Progressive Tumor Growth Research Articles

Reducing prostaglandin E2 production to raise cancer immunogenicity

ABSTRACTCyclooxygenases (COX), commonly upregulated in numerous cancers, generate prostaglandin E2 (PGE2), which has been implicated in key aspects of malignant growth including proliferation, invasion and angiogenesis. Recently, we showed that production of PGE2 by cancer cells dominantly enables progressive tumor growth via immune escape and that cyclooxygenase inhibitors synergize with immunotherapy to enhance tumor eradication.

Endoscopic endonasal surgery of paranasal sinus osteomas

This article was designed to summarize the experience gained withendoscopic endonasal removal of paranasal sinus osteomas during the period from January 2013 till February 2016. In addition a review of the relevant literature is presented encompassing the publicationsthat provide information about etiology, pathogenesis, clinical picture, diagnostics, and treatment of bone tumours. The objective of the study was to enhance the effectiveness and safety of the surgical treatment of the patients presenting with paranasal sinus osteomas. A total of 81 cases of paranasal sinus osteoma were documented in the patients admitted to I.P. Pavlov Saint-Peterburg First State Medical Universityduring the period from January 2013 till February 2016. Forty nine of them were given the surgical endoscopic endonasal treatment with the removal of the neoplasm. The remaining 32 patients were included in the group for the further dynamic follow up. The authors report the data of morphological studies and the results of computed tomography performed in the pre- and postoperative periods with special reference to the potential for the use of the electromagnetic navigation station (an image-guidance system) that makes it possible to significantly reduce the risk of development of possible complications. In addition, the findings suggestive of the progressive tumour growth in the group of the patients under dynamic observation are discussed.

Characteristics of the expression of KAI1/CD82 and PDGFRβ and their impact on glioma progression.

The biological features of glioma cells may define their clinical outcome. Little is known about the interactions between KAI1/CD82 metastatic suppressor protein and PDGFR in gliomas. The aim of the study was to examine KAI1/CD82 and PDGFR expression in gliomas in order to find the impact of these proteins on progression of the tumors. PDGFR, KAI1/CD82 protein expression and mRNA of genes were evaluated on eighty four paraffin-embedded tissue of gliomas using immunohistochemical staining and RT-PCR analysis. The PDGFR expression was higher in IV/III than in I/II glioma grades (p = 0.0004). The level of mRNA PDGFR was associated with the degree of PDGFR immunoreactivity. Downregulation of KAI1/CD82 was associated with tumor malignancy (p = 0.007). The increased level of KAI1/CD82 gene expression (3-4-fold) was found in gliomas with strong KAI1/CD82 immunoreactivity. The parallel KAI1/CD82 and PDGFR expression was more significantly associated with cases in a group graded as III and IV than in a group graded as I/II (p = 0.002). We found that a loss of KAI1/CD82 and an increase in PDGFR expression in gliomas relate to a progressive tumor growth. The correlation between PDGFR and KAI1 expression in high grade gliomas suggests that a direct or indirect interaction between these proteins might have an impact on cell motility and invasive behavior of the tumor.

Short-term postoperative surveillance imaging may be unnecessary in elderly patients with resected WHO Grade I meningiomas

The optimal timing and frequency of postoperative imaging surveillance after a meningioma resection are not well-established. The low recurrence rates and slow growth of World Health Organization (WHO) Grade I meningiomas in particular have raised doubts about the utility of postoperative imaging surveillance. We sought to analyze the cost and utility of asymptomatic surveillance imaging in elderly patients after the resection of a WHO Grade I meningioma. We conducted a retrospective cohort study on 45 patients who had a primary WHO Grade I meningioma resected at our institution between 2001–2013 at or above the age of 60 with a minimum of 2years of follow-up. All postoperative clinic notes were reviewed alongside imaging results to verify that patients were asymptomatic during the surveillance period. MRI and CT scan costs (all $USD) were estimated at $599.61 and $334.31 respectively based on the Centers for Medicare and Medicaid national averages. During an average follow-up period of 4.5years, the average number of total imaging studies performed per asymptomatic patient was 3.58 with an average total cost of $2086.30 per patient. Forty-two (93%) patients had no new abnormal findings on any of their imaging. Three (7%) patients demonstrated either a new meningioma or progressive growth of the postoperative residual tumor on imaging. No asymptomatic patient underwent a reoperation. Our data suggest that elderly patients with resected WHO Grade I meningiomas are at low risk for recurrence and may not need asymptomatic surveillance imaging for the first several postoperative years.

