Visceral Tumors Research Articles

Abstract 1233: WNT inhibitor ICG-001 prevents visceral metastatic triple negative breast cancer in a chemo-resistant patient derived xenograft -PDX-model

Abstract Triple negative breast cancer (TNBC) is characterized by absence of the estrogen receptor (ER) and progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) amplification. Such cancers are highly aggressive and frequently metastasize to the lung and brain. Unlike other breast cancer subtypes such as, ER+, PR+ and/or HER2+, TNBCs have no specific targeted-therapeutics; therefore, studies should be directed for development of targeted therapies to treat this condition. Recent studies indicate that Wnt/β-catenin signaling is particularly activated in TNBC and is associated with reduced overall survival in all patients. Therefore, pharmacological targeting of Wnt signaling pathway constitutes an ideal approach for treating TNBC and various Wnt inhibitors are currently in use in clinical trials, such as; ICG-001 in metastatic colon cancer. The inhibitory effects of ICG-001 have not been tested in chemoresistant TNBC PDX tumors. Herein, we report for the first time that ICG-001 compound selectively inhibited the growth of several European American (EA) and African American (AA) triple negative breast cancer subtypes MSL and BSL-1 cell lines both in vitro and in vivo models. To further investigate the precise mechanisms of action in the regulation of Wnt/β-catenin signaling by ICG-001, we performed Western blot analysis, apoptosis assays, cell cycle assays and quantitative real-time reverse transcriptase- polymerase chain reactions in human triple negative breast cancer cells. This compound significantly interfered with Wnt/β-catenin signaling, and its inhibition led to downregulation of important downstream targets such as Axin2, HMGA2, PCNA, c-myc and Cyclin D1, which in turn led to inhibition of proliferation, cell cycle progression and metastasis confirming our previous results too. In addition ICG-001 inhibited the invasion and motility of tumor cells and showed inhibition and prevention of visceral metastatic PDX tumors from both chemoresistant EA and AA women. These results indicate that the Wnt inhibitor ICG-001 could constitute a powerful new chemotherapeutic agent against triple negative breast cancer. Citation Format: Iram Fatima, Ikbale El Ayachi, Chidi Zacheaus, Joseph Kerby Gray, Raya Krutilina, Tiffany N. Seagroves, Susan A. Krum, Gustavo A. Miranda-Carboni. WNT inhibitor ICG-001 prevents visceral metastatic triple negative breast cancer in a chemo-resistant patient derived xenograft -PDX-model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1233. doi:10.1158/1538-7445.AM2017-1233

Abstract 67: Characterization and preclinical development of STRO-001, a novel CD74-targeting antibody-drug conjugate (ADC) for the treatment of B-cell malignancies

Abstract CD74 is a type II transmembrane glycoprotein involved in the formation and transport of MHC class II protein. CD74 is highly expressed in many B-cell malignancies with limited expression in normal tissues (Stein R. et al., CCR 2007). STRO-001 is a novel CD74-targeting ADC containing an anti-CD74 aglycosylated human IgG1 antibody (SP7219) conjugated to a non-cleavable dibenzocyclooctyne (DBCO)-maytansinoid linker-warhead. SP7219 was discovered from a Fab ribosome display library based on Sutro’s Xpress CFTM technology. Highly efficient site-specific conjugation enabled by our cell-free antibody production and click chemistry results in a well-defined homogeneous ADC drug product with a drug-antibody ratio (DAR) of 2. Conjugation sites were selected based on highest stability both in vitro and in vivo, thereby limiting loss of drug moiety from STRO-001 in circulation. Due to its limited cell permeability, the major catabolite released by STRO-001 has 1000X lower cell killing activity on CD74 positive and negative cells compared to the reference cytotoxic maytansine. In vitro cytotoxicity assays show potent activity of STRO-001 in a diverse panel of B-cell tumor lines including 4 multiple myeloma (MM), 9 germinal center B-cell (GCB) diffuse large B-cell lymphoma (DLBCL), 3 activated B-cell (ABC) DLBCL, and 3 mantle cell lymphoma (MCL) cell lines with IC50 ranging from 0.17-20 nM. CD74 cell surface expression is required for STRO-001 cytotoxic activity but expression level, as measured by antibody-binding capacity, does not correlate with in vitro potency (R2=0.4640). STRO-001 inhibits the formation of visceral tumors (p<0.004) and prevents growth of CD138+ plasma cells in bone marrow (BM) after 4 weekly doses of 3 mg/kg in the ARP-1 disseminated MM xenograft model. STRO-001 dosed at 3 mg/kg weekly x 3 also eradicates malignant BM plasma cells (p<0.0001) and prolongs survival in the MM.1S disseminated model (100% animals alive at >90 days). STRO-001 exhibits dose-dependent tumor growth inhibition in SU-DHL-6 xenografts starting at 2.5 mg/kg weekly x 3 doses. The combination of bendamustine/rituximab (BR) + STRO-001 further improves tumor suppression in SU-DHL-6 xenografts compared to vehicle (p = 0.002) or BR alone (p = 0.02). Preliminary studies with a MCL xenograft model, Jeko-1, demonstrate potent anti-tumor activity compared to vehicle (p<0.0001) starting at a single STRO-001 dose of 3 mg/kg, with ongoing tumor stasis up to 21 days after treatment. STRO-001 reduces normal B-cells in cynomologous monkeys, providing pharmacodynamic evidence of B-cell targeting. Based on these encouraging observations, STRO-001 is advancing to IND-enabling studies for the treatment of CD74-expressing B-cell malignancies. Citation Format: Cristina Abrahams, Xiaofan Li, Venita DeAlmeida, Millicent Embry, Abigail Yu, Stellanie Krim, Heidi Hoffmann, James Zawada, Maureen Bruhns, Shannon Matheny, Stuart Bussell, Toni Kline, Alice Yam, Ryan Stafford, Trevor Hallam, Mark Lupher, Arturo Molina. Characterization and preclinical development of STRO-001, a novel CD74-targeting antibody-drug conjugate (ADC) for the treatment of B-cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 67. doi:10.1158/1538-7445.AM2017-67

