Phase III HEAT Study Adding Lyso-Thermosensitive Liposomal Doxorubicin to Radiofrequency Ablation in Patients with Unresectable Hepatocellular Carcinoma Lesions.

Purpose: Lyso-thermosensitive liposomal doxorubicin (LTLD) consists of doxorubicin contained within a heat-sensitive liposome. When heated to ≥40°C, LTLD locally releases a high concentration of doxorubicin. We aimed to determine whether adding LTLD improves the efficacy of radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) lesions with a maximum diameter (dmax) of 3 to 7 cm.Experimental Design: The HEAT Study was a randomized, double-blind, dummy-controlled trial of RFA ± LTLD. The 701 enrolled patients had to have ≤4 unresectable HCC lesions, at least one of which had a dmax of 3 to 7 cm. The primary endpoint was progression-free survival (PFS) and a key secondary endpoint was overall survival (OS). Post hoc subset analyses investigated whether RFA duration was associated with efficacy.Results: The primary endpoint was not met; in intention-to-treat analysis, the PFS HR of RFA + LTLD versus RFA alone was 0.96 [95% confidence interval (CI), 0.79-1.18; P = 0.71], and the OS HR ratio was 0.95 (95% CI, 0.76-1.20; P = 0.67). Among 285 patients with a solitary HCC lesion who received ≥45 minutes RFA dwell time, the OS HR was 0.63 (95% CI, 0.41-0.96; P < 0.05) in favor of combination therapy. RFA + LTLD had reversible myelosuppression similar to free doxorubicin.Conclusions: Adding LTLD to RFA was safe but did not increase PFS or OS in the overall study population. However, consistent with LTLD's heat-based mechanism of action, subgroup analysis suggested that RFA + LTLD efficacy is improved when RFA dwell time for a solitary lesion ≥45 minutes. Clin Cancer Res; 24(1); 73-83. ©2017 AACR.

A new rapid methodological strategy to assess BRCA mutational status.

Hereditary cancers account for approximately 10 % of breast and ovarian cancers. Mutations of the BRCA1 and BRCA2 genes, encoding two proteins involved in DNA repair, underlie most cases of such hereditary cancers. Women with BRCA mutations develop breast cancer in 50-80 % of cases and ovarian cancer in 10-40 % of cases. Assessing BRCA mutational status is needed to direct the clinical management of women with predisposition to these hereditary cancers. However, BRCA screening constitutes a bottleneck in terms of costs and time to deliver results. We developed a PCR-based assay using 73 primer pairs covering the entire coding regions of BRCA1 and BRCA2. PCR primers, containing at the 5' end the universal M13 primer sequences, were pre-spotted in 96-well plates. Following PCR, direct sequencing was performed using M13 primers, allowing to standardize the conditions. PCR amplification and sequencing were successful for each amplicon. We tested and validated the assay on 10 known gDNAs from patients with Hereditary breast and ovarian cancer (HBOC). Our strategy is a promising time and cost-effective method to detect BRCA mutations in the clinical setting, which is essential to formulate a personalized therapy for patients with HBOC.

Expression of E-cadherin and α-catenin in T1 N0 laryngeal cancer.

AIM: To determine whether modulation of expression of cell adhesion molecules occurs in neoplastic transformation of laryngeal epithelium and to investigate their possible role in clinical outcome. MATERIALS AND METHODS: Fifty-five T1 N0 laryngeal biopsies were tested by immunohistochemistry for the E-cadherin/α-catenin adhesion complex. RESULTS: High immunohistochemical expression of E-cadherin and α-catenin was found in 18% and 53% cases, respectively. Expression of both adhesion molecules decreased according to histological grading; a significant relationship was particularly found between high E-cadherin expression and G1 cases (p=0.013). High E-cad-herin expression was statistically associated with in situ carcinoma (p=0.006). Non-statistical significance was evidenced between these adhesion molecules and tobacco use or site of occurence. Regarding clinical outcome, recurrence was associated with low expression of both adhesion molecules. CONCLUSION: E-cadherin and α-catenin down-regulation might be associated with neoplastic transformation in laryngeal tissues and might be regarded as a risk factor for clinical recurrence.

