Psychological impact of multigene cancer panel testing in patients with a clinical suspicion of hereditary cancer across Spain.

OBJECTIVE: Patients' psychological reactions to multigene cancer panel testing might differ compared with the single-gene testing reactions because of the complexity and uncertainty associated with the different possible results. Understanding patients' preferences and psychological impact of multigene panel testing is important to adapt the genetic counselling model. METHODS: One hundred eighty-seven unrelated patients with clinical suspicion of hereditary cancer undergoing a 25-gene panel test completed questionnaires after pretest genetic counselling and at 1 week, 3 months, and 12 months after results to elicit their preferences regarding results disclosure and to measure their cancer worry and testing-specific distress and uncertainty. RESULTS: A pathogenic variant was identified in 38 patients (34 high penetrance and 4 moderate penetrance variants), and 54 patients had at least one variant of uncertain significance. Overall, cancer panel testing was not associated with an increase in cancer worry after results disclosure (P value = .87). Twelve months after results, carriers of a moderate penetrance variant had higher distress and uncertainty scores compared with carriers of high penetrance variants. Cancer worry prior to genetic testing predicted genetic testing specific distress after results, especially at long term (P value <.001). Most of the patients reported the wish to know all genetic results. CONCLUSIONS: Our results suggest that patients can psychologically cope with cancer panel testing, but distress and uncertainty observed in carriers of moderate penetrance cancer variants in this cohort warrant further research.

Serum sCD26 for colorectal cancer screening in family-risk individuals: comparison with faecal immunochemical test.

BACKGROUND: The development of specific screening programs for individuals with a family history of colorectal cancer (CRC) is a priority. This study evaluates the diagnostic performance of serum soluble CD26 (sCD26) in family-risk individuals and compares this marker with the faecal immunochemical test for the detection of advanced neoplasia (AN) (CRC or advanced adenomas; AA). METHODS: Five hundred and sixteen asymptomatic individuals with at least one first-degree relative with CRC were included. Serum sCD26 was measured in all the individuals who also underwent a colonoscopy (53 AA and four cancer cases were found) and a faecal immunochemical test. RESULTS: Setting specificity to 90% and 95%, respectively, sCD26 showed a sensitivity of 39.6% and 28.3% for AA, and of 42.1% and 28.1% for AN. The combination of sCD26 and the faecal test detected AA and AN with a 52.8% and 56.1% sensitivity, corresponding to 93.5% specificity. CONCLUSIONS: The combination of serum sCD26 and the faecal blood test could result a valuable strategy for detecting AN in familial-risk CRC screening.

Effect of oral anticoagulants on the outcome of faecal immunochemical test.

BACKGROUND: We aimed to evaluate whether oral anticoagulants (OACs) alter faecal immunochemical test (FIT) performance in average-risk colorectal cancer (CRC) screening. METHODS: Individuals aged 50-69 years were invited to receive one FIT sample (cutoff 75 ng ml(-1)) between November 2008 and June 2011. RESULTS: Faecal immunochemical test was positive in 9.3% (21 out of 224) of users of OAC and 6.2% (365 out of 5821) of non-users (P-trend=0.07). The positive predictive value (PPV) for advanced neoplasia (AN) in non-users was 50.4% vs 47.6% in users (odds ratio, 0.70; 95% CI, 0.3-1.8; P=0.5). The PPV for AN in OAC more antiplatelets (aspirin or clopidogrel) was 75% (odds ratio, 2; 95% CI, 0.4-10.8; P=0.4). CONCLUSIONS: Oral anticoagulant did not significantly modify the PPV for AN in this population-based colorectal screening program. The detection rate of advanced adenoma was higher in the combination OAC more antiplatelets.

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.

Diagnostic accuracy of the faecal immunochemical test for colorectal cancer in symptomatic patients: comparison with NICE and SIGN referral criteria.

