iron Labeling and Pre-Clinical MRI Visualization of Therapeutic Human Neural Stem Cells in a Murine Glioma Model

BackgroundTreatment strategies for the highly invasive brain tumor, glioblastoma multiforme, require that cells which have invaded into the surrounding brain be specifically targeted. The inherent tumor-tropism of neural stem cells (NSCs) to primary and invasive tumor foci can be exploited to deliver therapeutics to invasive brain tumor cells in humans. Use of the strategy of converting prodrug to drug via therapeutic transgenes delivered by immortalized therapeutic NSC lines have shown efficacy in animal models. Thus therapeutic NSCs are being proposed for use in human brain tumor clinical trials. In the context of NSC-based therapies, MRI can be used both to non-invasively follow dynamic spatio-temporal patterns of the NSC tumor targeting allowing for the optimization of treatment strategies and to assess efficacy of the therapy. Iron-labeling of cells allows their presence to be visualized and tracked by MRI. Thus we aimed to iron-label therapeutic NSCs without affecting their cellular physiology using a method likely to gain United States Federal Drug Administration (FDA) approval.MethodologyFor human use, the characteristics of therapeutic Neural Stem Cells must be clearly defined with any pertubation to the cell including iron labeling requiring reanalysis of cellular physiology. Here, we studied the effect of iron-loading of the therapeutic NSCs, with ferumoxide-protamine sulfate complex (FE-Pro) on viability, proliferation, migratory properties and transgene expression, when compared to non-labeled cells. FE-Pro labeled NSCs were imaged by MRI at tumor sites, after intracranial administration into the hemisphere contralateral to the tumor, in an orthotopic human glioma xenograft mouse model.ConclusionFE-Pro labeled NSCs retain their proliferative status, tumor tropism, and maintain stem cell character, while allowing in vivo cellular MRI tracking at 7 Tesla, to monitor their real-time migration and distribution at brain tumor sites. Of significance, this work directly supports the use of FE-Pro-labeled NSCs for real-time tracking in the clinical trial under development: “A Pilot Feasibility Study of Oral 5-Fluorocytosine and Genetically modified Neural Stem Cells Expressing Escherichia coli Cytosine Deaminase for Treatment of Recurrent High-Grade Gliomas”.

Correlation between FDG PET/CT and the expression of Ki-67, MMP-2, micro-vessel density (MVD), and pathological grading in squamous cell carcinoma of the esophagus

e15556 Background: Variable uptake of 18FDG has been noticed in positron emission tomography (PET) studies of patients with esophageal squamous cell carcinoma (ESCC). The aim of the present study was to determine if 18F-FDG PET/CT standardized uptake value (SUV) could quantitatively reflect tumor proliferation, invasion and angiogenesis, and to reveal the relationship between SUV and pathological grading of ESCC. Methods: Preoperative PET scans were performed in 47 patients with histologically proven ESCC. 18FDG uptake was semiquantitatively measured by SUV.Tumour sections were HE stained to determine the pathological grading,and were stained by immunohistochemistry for proliferation marker (Ki67), invasion marker (MMP-2), and angiogenic marker (CD34). The correlations between FDG SUVmax and Ki67 expression, MMP-2 expression, corresponding MVD were statistically analysed respectively. Results: Among all the 47 cases,there were 13 well- differentiated squamous cell tumors, 16 moderately differentiated tumors and 18 poorly differentiated tumors,45 of 47 tumors revealed FDG. accumulation in primary tumor foci confirmed by subsequently histopathologically. The mean FDG SUVmax value was 12.504 ± 6.805. Average Ki-67 index was (7.837±29.798) %, average MMP-2 index was (71.551%±27.126) % and average MVD was (18.429±9.603) accordingly. The SUV and Ki-67 index, MMP-2 index were positively correlated (r=0.581,0.594), and it was not correlated with MVD(P&gt;0.05). The mean SUV of well-differentiated, moderately differentiated and poorly differentiated tumors were 9.787±1.477, 12.313±0.479, 15.053±2.147 respectively, and a significant difference could be determined between them by statistical analysis(P=0.000). Conclusions: A significant positive correlation is demonstrated between FDG PET/CT SUV and Ki-67 index, MMP-2 index of the primary ESCC. SUV could reflect proliferation and invasion potential of tumor. However, there is no significant correlation between SUV and MVD, thus it could not reflect tumor angiogenesis in ESCC. To some extent, SUV could reflect pathologic grading of ESCC. No significant financial relationships to disclose.