A Novel Pan-PIM Kinase Inhibitor, SEL24-B489, Induces Apoptosis and Inhibits Proliferation of Diffuse Large B-Cell Lymphoma Cells through Inhibition of Protein Translation and Attenuation of Myc and NFkB Activity

Introduction. In 1/3of diffuse large B-cell lymphoma (DLBCL) patients current treatment options are ineffective, underscoring the need for more effective targeted therapies. Simultaneous genetic ablation of PIM kinases (PIM-1/2/3) or their pharmacological inhibition induce apoptosis in DLBCL cell lines, providing proof of concept that these proteins are promising targets in this disease. To better understand mechanisms of toxicity of PIM inhibition in DLBCL, we investigated biochemical and biological consequences of PIM inhibition using novel pan-PIM inhibitor (SEL24-B489) in a panel of DLBCL cell lines in in vivo xenograft model.Methods. Protein expression and phosphorylation status of PIM substrates was assessed by immunobloting. Proliferation and apoptosis were assessed by MTS assay and PI/AnnexinV staining. Gene expression profiling was performed on Illumina HT-12 v4 Chip. NFkB target genes expression was assessed by Real-Time Quantitative PCR (qPCR). For xenograft studies, 9-11 weeks old SCID/beige CB17 mice were subcutaneously injected with 5x106 U2932 cells suspended in 0.1 ml mixture of PBS with Matrigel. When tumor volumes reached ~100 mm3, mice were randomized into uniform groups and subjected to the compound administration (50 mg/kg daily, BID, per os). Tumor volume was monitored every second day.Results. The newly developed pan-PIM inhibitor (SEL24-B489) was toxic to DLBCL cell lines in low-micromolar or sub-micromolar concentrations (IC50: 0,29 to 1,17µM). To determine mechanisms underlying toxicity of PIM inhibition in DLBCL, we first assessed the activity of 4EBP1 and ribosomal protein S6, proteins involved in protein translation. PIM inhibitor rapidly and uniformly decreased 4EBP1 and S6 phosphorylation in all tested DLBCL cell lines (DHL4, DHL6, Ly1, Ly7, Karpas 422, Pfeiffer, Toledo, U2932, HBL-1). Since PIM kinases have been shown to increase stability and/or activity of NFκB-p65 (RelA) and Myc, we assessed the abundance/activity of these transcription factors upon PIM inhibitor treatment. PIM inhibition led to downregulation of Myc protein in GCB DLBCL cell lines. Since Myc and PIMs cooperate in augmenting transcription of active genes, we assessed global RNA levels upon PIM inhibitor treatment. The RNA abundance in SEL24-B489-treated cells decreased by 22-37%. The underlying mechanism of the decrease in cellular mRNA content involved global inhibition of PIM-dependent histone H3 serine 10 (H3S10) phosphorylation and decreased phoshorylation of RNA polymerase II (serine 2).To test whether PIM inhibition also attenuates specifically NFκB-dependent transcription in DLBCL cell lines, we assessed gene expression profiles of vehicle- or SEL24-B489-treated HBL-1, U2932 and DHL4 cells. Following PIM inhibition, we observed significant downregulation of multiple validated NFκB target genes in HBL-1 and U2932 cells, but not in DHL4 cells. We further confirmed decreased transcript abundance of 4 NFκB target genes (NFKBIA, CD40, TNFAIP 3 and MIR 155) by qPCR. Since NFκB target gene expression in ABC-DLBCL is essential for their survival and can be specifically blocked with the BTK inhibitor ibrutinib, we hypothesized that simultaneous targeting of PIMs and BTK would synergistically inhibit NFkB activity and cell survival. To test this hypothesis, we incubated the ABC-DLBCL cell lines with the ibrutinib, SEL24-B489, or their combination. We identified synergistic growth inhibitory effects of the drug combination in ABC-DLBCL cell lines, with combination index (CI) of 0.51 and 0.2 for HBL-1 and U2932 cells, respectively. Finally, we investigated the efficacy of SEL24-B489 in vivo in the murine xenograft model using U2932 cells. In contrast to progressive tumor growth in animals exposed to vehicle alone, we observed marked inhibition of tumor growth (>90%) in SEL24-B489-treated mice.Conclusions. In conclusion, a novel pan-PIM inhibitor SEL24-B489 induces apoptosis of DLBCL cell lines in low/sub-micromolar concentrations and exhibits activity in a xenograft model. The mechanisms of SEL24-B489 toxicity include blocking of protein translation, induction of Myc degradation, decrease of RNA transcription and attenuation of NFκB activity. Moreover, we show marked synergy between the PIM inhibitor and ibrutinib. Hence, these results provide new insights into mechanism of action of PIM inhibitors and rationale for targeting PIM activity in DLBCLs. DisclosuresCzardybon:Selvita S.A.: Employment. Galezowski:Selvita S.A.: Employment. Windak:Selvita S.A.: Employment. Golas:Selvita S.A.: Employment. Brzozka:Selvita S.A.: Employment. Juszczynski:Selvita S.A.: Other: member of Selvita Scientific Advisory Board.