AIM: The diagnostic accuracy of the faecal immunochemical test (FIT) at a 100 ng/ml threshold for colorectal cancer (CRC) was compared with National Institute for Health and Care Excellence (NICE) and the Scottish Intercollegiate Guidelines Network (SIGN) referral criteria. METHOD: A multicentre, prospective, blind study of diagnostic tests was carried out in two Spanish health areas. In 787 symptomatic patients referred for a diagnostic colonoscopy, we determined whether patients met NICE and SIGN referral criteria. All patients performed one FIT determination (OCsensor(™) ). The sensitivity and specificity for CRC detection were determined with McNemar's test. The diagnostic odds ratio as well as the number needed to scope (NNS) to detect a CRC were calculated. RESULTS: We detected CRC in 97 (12.3%) patients; 241 (30.6%) had an FIT ≥ 100 ng/ml and 300 (38.1%) and 473 (60.1%) met NICE and SIGN referral criteria. The FIT had a higher sensitivity for CRC detection than NICE criteria (87.6%, 61.9%; P < 0.001) and SIGN criteria (82.5%; P = 0.4). The specificity of FIT was also higher than NICE and SIGN criteria (77.4%, 65.2%, 42.7%; P < 0.001). The odds ratios of FIT, NICE and SIGN criteria for the diagnosis of CRC were 24.24 (95% CI 12.91-45.53), 3.04 (95% CI 1.96-4.71) and 3.51 (95% CI 2.03-6.06). The NNS to detect a CRC in individuals with an FIT ≥ 100 ng/ml was 2.83 (95% CI 2.4-3.41) and in individuals who met NICE and SIGN criteria it was 5 (95% CI 3.98-6.37) and 5.95 (95% CI 4.85-7.35). CONCLUSION: Our study suggests that FIT is more accurate for the detection of CRC than the current NICE and SIGN referral criteria in symptomatic patients referred for colonoscopy.

Immunohistochemical alterations in invasive adenocarcinoma in endoscopically resected adenoma and factors associated with risk of residual or recurrent disease.

AIM: We determined the pattern of immunohistochemical expression in invasive adenocarcinoma in endoscopically resected adenoma, its relationship with the risk of residual or recurrent disease and the related factors. METHOD: We included individuals with malignant polyps resected endoscopically in the period 1999-2009. Clinical and endoscopic data were collected. All histological specimens were re-analysed. CD44, matrix metalloproteinase 9 (MMP-9), vascular endothelial growth factor-ß (VEGF-ß), ß-catenin, laminin and cyclooxygenase 2 (COX-2) expression were determined by immunohistochemistry. A multivariate logistic regression was performed to determine variables independently associated with the risk of residual or recurrent disease. RESULTS: One-hundred and fifty-one malignant polyps (114 pedunculated; mean size ± SD=22.61 ± 10.86 mm) were resected endoscopically. Resection was fragmented and incomplete in 26.5% and 8.6% of patients, respectively. Surgical resection was performed on 71 (47%) patients. After a median follow-up of 44 months, residual (n=12) or recurrent (n=6) disease was detected in 17 patients. Conventional histology showed that 32.1% met high-risk histological criteria. Immunohistochemical expression was positive for CD44, MMP-9, VEGF-ß, ß-catenin, laminin and COX-2 in 63.3%, 25.3%, 45%, 38.8%, 79% and 34.5% of specimens, respectively, with no differences between both groups. Variables associated with residual or recurrent disease in the univariate analysis were: nonpedunculated morphology (P=0.07); fragmented (P<0.001) or incomplete resection (P<0.001); margin infiltration (P=0.04); and histological high-risk lesion (P=0.003). Finally, incomplete resection (OR=12.16, 95% CI=3.15-46.98; P<0.001) and histological high risk (OR=4.73, 95% CI=1.33-16.74; P=0.002) were independently associated with the risk of residual or recurrent disease. CONCLUSION: Immunohistochemistry could not predict residual or recurrent disease. Only incomplete excision and histological high risk did so. The factors independently associated were histological high-risk lesion and incomplete resection.

Factors associated with complete endoscopic resection of an invasive adenocarcinoma in a colorectal adenoma.