Characteristics of disease activity able to identify risk categories and probability to respond to first-line endocrine therapy (ET) in HR+ve/HER2-ve metastatic breast cancer (MBC) patients (pts): Dream or reality? Evaluation of a composite risk score in a subgroup population of the GIM 13-AMBRA study.

1049 Background: The appropriate choice of 1st-line therapy in HR+ve/HER2-ve MBC pts is becoming more complicated since the data of front-line Fulvestrant and CDK 4/6 Inhibitors have been released. In the absence of predictive biomarkers of tumor response, one possible option is the recently proposed “composite score” (Schmid, ESMO 2016), composed by visceral tumor burden (VTB) and Disease-Free-Interval (DFI) to identify risk categories and the probability of response to ET or chemotherapy (CHT). Aim of the present analysis is to describe the choices of 1st-line treatment and the response rate, according to the mentioned score in a population of HR+/HER2-ve MBC. Methods: We used data of the HR+ve pts of the AMBRA study, a longitudinal cohort study, describing the choice of first and subsequent lines of treatment in HER2-ve MBC pts (SABCS 2016 P5-15-07 & P5-14-09). Using median DFI and VTB three categories of risk have been identified: Low (DFI > 24 months & VTB-), Intermediate (DFI £ 24 months & VTB- or DFI > 24 months & VTB+) and High (DFI £ 24 months & VTB+). This analysis describes the choices of 1st-line therapy and relative response rate according to these risk categories. Results: So far, 791/1500 pts have been registered into the AMBRA study, 673 of them (85%) with HR+ MBC and 659 (83.3%) are evaluable for this analysis. Risk categories and response to therapy are detailed in the table below. Conclusions: No conclusion can be done regarding the “High Risk” group because of the low number of pts treated with ET alone. Regarding the “Low” and “Intermediate” risk categories, we can conclude that the proposed “composite risk score” doesn’t seem to discriminate MBC patients who could be treated with ET alone or with a more aggressive treatment, at least in terms of response rate. [Table: see text]

Phylogenetic Variation of Chelonid Alphaherpesvirus 5 (ChHV5) in Populations of Green Turtles Chelonia mydas along the Queensland Coast, Australia.

Sea turtle fibropapillomatosis (FP) is a disease marked by the proliferation of benign but debilitating cutaneous and occasional visceral tumors, likely to be caused by chelonid alphaherpesvirus 5 (ChHV5). This study presents a phylogeny of ChHV5 strains found on the east coast of Queensland, Australia, and a validation for previously unused primers. Two different primer sets (gB-1534 and gB-813) were designed to target a region including part of the UL27 glycoprotein B (gB) gene and part of UL28 of ChHV5. Sequences obtained from FP tumors found on juvenile green turtles Chelonia mydas (<65 cm curved carapace length) had substantial homology with published ChHV5 sequences, while a skin biopsy from a turtle without FP failed to react in the PCRs used in this study. The resulting sequences were used to generate a neighbor-joining tree from which three clusters of ChHV5 from Australian waters were identified: north Australian, north Queensland, and Queensland clusters. The clusters reflect the collection sites on the east coast of Queensland with a definitive north-south trend. Received October 22, 2016; accepted May 7, 2017.

