Serial measurements of NT-proBNP are predictive of not-high-dose anthracycline cardiotoxicity in breast cancer patients.

BACKGROUND: The aim of this study was to assess the value of N-terminal pro-brain natriuretic peptide (NT-proBNP) in predicting late cardiotoxicity in patients treated with not-high-dose chemotherapy (NHDC), and to compare the predictive value of NT-proBNP and cardiac troponin I (cTnI). METHODS: In 71 patients undergoing NHDC with anthracyclines, NT-proBNP and cTnI levels were measured before and 24 h after each NHDC cycle. Left ventricular (LV) function was assessed by echocardiography at baseline, every two NHDC cycles, at the end of chemotherapy, and at 3-, 6- and 12-month follow-up. RESULTS: During NHDC, only NT-proBNP showed abnormal values. According to NT-proBNP behaviour, patients were divided into two groups: group A (n=50) with normal (n=23) or transiently elevated NT-proBNP levels (n=27), and group B (n=21) with persistently elevated NT-proBNP levels. At follow-up, LV impairment was significantly worse in group B than in group A. %Δ (baseline-peak) NT-proBNP was predictive of LV impairment at 3-, 6- and 12-month follow-up, with a cutoff of 36%. CONCLUSION: Serial measurements of NT-proBNP may be a useful tool for the early detection of patients treated with NHDC at high risk of developing cardiotoxicity.

General principles of chemotherapy.

BACKGROUND AND OBJECTIVE: Over the last 50 years, medical treatment of solid cancers gained major advances in terms of effectiveness through breakthrough knowledge of cancer biology, technology development and identification of fundamental active drugs. STATE OF THE ART: We conventionally discriminate between medical treatment of the advanced or metastatic disease and of the early disease, namely adjuvant and neoadjuvant or primary treatment, if administered after or before surgery. New drugs or treatment associations can be sequentially introduced in medical treatment of cancer patients in phase I, II and III clinical trials. No drug or drug association can be proposed in the adjuvant or neoadjuvant setting of treatment without proven effectiveness in the advanced disease. Primary endpoints of medical treatment according to the phase of the disease are safety, activity and efficacy. Different options of medical treatment may be selected for each tumor according to the specific phase of disease. In some metastatic cancers, such as colorectal cancer, the activity of medical treatment justified the development of strategies integrating also surgical resection of metastases, specifically liver, with the objective to increase efficacy. PERSPECTIVES: Open question in first and subsequent lines of treatment in advanced cancer patients, particularly in MCRC patients, is the proper individualization of medical treatment according to prognostic and predictive bio-markers.

Cardiovascular toxicity following sunitinib therapy in metastatic renal cell carcinoma: a multicenter analysis.

BACKGROUND: Recent data have shown that cardiotoxicity represents a potentially important side-effect in patients treated with sunitinib. We reviewed cardiac adverse events in patients with metastatic renal cell carcinoma (RCC) who underwent treatment with this agent. PATIENTS AND METHODS: The medical records of 175 patients with metastatic RCC treated with sunitinib at eight Italian institutions were retrospectively reviewed. Alterations in left ventricular ejection fraction (LVEF) and blood pressure were evaluated. Patients with preexisting cardiac risk factors were specifically scrutinized for increased expression of cardiac changes. RESULTS: Grade 3 hypertension was seen in 17 patients (9.7%); in 12 of these 17, hypertension developed after receiving the third sunitinib cycle. Among these 17 patients, 12 (70.6%) also experienced left ventricular systolic (LVEF) dysfunction; in all, 33 of the 175 patients (18.9%) developed some degree of cardiac abnormality, of which 12 were classified as grade 3 LVEF dysfunction and/or congestive heart failure (CHF) (6.9%). Significant univariate associations for predictors of CHF were history of hypertension (P = 0.008), history of coronary heart disease (P = 0.0005) and prior treatment with an angiotensin-converting enzyme inhibitor (P = 0.04). Multivariate analysis suggested that a history of coronary artery disease [odds ratio (OR) 18, 95% confidence interval (CI) 4-160, P = 0.005] and hypertension (OR 3, 95% CI 1.5-80, P = 0.04) was the only significant independent predictors of CHF. CONCLUSIONS: Patients undergoing sunitinib, especially those with a previous history of hypertension and coronary heart disease, are at increased risk for cardiovascular events and should be monitored for exacerbations of their hypertension and for evidence of LVEF dysfunction during treatment.