Vascular Lesions of Vocal Folds - Part 2: Perpendicular Vascular Lesions

The present work aims at a systematic pathogenetic description of perpendicular vascular changes in the vocal folds. Unlike longitudinal vascular changes, like ectasia and meander, perpendicular vascular changes can be observed in bening lesions. They predominantly occur as typical vascular loops in exophytic lesions, especially in recurrent respiratory papillomatosis (RRP), pre-cancerous and cancerous diseases of the larynx and vocal folds. Neoangiogenesis is caused by an epithelial growth stimulus in the early phase of cancerous genesis. In RRP the VVC impress by a single, long vessel loop with a narrow angle turning point in the each single papilla of the papilloma. In pre- and cancerous lesions the vascular loop is located directly underneath the epithelium. During progressive tumor growth, vascular loops develop an increasingly irregular, convoluted, spirally shape. The arrangement of the vascular loops is primarily still symmetrical. In the preliminary stage of tumor development occurs by neoangiogenesis to a microvascular compression. In advanced vocal fold carcinoma the regular vascular vocal fold structure is destroyed. The various stages of tumor growth are also characterized by typical primary epithelial and secondary connective tissue changes. The characteristic triad of vascular, epithelial and connective tissue changes therefore plays an important role in differential diagnosis.

Transdermal drug targeting and functional imaging of tumor blood vessels in the mouse auricle

Subcutaneously growing tumors are widely utilized to study tumor angiogenesis and the efficacy of antiangiogenic therapies in mice. To additionally assess functional and morphologic alterations of the vasculature in the periphery of a growing tumor, we exploited the easily accessible and hierarchically organized vasculature of the mouse auricle. By site-specific subcutaneous implantation of a defined preformed mouse B16/F0 melanoma aggregate, a solid tumor nodule developed within 14 d. Growth of the tumor nodule was accompanied by a 4-fold increase in its perfusion as well as a 2- to 4-fold elevated diameter and perfusion of peripheral blood vessels that had connected to the tumor capillary microvasculature. By transdermal application of the anticancer drug bortezomib, tumor growth was significantly diminished by about 50% without provoking side effects. Moreover, perfusion and tumor microvessel diameter as well as growth and perfusion of arterial or venous blood vessels supplying or draining the tumor microvasculature were decreased under these conditions by up to 80%. Collectively, we observed that the progressive tumor growth is accompanied by the enlargement of supplying and draining extratumoral blood vessels. This process was effectively suppressed by bortezomib, thereby restricting the perfusion capacity of both extra and intratumoral blood vessels.

