Alma Contegiacomo

BRCA1 and BRCA2 mutations in central and southern Italian patients

Statement of findingsProtein truncation test (PTT) and single-strand conformation polymorphism (SSCP) assay were used to scan the BRCA1 and BRCA2 genes in 136 unrelated Italian breast/ovarian cancer patients. In the sample tested, BRCA1 and BRCA2 equally contributed to site-specific breast cancer patients who reported one to two breast cancer-affected first-/ second-degree relative(s) or who were diagnosed before age 40 years in the absence of a family history of breast/ovarian cancer. BRCA1 and BRCA2 mutations were mostly found in patients with disease diagnosis before and after age 50 years, respectively. Moreover, in cases with familial clustering of site-specific breast cancer, BRCA1 mostly accounted for tumours diagnosed before age 40 years and BRCA2 for tumours diagnosed after age 50 years. The BRCA1 and BRCA2 mutation spectrum was consistent with a lack of significant founder effects in the sample of patients studied.

A prospective randomized trial of doxorubicin versus idarubicin in the treatment of advanced breast cancer

Seventy‐six patients with advanced breast cancer were entered into the current study. They were randomized to receive either idarubicin (IDA) 45 mg/m2 orally or doxorubicin (DX) 75 mg/m2 intravenously (IV), both drugs being administered every 3 weeks. Among 37 evaluable patients who received DX treatment the overall response rate was 46%, whereas it was 21% in 34 evaluable patients treated with IDA. This difference was statistically significant. In previously untreated patients the response rate with DX was 60% compared to 29% with IDA. Patients with prior chemotherapy had 29% response rate to DX in contrast to 12% with IDA. The median time to response, the median response duration, and the median time to progression were similar in both groups. The median survival of all patients was 20 months in DX arm and 14 months in IDA arm (95% confidence limits 16.69–23.31 and 10.77–17.23, respectively; P = 0.09). Both treatments produced equivalent incidence and severity of myelotoxicity. Gastrointestinal toxicity and alopecia were significantly lower in patients receiving IDA. As for cardiotoxicity, four cases of congestive heart failure were recorded among patients treated with DX whereas no cases occurred in the IDA group. The results of this study indicate that, although DX remains the best single agent available in the treatment of breast cancer, IDA may have a role in selected patients with this disease. Cancer 64:2431–2436, 1989.

Ornithine decarboxylase and diamine oxidase in human colon carcinoma cell line CaCo-2 in culture.

The human colon carcinoma cell line CaCo-2, grown in vitro under standard culture conditions and in the absence of differentiation inducers, spontaneously exhibits structural and functional characteristics of mature small bowel enterocytes. Differentiation is complete at late confluency. High activities of ornithine decarboxylase and diamine oxidase are present in enterocytes. Although these enzymes are involved in polyamine metabolism and therefore in cell replication, their function in small bowel epithelium remains to be defined. In this study ornithine decarboxylase and diamine oxidase activities were assessed in CaCo-2 cells at different stages of proliferation and differentiation. Diamine oxidase was also assayed in spent culture media to assess its spontaneous release by CaCo-2 cells. The trigger effect of medium replacement on ornithine decarboxylase activity was also investigated. Cell growth and cell cycle kinetics were determined by hemocytometric cell count and [3H]thymidine labeling index. Sucrase activity was assayed to evaluate brush-border functional maturation. Elevated ornithine decarboxylase activity was recorded during the replication phase (highest value 0.3 +/- 0.02 U/mg) characterized by high thymidine labeling index (43%), and was greatly enhanced by medium replacement (2.1 +/- 0.3 U/mg). Diamine oxidase activity was low in both cells and medium during the active phase of cell growth, and during the differentiation period it progressively increased (highest value 499 +/- 78 U/mg) along with sucrase activity. The high diamine oxidase activity recorded in the medium (highest value 1292 +/- 310 U/ml) and the evidence of diamine oxidase secretion through the basolateral membrane of the cells cultured on porous filters support the hypothesis of an extracellular role of intestinal diamine oxidase. The CaCo-2 cell line, which shows several analogies with small bowel enterocytes, can be proposed as an interesting in vitro model for studying many aspects of cell replication and differentiation depending on polyamine metabolism.

