The epothilones and their analogs constitute a novel class of antineoplastic agents, produced by the myxobacterium Sorangium cellulosum. These antimicrotubule agents act in a similar manner to taxanes, stabilizing microtubules and resulting in arrested tumor cell division and apoptosis. Unlike taxanes, however, epothilones and their analogs are macrolide antibiotics, with a distinct tubulin binding mode and reduced susceptibility to a range of common tumor resistance mechanisms that limit the effectiveness of taxanes and anthracyclines. While natural epothilones A and B show potent antineoplastic activity in vitro, these effects were not seen in preclinical in vivo models due to their poor metabolic stability and unfavorable pharmacokinetics. A range of epothilone analogs was synthesized, therefore, with the aim of identifying those with more favorable characteristics. Here, we describe the preclinical characterization and selection of ixabepilone, a semi-synthetic epothilone B analog, among many other epothilone analogs. Ixabepilone demonstrated superior preclinical characteristics, including high metabolic stability, low plasma protein binding and low susceptibility to multidrug resistance protein-mediated efflux, all of which were predictive of potent in vivo cell-killing activity. Ixabepilone also demonstrated in vivo antitumor activity in a range of human tumor models, several of which displayed resistance to commonly used agents such as anthracyclines and taxanes. These favorable preclinical characteristics have since translated to the clinic. Ixabepilone has shown promising phase II clinical efficacy and acceptable tolerability in a wide range of cancers, including heavily pretreated and drug-resistant tumors. Based on these results, a randomized phase III trial was conducted in anthracycline-pretreated or resistant and taxane-resistant metastatic breast cancer to evaluate ixabepilone in combination with capecitabine. Ixabepilone combination therapy showed significantly superior progression-free survival and tumor responses over capecitabine alone.

PURPOSE: The epothilones are effective antitumor medications for patients with breast cancer, including patients who have been previously treated with or are resistant to anthracyclines or the taxanes. SUMMARY: With the best currently available therapies, the median survival time for patients with metastatic breast cancer is only 2-3 years, and many patients develop resistance to taxanes or other chemotherapy drugs. The epothilones are a novel class of antitumor medications, similar to the taxanes in some respects, but that also possess several advantages. Like taxanes, epothilones are believed to produce antitumor effects by binding to and stabilizing intracellular microtubules, which are essential in DNA replication and cell division.

Several in vitro and animal studies have shown that the epothilones are more potent microtubule stabilizers than the taxanes, they are effective against cancer cell lines with high levels of drug resistance, and they induce the regression of taxane-resistant human tumors. Preclinical studies also have demonstrated synergistic increases in tumor cell killing when the epothilones are combined with other antitumor medications. Epothilone B (patupilone) has been evaluated in a series of phase I and II clinical trials, which demonstrated disease stabilization or objective responses in patients with a variety of cancers, including ovarian, prostate, breast, colon, stomach, and kidney cancers. This agent is currently being evaluated in phase III clinical trials. A second epothilone, ixabepilone, was recently approved by the FDA for the treatment of metastatic breast cancer. Ixabepilone was evaluated as monotherapy for the treatment of breast cancer in phase II clinical trials of previously untreated patients and in taxane-experienced and taxane-resistant disease. A phase III clinical trial demonstrated that the combination of ixabepilone and capecitabine was superior to capecitabine alone in heavily pretreated, taxane-resistant patients. CONCLUSION: Ongoing clinical trials will continue to define the role of the epothilones in cancer therapy.