A66: Changes in experimental tumors and surrounding tissue under antitumor influence of magnetite nanoparticles introduced into the peritumoral area

Background In previous experiments the self-dependent antitumor effect of magnetite nanoparticles (NPs) injected in peritumoral area in form of magnetic fluid (MF) was shown. Elucidation of the mechanisms of this phenomenon is of theoretical and practical interest. The aim of the study was to investigate the cellular and ultrastructural changes in the tissue tumors regressed under the influence of magnetite NPs, as well as the composition of the cells of the immune system in the peritumoral area. Materials and methods The study was carried on white male rats, 180–200 g, with transplanted sarcoma 45 (59) or Pliss lymphosarcoma (50). Special antitumor agents were not used. Magnetite NPs (10 ± 2 nm) were applied in the form of the water-based MF. Original MF (20 kA/m) was diluted with saline in different degree and was injected into peritumoral zone along the tumor borders at a distance of 1.5 cm twice a week in a volume of 0.4–0.9 ml (depending on the animal weight) within 3 weeks. Special anti-tumor agents were not used. At the end of the experiments fragments of the tumor and surrounding tissue were taken for research. The study of changes in the tumor and peritumoral area were performed by the methods of cytology, histology, histochemistry, electron microscopy (microscope JEOL JEM-1011, Japan), flow cytometry, X-ray fluorescence spectroscopy (spectrometer M4 Tornado Bruker). Results At a dilution of the original MF in 30 times the treatment was effective in 75% of animals. Complete and partial (more than 2-fold) tumor regression was observed in 2/3 cases. In rats with Pliss lymphosarcoma tumor regression on 70–100% has been reported in 20–40% cases. The results of microscopic examination of sarcoma 45 with partial regression showed significant changes in their immune microenvironment compared with the cases of progressive tumor growth (p Conclusion The study results reflect the changes in the immune microenvironment of experimental tumors under effective action of magnetite NPs and indicate significant activation of local immune processes caused by these factors.

IMCT-01PEMBROLIZUMAB: FIRST EXPERIENCE WITH RECURRENT PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS

Patients with progressive primary brain tumors (PBT) are attracted to promising new treatments, even prior to convincing data. Anti-PD1 immunotherapies have been in the spotlight since publication of groundbreaking results for metastatic melanoma with pembrolizumab (PBL). Our objective was to report on the response and toxicity of PBL in patients with advanced PBT. We retrospectively reviewed the charts of 22 patients (17 adults and 5 children) with recurrent central nervous system tumors treated with PBL. We analyzed prior antineoplastic therapies, steroid usage, and outcomes. Patients received a median of two neoplastic therapies prior to PBL, and a median of three infusions of PBL in adults and four in children. Twelve patients (9 adults and 3 children) started PBL on steroids (median dose in adults 4 mg; range 2–8, and in children 1.5 mg, range 0.5–4) and five patients received steroids later during PBL treatment. Twelve patients (10 adults and 2 children) received concomitant bevacizumab with PBL. Side effects were minimal. All patients showed progressive tumor growth during therapy. Median OS from the start of PBL was 2.6 months in adults and 3.2 months in children. Two GB patients underwent tumor resection following treatment with PBL. Tumor-lymphocytic response in these cases was unremarkable, and PD-L1 immuno-staining was negative. In this series of 22 patients with recurrent primary brain tumors, PBL showed no clinical or histologic efficacy. We do not recommend further use of PBL for recurrent PBT unless convincing prospective clinical trial data are published.

