Somatostatin receptor 2A expression in von Hippel-Lindau-related hemangioblastomas.

Background: Central nervous system hemangioblastomas are the most prevalent manifestation of von Hippel-Lindau (VHL) disease and remain the main cause of mortality. Surgical resection is the primary treatment strategy, but is not always possible, and should be used as restrictively as possible. There is an unmet need for less invasive treatment strategies, such as targeted therapy.

Characterization of discordance between mismatch repair deficiency and microsatellite instability testing may prevent inappropriate treatment with immunotherapy.

In the Drug Rediscovery Protocol (DRUP), patients with cancer are treated based on their tumor molecular profile with approved targeted and immunotherapies outside the labeled indication. Importantly, patients undergo a tumor biopsy for whole-genome sequencing (WGS) which allows for a WGS-based evaluation of routine diagnostics. Notably, we observed that not all biopsies of patients with dMMR/MSI-positive tumors as determined by routine diagnostics were classified as microsatellite-unstable by subsequent WGS.

External Quality Assessment on Molecular Tumor Profiling with Circulating Tumor DNA-Based Methodologies Routinely Used in Clinical Pathology within the COIN Consortium.

Background: Identification of tumor-derived variants in circulating tumor DNA (ctDNA) has potential as a sensitive and reliable surrogate for tumor tissue-based routine diagnostic testing. However, variations in pre(analytical) procedures affect the efficiency of ctDNA recovery. Here, an external quality assessment (EQA) was performed to determine the performance of ctDNA mutation detection work flows that are used in current diagnostic settings across laboratories within the Dutch COIN consortium (ctDNA on the road to implementation in The Netherlands).

Comparison of NTRK fusion detection methods in microsatellite-instability-high metastatic colorectal cancer.

Tropomyosin receptor kinase (TRK) inhibitors have been approved for metastatic solid tumors harboring NTRK fusions, but the detection of NTRK fusions is challenging. International guidelines recommend pan-TRK immunohistochemistry (IHC) screening followed by next generation sequencing (NGS) in tumor types with low prevalence of NTRK fusions, including metastatic colorectal cancer (mCRC). RNA-based NGS is preferred, but is expensive, time-consuming, and extracting good-quality RNA from FFPE tissue is challenging.

Nodular Fasciitis With Malignant Morphology and a Fusion: A Case Report (of a 10-Year-old Boy).

Nodular fasciitis is usually a benign lesion genetically characterized by ubiquitin-specific protease 6 () rearrangements. We present a case of a 10-year-old boy with a 1.5-week history of a painless mass on the right chest wall, which was excised.

Ethical considerations for modern molecular pathology.

Molecular pathology is becoming an increasingly important discipline in oncology as molecular tumor characteristics will increasingly determine targeted clinical cancer care. In recent years, many technological advances have taken place that contributed to the development of molecular pathology. However, attention to ethical aspects has been lagging behind as illustrated by the lack of publications or professional guidelines.

Targeted sequencing reveals TP53 as a potential diagnostic biomarker in the post-treatment surveillance of head and neck cancer.

Head and neck squamous cell carcinomas (HNSCC) form a large heterogeneous group of tumors and have a relatively poor outcome in advanced cases. Revealing the underlying genetic mutations in HNSCC facilitates the development of diagnostic biomarkers, which might lead to improved diagnosis and post treatment surveillance. We retrospectively analyzed mutational hotspots using targeted next-generation sequencing (NGS) of 239 HNSCC tumor samples in order to examine the mutational profile of HNSCC.

Stem cell dynamics and pretumor progression in the intestinal tract.

Colorectal carcinogenesis is a process that follows a stepwise cascade that goes from the normal to an invisible pretumor stage ultimately leading to grossly visible tumor progression. During pretumor progression, an increasing accumulation of genetic alterations occurs, by definition without visible manifestations. It is generally thought that stem cells in the crypt base are responsible for this initiation of colorectal cancer progression because they are the origin of the differentiated epithelial cells that occupy the crypt.

Targeted Next Generation Sequencing as a Reliable Diagnostic Assay for the Detection of Somatic Mutations in Tumours Using Minimal DNA Amounts from Formalin Fixed Paraffin Embedded Material.

