Expansion of the complex genotypic and phenotypic spectrum of FGFR2-associated neurocutaneous syndromes.

The fibroblast growth factor receptors comprise a family of related but individually distinct tyrosine kinase receptors. Within this family, FGFR2 is a key regulator in many biological processes, e.g., cell proliferation, tumorigenesis, metastasis, and angiogenesis. Heterozygous activating non-mosaic germline variants in FGFR2 have been linked to numerous autosomal dominantly inherited disorders including several craniosynostoses and skeletal dysplasia syndromes. We report on a girl with cutaneous nevi, ocular malformations, macrocephaly, mild developmental delay, and the initial clinical diagnosis of Schimmelpenning-Feuerstein-Mims syndrome, a very rare mosaic neurocutaneous disorder caused by postzygotic missense variants in HRAS, KRAS, and NRAS. Exome sequencing of blood and affected skin tissue identified the mosaic variant c.1647=/T > G p.(Asn549=/Lys) in FGFR2, upstream of the RAS signaling pathway. The variant is located in the tyrosine kinase domain of FGFR2 in a region that regulates the activity of the receptor and structural mapping and functional characterization revealed that it results in constitutive receptor activation. Overall, our findings indicate FGFR2-associated neurocutaneous syndrome as the accurate clinical-molecular diagnosis for the reported individual, and thereby expand the complex genotypic and phenotypic spectrum of FGFR-associated disorders. We conclude that molecular analysis of FGFR2 should be considered in the genetic workup of individuals with the clinical suspicion of a mosaic neurocutaneous condition, as the knowledge of the molecular cause might have relevant implications for genetic counseling, prognosis, tumor surveillance and potential treatment options.

SHMT2 inhibition disrupts the TCF3 transcriptional survival program in Burkitt lymphoma.

Burkitt lymphoma (BL) is an aggressive lymphoma type that is currently treated by intensive chemoimmunotherapy. Despite the favorable clinical outcome for most patients with BL, chemotherapy-related toxicity and disease relapse remain major clinical challenges, emphasizing the need for innovative therapies. Using genome-scale CRISPR-Cas9 screens, we identified B-cell receptor (BCR) signaling, specific transcriptional regulators, and one-carbon metabolism as vulnerabilities in BL. We focused on serine hydroxymethyltransferase 2 (SHMT2), a key enzyme in one-carbon metabolism. Inhibition of SHMT2 by either knockdown or pharmacological compounds induced anti-BL effects in vitro and in vivo. Mechanistically, SHMT2 inhibition led to a significant reduction of intracellular glycine and formate levels, which inhibited the mTOR pathway and thereby triggered autophagic degradation of the oncogenic transcription factor TCF3. Consequently, this led to a collapse of tonic BCR signaling, which is controlled by TCF3 and is essential for BL cell survival. In terms of clinical translation, we also identified drugs such as methotrexate that synergized with SHMT inhibitors. Overall, our study has uncovered the dependency landscape in BL, identified and validated SHMT2 as a drug target, and revealed a mechanistic link between SHMT2 and the transcriptional master regulator TCF3, opening up new perspectives for innovative therapies.

Dataset for reporting of thymic epithelial tumours: recommendations from the International Collaboration on Cancer Reporting (ICCR).

AIMS: Thymic epithelial tumours (TET), including thymomas and thymic carcinomas and thymic neuroendocrine neoplasms, are malignant neoplasms that can be associated with morbidity and mortality. Recently, an updated version of the World Health Organization (WHO) Classification of Thoracic Tumours 5th Edition, 2021 has been released, which included various changes to the classification of these neoplasms. In addition, in 2017 the Union for International Cancer Control (UICC) / American Joint Committee on Cancer (AJCC) published the 8th Edition Staging Manual which, for the first time, includes a TNM staging that is applicable to thymomas, thymic carcinomas, and thymic neuroendocrine neoplasms. METHODS AND RESULTS: To standardize reporting of resected TET and thymic neuroendocrine neoplasms the accrediting bodies updated their reporting protocols. The International Collaboration on Cancer Reporting (ICCR), which represents a collaboration between various National Associations of Pathology, updated its 2017 histopathology reporting guide on TET and thymic neuroendocrine neoplasms accordingly. This report will highlight important changes in the reporting of TET and thymic neuroendocrine neoplasms based on the 2021 WHO, emphasize the 2017 TNM staging, and also comment on the rigour and various uncertainties for the pathologist when trying to follow that staging. CONCLUSION: The ICCR dataset provides a comprehensive, standardized template for reporting of resected TET and thymic neuroendocrine neoplasms.

