Negative pigment network: an additional dermoscopic feature for the diagnosis of melanoma.

BACKGROUND: The negative pigment network (NPN) is seen as a negative of the pigmented network and it is purported to be a melanoma-specific structure. OBJECTIVES: We sought to assess the frequency, sensitivity, specificity, and odds ratios (ORs) of NPN between melanoma cases and a group of control lesions. METHODS: Digitalized images of skin lesions from 679 patients with histopathological diagnosis of dermatofibroma (115), melanocytic nevus (220), Spitz nevus (139), and melanoma (205) were retrospectively collected and blindly evaluated to assess the presence/absence of NPN. RESULTS: The frequency of occurrence of NPN was higher in the melanoma group (34.6%) than in Spitz nevus (28.8%), melanocytic nevus (18.2%), and dermatofibroma (11.3%) groups. An OR of 1.8 emerged for the diagnosis of melanoma in the presence of NPN as compared with nonmelanoma diagnosis. Conversely, for melanocytic nevi and dermatofibromas the OR was very low (0.5 and 0.3, respectively). For Spitz nevi the OR of 1.1 was not statistically significant. When comparing melanoma with dermatofibroma, melanocytic nevus, and Spitz nevus, we observed a significantly higher frequency of multicomponent pattern (68.1%), asymmetric pigmentation (92.9%), irregularly distributed NPN (87.3%), and peripheral location of NPN (66.2%) in melanomas. LIMITATIONS: Further studies can provide the precise dermoscopic-histopathologic correlation of NPN in melanoma and other lesions. CONCLUSIONS: The overall morphologic pattern of NPN, such as the irregular distribution and the peripheral location of NPN, along with the multicomponent pattern and the asymmetric pigmentation could be used as additional features in distinguishing melanoma from Spitz nevus and other benign lesions.

Facilitating the integration of emotional states in patients' personal disease experience with cancer: a new brief intervention for managing psychological distress.

PURPOSE: This paper describes an intervention performed at an Italian oncological institute to manage psychological distress related to the oncological experience. Its objectives are to encourage and normalize awareness of the importance of emotional aspects of the cancer experience, to provide psycho-education to patients on the importance of psycho-social care in promoting well-being, and to introduce our psychology service and promote its usage. METHODS: The intervention consists of three consecutive steps: the psychological distress screening; the clinical interview, which is conducted according to Rogers' client-centered model; and the collection of data regarding the appreciation and usefulness of the initiative, performed through a feedback questionnaire and the codification of the interview contents. RESULTS: Between September 2011 and February 2012, the intervention was administered to 484 consecutive new inpatients. Among them, the prevalence of psychological distress and its components of anxiety and depression are comparable to those found in the literature. The low percentage of participants who refuse the screening (15.4 %) as well as of those who do not wish to have the results returned to them (3.1 %), together with the high scores regarding the usefulness and effectiveness given to the intervention (all >80/100), documents the positive reception of this activity. Lastly, the analysis of the contents of the exit interview shows that a wide range of themes, far more varied and heterogeneous than just anxiety and/or depression symptoms, was discussed. CONCLUSIONS: Even though this was a clinical and not a research activity, it still offers important descriptive data.

Epirubicin and docetaxel as neoadjuvant treatment of hormone receptor positive, HER-2 negative breast cancer: findings from two successive phase II studies.

BACKGROUND: We report on the activity of the combination of epirubicin and docetaxel given in neoadjuvant setting for 4 and 8 cycles respectively in 2 successive series of patients with large operable or locally advanced, hormone receptor positive, HER-2 negative breast cancer. PATIENTS AND METHODS: Patients were treated from 2002 to 2006 with epirubicin 90 mg/m(2) and docetaxel 75 mg/m(2) intravenously, every 3 weeks for 4 cycles before and 4 cycles after surgery (Series I - 13 patients), and from 2006 to 2010 with the same regimen administered for 8 cycles preoperatively (Series II - 37 patients), plus hormonal therapy for 5 years and radiation therapy if indicated. All Series I and 32 Series II patients were able to complete the preoperative chemotherapy. RESULTS: A complete response was found in 1 patient from Series I and 13 patients from Series II and the partial remission in 10 patients from Series I and 21 patients from Series II. Two Series I and 3 Series II patients did not respond clinically. Response rate (Series I/Series II) was 84/92%. All 50 patients underwent surgery. In Series I patients, 3 pCR occurred in the breast and the axilla was histologically negative in 2 cases. No evidence of disease both in the breast and in the axilla was achieved in 7.6% (1/13) of patients. In Series II patients, 8 pCR occurred in the breast and axilla was histologically negative in 15 patients. No evidence of disease both in the breast and in the axilla occurred in 10.8% (4/37) of patients. G3-G4 toxicity included myelosuppression in 3 patients from Series I and all patients from Series II, and mucositis in 1 patient from Series I and 4 patients from series II. No other G3-4 toxicities or toxic deaths occurred. Five-year progression free survival was 38% and 90% in Series I and Series II patients respectively. CONCLUSIONS: The incidence of pathologic complete remissions was lower in our patient population, compared to reported data. A longer duration of the preoperative treatment might be associated with a longer progression-free survival.

