Synchronous Double Primary Angiosarcoma Originating from the Stomach and Rectum: A Case Report and a Literature Review.

Angiosarcomas originating from the gastrointestinal tract are rare but highly aggressive tumors with poor prognosis. These tumors can be misdiagnosed as benign and malignant gastrointestinal tract lesions. The definitive histological diagnosis of angiosarcomasis made by pathologists based on immunohistochemical analysis demonstrating cluster of differentiation 31 (CD31), factor VIII-related antigen (FVIIIRAg), erythroblast transformation specific related gene (ERG), and cluster of differentiation 34 (CD34). Angiosarcomas are treated with a single or multimodality approach that may include resection, radiotherapy, chemotherapy, and palliative care, depending on the stage of disease and the condition of the patient. No matter the treatment option, metastasis and death rates are substantially highin patients with angiosarcoma. In this context, a 59-year-old male with synchronous double primary angiosarcoma arising from the gastric and rectum who presented with the complaint of abdominal pain and distention to the outpatient clinic is presented in this case report, along with a brief literature review.

Clinicopathological Features of Three Rare EWSR1::NFATC2 Sarcomas of Bone and Soft Tissues.

Certain undifferentiated round cell sarcomas displaying EWSR1::NFATC2 fusion have recently been reported, mostly in the bones. This report presents clinicopathological features of 3 additional EWSR1::NFATC2 fusion sarcomas of bone and soft tissues. We present 2 soft tissue and 1 bone tumors: A 62-year-old man with pain and a slowly growing, 8-cm-sized soft tissue mass in the anterolateral compartment of his right calf, along with multiple pulmonary metastatic lesions; a 63-year-old man with a 5-cm sized axillary mass of 4 months duration and a cystic renal mass; and a 53-year-old man with a complaint of leg pain was found to have a 2-cm diameter, intramedullary, lytic mass in the diaphysis of his left femur. Microscopic examination of the tumors in all patients revealed round to epithelioid cells arranged in cords and trabeculae in a myxohyaline stroma. Immunohistochemically, the tumor cells were positive for MIC2/CD99 (3/3), EMA (3/3), NKX3.1 (3/3), NKX2.2 (2/2), CD10 (2/2), and aggrecan (1/1), while negative for S100P and GFAP. Various keratins were also negative except focal AE1/AE3 positivity in the third tumor. By fluorescence in-situ hybridization, 2 tumors (#1 and #3) revealed EWSR1 gene rearrangement and amplification. Furthermore, 2 tumors (#1 and #2) displayed EWSR1ex8::NFATC2ex3 fusion with next-generation sequencing (NGS). The first patient was offered chemotherapy. However, he died of pulmonary metastasis. This report highlights the value of combining histopathological features and immunostains such as NXK3.1, NKX2.2, CD10, and aggrecan, along with EWSR1 testing for triaging these tumors for rare gene fusions by NGS that has prognostic implications.

Diagnostic Value of Preparing Additional Liquid-Based Cytology Slides and Cell Blocks from Residue Material in Thyroid fine Needle Aspiration.

Background and Aims: After liquid-based cytology (LBC) technique developed for cervical cytology, it has been used for nongynecological samples and has been very successful. It offers having extra slides of the samples for further examination and ancillary tests. Moreover, cell blocks can be formed from the residue material. The study aimed to evaluate the importance of preparing a second LBC slide or a cell block from the residue material of thyroid fine needle aspiration (FNA) samples to reach a definitive diagnosis in cases diagnosed as nondiagnostic (ND) after the first slide. Material and Methods: Seventy five cases diagnosed as ND after the first slide were included in study. For 50 cases, the second LBC slides were prepared (LBC group); for 25 cases, cell block was performed from residue material (CB group). Two groups were compared in terms of reaching a definitive diagnosis. Results: At the end of secondary procedures, a definitive diagnosis was reached in a total of 24 cases (32%). Twenty of 50 cases (40%) in LBC group reached a definitive diagnosis while four cases (16%) in the CB group reached a definitive diagnosis. Achieving a definitive diagnosis was found statistically higher in the LBC group in which the second slide was formed compared to the CB group (P =0.036). Conclusion: Preparing a second slide with LBC method is more purposive than preparing a cell block from the residue material of thyroid FNA samples. Reducing the percentage of ND cases will protect patients from complications and morbidity that may arise from repeated FNA.

