Breast cancer patients with the same stage of disease can have markedly different treatment responses and overall outcome. The strongest predictors for metastases (for example, lymph node status and histological grade) fail to classify accurately breast tumours according to their clinical behaviour. Chemotherapy or hormonal therapy reduces the risk of distant metastases by approximately one-third; however, 70-80% of patients receiving this treatment would have survived without it. None of the signatures of breast cancer gene expression reported to date allow for patient-tailored therapy strategies. Here we used DNA microarray analysis on primary breast tumours of 117 young patients, and applied supervised classification to identify a gene expression signature strongly predictive of a short interval to distant metastases ('poor prognosis' signature) in patients without tumour cells in local lymph nodes at diagnosis (lymph node negative). In addition, we established a signature that identifies tumours of BRCA1 carriers. The poor prognosis signature consists of genes regulating cell cycle, invasion, metastasis and angiogenesis. This gene expression profile will outperform all currently used clinical parameters in predicting disease outcome. Our findings provide a strategy to select patients who would benefit from adjuvant therapy.

/pdf/gene-expression-profiling-predicts-clinical-outcome-of-5bu8dmnf6h.pdf

Gene expression profiling predicts clinical outcome of breast cancer

Background A more accurate means of prognostication in breast cancer will improve the selection of patients for adjuvant systemic therapy. Methods Using microarray analysis to evaluate our previously established 70-gene prognosis profile, we classified a series of 295 consecutive patients with primary breast carcinomas as having a gene-expression signature associated with either a poor prognosis or a good prognosis. All patients had stage I or II breast cancer and were younger than 53 years old; 151 had lymph-node–negative disease, and 144 had lymph-node–positive disease. We evaluated the predictive power of the prognosis profile using univariable and multivariable statistical analyses. Results Among the 295 patients, 180 had a poor-prognosis signature and 115 had a good-prognosis signature, and the mean (±SE) overall 10-year survival rates were 54.6±4.4 percent and 94.5±2.6 percent, respectively. At 10 years, the probability of remaining free of distant metastases was 50.6±4.5 percent in the group with a...

/pdf/a-gene-expression-signature-as-a-predictor-of-survival-in-1f6irz2ok6.pdf

A Gene-Expression Signature as a Predictor of Survival in Breast Cancer

background Trastuzumab, a recombinant monoclonal antibody against HER2, has clinical activity in advanced breast cancer that overexpresses HER2. We investigated its efficacy and safety after excision of early-stage breast cancer and completion of chemotherapy. methods This international, multicenter, randomized trial compared one or two years of trastuzumab given every three weeks with observation in patients with HER2-positive and either node-negative or node-positive breast cancer who had completed locoregional therapy and at least four cycles of neoadjuvant or adjuvant chemotherapy. results Data were available for 1694 women randomly assigned to two years of treatment with trastuzumab, 1694 women assigned to one year of trastuzumab, and 1693 women assigned to observation. We report here the results only of treatment with trastuzumab for one year or observation. At the first planned interim analysis (median follow-up of one year), 347 events (recurrence of breast cancer, contralateral breast cancer, second nonbreast malignant disease, or death) were observed: 127 events in the trastuzumab group and 220 in the observation group. The unadjusted hazard ratio for an event in the trastuzumab group, as compared with the observation group, was 0.54 (95 percent confidence interval, 0.43 to 0.67; P<0.0001 by the log-rank test, crossing the interim analysis boundary), representing an absolute benefit in terms of disease-free survival at two years of 8.4 percentage points. Overall survival in the two groups was not significantly different (29 deaths with trastuzumab vs. 37 with observation). Severe cardiotoxicity developed in 0.5 percent of the women who were treated with trastuzumab. conclusions One year of treatment with trastuzumab after adjuvant chemotherapy significantly improves disease-free survival among women with HER2-positive breast cancer. (clinicaltrials.gov number, NCT 00045032.)

/pdf/trastuzumab-after-adjuvant-chemotherapy-in-her2-positive-4t3ym1k39n.pdf

Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer

Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials.

Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Somatostatin and its analogues have been reported highly effective in reducing the clinical syndrome in endocrine tumours. The effects of a long-acting analogue of somatostatin, lanreotide, were evaluated in 10 patients with neuroendocrine tumours. In patients with carcinoid tumour, a relief of flushing was achieved in 7 of 8 patients, of diarrhoea in 7 of 7 patients and of bronchoconstriction in 2 of 2 patients. In 5 of 8 patients there was a decrease of more than 50% of 5-hidroxyindolacetic acid excretion. The activity on tumour size was assessed in all the patients. No objective responses were observed. The tolerance to lanreotide was excellent. For the high symptomatic effect and mild toxicity lanreotide seems to be an appropriate treatment in symptomatic patients.

Use of Long-Acting Somatostatin Analog, Lanreotide, in Neuroendocrine Tumors

Fibronectin concentration in the plasma of patients with malignant and benign breast disease.