The dynamic optical breast imaging in the preoperative workflow of women with suspicious or malignant breast lesions: development of a new comprehensive score.

Purpose. To determine the diagnostic accuracy of DOBIComfortScan in patients with Breast Imaging Reporting suspect breast lesions (BI-RADS) 4-5 breast lesions. Materials and Methods. One-hundred and thirteen patients underwent DOBIComfortScan examination before surgery. Twelve parameters were taken into consideration to define DOBI findings. Results. Twenty-seven radical mastectomies, 47 quadrantectomies and 39 wide excisions, were performed. Overall, 65 invasive cancer, 9 in situ carcinoma and 39 nonmalignant lesions, were observed. Ten out of 12 considered parameters resulted significantly in association with histology at discriminant analysis. A summation score of 30.5 resulted to be the best cut off at ROC analysis, giving a sensitivity and specificity of 80% and 87%, respectively, and a positive predictive value of 92.2%. Finally the following DOBI-BI-RADS model was developed: malignant B5 ≥ 38 score); possibly malignant (B4 = 25 - 37 score); benign but the possibility of malignancy cannot be excluded (B3 = 20 - 24 score); benign (B2 < 20 score). Conclusion. definition of other parameters permits to improve the accuracy of this procedure. Further studies are warranted to define the potential role of DOBIComfortScan in breast cancer imaging.

Phase I-II trial of gemcitabine-based first-line chemotherapies for small cell lung cancer in elderly patients with performance status 0-2: the G-STEP trial.

INTRODUCTION: Treatment of elderly patients with small cell lung cancer (SCLC) is based on scanty evidence. METHODS: Patients with extensive SCLC, age >70 years, and performance status 0-2 were eligible for a study looking for optimal two-drug combination of gemcitabine (Gem) with vinorelbine (Vin), etoposide (Eto), cisplatin (Cis), or carboplatin (Car). Gemcitabine dose was the same (1000 mg/m2, days 1-8) in all combinations. A two-stage minimax flexible design for response was applied to GemVin combination (Vin 25 mg/m2, days 1-8). For GemCar, GemCis, GemEto, a phase I-II Bayesian design was applied, looking for the optimal dose of the partner drugs. Objective response rate ≥ 60% and unacceptable toxicity ≤ 25% were required to define a combination worthy of further studies. RESULTS: Median age of 78 eligible patients was 74 years. GemVin produced a 36.7% objective response rate. GemEto and GemCis arms were found not sufficiently active. GemCar produced 16 responses (14 with area under the curve [AUC] 3.5 and 2 with AUC 4.0) in 26 patients (61.5%) and 6 cases of unacceptable toxicity (3 at each Car dose). CONCLUSIONS: In elderly patients with extensive SCLC, GemVin, GemEto, and GemCis are not enough active and do not merit further studies. Gem plus Car might deserve further attention.

Anticancer effect of bisphosphonates: new insights from clinical trials and preclinical evidence.

Bisphosphonates (BPs) are cornerstones in the treatment of patients with compromised skeletal integrity (either cancer related or not). However, a major indication for BPs use remains the treatment of patients with advanced cancer metastatic to the bone. Recently, several observations derived from clinical trials, primarily aimed at establishing the impact of BPs on the bone health of cancer patients, suggested a potential role for these agents as direct anti-tumor drugs. Consequently, a series of preclinical works were produced with the aim of clarifying the mechanism underlying this observed effect. However, the impact of such data is still under debate owing to the intrinsic weakness of observations from trials not adequately powered to support them. In conclusion, the entire matter remains one of the most intriguing in oncology, and data from ongoing and planned future studies will surely provide us with more information on the great potential of BPs in the adjuvant setting.

E-cadherin and alpha-catenin expression in normal, hyperplastic and neoplastic endometrium.