ATPS-89LOCAL DELIVERY OF A SMALL-MOLECULE INHIBITOR OF HYPOXIA INDUCIBLE FACTOR-1: A NEW CANDIDATE DRUG FOR BRAIN TUMOR THERAPY

This work investigated the efficacy of intracranial delivery of acriflavine (ACF), a small-molecule hypoxia-inducible factor 1α (HIF-1α) therapeutic inhibitor, for the treatment of primary brain malignancies. ACF, a mixture of two closely related acridine molecules, has only recently been recognized as a potent hypoxia-inducible factor 1α (HIF-1α) inhibitor, but has already demonstrated highly effective anti-tumor activity against a wide spectrum of cancers. Thus far, no study has reported its efficacy in either glioma cell lines or brain tumor models. In our in vitro study on rodent and human glioma cell lines, we showed that ACF suppressed cell viability and increased cell death in a dose-dependent manner. Our in vivo study examined the safety and efficacy of locally delivered ACF in monotherapy. To overcome ACF's poor systemic bioavailability and limited BBB penetration, we delivered ACF directly to the site of the tumor via biodegradable polymer wafers. Throughout three separate experiments, enrolling a total of 60 F334 Fisher rats, we showed that animals receiving local implantation of ACF wafers achieved an extraordinary 100% survival rate of up to 300 days (p <0.0001 vs. controls and 0.0002 vs. a Temozolomide-treated positive control), whereas the systemic administration of ACF provided no survival benefit compared to the control. Neuropathological examination at 120 days, as well as neuroimaging follow-up using MRI, confirmed tumor growth arrest in animals treated with ACF wafers, as opposed to progressive tumor growth in both untreated animals and animals treated with empty wafers. This is the first study to describe the extraordinary potential of ACF for the treatment of brain tumors as well as the effectiveness of interstitial local therapy via biodegradable polymer wafers for the use of ACF for brain tumor therapy.

Abstract 1143: EGF induces epithelial to mesenchymal transition and cancer stem-like cell properties in human head and neck cancer cells via promoting Warburg Effect

Abstract Head and neck cancer is one of the 10 most common cancers worldwide. Over-expression of EGFR has been demonstrated in approximately 90% of head and neck cancers, which is associated with progressive tumor growth, metastasis, recurrence, and resistance to chemo- and radiation therapies. Recurrent tumors are often therapy-resistant and may have their origin in resistant cancer stem cells (CSCs) and/or in tumor cells with an epithelial-mesenchymal transition (EMT) phenotype. Recently it is increasingly accepted that metabolic changes in cancer cells can drive tumor formation and progression. In our study, we used 20ng/ml EGF to treat human tongue cancer cell line, SCC-1 cells. Our results demonstrated that EGF induces EMT in oral SCC cells as characterized by a downregulation of E-cadherin (an epithelial marker), an upregulation of vimentin (a mesenchymal marker), increased invasive and metastatic capacities, and acquisition of stem-like properties such as the increased expression of ALDH1 and enrichment of CD44+/CD24− proportion of cancer cells. We also found that EGF treatment concomitantly enhanced L-lactate production and blocking glycolysis by 2-DG robustly reversed EGF-induced EMT and CSC-like phenotypes of OSCC cells. Then we further demonstrated that EGF regulates glycolysis/EMT/CSCs axis through downstream EGFR/PI3K signaling pathways in an EGFR/PI3K-dependent but AKT-independent manner. Importantly, we showed that in vivo treatment with 2-DG remarkably reduced the expression of ALDH1 and vimentin at both the in situ tumors and regional lymph nodes. Taken together, these findings have demonstrated that EGF drives tumor growth and metastasis through induction of EMT and CSC generation, which is orchestrated by an enhanced glycolytic metabolic program in OSCC cells. This work was supported by National Institute of Health Research Grant, R01DE 019932, Oral and Maxillofacial Surgery Foundation (OMSF) Research Grant, and the Schoenleber funding support Citation Format: Qilin Xu, Qunzhou Zhang, Ahn D. Le. EGF induces epithelial to mesenchymal transition and cancer stem-like cell properties in human head and neck cancer cells via promoting Warburg Effect. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1143. doi:10.1158/1538-7445.AM2015-1143

Cancer stem cells in glioblastoma.

