Nab-Paclitaxel related cystoid macular edema.

Objectives: Nab-paclitaxel is a chemotherapeutic drug used to treat various solid malignant tumors. It was conceived with a solvent free formulation to overcome toxicity events and hypersensitivity reactions associated with paclitaxel. However, it still carries ocular adverse effects. The present review examines nab-paclitaxel related cystoid macular edema (CME) and the available therapeutic options. Materials and Methods: The literature was reviewed on nab-paclitaxel related CME on published articles through January 2021 using the keywords "nab-paclitaxel "and "cystoid macular edema". Results: Bilateral CME is found in patients in treatment with nab-paclitaxel and causes considerable visual acuity decline. In ophthalmology multimodal imaging has an integral role in the diagnostic work up of patients and shows characteristic findings in nab-paclitaxel related CME. The case of a patient with treatment for bilateral CME is presented and analyzed. Conclusions: The preferred management strategy for nab-paclitaxel-related CME is drug cessation that leads to complete resolution of edema. When discontinuation of treatment is not possible due to the systemic conditions of patients, effective alternative therapeutic modalities are topical dorzolamide or steroidal treatment. Given the higher complication hazards of intravitreal therapy topical treatment should be preferred owing to comparable efficacy.

[Pulmonary artery percutaneous angioplasty for extrinsic compression induced by squamous cell carcinoma]. / Angioplastie percutanée d'une artère pulmonaire pour compression extrinsèque par un carcinome épidermoïde.

Pulmonary artery stenting is usually performed in congenital heart diseases and in cases of extrinsic compression due to a mediastinal tumor or fibrosis. We report one clinical case of a 61-year-old man treated by radiation and chemotherapy for T3N1M0 non-small cell lung carcinoma. He complained of disabling dyspnea. Pulmonary scintigraphy showed an absence of perfusion in the left lung. Chest computed tomography revealed a severe stenosis of the left pulmonary artery due to tumoral extrinsic compression. Under general anesthesia, we performed percutaneous angioplasty with self expandable nitinol stent. There was no peroperative complication. Dyspnea decreased immediately despite the natural course of the disease was not altered. Percutaneous stenting of pulmonary artery is safe and a feasible option for tumoral extrinsic compression. It is a palliative treatment but it can improve patient's quality of life.

L'angioplastie percutanée avec stent d'une artère pulmonaire est habituellement réalisée dans des pathologies cardiaques congénitales et en cas de compression extrinsèque par une masse médiastinale ou de la fibrose. Nous rapportons le cas d'un patient de 61 ans, traité par radio- et chimiothérapie pour un cancer pulmonaire non à petites cellules de stade T3N1M0. Le patient se plaignait de dyspnée invalidante. La scintigraphie pulmonaire montrait l'absence de perfusion du poumon gauche. La tomodensitométrie thoracique révélait une sténose sévère de l'artère pulmonaire gauche provoquée par une compression extrinsèque tumorale. Sous anesthésie générale, nous avons réalisé une angioplastie percutanée avec déploiement d'un stent en nitinol auto-expansible. Il n'y a pas eu de complication pendant la procédure. Le symptôme dyspnéique a régressé immédiatement, sans changer l'histoire naturelle de la maladie. L'angioplastie percutanée d'artère pulmonaire est une option faisable et sûre en cas de compression extrinsèque tumorale. C'est un traitement palliatif qui peut améliorer la qualité de vie des patients.

Arthrogenic human synovial cysts: immunohistochemical profile of interleukin-1beta, interleukin-6, tumour necrosis factor-alpha.

