Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition.

Inhibitors of the mechanistic target of rapamycin (mTOR) are currently used to treat advanced metastatic breast cancer. However, whether an aggressive phenotype is sustained through adaptation or resistance to mTOR inhibition remains unknown. Here, complementary studies in human tumors, cancer models and cell lines reveal transcriptional reprogramming that supports metastasis in response to mTOR inhibition. This cancer feature is driven by EVI1 and SOX9. EVI1 functionally cooperates with and positively regulates SOX9, and promotes the transcriptional upregulation of key mTOR pathway components (REHB and RAPTOR) and of lung metastasis mediators (FSCN1 and SPARC). The expression of EVI1 and SOX9 is associated with stem cell-like and metastasis signatures, and their depletion impairs the metastatic potential of breast cancer cells. These results establish the mechanistic link between resistance to mTOR inhibition and cancer metastatic potential, thus enhancing our understanding of mTOR targeting failure.

Consistency in recognizing microinvasion in breast carcinomas is improved by immunohistochemistry for myoepithelial markers.

Microinvasion is the smallest morphologically identifiable stage of invasion. Its presence and distinction from in situ carcinoma may have therapeutic implications, and clinical staging also requires the recognition of this phenomenon. Microinvasion is established on the basis of several morphological criteria, which may be difficult and not perfectly reproducible among pathologists. The aim of this study was to assess the consistency of diagnosing microinvasion in the breast on traditional haematoxylin and eosin (HE) stained slides and to evaluate whether immunohistochemistry (IHC) for myoepithelial markers could improve this. Digital images were generated from representative areas of 50 cases stained with HE and IHC for myoepithelial markers. Cases were specifically selected from the spectrum of in situ to microinvasive cancers. Twenty-eight dedicated breast pathologists assessed these cases at different magnifications through a web-based platform in two rounds: first HE only and after a washout period by both HE and IHC. Consistency in the recognition of microinvasion significantly improved with the use of IHC. Concordance rates increased from 0.85 to 0.96, kappa from 0.5 to 0.85, the number of cases with 100% agreement rose from 9/50 to 25/50 with IHC and the certainty of diagnosis also increased. The use of IHC markedly improves the consistency of identifying microinvasion. This corroborates previous recommendations to use IHC for myoepithelial markers to clarify cases where uncertainty exists about the presence of microinvasion. Microinvasive carcinoma is a rare entity, and seeking a second opinion may avoid overdiagnosis.

Doxorubicin and cyclophosphamide followed by weekly docetaxel as neoadjuvant treatment of early breast cancer: analysis of biological markers in a GEICAM phase II study.

INTRODUCTION: To evaluate the sequential administration of doxorubicin (A) and cyclophosphamide (C) followed by weekly docetaxel in women with stage II to IIIA breast cancer. PATIENTS AND METHODS: Patients received 60 mg/m(2) of A and 600 mg/m(2) of C every three weeks for four cycles followed by 12 infusions of weekly docetaxel at a dose of 36 mg/m(2) and with a 2-week resting period. RESULTS: Sixty-three women were included. On an intention-to- treat basis, clinical response rate was 90% (95% CI: 83-98), with 46% complete responses. Breast-conserving surgery could be performed in 43 patients (68%). Complete pathological responses in the breast were confirmed in 17% of patients. No correlations between levels of expression of topoisomerase II alpha, survivin or p27 and the pathological response were detected. The study treatment was generally well tolerated. CONCLUSION: Neoadjuvant AC followed by weekly docetaxel is a feasible regimen for patients with early-stage breast cancer.

[Calcific uraemic arteriolopathy (calciphylaxis): incidence, clinical features and long term outcomes]. / Arteriolopatía urémica calcificante (calcifilaxis): incidencia, formas de presentación y evolución.

