294 research outputs found
Differential loss of chromosome 11q in familial and sporadic parasympathetic paragangliomas detected by comparative genomic hybridization
Parasympathetic paragangliomas (PGLs) represent neuroendocrine tumors
arising from chief cells in branchiomeric and intravagal paraganglia,
which share several histological features with their sympathetic
counterpart sympathoadrenal paragangliomas. In recent years, genetic
analyses of the familial form of PGL have attracted considerable interest.
However, the majority of paragangliomas occurs sporadically and it remains
to be determined whether the pathogenesis of sporadic paraganglioma
resembles that of the familial form. Furthermore, data on comparative
genetic aberrations are scarce. To provide fundamental cytogenetic data on
sporadic and hereditary PGLs, we performed comparative genomic
hybridization using directly fluorochrome-conjugated DNA extracted from 12
frozen and 4 paraffin-embedded tumors. The comparative genomic
hybridization data were extended by loss of heterozygosity analysis of
chromosome 11q. DNA copy number changes were found in 10 (63%) of 16
tumors. The most frequent chromosomal imbalance involved loss of
chromosome 11. Six of seven familial tumors and two of nine sporadic
tumors showed loss of 11q (86% versus 22%, P = 0.012). Deletions of 11p
and 5p were found in two of nine sporadic tumors. We conclude that overall
DNA copy number changes are infrequent in PGLs compared to sympathetic
paragangliomas and that loss of chromosome 11 may be an important event in
their tumorigenesis, particularly in familial paragangliomas
Losses of chromosomes 1p and 3q are early genetic events in the development of sporadic pheochromocytomas
Despite several loss of heterozygosity studies, a comprehensive genomic
survey of pheochromocytomas is still lacking. To identify DNA copy number
changes which might be important in tumor development and progression and
which may have diagnostic utility, we evaluated genetic aberrations in 29
sporadic adrenal and extra-adrenal pheochromocytomas (19 clinically benign
tumors and 10 malignant lesions). Comparative genomic hybridization was
performed using directly fluorochrome-conjugated DNA extracted from frozen
(16) and paraffin-embedded (13) tumor tissues. The most frequently
observed changes were losses of chromosomes 1p11-p32 (86%), 3q (52%), 6q
(34%), 3p, 17p (31% each), 11q (28%), and gains of chromosomes 9q (38%)
and 17q (31%). No amplification was identified and no difference between
adrenal and extra-adrenal tumors was detected. Progression to malignant
tumors was strongly associated with deletions of chromosome 6q (60% versus
21% in clinically benign lesions, P = 0.0368) and 17p (50% versus 21%).
Fluorescence in situ hybridization confirmed the comparative genomic
hybridization data of chromosomes 1p, 3q, and 6q, and revealed aneuploidy
in some tumors. Our results suggest that the development of
pheochromocytomas is associated with specific genomic aberrations, such as
losses of 1p, 3q, and 6q and gains of 9q and 17q. In particular, tumor
suppressor genes on chromosomes 1p and 3q may be involved in early
tumorigenesis, and deletions of chromosomes 6q and 17p in progression to
malignancy
Estrogen receptor variants in ER-positive basal-type breast cancers responding to therapy like ER-negative breast cancers
Immunohistochemically ER-positive HER2-negative (ER+HER2−) breast cancers are classified clinically as Luminal-type. We showed
previously that molecular subtyping using the 80-gene signature (80-GS) reclassified a subset of ER+HER2− tumors to molecular
Basal-type. We report here that molecular reclassification is associated with expression of dominant-negative ER variants and
evaluate response to neoadjuvant therapy and outcome in the prospective neoadjuvant NBRST study (NCT01479101). The 80-GS
reclassified 91 of 694 (13.1%) immunohistochemically Luminal-type tumors to molecular Basal-type. Importantly, all 91 discordant
tumors were classified as high-risk, whereas only 66.9% of ER+/Luminal-type tumors were classified at high-risk for disease
recurrence (i.e., Luminal B) (P < 0.001). ER variant mRNA (ERΔ3, ERΔ7, and ERα-36) analysis performed on 84 ER+/Basal tumors and
48 ER+/Luminal B control tumors revealed that total ER mRNA was significantly lower in ER+/Basal tumors. The relative expression
of ERΔ7/total ER was significantly higher in ER+/Basal tumors compared to ER+/Luminal B tumors (P < 0.001). ER+/Basal patients
had similar pathological complete response (pCR) rates following neoadjuvant chemotherapy as ER−/Basal patients (34.3 vs.