BACKGROUND: Synovial cysts are currently classified as degenerative lesions affecting the joint capsule or adjacent structures. MATERIALS AND METHODS: In our study we describe the results obtained in an immunohistochemical study comprising 18 patients with synovial cysts, performed to evaluate the pathophysiological role of some inflammatory cytokines such as: interleukin (IL)-1ß, IL-6 and tumour necrosis factor-alpha (TNF-α). RESULTS: Results showed an over-expression of TNF-α, IL-1ß and IL-6 which appears to be involved in the onset and progression of the disease. At the present time it is not possible to affirm that these molecules play a direct role also due to the absence of further and more specific investigations. The authors therefore hypothesize that inhibition of inflammation may have a significant role in the pathogenesis and regression of synovial cysts. CONCLUSIONS: Hence, these inflammatory cytokines may be considered potential therapeutic targets. The development of synthetic inhibitors of these inflammatory factors could lead to a reduction in the intensity of inflammation, thus inhibiting the onset and development of the disease.

Histerectomías laparoscópicas en un hospital comarcal español: nuestros resultados / The outcomes of laparoscopic hysterectomies in a Spanish district hospital

OBJETIVO: Calcular la tasa de conversión y describir las indicaciones, tipos de cirugía y complicaciones de las histerectomías laparoscópicas en un hospital comarcal. Analizar los tiempos quirúrgicos y el peso uterino. MÉTODO: Estudio retrospectivo y descriptivo de la base de datos quirúrgica de las mujeres atendidas en el Servicio de Ginecología y Obstetricia del Hospital Comarcal de Valdeorras (Orense). Programamos a 78 mujeres para histerectomía laparoscópica desde mayo del 2011 hasta febrero de 2018. Describimos las características demográficas, clínica, tipo de cirugía y tratamientos previos. Realizamos 62 histerectomías totales, 15 subtotales y una operación de Manchester. Calculamos la tasa de conversión, porcentaje de morcelación, tiempo quirúrgico, complicaciones (clasificadas según la escala de Clavien-Dindo y el Comprehensive Complication Index) y los resultados de anatomía patológica. RESULTADOS: Nuestra tasa de conversión fue del 5,13%. El porcentaje de morcelación fue 35,90%. En las histerectomías totales calculamos un peso uterino teórico (190 g o más) a partir del cual la morcelación sería más probable. No hubo transfusiones. Encontramos mayor tiempo quirúrgico entre los cirujanos junior, pero no más complicaciones. Las complicaciones según Clavien-Dindo fueron: 10 pacientes grado I, 10 grado II, uno grado IIIa y 4 grado IIIb. Según el Comprehensive Complication Index, 20 pacientes obtuvieron una puntuación baja (<30 puntos) y 4 pacientes entre 31 y 40 puntos. La cesárea previa estaba asociada a mayor riesgo de lesión vesical. La estancia media fue de 2,48 días. No hubo resultados de malignidad entre los úteros morcelados. CONCLUSIONES: La histerectomía laparoscópica es una técnica quirúrgica fácilmente reproducible en hospitales comarcales, con baja tasa de conversión y escasas complicaciones

OBJECTIVE: To calculate the conversion rate and describe indications, type of surgery, and complications of laparoscopic hysterectomies in a district hospital, as well as to analyse surgical time and uterine weight. METHODS: A descriptive and retrospective study was carried using the database of the Surgical Record of Gynaecology (Canadian Task Force classification III). It was conducted in the Gynaecology and Obstetrics Department of Valdeorras District Hospital (Orense, Spain). The study included 78 women scheduled for laparoscopic hysterectomy from May 2011 to February 2018. A description is presented of the demographic characteristics, symptoms, type of surgery, and previous medical treatments. A total of 62 total and 15 subtotal hysterectomies, were performed, as well as one Manchester surgery. A calculation was made of the rate of conversion, morcellation percentage, operating time, complications (classified according to the Clavien-Dindo scale and the Comprehensive Complication Index), and pathology results. RESULTS: The conversion rate was 5.13%, and the morcellation percentage was 35.90%. A theoretical cut-off was calculated of a uterus weight of 190 grammes or more for being morcellated among total hysterectomies. There were no transfusions. There were longer operating times with junior surgeons, but no difference in surgical complications compared to senior surgeons. Complications according to the Clavien-Dindo scale: 10 patients grade I, 10 grade II, one grade IIIa, and 4 grade IIIb. Using the CCI, 20 patients attained a low score (<30 points), and 4 patients scored 31-40 points. A history of caesarean section was associated with a higher risk of bladder injury. Mean days to discharge was 2.48 days. There were no malignant samples among the morcellated uteruses. CONCLUSIONS: Laparoscopic hysterectomy is a technique that can be performed in a district hospital and in most cases with a minimum conversion rate and few complications