From adjuvant to preventive breast cancer treatment: bridging the gap over troubled waters.

Recently, chemoprevention trials have demonstrated the efficacy of preventive medical treatment (PMT) in reducing breast cancer (BC) detection rates in at-risk affected and unaffected women selected according to clinical and/or familial risk criteria, particularly with the use of tamoxifen (TAM). Major concerns limiting the routine use of TAM are the questionable benefit/risk ratio and poor patient compliance, which justify the studies undertaken to determine the efficacy of aromatase inhibitors (AIs) with respect to TAM. Issues such as therapy duration, impact on survival, incidence of side-effects and which subsets benefit most from treatment, still remain unsolved. Therefore, only ER+ BC patients are routinely subjected to PMT, independently of their BRCA1/2 status, using adjuvant hormonal therapy. More attention must be focused towards BRCA1/2 carriers as they are probably the women at highest risk of developing BC, in which available data remain controversial and in which hormone-therapy might be important. Hence, at-risk women (affected patients or unaffected women) should be carefully evaluated for inclusion into highly selected preventive clinical trials aimed at evaluating PMT independently of, or according to, BC predisposition status (unknown, positive or negative BRCA1/BRCA2 status) and with respect to menopausal status. BC patients, harboring a BRCA1/2 predisposition, may represent the best subset for extended adjuvant treatment, useful as PMT, simultaneously. Only the evolving differentiation of categories of at-risk women will allow physicians to discriminate PMT in a highly selective manner.

Novel P53 mutations detected by FAMA in colorectal cancers.

BACKGROUND: The aim of the study was to identify p53 gene mutations by FAMA (fluorescence-assisted mismatch analysis) in colorectal cancers. PATIENTS AND METHODS: Analytical scanning of the p53 gene (exons 5-9) was performed in colon cancer samples from 44 consecutive patients by FAMA. FAMA is a semiautomatic scanning approach based on the chemical cleavage of the mismatch in fluorescently labeled heteroduplex DNA, obtained from the combination of a normal and a mutated allele. FAMA has already shown optimal levels of diagnostic accuracy and sensitivity in detecting gene mutations (nucleotide substitutions, insertions/deletions) both at the germline and somatic level. The peculiar feature of FAMA is its ability to detect and localize mutations, by a redundant pattern of signals due to fluorescent DNA fragments generated by chemical cleavage. Moreover, previous data have demonstrated that normal contaminating DNA from stromal cells in the sample does not affect the sensitivity of the procedure, leading to the identification of the mutation even when the ratio mutant/normal allele is 10%. RESULTS: Eighteen mutations (12 missense, one nonsense, two deletions, three nucleotide substitutions at the level of the splice-junctions) and two polymorphisms were detected by FAMA in 17 patients (39%) and then confirmed by automated sequence analysis. Six of 18 mutations (33%) were not previously reported for colon cancer samples and two of 18 lesions (11%) were identified as novel p53 mutations. CONCLUSIONS: Analytical scanning of the p53 gene by FAMA in DNA from colon cancer samples provides a sensitive, accurate and specific diagnostic procedure for routine clinical application.

BRCA1 and BRCA2 genetic testing in Italian breast and/or ovarian cancer families: mutation spectrum and prevalence and analysis of mutation prediction models.