BACKGROUND AND OBJECTIVE: endoscopic polypectomy may allow curative resection of invasive adenocarcinoma on colorectal adenoma. Our goal was to determine the factors associated with complete endoscopic resection of invasive adenocarcinoma. METHODS: retrospective observational study. We included 151 patients with invasive adenocarcinoma on adenomas endoscopically resected between 1999 and 2009. We determined those variables independently related to incomplete resection by a logistic regression. Relation was expressed as Odds Ratio (OR) and its 95% confidence interval (95% CI). RESULTS: patients were predominantly male (66.2%) and their mean age was 68.03 ± 10.65 years. Colonoscopy was completein 84% of the patients and 60.3% had synchronous adenomas. Invasive adenocarcinoma was mainly located in distal colon (90.7%) and morphology was pedunculated in 75.5%. The endoscopic averagesize was 22.61 ± 10.86 mm. Submucosal injection was required in 32.5%. Finally, the resection was in one piece in 73.5% and incomplete in 8.6% of the adenocarcinomas. Factors independently associated with incomplete endoscopic resection were size (mm) (OR 1.08, 95% CI 1.03-1.14, p = 0.002), sessile or flat morphology (OR 8.78, 95% CI 2.24-34.38, p = 0.002) and incomplete colonoscopy (OR 4.73, 95% CI 1.15-19.34, p = 0.03). CONCLUSIONS: endoscopic polypectomy allows complete resection of 91.4% of invasive adenocarcinomas on colorrectal adenoma in our series. Factors associated with incomplete resection were the size of the lesion, sessile or flat morphology and incomplete colonoscopy.

[Usefulness of ultrasonography and computerized tomography in predicting resectability of pancreatic carcinoma]. / Utilidad de la ultrasonografía y la tomografía computarizada en la predicción de la resecabilidad del carcinoma pancreático.

BACKGROUND: Surgical resection is the only curative treatment of pancreatic carcinoma (PC). An accurate assessment of the extension of PC is mandatory to select appropriate patients to this therapeutic option. This study was aimed at assessing the usefulness of abdominal ultrasonography (US) and computed tomography (CT) to establish tumoral staging and to predict tumor resectability. PATIENTS AND METHODS: Between January 1990 and December 1995, 84 PC patients were submitted to surgical procedures (potentially curative resection in 30%, biliodigestive anastomosis in 51% and exploratory laparotomy in 13%). Preoperative staging was carried out by means of abdominal US and/or CT. Definitive staging was established according to surgical findings, using the TNM classification. RESULTS: Accuracy of preoperative evaluation with regard to tumoral staging was 65%, being underestimated in 29 (35%) patients. This underestimation was mainly due to lesions in stage I. In addition, preoperative staging predicted tumor unresectability with a 50% sensitivity and a 83% specificity. CONCLUSIONS: US and CT have a good specificity in the staging and unresectability prediction of pancreatic cancer. However, their usefulness is limited by their low sensitivity.

Endoscopic follow-up of patients after curative surgery for colorectal cancer: results of a medical assistance protocol.

AIMS: To evaluate the results of an endoscopic follow-up assistance protocol for colorectal cancer (CRC) after curative surgery. PATIENTS AND METHODS: Between 1994 and 1996, 205 patients with CRC were submitted to curative surgery in our hospital. An endoscopic follow-up was proposed to the patients based on an endoscopy six months following surgery, in the case they did not have a complete endoscopy prior to surgery, or one year after surgery if they did, another one two years later, and a third endoscopy between the third and fifth year. We retrospectively analyzed the follow-up outcome and endoscopic findings. RESULTS: 155 patients were submitted to follow-up, of which 74,2% completed the protocol. 3 synchronous tumours, 4 anastomosis relapses and 2 metachronous tumours were detected. Curative surgery was performed on 100% of the synchronous tumours, 50% of the relapses and 50% of the metachronous tumours. 48.3% and 20.6% of the patients had synchronous and metachronous polyps, respectively. 14.7% of the polyps were larger than 1 cm, 21.7% and 4.8% were tubulovillous and villous, respectively, and 3.7% had severe dysplasia. Finally, patients with synchronous polyps had higher risk of developing metachronous polyps (RR 7.1, CI 95% 2.3; 22.2, p<0.0001). CONCLUSIONS: The rate of adenomatous polyps with high risk of malignant degeneration, metachronous tumours or relapses detected by colonoscopy is low in our series. On the other hand, the detection of polyps during follow-up was related to the presence of synchronous polyps.