Resultados a largo plazo de la cirugía de prolapsos genitales con mallas de polipropileno / Long-term results of genital prolapse surgery with polypropylene mesh

Introducción y objetivo: El riesgo de intervención por prolapso urogenital en la vida de una mujer es del 11,1%. Las recidivas después de la cirugía clásica alcanzan el 38%. Para tratar de mejorar estos resultados se usan kits de mallas de polipropileno transvaginales. El propósito del estudio es describir los resultados de eficacia y seguridad a largo plazo de la cirugía de prolapsos vaginales con mallas de polipropileno, evaluar los síntomas subjetivos pre- y postoperatorios y el grado de satisfacción. Pacientes y métodos: Estudio descriptivo, retrospectivo de 58 mujeres con prolapsos genitales sintomáticos operadas con mallas de polipropileno entre septiembre de 2011 y noviembre de 2016. La edad media fue 66,53 años; el 98,27% eran menopáusicas, el 77,59% tenía sobrepeso/obesidad, el 29,31% contaba con cirugías ginecológicas previas y el 55,17% con prolapsos combinados. Se insertaron 46 Elevate anterior y 12 Elevate posterior. La media del seguimiento fue de 34,02 meses. Se aplicó el cuestionario PFDI pre- y posquirúrgico y un cuestionario de satisfacción. Resultados: El índice de curación fue del 91,38%. Las recidivas se asociaron con un mayor IMC y con el antecedente de recidiva de cirugía previa. Estancia media: 2,5 días. El 70,69% no necesitó analgesia al alta. Complicaciones Clavien-Dindo: una tipo I (retención urinaria), 5 tipo II (infección urinaria) y una tipo IIIa (erosión). La incontinencia urinaria de esfuerzo de novo se presentó en el 3,44%, mientras que la dispareunia de novo ocurrió en el 14,28%. El 89,36% de las pacientes habían mejorado de los síntomas subjetivos y el 95,92% se mostraron satisfechas. Conclusión: Esta cirugía consigue altas tasas de curación, con escasas complicaciones, mejoría subjetiva de los síntomas y alto grado de satisfacción de las pacientes

Introduction and objective: The risk of intervention due to urogenital prolapse in a woman's life is 11.1%. Recurrences after classic surgery reach up to 38%. With the aim of improving these results, transvaginal mesh kits are used. The purpose of the study is to describe the results of efficacy and long-term safety of vaginal prolapse surgery with polypropylene mesh, assess subjective symptoms before and after surgery and the level of satisfaction. Patients and methods: A descriptive, retrospective study of 58 women with symptomatic genital prolapses operated with polypropylene mesh between September / 2011-November / 2016. Mean age: 66.53 years, 98.27% menopausal women, 77.59% overweight/obesity, 29.31% with previous gynaecological surgery and 55.17% with combined prolapse. 46 Elevate anterior and 12 posterior were inserted. The mean follow-up period was 34.02 months. The PFDI questionnaire was used pre and post-surgery, as well as the satisfaction questionnaire. Results: Healing rate of 91.38%. Recurrences were associated with a higher BMI and with background of recurrence of previous surgery. Mean length of stay: 2.5 days. 70.69% did not need analgesia at discharge. Clavien-Dindo complications: 1 type I (urinary retention), 5 type II (urinary tract infection) and 1 type IIIa (erosion). De novo stress urinary incontinence occurred in 3.44%, while de novo dyspareunia 14.28%. 89.36% patients improved subjective symptoms, and 95.92% were satisfied. Conclusion: This surgery achieves high healing rates, with few complications, improvement of subjective symptoms and high level of satisfaction of the patients

Long-term results of genital prolapse surgery with polypropylene mesh. / Resultados a largo plazo de la cirugía de prolapsos genitales con mallas de polipropileno.