Expanding the Spectrum of the Soft Tissue Tumors with Kinase Gene Fusions: A Pediatric Spindle Cell Neoplasm Harboring MTAP-RAF1 Fusion.

Introduction: NTRK-rearranged spindled cell tumors have been increasingly recognized with the widespread use of molecular studies. We describe a pediatric spindle cell neoplasm with MTAP-RAF1 gene fusion that fits into this group. Case report: An 8-year-old girl presented with mandibular mass. Histopathologically, it was a moderate to increased cellular spindle cell tumor with mild-to-moderate nuclear pleomorphism, focal perivascular keloid-like collagen, that was positive for S-100 and CD34. MTAP-RAF1 fusion was detected by next generation sequencing, confirming a low-grade sarcoma with MTAP-RAF1 fusion that is presently included in the category of NTRK-rearranged spindled cell tumors. Discussion: MTAP-RAF1 fusion, in the spectrum of spindle cell neoplasms with kinase gene rearrangements, can occur in the pediatric age group.

Diagnostic Significance of Ki67 Staining Pattern in Benign Peripheral Nerve Sheath Tumors: An Additional Diagnostic Tool.

Introduction. Benign peripheral nerve sheath tumors involve mainly neurofibromas, schwannomas, and their variants. Ki67 is a widely used immunohistochemical marker that predicts the proliferation rate of tumors including the nerve sheath-derived neoplasms and it is helpful to differentiate them from their malignant counterparts. However, Ki67 score is not used in distinction of the benign peripheral nerve sheath tumors types from each other. Our aim is to contribute to the literature by identifying the hypothesized specific Ki67 staining patterns of benign peripheral nerve sheath tumors. Methods. Fifty-three tumors (distributed as follows: 26 schwannomas, 24 neurofibromas, and 3 hybrid schwannoma-neurofibroma tumors) from 49 patients were included in the study. Two researchers analyzed the slides independently. Tumors were classified according to their Ki67 staining patterns in 3 different groups: zonal (Z-Ki67), focal zonal or mixed (M-Ki67), and scattered Ki67 (S-Ki67). Results. There was a significant correlation among the types of benign peripheral nerve sheath tumor and the Ki67 staining patterns (P < .01). Level of inter-rater reliability was calculated as good (>0.7) and excellent (>0.8) according to 2 different calculations of kappa score. Conclusions. In conclusion, our study demonstrates that the Ki67 staining pattern may be used as an additional diagnostic tool in the diagnosis of benign peripheral nerve sheath tumors.

Accuracy of emergency physician bedside ultrasonography compared with private teleradiologist for acute appendicitis diagnosis.

BACKGROUND: Acute appendicitis (AA) is a common cause of abdominal pain resulting in admission to the emergency room. Imaging methods such as ultrasonography and CT are usually used for diagnosing acute appendicitis. Reports regarding CT scans conducted during night shifts are prepared by private teleradiologists. AIMS: The aim of this study was to compare the accuracy of point-of-care ultrasound performed by an emergency medicine specialist and private teleradiologists in the diagnosis of AA. METHODS: This study was conducted prospectively and in a single center in the emergency department of a tertiary hospital. Patients who were admitted to the study between 15.09.2020 and 15.09.2021 and were diagnosed with AA who met the study criteria were included. A total of 134 patients diagnosed with AA, who met the inclusion criteria, out of 158 operated patients were included in the study. RESULTS: In the study, 77 were male and 57 were female. The mean age of patients with histopathologically positive AA was 31 and 31.5 in negative patients. The sensitivity and specificity of POCUS performed by the emergency physician and private teleradiology for the diagnosis of AA were 78.4% and 59.3% and 58.8% and 53.1%, respectively. CONCLUSIONS: POCUS performed by an emergency medicine specialist showed a higher sensitivity for the diagnosis of AA compared with private teleradiology. Hence, POCUS is more successful in diagnosing AA than private teleradiology. In conclusion, we recommend the concurrent use of AS and POCUS in emergency departments rather than private teleradiology for the diagnosis of AA.