NFATc1 signaling drives chronic ER stress responses to promote NAFLD progression.

OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) can persist in the stage of simple hepatic steatosis or progress to steatohepatitis (NASH) with an increased risk for cirrhosis and cancer. We examined the mechanisms controlling the progression to severe NASH in order to develop future treatment strategies for this disease. DESIGN: NFATc1 activation and regulation was examined in livers from patients with NAFLD, cultured and primary hepatocytes and in transgenic mice with differential hepatocyte-specific expression of the transcription factor (Alb-cre, NFATc1c.a . and NFATc1Δ/Δ ). Animals were fed with high-fat western diet (WD) alone or in combination with tauroursodeoxycholic acid (TUDCA), a candidate drug for NAFLD treatment. NFATc1-dependent ER stress-responses, NLRP3 inflammasome activation and disease progression were assessed both in vitro and in vivo. RESULTS: NFATc1 expression was weak in healthy livers but strongly induced in advanced NAFLD stages, where it correlates with liver enzyme values as well as hepatic inflammation and fibrosis. Moreover, high-fat WD increased NFATc1 expression, nuclear localisation and activation to promote NAFLD progression, whereas hepatocyte-specific depletion of the transcription factor can prevent mice from disease acceleration. Mechanistically, NFATc1 drives liver cell damage and inflammation through ER stress sensing and activation of the PERK-CHOP unfolded protein response (UPR). Finally, NFATc1-induced disease progression towards NASH can be blocked by TUDCA administration. CONCLUSION: NFATc1 stimulates NAFLD progression through chronic ER stress sensing and subsequent activation of terminal UPR signalling in hepatocytes. Interfering with ER stress-responses, for example, by TUDCA, protects fatty livers from progression towards manifest NASH.

Gene-expression profiles of pretreatment biopsies predict complete response of rectal cancer patients to preoperative chemoradiotherapy.

PURPOSE: Preoperative (neoadjuvant) chemoradiotherapy (CRT) and total mesorectal excision is the standard treatment for rectal cancer patients (UICC stage II/III). Up to one-third of patients treated with CRT achieve a pathological complete response (pCR). These patients could be spared from surgery and its associated morbidity and mortality, and assigned to a "watch and wait" strategy. However, reliably identifying pCR based on clinical or imaging parameters remains challenging. EXPERIMENTAL DESIGN: We generated gene-expression profiles of 175 patients with locally advanced rectal cancer enrolled in the CAO/ARO/AIO-94 and -04 trials. One hundred and sixty-one samples were used for building, training and validating a predictor of pCR using a machine learning algorithm. The performance of the classifier was validated in three independent cohorts, comprising 76 patients from (i) the CAO/ARO/AIO-94 and -04 trials (n = 14), (ii) a publicly available dataset (n = 38) and (iii) in 24 prospectively collected samples from the TransValid A trial. RESULTS: A 21-transcript signature yielded the best classification of pCR in 161 patients (Sensitivity: 0.31; AUC: 0.81), when not allowing misclassification of non-complete-responders (False-positive rate = 0). The classifier remained robust when applied to three independent datasets (n = 76). CONCLUSION: The classifier can identify >1/3 of rectal cancer patients with a pCR while never classifying patients with an incomplete response as having pCR. Importantly, we could validate this finding in three independent datasets, including a prospectively collected cohort. Therefore, this classifier could help select rectal cancer patients for a "watch and wait" strategy. TRANSLATIONAL RELEVANCE: Forgoing surgery with its associated side effects could be an option for rectal cancer patients if the prediction of a pathological complete response (pCR) after preoperative chemoradiotherapy would be possible. Based on gene-expression profiles of 161 patients a classifier was developed and validated in three independent datasets (n = 76), identifying over 1/3 of patients with pCR, while never misclassifying a non-complete-responder. Therefore, the classifier can identify patients suited for "watch and wait".

Choroidal metastases from thymic carcinoma during pregnancy: Case Report.