Examining the Role of Transmission of Chelonid Alphaherpesvirus 5.

Marine turtle fibropapillomatosis (FP) is a devastating neoplastic disease characterized by single or multiple cutaneous and visceral fibrovascular tumors. Chelonid alphaherpesvirus 5 (ChHV5) has been identified as the most likely etiologic agent. From 2010 to 2013, the presence of ChHV5 DNA was determined in apparently normal skin, tumors and swab samples (ocular, nasal and cloacal) collected from 114 olive ridley (Lepidochelys olivacea) and 101 green (Chelonia mydas) turtles, with and without FP tumors, on the Pacific coasts of Costa Rica and Nicaragua. For nesting olive ridley turtles from Costa Rica without FP, 13.5% were found to be positive for ChHV5 DNA in at least one sample, while in Nicaragua, all olive ridley turtles had FP tumors, and 77.5% tested positive for ChHV5 DNA. For green turtles without FP, 19.8% were found to be positive for ChHV5 DNA in at least one of the samples. In turtles without FP tumors, ChHV5 DNA was detected more readily in skin biopsies than swabs. Juvenile green turtles caught at the foraging site had a higher prevalence of ChHV5 DNA than adults. The presence of ChHV5 DNA in swabs suggests a possible route of viral transmission through viral secretion and excretion via corporal fluids.

Postoperative CYFRA 21-1 and CEA as prognostic factors in patients with stage I pulmonary adenocarcinoma.

BackgroundPatients with pathological stage I pulmonary adenocarcinoma have different postoperative prognosis. The aim of this study is to evaluate the prognostic significance of preoperative and postoperative serum levels of carcinoembryonic antigen (CEA) and CYFRA 21-1 in patients with pathological stage I pulmonary adenocarcinoma.Material and MethodsWe retrospectively reviewed the data of 123 patients who had undergone a complete resection for pathological stage I pulmonary adenocarcinoma between 2004 and 2014. The clinical data of each patient including age, gender, preoperative and postoperative serum CEA and CYFRA 21-1 levels, and pathologic stage, was collected for analysis.ResultsThe CYFRA 21-1 and CEA level was persistently normal in 80.5% and 77.2% of all patients with p-stage I ADC, respectively. The preoperative level was elevated and postoperative level declined to normal for CYFRA 21-1 and CEA were in 10.6% and 13.0% of all patients, respectively. The postoperative CYFRA 21-1 and CEA level were high in 8.9% and 9.8% of all patients, respectively. The postoperative 5-year survival rate of patients with normal, only preoperative high, and postoperative high CYFRA 21-1 level was 92.6%, 92.3% and 43.8%, respectively. There was a significant difference between postoperative high group and the other two groups (p = 0.002). The postoperative 5-year survival rate of patients with normal, only preoperative high, and postoperative high CEA level was 90.8%, 92.3%, and 70.1%, respectively. There was a significant difference between postoperative high group and the other two groups (p = 0.019). In univariate analysis, degree of differentiation, visceral pleural invasion, tumor size, and pTNM stage, was found to be significant independent prognostic factor (p = 0.014). Multivariate analysis showed that pTNM stage, postoperative CYFRA 21-1 high level, and postoperative CEA high level was related to the poor prognosis.ConclusionsPatients of p-stage I ADC with postoperative high serum level of either CEA or CYFRA 21-1 had poor prognosis. Carefully followed-up might be necessary to rule out occult metastasis for these patients, and further clinical studies will be necessary to evaluate the efficacy of adjuvant chemotherapy or target therapy. Postoperative high serum level of CEA or CYFRA 21-1 might be a subtype of p-stage I ADC.

Rab23's genetic structure, function and related diseases: a review.

Rab23 has been proven to play a role in membrane trafficking and protein transport in eukaryotic cells. Rab23 is also a negative regulator of the Sonic hedgehog (Shh) signaling pathway in an indirect way. The nonsense mutation and loss of protein of Rab23 has been associated with neural tube defect in mice and aberrant expression in various diseases in human such as neural system, breast, visceral, and cutaneous tumor. In addition, Rab23 may play joint roles in autophagosome formation during anti-infection process against Group A streptococcus. In this review, we give a brief review on the functions of Rab23, summarize the involvement of Rab23 in genetic research, membrane trafficking, and potential autophagy pathway, especially focus on tumor promotion, disease pathogenesis, and discuss the possible underlying mechanisms that are regulated by Rab23.