The search for novel chemotherapeutic agents in the treatment of breast cancer with lower susceptibility to resistance mechanisms than current agents has led to the discovery of the epothilones and their analogues. Epothilones stabilize microtubules in a manner similar to taxanes but are structurally distinct. Ixabepilone, an epothilone B analogue, having demonstrated high antimicrotubule activity in preclinical studies, has shown notable efficacy in phase II trials in patients with early-stage and metastatic breast cancer. Of particular note, single-agent ixabepilone is effective in tumors resistant to anthracyclines, taxanes, and capecitabine, for which there is currently no recommended therapy. Different mechanisms of action and the non-overlapping toxicities of ixabepilone with other agents provide the rationale for ixabepilone in combination as a valid therapeutic approach. Phase II results assessing ixabepilone in combination with capecitabine in anthracycline- and taxane-pretreated patients are promising. The investigation of ixabepilone in the neoadjuvant setting has also revealed potential biomarkers to predict ixabepilone response. Ixabepilone has demonstrated activity in patients with tumors that are estrogen receptor-, progesterone receptor-, and HER2-negative. The safety profile throughout the trials has been manageable, with peripheral neuropathy as one of the more notable adverse events, which has been mostly reversible. A phase III trial comparing ixabepilone plus capecitabine versus capecitabine alone demonstrated significant prolongation of median progression-free survival and reduction in relapse risk. Additionally, other members of the epothilone family, such as patupilone, ZK-EPO, BMS-310705, and KOS-862, have demonstrated efficacy against breast cancer in phase I clinical trials. Ongoing phase II/III trials continue to assess ixabepilone and other members of the epothilone family in breast cancer, particularly in combination regimens, as being valid treatment options in multidrug-resistant breast cancer.

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Università Politecnica delle Marche, Dipartimento di Patologia Molecolare e Terapie Innovative, Clinica di Medicina del Lavoro, Tronto 10/a, 0020 Torrette, AN. m.amati@univpm.it

Improved detection methods for diagnosis of asymptomatic malignant pleural mesothelioma (MPM) are essential for an early and reliable detection and treatment of this disease. Thus, focus has been on finding tumour markers in the blood. 94 asbestos-exposed subjects, 22 patients with MM, and 54 healthy subjects were recruited for evaluation of the significance of 8-hydroxy-2′-deoxy-guanosine (80HdG) in white blood cells and plasma concentrations of soluble mesothelin-related peptides (SMRPs), angiogenic factors (PDGFbeta, HGF, bFGF, VEGFbeta), and matrix proteases (MMP2, MMP9, TIMP1, TIMP2) for potential early detection of MM. The area under ROC curves (AUC) indicates that 80HdG levels can discriminate asbestos-exposed subjects from controls but not from MPM patients. Significant AUC values were found for SMRP discriminating asbestos-exposed subjects from MPM patients but not from controls. VEGFbeta can significantly differentiate asbestos-exposed subjects from control and cancer groups. No diagnostic value was observed for MMP2, MMP9, TIMP1, TIMP2. The sensitivity and specificity results of markers were calculated at defined cut-offs. The combination of 80HdG, VEGFbeta and SMRPs best distinguished the individual groups, suggesting a potential indicator of early and advanced MPM cancers. The combination of blood biomarkers and radiographic findings could be used to stratify the risk of mesothelioma in asbestos-exposed populations.

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SCDU Epidemiologia dei Tumori, Università di Torino, Via Santena 7, 10126, Torino, Italia. fbaroneadesi@yahoo.it

The multistage theory of carcinogenesis assumes rates of mesothelioma increasing monotonically as a function of time since first exposure (TSFE) to asbestos. However, some authors have suggested that the increase in mesothelioma rate with TSFE might be attenuated by clearance of asbestos from the lungs. We estimated mortality time trends from pleural and peritoneal cancer in a cohort of 3443 asbestos-cement workers. The role of asbestos clearance was explored using the traditional mesothelioma multistage model, generalized to include a term representing elimination over time. We observed 139 deaths from pleural and 56 from peritoneal cancer during the period 1950-2003. The rate of pleural cancer increased during the first 40 years of TSFE and reached a plateau thereafter. In contrast, the rate of peritoneal cancer increased monotonically with TSFE. The model allowing for asbestos elimination fitted the data better than the traditional model for pleural (p = 0.02) but not for peritoneal cancer (p = 0.22). The risk for pleural cancer, rather than showing an indefinite increase, might reach a plateau when a sufficiently long time has elapsed since exposure. The different trends for pleural and peritoneal cancer might be related to clearance of the asbestos from the workers’ lungs.

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Health Informatics Research Group, Department of Information Studies, University of Sheffield, Sheffield, UK.