BACKGROUND: Rare sites of metastases, atypical symptoms and paraneoplastic syndromes are often neglected or misinterpreted, especially when they represent early symptoms of an underlying malignant disease. Hence, an interdisciplinary approach to these patients is essential to avoid tumor progression and metastatic spread in order to provide curative treatment options to the patients. We here report the case of a young woman presenting with visual loss which led to diagnosis of a thymic carcinoma. CASE PRESENTATION: A 28-year old white woman presented with subacute loss of vision in the last trimester of her first pregnancy which was first interpreted as an exacerbation of a pre-existing dermatomyositis and treated with steroids. After failure of steroid therapy choroidal metastases from an undifferentiated thymic carcinoma were diagnosed. This also shed a new light on the dermatomyositis the patient had been suffering from for seven years possibly representing a paraneoplastic syndrome from the tumor. Despite aggressive chemotherapy, the patient died from progressive disease eight years after first onset of dermatomyositis and 14 months after initial diagnosis of the thymic carcinoma. CONCLUSIONS: Choroidal metastases from a thymic carcinoma have never been reported before but should be included into the differential diagnosis of choroidal masses.

Expression of gemcitabine metabolizing enzymes and stromal components reveal complexities of preclinical pancreatic cancer models for therapeutic testing.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) poorly responds to antineoplastic agents. Discrepancies between preclinical success and clinical failure of compounds has been a continuous challenge and major obstacle in PDAC research. AIM: To investigate the association of the tumor microenvironment (TME) composition and gemcitabine metabolizing enzyme (GME) expression in vitro and several in vivo models. METHODS: mRNA expression and protein levels of GME (cytosolic 5'-nucleotidase 1 A; NT5C1A, cytidine deaminase; CDA, deoxycytidine kinase; DCK), gemcitabine transporters (ENT1, ENT2, RRM1, RRM2) and stromal components (hyaluroninc acid, podoplanin, masson trichrome, picrosirius) were assessed by qRT-PCR and immunohistochemistry in murine LSL-KrasG12D/+;LSL-Trp53R172 H/+; Pdx-1-Cre (KPC), orthotopically transplanted mice (OTM), human primary resected PDAC tissue (hPRT), corresponding patient-derived xenograft (PDX) mice, and KPC-SPARC-/- mice. mRNA expression of GME was analyzed in PDAC cell lines (Panc-1, MIA PaCa, BXPC3 and L3.6) upon incubation on collagen or pancreatic stellate cell (PSC) conditioned media by qRT-PCR. RESULTS: Endogenous KPC tumors exhibited significantly higher levels of GME compared to OTM. However, GME levels did not differ between hPRT and corresponding PDX mice. Using Kendalls Tau correlation coefficient we did not show a significant correlation of GME and components of the TME except for NT5C1A and hyaluronic acid in PDX mice (p=0.029). GME were not significantly altered upon SPARC depletion in vivo, and upon treatment with PSC-conditioned media or incubation on collagen plated dishes in vitro. CONCLUSIONS: Our findings suggest that the expression of GME is independent from the deposition of stromal components. KPC mice are most appropriate to study stromal composition whereas PDX mice maintain GME expression of the corresponding hPRT and could be best suited for pharmacokinetic studies.

Cure Is Possible: Extensively Metastatic HER2-Positive Gastric Carcinoma with 5 years of Complete Remission after Therapy with the FLOT Regimen and Trastuzumab.

Gastric cancer (GC) represents one of the most fatal neoplasms in gastrointestinal oncology and affected patients can only hope for cure in limited disease. In a metastatic situation however, patients have a worse prognosis finally resulting in cancer-related death. Some improvements were made by using intensified chemotherapy such as the FLOT protocol (5-FU, leucovorin, oxaliplatin and docetaxel). However, a breakthrough in the treatment of advanced GC has been achieved by pre-therapeutical tumor analysis for potentially targetable alterations. Microsatellite instability, PD-L1 expression, Epstein Barr virus, and human epidermal growth factor receptor-2 (HER2) overexpression or amplification are the most beneficial targets, if addressed, can prolong survival in a palliative situation. Whether the combination of these targeted therapeutics with chemotherapy can bring long-term survival or even a chance of cure in a metastatic situation is not clear. Here, we report the case of a 30-year-old man with GC and extensive metastases who was cured by anti-HER2 antibody Trastuzumab combined with the FLOT regime. Initial staging showed an exophytic Siewert type III tumor and extensive hepatic metastases. Histology resulted in gastric adenocarcinoma with HER2 overexpression (2+, FISH positive). Twelve courses of chemotherapy comprising Trastuzumab and FLOT were administered. After treatment, the extensive liver metastases had disappeared with no evidence of residual tumor growth on the CT scans. Monotherapy of Trastuzumab was continued until gastrectomy with D2 lymph node dissection and probing of liver tissue, which revealed no residual tumor cells. Five years after surgery, there is continued complete remission. In conclusion, Trastuzumab in combination with FLOT may have curative potential even for metastatic stages of HER-2-positive GC.

