Genomic characterisation of breast fibroepithelial lesions in an international cohort

Fibroepithelial lesions (FELs) are a heterogeneous group of tumours comprising fibroadenomas (FAs) and phyllodes tumours (PTs). Here we used a 16-gene panel that was previously discovered to be implicated in pathogenesis and progression, to characterise a large international cohort of FELs via targeted sequencing. The study comprised 303 (38%) FAs and 493 (62%) PTs which were contributed by the International Fibroepithelial Consortium. There were 659 (83%) Asian and 109 (14%) non-Asian FELs, while the ethnicity of the rest was unknown. Genetic aberrations were significantly associated with increasing grade of PTs, and were detected more in PTs than FAs for MED12, TERT promoter, RARA, FLNA, SETD2, TP53, RB1, EGFR, and IGF1R. Most borderline and malignant PTs possessed ≥ 2 mutations, while there were more cases of FAs with ≤ 1 mutation compared to PTs. FELs with MED12 mutations had significantly higher rates of TERT promoter, RARA, SETD2, EGFR, ERBB4, MAP3K1, and IGF1R aberrations. However, FELs with wild-type MED12 were more likely to express TP53 and PIK3CA mutations. There were no significant differences observed between the mutational profiles of recurrent FAs, FAs with a history of subsequent ipsilateral recurrence or contralateral occurrence, and FAs without a history of subsequent events. We identified recurrent mutations which were more frequent in PTs than FAs, with borderline and malignant PTs harbouring cancer driver gene and multiple mutations. This study affirms the role of a set of genes in FELs, including its potential utility in classification based on mutational profiles. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Evidence of a Role for Fibroblast Transient Receptor Potential Canonical 3 Ca2+ Channel in Renal Fibrosis

Transient receptor potential canonical (TRPC) Ca²⁺-permeant channels, especially TRPC3, are increasingly implicated in cardiorenal diseases. We studied the possible role of fibroblast TRPC3 in the development of renal fibrosis. In vitro, a macromolecular complex formed by TRPC1/TRPC3/TRPC6 existed in isolated cultured rat renal fibroblasts. However, specific blockade of TRPC3 with the pharmacologic inhibitor pyr3 was sufficient to inhibit both angiotensin II- and 1-oleoyl-2-acetyl-sn-glycerol–induced Ca²⁺ entry in these cells, which was detected by fura-2 Ca²⁺ imaging. TRPC3 blockade or Ca²⁺ removal inhibited fibroblast proliferation and myofibroblast differentiation by suppressing the phosphorylation of extracellular signal-regulated kinase (ERK1/2). In addition, pyr3 inhibited fibrosis and inflammation-associated markers in a noncytotoxic manner. Furthermore, TRPC3 knockdown by siRNA confirmed these pharmacologic findings. In adult male Wistar rats or wild-type mice subjected to unilateral ureteral obstruction, TRPC3 expression increased in the fibroblasts of obstructed kidneys and was associated with increased Ca²⁺ entry, ERK1/2 phosphorylation, and fibroblast proliferation. Both TRPC3 blockade in rats and TRPC3 knockout in mice inhibited ERK1/2 phosphorylation and fibroblast activation as well as myofibroblast differentiation and extracellular matrix remodeling in obstructed kidneys, thus ameliorating tubulointerstitial damage and renal fibrosis. In conclusion, TRPC3 channels are present in renal fibroblasts and control fibroblast proliferation, differentiation, and activation through Ca²⁺-mediated ERK signaling. TRPC3 channels might constitute important therapeutic targets for improving renal remodeling in kidney disease.     

Expression of CD markers' in immune thrombocytopenic purpura: prognostic approaches

Immune Thrombocytopenic Purpura (ITP) is a common autoimmune bleeding disorder characterized by a reduction in peripheral blood platelet counts. In this disease, autoantibodies (Auto‐Abs) are produced against platelet GPIIb/GPIIIa by B cells, which require interaction with T cells. In this review, the importance of B and T lymphocytes in ITP prognosis has been studied. Relevant literature was identified by a PubMed search (1990–2016) of English‐language papers using the terms B and T lymphocyte, platelet, CD markers and immune thrombocytopenic purpura. T and B lymphocytes are the main immune cells in the body. Defective function causes disrupted balance of different subgroups of lymphocytes, and abnormal expression of surface markers of these cells results in self‐tolerance dysfunction, as well as induction of Auto‐Abs against platelet glycoproteins (PG). Given the role of B and T cells in production of autoantibodies against PG, it can be stated that the detection of changes in CD markers' expression in these cells can be a good approach for assessing prognosis in ITP patients.     