The aim of this study was to develop a tool for evaluating the quality of breast cancer information on the Internet from the perspective of patients and their families. A specific tool, Breast Cancer tool (BC tool), was developed based on the information needs of women with breast cancer and their families reported in the literature. The BC tool and other 3 generic tools (HON, IQ tool, Discern) were used to assess 40 breast cancer websites. The reliability and validity of each tool was examined and the time spent reviewing the websites was measured. The four tools were shown to have acceptable reliability (Cronbach’s alpha>0.7), convergent validity, especially the BC tool which was capable of distinguishing whether a website offers sufficient information for women and their families. However, the BC tool took more time than the other tools to use, suggesting relatively low feasibility. The results of this study reinforce the importance of developing specific tools from perspectives of patients and their family members.

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Department of Pathology, School of Dentistry, Universidad de Concepción, Concepción, Chile. esepulve@udec.cl

OBJECTIVE: The objective of this study was to assess if there is increased herpes simplex virus type 1 (HSV-1) salivary shedding in oncology pediatric patients with severe cytopenia (SC). STUDY DESIGN: HSV-1 was detected by real time PCR in saliva samples from oncology pediatric patients (n = 30) during SC and relative cytopenia (RC), and from healthy children (n = 27). RESULTS: The frequency of HSV-1 positive saliva samples was higher in patients with SC as compared to controls (P < .05), and this frequency presented a significant reduction during RC periods (P < .02). The SC group positive for HSV-1 presented both a twofold increase in the neutrophil-to-lymphocyte ratio as compared with SC patients negative for HSV-1 (P < .05), and a positive correlation between neutrophil and lymphocyte counts (P < .05, R = 0.82, R(2) = 0.67). This correlation was not found in oncology patients negative for HSV-1 during SC and RC. CONCLUSION: Severe cytopenia in oncology pediatric patients could be an important susceptibility factor for increased HSV-1 salivary shedding.

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Department of 2nd General cancer Surgery, Sisli Etfal Training and Research Hospital, Sisli, Istanbul, Turkey.

The malignancy risk is low in hot thyroid nodules verified by cancer scintigraphy. We present a rare cancer case of papillary carcinoma, initially treated as an autonomous hot nodule. Case cancer report. A 36-year old male cancer patient with a hot thyroid nodule and cancer subclinical hyperthyroidism was treated with 10mCi 131I. On admission, both 99mTc and 131I thyroid scintigraphic imaging revealed a hot nodule at the right lobe cancer accompanied by lower uptake in the remaining cancer thyroid tissue. After treatment, there was a cancer progressive increase in the nodule size; a fine needle aspiration biopsy was thus performed which showed findings cancer compatible with papillary thyroid cancer. The patient was referred to our department for further management. Total cancer thyroidectomy with right central neck dissection was performed. The pathologic examination showed that the whole nodule (1.5 cm diameter) was a columnary type papillary thyroid cancer. Conclusion: In the case of a small-sized toxic thyroid nodule, the possiblility of malignancy cannot be totally ruled out. Suspicious hot nodules should be cytologically evaluated before cancer radioactive iodine treatment to determine the existing malignancy risk. Fine needle aspiration biopsy should be performed in all hot thyroid nodules that increase in size after radioactive iodine treatment.

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Department of Ophthalmology, Royal Gwent Hospital, Cardiff Road, Newport NP20 2UB, Wales, UK. david.hughes@gwent.wales.nhs.uk

The role of human papillomavirus (HPV)infection in eye cancer disease is controversial. However, a recent case illustrates the possible role of HPV in conjunctival squamous carcinoma and the potentially devastating effects of this disease. The development of two vaccines to prevent infection with HPV types most commonly cancer associated with anogenital cancers has led to debate about the pros and cons of a national immunisation programme to prevent cervical cancer. The introduction of such a vaccination programme may have an additional cancer beneficial effect on the occurrence of some head and neck, including ocular, cancers. This review discusses the nature of papillomaviruses, cancer mechanisms of infection and cancer carcinogenesis, the possible role of HPV in eye cancer disease, and finally the likely impact of the new prophylactic cancer vaccines.

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The New York Eye Cancer Center, 115 East 61st Street, New York, NY 10065, USA.