BACKGROUND: Breast cancer is an extremely complex disease, characterized by a progressive multistep process caused by interactions of both genetic and non-genetic factors. A combination of BRCA1 and BRCA2 gene mutations appears responsible for about 20%-30% of the cases with breast cancer familial history. The prevalence of BRCA1/2 pathogenic mutations largely varies within different populations; in particular, the rate of mutations in Italian breast and/or ovarian cancer families is rather controversial and ranges from 8% to 37%. PATIENTS AND METHODS: Of the 152 breast/ovarian cancer families counseled in our centre, 99 were selected for BRCA1/2 mutation screening according to our minimal criteria. The entire coding sequences and each intron/exon boundary of BRCA1/2 genes were screened by direct sequencing (PTT limited to BRCA1 exon 11). For each proband, the a priori probability of carrying a pathogenic BRCA1/2 germline mutation was calculated by means of different mutation prediction models (BRCApro, IC and Myriad Table) in order to evaluate their performances. RESULTS: Our analysis resulted in the identification of 25 and 52 variants in the BRCA1 and BRCA2 genes, respectively. Seventeen of them represent novel variants, including four deleterious truncating mutations in the BRCA2 gene (472insA, E33X, C1630X and IVS6+1G>C). Twenty-seven of the 99 probands harbored BRCA1 (n = 15) and BRCA2 (n = 12) pathogenic germline mutations, indicating an overall detection rate of 27.3% and increasing by more than 15% the spectrum of mutations in the Italian population. Furthermore, we found the lowest detection rate (19.4%) in pure hereditary breast cancer family subset. All of the prediction models showed praises and faults, with the IC software being extremely sensitive but poorly specific, compared to BRCApro. In particular all models accumulated most false-negative prediction in the HBC subset. Interestingly preliminary results of a study addressing the presence of genomic rearrangements in HBC probands with BRCApro or IC prediction scores >/=95%, provided evidence for additional mutations undetectable with our conventional screening for point mutations. CONCLUSIONS: Altogether our results suggest that HBC families, the largest pool in our series, represent an heterogeneous group where the apparently faulty performances of the prediction models might be at least partially explained by the presence of additional kinds of BRCA1/2 alteration (such as genomic rearrangements) or by mutations on different breast cancer related genes.

Increased tolerability of bimonthly 12-hour timed flat infusion 5-fluorouracil/irinotecan regimen in advanced colorectal cancer: A dose-finding study.

A dose-finding study was designed to determine the maximum tolerated dose (MTD) of a bimonthly 12-h (10:00 p.m to 10:00 a.m), timed flat infusion (TFI) of 5-fluorouracil (5-FU) plus irinotecan (CPT-11), without leucovorin (LV), for metastatic colorectal carcinoma (CRC). A total of 33 patients were treated. Seven dose levels included a fixed CPT-11 dose of 180 mg/m2 on days 1 and 15 (d(1,15)) and escalating doses of 5-FU 600-1200 mg/m2 on days 1-4 and 15-18 (d(1-4,15-18)). Dose-limiting toxicities (DLTs) were: grade 3-4 non-hematologic, grade 4 hematologic and any toxicity causing a more than a 2-week delay in treatment. The MTD was reached at the seventh dose level. DLTs were observed in 5/8 patients (63%): G3 diarrhea, 2 patients, associated with G3 mucositis in one instance; G4 neutropenia, 2 patients, associated with severe asthenia in 1 patient; G3 hand-foot syndrome, 1 patient. The recommended doses (RDs) were established at the sixth dose level: 5-FU, 1100 mg/m2/d(1-4,15-18); CPT-11 180 mg/m2/d(1,15) [5-FU and CPT-11 dose intensity (DI), 2200 and 90 mg/m2 per week (w), respectively]. At the recommended dose, the DLTs in 38 cycles were: mucositis, 2 cycles (5%); afebrile G4 neutropenia and hand-foot syndrome, 1 cycle (3%). In 24 assessable patients, the overall response rate was 37.5%. The present CPT-11/5-FU schedule is highly tolerable in an outpatient setting using the highest recommended 5-FU dose effective in advanced CRC.

Arsenic speciation and susceptibility to oxidative stress in the fanworm Sabella spallanzanii (Gmelin) (Annelida, Sabellidae) under naturally acidified conditions: An in situ transplant experiment in a Mediterranean CO2 vent system.

