Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety for Imaging and Endoradiotherapy of Prostate Cancer.

Unlabelled: Despite many advances in the past years, the treatment of metastatic prostate cancer still remains challenging. In recent years, prostate-specific membrane antigen (PSMA) inhibitors were intensively studied to develop low-molecular-weight ligands for imaging prostate cancer lesions by PET or SPECT. However, the endoradiotherapeutic use of these compounds requires optimization with regard to the radionuclide-chelating agent and the linker moiety between chelator and pharmacophore, which influence the overall pharmacokinetic properties of the resulting radioligand.

Tall cell papillary thyroid carcinoma: new diagnostic criteria and mutations in BRAF and TERT.

The tall cell (TC) variant of papillary thyroid carcinoma (PTC) has an unfavorable prognosis. The diagnostic criteria remain inconsistent, and the role of a minor TC component is unclear. Molecular diagnostic markers are not available; however, there are two potential candidates: BRAF V600E and telomerase reverse transcriptase (TERT) promoter mutations.

An individual patient data meta-analysis on characteristics, treatments and outcomes of glioblastoma/ gliosarcoma patients with metastases outside of the central nervous system.

Purpose: To determine the characteristics, treatments and outcomes of patients with glioblastoma multiforme (GBM) or gliosarcoma (GS) and metastases outside of the central nervous system (CNS).

Methods: PubMed and Web of Science searches for peer-reviewed articles pertaining to GBM/ GS patients with metastatic dissemination were conducted using the keywords gliosarcoma, glioblastoma, GBM, metastasis, metastases and metastatic. Additionally, we performed hand search following the references from the selected papers.

Mismatch repair-deficient crypt foci in Lynch syndrome--molecular alterations and association with clinical parameters.

Lynch syndrome is caused by germline mutations of DNA mismatch repair (MMR) genes, most frequently MLH1 and MSH2. Recently, MMR-deficient crypt foci (MMR-DCF) have been identified as a novel lesion which occurs at high frequency in the intestinal mucosa from Lynch syndrome mutation carriers, but very rarely progress to cancer. To shed light on molecular alterations and clinical associations of MMR-DCF, we systematically searched the intestinal mucosa from Lynch syndrome patients for MMR-DCF by immunohistochemistry.

Intramedullary Solitary Fibrous Tumor--A Benign Form of Hemangiopericytoma? Case Report and Review of the Literature.

Background: Solitary fibrous tumors (SFTs) are benign tumors of the soft tissue occurring anywhere in the human body but arise predominantly in the visceral pleura. SFTs of the central nervous system are rare, especially when they occur within the spinal cord.

Case Description: We present a case of an 83-year-old female patient presenting with acute spastic paralysis of the lower extremities after a history of progressive weakness and incontinence.

Selective inhibition of HDAC8 decreases neuroblastoma growth in vitro and in vivo and enhances retinoic acid-mediated differentiation.

For differentiation-defective malignancies, compounds that modulate transcription, such as retinoic acid and histone deacetylase (HDAC) inhibitors, are of particular interest. HDAC inhibitors are currently under investigation for the treatment of a broad spectrum of cancer diseases. However, one clinical drawback is class-specific toxicity of unselective inhibitors, limiting their full anticancer potential.

Validation of a Manual Protocol for BRAF V600E Mutation-specific Immunohistochemistry.

Detection of BRAF V600E has diagnostic, prognostic, and therapeutic relevance. The recently developed BRAF V600E mutation-specific antibody has evolved into a feasible alternative to DNA analysis. The plethora of immunohistochemical protocols makes implementation tedious and, here we tested a set of manual and automated protocols and compared test performance with sequencing results.

p16INK4a immunohistochemistry in cervical biopsy specimens: A systematic review and meta-analysis of the interobserver agreement.

Objectives: The interpretation of cervical biopsy specimens guides management of women with suspected cervical cancer precursors. However, morphologic evaluation is subjective and has low interobserver agreement. Addition of p16(INK4a) immunohistochemistry may improve interpretation.

No evidence of oncogenic KRAS mutations in squamous cell carcinomas of the anogenital tract and head and neck region independent of human papillomavirus and p16(INK4a) status.