Syndrome de Muir-Torre et syndrome de Turcot

Lynch syndrome (LS) is a syndrome that carries a genetic predisposition to certain cancers associating, either in a single individual or in a family, a visceral tumour, mainly colorectal, with a high risk of other synchronous or metachronous cancers. LS is linked with mutations in the genes coding for proteins in the DNA repair system. Phenotypic variants of SL exist, including Muir-Torre syndrome (MTS) and Turcot syndrome (TS), both of which predispose to colorectal cancer. They may be distinguished by the presence of benign or malignant sebaceous tumours in MTS, and tumours of the central nervous system in TS. A 59-year-old man, with a history of right colon cancer at the age of 36 years, consulted for a nose lesion shown by histopathological examination to be a sebaceous tumour. Immunohistochemistry revealed loss of expression of proteins MSH2 and MSH6, strongly suggesting a diagnosis of MTS. Eight years earlier, the man's son had developed a fatal glioblastoma; given the paternal phenotype of MTS, the hypothesis of TS in the son is probable. This case suggests that several variants of Lynch syndrome may be seen within the same family. It raises the issue of screening for cerebral tumours in patients with MTS and in their family members, even though such a recommendation does not exist; current recommendations in fact consist primarily of gastrointestinal and gynaecological monitoring.

Dietary soy protein improves adipose tissue dysfunction by modulating parameters related with oxidative stress in dyslipidemic insulin-resistant rats.

The present study investigates the benefits of the dietary intake of soy protein on adipose tissue dysfunction in a rat model that mimics several aspects of the human metabolic syndrome. Wistar rats were fed a sucrose-rich diet (SRD) for 4 months. After that, half of the animals continued with SRD until month 8 while in the other half, casein protein was replaced by isolated soy protein for 4 months (SRD-S). A reference group consumed a control diet all the time. In adipose tissue we determined: i) the activities of antioxidant enzymes, gene expression of Mn-superoxide dismutase (SOD) and glutathione peroxidase (GPx), and glutathione redox state ii) the activity of xanthine oxidase (XO), ROS levels and the gene expression of NAD(P)H oxidase iii) the expression of the nuclear factor erythroid-2 related factor-2 (Nrf2). Besides, adiposity visceral index, insulin sensitivity, and tumor necrosis factor-α (TNF-α) in plasma were determined. Compared with the SRD-fed rats, the animals fed a SRD-S showed: activity normalization of SOD and glutathione reductase, improvement of mRNA SOD and normalization of mRNA GPx without changes in the expression of the Nrf2, and improvement of glutathione redox state. These results were accompanied by a normalization of XO activity and improvement of both the ROS production as well as TNF-α levels in plasma. Besides, adipocyte size distribution, adiposity visceral index and insulin sensitivity improved. The results suggest that soy protein can be a complementary nutrient for treating some signs of the metabolic syndrome.

Diagnostic value of additional 68Ga-PSMA-PET before 223Ra-dichloride therapy in patients with metastatic prostate carcinoma.

Medical imaging plays an important role in selecting patients with metastatic castration-resistant prostate cancer for 223Ra-dichloride therapy of bone metastases. The purpose of this study was to investigate whether 68Ga-PSMA-PET has incremental value over conventional imaging for selecting patients suitable for 223Ra-dichloride therapy. In 27 consecutive patients referred for 223Ra-dichloride therapy additional 68Ga-PSMA-PET/CT was performed and tracer distribution was evaluated systematically with respect to the detection of visceral metastases and bone metastases with inadequate uptake on bone scintigraphy. In 4 patients (15 %) 68Ga-PSMA-PET revealed previously unknown visceral metastases (3 liver, 1 adrenal gland), which changed the therapeutic decision in 2 cases. PET revealed more extended tumour involvement in the bone compared to bone scintigraphy in 9 patients (33 %). In 3 of these, the mismatch was extensive enough to question suitability for 223Ra-dichloride therapy. Additional 68Ga-PSMA-PET as a gatekeeper between conventional staging and 223Ra-dichloride therapy can provide valuable additional information with regard to visceral metastases and tumour manifestations without adequate bone mineral turnover. It may lead to a change in therapeutic management in a significant number of patients and should therefore be considered in future clinical trials.