INTRODUCTION AND OBJECTIVE: The risk of intervention due to urogenital prolapse in a woman's life is 11.1%. Recurrences after classic surgery reach up to 38%. With the aim of improving these results, transvaginal mesh kits are used. The purpose of the study is to describe the results of efficacy and long-term safety of vaginal prolapse surgery with polypropylene mesh, assess subjective symptoms before and after surgery and the level of satisfaction. PATIENTS AND METHODS: A descriptive, retrospective study of 58 women with symptomatic genital prolapses operated with polypropylene mesh between September / 2011-November / 2016. Mean age: 66.53 years, 98.27% menopausal women, 77.59% overweight/obesity, 29.31% with previous gynaecological surgery and 55.17% with combined prolapse. 46 Elevate anterior and 12 posterior were inserted. The mean follow-up period was 34.02 months. The PFDI questionnaire was used pre and post-surgery, as well as the satisfaction questionnaire. RESULTS: Healing rate of 91.38%. Recurrences were associated with a higher BMI and with background of recurrence of previous surgery. Mean length of stay: 2.5 days. 70.69% did not need analgesia at discharge. Clavien-Dindo complications: 1 type I (urinary retention), 5 type II (urinary tract infection) and 1 type IIIa (erosion). De novo stress urinary incontinence occurred in 3.44%, while de novo dyspareunia 14.28%. 89.36% patients improved subjective symptoms, and 95.92% were satisfied. CONCLUSION: This surgery achieves high healing rates, with few complications, improvement of subjective symptoms and high level of satisfaction of the patients.

Clinical features and structured clinical evaluation of vasculitis.

Systemic vasculitides are a group of heterogeneous conditions with overlapping patterns of clinical and laboratory manifestations. Moreover, clinical features can be non-specific and seemingly disparate. A major factor in defining optimal therapy and measuring treatment response is careful disease assessment targeting four main domains: activity, damage, prognosis and quality of life/function. Assessment tools such as the Birmingham Activity Score and the Vasculitis Damage Index have become a core feature of clinical trials in ANCA-associated vasculitis (AAV) and formed the basis for sound clinical management of these complex conditions. We are still lacking accurate definitions of disease activity and damage progression in large-vessel vasculitis. There is an increasing interest in the role of patient-reported outcomes as a measure of disease impact; a disease-specific measure for use in AAV is being validated. We review how best to evaluate patients with large-, medium- and small-vessel vasculitis.

The patterns of in vitro cell-death and inflammatory cytokines induced by distinct BCG vaccine strains are differentially induced in human mononuclear cells.

Tuberculosis (TB) remains among the world's leading cause of mortality. For its control, studies of TB vaccines are needed. Since live-attenuated Mycobacterium bovis bacillus Calmette-Guérin (BCG) is the only TB vaccine currently in use, studies on the protective role of BCG are required. In this study, we analyzed host cells purified directly from whole blood of human immunodeficiency virus (HIV)-negative volunteers, comprising adult healthy donors (HD) and neonates (umbilical cord bloods, UCB), with the aim to directly compare in vitro immune responses with distinct BCG strains in human mononuclear cells. The Moreau, Pasteur, and Danish BCG strains were used to infect mononuclear cells in vitro for 48 h; bacilli viability and cell-death were subsequently detected by flow cytometry. In addition, cell culture supernatants were used in cytokine detection assays. Overall, the Moreau BCG strain induced higher levels of apoptosis than the Pasteur and Danish BCG strains in both the HD and UCB groups (p-value < 0.05), and a human monocytic cell-line mirrored those cell-death patterns after BCG infection. The Moreau BCG strain, exclusively, induced Th1 cytokines at the highest levels in cells from adults (p-value < 0.05) when compared with both Pasteur and Danish BCG strains, whereas TGF-ß1 levels were reduced significantly (p-value < 0.01) in the HD group when cells were infected with the Moreau BCG vaccine. As expected, eight out of 22 pro-inflammatory cytokines were secreted at significant levels (p-value < 0.05) above the baseline rates in all BCG-infected cell cultures, in the HD group only. When analyzing these results, we excluded confounding factors related to storage and viability of the BCG strains used. These findings suggest that Moreau BCG is a more potent immunostimulating agent than the Pasteur and Danish BCG strains. Clinical trials will be needed to confirm these findings.