The value of molecular diagnostics in primary cutaneous B-cell lymphomas in the context of clinical findings, histology, and immunohistochemistry.

BACKGROUND: Primary cutaneous B-cell lymphoma (PCBCL) is classified into 3 major subtypes: primary cutaneous follicle center lymphoma (PCFCL); primary cutaneous marginal zone B-cell lymphoma (PCMZL); and primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL, LT). Diagnosis of PCBCL is mainly based on clinical and (immuno)-histochemical grounds. OBJECTIVE: We investigated the diagnostic value of the BIOMED-2 Concerted Action BMH4 CT98-3936 protocol in PCBCL. METHODS: We analyzed with the BIOMED-2 Concerted Action BMH4 CT98-3936 protocol skin specimens from patients with well-defined clinical and (immuno)-histologic PCBCL (n = 18) in comparison with benign lymphocytic infiltrates (n = 9). For molecular staging we also investigated 13 extracutaneous samples from 6 patients with PCLBCL, LT. Each sample was investigated at least twice. RESULTS: Monoclonality was detected in all of 5 PCFCL; 5 of 6 PCMZL; all of 6 PCLBCL, LT; and 2 of 9 benign lymphocytic infiltrates. In 5 of 6 patients with PCLBCL, LT, a clone corresponding to the clone detected in the skin was detected in 3 of 5 bone-marrow, 4 of 5 blood, and 1 of 3 lymph node specimens. DNA amplification using tubes A and B of IgH was not possible in PCFCL/PCMZL, benign lymphocytic infiltrates, and extracutaneous specimens of PCLBCL, LT, even after repeated analysis up to 11 times. Pseudomonoclonality was identified by repeated analyses in one case of PCMZL and in one case of benign lymphocytic infiltrate. LIMITATIONS: A multicentric, randomized, blinded study is necessary to confirm our results. CONCLUSION: Molecular diagnosis supports the clinical and (immuno)-histologic diagnosis in PCBCL. In PCLBCL, LT, molecular staging may be useful. Tubes C through E of IgH and Igκ analyses seem to be superior to tubes A and B of IgH. Each sample should be analyzed at least twice to assess the possibility of pseudomonoclonality.

PMA up-regulates the transcription of Axl by AP-1 transcription factor binding to TRE sequences via the MAPK cascade in leukaemia cells.

BACKGROUND: Axl is a receptor tyrosine kinase promoting anti-apoptosis, invasion and mitogenesis, and is highly expressed in different solid cancers. Axl basal transcriptional activity is driven by Sp1/Sp3, and overexpression of MZF-1 (myeloid zinc-finger 1) induces Axl transcription and gene expression. Furthermore, Axl expression is epigenetically controlled by CpG hypermethylation; however, little is known about inducible Axl gene expression and Axl regulation in haematopoetic malignancies. RESULTS: In the present study, we studied Axl transcriptional regulation under PMA-stimulated conditions in leukaemia cells. Luciferase analysis with sequential 5'-deletion constructs revealed that the -660/-580 region of the Axl promoter is indispensable for induced promoter activity under PMA stimulation. This region includes AP-1 (activator protein 1)/CREB [CRE (cAMP-response-element)-binding protein] motifs, five times partially overlapping TGCGTG repeats and multiple GT repeats. Mutational, supershift and ChIP (chromatin immunoprecipitation) analysis determined that AP-1 family members bind to AP-1 motifs and to the 5 × TGCGTG overlapping repeats, thus transactivating Axl promoter activity. Furthermore, specific inhibitors of PKC (protein kinase C), ERK1/2 (extracellular-signal-regulated kinase 1/2) and p38 reduced Axl expression. Additionally, mithramycin treatment abolished constitutive and PMA-induced Axl expression. CONCLUSIONS: Taken together the results of the present study suggest that PMA-induced Axl gene expression in leukaemia cells is mediated by AP-1 motifs and 5 × TGCGTG repeats within the promoter region -660/-580, and through the PKC/ERK1/2/AP-1 or PKC/p-38/AP-1 signalling axis.

