The Yes-associated protein controls the cell density regulation of Hedgehog signaling.

The evolutionarily conserved Hedgehog (Hh) signaling pathway is essential for correct embryogenesis and is misregulated in several malignancies. In cell culture, Hh-sensitive cells display a striking dependence on cell density with active Hh signaling requiring cell-to-cell contact. As the Hippo/YAP system is tightly linked to cell density control and contact inhibition, we investigated the cross-talk between the two pathways.

Hippo signaling mediates proliferation, invasiveness, and metastatic potential of clear cell renal cell carcinoma.

Recent work has identified dysfunctional Hippo signaling to be involved in maintenance and progression of various human cancers, although data on clear cell renal cell carcinoma (ccRCC) have been limited. Here, we provide evidence implicating aberrant Hippo signaling in ccRCC proliferation, invasiveness, and metastatic potential. Nuclear overexpression of the Hippo target Yes-associated protein (YAP) was found in a subset of patients with ccRCC.

Development of a comprehensive prognostic index for patients with chronic lymphocytic leukemia.

In addition to clinical staging, a number of biomarkers predicting overall survival (OS) have been identified in chronic lymphocytic leukemia (CLL). The multiplicity of markers, limited information on their independent prognostic value, and a lack of understanding of how to interpret discordant markers are major barriers to use in routine clinical practice. We therefore performed an analysis of 23 prognostic markers based on prospectively collected data from 1948 CLL patients participating in phase 3 trials of the German CLL Study Group to develop a comprehensive prognostic index.

Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids.

Pulmonary carcinoids are rare neuroendocrine tumours of the lung. The molecular alterations underlying the pathogenesis of these tumours have not been systematically studied so far. Here we perform gene copy number analysis (n=54), genome/exome (n=44) and transcriptome (n=69) sequencing of pulmonary carcinoids and observe frequent mutations in chromatin-remodelling genes.

Interactions between comorbidity and treatment of chronic lymphocytic leukemia: results of German Chronic Lymphocytic Leukemia Study Group trials.

This study investigated the impact of comorbidity in 555 patients with chronic lymphocytic leukemia enrolled in two trials of the German Chronic Lymphocytic Leukemia Study Group on first-line treatment with fludarabine plus cyclophosphamide, fludarabine, or chlorambucil. Patients with two or more comorbidities and patients with less than two comorbidities differed in overall survival (71.7 versus 90.

CD74-NRG1 fusions in lung adenocarcinoma.

Unlabelled: We discovered a novel somatic gene fusion, CD74-NRG1, by transcriptome sequencing of 25 lung adenocarcinomas of never smokers. By screening 102 lung adenocarcinomas negative for known oncogenic alterations, we found four additional fusion-positive tumors, all of which were of the invasive mucinous subtype. Mechanistically, CD74-NRG1 leads to extracellular expression of the EGF-like domain of NRG1 III-β3, thereby providing the ligand for ERBB2-ERBB3 receptor complexes.

Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions.

Background: The monoclonal anti-CD20 antibody rituximab, combined with chemotherapeutic agents, has been shown to prolong overall survival in physically fit patients with previously untreated chronic lymphocytic leukemia (CLL) but not in those with coexisting conditions. We investigated the benefit of the type 2, glycoengineered antibody obinutuzumab (also known as GA101) as compared with that of rituximab, each combined with chlorambucil, in patients with previously untreated CLL and coexisting conditions.

Methods: We randomly assigned 781 patients with previously untreated CLL and a score higher than 6 on the Cumulative Illness Rating Scale (CIRS) (range, 0 to 56, with higher scores indicating worse health status) or an estimated creatinine clearance of 30 to 69 ml per minute to receive chlorambucil, obinutuzumab plus chlorambucil, or rituximab plus chlorambucil.

Second-line therapies of patients initially treated with fludarabine and cyclophosphamide or fludarabine, cyclophosphamide and rituximab for chronic lymphocytic leukemia within the CLL8 protocol of the German CLL Study Group.

Updated results of the CLL8 trial confirm that the addition of rituximab to chemotherapy with fludarabine and cyclophosphamide (FC) leads to a prolongation of progression-free (PFS) and overall survival (OS) in first-line treatment of physically fit patients. After a median observation time of 47 months, median PFS was 57.9 months for patients treated with FC and rituximab (FCR) and 32.

Clinical safety and pharmacological profile of the HLA-DR antibody 1D09C3 in patients with B cell chronic lymphocytic leukemia and lymphoma: results from a phase I study.

1D09C3 is a human monoclonal IgG4-type antibody against human leukocyte antigen-DR (HLA-DR) which has demonstrated pro-apoptotic activity against lymphoid tumors in vitro and in vivo. We report results from a phase I dose-escalation study which aimed to identify tolerated dosing, and the pharmacokinetic and pharmacodynamic profile of 1D09C3. Fourteen patients with relapsed/refractory B cell type leukemia/lymphoma were treated and followed after up to 4 weekly infusions of 1D09C3, administered in 6 dose levels at 0.