Weekly paclitaxel in heavily pretreated ovarian cancer patients: does this treatment still provide further advantages?

OBJECTIVE: To evaluate the disease control rate (DCR) in heavily pretreated and relapsed ovarian cancer patients re-challenged with a weekly paclitaxel schedule and to establish whether a correlation between dose intensity, progression-free interval (PFI) and overall survival (OS) exists. METHODS: Retrospective data were collected from 30 heavily pretreated metastatic ovarian cancer patients who received 80 mg/m(2)/week paclitaxel regimen. RESULTS: The treatment was well tolerated and showed a DCR in 70% of the patients, with only one case of grade 3 hematological toxicity. One patient (3%) showed a complete response, 15 patients (50%) a partial response and five patients (17%) a stabilization of their disease. The regimen was mostly used as a fourth-line chemotherapy (range 2-7). The median dose intensity in responding patients was 57.5 mg/m(2)/week and in those with progressive disease 49.7 mg/m(2)/week. (p = 0.20). PFI and OS were increased in the responder patient groups with a log-rank test of 25.64 (p < 0.001) and 15.10 (p = 0.0001), respectively. CONCLUSIONS: Weekly administration of paclitaxel was active and well tolerated as a salvage therapy for heavily pretreated ovarian cancer patients.

Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial.

BACKGROUND: Treatment with adjuvant trastuzumab for 1 year improves disease-free survival and overall survival in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. We aimed to assess disease-free survival and overall survival after a median follow-up of 4 years for patients enrolled on the Herceptin Adjuvant (HERA) trial. METHODS: The HERA trial is an international, multicentre, randomised, open-label, phase 3 trial comparing treatment with trastuzumab for 1 and 2 years with observation after standard neoadjuvant, adjuvant chemotherapy, or both in patients with HER2-positive early breast cancer. The primary endpoint was disease-free survival. After a positive first interim analysis at a median follow-up of 1 year for the comparison of treatment with trastuzumab for 1 year with observation, event-free patients in the observation group were allowed to cross over to receive trastuzumab. We report trial outcomes for the 1-year trastuzumab and observation groups at a median follow-up of 48·4 months (IQR 42·0-56·5) and assess the effect of the extensive crossover to trastuzumab. Our analysis was by intention-to-treat. The HERA trial is registered with the European Clinical Trials Database, number 2005-002385-11. FINDINGS: The HERA trial population comprised 1698 patients randomly assigned to the observation group and 1703 to the 1-year trastuzumab group. Intention-to-treat analysis of disease-free survival showed a significant benefit in favour of patients in the 1-year trastuzumab group (4-year disease-free survival 78·6%) compared with the observation group (4-year disease-free survival 72·2%; hazard ratio [HR] 0·76; 95% CI 0·66-0·87; p<0·0001). Intention-to-treat analysis of overall survival showed no significant difference in the risk of death (4-year overall survival 89·3%vs 87·7%, respectively; HR 0·85; 95% CI 0·70-1·04; p=0·11). Overall, 885 patients (52%) of the 1698 patients in the observation group crossed over to receive trastuzumab, and began treatment at median 22·8 months (range 4·5-52·7) from randomisation. In a non-randomised comparison, patients in the selective-crossover cohort had fewer disease-free survival events than patients remaining in the observation group (adjusted HR 0·68; 95% CI 0·51-0·90; p=0·0077). Higher incidences of grade 3-4 and fatal adverse events were noted on 1-year trastuzumab than in the observation group. The most common grade 3 or 4 adverse events, each in less than 1% of patients, were congestive cardiac failure, hypertension, arthralgia, back pain, central-line infection, hot flush, headache, and diarrhoea. INTERPRETATION: Treatment with adjuvant trastuzumab for 1 year after chemotherapy is associated with significant clinical benefit at 4-year median follow-up. The substantial selective crossover of patients in the observation group to trastuzumab was associated with improved outcomes for this cohort. FUNDING: F Hoffmann-La Roche, Michelangelo Foundation.