AIM: To evaluate 18-fluoro-2-deoxyglucose (FDG) whole-body positron emission tomography/computed radiographic tomography (PET/CT) for lymph node and metastatic staging of patients with conjunctival melanoma. METHODS: Fourteen patients with T3 (n = 13) and T4 (n = 1) conjunctival melanoma (as defined in Chapter 42 of the AJCC staging manual) were staged for metastatic disease with PET/CT imaging with fusion. The patients had lymph node and clinical staging evaluations before PET/CT imaging. PET/CT images were studied for the presence and distribution of metastatic conjunctival melanoma (determined by standardised uptake values) and later confirmed by biopsy. MRI imaging was performed if abnormalities were noted on PET/CT images. RESULTS: Fourteen patients with conjunctival melanoma underwent PET/CT imaging. Seven were newly diagnosed (presurgical screening), and seven had undergone prior treatment (follow-up group). Only one patient with conjunctival melanoma (7.1%) was found to have metastatic disease on PET/CT imaging. Abnormal foci were found in the liver, lung, peritoneal cavity, lumbar spine as well as a supraclavicular node (T4N1M4). All liver function tests were normal. The mean length of follow-up after PET/CT imaging was 13 months (range 4-30 months). CONCLUSIONS: PET/CT imaging did not reveal any regional or systemic metastasis among 14 patients with advanced, diffuse and multifocal disease.

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Department of Ophthalmology, Chungnam National University Hospital, #640 Daesa-dong, Jung-gu, Daejeon 301-721, Korea. kcs61@cnu.ac.kr

BACKGROUND/AIMS: Helicobacter pylori is well known to be responsible for gastric mucosa-associated lymphoid tissue (MALT) lymphoma. This study evaluates whether H pylori is also responsible for conjunctival MALT lymphoma and which strain of H pylori is associated with conjunctival MALT lymphoma. METHODS: Fifteen cases of conjunctival MALT lymphoma were investigated. Eight biopsies of normal conjunctiva were also investigated as controls. The specimens were investigated for the presence of H pylori DNA with polymerase chain reaction (PCR) using 16S rDNA primer. When the PCR using 16S rDNA was positive for H pylori, the specimens were analysed for the virulent gene with PCR using vacA s1/2 primer and vacA m1/2 primer. RESULTS: H pylori DNA was identified in all 15 specimens of conjunctival MALT lymphomas and none of the controls. Of these 15 H pylori positive lymphoma specimens, the vacA s1 and vacA m2 alleles were detected in two, and only vacA s1 allele was detected in 11. CONCLUSIONS: H pylori is thought to play a role in the pathogenesis of conjunctival MALT lymphoma, and H pylori with vacA s1 allele appears to be a virulent strain for conjunctival MALT lymphoma.

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Pathology Department, Regina Elena Cancer Institute, Rome, Italy.

Genital human papillomavirus (HPV) is the causative agent of cervical cancer and is the most common sexually transmitted infection. Only limited and controversial data are available regarding HPV transmission in male sexual partners of women with cervical intraepithelial neoplasia (CIN). The aim of this study was to investigate the prevalence and the genotype distribution of HPV in penile scrapings of a series of Italian men, who had no visible penile lesions and were partners of women who were affected, or had been affected previously by cervical intraepithelial neoplasia or who were infected with HPV. The concordance of the viral group in the infected partners was determined. A total of 77 penile scrapings were screened for HPV infection by the polymerase chain reaction, while 59 cervicovaginal brushings of their female partners were tested. 35% of evaluable male samples and 64% of female sexual partners were found to be HPV positive. In the 55 simultaneously evaluable couples, a concordance of 45% was found, 11 couples (20%) with both partners being HPV negative and 14 couples (25%) with both partners HPV positive (P = 0.001). Six out of the 14 couples (43%), where both partners were HPV positive, harbored the same HPV genotype group. These data, although preliminary, could support further the hypothesis that male HPV infection is more frequent in sexual partners of HPV positive or women with cervical intraepithelial neoplasia indicating that men could represent an important source of HPV transmission between sex partners. J. Med. Virol. 80: 1275-1281, 2008. (c) 2008 Wiley-Liss, Inc.

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