Background: Targeted Next Generation Sequencing (NGS) offers a way to implement testing of multiple genetic aberrations in diagnostic pathology practice, which is necessary for personalized cancer treatment. However, no standards regarding input material have been defined. This study therefore aimed to determine the effect of the type of input material (e.

Mice lacking functional CD95-ligand display reduced proliferation of the intestinal epithelium without gross homeostatic alterations.

Homeostasis of the continuously self-renewing intestinal tract involves cell proliferation, migration, differentiation along the crypt-villus-axis and shedding of cells into the gut lumen. CD95-ligand (FAS-ligand, CD95L) is a cytokine that is known for its capacity to induce apoptosis by binding its cognate receptor, CD95 (Fas). More recently, it was discovered that CD95L can also induce other cellular responses, such as proliferation, differentiation and cell migration.

OnabotulinumtoxinA improves quality of life in patients with neurogenic detrusor overactivity.

Objective: To evaluate the effects of onabotulinumtoxinA on patient-reported outcomes including health-related quality of life (HRQOL), treatment satisfaction, and treatment goal attainment in patients with urinary incontinence (UI) due to neurogenic detrusor overactivity (NDO).

Methods: In this multicenter, double-blind, randomized, placebo-controlled, phase III, 52-week study (ClinicalTrials.gov NCT00311376), patients with UI due to NDO who were not adequately managed with anticholinergic therapy were treated with intradetrusor injections of onabotulinumtoxinA (200 or 300 U) or placebo (0.

Monoclonal origin of primary unilateral multifocal pleomorphic adenoma of the parotid gland.

Primary multiple pleomorphic adenomas in a unilateral parotid gland in previously untreated patients is a rare finding, and little is known about the etiology and pathogenesis. Here, a highly unusual case of a primary multifocal pleomorphic adenoma consisting of 15 individual nodules is presented. It is shown that all nodes are clonally related and thus share a common cell of origin excluding an independent multifocal pathogenesis.

InterStim Sacral Neuromodulation and Botox Botulinum-A Toxin Intradetrusor Injections for Refractory Urge Urinary Incontinence: A Decision Analysis Comparing Outcomes Including Efficacy and Complications.

Objective: : Overactive bladder is a common disease for which current pharmaceutical therapy is often unsatisfactory. Newer modalities, including Botox and InterStim, can be used when antimuscarinics fail. We compare InterStim and Botox using decision analysis.

Urodynamic changes associated with successful stress urinary incontinence surgery: is a little tension a good thing?

Objective: To identify urodynamic changes that correlate with successful outcomes after stress urinary incontinence (SUI) surgery.

Methods: Six-hundred fifty-five women were randomized to Burch colposuspension or autologous fascial sling as part of the multicenter Stress Incontinence Surgical Treatment Efficacy Trial. Preoperatively and 24 months after surgery, participants underwent standardized urodynamic testing that included noninvasive uroflowmetry, cystometrogram, and pressure flow studies.

Changes in urodynamic measures two years after Burch colposuspension or autologous sling surgery.

Objective: To characterize the urodynamic (UDS) changes in subjects 24 months after Burch urethropexy and autologous fascial sling surgery for stress urinary incontinence.

Methods: In the Stress Incontinence Surgical Treatment Efficacy Trial (SISTEr), 655 women underwent standardized UDSs before and 2 years after Burch or sling surgery. Paired t tests were used to compare the pre- and postoperative UDS measures by treatment group.

Pancreatic ductal adenocarcinoma in hereditary diffuse gastric cancer. A case report.

Hereditary diffuse gastric cancer is an autosomal dominant cancer syndrome characterized by highly penetrant diffuse gastric cancer. It is caused by germ line mutations in CDH1, encoding the cell-cell adhesion protein E-cadherin. Pancreatic ductal adenocarcinoma is one of the most dismal malignancies in humans.

Aberrant intestinal stem cell lineage dynamics in Peutz-Jeghers syndrome and familial adenomatous polyposis consistent with protracted clonal evolution in the crypt.