Diagnosis of Lung Adenocarcinoma with Clear Cell Features in Pleural Effusion: Cytomorphologic Features, Immunocytochemical Studies, and Differential Diagnosis.

Clear cell adenocarcinoma (CCA) of the lungs is no longer referred to as a subtype in recent classifications of lung adenocarcinoma. Like signet ring features, clear cell features are regarded as cytological features rather than histological subtypes. Additionally, in serous fluids, adenocarcinoma metastasis with clear cell features is a diagnostic challenging entity due to other tumors that come to mindfirst during the differential diagnosis. Here we report a case, diagnosed as CCA of lung metastasis in pleural fluid and evaluated its differential diagnosis.

Comparison of Morphological Similarities and Differences between Liquid-Based Cytology and Conventional Techniques of Serous Effusion Cytology Specimens.

INTRODUCTION: The aim of this study is to discover a fast and efficient method for the diagnosis of serous effusion cytology specimens by comparing the cytomorphological features of SurePath (SP) smears and smears prepared by cytospin. After the macroscopic features of the incoming material were recorded, it was divided into 2 for conventional technique (CT) and liquid-based technique. Cytospin was used for CT and SurePath for liquid-based technique in this study. MATERIALS AND METHODS: 243 serous effusions (33 thoracentesis and 92 paracentesis fluids, 118 peritoneal lavage fluids) were investigated. After shaking the effusion gently, it was centrifuged for 5 min at 1,250 rpm for cytospin smear. SP smear was prepared according to the "BD PrepStain slide processor". Two smears were prepared with these 2 methods and then stained with Papanicolaou. The smears were examined under a light microscope in terms of fixation, background, cellularity, nucleus, and structural features. All statistical analysis of the data was performed using the SPSS 17.0 software. For each microscopic feature, the χ2 test was used to assess the significance of the relationship between cytospin and SP, and level of agreement in between the methods was assessed using the kappa statistic. RESULTS: A statistically significant difference was observed between the 2 methods in background (p < 0.001), cellularity (p < 0.001), nucleus features (p < 0.001), and structural features (p < 0.05). There was no significant difference in fixation. Low level of agreement was observed with the kappa statistic in fixation, background, and cellularity. Moderate level of agreement was observed in the nucleus and structural feature groups with the kappa statistic. DISCUSSION/CONCLUSION: Although there are advantages of liquid-based technique such as standardized fixation and cleaner background, since the cellular and background components required for morphological analysis and diagnosis are better preserved in cytospin, it is considered to be better to use liquid-based technique not alone but together with CT.

Clear cell sarcoma of soft tissue with eccrine differentiation: A case report and review of the literature.

