Genomic alterations accompanying tumour evolution in colorectal cancer: tracking the differences between primary tumours and synchronous liver metastases by whole-exome sequencing.

BACKGROUND: Colorectal cancer (CRC) patients with metastatic disease can become cured if neoadjuvant treatment can enable a resection. The search for predictive biomarkers is often performed on primary tumours tissue. In order to assess the effectiveness of tailored treatment in regard to the primary tumour the differences in the genomic profile needs to be clarified. METHODS: Fresh-frozen tissue from primary tumours, synchronous liver metastases and adjacent normal liver was collected from 21 patients and analysed by whole-exome sequencing on the Illumina HiSeq 2500 platform. Gene variants designated as 'damaging' or 'potentially damaging' by Ingenuity software were used for the subsequent comparative analysis. BAM files were used as the input for the analysis of CNAs using NEXUS software. RESULTS: Shared mutations between the primary tumours and the synchronous liver metastases varied from 50 to 96%. Mutations in APC, KRAS, NRAS, TP53 or BRAF were concordant between the primary tumours and the metastases. Among the private mutations were well-known driver genes such as PIK3CA and SMAD4. The number of mutations was significantly higher in patients with right- compared to left-sided tumours (102 vs. 66, p = 0.004). Furthermore, right- compared to left-sided tumours had a significantly higher frequency of private mutations (p = 0.023). Similarly, CNAs differed between the primary tumours and the metastases. The difference was mostly comprised of numerical and segmental aberrations. However, novel CNAs were rarely observed in specific CRC-relevant genes. CONCLUSION: The examined primary colorectal tumours and synchronous liver metastases had multiple private mutations, indicating a high degree of inter-tumour heterogeneity in the individual patient. Moreover, the acquirement of novel CNAs from primary tumours to metastases substantiates the need for genomic profiling of metastases in order to tailor metastatic CRC therapies. As for the mutational status of the KRAS, NRAS and BRAF genes, no discordance was observed between the primary tumours and the metastases.

Microscopic colitis: clinical findings, topography and persistence of histopathological subgroups.

BACKGROUND: Uncertainty remains on topography and persistence of histological subgroups of microscopic colitis (MC). AIM: To assess longitudinal clinical, endoscopic, histological, and therapeutic description of MC subgroups including patients with incomplete findings of MC (MCi). METHODS: Retrospective review of a consecutive cohort with MC and histological reassessment of MCi. RESULTS: Clinical characteristics of 168 patients with lymphocytic colitis (LC), 270 with collagenous colitis (CC) and 101 with MCi were similar. At colonoscopy 95% (95% CI: 91-98%) of CC and 98% (93-100%) of LC cases had diagnostic histopathology of MC in both left and right colon. Eight and three patients had characteristics of MC only in the left and right colon, respectively. Histology findings resembling coexistence of the other MC subtype was present in 48% (40-55%) with CC and 24% (18-31%) with LC. A first diagnosis of MC was made in 49 (30%) of 164 patients only at repeat endoscopy. Another 34 of 115 (30%) with MC in the first endoscopy did not fulfil the MC criteria at repeat endoscopy. Only seven cases had a primary endoscopy without histopathological abnormalities. Fifteen percentage of MCi were reclassified as MC. Ileal inflammation was present in 33 of 81 patients. Budesonide was efficacious in all MC subgroups irrespective of bile acid malabsorption. CONCLUSIONS: Clinical characteristics of microscopic colitis subgroups are indistinguishable. Biopsies from the left colon suffice to exclude microscopic colitis, and the histological diagnosis of microscopic colitis is inconsistent over time. Ileal inflammation is common. The term microscopic colitis should perhaps be considered one clinical entity and include lymphocytic colitis, collagenous colitis, and incomplete findings of microscopic colitis.

Inhaled iloprost for sarcoidosis associated pulmonary hypertension.

RATIONALE: Patients with sarcoidosis associated pulmonary hypertension (SAPH) have responded to systemic prostacyclin therapy. OBJECTIVES: To determine the rate of response to inhaled prostacyclin, iloprost, in SAPH. METHODS: Sarcoidosis patients with pulmonary hypertension and no evidence for left ventricular dysfunction were enrolled in an open label, prospective study. Patients underwent right heart catheterization and six minute walk (6MW) test. Quality of life was evaluated using several instruments, including the Saint George Respiratory Questionnaire (SGRQ). Patients received 5 mcg of inhaled iloprost every 2-3 hours while awake. After four months of therapy, patients underwent repeat cardiac catheterization, 6 MW test, and completed quality of life questionnaires. MEASUREMENTS AND MAIN RESULTS: Of the 22 patients enrolled, 15 completed all 16 weeks of therapy. The most common reasons for study discontinuation included drug associated cough (3 patients) and compliance with the prescribed number of treatments per day (2 patients). Six patients experienced a 20% or greater decrease in pulmonary vascular resistance (PVR) from baseline with five of these six patients also showing > or = 5 mm Hg reduction in PA mean. Although three patients improved the 6MW distance by at least 30 meters, only one had a decrease in PVR. At 16 weeks a significant decrease was reported in the SGRQ activity score (p = 0.0273), with seven patients having a 4 point or greater decrease. CONCLUSION: Inhaled iloprost as monotherapy was associated with an improvement in pulmonary hemodynamics and quality of life as assessed by the SGRQ activity score in some sarcoidosis patients with SAPH.