Peritoneal and intestinal tuberculosis: an ancestral disease that poses new challenges in the technological era. Case report and review of the literature

Tuberculosis is a public health problem. The most common presentation is pulmonary disease. The diagnosis of any extrapulmonary forms are quite difficult. Clinical manifestations of gastrointestinal tuberculosis are non-specific and compatible with pathologies such as inflammatory bowel disease, advanced ovarian cancer, deep mycosis, yersinia infection and amebomas. Abdominal form is located at 6th place of the extrapulmonary forms, after lymphatic, genitourinary, osteoarticular, miliary and meningeal infections. Eventually, 25 to 75% of patients with abdominal tuberculosis will require surgery. These procedures should be limitated with the purpose to preserve small bowel. Resection should be limitated for complicated cases. The surgical indications include: Intestinal occlusion (15-60%), perforation (1-15%), abscesses and fistulas (2-30%) and hemorrhage (2%). CONCLUSIONS: In most of the cases, the diagnosis of peritoneal or intestinal tuberculosis is made during a laparoscopy or laparotomy even during surgery performed by different purposes. Excessive manipulation of the intraabdominal organs may produced unexpected bowel lesions, increasing morbidity and mortality. Medical treatment is highly effective in the resolution of moderate complications such as bowel obstruction. Resectional procedures should be reserved for complications like perforation, bleeding or stenosis non-suitable for stricturoplasty.     

The Ross operation: clinical results and echocardiographic findings

Between November 2001 and September 2004, 80 patients aged 11 to 56 years (mean, 27.6 years) underwent the Ross operation. The mean preoperative New York Heart Association functional class was 2.37 +/- 0.72, and the mean ejection fraction was 52.8% +/- 16%. Aortic involvement included stenosis in 19 (24%) patients, regurgitation in 22 (28%), and both in 39 (49%). Root replacement was the technique used in all cases. The mean hospital stay was 5 days, and 74 patients (93%) were followed up for 4-48 months. Four-year actuarial survival rate was 96.25%. Postoperative echocardiography revealed no pulmonary autograft insufficiency in 50 patients (63%), trivial to mild insufficiency in 22 (28%), moderate insufficiency in 2 (3%), and severe insufficiency in one (1%). Two patients required autograft re-intervention. Postoperative echocardiography of the pulmonary homograft valve showed severe stenosis (peak gradient > 50 mm Hg) in 2 patients, and moderate stenosis (peak gradient 25-50 mm Hg) in one. The mean postoperative left ventricular ejection fraction was 51.4%. The Ross operation can be considered an elegant alternative to prosthetic valves in the treatment of aortic valve diseases in developing countries.     

Cardiac troponin T levels are associated with poor short- and long-term prognosis in patients with acute cardiogenic pulmonary edema

Background The clinical determinants of increased cardiac troponin T (cTnT) in patients with acute cardiogenic pulmonary edema are not well defined, and the ability of this marker to predict long-term mortality has not yet been documented. Methods Eighty-four patients with acute cardiogenic pulmonary edema without acute myocardial infarction were prospectively enrolled. cTnT was measured in samples obtained 6 and 12 hours after admission. Results cTnT levels of 0.1 ng/mL or greater were found in 46 patients (55%). Thirty-two patients (38%) died during follow-up. The area under the receiver operating characteristic curve for cTnT was 0.70 and 0.69 at 6 and 12 hours (P = .47), and the cTnT cutoff value of 0.1 ng/mL was 66% and 69% sensitive and 63% and 71% specific, respectively, in predicting subsequent mortality. Patients were assigned to group 1 if they had cTnT lower than 0.1 ng/mL and to group 2 if they had cTnT levels of 0.1 ng/mL or greater. A history of coronary artery disease was present in 72% of group 2 versus 50% of group 1 patients (P = .04). Patients in group 2 were also older than those in group 1 (mean age, 68 years vs 61 years; P = .021). The 3-year survival in group 1 was 76% compared with 29% in group 2 (log-rank test, P < .001). In a Cox proportional hazards model, elevated cTnT emerged as the only prognostic marker of long-term mortality (risk ratio [RR] = 2.31; 95% CI, 1.011-5.280; P = .047). Conclusions A cTnT level of 0.1 ng/mL or greater was associated with poor long-term survival and emerged as a powerful independent predictor of mortality in patients with acute cardiogenic pulmonary edema. (Am Heart J 2002;143:814-20.)     

Reduced intensity conditioning regimen followed by glycosylated G-CSF mobilized PBSCT in patients with solid tumors and malignant lymphomas

The aim of this pilot study was to exploit the graft-versus-tumor potential of allogeneic transplants while improving safety of the procedure. Twelve patients with advanced hematological malignancies and solid tumors underwent a low intensity conditioning regimen (fludarabine and cyclophosphamide) followed by an allogeneic peripheral blood stem cell transplantation. The median time to achieve an absolute neutrophil count of more than 0.5 x 10(9)/l and an untransfused platelet count of more than 20 x 10(9)/l was 15 and 14 days, respectively. The main extra-hematological toxicities were mucositis and infections. Acute graft-versus-host (GVHD) disease was experienced by 62% of evaluable patients (grade II/B or III/C 80%) responsive to steroids. Extensive chronic GVHD was observed in 62% of patients. Non-relapse transplant-related mortality by day +30 was observed in three patients (25%). Eight out of 12 patients were full donor chimeric by day +100. One patient showed a mixed chimerism at day +37 when he died from progressive disease. One patient was in complete remission (CR) before allogeneic transplantation, and after transplantation four patients achieved CR and four experienced progressive disease. Our study confirms that a low intensity conditioning regimen for allogeneic stem cell transplantation is feasible and effective in heavily pretreated patients.