UNLABELLED: The aim of this study was to determine whether modulation of expression of cell adhesion molecules may occur in neoplastic transformation of endometrial epithelium. MATERIALS AND METHODS: E-Cadherin and α-catenin protein expression were evaluated by immunohistochemistry in 124 biopsies representative of normal, hyperplastic and neoplastic endometrium. RESULTS: In normal endometrium (proliferative, secretive and atrophic endometrium) strong homogeneous, E-cadherin and α-catenin reactivity was found; 58.3% and 66.6% of biopsies representative of simple hyperplastic endometrium were homogeneously positive for E-cadherin and α-catenin, respectively, whereas no samples representative of atypical hyperplasia showed evidence of homogeneous E-cadherin or α-catenin expression. No expression of homogeneous E-cadherin was seen in endometrial adenocarcinomas; α-catenin homogeneous immunostaining was observed in 2 G1 and 2 G2 out of 22 adenocarcinoma samples (18.2%). A homogeneous co-expression of both molecules was seen only in normal (70%) and simple hyperplastic (46%) endometrium. CONCLUSION: These results suggest that E-cadherin and α-catenin down-regulation might be associated with neoplastic transformation of endometrial tissues.

Metabolic syndrome affects breast cancer risk in postmenopausal women: National Cancer Institute of Naples experience.

Postmenopausal women show the highest incidence of breast cancer in the female population and are often affected by metabolic syndrome. Metabolic syndrome (MS)--characterized by central adiposity, insulin resistance, low serum high-density lipoprotein cholesterol (HDL-C), high serum triglyceride and high blood pressure--seems to be strictly correlated to breast carcinogenesis. We enrolled 777 healthy women and women with breast cancer in our nested case-control study to evaluate the association between MS and breast cancer, analyzing anthropometric parameters (weight, height, BMI, waist and hip circumference), blood pressure, serum HDL-C, triglyceride, fasting plasma glucose, insulin, testosterone and uric acid levels and administering a questionnaire about physical activity, food intake, tobacco use, alcohol abuse, personal and familial history of disease. We found an higher prevalence of metabolic syndrome (30%) in postmenopausal breast cancer patients compared to healthy women (19%). None of the individual MS features was strong enough to be considered responsible for breast carcinogenesis alone. However, of the 63 postmenopausal breast cancer cases associated to MS, 30% presented three or more MS features, suggesting that the activation of multiple molecular pathways underlying MS might contribute to tumorigenesis. Our data support the hypothesis that MS may be an indicator of breast cancer risk in postmenopausal women. The unsettlement of the hormonal arrangement in postmenopausal, along with an increase in visceral adiposity, probably favour the hormone-dependent cell proliferation, which drives tumorigenesis. Adjustments in lifestyle with physical activity intensification and healthy diet could represent modifiable factors for the primary prevention of sporadic breast cancer.

Oncosuppressor proteins of fragile sites are reduced in cervical cancer.

FHIT and WWOX are tumor suppressor genes that span the common fragile sites FRA3B and FRA16D, respectively. To analyze possible synergisms among these genes in cervical cancer progression, we considered 159 cervical intraepithelial neoplasias, and 58 invasive squamous cell carcinomas of the uterine cervix. All cases were previously selected as high risk HPV. FHIT and WWOX proteins were examined by immunohistochemistry and their expression was inversely correlated with precancerous vs. invasive lesions. Statistics among biological markers indicated an association between FHIT and WWOX. Protein expression of these two genes was also absent or reduced in cancer cell lines. Thus, WWOX may be considered as a novel important genetic marker in cervical cancer and the association between the altered expression of FHIT and WWOX may be a critical event in the progression of this neoplasia.

Adhesion molecules and p16 expression in endocervical adenocarcinoma.

