Endometrial Cancer: What Is New in Adjuvant and Molecularly Targeted Therapy?

Endometrial cancer is the most common gynaecological cancer in western countries. Radiotherapy remains the mainstay of postoperative management, but accumulating data show that adjuvant chemotherapy may display promising results after staging surgery. The prognosis of patients with metastatic disease remains disappointing with only one-year survival. Progestins represent an effective option, especially for those patients with low-grade estrogen and/or progesterone receptor positive disease. Chemotherapy using the combination of paclitaxel, doxorubicin, and cisplatin is beneficial for patients with advanced or metastatic disease after staging surgery and potentially for patients with early-stage disease and high-risk factors. Toxicity is a point in question; however, the combination of paclitaxel with carboplatin may diminish these concerns. In women with multiple medical comorbidities, single-agent chemotherapy may be better tolerated with acceptable results. Our increased knowledge of the molecular aspects of endometrial cancer biology has paved the way for clinical research to develop novel targeted antineoplastic agents (everolimus, temsirolimus, gefitinib, erlotinib, cetuximab, trastuzumab, bevacizumab, sorafenib) as more effective and less toxic options. Continued investigation into the molecular pathways of endometrial cancer development and progression will increase our knowledge of this disease leading to the discovery of novel, superior agents

Evaluation of the Revised International Staging System in an independent cohort of unselected patients with multiple myeloma

The Revised International Staging System (R-ISS) was recently introduced in order to improve risk stratification over that provided by the widely used standard International Staging System. In addition to the parameters of the standard system, the R-ISS incorporates the presence of chromosomal abnormalities detected by interphase fluorescence in situ hybridization [t(4;14), t(14;16) and del17p] and elevated serum lactate dehydrogenase. The R-ISS was formulated on the basis of a large dataset of selected patients who had participated in clinical trials and has not been validated in an independent cohort of unselected patients. Thus, we evaluated the R-ISS in 475 consecutive, unselected patients, treated in a single center. Our patients were older and more often had severe renal dysfunction than those in the original publication on the R-ISS. As regards distribution by group, 18% had R-ISS-1, 64.5% R-ISS-2 and 18% R-ISS-3. According to R-ISS group, the 5-year survival rate was 77%, 53% and 19% for R-ISS-1, -2 and -3, respectively (P75 years. However, in patients with severe renal dysfunction the distinction between groups was less clear. In conclusion, our data in consecutive, unselected patients, with differences in the characteristics and treatment approaches compared to the original International Myeloma Working Group cohort, verified that R-ISS is a robust tool for risk stratification of newly diagnosed patients with symptomatic myeloma

Whole exome sequencing of familial, combined or complex dystonia

Background: To determine the usefulness of whole exome sequencing(WES) in the diagnostic evaluation of patients and small families withfamilial, combined and/or complex forms of dystonia identified from anadult neurology clinic at a tertiary center, and to set up a computationalpathway for the bioinformatics analyses.Methods: By mail, we contacted all 347 patients from our department whoduring a 4-year period had an ICD-10 diagnosis of dystonia. Of these, 122were re-examined within our research study. Patients who had combinedand/or complex dystonia phenotypes and patients who reported closefamily members with dystonia were examined by WES. Differentcomputational approaches followed (co-segregation or trio analysis,filtering variants based on an in-house gene list with more than 500 dystonia nuclear and mitochondrial genes etc.). Copy number variants (CNVs)were also detected by using in-silico tools.Results: Re-examination revealed that 11 of 122 (9.0%) of patients hadother disorders. Of the remaining 111 patients, fourteen had familial, combined or complex dystonia phenotypes starting at mean 37.6 (SD 14.9)years and were analysed by WES. For 5 of these, a definite or candidatemonogenic disease cause was identified (table).The diagnostic yield in this project was 35,7% with positive or likely positive findings. Two of 5 patients had variants that had been described previously (40%) and the remaining 3 carried putatively pathogenic variants (60%).Conclusions: Candidate disease-causing variants were identified in 5 out of 14 cases investigated, all these had combined or complex dystonia and relatively young onset (mean 22.3, SD 11.3 years). CNV analysis is relevant in the genetic workup of familial/combined/complex dystonia

Genomic analyses of a large Swedish multi-incident kindred with autosomal dominant Parkinson’s disease with dementia

Background:The known genetic causes for Parkinson’s disease (PD) onlyexplain a small proportion of the familial aggregation of PD. Despiteintensive efforts by researchers internationally, identifying and confirmingadditional monogenic causes for PD has been difficult.Methods:We examined 16 members of a large family with multi-incidentPD and dementia. Eight members were examined by whole exome (WES)or whole genome sequencing. Rare variants co-segregating with the disease were evaluated based on their distribution in additional familymembers and known gene functions. WES data from 843 PD cases and 885controls were screened for the two most highly ranked candidate variantsand used for gene burden analysis.Results:Clinically, all affected family members had typical PD withcognitive decline. Two affected individuals showed typical PD neuropathology. Out of nine genetic variants identified, we highlighted two as goodcandidates for causing this family’s PD. However, co-segregation with PDwas imperfect and this study was complicated by the fact that somegenotyped family members showed mild motor symptoms of uncertaincause, or cognitive decline without apparent motor dysfunction. Geneburden analysis showed no difference between cases and controls in thefrequency of potentially deleterious variants in the top-candidate genes.Nonetheless, factors that could indicate an impact of either of the two topcandidate genetic variants were found as one of the variants was identifiedin one additional familial PD proband from the case series and geneticvariants in the other top-candidate gene had previously been associatedwith an increased risk for PD in humans.Conclusions: Our study was not able to determine a single high-impactvariant as the cause of PD with cognitive decline in the family despitedetailed clinical and genetic assessments, but we nominate two potentialcandidate variants. Reduced penetrance and phenocopies may complicategenomic studies of families with PD

Giant cell arteritis of the breast and breast cancer: Paraneoplastic manifestation or concomitant disease? A case report

Background: Giant cell arteritis (GCA) of the breast is one of the less recognized variants of this vasculitis and may represent an isolated finding or a manifestation of a more widespread disease. Case Report: We present the case of a 74-year-old woman with malaise and a 14-day persistent fever, reaching 38°C. There was a bilateral, painless and mobile axillary lymphadenopathy and a slight tenderness over the medial and lateral upper quadrants of her left breast, as well as an independent palpable tender mass in the upper outer quadrant of the same breast measuring 2 cm in its greatest diameter. Constitutional symptoms, anemia and an elevated erythrocyte sedimentation rate suggestive of polymyalgia rheumatica were also present. An invasive ductal carcinoma of the breast with coincidental pathologic findings of GCA in the same biopsy specimen was revealed. In this case, arteritis was limited to the breast and presented with diffuse breast tenderness. No other artery was involved by GCA. All arteritis-related symptoms disappeared after the removal of the tumor. Conclusions: There is a relationship between cancer, particularly breast cancer, and GCA of the same organ, but the real nature of this association still remains unknown. Copyright © 2008 S. Karger AG