UNLABELLED: Calcific uraemic arteriolopathy, also named calciphylaxis, is a rare but serious disorder characterized by medial mural calcification of small vessel leading to tissue ischaemia. It most commonly occurs in end stage renal disease patients on dialysis or recently received renal transplant with chronic nephropathy allograft. The pathogenesis of calciphylaxis is poorly understood. Abnormalities in mineral metabolism are clearly involved, but the specific factors that induces this disorder are not completely known. OBJECTIVES: Describe the main clinical features, outcomes and follow up of all calciphylaxis cases recorded in our dialysis unit in order to analyse the incidence, the main biologic parameters and the therapeutic background in which calciphylaxis appeared. MATERIAL AND METHODS: We performed a descriptive study about all the calciphylaxis cases diagnosed at our dialysis unit between the years 1991 and 2005. RESULTS: 8 cases, 6 women. Mean age: 65.3 years. All the patients were on haemodialysis treatment (one previous renal transplant). Mean time on dialysis was 76.6 months. Cumulative incidence was 1.17%. The principal end stage renal disease aethiology was neprhoangioeslerosis in four patients. Secondary hiperparatyrhoidism was present in 4 patients and 2 of them had been paratyrhoidectomized previously. A second cutaneous biopsy was needed for correct diagnosis in 3 patients. Calciphylaxis distal lesions were present in 7 patients. Two cases required urgent paratyrhoidectomy in order to control calciphylaxis. Only in 2 cases a Ca x P product > 60 mg/dL was present and 3 cases had PTHi values higher than 300 pg/mL. Calcium phosphate binders and vitamin D were present in 2 and 4 cases, respectively. One patient with proximal calciphylaxis died due to skin injury infection. CONCLUSIONS: Calciphylaxis is a rare disorder but not exceptional, related to end stage renal disease patients. The diagnosis requires a high clinical suspicion, being sometimes difficult to distinguish from other entities in spite of pathological study. Proximal distribution of calciphylaxis had worst prognostic. Metabolic disorders and therapeutics background were not different from other patients included in dialysis treatment.

[Secondary amyloidosis (AA-type) due to localized cutaneous vasculitis]. / Amiloidosis secundaria asociada a vasculitis cutánea localizada.

We report a case of a 49 year old man, diagnosed soon after the outcome of casual proteinuria, of AA-type amyloidosis in relation to small and medium vessel cutaneous vasculitis without systemic involvement. This combination is a rare entity and only two cases of cutaneous hypersensibility vasculitis complicated with AA-type amyloidosis had been reported. We describe the results of the use of several immunosuppressive drugs during four years follow up with temporally total remission of the disease.

[Renal involvement in amyloidosis. Clinical outcomes, evolution and survival]. / Afectación renal en la amiloidosis. Características clínicas, evolución y supervivencia.

BACKGROUND: Systemic amyloidosis is a disease resulting from extracellular deposition of fibrillar protein in various organs. Main systemic amyloidosis are: primary (AL) and Secondary (AA). The kidney is usually involved, conferring and adverse prognosis. In the last decade there has been a change in the aetiology of AA amyloidosis. OBJECTIVES: To analyse the incidence of AL and AA amyloidosis in our current population as well as the aetiology of AA amyloidosis. To describe clinical outcomes, renal involvement and survival. PATIENTS AND METHODS: We performed a descriptive analysis of all cases of amyloidosis diagnosed from 1992 to 2004 in our hospital. Diagnosis was assessed on histological criteria: positivity Congo Red stain. Clinical data, renal involvement, dialysis treatment and survival were analysed. RESULTS: 76 cases, 44 women, mean age 70.7 +/- 12. Types: 55 AA (72%), 21 AL (28%) systemic amyloidosis. AA aetiology was: 66% rheumatic disorders, 28% infectious disease, 6% others. Incidence for AL was 4.6 and for AA 12.2 cases/million. Renal involvement was present in 75% at diagnosis (69% Creatinine clearance < 60 ml/min, 37% urinary protein > 3 g/24 hours). 21 cases (28%) progressed to renal disease stage V in the 8.1 +/- 9.8 months follow up period, and 14 cases started dialysis treatment (10 HD, 4 CAPD). In 7 cases (33%) dialysis was not indicated due to their poor clinical condition, short life expectancy and bad quality of life. Mean global survival at diagnosis was 55% and 40% at 12 and 24 months (AL 58% and 19%; AA 55% and 44%). Mean survival from the start of dialysis was 30% and 5% at 12 and 24 months. CONCLUSIONS: Although amyloidosis has a low incidence in our population, the kidney is usually involved. Rheumatological disorders are the principal aetiology of AA amyloidosis. Long term survival is poor, specially for AL.