An immunohistochemical (IHC) study has been conducted on 34 cases of untreated endocervical adenocarcinomas collected among three institutions (Ospedale S. Andrea, Rome; Istituto Nazionale Tumori "Fondazione G. Pascale", Naples; and Clinica Malzoni, Avellino). The E-cadherin and alpha- and beta-catenin complex status has been investigated along with p16INK4a in all studied cases with the aim to study whether the pattern of expression of the cadherin-catenin complex could be causally related to the expression of P16INK4a protein. Results were evaluated for statistical significance by a non-parametric test (Kruskal-Wallis). Endocervical adenocarcinomas as a group were uniformly expressing p16INK4a except for two cases, and all lesions displayed downregulation of the cadherin-catenin complex, without demonstrating statistically significant differences among the different histotypes. The lack of nuclear accumulation of beta-catenin found in this group of lesions probably implies that no alteration of the beta-catenin/Wnt metabolic pathway is present in endocervical adenocarcinoma, as opposed to what is found in the literature for squamous carcinoma of the cervix. The diffuse expression of p16INK4a protein in this group of neoplasms stresses the important role of high-risk human papillomavirus infection in neoplastic causation possibly via the viral E7-mediated inactivation of pRB tumor-suppressor protein and also underlines the useful role of p16INK4a immunostaining in the diagnostic algorithm of endocervical adenocarcinomas. In consideration of these findings, investigation of downstream beta-catenin genes c-myc and cyclin D1 is sought as possibly contributive in the molecular pathogenesis of endocervical adenocarcinoma.

Effect of age on hemoglobin levels and quality of life following treatment with epoetin alfa in cancer patients.

A subgroup analysis comparing elderly (age > or =70 years; n=95) with younger (age <70 years; n=390) patients was performed on data from a prospective, multicenter, open-label study assessing the effects of once-weekly epoetin alfa 40,000 International Units (IU) for 16-20 weeks on hemoglobin (Hb) levels and quality of life (QoL) in anemic adult patients undergoing chemotherapy for solid tumors. There were significant increases in mean Hb levels at 4, 8, 12, 16-20 weeks in both age groups (p<0.0001), but no significant differences between groups (p=0.7). No significant difference was observed in terms of blood transfusion rates across the study between elderly and younger patients (3.2% vs 6.7%, p=0.2). Although QoL was lower in elderly patients at baseline, the relative percentage increases in QoL scores during treatment were similar for both age groups. Thus, once-weekly epoetin alfa was equally effective in treating chemotherapy-related anemia in elderly and younger adult patients, with similar tolerability.

Galectin-3-expression analysis in the surgical selection of follicular thyroid nodules with indeterminate fine-needle aspiration cytology: a prospective multicentre study.

BACKGROUND: In the USA, about 30 200 well-differentiated thyroid carcinomas were diagnosed in 2007, but the prevalence of thyroid nodules is much higher (about 5% of the adult population). Unfortunately, the preoperative characterisation of follicular thyroid nodules is still a challenge, and many benign lesions, which remain indeterminate after fine-needle aspiration (FNA) cytology are referred to surgery. About 85% of these thyroid nodules are classified as benign at final histology. We aimed to assess the diagnostic effect of galectin-3 expression analysis in distinguishing preoperatively benign from malignant follicular thyroid nodules when FNA findings were indeterminate. METHODS: 544 patients were enrolled between June 1, 2003, and Aug 30, 2006. We used a purified monoclonal antibody to galectin-3, a biotin-free immunocytohistochemical assay, and a morphological and phenotypic analysis of FNA-derived cell-block preparations. Galectin-3-expression analysis was applied preoperatively on 465 follicular thyroid proliferations that were candidates for surgery, and its diagnostic accuracy was compared with the final histology. FINDINGS: 31 patients were excluded because they had small galectin-3-negative thyroid nodules; we did not have data for 47 patients; and one patient with an oncocytic nodule was excluded. 331 (71%) of the assessable 465 preoperative thyroid FNA samples did not express galectin-3. 280 (85%) of these galectin-3-negative lesions were classified as benign at final histology. Galectin-3 expression was detected, instead, in 134 of 465 (29%) thyroid proliferations, 101 (75%) of which were confirmed as malignant. The overall sensitivity of the galectin-3 test was 78% (95% CI 74-82) and specificity was 93% (90-95). Estimated positive predictive value was 82% (79-86) and negative predictive value was 91% (88-93). 381 (88%) of 432 patients with follicular thyroid nodules who were referred for thyroidectomy were correctly classified preoperatively by use of the galectin-3 test. However, 29 (22%) of 130 cancers were missed by the galectin-3 method. INTERPRETATION: Our findings show that if the option of surgery was based theoretically on galectin-3 expression alone, only 134 thyroid operations would have been done in 465 patients; therefore a large proportion (71%) of unnecessary thyroid surgical procedures could be avoided, although a number of galectin-3-negative cancers could be potentially missed. The galectin-3 test proposed here does not replace conventional FNA cytology, but represents a complementary diagnostic method for those follicular nodules that remain indeterminate.