Objective: Genetic predisposition to cancer in Peutz-Jeghers syndrome (PJS) and the role of germline serine-threonine kinase (LKB1) mutations are poorly understood. The authors studied the effect of germline LKB1 mutations on intestinal stem cell dynamics in unaffected flat PJS mucosa. Recent research has documented that the intestinal crypt houses multiple equipotent stem cell lineages.

Intestinal renin-angiotensin system is stimulated after deletion of Lkb1.

Background And Aims: LKB1 is a serine-threonine kinase, mutation of which can lead to the development of multiple benign intestinal hamartomas (Peutz-Jeghers syndrome). In this study, the authors investigate the mechanisms underlying this phenotype by exploring the transcriptional changes associated with Lkb1 deletion in intestinal epithelium.

Methods: The authors used mice with Lkb1 deleted in the intestinal epithelium using a Cyp1a1-specific inducible Cre recombinase and used Affymetrix (Santa Clara, California, USA) microarray analysis to examine the transcriptional changes occurring immediately after Lkb1 loss.

LKB1 as the ghostwriter of crypt history.

Familial cancer syndromes present rare insights into malignant tumor development. The molecular background of polyp formation and the cancer prone state in Peutz-Jeghers syndrome remain enigmatic to this day. Previously, we proposed that Peutz-Jeghers polyps are not pre-malignant lesions, but an epiphenomenon to the malignant condition.

Analysis of LKB1 mutations and other molecular alterations in pancreatic acinar cell carcinoma.

Acinar cell carcinoma is a rare non-ductal neoplasm of the pancreas with poorly defined molecular genetic features. Recently, biallelic inactivation of LKB1 was described in an acinar cell carcinoma of a Peutz-Jeghers patient carrying a heterozygous germline LKB1 mutation, and inhibition of mTOR signaling resulted in partial remission of the tumor. To explore the potential of mTOR inhibitors in sporadic acinar cell carcinoma, the LKB1 gene was investigated in five sporadic acinar cell carcinomas by sequence analysis, methylation analysis and mRNA expression.

Histologic variations in juvenile polyp phenotype correlate with genetic defect underlying juvenile polyposis.

Background: Juvenile polyps are distinct hamartomatous malformations of the gastrointestinal tract that may occur in the heritable juvenile polyposis syndrome (JPS) or sporadically. Histologically, juvenile polyps are characterized by a marked increase of the stromal cell compartment, but an epithelial phenotype has also been reported. JPS has an increased risk of colorectal cancer but sporadic juvenile polyps do not.

Botulinum toxin therapy for neurogenic detrusor overactivity.

Detrusor injection of botulinum toxin (BTX) has shown great promise in the treatment of neurogenic detrusor overactivity (NDO) refractory to conservative therapy. Despite a paucity of prospective evidence, there exists a growing consensus that BTX injection therapy is a well-tolerated, low-risk therapy. Injections result in substantial subjective improvement in continence and quality of life.

SMAD4 immunohistochemistry reflects genetic status in juvenile polyposis syndrome.

Purpose: Juvenile polyposis syndrome (JPS) can be caused by a germline defect of the SMAD4 gene. Somatic inactivation of SMAD4 occurs in pancreatic and colorectal cancers and is reflected by loss of SMAD4 immunohistochemistry. Here, SMAD4 immunohistochemistry as a marker of SMAD4 gene status and the role of SMAD4 in the adenoma-carcinoma sequence in neoplastic progression in JPS are studied.

Increased nerve growth factor in neurogenic overactive bladder and interstitial cystitis patients.

Objectives: Studies have suggested that pathology of the lower urinary tract can be detected by following changes in urinary proteins. We evaluated urine nerve growth factor (NGF) levels from patients with a variety of urologic conditions to examine NGF's role as a future biomarker.

Materials And Methods: Urine samples were obtained from 72 patients with normal non-diseased urinary tracts (n = 13), neurogenic overactive bladder (NOAB) (n = 13), idiopathic overactive bladder (OAB) (n = 17), interstitial cystitis/painful bladder syndrome (IC/PBS) (n = 8), prostate cancer (n = 7), history of prostate cancer status post robot-assisted laparoscopic prostatectomy (RALP) (n = 6), active bladder cancer (n = 4), and nephrolithiasis (n = 4).