[Autoimmune hepatitis associated with thyroiditis and hypophysitis. A case report]. / Hepatitis autoinmune asociada a tiroiditis e hipofisitis. Presentación de un caso.

Autoimmune hepatitis primarily affects women and 40% of cases are associated with extrahepatic autoimmune dysfunction. Thyroiditis, ulcerative colitis and rheumatoid arthritis are the most commonly implicated entities. We present a 46-year-old woman with type-II autoimmune hepatitis and Graves disease who presented deterioration in level of consciousness, her symptoms mimicking severe liver failure. Hormone studies and nuclear magnetic resonance imaging revealed hypophysitis, which led to hypothyroidism and metabolic encephalopathy. The syndrome was resolved with hormone replacement therapy.

[Simultaneous presentation of autoimmune thyroiditis and celiac disease in an adult]. / Tiroiditis autoinmune y enfermedad celíaca del adulto de presentación simultánea.

Celiac disease may be associated with other underlying autoimmune diseases. Among these, thyroid disease has been described in around 10% of the cases with hypothyroidism being the most frequently reported. Clinical suspicion of thyroid involvement in patients with celiac disease is difficult since the symptomatology is scarce or is masked by the picture of malabsorption. Nonetheless, its detection is important since it is not solved by gluten free diet and its correction requires specific treatment. Thyroid function studies, in addition to determination of antithyroglobulin and antimicrosomal antibodies, should be considered in celiac patients refractory to conventional dietetic treatment. We herein present the case of a 65-year-old woman who consulted for a malabsorption syndrome in whom celiac disease of the adult was simultaneously presented with hyperthyroidism secondary to autoimmune thyroiditis.

[Purtscher's retinopathy: a rare complication of acute non-alcoholic pancreatitis]. / Retinopatía de Purtscher: complicación infrecuente de la pancreatitis aguda no alcohólica.

Purtscher's retinopathy is a rare complication of acute alcoholic pancreatitis that is characterized by the development of cotton-wool exudates and retinal hemorrhages located around the optic disk. Its development is due to ischemic phenomena in the posterior pole of the retina due to microemboli in the retinal arterioles and capillaries. This complication is not related to a poorer prognosis of acute pancreatitis and the retinopathy usually has a favorable outcome with disappearance of the ophthalmic lesions and restoration of visual acuity after 4-6 weeks in most cases. However, some patients may show residual lesions, especially if optical atrophy occurs. We present a 40-year-old woman with loss of visual acuity due to Purtscher's retinopathy during the course of mild acute idiopathic pancreatitis.

[Infectious complications associated with liver transplantation: analysis of 104 patients]. / Complicaciones infecciosas asociadas al trasplante hepático: análisis de 104 pacientes.

OBJECTIVE: Infectious complications are the main cause of morbidity and mortality during the first year after liver transplantation. The aim of the present study was to determine the incidence, microorganisms and factors associated with the development of infectious complications. PATIENTS AND METHOD: Retrospective analysis of infectious episodes during the first year after transplantation in 104 patients undergoing transplantation between April 1995 and December 1996. The various clinical variables related to the pre-transplant disease, the surgical intervention and post-transplant evolution were evaluated with the aim of identifying predictive factors for the development of bacterial infectious complications. RESULTS: During the first year, 51 patients (49%) presented 111 infectious episodes. The most frequent infections were bacterial (66%); 21% were cytomegalovirus infections and 22% were fungal. The incidence of bacterial infections was highest during the first month (80% of all infectious episodes in this period). Two variables were independently associated with the development of bacterial infections in the first month following transplantation: prolonged ischemia of the graft (p = 0.002) and length of stay in the intensive care unit (p = 0.002). Infectious complications caused 8 of the 11 deaths that occurred during the 1-year follow-up. Mortality associated with invasive fungal infections was 100%. CONCLUSIONS: Although the overall incidence of infections and associated mortality has decreased, it remains the main cause of mortality and morbidity in the first year after transplantation.