[Allopurinol-induced chronic granulomatous interstitial nephritis]. / Nefritis intersticial granulomatosa cronica por alopurinol.

Although drug induced interstitial nephritis is a relatively common cause of renal failure,granulomatous forms remain a rare condition. The development of a chronic granulomatous interstitial nephritis due to allopurinol is exceptional, only three cases have been described previously. We report on a patient who presented a granulomatous interstitial nephritis after 10 years of allopurinol administration (300 mg/day). At diagnosis, he had end stage renal disease and dialysis treatment was needed. Two months after drug withdrawal and on corticoid treatment a slow recovery of renal function was observed, allowing the interruption of dialysis. Two years after, the creatinine clearance is 23 ml/min,being dialysis free. We discuss the differential diagnosis of granulomatous interstitial nephritis and its rare association with allopurinol treatment.

[Type II essential mixed cryoglobulinemia and renal disease. Hepatitis C virus association]. / Afectación renal en la crioglobulinemia mixta tipo II.

UNLABELLED: Recently a number of studies have implicated C virus as a major cause of mixed cryoglobulinemia. Several authors described that up to 95% of "essential" mixed cryoglobulinemia could be attributed to this viral infection. Nevertheless, its prevalence and clinical significance are not well known. We review our experience in relation with the clinical, biological and evolutive characteristics of patients diagnosed of type II mixed cryoglobulinemia. METHODS: Descriptive and protocolized study of all cases found to have type II mixed cryoglobulinemia over a period of 8 years. Secondary cryoglobulinemic nephropathy was defined in a restrictive way: a plasma creatinine > 1.5 mg/dl and/or proteinuria > 500 mg/24 h and/or hematuria (> 15 red blood cells) need to be present in the absence of any other pathological conditions that could justify these alterations. Furthermore, the information obtained from available kidney biopsies was considered. RESULTS: 62 patients have been detected. C virus infection was demonstrated in 44 (72%). 52% had clinical symptoms related with cryoglobulinemia. 56% had alteration of renal tests, and 17 (27%) fulfil the conditions for the diagnosis of cryoglobulinemic nephropathy (nearly all with persistent microhematuria, median proteinuria 4.2 +/- 3.9 g/24 h; median plasma creatinine 2.8 +/- 1.8 mg/dl). Nine patients had been histologically examined, showing 6 cases a membranoproliferative glomerulonephritis pattern, one with associated extraglomerular vasculitis; two with mesangial proliferative pattern and one with membranous glomerulonephritis. The most striking differences between cryoglobulinemic nephropathy patients and the rest has been: higher amount of cryoglobulins (49 +/- 28 vs 20 +/- 22); more frequent hypocomplementemia, especially C4 (93% vs 59%) and recurrent purpura (75% vs 32%). No differences in the presence of C virus infection could be observed (75% vs 71%). IN CONCLUSION: 72% of patients with type II mixed cryoglobulinemia are infected by C virus (so 28% in our serie are "essential"); 52% have symptoms related with the presence of cryoglobulins, half of them with cryoglobulinemic nephropathy.

Enhancement of intramammary lymph nodes with lymphoid hyperplasia: a potential pitfall in breast MRI.

We present three cases of breast lesions labeled as probable intramammary lymph nodes that showed an increase in size on follow-up mammography. Contrast-enhanced MRI was performed and the three lesions showed strong and rapid uptake of the intravenous contrast. Core needle biopsy established the diagnosis of lymphoid hyperplasia in all three patients. Because intramammary lymph nodes affected by benign processes can present findings similar to malignant lesions, the usefulness of contrast-enhanced MRI in these cases is controversial.