A different immunologic profile characterizes patients with HER-2-overexpressing and HER-2-negative locally advanced breast cancer: implications for immune-based therapies.

INTRODUCTION: The clinical efficacy of trastuzumab and taxanes is at least partly related to their ability to mediate or promote antitumor immune responses. On these grounds, a careful analysis of basal immune profile may be capital to dissect the heterogeneity of clinical responses to these drugs in patients with locally advanced breast cancer undergoing neoadjuvant chemotherapy. METHODS: Blood samples were collected from 61 locally advanced breast cancers (36 HER2- and 25 HER2+) at diagnosis and from 23 healthy women. Immunophenotypic profiling of circulating and intratumor immune cells, including regulatory T (Treg) cells, was assessed by flow cytometry and immunohistochemistry, respectively. Serum levels of 10 different cytokines were assessed by multiplex immunoassays. CD8+ T cell responses to multiple tumor-associated antigens (TAA) were evaluated by IFN-γ-enzyme-linked immunosorbent spot (ELISPOT). The Student's t test for two tailed distributions and the Wilcoxon two-sample test were used for the statistical analysis of the data. RESULTS: The proportion of circulating immune effectors was similar in HER2+ patients and healthy donors, whereas higher percentages of natural killer and Treg cells and a lower CD4+/CD8+ T cell ratio (with a prevalence of naïve and central memory CD8+ T cells) were observed in HER2- cases. Higher numbers of circulating CD8+ T cells specific for several HLA-A*0201-restricted TAA-derived peptides were observed in HER2+ cases, together with a higher prevalence of intratumor CD8+ T cells. Serum cytokine profile of HER2+ patients was similar to that of controls, whereas HER2- cases showed significantly lower cytokine amounts compared to healthy women (IL-2, IL-8, IL-6) and HER2+ cases (IL-2, IL-1ß, IL-8, IL-6, IL-10). CONCLUSIONS: Compared to HER2- cases, patients with HER2-overexpressing locally advanced breast cancer show a more limited tumor-related immune suppression. This may account for the clinical benefit achieved in this subset of patients with the use of drugs acting through, but also promoting, immune-mediated effects.

Late tamoxifen in patients previously operated for breast cancer without postoperative tamoxifen: 5-year results of a single institution randomised study.

BACKGROUND: A population of breast cancer patients exists who, for various reasons, never received adjuvant post-operative tamoxifen (TAM). This study was aimed to evaluate the role of late TAM in these patients. METHODS: From 1997 to 2003, patients aged 35 to 75 years, operated more than 2 years previously for monolateral breast cancer without adjuvant TAM, with no signs of metastases and no contraindication to TAM were randomized to TAM 20 mg/day orally for 2 years or follow-up alone. Events were categorized as locoregional relapse, distant metastases, metachronous breast cancer, tumours other than breast cancer and death from any causes, whichever occurred first. The sample size (197 patients per arm, plus 10% allowance) was based on the assumption of a 30% decrease in the number of events occurring at a rate of 5% annually in the 10 years following randomization. Four hundred and thirty-three patients were randomized in the study (TAM 217, follow-up 216). Patients characteristics (TAM/follow-up) included: median age 55/55 years, median time from surgery 25/25 months (range, 25-288/25-294), in situ carcinoma 18/24, oestrogen receptor (ER) positive in 75/68, negative in 70/57, unknown in 72/91 patients. Previous adjuvant treatment included chemotherapy in 131/120 and an LHRH analogue in 11/13 patients. RESULTS: Thirty-six patients prematurely discontinued TAM after a median of 1 month, mostly because of subjective intolerance. Eighty-three events (TAM 39, follow-up 44) occurred: locoregional relapse in 10/8, distant metastases in 14/16, metachronous breast cancer in 4/10, other tumours in 11/10 patients. Less ER-positive secondary breast cancers occurred in the TAM treated patients than in follow-up patients (1 vs 10, p = 0.005). Event-free survival was similar in both groups of patients. CONCLUSIONS: This 5-year analysis revealed significantly less metachronous ER-positive breast cancers in the TAM treated patients. No other statistically significant differences have emerged thus far.

