The Cooperative Human Tissue Network of the National Cancer Institute: Supporting Cancer Research for 35 Years.

The Cooperative Human Tissue Network was created by the NCI in 1987 to support a coordinated national effort to collect and distribute high quality, pathologist-validated human tissues for cancer research. Since then, the network has expanded to provide different types of tissue samples, blood and body fluid samples, immunohistologic and molecular sample preparations, tissue microarrays, and clinical datasets inclusive of biomarkers and molecular testing. From inception through the end of 2021, the network has distributed 1,375,041 biospecimens.

Molecular Features of Cancers Exhibiting Exceptional Responses to Treatment.

A small fraction of cancer patients with advanced disease survive significantly longer than patients with clinically comparable tumors. Molecular mechanisms for exceptional responses to therapy have been identified by genomic analysis of tumor biopsies from individual patients. Here, we analyzed tumor biopsies from an unbiased cohort of 111 exceptional responder patients using multiple platforms to profile genetic and epigenetic aberrations as well as the tumor microenvironment.

The Exceptional Responders Initiative: Feasibility of a National Cancer Institute Pilot Study.

Background: Tumor molecular profiling from patients experiencing exceptional responses to systemic therapy may provide insights into cancer biology and improve treatment tailoring. This pilot study evaluates the feasibility of identifying exceptional responders retrospectively, obtaining pre-exceptional response treatment tumor tissues, and analyzing them with state-of-the-art molecular analysis tools to identify potential molecular explanations for responses.

Methods: Exceptional response was defined as partial (PR) or complete (CR) response to a systemic treatment with population PR or CR rate less than 10% or an unusually long response (eg, duration >3 times published median).

Toward Improving Practices for Submission of Diagnostic Tissue Blocks for National Cancer Institute Clinical Trials.

Objectives: The National Cancer Institute (NCI) National Clinical Trials Network performs phase II and III clinical trials, which increasingly rely on the submission of diagnostic formalin-fixed, paraffin-embedded tissue blocks for biomarker assessment. Simultaneously, advances in precision oncology require that clinical centers maintain diagnostic specimens for ancillary, standard-of-care diagnostics. This has caused tissue blocks to become a limited resource for advancing the NCI clinical trial enterprise and the practice of modern molecular pathology.

Low-cost technologies for medical diagnostics in low-resource settings.

Introduction: Medical diagnostics is a critical element of effective medical treatment. However, many modern and emerging diagnostic technologies are not affordable or compatible with the needs and conditions found in low- and middle-income countries. Resource-poor countries require low-cost, robust, easy-to-use, and portable diagnostic devices compatible with telemedicine that can be adapted to meet diverse medical needs.

A von Hippel-Lindau disease-associated microcystic adenoma of the ethmoid sinus: case report.

Background And Importance: We present a unique case of an anterior cranial base von Hippel-Lindau disease (VHL)-associated microcystic neoplasm. To determine the lesion's relationship with VHL and its appropriate management, we discuss its salient clinical, pathological, and molecular features.

Clinical Presentation: A 36-year-old woman with VHL presented with a 3-month history of phantosmia.

Troglitazone reduces glyoxalase I protein expression in glioma and potentiates the effects of chemotherapeutic agents.

Despite resistance of most gliomas to chemotherapy, approximately 2/3 of oligodendrogliomas show sensitivity to such agents. This sensitivity has been associated with deletions on chromosome 1p alone or in combination with 19q. Higher expression of the enzyme glyoxalase I has been found in oligodendrogliomas with chromosome 1p intact compared to those with a deletion.

Overexpression of interleukin-13 receptor-alpha2 in neuroendocrine malignant pheochromocytoma: a novel target for receptor directed anti-cancer therapy.

Context: Pheochromocytomas and paragangliomas are rare catecholamine-secreting neuroendocrine tumors arising from the adrenal medulla and sympathetic tissues. When complete surgical resection is not an option, the treatment of pheochromocytoma is limited.