37.6%), and much higher than ER+/Luminal A or B patients (2.3 and 5.8%, respectively). Furthermore, 3-year distant metastasis-free
interval (DMFI) for ER+/Basal patients was 65.8%, significantly lower than 96.3 and 88.9% for ER+/Luminal A and B patients,
respectively, (log-rank P < 0.001). Significantly lower total ER mRNA and increased relative ERΔ7 dominant-negative variant
expression provides a rationale why ER+/Basal breast cancers are molecularly ER-negative. Identification of this substantial subset
of patients is clinically relevant because of the higher pCR rate to neoadjuvant chemotherapy and correlation with clinical outcome
A new anode material for oxygen evolution in molten oxide electrolysis
Molten oxide electrolysis (MOE) is an electrometallurgical technique that enables the direct production of metal in the liquid state from oxide feedstock and compared with traditional methods of extractive metallurgy offers both a substantial simplification of the process and a significant reduction in energy consumption. MOE is also considered a promising route for mitigation of CO[subscript 2] emissions in steelmaking, production of metals free of carbon, and generation of oxygen for extra-terrestrial exploration. Until now, MOE has been demonstrated using anode materials that are consumable (graphite for use with ferro-alloys and titanium) or unaffordable for terrestrial applications (iridium for use with iron). To enable metal production without process carbon, MOE requires an anode material that resists depletion while sustaining oxygen evolution. The challenges for iron production are threefold. First, the process temperature is in excess of 1,538 degrees Celsius. Second, under anodic polarization most metals inevitably corrode in such conditions. Third, iron oxide undergoes spontaneous reduction on contact with most refractory metals and even carbon. Here we show that anodes comprising chromium-based alloys exhibit limited consumption during iron extraction and oxygen evolution by MOE. The anode stability is due to the formation of an electronically conductive solid solution of chromium(iii) and aluminium oxides in the corundum structure. These findings make practicable larger-scale evaluation of MOE for the production of steel, and potentially provide a key material component enabling mitigation of greenhouse-gas emissions while producing metal of superior metallurgical quality.American Iron and Steel Institut
Loss of Y-Chromosome during Male Breast Carcinogenesis
Loss of Y-chromosome (LOY) is associated with increased cancer mortality in males. The prevalence of LOY in male breast cancer (BC) is unknown. The aim of this study is to assess the presence and prognostic effect of LOY during male BC progression. We included male BC patients diagnosed between 1989 and 2009 (n = 796). A tissue microarray (TMA) was constructed to perform immunohistochemistry and fluorescent in situ hybridization (FISH), using an X and Y probe. We also performed this FISH on a selected number of patients using whole tissue slides to study LOY during progression from ductal carcinoma in situ (DCIS) to invasive BC. In total, LOY was present in 12.7% (n = 92) of cases, whereby LOY was associated with ER and PR negative tumors (p = 0.017 and p = 0.01). LOY was not associated with the outcome. Using whole slides including invasive BC and adjacent DCIS (n = 22), we detected a concordant LOY status between both components in 17 patients. In conclusion, LOY is an early event in male breast carcinogenesis, which generally starts at the DCIS stage and is associated with ER and PR negative tumors
Paraganglioma and pheochromocytoma upon maternal transmission of SDHD mutations
The SDHD gene encodes a subunit of the mitochondrial tricarboxylic acid cycle enzyme and tumor suppressor
Incentive Compatible Reimbursement Schemes for Physicians
We consider physicians with fixed capacity levels. If a physician’s capacity exceeds demand, she may have an incentive to overtreat, i.e., she may provide unnecessary treatments to use up idle capacity. By contrast, with excess demand she may undertreat, i.e., she may not provide necessary treatments since other activities are financially more attractive. We first show that simple fee-for-service reimbursement schemes do not provide proper incentives.
If insurers use, however, fee-for-service schemes with quantity restrictions, they solve the fraudulent physician problem
Implementation of Novel Molecular Biomarkers for Non-small Cell Lung Cancer in the Netherlands:How to Deal With Increasing Complexity
The diagnostic landscape of non-small cell lung cancer (NSCLC) is changing rapidly with the availability of novel treatments. Despite high-level healthcare in the Netherlands, not all patients with NSCLC are tested with the currently relevant predictive tumor markers that are necessary for optimal decision-making for today's available targeted or immunotherapy. An expert workshop on the molecular diagnosis of NSCLC involving pulmonary oncologists, clinical chemists, pathologists, and clinical scientists in molecular pathology was held in the Netherlands on December 10, 2018. The aims of the workshop were to facilitate cross-disciplinary discussions regarding standards of practice, and address recent developments and associated challenges that impact future practice. This paper presents a summary of the discussions and consensus opinions of the workshop participants on the initial challenges of harmonization of the detection and clinical use of predictive markers of NSCLC. A key theme identified was the need for broader and active participation of all stakeholders involved in molecular diagnostic services for NSCLC, including healthcare professionals across all disciplines, the hospitals and clinics involved in service delivery, healthcare insurers, and industry groups involved in diagnostic and treatment innovations. Such collaboration is essential to integrate different technologies into molecular diagnostics practice, to increase nationwide patient access to novel technologies, and to ensure consensus-preferred biomarkers are tested
Chemotherapy followed by surgery versus surgery alone in patients with resectable oesophageal squamous cell carcinoma: Long-term results of a randomized controlled trial
Background: This is a randomized, controlled trial of preoperative chemotherapy in patients undergoing surgery for oesophageal squamous cell carcinoma (OSCC). Patients were allocated to chemotherapy, consisting of 2-4 cycles of cisplatin and etoposide, followed by surgery (CS group) or surgery alone (S group). Initial results reported only in abstract form in 1997, demonstrated an advantage for overall survival in the CS group. The results of this trial have been updated and discussed in the timeframe in which this study was performed.Methods: This trial recruited 169 patients with OSCC, 85 patients assigned to preoperative chemotherapy and 84 patients underwent immediate surgery. The primary study endpoint was overall survival (OS), secondary endpoints were disease free survival (DFS) and pattern of failure. Survival has been determined from Kaplan-Meier curves and treatment comparisons made with the log-rank test.Results: There were 148 deaths, 71 in the CS and 77 in the S group. Median OS time was 16 months in the CS group compared with 12 months in the S group; 2-year survival rates were 42% and 30%; and 5-year survival rates were 26% and 17%, respectively. Intention to treat analysis showed a significant overall survival benefit for patients in the CS group (P = 0.03, by the log-rank test; hazard ratio [HR] 0.71; 95%CI 0.51-0.98). DFS (from landmark time of 6 months after date of randomisation) was also better in the CS-group than in the S group (P = 0.02, by the log-rank test; HR 0.72; 95%CI 0.52-1.0). No difference in failure pattern was observed between both treatment arms.Conclusions: Preoperative chemotherapy with a combination of etoposide and cisplatin significantly improved overall survival in patients with OSCC
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