Epirubicin and docetaxel as neoadjuvant treatment of locally advanced breast cancer: a phase II study.

AIMS AND BACKGROUND: Neoadjuvant chemotherapy is the standard treatment for locally advanced breast cancer. The combination of anthracyclines and taxanes is considered the first choice chemotherapy in advanced breast cancer. We report here the overall results of a phase II study of epirubicin and docetaxel as neoadjuvant chemotherapy in advanced breast cancer. PATIENTS AND METHODS: Forty-five patients with locally advanced, nonmetastatic breast carcinoma were treated with epirubicin, 90 mg/m2, docetaxel, 75 mg/m2, intravenously, every 3 weeks for 4 cycles before and 4 cycles after surgery, followed by tamoxifen for 5 years if estrogen receptor positive and radiation therapy if indicated. Patient characteristics included a median age of 45 years; pre Ipostmenopausal, 311/14 patients; T3-T4 in 33, N0/N1 in 12/33; ductal/lobular in 42/3; ER+ in 23; and HER2 overexpression in 23. RESULTS: Clinical response included complete remission in 7 patients and partial remission in 27 (response rate, 75%). All 45 patients underwent surgery (quadrantectomy in 7). Histological examination of the breast and lymph nodes revealed no signs of disease in 3 patients and ductal carcinoma in situ only in 2. Twenty-five patients completed the chemotherapy program. G3-G4 toxicity included neutropenia in 39 patients. No other G3-4 toxicity nor toxic deaths occurred. Median relapse-free and overall survival were 35 and 56 months, respectively. CONCLUSIONS: The neoadjuvant treatment was active and well tolerated, but the incidence of pathologic complete remissions was relatively low.

Selecting for BRCA1 testing using a combination of homogeneous selection criteria and immunohistochemical characteristics of breast cancers.

BACKGROUND: BRCA1 gene-related tumours are more frequently estrogen receptor (ER) and progesterone receptor (PR) negative with a lower prevalence of human epidermal growth factor receptor 2 (HER2) overexpression or amplification. We evaluated the effectiveness of a combination of homogeneously selected criteria and immunohistochemical (IHC) characteristics of Familial Breast Cancers (FBCs) in detecting BRCA1 mutation carriers. METHODS: Primary breast tumours from 93 FBC patients defined by specific eligibility criteria, based on personal and familial tumour history, were evaluated by Allred's method. The BRCA1 molecular analysis, including Multiplex Ligation-dependent Probe Amplification (MLPA), was considered as the gold standard assay. RESULTS: A total of 10 BRCA1 pathogenetic mutations was found. With the exclusion of the tumours characterized by double positive receptorial status and/or strong HER2 positivity (3+), we identified 22 patients, 10 of whom resulted as BRCA1 mutation carriers. The sensitivity, specificity, positive and negative predictive values were 100%, 83.3%, 45.4% and 100% respectively. CONCLUSION: Our findings suggest that the IHC analysis by Allred's method improves our ability to select patients for BRCA1 testing.

Targeted intraoperative radiotherapy impairs the stimulation of breast cancer cell proliferation and invasion caused by surgical wounding.

PURPOSE: After apparently successful excision of breast cancer, risk of local recurrence remains high mainly in the area surrounding the original tumor, indicating that wound healing processes may be implicated. The proportional reduction of this risk by radiotherapy does not depend on the extent of surgery, suggesting that radiotherapy, in addition to killing tumor cells, may influence the tumor microenvironment. EXPERIMENTAL DESIGN: We studied how normal and mammary carcinoma cell growth and motility are affected by surgical wound fluids (WF), collected over 24 h following breast-conserving surgery in 45 patients, 20 of whom had received additional TARGeted Intraoperative radioTherapy (TARGIT), immediately after the surgical excision. The proteomic profile of the WF and their effects on the activation of intracellular signal transduction pathways of breast cancer cells were also analyzed. RESULTS: WF stimulated proliferation, migration, and invasion of breast cancer cell lines. The stimulatory effect was almost completely abrogated when fluids from TARGIT-treated patients were used. These fluids displayed altered expression of several cytokines and failed to properly stimulate the activation of some intracellular signal transduction pathways, when compared with fluids harvested from untreated patients. CONCLUSIONS: Delivery of TARGIT to the tumor bed alters the molecular composition and biological activity of surgical WF. This novel antitumoral effect could, at least partially, explain the very low recurrence rates found in a large pilot study using TARGIT. It also opens a novel avenue for identifying new molecular targets and testing novel therapeutic agents.