Mismatch repair status in the prediction of benefit from adjuvant fluorouracil chemotherapy in colorectal cancer.

AIM: Some retrospective studies have shown a lack of benefit of 5-fluorouracil (5-FU) adjuvant chemotherapy in patients with mismatch repair (MMR) deficient colorectal cancer. Our aim was to assess if this molecular marker can predict benefit from 5-FU adjuvant chemotherapy. A second objective was to determine if MMR status influences short term survival. METHODS: We included 754 patients with a median follow up of 728.5 days (range 1-1097). A total of 260 patients with stage II or III tumours received 5-FU adjuvant chemotherapy, according to standard clinical criteria and irrespective of their MMR status. A tumour was considered MMR deficient when either BAT-26 showed instability or there was loss of MLH1 or MSH2 protein expression. RESULTS: At the end of the follow up period, 206 patients died and 120 presented with tumour recurrence. Sixty six (8.8%) patients had MMR deficient tumours. There were no significant differences in overall survival (MMR competent 72.1%; MMR deficient 78.8%; p = 0.3) or disease free survival (MMR competent 61.3%; MMR deficient 72.3%; p = 0.08). In patients with stage II and III tumours, benefit from 5-FU adjuvant chemotherapy was restricted to patients with MMR competent tumours (overall survival: chemotherapy 87.1%; non-chemotherapy 73.5%; log rank, p = 0.00001). Patients with MMR deficient tumours did not benefit from adjuvant chemotherapy (overall survival: chemotherapy 89.5%; non-chemotherapy 82.4%; log rank, p = 0.4). CONCLUSIONS: Benefit from 5-FU adjuvant chemotherapy depends on the MMR status of tumours in patients with colorectal cancer. 5-FU adjuvant chemotherapy improves survival in patients with MMR competent tumours but this benefit from chemotherapy cannot be extended to patients with MMR deficient tumours.

Pulmonary abscess as a complication of transarterial embolization of multinodular hepatocellular carcinoma.

Hepatic transarterial embolization has been widely used in the treatment of hepatocellular carcinoma and other liver tumors. Despite being a safe treatment, some complications associated with this procedure have been described. The most frequent adverse effect of transarterial embolization is postembolization syndrome, whereas infections account for only 3.4% of complication. We report the first case of lung abscess as a complication of transarterial embolization used in the treatment of multinodular hepatocellular carcinoma.

Prognostic factors in nonresectable pancreatic adenocarcinoma: a rationale to design therapeutic trials.

OBJECTIVE: Most patients with pancreatic cancer show an advanced tumor at the time of diagnosis. In recent years, new therapies have been developed in such patients, thus forcing the analysis of factors that influence their survival. The present study was aimed at determining the prognostic factors in a series of 134 consecutive patients with pancreatic carcinoma not suitable for surgical resection, due to either locally advanced tumors or metastatic spread. METHODS: First, 34 epidemiological, clinical, analytical, and tumor-related parameters recruited at admission were included in a univariate analysis of survival by using the Kaplan-Meier method. Those significant variables in the previous step were thereafter introduced in a Cox regression procedure. A prognostic index for calculating the relative risk of death of each patient was also proposed. RESULTS: The median survival time in the whole series was 3.11 months, the 3, 6, and 12 months probability of survival being 51%, 28%, and 8%, respectively. Eight of 34 variables (jaundice and toxic syndrome at admission, serum cholesterol, iron and alanine aminotransferase concentrations, leukocyte count, baseline performance status, and the presence of distant metastases) were selected in the univariate analysis. Of these eight parameters, the Cox regression analysis identified a preserved baseline performance status (OR = 2.14, 95% CI = 1.49-3.04) and the absence of metastases (OR = 1.34, 95% CI = 1.03-1.73) as the only variables independently associated with a longer survival. Therefore, a prognostic index was constructed allowing the division of patients in three different groups according to their relative risk of death (RRD) = exp (performance status x 0.7589 + presence of metastases x 0.2891). CONCLUSIONS: The results of the present investigation suggest that baseline performance status and distant metastases should be considered in designing and evaluating any therapeutic trial in patients with nonresectable pancreatic carcinoma.