Clear cell sarcoma of soft tissue (CCSST) is a deep soft tissue tumor presenting in the extremities of young adults. Histopathologically, nests and sheets of polygonal cells with clear to eosinophilic cytoplasm separated by fibrous septa as well as occasional "wreath-like" giant cells are visualized. However, CCSST has been noted to have atypical histopathological features, such as epidermotropism or myxoid differentiation, or occurrence at unusual sites. Here, we present a case of eccrine ductal differentiation in CCSST. The patient, a 21-year-old woman, presented with a lump of 10-year duration sized 3 × 5 cm on the plantar surface of the fourth and fifth interdigital spaces. There had been an increase in size as well as pain and redness over 6 years. Besides the characteristic findings, there were ductal structures in continuity with the upper dermis indicative of ductal differentiation. The tumor stained positively for S100, HMB45, and succinic dehydrogenase; ducts stained positively for epithelial membrane antigen (EMA) and carcinoembryonic antigen (CEA). CCSST was confirmed with cytogenetic analysis showing the translocation associated with EWSR1-ATF1 fusion gene. Therefore, ductal differentiation is a unique finding that should be considered when evaluating for CCSST.

Histopathological Comparison of 2-Octyl Cyanoacrylate and Primary Suturing for Tongue Lacerations.

OBJECTIVE: To enable tongue incisions to be repaired more easily, rapidly, and practically, particularly in pediatric patients by using 2-octyl cyanoacrylate (OCA) tissue adhesive. METHODS: A single linear incision was made on the midline dorsal part of the tongue. Twenty-four rats were randomly divided into the four groups: Group 1 (n = 6), OCA healing at day 5; group 2 (n = 6), OCA healing at day 21; group 3 (n = 6), Vicryl healing at day 5; group 4 (n = 6), Vicryl healing at day 21. In groups 1 and 2, OCA was applied to the incision site. The incisions of the rats in groups 3 and 4 were closed using Vicryl sutures. Histopathological examination was compared between and within the groups at day 5 and 21. RESULTS: The operation duration was significantly shorter with OCA than with Vicryl sutures(P < 0.001). Regarding the histopathological results, there were no differences between group 1 and group 3 in epithelial regeneration, inflammation, fibroblastic activity, edema, presence of giant cells, fibrin deposition, ulceration, abscess formation, and granulation tissue. However, moderate infiltration of acute inflammatory cells was significantly more frequent in group 1 than in group 3. At day 5, the incidence of moderate foreign body residue was significantly higher in group 1 than in group 3. No difference was observed between group 2 and group 4 at day 21 (P > 0.05). CONCLUSION: OCA is a practical, rapid, and effective method for repairing tongue lacerations. Although infiltration by inflammatory cells and foreign bodies increased in the early period, the long-term results of OCA were indistinguishable from those of suturing.

Morphological assessment of lamina cribrosa in idiopathic intracranial hypertension.

Purpose: Technological development of optic coherence tomography has enabled a detailed assessment of the optic nerve and deeper structures and in vivo measurements. The aim of this study was to compare the lamina cribrosa morphology of the optic nerve in idiopathic intracranial hypertension (IIH) and healthy individuals. Methods: The lamina cribrosa morphology of optic nerve in 15 eyes with IIH and 17 eyes of healthy individuals were compared. Four parameters such as Bruch membrane opening (BMO), lamina cribrosa thickness (LCT), prelaminar tissue thickness (PTT), and anterior lamina cribrosa surface depth (ALCSD) were retrospectively evaluated. Results: By enhanced depth imaging-optic coherence tomography (EDI-OCT), PTT and BMO were found to be significantly greater (574,35 ± 169,20 µm and 1787,40 ± 140,87 µm, respectively) in IIH patients than healthy individuals (187,18 ± 132,15 µm and 1632,65 ± 162,58 µm, respectively), whereas ALSCD was found to be significantly less in IIH patients (234,49 ± 49,31 µm) than healthy individuals (425,65 ± 65,23 µm). There was not a statistically significant difference regarding LCT between the IIH patients (238,59 ± 17,31 µm) and healthy individuals (244,96 ± 15,32 µm). Conclusion: Increased intracranial pressure causes morphological changes in lamina cribrosa. Assessment of lamina cribrosa with EDI-OCT is important for diagnosis and follow-up of patients with IIH. EDI-OCT is objective, reproducible, and cost-effective assistive imaging tool in IIH patients.