Absence of latent Epstein-Barr virus in thymic epithelial tumors as demonstrated by Epstein-Barr-encoded RNA(EBER) in situ hybridization.

BACKGROUND: Several studies have established that Epstein-Barr virus (EBV) is associated with lympho-proliferative disorders such as Burkitt's lymphoma and Hodgkin's disease. EBV is also present in undifferentiated nasopharyngeal carcinomas and in tumors of similar morphology (lymphoepithelioma-like carcinomas) arising in a variety of organs, predominantly in stomach, salivary gland and thymus. As reports of EBV-positive thymic epithelial tumors (TET) have been divergent and as different methods have been used to detect EBV, the aim of this study was to investigate the possible role of EBV in TET of Danish patients. MATERIAL AND METHODS: Archival material of 157 cases of TET (105 thymomas and 52 thymic carcinomas, including 4 lymphoepithelioma-like thymic carcinomas (LELTC)) was analyzed for EBV by applying a sensitive and specific method for detecting latently EBV-infected cells (in situ hybridization for EBV-encoded RNA (EBER)). RESULTS: All investigated cases were EBER negative. CONCLUSIONS: EBV does not seem to be implicated in the pathogenesis of TET. However, a review of the literature showed that 28% of LELTC were EBER ISH positive. As they occurred in young people (mean 18 years), at an age when the patients were susceptible to infection by EBV, it is suggested that EBV merely acts as an innocent bystander.

[Thymomoa in Denmark]. / Tymomer i Danmark.

This is a descriptive study of thymomas notified to the national Danish Cancer Registry and registered by the departments of pathology during the years 1943-1993. A total of 433 cases of benign and malignant thymomas were included over these 50 years with an increase of the incidence to a stable rate of 2.5/million/year from start to 1973. The male:female ratio is 1:1. While the age-specific incidence rate for persons below 40 years is constantly low throughout the period of investigation, a doubling of the rate is registered for persons between 70 and 79 during the period 1978-1993. The incidence rate in Copenhagen is much higher compared to other regions of Denmark. The above-mentioned increase in incidence is due mainly to an underreporting of benign thymomas during the first period of investigation (1943-1977), but may also be due to improved diagnostic capabilities and to more uniform methods of registration during the last period (1978-1993).

Heart disease and pregnancy.

Pregnancy is associated with major hemodynamic changes in the cardiovascular system that can contribute to greater morbidity and mortality in women with underlying heart disease. Therefore, the diagnosis and management of these disorders in the pregnant patient require understanding of cardiovascular physiology during pregnancy, labor, delivery, and the puerperium. It is also essential to have knowledge about safety and utility of various diagnostic modalities and drugs during pregnancy to treat maternal heart disease without compromising fetal well-being.

[Malignant mesothelioma of the pleura with an unusual course]. / Malignt mesoteliom i pleura med usaedvanligt forløb.

An unusual case of malignant mesothelioma of the pleura in a man aged 73 years is described. Four years after debut of symptoms a tumour emerged at the site of a previous pleural drainage and grew during the next two years to the size of a man's head. After removal of the tumour, the histological diagnosis was reviewed and confirmed. Six and a half years after the first diagnosis, the patient is still alive and in a reasonable condition in spite of bilateral pleural involvement.

Acute rheumatic carditis: diagnostic and therapeutic challenges in the era of heart transplantation.

Heart transplantation as a treatment for end-stage heart failure has spawned numerous important challenges in patient care. A heart transplant patient with clinically unsuspected acute rheumatic carditis had an ultimately fatal course marked by refractory rejection and early death after transplantation. The patient had several immune abnormalities. Peripheral blood T lymphocytes (CD2+) were significantly elevated (p < 0.05) by flow cytometry in active rheumatic carditis versus 76 healthy individuals. The CD4+:CD8+ T-cell ratio was 5.5:1 in rheumatic disease and only 2.7:1 in healthy individuals. Numbers of peripheral blood B lymphocytes (CD19+), macrophages (CD14+), and interleukin-2 receptor-positive cells (CD25+) were also elevated in rheumatic disease. Natural killer cells (CD16+) were slightly reduced in number and appeared functionally deficient, and antibody-dependent cellular cytotoxicity was also reduced. Immunohistochemically, infiltrating cells in Aschoff lesions of the rheumatic native heart were mainly T cells, with putative TH/I cells predominating. The striking immune accompaniments of acute rheumatic fever may have heralded profound immune-mediated allograft intolerance leading to the patient's demise. Considering the recrudescence of rheumatic heart disease in this country and its remaining worldwide importance, such patients as the one discussed offer daunting clinical challenges when transplantation is an obvious management choice for severe, end-stage dilated cardiomyopathy.

[Vaginitis emphysematosa]. / Vaginitis emphysematosa.