Carcinogenesis of squamous cell carcinomas (SCCs) in the anogenital tract and head and neck region is heterogeneous. A substantial proportion of SCC in the vulva, anus, and head and neck follows a human papillomavirus (HPV)-induced carcinogenic pathway. However, the molecular pathways of carcinogenesis in the HPV-independent lesions are not completely understood.

p16(INK4a) /Ki-67 co-expression specifically identifies transformed cells in the head and neck region.

p16(INK4a) immunohistochemical overexpression is an overall reliable surrogate marker of human papillomavirus (HPV)-associated head and neck squamous cell carcinomas (HNSCC). However, cases of ambiguous p16(INK4a) overexpression are regularly detected in the head and neck: p16(INK4a) expression can be observed in non-malignant tissue, such as tonsillar crypt epithelium and a proportion of branchial cleft cysts. Additionally, diverse patterns of p16(INK4) expression can complicate interpretation of "p16(INK4a) -positivity".

p53-dependent Nestin regulation links tumor suppression to cellular plasticity in liver cancer.

The p53 tumor suppressor coordinates a series of antiproliferative responses that restrict the expansion of malignant cells, and as a consequence, p53 is lost or mutated in the majority of human cancers. Here, we show that p53 restricts expression of the stem and progenitor-cell-associated protein nestin in an Sp1/3 transcription-factor-dependent manner and that Nestin is required for tumor initiation in vivo. Moreover, loss of p53 facilitates dedifferentiation of mature hepatocytes into nestin-positive progenitor-like cells, which are poised to differentiate into hepatocellular carcinomas (HCCs) or cholangiocarcinomas (CCs) in response to lineage-specific mutations that target Wnt and Notch signaling, respectively.

Spinal metastasis of gliosarcoma: array-based comparative genomic hybridization for confirmation of metastatic spread.

We report a 64-year-old woman who underwent craniotomy and gross total resection of a left frontal lobe tumor initially diagnosed as glioblastoma. Multiple wound revisions were necessary due to repeated wound healing disorders under concomitant radio-chemotherapy. After 9 months there was local cranial tumor recurrence, requiring re-operation.

Peripheral neuropathy: detection with diffusion-tensor imaging.

Purpose: To investigate the ability of diffusion-tensor imaging (DTI) and T2 to help detect the mildest nerve lesion conceivable, that is, subclinical ulnar neuropathy at the elbow.

Materials And Methods: This prospective study was approved by the institutional ethics board. Written informed consent was obtained from all participants.

High rate of FGFR1 amplifications in brain metastases of squamous and non-squamous lung cancer.

Objectives: FGFR1 amplifications are common in squamous cell carcinoma and rare in adenocarcinoma of the lung, but have not been investigated in brain metastases of non-small cell lung cancer (NSCLC).

Materials And Methods: We performed fluorescent in situ hybridization (FISH) for FGFR1 and immunohistochemistry for pAKT, PI3K, HIF1a and Ki67 in 175 NSCLC brain metastases and 11 matched primary tumors. ALK gene rearrangement status was available from a previous study.

Development, characterization, and reversal of acquired resistance to the MEK1 inhibitor selumetinib (AZD6244) in an in vivo model of childhood astrocytoma.

Purpose: The BT-40 low-grade childhood astrocytoma xenograft model expresses mutated BRAF(V600E) and is highly sensitive to the MEK inhibitor selumetinib (AZD6244). In this study, we developed and characterized selumetinib resistance and explored approaches to circumventing the mechanisms of acquired resistance.

Experimental Design: BT-40 xenografts were selected in vivo for selumetinib resistance.

Prognostic or predictive value of MGMT promoter methylation in gliomas depends on IDH1 mutation.

Objective: To explore whether the isocitrate dehydrogenase 1 (IDH1) or 1p/19q status determines the prognostic vs predictive role of O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation in the Neuro-Oncology Working Group of the German Cancer Society (NOA)-04 trial anaplastic glioma biomarker cohort.