The fanworm Sabella spallanzanii (Gmelin, 1791) (Annelida, Sabellidae) is considered tolerant to several types of stressors but is generally absent from the CO2 vents. A peculiar characteristic of this species is the elevated content of arsenic in the gills, particularly dimethylarsinic acid (DMA), stored as an anti-predatory compound. In this study, modulation of trace metal levels, chemical speciation of arsenic and oxidative stress biomarkers were quantified in S. spallanzanii after a 30days transplant experiment into naturally acidified conditions in a Mediterranean vent system. No significant bioaccumulation of metals was observed in the thoracic tissues and branchial crowns after the translocation period, whereas variations occurred in the relative abundance of different arsenic compounds with the appearance of inorganic forms. The antioxidant system of translocated polychaetes exhibited a significant decrease of enzymatic activities of both catalase and glutathione peroxidases, and the impairment of the overall capability to neutralize hydroxyl radicals (OH). This highlighted an oxidative challenge primarily on the detoxification pathway of hydrogen peroxide. Overall low pH-elevated pCO2 may have detrimental effects on arsenic metabolism and oxidative status of S. spallanzanii, supporting the hypothesis of species-specific differences in vulnerability to ocean acidification.

Tailoring the dosing schedule of nab-paclitaxel in metastatic breast cancer according to patient and disease characteristics: Recommendations from a panel of experts.

The choice of chemotherapy for patients with metastatic breast cancer (MBC) depends on disease- and patient-related factors, but there is little guidance on dosing modifications for patients unable to receive the licensed dose. Nab-paclitaxel is a solvent-free form of paclitaxel that uses albumin as a drug carrier and exploits endogenous albumin transport pathways to achieve enhanced drug targeting and tumour penetration with reduced toxicity. It is approved for use at a dose of 260 mg/m(2) every three weeks in adults who have failed first-line treatment for MBC and for whom standard anthracycline-based therapy is not indicated. Emerging data suggest that weekly dosing schedules of nab-paclitaxel may provide clinical benefit in some patients, but the utility of these alternative dosing schedules remains unclear. A panel of breast cancer experts convened to review available literature for nab-paclitaxel in MBC and, taking into account their clinical experience, recommended that alternative dosing schedules may be considered according to the aggressiveness of disease and patient condition as follows: 125 mg/m(2) QW 3/4 (aggressive disease and fit), 100mg/m(2) QW 3/4 (aggressive or indolent disease and unfit). All dosing schedules were considered acceptable for fit patients with indolent disease. These recommendations are based on current evidence, and emerging data from ongoing trials may reinforce or modify the recommendations provided.

Diagnostic strategy for analytical scanning of BRCA1 gene by fluorescence-assisted mismatch analysis using large, bifluorescently labeled amplicons.

The aim of this study was to develop a protocol for reliable, sensitive, and cost-effective mutation scanning of the BRCA1 gene, based on a modification of fluorescence-assisted mismatch analysis. The main features of this method are: (a) robust PCR amplification and strandspecific labeling of 25 large amplicons using uniform conditions and universal fluorescent primers; and (b) sensitive characterization of the position of sequence changes. The diagnostic accuracy of this method was tested by scanning the large exon 11 in 12 DNA samples with reported mutations. In a blind test, specific patterns of fluorescence profiles were obtained, and all were attributed correctly, without sequencing, to each mutation or polymorphism. Seven breast/ovarian cancer families with high probability of BRCA1-related predisposition were screened. Three truncating mutations (of which one was novel and three were missense changes, including two novel ones) were detected. The three missense mutations affect the highly conserved BRCT domain. Scanning by FAMA appears to be free of biases for particular types of sequence changes-except for exon deletions/duplications, which cannot be detected by conventional PCR-based methods-and allows substantial savings in the number of sequencing reactions and in the time invested in their interpretation. Therefore, it lends itself to screening structurally complex loci in the diagnostic context and in other fields of genetic analysis.

Antioxidant capacity of polychaetes occurring at a natural CO2 vent system: Results of an in situ reciprocal transplant experiment.