The insulin-like growth factor-I-mTOR signaling pathway induces the mitochondrial pyrimidine nucleotide carrier to promote cell growth.

The insulin/insulin-like growth factor (IGF) signaling pathway to mTOR is essential for the survival and growth of normal cells and also contributes to the genesis and progression of cancer. This signaling pathway is linked with regulation of mitochondrial function, but how is incompletely understood. Here we show that IGF-I and insulin induce rapid transcription of the mitochondrial pyrimidine nucleotide carrier PNC1, which shares significant identity with the essential yeast mitochondrial carrier Rim2p. PNC1 expression is dependent on PI-3 kinase and mTOR activity and is higher in transformed fibroblasts, cancer cell lines, and primary prostate cancers than in normal tissues. Overexpression of PNC1 enhances cell size, whereas suppression of PNC1 expression causes reduced cell size and retarded cell cycle progression and proliferation. Cells with reduced PNC1 expression have reduced mitochondrial UTP levels, but while mitochondrial membrane potential and cellular ATP are not altered, cellular ROS levels are increased. Overall the data indicate that PNC1 is a target of the IGF-I/mTOR pathway that is essential for mitochondrial activity in regulating cell growth and proliferation.

Topoisomerase I expression correlates to response to neoadjuvant irinotecan-based chemoradiation in rectal cancer.

Biomarkers may help predict the efficacy of neoadjuvant chemoradiation in patients with rectal cancer. We hypothesized that the expression of topoisomerase I (Topo I) and thymidylate synthase (TS) may help predict the treatment response in patients undergoing irinotecan and capecitabine-based chemoradiation. Patients with rectal cancer (cT3/4Nx or Tx/N+) received neoadjuvant chemoradiotherapy within clinical studies with irinotecan and capecitabine. Samples of normal and tumour tissues were collected before the start of the treatment and during surgical resection. Topo I and TS were measured using real-time PCR. The results of gene expression levels were compared between responders (defined as ypT0-2 ypN0) and nonresponders (ypT3-4 or ypN1/2). A total of 38 patients were analysed, 18 of them were responders. The biopsies of the untreated tumour tissue of responding patients showed a significant higher expression of Topo I compared with nonresponding patients (P = 0.015). Normal tissue did not show this difference (P = 0.126). During chemoradiation, the Topo I expression in tumour tissue of responders decreased significantly. TS did not show any differences between responders and nonresponders before treatment, but a significant decrease in the tumour tissue of responders was noted at the end of the treatment. Our data suggest that Topo I expression in rectal tumour mucosa might serve as a predictor of response to the neoadjuvant irinotecan-based chemoradiation, and hence might be a factor contributing to the development of individualized treatment.

Treatment monitoring with 18F-FDG PET in metastatic thymoma after 90Y-Dotatoc and selective internal radiation treatment (SIRT).

A 39 years old male patient with a history of an unresectable thymoma and synchronous liver metastases was referred tor our position. The patient had been originally treated with systemic chemotherapy followed by imatinib (Glivec) and sunitinib (Sutent). Since the therapeutic response was unsatisfactory, a gallium-68 ((68)Ga)-Dotatoc-positron emission tomography (PET) was performed and demonstrated an enhanced SSTR 2 expression in the primary tumor but not in the liver metastases. Three cycles of yttrium-90 ((90)Y)-Dotatoc were then administered. Outcome after treatment was monitored by (18)F-FDG-PET and CT and showed a response only of the primary tumor. Selective internal radiation treatment (SIRT) with (90)Y microspheres was then applied for the liver metastases. (18)F-FDG uptake showed that metabolism in the liver metastases decreased after SIRT. MRI of the liver demonstrated a decrease in vascularization and a modest decrease in tumor volume. Therefore, surgical resection of the primary thymoma was initiated.

Signs heralding appearance of thymomas after extended thymectomy for myasthenia gravis.

