Anaplastic thyroid cancer evolved from papillary carcinoma: demonstration of anaplastic transformation by means of the inter-simple sequence repeat polymerase chain reaction

BACKGROUND: In thyroid tumors, the coexistence of well- and poorly differentiated tumor types has led to the hypothesis that poorly differentiated thyroid tumors develop from well-differentiated thyroid tumors. By evaluating the genomic instability of histologically distinct but coexisting tumor foci, this study aimed to develop an improved understanding of thyroid tumorigenesis and tumor evolution. DESIGN: Laser capture microdissection (LCM) was carried out on archival formalin-fixed, paraffin-embedded sections from a tumor containing foci of classic papillary thyroid cancer and anaplastic thyroid cancer. DNA was extracted from each microdissected tumor focus. In addition, cryopreserved bulk normal and neoplastic thyroid tissue underwent DNA extraction. All DNA samples were subsequently evaluated for genomic instability by means of inter-simple sequence repeat polymerase chain reaction. RESULTS: The LCM DNA from each archival paraffin-embedded tumor focus demonstrated unique patterns of banding as compared with the cryopreserved tumor and normal tissue DNA. Thus, intratumoral variability in genomic instability was observed. Comparison of inter-simple sequence repeat polymerase chain reaction patterns of LCM DNA from adjacent foci of papillary and anaplastic tumors showed conserved genome alterations. CONCLUSIONS: At the genome level, thyroid tumors may be highly heterogeneous. The intratumoral histologic heterogeneity observed in thyroid neoplasms reflects genetically heterogeneous underlying tumor cell populations that are demonstrated by the observed differences in their rates and extents of genomic instability. The conserved genomic alterations in the microdissected papillary and anaplastic foci suggest intratumoral evolution, with transformation of a preexisting papillary tumor to anaplastic carcinoma.     

Distribution of Organic Microcontaminants, Butyltins, and Metals in Mussels From the Estuary of Bilbao

Mussels are used as bioindicators of chemical pollution in coastal and estuarine waters. We measured the concentrations of polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), phthalate esters (PEs), butyltins, and metals (Cd, Co, Cr, Cu, Hg, Mn, Ni, Pb, V, and Zn) in mussel tissues collected from the lower Bilbao estuary (Arriluze, north of Spain) every 2 months from November 2002 to March 2004. The concentration (μg g⁻¹ dry weight) of PAHs, PCBs, and PEs ranged from 5.1 to 18.3, from 0.04 to 0.2, and from 1.5 to 27.6, respectively. Temporal pattern variations, including maximum and minimum values, were determined for metals and BTs from their concentration profiles during a period of 1 year. The main feature of organic microcontaminants was relatively high concentration values, reflecting the overall industrial and harbour activities of the site. Moreover, the ratios of methylated species and certain other diagnostic ratios suggested a petrogenic origin for PAHs. Finally, the relations among the concentrations found in mussel tissues and the levels of several cell biomarkers were established by a partial least squares model.     

Outcomes and cost-effectiveness of alternative staging strategies for non-small-cell lung cancer.

PURPOSE: To identify the optimal strategy for staging the mediastinum of patients with known non-small-cell lung cancer (NSCLC), stratified by tumor (T) classification. METHODS: We used a decision-analytic model to compare the health outcomes and cost-effectiveness of three staging strategies: (1) chest computed tomography alone, (2) selective mediastinoscopy, and (3) routine mediastinoscopy. The overall effectiveness and cost of each strategy was a function of the proportion of patients accurately staged and the risks, benefits, and costs of the diagnostic tests and treatments used. Probability estimates and costs were derived from primary data and the literature. We adopted a societal perspective and calculated incremental cost-effectiveness ratios (ICERs) as cost per quality-adjusted life year (QALY) gained. RESULTS: Both mediastinoscopy strategies correctly identified more patients with mediastinal involvement (N2/N3 disease) and assigned them to multimodal regimens. Routine mediastinoscopy maximized quality-adjusted life expectancy in all patients, irrespective of T classification, and this result was robust to varying the model estimates over their reported ranges. In T1 patients, selective mediastinoscopy cost $24,500 per QALY gained, compared with $78,800 per QALY gained for routine mediastinoscopy. In T2 and T3 patients, the ICER of routine mediastinoscopy was more favorable ($42,800 and $53,400 per QALY gained, respectively). CONCLUSION: Routine mediastinoscopy maximizes quality-adjusted life expectancy in patients with known NSCLC, and its ICER compares favorably with other currently accepted medical technologies. The survival benefit and cost-effectiveness of this strategy are greater in patients with T2 and T3 tumors and are likely to improve with advances in multimodal therapy.     

Expression profiling reveals alternative macrophage activation and impaired osteogenesis in periprosthetic osteolysis

Interactions between periprosthetic cells and prosthetic wear debris have been recognized as an important event in the development of osteolysis and aseptic loosening. Although the ability of wear debris to activate pro‐inflammatory macrophage signaling has been documented, the full repertoire of macrophage responses to wear particles has not been established. Here, we examined the involvement of alternative macrophage activation and defective osteogenic signaling in osteolysis. Using real‐time RT‐PCR analysis of periprosthetic soft tissue from osteolysis patients, we detected elevated levels of expression of alternative macrophage activation markers (CHIT1, CCL18), chemokines (IL8, MIP1 α) and markers of osteoclast precursor cell differentiation and multinucleation (Cathepsin K, TRAP, DC‐STAMP) relative to osteoarthritis controls. The presence of cathepsin K positive multinuclear cells was confirmed by immunohistochemistry. Reduced expression levels of the osteogenic signaling components BMP4 and FGF18 were detected. Expression levels of TNF‐α, IL‐6, and RANKL were unchanged, while the anti‐osteoclastogenic cytokine OPG was reduced in osteolysis patients, resulting in elevated RANKL:OPG ratios. In vitro studies confirmed the role of particulate debris in alternative macrophage activation and inhibition of osteogenic signaling. Taken together, these results suggest involvement in osteolysis of alternative macrophage activation, accompanied by elevated levels of various chemokines. Increased recruitment and maturation of osteoclast precursors is also observed, as is reduced osteogenesis. These findings provide new insights into the molecular pathogenesis of osteolysis, and identify new potential candidate markers for disease progression and therapeutic targeting. © 2007 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 26:106–116, 2008     