Ocean acidification (OA) is occurring at a fast rate, resulting in changes of carbonate chemistry in the oceans and in lowering of the pH. Previous studies have documented significant changes in the antioxidant defenses of marine species in response to OA. Here, selected polychaete species, Platynereis dumerilii, Polyophthalmus pictus and Syllis prolifera, were sampled from a natural CO2 vent system (pH = 7.3) and from a non-venting 'control' site (pH = 8.1), and reciprocally transplanted in these areas for 30 days. Total antioxidant capacity toward different forms of oxyradicals was compared in native and transplanted polychaetes: the aim was to assess whether the environmental conditions at the vent site would act as a prooxidant stressor, and the capability of polychaetes to modulate their antioxidant capacity to counteract a varied oxyradicals formation. None of the investigated species enhanced the antioxidant potential during the experiment. A significant reduction of the capability to neutralize different forms of oxyradicals was observed in P. pictus and, partially, in S. prolifera when transplanted from control to naturally-acidified conditions. On the other hand, populations of P. dumerilii originating from the vent and of S. prolifera from both control and acidified sites, showed higher constitutive antioxidant efficiency toward peroxyl radicals and peroxynitrite, which may allow them to cope with short-term and chronic exposure to higher oxidative pressure without further enhancement of antioxidant defenses. Since low pH - high pCO2 is the greatest environmental difference between the control and the vent sites, we suggest that the pro-oxidant challenge due to such peculiarities may have different biological consequences in different polychaete species. Some appear more susceptible to oxidative effects, while others acquire a long term acclimatization to vent conditions through the enhancement of their basal antioxidant protection.

Evidence of a founder mutation of BRCA1 in a highly homogeneous population from southern Italy with breast/ovarian cancer.

Several genes have been involved in the pathogenesis of hereditary breast/ovarian cancer (BOC), but mutations in the BRCA1 gene are by far the most recurrent. In this study, we report the identification of a founder mutation in a geographically and historically homogeneous population from Calabria, a south Italian region. A screening performed on 24 patients from unrelated families highlighted the high prevalence of a 5083del19 alteration in the BRCA1 gene, which accounts for 33% of the overall gene mutations. The same mutation was also detected in 4 patients, all of Calabrian origin, referred to us by research centres from the north of Italy. Allelotype analysis, performed on probands and unaffected family members revealed the presence a common allele, therefore suggesting a founder effect due to a common ancestor. Our findings underscore the importance of ethnic background homogeneity in patients' selection and highlight the usefulness of founder mutations as a potential tool for optimisation of preclinical diagnosis in gene carriers and therapeutic approaches in affected individuals.

Advanced non-small-cell lung cancer (NSCLC) treated with folinic acid (F), fluorouracil (FU), vincristine (O), and mitomycin-C (Mi), (F-FOMi).

Thirty-one patients with advanced non-small-cell lung cancer (NSCLC) were treated with a combination of folinic acid, fluorouracil, vincristine, and mitomycin (F-FOMi). Eight partial responses (26%), eight stable disease (26%), and 15 progressive disease (48%) were obtained. Patients with performance status (PS) 0-1 had a significantly better response rate than those with PS 2-3. Overall actuarial survival was 10 months. Toxicity was mild and mainly gastrointestinal with mucositis and diarrhea. F-FOMi seems to be comparable to regimens more widely used in the treatment of NSCLC.

Short-term weekly neoadjuvant chemotherapy in the treatment of locally advanced cervical cancer.

Twenty patients with locally advanced cervical cancer (FIGO stage Ib-IIa "bulky"/IIb) were treated with three courses of weekly PVB (day 1: cisplatin, 50 mg/m2; vincristin, 1 mg/m2; bleomycin, 30 IU over 24-hr) in a neoadjuvant setting. Toxicity was generally mild (no grade 3-4 toxicity was observed), and the treatment was well tolerated without reduction of programmed dose intensity. Fourteen patients (70%) experienced a clinical response and underwent surgery within 20 days after the third course of chemotherapy. Six patients (30%) with stable disease were treated with salvage radiotherapy. Two of the 14 responders experienced a pathologic complete response (14.2%); microscopic disease was detected in one patient with clinical complete response. Pelvic node metastases were found in 4/14 patients (28.5%) and microscopic parametrium involvement in 3/14 (21.4%). All 14 patients had free margins of resection. A short-term weekly platinum-based chemotherapy is highly effective, has little toxicity, and allows a prompt salvage therapy for nonresponding patients.

Role of immunoscintigraphy in clinical assessment of gastrointestinal tumors.