Everolimus for the treatment of pancreatic neuroendocrine tumors.

Introduction: Pancreatic neuroendocrine tumors (PNET) represent the second most common primary malignancy of the pancreas. Until recently, therapeutic options for advanced PNET have been limited.

Areas Covered: A recently published Phase III clinical trial demonstrated striking therapeutic activity of the mTOR inhibitor everolimus in advanced PNET and led to its approval for this indication by the FDA.

Comparison of the effects of two kinase inhibitors, sorafenib and dasatinib, on chronic lymphocytic leukemia cells.

Background: With sorafenib displaying the highest affinities for Flt3, VEGFR (vascular endothelial growth factor receptor) and Raf and dasatinib for Abl and Src kinases, the profiles of kinases targeted by these inhibitors differ strongly.

Materials And Methods: Dose-dependent effects of the inhibitors on freshly isolated chronic lymphocytic leukemia (CLL) cells were assessed as increased phosphatidylserine exposure. Inhibition by sorafenib and dasatinib of survival and anti-apoptotic signaling in CLL cells was examined by Western blot analysis.

Sentinel lymph node status as most important prognostic factor in patients with high-risk cutaneous melanomas (tumour thickness >4.00 mm): outcome analysis from a single institution.

Purpose: Sentinel lymph node biopsy (SLNB) is considered the most powerful prognostic indicator of survival in patients with cutaneous melanoma of intermediate thickness (1-4 mm). The use of SLNB in patients with melanoma with a tumour thickness >4.0 mm is still controversial.

Analysis of Tie2-expressing monocytes (TEM) in patients with colorectal cancer.

Tie2-expressing monocytes (TEM) promote tumor angiogenesis and growth in experimental cancer models. The role of TEM in cancer patients is unknown. We studied TEM in healthy volunteers and colorectal cancer (CRC) patients.

Management of dermatofibrosarcoma protuberans with fibrosarcomatous transformation: an evidence-based review of the literature.

Fibrosarcomatous transformation represents a rare event in dermatofibrosarcoma protuberans (DFSP) with unpredictable biological behaviour. No guidelines for the adequate treatment of patients with this rare neoplasm have been published. Herein, we present a comprehensive review of the literature comprising 157 patients with transformed DFSP focussing on surgical and adjuvant treatment modalities for this tumour.

Inactivation of Brca2 cooperates with Trp53(R172H) to induce invasive pancreatic ductal adenocarcinomas in mice: a mouse model of familial pancreatic cancer.

An inactivating germline mutation in BRCA2 is the most common known genetic basis for familial pancreatic cancer (FPC), accounting for 5-10% of inherited cases. A genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC) arising on the backdrop of Brca2 deficiency is likely to elucidate valuable diagnostic and therapeutic insights for FPC. Both Brca2 alleles were conditionally deleted during development within the pancreatic epithelium by generating Pdx1-Cre; Brca2(f/f) (CB) mice; in addition, triple transgenic Pdx1-Cre; Brca2(f/f); LSL-Trp53(R172H) (CBP) mice were generated, in order to determine the impact of p53 deregulation on Brca2-deficient carcinogenesis.

Recent developments of transgenic and xenograft mouse models of pancreatic cancer for translational research.

Importance Of The Field: Pancreatic cancer is a devastating disease associated with near uniform mortality. Usually diagnosed at advanced, metastatic stages when surgical resection with curative intention is not possible any more, most patients succumb to progressive disease after a few months. Despite recent advances in understanding pancreatic carcinogenesis and continuous efforts in translational research, so far these results failed to translate into clinically relevant improvements of patient survival.

Agents targeting the Hedgehog pathway for pancreatic cancer treatment.

Recent evidence has demonstrated that aberrant reactivation of the Hedgehog signaling pathway contributes to tumor initiation and progression in various human malignancies, including pancreatic cancer; therefore, the Hedgehog pathway has emerged as a promising novel therapeutic target. Initial translational studies conducted using cyclopamine, a small-molecule inhibitor of the Smoothened (SMO) component of the Hedgehog pathway, demonstrated that pharmacological blockade of aberrant Hedgehog signaling has the potential to inhibit tumor initiation, progression and metastatic spread. This concept has been corroborated using different compounds in various preclinical models of pancreatic cancer and other malignancies; several of these studies suggest possible therapeutic synergisms of Hedgehog inhibitors with established antineoplastic agents.

Identification of serum angiopoietin-2 as a biomarker for clinical outcome of colorectal cancer patients treated with bevacizumab-containing therapy.

Background: The combination of chemotherapy with the vascular endothelial growth factor (VEGF) antibody bevacizumab is a standard of care in advanced colorectal cancer (CRC). However, biomarkers predicting outcome of bevacizumab-containing treatment are lacking. As angiopoietin-2 (Ang-2) is a key regulator of vascular remodelling in concert with VEGF, we investigated its role as a biomarker in metastatic CRC.