Tissues with defined cellular hierarchies in development and homeostasis give rise to tumors with cellular hierarchies, suggesting that tumors recapitulate specific tissues and mimic their origins. Glioblastoma (GBM) is the most prevalent and malignant primary brain tumor and contains self-renewing, tumorigenic cancer stem cells (CSCs) that contribute to tumor initiation and therapeutic resistance. As normal stem and progenitor cells participate in tissue development and repair, these developmental programs re-emerge in CSCs to support the development and progressive growth of tumors. Elucidation of the molecular mechanisms that govern CSCs has informed the development of novel targeted therapeutics for GBM and other brain cancers. CSCs are not self-autonomous units; rather, they function within an ecological system, both actively remodeling the microenvironment and receiving critical maintenance cues from their niches. To fulfill the future goal of developing novel therapies to collapse CSC dynamics, drawing parallels to other normal and pathological states that are highly interactive with their microenvironments and that use developmental signaling pathways will be beneficial.

Tumor fibrohistiocítico plexiforme con metástasis ganglionar: reporte de un caso

Plexiform fibrohistiocytic tumour (TFHP) is a rare mesenchymal neoplasm of intermediate malignancy but with a high rate of local recurrence and potential for lymph node or pulmonary metastases. It usually affects superficial soft tissues of the upper extremities of children and young adults and is more frequent in females.We report a case of a 10 year old boy with progressive tumour growth, under the skin in the right knee with ipsilateral inguinal lymphadenopathy. He underwent wide resection of the lesion with inguinal lymphadenectomy. Histopathology revealed a plexiform pattern with a biphasic component (mononuclear histiocytic cells associated with CD68 positive osteoclast-like giant cells and smooth muscle actin-positive spindle cells); favoring the diagnosis of TFHP with lymph node metastasis.

Risk factors associated with secondary enucleation after fractionated stereotactic radiotherapy in uveal melanoma.

To evaluate risk factors for secondary enucleation after fractionated stereotactic radiotherapy (fSRT) in uveal melanoma. In this retrospective study, clinical data of 118 consecutive patients who had initially been treated with fSRT between 1999 and 2009 were collected and analysed. The patients who had undergone secondary enucleation were identified and examined for clinical, histopathological and cytogenetical (fluorescence in situ hybridization determined) data. Also, the reasons for secondary enucleation, such as treatment failure (progressive tumour growth or tumour recurrence) or complications following fSRT (painful blind eye), were recorded and examined. The secondary enucleation rate was 16% after a median follow-up of 4.7 years, with 5% due to treatment failure and 11% due to complications. In the univariate analysis, large tumour diameter (p = 0.019) and large tumour height (p = 0.001) were associated with secondary enucleation, tumour involvement of the optic disc showed borderline significance (p = 0.068). Cox regression multivariate analysis displayed large tumour height as independent prognostic factor (HR 1.42, 95% CI 1.12-1.81, p = 0.004). Following secondary enucleation, mitotic figures were present in five of 18 tumours, and gain of chromosome 8q was also present in five tumours. Within the subgroup of patients who required secondary enucleation due to failed tumour control by fSRT (N = 6), mitotic figures were present in four of six tumours while gain of 8q was present in three of six tumours. Secondary enucleation after previous fSRT was associated with large tumour height. High mitotic counts and gain of chromosome 8q were frequently found in secondary enucleations and possibly indicate a more aggressive or radiation-resistant tumour.

P21 Immunohistochemical analysis of clinical and pathological relevance of LOXL4- and survivin expressions in oropharyngeal carcinomas

Introduction Gene expression analyses have shown the overexpression of both lysyloxidase isotype 4 (LOXL4) and survivin in oropharyngeal carcinomas in comparison to normal epithelial phenotype. The purpose of this study was to analyse comparatively LOXL4 and survivin expressions in oropharyngeal carcinomas with respect to their diagnostic, prognostic, and if appropriate therapeutic value. Material and methods 138 LOXL4- and survivin positive oropharyngeal carcinoma biopsies were confirmed by histopathological examination and analysed in relation to TNM staging, grading, and overall survival. The antibody reactivity was scored on a semi quantitative scale (negative expression, weak positive, moderately positive, and strong positive). Results Of the samples involved in the analysis 129 (93.5%) and 115 (83.3%) were LOXL4 and survivin positive respectively. Although the LOXL4 staining scores correlated with TNM staging (p = 0.018), no correlations were found between LOXL4 expression and survival as well as metastatic rates. In contrast, surviving expression significantly correlated with both tumor grading (p = 0.001) and nodal status (p Conclusion In primary tumors the elevated survivin expression correlated both with progressive tumor growth and local lymph nodes. Therefore, its expression seems to be more suitable for the evaluation of tumor staging than the expression of LOXL4 which makes it more suitable as a diagnostic marker for oropharyngeal carcinomas.