Prognostic value of ocular trauma score for open globe injuries associated with metallic intraocular foreign bodies.

BACKGROUND: The prognostic value of the ocular trauma score (OTS) in patients who underwent 23-gauge pars plana vitrectomy (23-G PPV) for surgical removal of posterior segment metallic intaocular foreign bodies (IOFB) was evaluated. METHODS: Patients who underwent 23-G PPV for surgical removal of retained metallic IOFBs were retrospectively analyzed. OTS score for each patient was calculated and raw scores were converted to their corresponding OTS categories. The final VAs in study patients were compared with their respective OTS categories. RESULTS: Twenty-five eyes from 25 patients were examined. Twenty-four (96%) of the patients were male, and the mean age was 34 ± 12 years. The time from injury to 23-G PPV was 9 ± 4 days. Fourteen (56%) patients had zone 1 trauma, eight (32%) patients had zone 2 trauma, and three (12%) patients had zone 3 trauma. Postoperative visual acuity was ≥ 20/200 in 14 (56%) of the patients and ≥ 20/40 in seven (28%) eyes. At the final visit, anatomical success was achieved in 86% of patients with retinal detachment at presentation. No statistically significant differences were found between our final VAs and OTS scores. CONCLUSION: OTS, which provides prognostic information after general ocular trauma, may also provide valuable prognostic information for patients who undergo 23-G PPV for the surgical removal of metallic posterior segment IOFBs.

Pediatric Traumatic Retinal Detachment: Clinical Features, Prognostic Factors, and Surgical Outcomes.

PURPOSE: We report the clinical characteristics, prognostic factors, and surgical outcomes for 23-gauge pars plana vitrectomy (23-G PPV) in pediatric cases of traumatic retinal detachment (RD). METHODS: Medical records of pediatric patients who underwent 23-G PPV to treat traumatic retinal detachment were retrospectively reviewed. These patients underwent a follow-up examination at least 1 year following surgery. Associations between various preoperative factors and anatomical and visual outcomes were analyzed. An Ocular Trauma Score (OTS) and a Pediatric Ocular Trauma Score (POTS) were calculated for each patient. Raw scores were converted to their corresponding OTS and POTS categories. Final visual acuities by categories were compared with those in the OTS and POTS studies. RESULTS: The mean age of the patients was 9 ± 4 years, and the male-to-female ratio was 4.7 : 1. The mean follow-up time was 23 ± 14 months. Anatomical success was achieved in 72% of the eyes, and functional success (>5/200) was achieved in 37% of the eyes. Functional success was less common among patients with visual acuities less than hand motion, macula-off retinal detachment, proliferative vitreoretinopathy at presentation, and recurrent retinal detachment during follow-up. When we compared the categorical distribution of final visual acuities in all categories, our results were significantly different than those suggested by OTS and POTS. CONCLUSIONS: Visual outcomes are poorer compared to anatomical outcomes. OTS and POTS do not provide reliable prognostic information if the patient has RD. Presenting visual acuity, the presence of macula-off RD, and PVR are all important predictors of final visual acuity.

Coupling of oceanic carbon and nitrogen facilitates spatially resolved quantitative reconstruction of nitrate inventories.

Anthropogenic impacts are perturbing the global nitrogen cycle via warming effects and pollutant sources such as chemical fertilizers and burning of fossil fuels. Understanding controls on past nitrogen inventories might improve predictions for future global biogeochemical cycling. Here we show the quantitative reconstruction of deglacial bottom water nitrate concentrations from intermediate depths of the Peruvian upwelling region, using foraminiferal pore density. Deglacial nitrate concentrations correlate strongly with downcore δ13C, consistent with modern water column observations in the intermediate Pacific, facilitating the use of δ13C records as a paleo-nitrate-proxy at intermediate depths and suggesting that the carbon and nitrogen cycles were closely coupled throughout the last deglaciation in the Peruvian upwelling region. Combining the pore density and intermediate Pacific δ13C records shows an elevated nitrate inventory of >10% during the Last Glacial Maximum relative to the Holocene, consistent with a δ13C-based and δ15N-based 3D ocean biogeochemical model and previous box modeling studies.