From June 1986 until April 1989 31 patients with gastrointestinal tumors were studied at follow-up for recurrences by immunoscintigraphy (IS) using F(ab)2 fragments of monoclonal antibodies anti CEA and anti CA 19-9. IS was employed to confirm the presence of metastases already found (group A) and to verify metastases suspected following physical and instrumental examinations and/or increases in CEA and/or CA 19-9 (group B). Thirty-four IS findings have been evaluated to date: 19 in group A, with 18 true positive and 1 false negative results; 15 in group B. In these patients there were 12 cases of pathologic high fixation: 6 were confirmed using standard examinations after a median follow-up of 1 month (range 1-12); 6 cases had no metastatic evolution at the suspected site after a follow-up of 5-28 months. In 3 cases IS was negative, these patients are disease free at 13, 14 and 24 months. In group B, 5 of 8 abdominal intense fixations were early diagnoses of local or peritoneal recurrences. The overall accuracy was 79.4% and it was not affected by circulating CEA levels; sensitivity was 96%. IS can be considered useful as a primary diagnostic examination in the follow-up of patients with suspected abdominal metastases.

[Can analysis of the molecular status of the p53 gene contribute to improving the therapeutic strategy for breast carcinoma?]. / L'analisi dello stato molecolare del gene p53 può contribuire ad innovare le strategie terapeutiche nel carcinoma della mammella?

The occurrence of mutations in the p53 tumor suppressor gene is a specific and recurring genetic event in solid tumors. P53 plays a pivotal role in multiple cellular processes such as cell growth control, DNA repair and programmed cell death. Genotoxic damage, also induced by chemotherapy or radiotherapy, induces p53 overexpression in order to control the rate of proliferating damaged cells, thus triggering the mismatch repair or apoptotic pathways. P53 inactivation determines a condition of genetic instability, justifying the subsequent susceptibility to acquire mutations of different other genes. P53 mutations are associated with worse prognosis and with chemo/radioresistance, due to the inability to trigger p53-dependent programmed cell death. Molecular diagnostic strategies show 32% p53 mutations in breast cancer. The analysis of the p53 gene performed by FAMA (Fluorescence Assisted Mismatch Analysis) in high-risk breast cancer patients with > or = 10 involved axillary nodes may help identify a subset of very high risk BC patients (vHR-BC) with poorer prognosis and a subset with better prognosis, potentially responsive to medical treatments. The accurate evaluation of the p53 status can predict prognosis and sensitivity to chemotherapy, thus representing the first step toward better definition of therapeutic strategies according to the molecular characterization of the individual patient.

Cervical sarcoma botryoides treated with conservative surgery and adjuvant chemotherapy: a case report.

A case of cervical sarcoma botryoides treated with conservative surgery and adjuvant monochemotherapy is presented.

Hypersensitivity reaction to carboplatin: successful resolution by replacement with cisplatin.

Hypersensitivity reactions caused by carboplatin rarely occur. These reactions can cause lethal complications and make subsequent therapeutic approaches difficult. To date, only a few cases of successful resolution of hypersensitivity by replacement of carboplatin with cisplatin have been reported. We report on a patient with serous papillary extra-ovarian peritoneal carcinoma who developed a hypersensitivity reaction after the 10th weekly administration of carboplatin. Two weeks after reaction, intradermal skin testing with paclitaxel, carboplatin, cisplatin, and mannitol showed intense reaction only to carboplatin. On the basis of these results, the patient was changed to a chemotherapy with cisplatin and paclitaxel. A further eight courses of chemotherapy were administered without evidence of hypersensitivity reactions. Carboplatin seems to be successfully replaceable by cisplatin in case of hypersensitivity reactions.

[Medical emergencies in oncology: hypercalcemia. II. Diagnosis and therapy]. / Emergenze metaboliche in oncologia: l'ipercalcemia. Parte II--Diagnosi e terapia.

The acute metabolic abnormalities associated with cancer may cause symptoms that require urgent medical treatment and may constitute a more dangerous threat to life than the cancer itself. Hypercalcaemia is probably the most common metabolic complication of neoplastic disease (occurring in up to 30% of cancer patients) and its timely treatment may often save the patient and may permit subsequent chemotherapy. In this communication we focused our attention on the pathogenetic mechanism (part 1), diagnosis and subsequent treatment of this metabolic disorder (part 2).