Two separate effects contribute to regulatory T cell defect in systemic lupus erythematosus patients and their unaffected relatives.

Forkhead box P3 (FoxP3)+ regulatory T cells (Tregs ) are functionally deficient in systemic lupus erythematosus (SLE), characterized by reduced surface CD25 [the interleukin (IL)-2 receptor alpha chain]. Low-dose IL-2 therapy is a promising current approach to correct this defect. To elucidate the origins of the SLE Treg phenotype, we studied its role through developmentally defined regulatory T cell (Treg ) subsets in 45 SLE patients, 103 SLE-unaffected first-degree relatives and 61 unrelated healthy control subjects, and genetic association with the CD25-encoding IL2RA locus. We identified two separate, uncorrelated effects contributing to Treg CD25. (1) SLE patients and unaffected relatives remarkably shared CD25 reduction versus controls, particularly in the developmentally earliest CD4+ FoxP3+ CD45RO- CD31+ recent thymic emigrant Tregs . This first component effect influenced the proportions of circulating CD4+ FoxP3high CD45RO+ activated Tregs . (2) In contrast, patients and unaffected relatives differed sharply in their activated Treg CD25 state: while relatives as control subjects up-regulated CD25 strongly in these cells during differentiation from naive Tregs , SLE patients specifically failed to do so. This CD25 up-regulation depended upon IL2RA genetic variation and was related functionally to the proliferation of activated Tregs , but not to their circulating numbers. Both effects were found related to T cell IL-2 production. Our results point to (1) a heritable, intrathymic mechanism responsible for reduced CD25 on early Tregs and decreased activation capacity in an extended risk population, which can be compensated by (2) functionally independent CD25 up-regulation upon peripheral Treg activation that is selectively deficient in patients. We expect that Treg -directed therapies can be monitored more effectively when taking this distinction into account.

Candidate predisposing germline copy number variants in early onset colorectal cancer patients

Purpose. A great proportion of the heritability of colorectal cancer (CRC) still remains unexplained, and rare variants, as well as copy number changes, have been proposed as potential candidates to explain the so-called ‘missing heritability’. We aimed to identify rare high-to-moderately penetrant copy number variants (CNVs) in patients suspected of having hereditary CRC due to an early onset. Methods/patients. We have selected for genome-wide copy number analysis, 27 MMR-proficient early onset CRC patients (<50 years) without identifiable germline mutations in Mendelian genes related to this phenotype. Rare CNVs were selected by removing all CNVs detected at MAF >1% in the in-house control CNV database (n = 629 healthy controls). Copy number assignment was checked by duplex real-time quantitative PCR or multiplex ligation probe amplification. Somatic mutation analysis in candidate genes included: loss of heterozygosity studies, point mutation screening, and methylation status of the promoter. Results. We have identified two rare germline deletions involving the AK3 and SLIT2 genes in two patients. The search for a second somatic mutational event in the corresponding CRC tumors showed loss of heterozygosity in AK3, and promoter hypermethylation in SLIT2. Both genes have been previously related to colorectal carcinogenesis. Conclusions. These findings suggest that AK3 and SLIT2 may be potential candidates involved in genetic susceptibility to CRC (AU)

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Candidate predisposing germline copy number variants in early onset colorectal cancer patients.