Discovery and Preclinical Development of Novel CD74-Targeting Antibody-Drug Conjugates (ADCs) with Significant Activity in Multiple Myeloma (MM) Cell Lines and Xenograft Models

CD74, also known as HLA-DR-associated invariant chain, is a type II transmembrane glycoprotein highly expressed in many B-cell malignancies. The limited expression of CD74 in normal tissues suggests it may be a suitable ADC target for these tumor types. Accordingly, we engineered an anti-CD74 human IgG1 antibody (SP7219) using novel Fab-based ribosome display methods. The selected Fabs were readily reformatted and directly screened as IgGs using Sutro’s unique high-throughput, cell-free protein synthesis platform, Xpress CFTM. We then developed novel, potent ADCs, SP7676 and SP7675 (STRO-001), comprised of our lead antibody (SP7219) conjugated to non-cleavable DBCO-maytansinoid linker-warheads with an average drug-antibody ratios (DAR) of 2. We used site-specific conjugation technology which results in a high degree of homogeneity characterized by the drug linker covalently binding to a single defined site. The sites for conjugation were selected based on highest cell killing activity and stablity in vitro and in vivo. Both ADCs demonstrate potent cell killing activity across multiple B-cell tumor lines in vitro, and anti-tumor activity in preclinical multiple myeloma xenograft models. In vitro cytotoxicity assays show nanomolar potency of STRO-001 in four MM cell lines: Mc/CAR (IC50 0.8 nM), MM.1S (IC50 10-11 nM), U266B1 (IC50 8.5 -9.3 nM), and ARP-1 (IC50 4.3-22 nM). CD74 cell surface expression is required for ADC anti-proliferative effect but the expression level does not seem to correlate with in vitro potency. SP7676 elicited a robust anti-tumor response in the ANBL-6 multiple myeloma xenograft model. Durable regressions were observed in all mice at ≥ 3 mg/kg, with equivalent efficacy (regression) at 3 mg/kg (every 3 days x5) and 10 mg/kg (every 3 days x5 or weekly x3). SP7676 also elicited a clear survival benefit in a disseminated multiple myeloma CAG xenograft model starting at 1mg/kg every 3 days x 5 doses. Similarly, both SP7676 and STRO-001 inhibited the formation of internal visceral tumors in the ARP-1 xenograft model after 3 weekly doses of 3 mg/kg. Evaluation of our lead candidate, STRO-001 in additional MM cell lines and primary patient samples is planned. The tolerability of STRO-001 in non-human primates is under evaluation. STRO-001 was administered to cynomolgous monkeys in an exploratory dose-escalating study up to 30 mg/kg x 2 doses on Day 1 and 15. STRO-001 reduces normal B-cell populations at ≥1 mg/kg after a single dose, providing pharmacodynamic evidence of B-cell targeting while other hematopoietic lineages are mostly affected only at the highest dose studied. Anticipated hematologic toxicities were readily reversible at 1, 3 and 10 mg/kg and target organs of interest were identified. Based on these encouraging data, STRO-001 is advancing to IND-enabling studies for the treatment of CD74 expressing multiple myeloma and other B-cell malignancies. DisclosuresAbrahams:Sutro Biopharma: Employment. Li:Sutro Biopharma: Employment. Yu:Sutro Biopharma: Employment. Krimm:Sutro Biopharma: Employment. Kahana:Celgene: Employment. Narla:Celgene: Employment. Schwartz:Celgene: Employment. Boylan:Celgene: Employment. Hoffmann:Sutro Biopharma: Employment. Steiner:Sutro Biopharma: Employment. Zawada:Sutro Biopharma: Employment. Stephenson:Sutro Biopharma: Employment. Bruhns:Sutro Biopharma: Employment. DeAlmeida:Sutro Biopharma: Employment. Matheny:Sutro Biopharma: Employment. Bussell:Sutro Biopharma: Employment. Galan:Sutro Biopharma: Employment. Kline:Sutro Biopharma: Employment. Vasquez:Sutro Biopharma: Employment. Yam:Sutro Biopharma: Employment. Stafford:Sutro Biopharma: Employment. Heinsohn:Sutro Biopharma: Employment. Sato:Sutro Biopharma: Employment. Molina:Sutro Biopharma: Employment. Hallam:Sutro Biopharma: Employment. Lupher:Sutro Biopharma: Employment.

Retraction Note to: Diagnostic procedures for improving of the KIT (CD117) expressed allele burden for the liver metastases from uterus mast cell tumors: prognostic value of the metastatic pattern and tumor biology.