Vaginitis emphysematosa is a benign, uncommon condition characterised by the presence of gas-filled cysts beneath the vaginal epithelium. Cases has been reported in pregnant women, in patients with diseases of the cardiovascular system and in patients with Trichomonas or Gardnerella vaginitis. To date the etiology and pathogenesis have not been fully elucidated. A case of vaginitis emphysematosa in a patient with cardiovascular disease is described.

Home intravenous dobutamine therapy in patients awaiting heart transplantation.

Lack of donor availability has heightened our awareness of the need for suitable long-term management of heart failure in patients awaiting heart transplantation. Frequently patients become dependent on intravenous inotropic agents despite attempts to discontinue these agents. This can lead to prolonged hospitalizations, separation anxiety and depression in families, high hospitalization costs, and poor quality of life. Between June 1987 and April 1988 three patients awaiting heart transplantation at the University of Cincinnati Hospital were sent home while receiving constant intravenous infusion of dobutamine. All three patients had had prolonged hospitalizations and were unable to be weaned from dobutamine without clinical compromise. The patients were New York Heart Association functional class III to IV, had cardiac indices between 1.5 to 2.13 L/min/m2, cardiac output less than 4.0 L/min, pulmonary capillary wedge pressures 17 to 27 mm Hg, and left ventricular ejection fraction less than 20% in two of the patients (idiopathic cardiomyopathy), and 30% in the third patient who was awaiting retransplantation (refractory repeated acute rejections). Dobutamine was infused by means of a constant-rate portable cassette pump at 3.17 micrograms/kg/min in patient 1, 10 micrograms/kg/min in patient 2, and 5 micrograms/kg/min in patient 3. A critical care home health nursing agency was used for follow-up home care. All three patients had central lines placed before discharge from the hospital. Each patient was instructed in proper care of the central line and infusion pump and was able to demonstrate accurate technique before being discharged home. Complications were minimal and were related to central line placement. No patient required rehospitalization for complications. No wound infections were reported.(ABSTRACT TRUNCATED AT 250 WORDS)

Spontaneous cyclic severe mitral regurgitation.

Two patients are described with spontaneous wide fluctuations in the size of pulmonary capillary wedge pressure V waves thought to be related to cyclic spontaneous variations in the degree of mitral regurgitation over very short periods of time. The findings are thought to represent a hemodynamically distinct syndrome intermediate between chronic severe and acute severe mitral regurgitation.

Emergency bypass system: analysis of gas transfer.

A portable emergency bypass system using a membrane oxygenator device (CPS) was evaluated. The ability of the CPS to supply the oxygen transfer needs of five anesthetized dogs consistently over six hours and the system's effects on hemoglobin concentration, platelet count, and degree of hemolysis were assessed. The animals maintained spontaneous heart beats, pump flows averaged 100 ml/kg/min; mean arterial pressures were maintained at from 114 to 144 mm Hg. Immediate dilution of hemoglobin and platelet levels occurred in the first 30 minutes. Further hemodilution was limited during the first two hours, although three of the animals required transfusions during the six-hour period to maintain their hematocrits. Plasma free hemoglobin did not significantly increase during the six hours. Baseline oxygen consumption data obtained in three animals ranged from 44.5 to 96 (ml oxygen/min/m2). Oxygen and carbon dioxide transfer measurements during the first hour of bypass were not significantly different from measurements during the last hour of perfusion. The study suggests that optimal use of the CPS could supply much if not all of a patient's basal oxygen transfer requirements for at least six hours.

Sequelae of injury to the heart caused by multiple needles.

A case is reported in which multiple needles were inserted into the heart by a patient, resulting in the unusual combination of a coronary artery-cameral fistula to the left ventricle, an intramural defect of the left ventricular free wall and a ventricular septal defect. This unique lesion was suspected on the basis of two-dimensional and Doppler echocardiography and contrast computed tomographic imaging. Its presence was confirmed during cardiac catheterization and cineangiography.

Hemodynamics of transcutaneous cardiac pacing.

Transcutaneous cardiac pacing has recently been rediscovered as a rapid means of initiating emergency cardiac pacing. Potential myocardial injury from extended transcutaneous pacing could adversely affect cardiac hemodynamics during pacing. This canine study compares the hemodynamics of transcutaneous and transvenous cardiac pacing in animals with induced chronic heart block. One to two weeks following chemical ablation of the His bundle, hemodynamic measurements were made during 60 minutes of transcutaneous and 5-minute periods of conventional right ventricular endocardial pacing. Cardiac index and output were found to increase significantly (P less than 0.005), and systemic vascular resistance was found to decrease significantly (P less than 0.005) from baseline values with both pacing techniques. A hemodynamic difference between pacing techniques was evident only for mean arterial blood pressure; pressure measurements during transvenous pacing were slightly greater than those during transcutaneous cardiac pacing. The hemodynamic measurements were found to be stable during a 60-minute period of transcutaneous cardiac pacing. This study demonstrates that transcutaneous cardiac pacing is as effective hemodynamically as conventional transvenous pacing in animals with induced chronic heart block.