Genitourinary cancers represent a heterogeneous group of malignancies arising from genitourinary tract, and are responsible for almost 359 000 newly diagnosed cases and 58 420 related deaths in USA. Continuous advances in cancer genetics and genomics have contributed towards changing the management

Genitourinary tumours in the targeted therapies era: new advances in clinical practice and future perspectives.

Background Etoposide phosphate (VP-16) is a topoisomerase 2 (TOP2) inhibitor that demonstrated activity in patients with metastatic castration-resistant prostate cancer (mCRPC). We investigated the sensitivity of prostate cancer (PCa) cells (LNCaP, 22Rv1, PC3, DU145, PDB and MDB) to VP-16 and the possible relationship between VP-16 activity and TOP2 expression. The activity of VP-16 was compared with that of docetaxel, enzalutamide and olaparib. The prevalence and clinical significance of TOP2 genetic and transcriptomic alterations was also explored in mCRPC. Methods Cell cultures and crystal violet cell proliferation assays were performed. Specific antibodies were used in western blots analyses of cell protein extracts. Datasets were analyzed in cBioportal. Results VP-16 was active in all PCa cell lines analyzed and demonstrated increased activity in PC3 and DU145 cells. VP-16 was more cytotoxic compared to the other treatments, except for LNCaP and 22Rv1, which were more sensitive to docetaxel. Maintenance of antiandrogen treatment in MDB and PDB increased sensitivity to VP-16, docetaxel and enzalutamide. TOP2A was found overexpressed in 22Rv1, DU145 and PC3, whereas TOP2B was overexpressed in 22Rv1 and PDB. In the mCRPC datasets analysis, TOP2A mRNA overexpression was associated with worse patients’ prognosis, with the molecular features of neuroendocrine prostate cancer (NEPC) and with lower androgen receptor (AR) score. Patients overexpressing TOP2A mRNA were more likely to harbor RB1 loss. Conclusions Specific subpopulations of patients with aggressive variant prostate cancer (AVPC) could benefit from VP-16 treatment. TOP2A overexpression, rather than TOP2B, might be a good biomarker to predict response to VP-16.

Etoposide and topoisomerase II inhibition for aggressive prostate cancer: Data from a translational study.

The term fibronectin (FN) describes a family of structurally and immunologically related high molecular weight glycoproteins that are present in vertebrates in two forms, soluble and insoluble.’4 The soluble form has been observed in many different biological fluids, including plasma, cerebrospinal, amniotic and synovial fluid, milk, urine, and seminal plasma. The insoluble form has been reported to be present in connective tissue and associated with the basement membranes. Many types of cultured cells, in particular fibroblasts, produce fibronectin. The amount of fibronectin present on the surface of transformed or neoplastic cells is generally greatly reduced. Fibronectin has been shown to be involved in cellular aggregation and cell substratum adhesiveness, to partially restore transformed fibroblasts to a more normal phenotype, to promote locomotion of certain type of cells and to facilitate reticuloendothelial system clearance of particles. More recently fibronectin has been shown to be a potent chemoattractant for monocytes, fibroblasts, and endothelial cells in virro. Fibronectin binds to macromolecules such as collagen, fibrin, fibrinogen, heparin, actin, and DNA. The ability of fibronectin to bind many different kinds of macromolecules may be essential to its functions as a nonspecific opsonin. Although the numerous properties of fibronectin in vitro have been well documented, the in vivo function of this protein is still unknown. Elevated plasma FN levels have been described in mice with tumors and in patients affected by malignancy, although results are contradictory. To contribute to the understanding of the function of fibronectin in vivo we have studied fibronectin levels in plasma of subjects with breast cancer, benign breast disease, and healthy donors. Blood samples were obtained from 62 healthy donors (ages ranging from 30 to 75 years), 33 patients with nonmetastatic breast cancer (ages ranging from 45 to 75 years), 22 patients with metastatic breast cancer (ages ranging from 45 to 75 years), and 43 patients with histologically proven benign breast disease, including 22 patients with fibroadenomas and 21 patients with fibrocistic disease (ages ranging from 30 to 60 years). Fibronectin concentration was evaluated by rocket immunoelectrophoresi~~ using monospecific antibodies to human plasma fibronectin. Total plasma protein concentration was determined using the biuret method (Boehringher, Mannheim, F.R.G.). TABLE 1 shows the median values of plasma fibronectin concentration for the subjects of the different groups. Plasma fibronectin concentrations of the subjects in

Francesco Boccardo

Papers

Use of Long-Acting Somatostatin Analog, Lanreotide, in Neuroendocrine Tumors

Fibronectin concentration in the plasma of patients with malignant and benign breast disease.

Genitourinary tumours in the targeted therapies era: new advances in clinical practice and future perspectives.

Etoposide and topoisomerase II inhibition for aggressive prostate cancer: Data from a translational study.

Fibronectin concentration in plasma of patients with breast cancer