PURPOSE: A great proportion of the heritability of colorectal cancer (CRC) still remains unexplained, and rare variants, as well as copy number changes, have been proposed as potential candidates to explain the so-called 'missing heritability'. We aimed to identify rare high-to-moderately penetrant copy number variants (CNVs) in patients suspected of having hereditary CRC due to an early onset. METHODS/PATIENTS: We have selected for genome-wide copy number analysis, 27 MMR-proficient early onset CRC patients (<50 years) without identifiable germline mutations in Mendelian genes related to this phenotype. Rare CNVs were selected by removing all CNVs detected at MAF >1% in the in-house control CNV database (n = 629 healthy controls). Copy number assignment was checked by duplex real-time quantitative PCR or multiplex ligation probe amplification. Somatic mutation analysis in candidate genes included: loss of heterozygosity studies, point mutation screening, and methylation status of the promoter. RESULTS: We have identified two rare germline deletions involving the AK3 and SLIT2 genes in two patients. The search for a second somatic mutational event in the corresponding CRC tumors showed loss of heterozygosity in AK3, and promoter hypermethylation in SLIT2. Both genes have been previously related to colorectal carcinogenesis. CONCLUSIONS: These findings suggest that AK3 and SLIT2 may be potential candidates involved in genetic susceptibility to CRC.

The RUDY study platform - a novel approach to patient driven research in rare musculoskeletal diseases.

BACKGROUND: Research into rare diseases is becoming more common, with recognition of the significant diagnostic and therapeutic care gaps. Registries are considered a key research methodology to address rare diseases. This report describes the structure of the Rare UK Diseases Study (RUDY) platform that aims to improve research processes and address many of the challenges of carrying out rare musculoskeletal disease research. RUDY is an internet-based platform with online registration, initial verbal consent, online capture of patient reported outcome measures and events within a dynamic consent framework. The database structure, security and governance framework are described. RESULTS: There have been 380 participants recruited into RUDY with completed questionnaire rates in excess of 50 %. There has been one withdrawal and two participants have amended their consent options. CONCLUSIONS: The strengths of RUDY include low burden for the clinical team, low research administration costs with high participant recruitment and ease of data collection and access. This platform has the potential to be used as the model for other rare diseases globally.

In vitro T-cell profile induced by BCG Moreau in healthy Brazilian volunteers.

Tuberculosis (TB) remains the world's leading cause of morbidity and mortality. Although Mycobacterium bovis bacillus Calmette-Guérin (BCG) is the only vaccine currently in use, its efficacy is highly variable. It has been suggested that early antigenic presentation is a pivotal event leading to a better immune response in TB vaccine models. To investigate this further, we compared in vitro cell-mediated immune responses in the context of early sensitization with TB (i.e. healthy adults vaccinated with BCG when they were young, HD; n = 25) to those in its absence (i.e., newborns with naïve immunity to TB, UV; n = 10) by challenging mononuclear cells with BCG Moreau. After 48 hours, CD4+ and CD8+ T cells were harvested from both groups and stained for PD-1/CD25/ FOXP3. In addition, supernatants were assayed for a broad range of cytokines using an array system. The HD group showed robust reactivity to Protein Purified Derivative and BCG while the naïve, UV group did not. Similarly, in terms of PD-1 expression and Treg cells (CD4+/CD25high(+)/FOXP3+), only the HD group showed higher levels in CD4 lymphocytes. Otherwise, only the UV group showed expression of CD25dim+ as an activation marker dependent on BCG infection. In terms of cytokines, the HD group showed higher levels of Th1 (IL-2/TNF-α/IFN-γ) and regulatory (IL-10) profiles, with monocytes, but not Tr1 cells, acting as the main source of IL-10. Taken together, our results highlight critical roles of early sensitization with TB in mounting cell-mediated immune responses.

Optimisation of vasculitis disease assessments in clinical trials, clinical care and long-term databases.

The systemic vasculitides are a group of rare, chronic, relapsing, but often progressive inflammatory conditions. They are associated with a significant burden of morbidity both due to scarring from the disease itself and as a consequence of treatment with glucocorticoids and other potent immunosuppressive agents. Careful assessment of disease activity is critical to guide appropriate use of these potentially toxic therapies. It is also important to differentiate features of active disease from those attributable to damage, which will not respond to immunosuppression. As these are chronic complex conditions, the impact on a patient's functional ability and quality of life are also important considerations. Given the lack of a reliable biomarker for assessment of disease activity or damage in systemic vasculitis, clinical tools developed and validated for use initially in clinically trials are key outcome measures in the evaluation of these patients. While the conduct of randomised clinical trials in vasculitis has been significantly enhanced by the development and use of validated outcome measures, regular use of validated disease activity and damage measurements as part of routine care offers a structured approach, which can serve as the basis of justifying treatment decisions. The authors review the concepts of clinical assessment tools used in the evaluation of patients with systemic vasculitis in the setting of clinical practice, clinical trials and long term databases with particular emphasis on disease activity, damage, prognosis and function.