Incidence of palmar-plantar erythrodysesthesia in pretreated and unpretreated patients receiving pegylated liposomal doxorubicin.

AIMS AND BACKGROUND: Association between pegylated liposomal doxorubicin-based regimens and palmar-plantar erythrodysesthesia have just been emphasized, whereas the relationship between previous treatment and palmar-plantar erythrodysesthesia is still a matter of discussion. We evaluate the relationship between previous chemotherapy treatments and the development of palmar-plantar erythrodysesthesia in patients receiving pegylated liposomal doxorubicin-based regimens. METHODS: Between January 2005 and November 2006, 92 patients received regimens including pegylated liposomal doxorubicin. Patients were divided into three groups based on pegylated liposomal doxorubicin dosing interval length, different dose chosen, and previous chemotherapy. RESULTS: Among pretreated patients receiving regimens including 30 mg/m2 of pegylated liposomal doxorubicin repeated every three weeks, the incidence of palmar-plantar erythrodysesthesia was not significantly higher than in unpretreated patients receiving the same weekly schedule (P = 0.4). There was no difference in the incidence of palmar-plantar erythrodysesthesia between pretreated patients with regimens including 30 mg/m2 of pegylated liposomal doxorubicin every three weeks and pretreated patients receiving 20 mg/m2 of pegylated liposomal doxorubicin every two weeks (P = 0.8). The prevalence of palmar-plantar erythrodysesthesia observed in the unpretreated group exposed to 30 mg/m2 every three weeks was comparable to that of the pretreated group receiving 20 mg/m2 biweekly (P = 0.3). However, excluding all the patients who developed grade 1 palmar-plantar erythrodysesthesia, the incidence of grade 2 and 3 palmar-plantar erythrodysesthesia observed in pretreated patients receiving regimens including 20 mg/m2 of pegylated liposomal doxorubicin biweekly was significantly higher than in unpretreated patients receiving 30 mg/m2 of pegylated liposomal doxorubicin every three weeks (P = 0.001). CONCLUSIONS: Our findings indicate that the pretreatment is not involved in the increased incidence of any grade palmar-plantar erythrodysesthesia. On the contrary, the study could suggest that the type of previous treatment may be an important factor in the development of more severe forms of palmar-plantar erythrodysesthesia.

Trastuzumab and vinorelbine as highly effective and safe therapy for HER-2-overexpressing metastatic breast cancer. A single institution experience.

AIMS AND BACKGROUND: Trastuzumab-based therapy has improved survival of women with human epidermal growth factor receptor 2 (HER2)-overexpressing metastatic breast cancer. STUDY DESIGN: From September 2002 to July 2006, 45 women with metastatic breast cancer HER2 3+, or 2+ and positive for HER2 gene amplification, were enrolled in the study and received a combination therapy with vinorelbine, 25 mg/m2 weeks 1 and 2, plus trastuzumab, 4 mg/kg loading dose and then 2 mg/kg weekly, in a three weeks cycle. Eligibility criteria included measurable disease and a baseline ejection fraction > or = 50%. Forty-two percent of the patients were not pretreated, whereas 58% had received a previous chemotherapy regimen for metastatic disease, including anthracyclines and/or taxanes (47%), and trastuzumab plus taxol (11%). RESULTS: We observed 14 (31%) complete responses and 21 (47%) partial responses, with an overall response rate of 78%. Stable disease > 6 months was assessed for 5 (11%) patients with a clinical benefit of 89%. Five (11%) patients progressed. With a median follow-up of 11 months, median time to progression was 9 months and median duration of response was 7.6 months for complete remissions and 4 months for partial remissions. Median survival was 29 months. CONCLUSIONS: In spite of a smaller dose intensity of vinorelbine than previously reported, the regimen evaluated was notably effective in terms of response rate, time to progression and survival, with very mild toxicity.

Phenotypic features and genetic characterization of male breast cancer families: identification of two recurrent BRCA2 mutations in north-east of Italy.