Vitiligo-like Depigmentation Associated with Metastatic Melanoma of an Unknown Origin

Although malignant melanoma usually occurs after the diagnosis of vitiligo-like depigmentation, the latter is rarely followed by the former. We herein report on such a case in which recognition of the vitiligo-like depigmentation preceded diagnosing the metastatic melanoma by several months. A 56-year-old woman had first developed vitiligo-like depigmentation on the forehead, eyelids, neck and back 18 months previously and thereafter she detected a hard mass in the left axilla 2 months previously. Based on the histologic findings, the axillary mass was diagnosed as metastatic melanoma. To evaluate the primary tumor focus, thorough examinations that included PET-CT, bone scan and sigmoidoscopy were performed, but we couldn't find any the original primary tumor. Our case suggests that the vitiligo-like depigmentation could be a sign that heralds metastatic melanoma.

Glucocorticoid Receptor-mediated Expression of Caldesmon Regulates Cell Migration via the Reorganization of the Actin Cytoskeleton

Glucocorticoids (GCs) play important roles in numerous cellular processes, including growth, development, homeostasis, inhibition of inflammation, and immunosuppression. Here we found that GC-treated human lung carcinoma A549 cells exhibited the enhanced formation of the thick stress fibers and focal adhesions, resulting in suppression of cell migration. In a screen for GC-responsive genes encoding actin-interacting proteins, we identified caldesmon (CaD), which is specifically up-regulated in response to GCs. CaD is a regulatory protein involved in actomyosin-based contraction and the stability of actin filaments. We further demonstrated that the up-regulation of CaD expression was controlled by glucocorticoid receptor (GR). An activated form of GR directly bound to the two glucocorticoid-response element-like sequences in the human CALD1 promoter and transactivated the CALD1 gene, thereby up-regulating the CaD protein. Forced expression of CaD, without GC treatment, also enhanced the formation of thick stress fibers and focal adhesions and suppressed cell migration. Conversely, depletion of CaD abrogated the GC-induced phenotypes. The results of this study suggest that the GR-dependent up-regulation of CaD plays a pivotal role in regulating cell migration via the reorganization of the actin cytoskeleton.

Comparative Analysis of Coagulation System Proteins Distribution in Breast Cancer Primary Lesions and Lymph Node Metastases.

Breast cancer is the most frequent cause of morbidity and mortality due to cancer in women. Thromboembolic episodes are relatively common complication during the course of the disease. It was widely documented, that components of blood coagulation play a role in tumor progression and metastasis formation. Presence of hemostatic proteins was observed in primary lesions of different malignant tumors. However, information on expression and role of coagulation system components in regional lymph node metastases is scanty. The purpose of the study was to assess and compare the distribution of selected coagulation proteins - in primary versus metastatic lesions of breast cancer. Specimens of primary tumor of different degree of malignancy and metastatic lesions localized in regional lymph nodes were obtained during surgical treatment of previously untreated twenty five breast cancer patients and fixed in formalin. Immunohistochemical procedure was employed using monoclonal and polyclonal antibodies against tissue factor (TF), tissue factor pathway inhibitor (TFPI), factor IX, factor X, fibrinogen and fibrin. A strong expression of TF was demonstrated in cancer cells of both primary tumors and lymph node metastases. Coagulation factors IX and X were also present in primary and metastatic breast cancer lesions. However, the expression of the proteins was weaker in regional lymph node metastases than in primary tumor. Strong staining for fibrinogen was detected in the stroma of primary breast cancer, particularly at the area adjacent to the cancer foci. Stroma of metastatic lesions was characterized by much weaker staining for fibrinogen. Strong expression of fibrin and TFPI was demonstrated in cancer cells of primary tumor while much weaker expression of the antigens was visualized in cancer cells localized in lymph node metastatic lesions. Furthermore, the presence of all examined proteins was observed in small blood vessel walls and in macrophages infiltrating both primary tumor tissue as well as metastatic lesions. The results of the study indicate extravascular activation of blood coagulation in loco in breast cancer, both in the primary tumor and in the regional lymph node metastatic lesions. The presence of coagulation system proteins in cancer tissue (primary tumor and metastatic foci) suggests that they may play a role in the biology of breast cancer growth as well as they may modulate breast cancer metastatic dissemination.