PURPOSE OF REVIEW: Thymomas appear very rarely after extended thymectomy for early-onset myasthenia gravis (EOMG). We describe 2 such cases that highlight potential early warning signs. RECENT FINDINGS: In their 20s, one woman and one man developed EOMG (AChR antibody-positive), requiring extended transsternal removal of hyperplastic thymi at ages 35 and 27, respectively. Their myasthenia gravis was readily controlled for the next 10 and 7 years before deteriorating in both, with appearance of late clinical features and anticytokine autoantibodies suggesting underlying thymomas, namely respiratory infections, genital herpes, chronic candidiasis, and alopecia in the woman and erythroderma and lichen planus in the man, followed by Pseudomonas, Klebsiella, and cytomegalovirus infections plus chronic hepatitis during intensifying immunosuppressive therapy. Type B thymomas were then detected. Despite surgery or radiotherapy, and intensive drug therapy, the patients died 7 and 1 years later. SUMMARY: Certain infections/dermatologic manifestations that associate with long-standing thymomas may herald their late appearance, despite previous thymectomy.

Clinicopathological hallmarks and biomarkers of colorectal neuroendocrine neoplasms.

Chromogranin A (CgA) is a well-established marker for diagnosis and follow up of patients with gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN). Recently, it has been shown that plasma levels of CgA correlate with tumor load and predict survival of patients with NEN of the small bowel. It is assumed that this is as well valid for NEN of the colon and rectum, however, this is not supported by data. To evaluate this assumption, we analyzed 62 patients with NEN of the colon and rectum listed in the Marburg GEP-NEN registry for clinicopathological characteristics, expression and plasma levels of CgA. The present study demonstrates that immunohistochemical CgA and synaptophysin are good markers for histological diagnosis in patients with NEN of the colon and rectum. However, plasma CgA is a poor marker to follow-up these patients because only a minority exhibited increased levels which did not increase significantly during tumor progression. In contrast to NEN of the small bowel, there is no correlation of CgA plasma levels with tumor burden or survival. Patients with NEN of the colon and rectum displayed a relatively good prognosis resulting in a median survival of 8.5 years. However, a subset of patients affected by G3 neoplasms, exhibited a poorer prognosis with a median survival of 2.5 years. Taken together, CgA is a valuable marker for immunohistochemical diagnosis, but CgA plasma concentration is not suitable to mirror tumor burden or prognosis in patients with NEN of the colon and rectum.

The role of lymph vessel density and lymphangiogenesis in metastatic tumor spread of nonseminomatous testicular germ cell tumors.

OBJECTIVES: To evaluate the role of lymph vessel density (LVD) and lymphangiogenesis in nonseminomatous testicular germ cell tumors (NSGCT) using the specific lymphatic endothelial cell (LEC) marker LYVE-1. MATERIALS AND METHODS: NSGCT specimens of 77 patients (32 with and 45 without metastases) were stained immunohistochemically using a LYVE-1 antibody. LVD was measured in different representative areas by the standardized "hot spot" method. Fluorescence double stainings for LYVE-1 and Ki-67 were performed. The median follow-up period was 46 (range 3-170) months. RESULTS: The mean peritumoral (2.16 ± 2.17) and nontumoral LVD (3.17 ± 3.24) were significantly higher than intratumoral LVD (0.16 ± 0.73) (both: P = < 0.001). In 5 patients proliferating LECs were observed. The peritumoral LVD was 2.66 (± 2.31) and 1.80 (± 2.02) in metastatic and nonmetastatic NSGCT, respectively. A higher peritumoral LVD was associated with the presence of metastases at the time of diagnosis (P = 0.087). The mean peritumoral LVD in tumors with and without lymphovascular invasion (LVI) was 3.33 (± 2.20) and 1.62 (± 1.95), respectively (P < 0.001). The presence of LVI detected by LYVE-1 (LVI-LYVE-1) was independently associated with metastatic disease (logistic regression; P = 0.045). CONCLUSIONS: The presence of a high peritumoral LVD and LVI-LYVE-1 are both associated with metastatic disease in NSGCT. LVI-LYVE-1 was independently associated with the presence of metastases at the time of diagnosis. Proliferating LECs are present, suggesting that lymphangiogenesis may promote metastatic dissemination of tumor cells in NSGCT.

Real-time sonoelastography compared to magnetic resonance imaging using four different modalities at 3.0 T in the detection of prostate cancer: strength and weaknesses.