p53 expression is decreased in primary breast carcinomas with microsatellite instability

Abstractp53 and p185 expression in primary breast cancer with microsatellite instability (MSI) is still largely unexplored. To investigate the relationship between these oncoproteins and the pathways of genomic instability, we examined 52 primary invasive breast cancers stratified by the presence and absence of MSI. We determined the status of eight microsatellite loci using radioactive and silver staining methods, and evaluated the immunohistochemical expression of p53 and p185 in a consecutive series of Italian cancer patients characterized by clinical-pathological and biological parameters. Nineteen cases (36.5%) were MSI-positive in at least two loci. p53 was expressed in 15 cases (28.8%) and p185 in eight (15.4%). MSI-positive tumors were inversely correlated with p53 expression ( p = 0.0007); in addition, the percent of p53-expressing cells decreased as the number of MSI-positive loci increased. MSI-positive tumors were correlated with a larger tumor size ( p = 0.04), lymph-node metastasis ( p = 0.001), and advanced clinical stage ( p = 0.0006). These data demonstrate the existence of two subsets of primary breast cancers: one characterized by MSI, the other by p53 expression. MSI-positive patients had a more advanced and/or aggressive disease.

Irradiation of the hypothalamic–hypophyseal area induces complete regression of mucocutaneous lesions in disseminated histiocytosis X

We report on a 54‐year‐old woman with disseminated histiocytosis X who had a complete regression of all mucocutaneous lesions within 1 month from the completion of radiation therapy (4500 cGy) to the hypothalamic‐hypophyseal (H–H) area. This response lasted 12 months, after which new cutaneous and bone lesions appeared.

Triple negative versus non-triple negative breast cancers in high-risk women: Phenotype features and survival from the HIBCRIT-1 MRI-including screening study

Purpose: To compare phenotype features and survival of triple-negative breast cancers (TNBC) versus non-TNBCs detected during a multimodal annual screening of high-risk women. Experimental Design: Analysis of data from asymptomatic high-risk women diagnosed with invasive breast cancer during the HIBCRIT-1 study with median 9.7-year follow-up. Results: Of 501 enrolled women with BRCA1/2 mutation or strong family history (SFH), 44 were diagnosed with invasive breast cancers: 20 BRCA1 (45%), 9 BRCA2 (21%), 15 SFH (34%). Magnetic resonance imaging (MRI) sensitivity (90%) outperformed that of mammography (43%, P < 0.001) and ultrasonography (61%, P = 0.004). The 44 cases (41 screen-detected; 3 BRCA1-associated interval TNBCs) comprised 14 TNBCs (32%) and 30 non-TNBCs (68%), without significant differences for age at diagnosis, menopausal status, prophylactic oophorectomy, or previous breast cancer. Of 14 TNBC patients, 11 (79%) were BRCA1; of the 20 BRCA1 patients, 11 (55%) had TNBC; and of 15 SFH patients, 14 (93%) had non-TNBCs (P = 0.007). Invasive ductal carcinomas (IDC) were 86% for TNBCs versus 43% for non-TNBCs (P = 0.010), G3 IDCs 71% versus 23% (P = 0.006), size 16 ± 5 mm versus 12 ± 6 mm (P = 0.007). TNBC patients had more frequent ipsilateral mastectomy (79% vs. 43% for non-TNBCs, P = 0.050), contralateral prophylactic mastectomy (43% vs. 10%, P = 0.019), and adjuvant chemotherapy (100% vs. 44%, P < 0.001). The 5-year overall survival was 86% ± 9% for TNBCs versus 93% ± 5% (P = 0.946) for non-TNBCs; 5-year disease-free survival was 77% ± 12% versus 76% ± 8% (P = 0.216). Conclusions: In high-risk women, by combining an MRI-including annual screening with adequate treatment, the usual reported gap in outcome between TNBCs and non-TNBCs could be reduced. Clin Cancer Res; 22(4); 895–904. ©2015 AACR.