Correlation between variation in quality of life and change in hemoglobin level after treatment with epoetin alfa 40,000 IU administered once-weekly.

INTRODUCTION: Anemia is frequently associated with cancer due to the disease itself and antineoplastic treatments. This open-label, uncontrolled, multi-center study evaluated the effects of once-weekly (qw) epoetin alfa 40,000 IU on hemoglobin (Hb) levels and quality of life (QoL) in anemic patients receiving chemotherapy for solid tumors. MATERIALS AND METHODS: A total of 522 patients with Hb level < or =12 g/dL received epoetin alfa 40,000 IU qw subcutaneously for 9-20 weeks to reach and maintain Hb range of 12-14 g/dL. QoL was assessed with the Functional Assessment of Cancer Therapy-Anemia (FACT-An [anemia sub-scale]) and Cancer Linear Analogue Scale (CLAS) at study entry, after two chemotherapy cycles, and at study end. RESULTS: Mean baseline Hb was 10.43 g/dL. Hb increases (g/dL) from baseline after 4, 8, 12 weeks and at study end were 1.07, 1.77, 1.92 and 1.71 g/dL, respectively. Response rates (Hb increase > or =1 and > or =2 g/dL during trial) were 81% and 61%, respectively. Mean increases in the FACT-An score from baseline (mean 55.4) were 3.1 after two chemotherapy cycles and 3.3 at study end; mean increases in the CLAS score from baseline (58.4 mm) were 5.9 mm after two chemotherapy cycles and 6.5 mm at study end. DISCUSSION: The greatest QoL increase was recorded when patients approached Hb level of 12 g/dL, independent of the baseline Hb level. Hb changes from baseline to trial end were related to corresponding changes in the FACT-An score. A positive correlation was also observed in patients with progressive disease. Adverse events were essentially those associated with chemotherapy. Incidence of thrombovascular events (6.7%) did not differ from the expected standard treatment in cancer patients. Epoetin alfa 40,000 IU qw increased Hb levels and improved or preserved QoL.

Bisphosphonates and oral cavity avascular bone necrosis: a review of twelve cases.

BACKGROUND: Intravenous bisphosphonates are the current standard of care for the treatment of hypercalcemia of malignancy and for the prevention of skeletal complications associated with bone metastases. Recently, retrospective case studies have reported an association between long-term bisphosphonate therapy and osteonecrosis of the jaws. PATIENTS AND METHODS: The data for twelve patients, referred to either an oral and maxillofacial surgeon or to an oral medicine specialist for the management of clinically apparent chronic oral osteonecrosis of unknown etiology, were reviewed. All had received cancer-related therapy simultaneously with bisphosphonate management. RESULTS: The typical presenting symptoms were pain and exposed bone at the site of a previous tooth extraction. In most patients, the lesions initially occurred after dental extraction or other odontostomatological procedures, while five had a spontaneous event. Biopsy of the involved area showed the presence of necrotic lacunae, with infiltration of lymphocytes and histiocytes. In nine cases, there was histological or cytological diagnosis of suspicious osteomyelitis. No correlation was observed between the intraoral lesions and myelosuppression secondary to antineoplastic therapy. CONCLUSION: Based on the patients' respective histories, clinical presentations and responses to surgical and antibiotic treatments, it appears that the pathogenesis of this osteonecrotic process is most consistent with localized vascular insufficiency. In our opinion, the mechanism by which bisphosphonates compromise bone vascularity may be related to their effect on the osteoclasts. The potent bisphosphonate-mediated inhibition of osteoclast function serves to decrease bone resorption and inhibit normal bone turnover remodeling, resulting in microdamage accumulation and a reduction in some mechanical properties of the bone.

Prevalence of acetowhite areas in male partners of women affected by HPV and squamous intra-epithelial lesions (SIL) and their prognostic significance. A multicenter study.