Objective: The objective of the study was to identify and characterize overexpression of IL-13 receptor-alpha2 (IL-13Ralpha2) gene expression in human and murine tumors and verify xenograft mouse pheochromocytoma cell (MPC)-derived tumor's response to a selective cytotoxin.

Deciphering von Hippel-Lindau (VHL/Vhl)-associated pancreatic manifestations by inactivating Vhl in specific pancreatic cell populations.

The von Hippel-Lindau (VHL) syndrome is a pleomorphic familial disease characterized by the development of highly vascularized tumors, such as hemangioblastomas of the central nervous system, pheochromocytomas, renal cell carcinomas, cysts and neuroendocrine tumors of the pancreas. Up to 75% of VHL patients are affected by VHL-associated pancreatic lesions; however, very few reports in the published literature have described the cellular origins and biological roles of VHL in the pancreas. Since homozygous loss of Vhl in mice resulted in embryonic lethality, this study aimed to characterize the functional significance of VHL in the pancreas by conditionally inactivating Vhl utilizing the Cre/LoxP system.

Characterization of an animal model of aggressive metastatic pheochromocytoma linked to a specific gene signature.

Pheochromocytomas are chromaffin cell-derived neuroendocrine tumors. There is presently no cure for metastatic pheochromocytoma and no reliable way to distinguish malignant from benign tumors before the development of metastases. In order to successfully manage pheochromocytoma, it is necessary to better understand the biological determinants of tumor behavior.

Molecular genetic events in gastrointestinal and pancreatic neuroendocrine tumors.

Gastrointestinal and pancreatic neuroendocrine tumors originate from the cells of the diffuse endocrine system. Their molecular genetic mechanism of development and progression is complex and remains largely unknown, and they are different in genetic composition from the gastrointestinal epithelial tumors. The current literature suggests that multiple genes are involved in their tumorigenesis with significant differences for tumors of different embryological derivatives: foregut, midgut and hindgut.

ErbB-2 induces bilateral adrenal pheochromocytoma formation in mice.

Pheochromocytoma (PCC) is a rare catecholamine-producing tumor that arises from the adrenal medulla and is often familial. The genetic basis for familial PCC involves mutations of RET, VHL, SHDx or NF-1 in more than 20% of cases. Additional genes may be important in pathogenesis of both familial and sporadic PCC.

Multifocal microcysts and papillary cystadenoma of the lung in von Hippel-Lindau disease.

von Hippel-Lindau disease is an autosomal dominant inherited disorder characterized by a predisposition to multiple neoplasms. Renal cell carcinoma and hemangioblastomas of the retina and cerebellum are the most common of these, but other neoplasms and cysts also occur throughout the body. We report a distinctive, yet never described lung lesion in a 43-year-old woman with von Hippel-Lindau disease.

N-CoR pathway targeting induces glioblastoma derived cancer stem cell differentiation.

Nuclear receptor corepressor (N-CoR) is a critical regulator of neural stem cell differentiation. Nuclear localization of N-CoR is a feature of undifferentiated neural stem cells and cytoplasmic translocation of N-CoR leads to astrocytic differentiation. Comparative proteomic analysis of microdissected glioblastoma multiforme (GBM) specimens and matched normal glial tissue reveals increased expression of N-CoR in GBM.

von Hippel-Lindau disease-associated hemangioblastomas are derived from embryologic multipotent cells.

Background: To determine the origin of the neoplastic cell in central nervous system (CNS) hemangioblastomas in von Hippel-Lindau disease (VHL) and its role in tumor formation and distribution, we characterized and differentiated neoplastic cells from hemangioblastomas removed from VHL patients.

Methods And Findings: A total of 31 CNS hemangioblastomas from 25 VHL patients were resected and analyzed. Tumor cells from the hemangioblastomas were characterized, grown, and differentiated into multiple lineages.