Methods: Patients (n = 183) of the NOA-04 trial with known MGMT and IDH1 status were analyzed for interdependency of the prognostic vs predictive role of MGMT promoter methylation from IDH1 or 1p/19q status and treatment, using progression-free survival (PFS) as an endpoint. An independent validation cohort of the German Glioma Network (n = 75) and the NOA-08 trial (n = 34) served as a confirmation cohort.

Detection of BRAF p.V600E Mutations in Melanoma by Immunohistochemistry Has a Good Interobserver Reproducibility.

Context: Assessment of BRAF p.V600E mutational status has become necessary for treatment of patients with metastatic melanoma. Detection of p.

BRAF V600E-specific immunohistochemistry for the exclusion of Lynch syndrome in MSI-H colorectal cancer.

The differentiation between hereditary and sporadic microsatellite-unstable (MSI-H) colorectal cancer is a crucial step in Lynch syndrome diagnostics. Within MSI-H colorectal cancers, the BRAF V600E mutation is strongly associated with sporadic origin. Here, we asked whether BRAF V600E-specific immunohistochemistry (clone VE1) is helpful in separating sporadic from Lynch syndrome-associated MSI-H colorectal cancers.

Diagnostic markers for glioblastoma.

Glioblastoma (GBM) is the most malignant form of cerebral gliomas, and despite distinct progress in surgical resection, radiation and chemotherapy, the prognosis of patients with GBM is still very poor. In the past decades knowledge of genomics and proteomics and of diagnostic, prognostic, predictive and pharmakodynamic markers measured in cerebrospinal-fluid (CSF), serum, or tumor tissue biomarkers has improved. This review briefly compiles our concepts on diagnostic markers for GBM, focusing on the latest developments.

Evaluation of cervical cone biopsies for coexpression of p16INK4a and Ki-67 in epithelial cells.

Diffuse overexpression of p16(INK4a) in basal and parabasal cells of cervical epithelium is a hallmark of human papillomavirus-mediated transformation. Focal p16(INK4a) expression is occasionally observed in nondysplastic epithelium. In normal cells, expression of p16(INK4a) triggers cell cycle arrest.

The next generation of glioma biomarkers: MGMT methylation, BRAF fusions and IDH1 mutations.

For some, glioma biomarkers have been expected to solve common diagnostic problems in routine neuropathology service caused by insufficient material, technical shortcomings or lack of experience. Further, biomarkers should predict patient outcome and direct optimal therapy for the individual patient. Unfortunately, current biomarkers still fall somewhat short of these grand expectations.

Outcome prediction in pediatric medulloblastoma based on DNA copy-number aberrations of chromosomes 6q and 17q and the MYC and MYCN loci.

Purpose: Medulloblastoma is the most common malignant brain tumor in children. Current treatment decisions are based on clinical variables. Novel tumor-derived biomarkers may improve the risk stratification of medulloblastoma patients.

Involvement of Hif-1 in desferrioxamine-induced invasion of glioblastoma cells.

Glioblastoma multiforme are highly invasive brain tumors. Experimental approaches focus on unravelling the mechanisms of invasion, this being a major reason for the poor prognosis of these tumors. Our previous results hinted towards involvement of the iron metabolism in invasion.

Functional genomics and radioisotope-based imaging procedures.

After the sequencing of the human genome has been completed, non-invasive imaging studies are needed to assess the function of new genes in living organisms. The evaluation of genetically manipulated animals or new designed biomolecules will require a thorough understanding of physiology, biochemistry and pharmacology, and the experimental approaches will involve many new technologies including in vivo imaging with single photon emission computed tomography (SPECT) and positron emission tomography (PET). Nuclear medicine procedures may be applied for the determination of gene function and regulation using established and new tracers or using in vivo reporter genes such as enzymes, receptors, antigens or transporters.

Gene therapy with sodium/iodide symporter in hepatocarcinoma.

The ability of thyroid cells to accumulate iodide is a prerequisite for successful radioiodide therapy of benign thyroid diseases and differentiated thyroid carcinoma. The transport of iodide across the cell membrane is mediated by the sodium iodide symporter (hNIS). Employing a bicistronic retroviral vector for the transfer of the hNIS coding sequence and the hygromycin resistance gene stable hNIS expressing rat Morris hepatoma (MH3924A) cell lines were generated by hygromycin selection.