Mucinous adenocarcinoma of the prostate: A case report

Mucinous aenocarcinoma is one of the least common variant of prostate cancer. The prognosis of this variant of prostate cancer remains controversial. We report the case of 67-year old men with severe lower urinary tract symptoms (LUTS), bladder outlet obstruction (BOO), and sense of urinary retention. The serum level of prostate specific antigen (PSA) was 10.4ng/mL. Prostate was large (56mL), hard, lobulated, with extraprostatic extension and infiltration of surrounding structures, unsuitable for radical operative treatment. The patient demonstrated poor response to complete androgen blockade (CAB) (bilateral orchiectomy, steroidal antiandrogen) after 6 months of treatment with minimal decline of PSA (7.1ng/mL) and progressive growth of the primary tumor (110mL). The patient is submitted to antiandrogen withdrawal consisted of simultaneous addition of ketoconazole with hydrocortison substitution, resulting in normalisation of PSA (<1.0ng/mL) and diminution of prostate volume (PV) (63 mL) after 2 months, followed by adjunctive radiotherapy. Ketoconazole in reduced doses was stopped 6 months after completion of radiotherapy with PSA level < 0.002ng/mL and PV 16mL. The patient is alive with no evidence of disease more than 9 years after diagnosis of primary tumor. This case demonstrated modest hormonal sensitivity of mucinous adenocarcinoma of the prostate, whereas ketoconazole combined with radiotherapy, resulted in long term survival.

Standardized orthotopic xenografts in zebrafish reveal glioma cell-line-specific characteristics and tumor cell heterogeneity.

ABSTRACTGlioblastoma (GBM) is a deadly brain cancer, for which few effective drug treatments are available. Several studies have used zebrafish models to study GBM, but a standardized approach to modeling GBM in zebrafish was lacking to date, preventing comparison of data across studies. Here, we describe a new, standardized orthotopic xenotransplant model of GBM in zebrafish. Dose-response survival assays were used to define the optimal number of cells for tumor formation. Techniques to measure tumor burden and cell spread within the brain over real time were optimized using mouse neural stem cells as control transplants. Applying this standardized approach, we transplanted two patient-derived GBM cell lines, serum-grown adherent cells and neurospheres, into the midbrain region of embryonic zebrafish and analyzed transplanted larvae over time. Progressive brain tumor growth and premature larval death were observed using both cell lines; however, fewer transplanted neurosphere cells were needed for tumor growth and lethality. Tumors were heterogeneous, containing both cells expressing stem cell markers and cells expressing markers of differentiation. A small proportion of transplanted neurosphere cells expressed glial fibrillary acidic protein (GFAP) or vimentin, markers of more differentiated cells, but this number increased significantly during tumor growth, indicating that these cells undergo differentiation in vivo. By contrast, most serum-grown adherent cells expressed GFAP and vimentin at the earliest times examined post-transplant. Both cell types produced brain tumors that contained Sox2+ cells, indicative of tumor stem cells. Transplanted larvae were treated with currently used GBM therapeutics, temozolomide or bortezomib, and this resulted in a reduction in tumor volume in vivo and an increase in survival. The standardized model reported here facilitates robust and reproducible analysis of glioblastoma tumor cells in real time and provides a platform for drug screening.