Clinical Utility of Breast Magnetic Resonance Imaging in Patients Presenting with Primary Breast Cancer

Since magnetic resonance imaging (MRI) of the breast has been shown to be sensitive in identifying the extent of the primary tumor and other foci of cancer, we examined its clinical utility in the surgical management of breast cancer patients. From January 2004 to April 2007, 117 patients with newly diagnosed breast cancer underwent bilateral MRI prior to definitive surgical management. Additional lesions were found in 27 patients (23.1%) in the ipsilateral breast and 19 patients (16.2%) in the contralateral breast. Twelve patients (10.3%) had more than one new lesion identified. Six patients (5.1%) had a larger area of tumor than detected by mammography or ultrasound. Additional biopsies were performed in 27 patients (23.1%). Additional foci of cancer were identified in 17 patients (14.5%): 12 (10.2%) in the ipsilateral breast and 5 (4.3%) in the contralateral breast. This information changed the clinical management in 23 cases (19.7%). Further studies are needed to confirm the benefits of MRI relative to its costs and to further identify the appropriate patients to undergo this imaging procedure.

Correlation of GLUT-1 Overexpression, Tumor Size, and Depth of Invasion with 18F-2-fluoro-2-deoxy-d-glucose Uptake by Positron Emission Tomography in Colorectal Cancer

We investigated the wide variability of 18F-2-fluoro-2-deoxy-D: -glucose (FDG) uptake, semiquantified as standardized uptake value (SUV), in positron emission tomography (PET) scanning, in 20 patients with colorectal cancer (CRC), including 1 with synchronous hepatic metastasis. The sensitivity of PET in CRC diagnosis was 100%, with a mean SUV of 8.0 (3.1-11.9). Tumor size and depth of invasion were associated with higher SUVs (P=.0004, .042, respectively). Strong glucose transporter-1 (GLUT-1) expression had significantly positive correlation with the SUV (r=.619, P=.003). GLUT-1 expression revealed positive staining in 17 (85%) of the 20 primary lesions. The central part of the tumor, thought to be relatively hypoxic, had stronger GLUT-1 expression and a higher SUV than the periphery, in both the primary tumor and hepatic metastatic foci. Our data suggest that the SUVs of FDG uptake in PET may be a noninvasive biomarker for advanced CRC, indicative of a large hypoxic tumor with deep invasion.

Malignant neoplasms of the head and neck

Head and neck masses represent a common clinical entity in children. In general, these masses are classified as developmental, inflammatory, or neoplastic. Having a working knowledge of lesions within this region and conducting a thorough history and physical examination generally enables the clinician to facilitate an appropriate workup and establish a diagnosis. The differential diagnosis is broad, and expeditiously distinguishing benign from malignant masses is critical for instituting a timely multidisciplinary approach to the management of malignant lesions. Neoplasms of the head and neck account for approximately 5% of all childhood malignancies. A diagnosis of malignancy may represent a primary tumor or metastatic foci to cervical nodes. In this review, we discuss the general approach to evaluating suspicious masses and adenopathy in the head and neck region and summarize the most common malignant neoplasms of the head and neck with regard to their incidence, clinical presentation, diagnostic evaluation, staging, and management. Thyroid, parathyroid, and salivary gland tumors are discussed elsewhere in this issue of Seminars in Pediatric Surgery.