BACKGROUND: Breast cancer in men is an infrequent occurrence, accounting for approximately 1% of all breast tumors with an incidence of about 1:100,000. The relative rarity of male breast cancer (MBC) limits our understanding of the epidemiologic, genetic and clinical features of this tumor. METHODS: From 1997 to 2003, 10 MBC patients were referred to our Institute for genetic counselling and BRCA1/2 testing. Here we report on the genetic and phenotypic characterization of 10 families with MBC from the North East of Italy. In particular, we wished to assess the occurrence of specific cancer types in relatives of MBC probands in families with and without BRCA2 predisposing mutations. Moreover, families with recurrent BRCA2 mutations were also characterized by haplotype analysis using 5 BRCA2-linked dinucleotide repeat markers and 8 intragenic BRCA2 polymorphisms. RESULTS: Two pathogenic mutations in the BRCA2 gene were observed: the 9106C>T (Q2960X) and the IVS16-2A>G (splicing) mutations, each in 2 cases. A BRCA1 mutation of uncertain significance 4590C>G (P1491A) was also observed. In families with BRCA2 mutations, female breast cancer was more frequent in the first and second-degree relatives compared to the families with wild type BRCA1/2 (31.9% vs. 8.0% p = 0.001). Reconstruction of the chromosome phasing in three families and the analysis of three isolated cases with the IVS16-2A>G BRCA2 mutation identified the same haplotype associated with MBC, supporting the possibility that this founder mutation previously detected in Slovenian families is also present in the North East of our Country. Moreover, analysis of one family with the 9106C>T BRCA2 mutation allowed the identification of common haplotypes for both microsatellite and intragenic polymorphisms segregating with the mutation. Three isolated cases with the same mutation shared the same intragenic polymorphisms and three 5' microsatellite markers, but showed a different haplotype for 3' markers, which were common to all three cases. CONCLUSION: The 9106C>T and the IVS16-2A>G mutations constitute recurrent BRCA2 mutations in MBC cases from the North-East of Italy and may be associated with a founder effect. Knowledge of these two recurrent BRCA2 mutations predisposing to MBC may facilitate the analyses aimed at the identification of mutation carriers in our geographic area.

Familial breast cancer: characteristics and outcome of BRCA 1-2 positive and negative cases.

BACKGROUND: The clinical and pathological characteristics and the clinical course of patients with breast cancer and BRCA 1-2 mutation are poorly known. METHODS: From 1997, patients with breast cancer and a family history of breast or ovarian cancer were offered BRCA testing. The clinical and pathological features of patients with known BRCA status were retrospectively assessed and comparisons were made between cancers arising in BRCA positive and BRCA wild type (WT) patients respectively. Type of treatment, pattern of relapse, event (local relapse, contralateral breast cancer, metastases) free and overall survival were also compared in the two groups. Out of the 210 patients tested, 125 had been treated and followed-up at our Institution and were evaluated in this study. RESULTS: BRCA positive patients tended to be more often premenopausal (79% vs 65%) and to have positive lymphnodes (63% vs 49%), poorly differentiated tumours (76% vs 40%--p = 0.002 at univariate analysis, not significant at multivariate analysis) and negative estrogen receptors (43% vs 29%). Treatment was not different in the two groups. In the 86 BRCA-WT patients, the first event was a local relapse in 3 (3%), metachronous contralateral breast cancer in 7 (8%) and distant metastases in 16 (19%). In the 39 BRCA positive patients, the corresponding figures were 3 (8%), 8 (21%) and 3 (8%). There was no difference in event free survival, with a median of 180 months in both groups of patients. At 20 years, projected survival was 85% for BRCA positive patients and 55% for BRCA-WT, but this difference was not statistically significant. CONCLUSION: Although BRCA positive patients have more frequently negative prognostic factors, their prognosis appears to be equal to or better than in patients with BRCA-WT.

Combined chemoimmunotherapy of metastatic melanoma: a single institution experience.