Abstract 2551: B cells induced during CD4+ T-cell mediated destruction of primary tumors in neuN mice produce mAbs that are capable of inhibiting spontaneous tumor growth

Abstract We previously identified an induced serologic response in FVB-neuN mice bearing primary breast tumors following adoptive therapy with CD4+ T cells. Because the CD4+ T cells were initially primed with breast tumor progenitor cells, we tested whether the B cells induced in treated mice also recognized antigens expressed specifically by breast tumor progenitor cells. We generated hybridomas and then screened supernatant for binding to target cells by FACS analysis. We isolated three clones that produced IgG (mAb1-2, mAb2, and mAb3) which recognized cell surface molecules on tumorsphere cultures from a NeuN breast tumor line but not the parental adherent culture from which they were derived. We used a Her-2/neu antigen loss variant to show that Her-2/neu was not itself the antigen. Interestingly, the three mAbs also recognized 4T1tumorspheres, an independently derived breast tumor from another mouse strain, but not adherent 4T1 cultures. Moreover, the mAbs were not reactive with normal spleen, liver, or kidney cells. To investigate whether any of these mAbs had anti-tumor function we used Her-2/neuN transgenic mice which develop mammary adenocarcinoma starting at 5 months of age. We selected mice with a single spontaneous tumor in situ when tumors became palpable and visible. The mice received mAb1-2, mAb2, mAb3 (150 μg/dose) or PBS on day 0, day 1 then every other day until day 23. There was no toxicity from the treatment and mice treated with PBS or mAb3 all showed progressive tumor growth. However, administration of mAb1-2 inhibited primary tumor progression in 5/8 mice and mAb2 inhibited tumor progression in 9/13 mice (p&amp;lt;0.05). Some mice with response to mAb had ongoing attenuation of tumor growth even after completion of mAb treatments. These data suggest that mice responding to CD4 T cell immunotherapy were able to stimulate endogenous B cells with reactivity against auto-antigens expressed by tumor progenitor cells. Our approach restricted our screen to cell surface antigens because we used FACS to identify hybridoma supernatant which specifically bound to tumor progenitor cells. This allowed us to focus on mAb that might have some direct therapeutic effect and two of the antibodies did inhibit tumor growth. At this point we do not know whether mAb1-2 or mAb2 inhibit tumor growth through blockade of signaling or through cytotoxic mechanisms but the antigen seems to be expressed by the majority of spontaneous breast tumors arising in FVB-neuN mice. Our current studies are attempting to identify the antigen recognized by each mAb. Citation Format: Li-Xin Wang, Mona Patel, Michael Berk, Gregory Plautz. B cells induced during CD4+ T-cell mediated destruction of primary tumors in neuN mice produce mAbs that are capable of inhibiting spontaneous tumor growth. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2551. doi:10.1158/1538-7445.AM2014-2551

Multimodal treatment of patients with advanced cervical cancer

Local progressive tumor growth involving the urinary tract with no distant metastases is known to be one of the features of cervical cancer in the advanced stages. Approximately 68 % of patients in stage T3-T4 have various uroevolution disorders. The severity of their condition often is caused by an increasing renal failure or a fever, those are associated with obstructive pyelonephritis and often are interpreted as the carcinogenic intoxication. Therefore, any special antineoplastic therapy methods are considered as unpromising even for patients without concomitant diseases. The authors conducted a retrospective analysis of 11 patients with the treatment of advanced non-metastatic cervical cancer, which included both surgery and neoadjuvant polychemotherapy (PCT). Our results demonstrate the advisability of multimodal phasing treatment of those patients, compared with palliative radiotherapy and symptomatic treatment.

Desmoid tumour around the DIEP anastomosis - a rare complication after breast reconstruction

Abdominal desmoid tumors are so called non-metastatic tumors. They occur by proliferation of fibroblasts of muscle, fascia or aponeuroses. After breast reconstruction with a DIEP flap (Deep Inferior epigastric Artery Perforator Flap), a progressive growth of a desmoid tumor was seen around the DIEP-anastomosis. A total excision was not possible without compromising the vascular pedicle. With taking into account a recurrence rate up to 65% another operation is probably necessary. In this case the main vessels of the graft have to be cut out and a necrosis of the flap can or may appear.