BACKGROUND: Estimates for the prevalence of cervical HPV infection vary and are only available for a few populations with regard to male partners. Attention has been drawn to the male role in cancer progression from cervical intra-epithelial neoplasia, but most of the male lesions are subclinical and only visible after acetowhite staining. The prognostic significance of acetowhite areas, of male partners of women affected by HPV and preneoplastic lesions, was evaluated. MATERIALS AND METHODS: A cohort of 3210 male partners of women affected by HPV infection and/or preneoplastic lesion of the lower genital tract was observed from 1987 to 2001. Acetowhite changes were assessed 5 min after the application of 5% solution of acetic acid and biopsies were tested for HPV-DNA by PCR. Patients with HPV lesions underwent CO2 laser surgery and follow-up. RESULTS: Of the 3210 male partners, 39.12% exhibited clinical HPV lesions and 3.64% subclinical lesions identified as acetowhite areas. In the group of 117 male partners with acetowhite areas, the HPV-DNA test was positive (HPV 6-11) in 36.75% and negative in 63.24% (p<0.001). No statistical differences were observed between HPV+/- groups regarding their sexual habits. The HPV-positive infection group compared to the HPV-negative group showed a statistically significant difference for CO2 laser surgery (p<0.001). CONCLUSION: The acetic acid test can give false-positives and is not a specific indicator of HPV infection, and thus the limited efficacy of tests for acetowhite areas was confirmed. The treatment of clinical lesions is necessary. Follow-up represents the major route to the diagnosis of preneoplastic lesions in men and for the prevention of cervical carcinoma in their female partners.

Follow-up of high-grade squamous intra-epithelial lesions (H-SIls) in human immunodeficiency virus (HIV)-positive and human papillomavirus (HPV)-positive women. analysis of risk factors.

BACKGROUND: Human immunodeficiency virus (HIV)-positive women are at high risk of co-infection from human papillomavirus (HPV) and of developing squamous intraepithelial lesions of the cervix. MATERIALS AND METHODS: From April 1997 to March 1999, 86 women, affected by high-grade squamous intra-epithelial lesions (H-SILs), were enrolled: 41 were HIV+ (CD4+ count >500/ml) and 45 were HIV-. The diagnosis of high-grade squamous intra-epithelial lesion (H-SIL) was established for each patient by Pap test, colposcopy and guided biopsy. For all samples, the HPV/DNA test was also performed by PCR. The patients' lesions and recurrence were treated by cone biopsy or large loop excision (LEEP). Annual controls were performed for 5 years. RESULTS: A high rate of alcohol and drug use (60.7% vs. 31.4%; p=0.004; 80% vs. 27.5%; p<0.001, respectively) and number of male partners (4.5 vs. 3.0; p<0.001) were found in the HIV+ patients, compared to the HIV- patients. Both groups were HPV+ for high-risk types. No difference was found in the percentage of patients who had received a second LEEP. CONCLUSION: Our findings suggest the treatment of H-SIL in HIV-positive women, for a longer disease-free survival, or a lower risk of developing cervical cancer.

Cytological value of sputum in workers daily exposed to air pollution.

In this study, quantitative modifications of dust cells, siderocytes, Curschmann's spirals and asbestos bodies and qualitative modifications (cellular changes and inflammatory infiltrate) in the sputum of 164 traffic police officers and 218 railway workers, occupationally exposed to environmental pollution, and the sputum of 119 inhabitants of a rural area, were evaluated. The results were correlated with time of exposure and smoking habits. Seventy-three (45%) traffic police officers (TPO), 76 (35%) railway workers (RW) and 29 (24%) of the rural population (RP) were smokers. The sputum, collected over a 3-day period, was smeared on glass slides and stained according to the Papanicolaou, Perl and yellow eosin methods. The results of the qualitative cytological diagnosis revealed a statistically significant difference between the TPO, RW and the RP (p < 0.001). The results of the qualitative and quantitative cytological examinations were not significantly correlated to time of occupational exposure, which was considered to be a continuous variable. The qualitative cytological examination of sputa was not statistically significant for the smoking habits of the TPO and the RP, but was significant for the RW (p < 0.0067). In the TPO, the number of dust cells was higher in smokers, and the relative risk (RR) was 3.95. In the RW, the RR was 2.84. The results of our study revealed that for the RW, the qualitative-quantitative cytological alterations in sputum were due much more to smoking habits than to occupational exposure, while the presence of asbestos bodies correlated with work activity. The qualitative-quantitative cytological examinations of the TPO differed significantly from that of the other two populations.