OBJECTIVE: To compare the results of RTE with four different modalities at 3.0 T using endorectal and body phased array coil in the detection of PC. PATIENTS AND METHODS: Between May 2009 and July 2010, 50 patients with biopsy proven PC scheduled for radical prostatectomy (RP) were examined. All patients underwent RTE of the prostate and 3.0 T endorectal MRI. The investigators were unaware of the clinical data and of each others results. RESULTS: RTE detected PC in 46 (92%) and MRI in 42 (84%) of the patients. Depending on the analysis sensitivity was 44.1-58.9% for RTE and 36.7-43.1% for MRI. Specificity was 83.0-74.8% for RTE and 85.9-79.8% for MRI. Sensitivity was significantly higher for RTE (16-sectors: p=0.0348; 8-sectors: p=0.0002) and showed better results in the dorsal (RTE: 51.9%; MRT: 37.7%) and apical to middle (RTE: 66.7%-80.0%; MRI: 41.7%-60.0%) parts of the prostate. MRI showed better results in the base (MRI: 19.4%; RTE: 14.9%) and transitional zone (TZ) (MRI: 34.7%; RTE: 29.6%). Concerning capsular involvement the results were comparable with sensitivity and specificity of RTE being 79.2% and 80.0% compared to 80.8% and 70.0% of MRI. CONCLUSIONS: Concerning sensitivity RTE showed advantages in apical and middle parts whereas MRI may provide advantages in the glands' base and TZ. Both RTE and MRI have limitations particularly in basal and ventral parts. Most of the undetected tumours were of low tumour volume and Gleason Score. Considering capsular involvement both techniques showed comparable results.

Distinct microRNA expression profile in prostate cancer patients with early clinical failure and the impact of let-7 as prognostic marker in high-risk prostate cancer.

BACKGROUND: The identification of additional prognostic markers to improve risk stratification and to avoid overtreatment is one of the most urgent clinical needs in prostate cancer (PCa). MicroRNAs, being important regulators of gene expression, are promising biomarkers in various cancer entities, though the impact as prognostic predictors in PCa is poorly understood. The aim of this study was to identify specific miRNAs as potential prognostic markers in high-risk PCa and to validate their clinical impact. METHODOLOGY AND PRINCIPAL FINDINGS: We performed miRNA-microarray analysis in a high-risk PCa study group selected by their clinical outcome (clinical progression free survival (CPFS) vs. clinical failure (CF)). We identified seven candidate miRNAs (let-7a/b/c, miR-515-3p/5p, -181b, -146b, and -361) that showed differential expression between both groups. Further qRT-PCR analysis revealed down-regulation of members of the let-7 family in the majority of a large, well-characterized high-risk PCa cohort (n = 98). Expression of let-7a/b/and -c was correlated to clinical outcome parameters of this group. While let-7a showed no association or correlation with clinical relevant data, let-7b and let-7c were associated with CF in PCa patients and functioned partially as independent prognostic marker. Validation of the data using an independent high-risk study cohort revealed that let-7b, but not let-7c, has impact as an independent prognostic marker for BCR and CF. Furthermore, we identified HMGA1, a non-histone protein, as a new target of let-7b and found correlation of let-7b down-regulation with HMGA1 over-expression in primary PCa samples. CONCLUSION: Our findings define a distinct miRNA expression profile in PCa cases with early CF and identified let-7b as prognostic biomarker in high-risk PCa. This study highlights the importance of let-7b as tumor suppressor miRNA in high-risk PCa and presents a basis to improve individual therapy for high-risk PCa patients.

Circulating fibronectin controls tumor growth.

Fibronectin is ubiquitously expressed in the extracellular matrix, and experimental evidence has shown that it modulates blood vessel formation. The relative contribution of local and circulating fibronectin to blood vessel formation in vivo remains unknown despite evidence for unexpected roles of circulating fibronectin in various diseases. Using transgenic mouse models, we established that circulating fibronectin facilitates the growth of bone metastases by enhancing blood vessel formation and maturation. This effect is more relevant than that of fibronectin produced by endothelial cells and pericytes, which only exert a small additive effect on vessel maturation. Circulating fibronectin enhances its local production in tumors through a positive feedback loop and increases the amount of vascular endothelial growth factor (VEGF) retained in the matrix. Both fibronectin and VEGF then cooperate to stimulate blood vessel formation. Fibronectin content in the tumor correlates with the number of blood vessels and tumor growth in the mouse models. Consistent with these results, examination of three separate arrays from patients with breast and prostate cancers revealed that a high staining intensity for fibronectin in tumors is associated with increased mortality. These results establish that circulating fibronectin modulates blood vessel formation and tumor growth by modifying the amount of and the response to VEGF. Furthermore, determination of the fibronectin content can serve as a prognostic biomarker for breast and prostate cancers and possibly other cancers.