Dietary Depletion of Vitamin E and Vitamin A Inhibits Mammary Tumor Growth and Metastasis in Transgenic Mice

We showed previously that dietary antioxidant depletion enhances tumor reactive oxygen species (ROS) and apoptosis, resulting in a reduction in brain tumor size in the TgT(121) transgenic mouse model, a nonmetastatic tumor model. Here, in a transgenic mouse model of mammary tumorigenesis with defined rates of tumor growth and lung-targeted metastasis, we determined the ability of dietary antioxidant depletion to inhibit tumor growth and metastasis. Compared with control mice fed a standard diet, antioxidant-depleted mice exhibited tumor-targeted generation of ROS manifested by increased levels of oxidatively modified DNA/RNA (8- hydroxy-2'-deoxyguanine, 8-hydroxyguanine) and lipid peroxidation (4-hydroxy-2-nonenal) in primary and metastatic tumor foci. In addition to increased tumor-targeted ROS, the number of apoptotic cells was increased approximately 500% (P < 0.01) and terminal dUTP nucleotide DNA end-labeling-positive cells 200% (P < 0.01) in mice fed the antioxidant-depleted diet, whereas the percentage of tumor cells undergoing mitosis was >50% lower than in controls (P < 0.01). The proportional distribution of small (<1.5 cm) and large (> or = 1.5 cm) primary mammary tumors differed. The mice fed the antioxidant-depleted diet had more small primary tumors (P <0.05) and fewer large primary tumors (P < 0.05). Importantly, they also had fewer lung metastatic tumor foci compared with mice fed the control diet (4.5 +/- 1.3 vs. 15.8 +/- 8.5 foci/lung, P < 0.01). These findings may be important in understanding the role of dietary antioxidant vitamins in tumor growth and metastasis.

Progression to Malignancy in the Polyoma Middle T Oncoprotein Mouse Breast Cancer Model Provides a Reliable Model for Human Diseases

Animal models are powerful tools to analyze the mechanism of the induction of human breast cancer. Here we report a detailed analysis of mammary tumor progression in one mouse model of breast cancer caused by expression of the polyoma middle T oncoprotein (PyMT) in the mammary epithelium, and its comparison to human breast tumors. In PyMT mice, four distinctly identifiable stages of tumor progression from premalignant to malignant stages occur in a single primary tumor focus and this malignant transition is followed by a high frequency of distant metastasis. These stages are comparable to human breast diseases classified as benign or in situ proliferative lesions to invasive carcinomas. In addition to the morphological similarities with human breast cancer, the expression of biomarkers in PyMT-induced tumors is also consistent with those associated with poor outcome in humans. These include a loss of estrogen and progesterone receptors as well as integrin-beta1 expression and the persistent expression of ErbB2/Neu and cyclinD1 in PyMT-induced tumors as they progress to the malignant stage. An increased leukocytic infiltration was also closely associated with the malignant transition. This study demonstrates that the PyMT mouse model is an excellent one to understand the biology of tumor progression in humans.

Virotherapy clinical trials for regional disease: in situ immune modulation using recombinant poxvirus vectors.

The ability of viruses to readily infect tumor cells both in vitro and in vivo has resulted in their study as antitumor agents through a variety of strategies. Replicating and conditionally replicating viruses and recombinant viruses encoding genes for toxins and/or prodrugs have been studied for their direct antitumor activity with promising results. However, to date, the lack of a targettable construct able to localize to all tumors following systemic administration has proven to be a major limitation in their use for metastatic disease. The ability of a variety of well-characterized viruses to serve as vectors for expression of tumor antigens and/or cytokines has also resulted in their study as immunotherapeutic agents. In this review, we discuss preclinical and clinical data that support the use of recombinant poxviruses as vectors for in situ tumor transfection with immune-enhancing cytokines and immune costimulatory antigens. We hypothesize that such an approach will ultimately lead to enhanced immune recognition of tumor and the development of an effective systemic antitumor immune response capable of eradicating primary and metastatic tumor foci.