Fractionated ionizing radiation exposure induces apoptosis through caspase-3 activation and reactive oxygen species generation.

BACKGROUND: Radiation therapy (RT) is a well established therapeutic modality for the treatment of solid tumors. In particular, post-operative RT is considered the standard treatment adjuvant to surgery since its ability to prolong median survival of patients with malignant astrocytoma has been shown; nevertheless the ionizing radiation (IR) treatment fails in a considerable number of astrocytoma patients. MATERIALS AND METHODS: Using an ADF human astrocytoma cell line the molecular mechanisms involved in the DNA damage induced by fractionated irradiation (FIR) and single IR treatment have been investigated. RESULTS: FIR and single IR treatment inhibited the growth of the ADF human astrocytoma cell line. FACS analysis revealed that FIR treatment, but not single IR treatment, induced growth inhibition associated with the induction of apoptosis. Apoptosis was related to caspase-3 activation and reactive oxygen species (ROS) generation. ROS formation depends on the up-regulation of the cytochrome P450 enzyme gene. On the contrary, 12.5 Gy induced necrotic cell death up-regulating the HSPD1, HSPCB, HSPCA and HSPB1 genes. CONCLUSION: FIR treatment induced cell death through caspase-3 and ROS-mediated apoptosis.

PRb2/p130, p107 and p53 expression in precancerous lesions and squamous cell carcinoma of the uterine cervix.

The aim of this study was to investigate pRb2/p130, p107 and p53 expressions in precancerous lesions and squamous cell carcinoma (SCC) of the uterine cervix. We evaluated Human Papillomavirus (HPV) testing and typing and pRb2/p130, p107 and p53 expressions (antibody D07) of 48 patients showing low-grade cervical intraepithelial neoplasia (LCIN, 18 cases), high-grade CIN (HCIN, 13 cases) and SCC (17 cases). Paraffin-embedded tissue sections were analyzed for the study. High-risk HPV types were present in 67%, 89% and in 100% of HPV-positive LCIN, HCIN and SCC, respectively (Spearman's correlation coefficient: 0.393, p=0.035). Positive pRb2/p130 expression was detected in 89% of LCIN, 77% of HCIN and in 35% of SCC (p=0.001), whereas diffuse p107 expression was 72%, 62% and 100%, respectively (p=0.024). The results of p53 expression in CINs and SCCs showed values (not statistically significant) comparable with the literature data concerning the antibody D07. For the first time, we tested pRb2/p130 and p107 expressions in CINs and SCCs. We found a progressive decrease in pRb2 expression from CINs to SCCs that suggests an important role of pRb2 in cervical carcinogenesis. Indeed, p107 expression does not seem to be a useful factor. In our opinion, confirmed by the literature data, p53 immunostaining helps to biologically characterize CIN (in particular LCIN) when each case is evaluated separately considering HPV testing/typing.

Nail disorders in a woman treated with ixabepilone for metastatic breast cancer.

Ixabepilone (Ix) (BMS-247550) is a potent member of a new class of microtubule-stabilizing cytotoxic agents known as epothilones. In pre-clinical studies, Ix has shown anticancer activity against several cancer types, including paclitaxel-resistant models, both in vitro and in vivo. The major toxicities associated with Ix are myelosuppression, sensory neuropathy and neutropenia. Other minor side-effects include asthenia/fatigue, stomatitis, anorexia, alopecia, skin reaction, hypersensitivity reactions and a fluid-retention syndrome. Although Ix is functionally correlated to taxanes, no previous evidence exists regarding Ix-related nail disorders. Here, we report a case of a 59-year-old woman treated with Ix at 40 mg/m2 day 1 q 21 days who, after 8 cycles of therapy, developed onycholysis and subungual hemorrhagic bullas in the fingernails.