Proteomic profiling identifies markers for inflammation-related tumor-fibroblast interaction.

BACKGROUND: Cancer associated fibroblasts are activated in the tumor microenvironment and contribute to tumor progression, angiogenesis, extracellular matrix remodeling, and inflammation. METHODS: To identify proteins characteristic for fibroblasts in colorectal cancer we used liquid chromatography-tandem mass spectrometry to derive protein abundance from whole-tissue homogenates of human colorectal cancer/normal mucosa pairs. Alterations of protein levels were determined by two-sided t test with greater than threefold difference and an FDR of < 0.05. Public available datasets were used to predict proteins of stromal origin and link protein with mRNA regulation. Immunohistochemistry confirmed the localization of selected proteins. RESULTS: We identified a set of 24 proteins associated with inflammation, matrix organization, TGFß receptor signaling and angiogenesis mainly originating from the stroma. Most prominent were increased abundance of SerpinB5 in the parenchyme and latent transforming growth factor ß-binding protein, thrombospondin-B2, and secreted protein acidic-and-cysteine-rich in the stroma. Extracellular matrix remodeling involved collagens type VIII, XII, XIV, and VI as well as lysyl-oxidase-2. In silico analysis of mRNA levels demonstrated altered expression in the tumor and the adjacent normal tissue as compared to mucosa of healthy individuals indicating that inflammatory activation affected the surrounding tissue. Immunohistochemistry of 26 tumor specimen confirmed upregulation of SerpinB5, thrombospondin B2 and secreted protein acidic-and-cysteine-rich. CONCLUSIONS: This study demonstrates the feasibility of detecting tumor- and compartment-specific protein-signatures that are functionally meaningful by proteomic profiling of whole-tissue extracts together with mining of RNA expression datasets. The results provide the basis for further exploration of inflammation-related stromal markers in larger patient cohorts and experimental models.

Irinotecan Upregulates Fibroblast Growth Factor Receptor 3 Expression in Colorectal Cancer Cells, Which Mitigates Irinotecan-Induced Apoptosis.

BACKGROUND: Irinotecan (IRI) is an integral part of colorectal cancer (CRC) therapy, but response rates are unsatisfactory and resistance mechanisms are still insufficiently understood. As fibroblast growth factor receptor 3 (FGFR3) mediates essential survival signals in CRC, it is a candidate gene for causing intrinsic resistance to IRI. METHODS: We have used cell line models overexpressing FGFR3 to study the receptor's impact on IRI response. For pathway blockade, a dominant-negative receptor mutant and a small molecule kinase inhibitor were employed. RESULTS: IRI exposure induced expression of FGFR3 as well as its ligands FGF8 and FGF18 both in cell cultures and in xenograft tumors. As overexpression of FGFR3 mitigated IRI-induced apoptosis in CRC cell models, this suggests that the drug itself activated a survival response. On the cellular level, the antiapoptotic protein bcl-xl was upregulated and caspase 3 activation was inhibited. Targeting FGFR3 signaling using a dominant-negative receptor mutant sensitized cells for IRI. In addition, the FGFR inhibitor PD173074 acted synergistically with the chemotherapeutic drug and significantly enhanced IRI-induced caspase 3 activity in vitro. In vivo, PD173074 strongly inhibited growth of IRI-treated tumors. CONCLUSION: Together, our results indicate that targeting FGFR3 can be a promising strategy to enhance IRI response in CRC patients.

An Epigenomic Approach to Improving Response to Neoadjuvant Cisplatin Chemotherapy in Bladder Cancer.