High incidence of large deletions in the PMS2 gene in Spanish Lynch syndrome families.

Lynch syndrome (LS) is caused by germline mutations in one of the four mismatch repair (MMR) genes. Defects in this pathway lead to microsatellite instability (MSI) in DNA tumors, which constitutes the molecular hallmark of this disease. Selection of patients for genetic testing in LS is usually based on fulfillment of diagnostic clinical criteria (i.e. Amsterdam criteria or the revised Bethesda guidelines). However, following these criteria PMS2 mutations have probably been underestimated as their penetrances appear to be lower than those of the other MMR genes. The use of universal MMR study-based strategies, using MSI testing and immunohistochemical (IHC) staining, is being one proposed alternative. Besides, germline mutation detection in PMS2 is complicated by the presence of highly homologous pseudogenes. Nevertheless, specific amplification of PMS2 by long-range polymerase chain reaction (PCR) and the improvement of the analysis of large deletions/duplications by multiplex ligation-dependent probe amplification (MLPA) overcome this difficulty. By using both approaches, we analyzed 19 PMS2-suspected carriers who have been selected by clinical or universal strategies and found five large deletions and one frameshift mutation in PMS2 in six patients (31%). Owing to the high incidence of large deletions found in our cohort, we recommend MLPA analysis as the first-line method for searching germline mutations in PMS2.

A genome-wide association study on copy-number variation identifies a 11q11 loss as a candidate susceptibility variant for colorectal cancer.

Colorectal cancer (CRC) is a complex disease, and therefore its development is determined by the combination of both environmental factors and genetic variants. Although genome-wide association studies (GWAS) of SNP variation have conveniently identified 20 genetic variants so far, a significant proportion of the observed heritability is yet to be explained. Common copy-number variants (CNVs) are one of the most important genomic sources of variability, and hence a potential source to explain part of this missing genetic fraction. Therefore, we have performed a GWAS on CNVs to explore the relationship between common structural variation and CRC development. Phase 1 of the GWAS consisted of 881 cases and 667 controls from a Spanish cohort. Copy-number status was validated by quantitative PCR for each of those common CNVs potentially associated with CRC in phase I. Subsequently, SNPs were chosen as proxies for the validated CNVs for phase II replication (1,342 Spanish cases and 1,874 Spanish controls). Four common CNVs were found to be associated with CRC and were further replicated in Phase II. Finally, we found that SNP rs1944682, tagging a 11q11 CNV, was nominally associated with CRC susceptibility (p value = 0.039; OR = 1.122). This locus has been previously related to extreme obesity phenotypes, which could suggest a relationship between body weight and CRC susceptibility.

Pharmacogenomics in colorectal cancer: a genome-wide association study to predict toxicity after 5-fluorouracil or FOLFOX administration.

The development of genotyping technologies has allowed for wider screening for inherited causes of variable outcomes following drug administration. We have performed a genome-wide association study (GWAS) on 221 colorectal cancer (CRC) patients that had been treated with 5-fluorouracil (5-FU), either alone or in combination with oxaliplatin (FOLFOX). A validation set of 791 patients was also studied. Seven SNPs (rs16857540, rs2465403, rs10876844, rs10784749, rs17626122, rs7325568 and rs4243761) showed evidence of association (pooled P-values 0.020, 9.426E-03, 0.010, 0.017, 0.042, 2.302E-04, 2.803E-03) with adverse drug reactions (ADRs). This is the first study to explore the genetic basis of inter-individual variation in toxicity responses to the administration of 5-FU or FOLFOX in CRC patients on a genome-wide scale.