The activating KIT marker plays a central role in the pathogenesis, diagnosis, and targeted treatment of systemic mastocytosis (SM). Recent studies have identified the KIT (CD117) as a marker that distinguishes nonneoplastic from neoplastic mast cells in human systemic mastocytosis. In this study, we conclude that immunohistopathology assays for KIT staining pattern are useful complimentary tools for diagnosis and evaluation of prognosis in uterus mast cell tumor (MCT) metastasis to the liver in 10 patients. Uterine and hepatic cytology revealed mast cell neoplasia, which was confirmed as visceral mast cell tumor on postmortem examination. Histological changes of densely packed, poorly differentiated neoplastic mast cells, sheets of neoplastic round to pleomorphic cells that formed nonencapsulated nodules, high mitotic figures, necrosis, and fibrosis were found. In addition, eosinophils were scattered among the mast cells at the periphery of the nodules. These findings indicate tumors of high-grade malignancy with infiltrative cells resembling the uterus MCT in the intraparenchymal and periparenchymal areas of the liver. Immunohistochemically, tumors were positive for KIT. The histopathologic features coupled with the KIT immunoreactivity led to diagnosis of high-grade uterus MCTs. Taken together, these findings suggest that CD117 may play a critical role in early uterus MCT development and may be a stimulatory factor in grade 3 MCT. Therefore, the result has supported our hypothesis that there was an increased opportunity to observe a higher CD117 staining pattern in high-grade MCTs.

Retraction note: Uterine mast cell tumor: a clinical and cytohistopathological study.

Mast cells are one of the characteristic factors in angiogenesis, growth, and metastatic spread of tumors. Further studies are suggested to determine the type of these cells which might be useful in the assessment of biological nature of the tumor and its future treatment modality. Few studies have evaluated mast cell infiltration in visceral tumors, especially uterine tumors. In this study, age, sex, death rate, and histologic patterns were in agreement with those of previous reports on canine mast cell tumors. Cytopathology assays are widely used to prognosticate canine uterine mast cell tumors (MCT). There is limited information about these prognostic assays used on MCT that arise in the uterine. The anisocytosis and anisocytosis and giant cells were present in the tumor. Furthermore, the tumor had nuclear atypia with scattered multinucleated cells and prominent nucleoli and tumor were classified as poorly granulated. Under microscopic examination, we observed diffuse infiltration and proliferation of tumor cells from the uterine different area and the infiltrative characteristics and distribution patterns of neoplastic cells were observed. This tumor consisted of sheets and cords of uniform round cells with discrete cytoplasmic margins. Microscopically, the neoplastic masses were poorly-demarcated and lacked capsules and tumor cell usually showed a distinct cell boundary. Nevertheless, the neoplastic cells were located between collagen bundles forming small clusters and sheets and had large, centrally located, round to ovoid nuclei. In addition, eosinophils were scattered among the mast cells at the periphery of the masses. The presence of eosinophils and the observation, at high magnification, of cells with cytoplasmic metachromatic granules. Based on these findings, a diagnosis of poorly-differentiated mast cell tumor was made and data histologic grading was available for tumor. Neoplasm was poorly differentiated or gradeIII.

Prognostic Factors and Treatment Results After Bleomycin, Etoposide, and Cisplatin in Germ Cell Cancer: A Population-based Study

BackgroundFirst-line treatment for patients with disseminated germ cell cancer (GCC) is bleomycin, etoposide, and cisplatin (BEP). A prognostic classification of patients receiving chemotherapy was published by the International Germ Cell Cancer Collaborative Group (IGCCCG) in 1997, but only a small proportion of the patients received BEP. ObjectiveTo estimate survival probabilities after BEP, evaluate the IGCCCG prognostic classification, and propose new prognostic factors for outcome. Design, setting, and participantsOf a Danish population-based cohort of GCC patients (1984–2007), 1889 received first-line BEP, with median follow-up of 15 yr. Covariates evaluated as prognostic factors were age, year of treatment, primary site, non-pulmonary visceral metastases, pulmonary metastases, and tumor markers. Outcome measurements and statistical analysisOutcomes measured were 5-yr progression-free survival (PFS), 5-yr disease-specific survival (DSS), and 5-yr overall survival (OS) as calculated using the Kaplan-Meier method and the Cox proportional hazards model. Results and limitationsThe 5-yr PFS, DSS, and OS were 87%, 95%, and 93%, respectively, for patients with seminomatous GCC (SGCC) and good prognosis. For nonseminomatous GCC (NSGCC) with good, intermediate, and poor prognosis, the 5-yr probabilities were 90%, 76%, and 55% for PFS; 97%, 87%, and 66% for DSS; and 95%, 85%, and 64% for OS, respectively. For SGCC patients, new adverse prognostic factors not included in the IGCCCG classification were higher age and lactate dehydrogenase ≥1.5 times the upper limit of normal. For NSGCC patients, higher age and pulmonary metastases were additional adverse prognostic factors. Treatment in earlier years was associated with higher mortality. Limitations include the small number of patients in the prognostic groups, and the inability to adjust for performance status and comorbidity. ConclusionsOur study reveals improved survival for disseminated GCC throughout the study period. We propose new prognostic factors for outcome for validation in larger cohorts of patients. Patient summaryIn this study of testicular cancer patients, we evaluated prognostic factors for outcome and calculated survival after standard chemotherapy. We find that survival has improved over the years and we propose new prognostic factors for outcome for validation in larger patient cohorts.