Bladder cancer is among the five most common cancers diagnosed in the Western world and causes significant mortality and morbidity rates in affected patients. Therapeutic options to treat the disease in advanced muscle-invasive bladder cancer (MIBC) include cystectomy and chemotherapy. Neoadjuvant cisplatin-based combination chemotherapy is effective in MIBC; however, it has not been widely adopted by the community. One reason is that many patients do not respond to neoadjuvant chemotherapy, and no biomarker currently exists to identify these patients. It is also not clear whether a strategy to sensitize chemoresistant patients may exist. We sought to identify cisplatin-resistance patterns in preclinical models of bladder cancer, and test whether treatment with the epigenetic modifier decitabine is able to sensitize cisplatin-resistant bladder cancer cell lines. Using a screening approach in cisplatin-resistant bladder cancer cell lines, we identified dysregulated genes by RNA sequencing (RNAseq) and DNA methylation assays. DNA methylation analysis of tumors from 18 patients receiving cisplatin-based chemotherapy was used to confirm in vitro results. Cisplatin-resistant bladder cancer cells were treated with decitabine to investigate epigenetic sensitization of resistant cell lines. Our results show that HOXA9 promoter methylation status is associated with response to cisplatin-based chemotherapy in bladder cancer cell lines and in metastatic bladder cancer. Bladder cancer cells resistant to cisplatin chemotherapy can be sensitized to cisplatin by the DNA methylation inhibitor decitabine. Our data suggest that HOXA9 promoter methylation could serve as potential predictive biomarker and decitabine might sensitize resistant tumors in patients receiving cisplatin-based chemotherapy.

Is fibroblast growth factor receptor 4 a suitable target of cancer therapy?

Fibroblast growth factors (FGF) and their tyrosine kinase receptors (FGFR) support cell proliferation, survival and migration during embryonic development, organogenesis and tissue maintenance and their deregulation is frequently observed in cancer development and progression. Consequently, increasing efforts are focusing on the development of strategies to target FGF/FGFR signaling for cancer therapy. Among the FGFRs the family member FGFR4 is least well understood and differs from FGFRs1-3 in several aspects. Importantly, FGFR4 deletion does not lead to an embryonic lethal phenotype suggesting the possibility that its inhibition in cancer therapy might not cause grave adverse effects. In addition, the FGFR4 kinase domain differs sufficiently from those of FGFRs1-3 to permit development of highly specific inhibitors. The oncogenic impact of FGFR4, however, is not undisputed, as the FGFR4-mediated hormonal effects of several FGF ligands may also constitute a tissue-protective tumor suppressor activity especially in the liver. Therefore it is the purpose of this review to summarize all relevant aspects of FGFR4 physiology and pathophysiology and discuss the options of targeting this receptor for cancer therapy.

2-deprenyl-rheediaxanthone B isolated from Metaxya rostrata induces active cell death in colorectal tumor cells.

Metaxya rostrata C. Presl (Metaxyaceae) is a common tree fern in Central and South America that is used for the treatment of intestinal ulcers and tumours in ethnic medicine. Using a bioactivity-guided strategy 2-deprenyl-rheediaxanthone B (XB) has been isolated as one of the active principles in this plant. XB induced loss of cell viability in colorectal cancer cell lines at IC50 concentrations of 11-23 µM. This was caused by both accumulation of cells in the G2- and S-phase as well as by induction of active cell death in a time and concentration-dependent manner. Cells exposed to XB were incapable of undergoing regular mitosis due to down-regulation of FoxM1 and absence of chromosome condensation. The apoptosis-related proteins Bcl2 and Bclxl were up-regulated so that Caspase 3 was not activated and classical apoptosis was not observed. However, XB triggered damage pathways down-stream of ATR and activated Caspase 2 causing cell death by a mechanism similar to mitotic catastrophe. Our observations are the first to show the cytotoxic activity of 2-deprenyl-rheediaxanthone B and indicate that XB is an interesting new lead compound for cancer therapy that merits further development.