The addition of cytokines, such as interferon alpha-2b and interleukin-2, to chemotherapy in metastatic melanoma has produced conflicting results in phase II and III trials. We report our experience with a chemoimmunotherapeutic regimen using subcutaneous cytokines. Twenty-eight patients with advanced melanoma (median age, 45 years; male to female ratio, 19 : 9) were treated. Doses were as follows: cisplatin, 20 mg/m intravenously (iv) days 1-4; vinblastine, 1.6 mg/m iv days 1-4; dacarbazine, 800 mg/m iv day 1; interferon alpha-2b, 5 MIU/m subcutaneously (sc) days 1-5; interleukin-2, 9 MIU/m sc days 1-5 and 8-12. Treatment was repeated every 3 weeks for a maximum of six cycles. The response was assessed after two cycles and toxicity at every cycle, according to World Health Organization (WHO) and National Cancer Institute (NCI) criteria, respectively. At a median follow-up of 8 months, only four patients (14%) were still alive. The overall response rate was 33%, with three (11%) complete responses lasting for 17, 14 and >24 months. There were six (22%) partial responses and three stable disease. Amongst the responders, three patients progressed at the level of the central nervous system. The median time to progression and overall survival were 3.5 and 9 months, respectively. The most common grade 3-4 toxicity was neutropenia, reported in 25 of the 28 patients (92%). Only two patients (7%) experienced neutropenic fever. Thrombocytopenia grade 3-4 occurred in seven of the 28 patients (25%), with only one patient needing transfusional support. One toxic death due to neutropenic fever occurred. It can be concluded that the chemoimmunotherapy schedule evaluated is active and may be considered for patients with metastatic melanoma who have a good performance status and a limited disease burden.

New oral drugs in older patients: a review of idarubicin in elderly patients.

Idarubicin (IDA) is a structural analogue of daunorubicin with the same mechanism of action. Unlike the other currently available anthracyclines, it has a significant oral bioavailability, which makes it particularly attractive for the treatment of elderly patients. IDA resulted at least as effective as daunorubicin for acute nonlymphocytic leukemia and additional data are in analysis as far as lymphomas and breast cancer are concerned. Adverse effects are mainly hematological, while hair loss, mucositis and cardiotoxicity are less frequently reported with IDA than with other anthracyclines. The pharmacokinetics, activity, adverse effects and new modalities of oral administration are reviewed.

Pigmented mammary Paget's disease mimicking melanoma.

Our case of pigmented mammary Paget's disease simulated melanoma clinically and dermoscopically. Histologically, the lesion was characterized by microscopic features similar to those seen in malignant melanoma and, to a lesser extent, in Bowen's disease (intra-epidermal squamous cell carcinoma). Immunohistochemical studies demonstrated that the tumor cells were positive for keratins (Cam 5.2+MNF 116) and AE1-AE3 and negative for HMB-45 and S-100 proteins. In conclusion clinical and dermoscopic examination cannot reliably distinguish melanoma from epithelial pre-neoplastic or neoplastic disease, therefore the differentiation of pigmented Paget's disease from superficial spreading of melanoma and Bowen's disease is based on histopathologic integrated with immunohistochemical criteria.

A two-year regional program for the early detection of cutaneous melanoma.

BACKGROUND: A regional program for the early diagnosis of cutaneous melanoma involving general practitioners was effective in 1997-1998 in the Friuli Venezia Giulia region in Northern Italy. The aim of the 2-year program was to evaluate the role of a skin examination performed by general practitioners in people older than 18 years without known skin lesions and spontaneously presenting to their offices for any reason, with referral of suspect cases to a pre-identified regional dermatology or plastic surgery institution. METHODS: In the preparatory phase (late 1995 and 1996), all general practitioners operating in the Friuli Venezia Giulia region (n = 1,038) were asked to participate in the program. Support from all regional dermatology, pathology and plastic surgery institutions was obtained. Operational procedures for the management of referred people were defined, and educational meetings directed to general practitioners interested in the program were held. Skin examinations by general practitioners started at the end of 1996 and took place during 1997 and 1998. Subsequently, information was obtained from participating general practitioners and from pathology institutions about the number and thickness of diagnosed melanomas, as well as the number of diagnosed skin carcinomas and dysplastic nevi. In addition, the thickness distribution of all melanomas diagnosed in the Friuli Venezia Giulia region before and during the program was obtained. RESULTS: A total of 153 general practitioners participated in the program, but only 74 were active and assessable. A total of 11,040 skin examinations was performed by these 74 general practitioners (median, 75 per general practitioner). In all, 820 people (7.4%) were referred for dermatological evaluation (median, 8 per general practitioner). Among these 820 people, at least 38 melanomas (4.6% of referred cases) were detected (18 < or = 1.5 mm, 11 > 1.5 mm thick, unknown in 9). The dermatological examinations/diagnosed melanomas ratio was 21. In addition, 94 skin carcinomas and 50 dysplastic nevi were detected. At the regional level, the percentage of thin melanomas rose from 65.3% in 1995-96 to 72.2% in 1997-98 (P = 0.04), whereas the number of thick melanomas declined. CONCLUSIONS: In our study, only a few general practitioners chose, in the absence of incentives, to participate in the study. However, the yield of melanomas, most of which were thin, was considerably high and the workload was acceptable. This compares favorably to experiences where dermatologists were involved directly without a filter work by general practitioners.