Proteomic comparison of oligodendrogliomas with and without 1pLOH.

Objective: Chemoresistance is a widespread therapeutic challenge in glial tumors. The molecular basis of chemoresistance is poorly understood, precluding advances in glioma treatment and leaving gliomas among the most lethal tumors. Oligodendrogliomas provide a unique model to study the molecular basis of chemoresistance, as there are two distinct genetic subtypes with significant differences in chemosensitivity.

Proteomic analysis of hemangioblastoma cyst fluid.

Objective: Hemangioblastomas are benign CNS tumors that occur sporadically or in patients with von Hippel-Lindau (VHL) disease. These tumors are characteristically associated with formation of intra- or peritumoral cysts. Hemangioblastoma cyst formation is a major cause of morbidity and mortality with these tumors.

Identification of tumor precursor cells in the brains of primates with radiation-induced de novo glioblastoma multiforme.

The pathogenesis of de novo glioblastoma multiforme (GBM) is poorly understood and precursor cells are not known. To gain insight into the pathogenesis of GBM we analyzed brains from primates that developed de novo tumors ten years after whole brain radiation. Four animals had clinical and radiological evidence of GBM, and two animals had no evidence of GBM at the time of euthanization.

From tissue phenotype to proteotype: sensitive protein identification in microdissected tumor tissue.

Correlation of disease phenotype with protein profile (proteotype) is a significant challenge for biomedical research. The main obstacles have been the need to insure sufficient quantities of pure protein sample, the reproducibility of protein display, and rapid and accurate protein identification. We present a modified approach that combines enhanced detection sensitivity with tissue microdissection from frozen primary renal cancer tissues of different histological subtypes, followed by 2D gel analysis and protein identification with MALDI mass spectrometry.

Individual adult human neurons display aneuploidy: detection by fluorescence in situ hybridization and single neuron PCR.

Neurons, once committed, exit the cell cycle and undergo maturation that promote specialized activity and are believed to operate upon a stable genome. We used fluorescence in situ hybridization, selective cell microdissection, and loss of heterozygosity analysis to assess degree of aneuploidy in patients with a neurodegenerative disease and in normal controls. We found that aneuploidy occurs in approximately 40% of mature, adult human neurons in health or disease and may be a physiological mechanism that maintains neuronal fate and function; it does not appear to be an unstable state.

Premeiotic origin of teratomas: is meiosis required for differentiation into mature tissues?

By virtue of meiotic cell division, primordial germ cells with heterozygous alleles develop into postmeiotic germ cells with homozygous alleles. Female and male germ cells may develop tumors--so-called teratomas--with a unique coexistence of a variety of histological elements from all three embryonic germ layers. In particular, mature teratomas consist exclusively of developmentally mature tissues whereas immature teratomas contain variable amounts of mature and immature tissues.

Coexpression of erythropoietin and its receptor in endolymphatic sac tumors.

Object: Von Hippel-Lindau (VHL) disease is characterized by multiple tumors in specific organs. The cell of origin and the reason for the particular organ distribution of the tumors remains unknown. Endolymphatic sac tumor (ELST) is one of the lesions associated with VHL disease.

Differential expression of erythropoietin and its receptor in von hippel-lindau-associated and multiple endocrine neoplasia type 2-associated pheochromocytomas.

Pheochromocytoma is a neuroendocrine tumor associated with a variety of genetic disorders, which include von Hippel-Lindau disease (VHL), multiple endocrine neoplasia type 2 (MEN 2), neurofibromatosis type 1, hereditary paraganglioma, and succinate dehydrogenase gene-related tumors. Previous studies of VHL-associated and MEN 2-associated pheochromocytomas suggest morphological, biochemical, and clinical differences exist among the tumors, but the process by which they develop remains unclear. Studies in other VHL-associated tumors suggest that VHL gene deficiency causes coexpression of erythropoietin (Epo) and its receptor (Epo-R), which facilitates tumor growth.