Chances, risks and limitations of neoadjuvant therapy in surgical oncology.

Over the last decades, neoadjuvant treatment has been established as a standard of care for a variety of tumor types in visceral oncology. Neoadjuvant treatment is recommended in locally advanced esophageal and gastric cancer as well as in rectal cancer. In borderline resectable pancreatic cancer, neoadjuvant therapy is an emerging treatment concept, whereas in resectable colorectal liver metastases, neoadjuvant treatment is often used, although the evidence for improvement of survival outcomes is rather weak. What makes neoadjuvant treatment attractive from a surgical oncology viewpoint is its ability to shrink tumors to a smaller size and to increase the chances for complete resection with clear surgical margins, which is a prerequisite for cure. Studies suggest that local tumor control is increased in some visceral tumor types, especially with neoadjuvant chemoradiotherapy. In some other studies, a better control of systemic disease has contributed to significantly improved survival rates. Additionally, delaying surgery offers the chance to bring the patient into a better general condition for major surgery, but it also confers the risk of progression. Although it is a relatively rare event, cancers may progress locally during neoadjuvant treatment or distant metastases may occur, jeopardizing a curative surgical treatment approach. Although this is seen as risk of neoadjuvant treatment, it can also be seen as a chance to select only those patients for surgery who have a better control of systemic disease. Some studies showed increased perioperative morbidity in patients who underwent neoadjuvant treatment, which is another potential disadvantage. Optimal multidisciplinary teamwork is key to controlling that risk. Meanwhile, the neoadjuvant treatment period is also used as a “window of opportunity” for studying the activity of novel drugs and for investigating predictive and prognostic biomarkers of chemoradiotherapy and radiochemotherapy. Although the benefits of neoadjuvant treatment have been clearly established, the risk of overtreatment of cancers with an unfavorable prognosis remains an issue. All indications for neoadjuvant treatment are based on clinical staging. Even if staging is done meticulously, making use of all recommended diagnostic modalities, the risk of overstaging and understaging remains considerable and may lead to false indications for neoadjuvant treatment. Finally, despite all developments and emerging concepts in medical oncology, many cancers remain resistant to the currently available drugs and radiation. This may in part be due to specific molecular resistance mechanisms that are marginally understood thus far. Neoadjuvant treatment has been one of the major advances in multidisciplinary oncology in the last decades, requiring a dedicated treatment team and an optimal infrastructure for complex oncology care. This article discusses the goals and novel directions as well as limitations in neoadjuvant treatment of visceral cancers.

A Case of Malignant PEComa of the Uterus Associated with Intramural Leiomyoma and Endometrial Carcinoma

Perivascular epithelioid cell tumors (PEComas) refers to a family of mesenchymal neoplasms composed of angiomyolipomas, clear cell “sugar” tumors of the lung, and lymphangioleiomyomatoses. These tumors have a distinctive and common component of perivascular epithelioid cells that show an association with blood vessel walls and immunohistochemically display myomelanocytic differentiation. The unique neoplasms have been shown to have an expanded range through a variety of case reports, including visceral, intra-abdominal, soft tissue, and bone tumors. The retroperitoneum, abdominopelvic region, and uterus have been reported to be the most common sites. Most PEComas follow a benign course. However, reports of malignant PEComas are increasing. Many papers have described uterine PEComas, but to our knowledge, there have not yet been any reports of a malignant PEComa arising concomitant with another epithelial tumor and mesenchymal tumor. We report herein the case of a 67-year-old woman who experienced a malignant uterine PEComa infiltrating a preexisting intramural leiomyoma with synchronous well differentiated endometrial carcinoma and multiple liver and lung metastases.