Plasma postheparin diamine oxidase in patients with small intestinal lymphoma

Diamine oxidase (DAO) is an enzyme located almost exclusively in villus tip enterocytes. Its plasma activity is enhanced by intravenous heparin which releases the enzyme from small bowel enterocytes into the blood. Plasma postheparin DAO (PHD) values have been shown to be significantly lower in patients with malabsorption and villous atrophy, thus suggesting that PHD reflects the mature enterocytic mass. In this study we have assayed PHD in five patients with small bowel lymphoma (two with immunoproliferative small intestinal disease [IPSID] and three with non‐IPSID lymphoma) associated with malabsorption syndrome and small bowel mucosa atrophy. The PHD test was performed at diagnosis, after partial or complete remission induced by chemotherapy, and during the follow‐up. The PHD values, very low at diagnosis (0.66 ± 0.12 U/ml), increased during chemotherapy and reached the normal range (< 3.7 U/ml) when complete remission occurred. The PHD values rapidly and consistently decreased whenever the disease relapsed. Our data indicate that in patients with small bowel lymphoma PHD test is a sensitive marker of small bowel mucosa damage and suggest that it could be useful in monitoring the recovery of mucosal lesions induced by chemotherapy.

Failure to Demonstrate Plasma Hormone Abnormalities in Women with Operable Breast Cancer

The endocrine profile of patients with breast cancer has been the object of extensive studies during the past several years. Abnormal secretion of a variety of hormones has been described on different occasions in patients with breast cancer (Gambrell, 1982; Henderson et al., 1982; Kirschner et al., 1982; Kwa and Wang, 1977; Ohgo et al., 1976), and has been considered a possible risk factor. However, conclusive evidence has not yet been presented to show that the cancer patients are significantly different in endogenous hormone profiles from their healthy counterparts. The main purpose of the present study was to critically reevaluate this controversial issue and possibly identify hormonal changes in a large population of patients with operable breast cancer not present in a comparable population of normal healthy women.

The Cancer Spectrum Related to Hereditary and Familial Breast and Ovarian Cancers

Multiple factors are associated with an increased risk of developing breast cancer, including age, family history, exposure to reproductive hormones, dietary factors, benign breast diseases, and environmental factors. Recently, increasing interest has been devoted to the interaction between environmental and genetic factors. Family history has been recognized as an important risk factor for developing breast cancer. Individuals with a first-degree family member affected with breast cancer have a relative risk of 2.1 (95% CI = 2.0–2.2). Moreover, risk varies with the age at which the affected relative was diagnosed, the number of affected and unaffected family members and, finally, the closeness of the relationship.

BRCA1 and BRCA2 Gene Mutations in Breast/Ovarian Cancer Patients from Central and Southern Italy

Laura Ottini, Cristina D’Amico, Cristiana Noviello, Salvatore Lauro, Giuseppe Fornarini, Anna Colantuoni, Enrico Cortesi, Sandro Carlini, Fiorella Guadagni, Giovanna Masala, Angelo Raffaele Bianco, Alma Contegiacomo, Domenico Palli and Renato Mariani-Costantini Department of Oncology and Neurosciences, University Gabriele D’Annunzio, Chieti, Italy Department of Experimental Medicine and Pathology, University La Sapienza, Rome, Italy Department of Endocrinology and Oncology, University Federico II, Naples, Italy Regina Elena Cancer Institute, Rome, Italy Epidemiology Unit, CSPO, A.O. Careggi, Florence, Italy