Opioid consumption in hospitals of the Friuli-Venezia Giulia region: a four-year retrospective study.

AIMS AND BACKGROUND: Opioid consumption for analgesic purposes is considered an important indicator of the quality of cancer pain treatment. Italy's consumption ranks among the lowest in economically developed countries. A lack of systematic education of health care professionals regarding pain control and a sort of "opiophobia" induced by measures designed to control the improper use of drugs have been indicated as possible reasons for this trend. The aim of this study was firstly to evaluate the level of opioid consumption at inpatient institutions (where opioid prescription rules have never been subjected to any restriction) and secondly to survey the attitude of the physicians working in general hospitals and specialized oncology institutions (oncology centers and hospices) towards opioid administration. METHODS: The authors performed a four-year survey (1996-1999) on the consumption of major opioids (morphine, meperidine, buprenorphine, transdermal fentanyl) among all the inpatient institutions (six regional/provincial hospitals, eleven district hospitals, the Aviano Oncology Institute and two hospices) of the Friuli-Venezia Giulia region in North-Eastern Italy. To facilitate data interpretation, all the opioids were converted to milligrams equivalent of oral morphine (mg OME). Data on the number of days of hospitalization of oncological patients in every institution were also collected. RESULTS: The overall consumption of opioids was 9,299,177 mg OME (83.3%) and 1,845,060 mg OME (16.7%) in general hospitals and specialized oncology institutions, respectively. Overall, the number of days of hospitalization of oncological patients was 1,121,142 (87%) and 167,665 (13%) in general hospitals and specialized oncology institutions, respectively. The ratio between the total dosage of mg OME administered and the total number of hospitalization days in general hospitals and specialized oncology institutions was 8.29 mg OME/day and 11 mg OME/day, respectively. CONCLUSIONS: Our data show that in specialized oncology institutions, opioid consumption was proportionally higher than in general hospitals. This result indicates the attitude of the physicians of these institutions towards opioid administration, probably due to the training received on cancer pain treatment, and emphasizes the need to educate all health care workers involved in the management of cancer patients.

Interobserver agreement of the dermoscopic diagnosis of 129 small melanocytic skin lesions.

AIM AND BACKGROUND: Dermoscopic diagnosis of pigmented skin lesions is based on the evaluation of dermoscopic criteria (classical pattern analysis) and on alternative diagnostic methods, such as the ABCD (A, asymmetry; B, border; C, color; D, differential structures) rule based on the total dermatoscopic score. The aim of the study was to investigate the interobserver agreement of standard dermoscopic criteria between two observers and the diagnostic validity of dermoscopic diagnosis by pattern analysis and by the ABCD rule. STUDY DESIGN: The study included a total of 129 small (< or = 5 mm) melanocytic skin lesions selected from all lesions observed in consecutive patients between April 1996 and September 1998. Before surgery, each lesion was photographed with a Dermaphot. Dermoscopic images were examined independently by two observers to evaluate the presence or absence of standard dermoscopic criteria and to establish the dermoscopic diagnosis by pattern analysis and by the ABCD rule. RESULTS: Interobserver agreement for dermoscopic criteria varied from moderately good to good, with the highest agreement for radial streaks (k = 0.96) and the lowest for pseudopods (k = 0.49). Interobserver agreement was moderately good in dermoscopic diagnosis by pattern analysis (k = 0.48) and by the total dermatoscopic score (k = 0.44). The sensitivity and specificity of dermoscopic diagnosis by pattern analysis were 40% and 99%, respectively, for both observers. As regards the total dermatoscopic score (a cutoff score of < or = 5.45 vs > 5.45), sensitivity ranged from 80% to 100% and specificity from 48% to 59%. CONCLUSIONS: The study showed that the pattern analyses as well as the ABCD rule give a poor discrimination between benign and malignant lesions and do not add relevant information for management decision in small melanocytic lesions. However, close follow-up examinations of small equivocal melanocytic lesions using digital equipment allow evaluation of their dermoscopic features during progression and whether their rather commonly found atypical dermoscopic features are lost during their natural course of growth.