Personalized Medicine for Nervous System Manifestations of von Hippel-Lindau Disease.

von Hippel–Lindau disease (VHL) is a familial neoplasia syndrome associated with multisystem tumor development. Depending on tumor type and location, current treatments for VHL-associated tumors can include a combination of chemotherapy, radiation therapy, and/or surgery. Central nervous system (CNS) manifestations of VHL include craniospinal hemangioblastomas and endolymphatic sac tumors (ELSTs). While the first-line treatment for both types of VHL-associated CNS tumors is surgery, the indications for treatment are patient specific and different for each tumor type. Although early sign/symptom formation is the primary indication for resection of craniospinal hemangioblastomas, radiographic discovery (asymptomatic and symptomatic) of ELSTs can be an indication for resection of ELSTs in VHL patients. Recently, research has revealed that specific VHL germline mutations may permit targeted medical treatments of not only CNS manifestations of VHL-associated tumors but also visceral tumors. Specifically, missense mutations can result in the translation of functional VHL protein (pVHL) that is rapidly degraded resulting in functional loss of the pVHL, and inhibitors of pVHL degradation may slow protein degradation and restore pVHL function. Emerging research will investigate the safety and practicality of using potential targeted therapies.

Diversity of Meq gene from clinical Marek's disease virus infection in Saudi Arabia.

Aim:The aim of this study was to demonstrate the genomic features of Meq gene of Marek’s disease virus (MDV) recently circulating in Saudi Arabia (SA).Materials and Methods:Two poultry flocks suffering from mortalities and visceral tumors were presented to the Veterinary Teaching Hospital, King Faisal University, SA. Subjected to different diagnostic procedures: Case history, clinical signs, and necropsy as well as polymerase chain reaction followed by Meq gene sequence analysis.Results:Case history, clinical signs, and necropsy were suggestive of MDV infection. The Meq gene was successfully detected in liver and spleen of infected chickens. A 1062 bp band including the native Meq ORF in addition to a 939 bp of S-Meq (short isoform of Meq) were amplified from Saudi 01-13 and Saudi 02-13, respectively. The nucleotide and deduced amino acids sequences of the amplified Meq genes of both Saudi isolates showed distinct polymorphism when compared with the standard USA virulent isolates Md5 and GA. The sequence analysis of the S-Meq gene showed a 123 bp deletion representing 41 amino acids between two proline-rich areas without any frameshift. The Meq gene encoded four repeats of proline-rich repeats (PRRs sequences), whereas the S-Meq contains only two PRRs. Interestingly, the phylogenetic analysis revealed that both of SA MDV isolates are closely related to the MDV strains from Poland.Conclusion:The two MDV isolates contain several nucleotide polymorphisms resulting in distinct amino acid substitutions. It is suggested that migratory and wild birds, as well as world trading of poultry and its by-products, have a great contribution in the transmission of MDVs overseas.

Detection of a Tumor Suppressor Gene Variant Predisposing to Colorectal Cancer in an 18th Century Hungarian Mummy

Mutations of the Adenomatous polyposis coli (APC) gene are common and strongly associated with the development of colorectal adenomas and carcinomas. While extensively studied in modern populations, reports on visceral tumors in ancient populations are scarce. To the best of our knowledge, genetic characterization of mutations associated with colorectal cancer in ancient specimens has not yet been described. In this study we have sequenced hotspots for mutations in the APC gene isolated from 18th century naturally preserved human Hungarian mummies. While wild type APC sequences were found in two mummies, we discovered the E1317Q missense mutation, known to be a colorectal cancer predisposing mutation, in a large intestine tissue of an 18th century mummy. Our data suggests that this genetic predisposition to cancer already existed in the pre-industrialization era. This study calls for similar investigations of ancient specimens from different periods and geographical locations to be conducted and shared for the purpose of obtaining a larger scale analysis that will shed light on past cancer epidemiology and on cancer evolution.

A clinical and molecular investigation of two South African families with Simpson-Golabi-Behmel syndrome.

Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked recessive overgrowth syndrome manifesting primarily in boys and characterised by macrosomia, distinctive facial features and multiple congenital abnormalities. Although this rare condition is thought to be underdiagnosed, making a diagnosis is important as affected boys have a 7.5% risk of developing visceral tumours and surveillance is warranted. Mutations in GPC3 are found in up to 70% of boys affected with SGBS. A clinical and molecular investigation of two boys with SGBS, probands B and S, and their mothers. Documentation of the clinical phenotype could assist with diagnosis in affected boys and will lead to early initiation of tumour surveillance. Hospital folders were reviewed and clinical consultations arranged for both probands and their mothers. Molecular investigations initially searched for whole-exon deletions in GPC3 followed by gene sequencing. The clinical phenotype of both probands was consistent with that previously reported in the literature. The main features pointing towards the diagnosis were macrosomia, coarse facial features and macroglossia with a midline groove in the tongue. Proband B developed a Wilms tumour. He was found to have a novel mutation causing a premature stop codon. This research represents the first published report of SGBS in South Africa. Early recognition and confirmation of this condition is important in order to institute tumour surveillance and assist families with accurate recurrence risks.