Dose received by the sentinel node volume during tangential radiation therapy to the breast.

The dose received by the sentinel node (SN) volume during tangential irradiation was studied on 31 patients. Of the 50Gy prescribed to the breast volume 95% of the SN volume received from 6.9 to 27.5Gy. In 19 patients the SN volume overlapped with the tangential field deep side.     

Outcome in subgroups of mild cognitive impairment (MCI) is highly predictable using a simple algorithm

Although it is well recognized that MCI represents a risk state for subsequent dementia, estimates of conversion vary widely according to the diagnostic criteria employed. There are currently no simple cognitive predictors of high and low risk of progression. We followed 107 non-demented non-depressed subjects from an original cohort of 124—sub-classified as follows: pure amnestic MCI (22), multi-domain MCI (54), non-amnestic MCI (10) and worried well (21). At 2 years, outcome varied considerably. Of the multi-domain MCI group 59% progressed to dementia and only 5% improved. By contrast, in pure amnestic MCI only 18% progressed and 41% improved. Of non-amnestic MCI patients 70% improved. The best predictor of progression was a combination of the Addenbrooke’s cognitive examination (ACE) and the paired associate learning task (PAL), which produced high negative predictive (90%) and sensitivity (94%) values. The results indicate very different outcomes according to whether patients have pure amnestic versus multi-domain MCI. While the latter is an aggressive disorder, the former is more benign and unstable even in a clinic setting. Patients with scores >88 on the ACE and/or <14 errors on the PAL can be confidently reassured of a good prognosis.     

Roux‐en‐Y gastric bypass is an effective bridge to kidney transplantation: Results from a single center

Body mass index (BMI) > 35‐40 kg/m² is often a contraindication, while Roux‐en‐Y gastric bypass (RYGB) is performed to enable kidney transplantation. This single‐center retrospective study evaluated pre‐ and post‐transplant outcomes of 31 morbidly obese patients with end‐stage renal disease having RYGB before kidney transplantation between July 2009 and June 2014. Fourteen RYGB patients were subsequently transplanted. Nineteen recipients not having GB with a BMI ≥ 36 kg/m² at transplantation were used as historical controls. Mean BMI (±SE) before RYGB was 43.5 ± 0.7 kg/m² (range: 35.4‐50.5 kg/m²); 87.1% (27/31) achieved a BMI < 35 kg/m². The percentage having improved diabetes/hypertension control was 29.0% (9/31); 25.8% (8/31) had complications (mostly minor) after RYGB. Among transplanted patients, blacks/Hispanics comprised 78.6% (11/14) and 84.2% (16/19) of RYGB and controls; 57.1% (8/14) and 63.2% (12/19) had a (mostly long‐standing) pretransplant history of diabetes. While biopsy‐proven acute rejection (BPAR) occurred significantly higher among RYGB vs control patients (6/14 vs 3/19, P = .03), patients developing T‐cell BPAR were also significantly more likely to have a tacrolimus (TAC) trough level < 4.0 ng/mL within 3 weeks of T‐cell BPAR (P = .0007). In Cox's model, the impact of having a TAC level < 4.0 ng/mg remained significant (P = .007) while the effect of RYGB was no longer significant (P = .13). Infections, graft, and patient survival were not significantly different. Despite obvious effectiveness in achieving weight loss, RYGB will need more careful post‐transplant monitoring given the observed higher BPAR rate.     

Characteristics of lentiviral vectors harboring the proximal promoter of the vav proto-oncogene: a weak and efficient promoter for gene therapy.

Recent published data have shown the efficacy of gene therapy treatments of certain monogenic diseases. Risks of insertional oncogenesis, however, indicate the necessity of developing new vectors with weaker or cell-restricted promoters to minimize the trans-activation activity of integrated proviruses. We have inserted the proximal promoter of the vav proto-oncogene into self-inactivating lentiviral vectors (vav-LVs) and investigated the expression pattern and therapeutic efficacy of these vectors. Compared with other LVs frequently used in gene therapy, vav-LVs mediated a weak, though homogeneous and stable, expression in in vitro-cultured cells. Transplantation experiments using transduced mouse bone marrow and human CD34(+) cells confirmed the stable activity of the promoter in vivo. To investigate whether the weak activity of this promoter was compatible with a therapeutic effect, a LV expressing the Fanconi anemia A (FANCA) gene was constructed (vav-FANCA LV). Although this vector induced a low expression of FANCA, compared to the expression induced by a LV harboring the spleen focus-forming virus (SFFV) promoter, the two vectors corrected the phenotype of cells from a patient with FA-A with the same efficacy. We propose that self-inactivating vectors harboring weak promoters, such as the vav promoter, will improve the safety of gene therapy and will be of particular interest for the treatment of diseases where a high expression of the transgene is not required.