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Background: This retrospective analysis was planned as a direct comparison of taxanes plus trastuzumab to the less toxic combination of oral vinorelbine (OV) plus trastuzumab as a first-line therapy for metastatic HER2-positive breast cancer. Patients and Methods: Patients (n = 76) receiving either taxanes (group A) or OV (group B) in combination with trastuzumab were identified from a breast cancer database. Progression-free survival (PFS) was defined as the primary study endpoint; secondary endpoints were overall survival (OS), response rate (RR), incidence of brain metastases, and brain metastases-free survival (BMFS). Results: 36 patients received taxanes and 40 patients OV in combination with trastuzumab. At a median follow-up of 47.5 months, median PFS was 7 months (group A) and 9 months in group B (log-rank; non-significant), respective numbers for OS were 49 and 59 months (p = 0.033). The incidence of brain metastases did not differ significantly between the 2 treatment groups, whereas BMFS was significantly longer in patients receiving OV. Conclusions: OV plus trastuzumab yielded similar results in terms of PFS and RR and was superior in terms of OS and BMFS. These results add to the growing body of evidence that vinorelbine is a viable alternative to taxanes in HER2-positive metastatic breast cancer. © 2014 S. Karger GmbH, Freiburg.

Background: The mesenchymal-epithelial transition (MET) pathway is frequently altered in tumours. The purpose of our study was to determine the prognostic value of tumour MET expression levels in patients with triple-negative breast cancer (TNBC), in order to strengthen the rationale for targeted therapy of TNBC using MET inhibitors. Methods: We determined expression of MET in formalin-fixed paraffin-embedded surgical specimens of TNBC by immunohistochemistry. Recurrence-free and overall survival was analysed with Cox models adjusted for clinical and pathological factors.Results:Immunostaining for MET was classified as high in 89 of 170 (52%) tumours. MET expression was more frequently observed in G3 carcinomas (P=0.02) but was not significantly associated to any of the other clinical or pathological parameters. High MET expression predicted shorter survival of the patients. Multivariate Cox proportional hazards regression analyses identified MET to be an independent prognostic factor for recurrence (adjusted hazard ratio (HR) for recurrence 3.43; 95% confidence interval (CI) 1.65-7.12; P=0.001) and death (adjusted HR for death 3.74; 95% CI 1.65-8.46; P=0.002). Conclusion: These results provide further evidence that the MET pathway could be exploited as a target for TNBC. © 2013 Cancer Research UK. All rights reserved.

Pertuzumab is a monoclonal antibody that represents the first among a new class of agents known as human epidermal growth factor receptor (HER) dimerization inhibitors. This is the first systematic review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to synthesize all available data of pertuzumab in breast cancer. The search strategy retrieved 11 studies that evaluated pertuzumab. One study was conducted in the neoadjuvant setting (417 patients), whereas all the others dealt with patients with recurrent, metastatic, or refractory disease (1023 patients). Six studies were conducted in HER2+ breast cancer population (1354 patients), whereas 5 studies (86 patients) were conducted in HER2- (or unknown HER2 status) disease. Pertuzumab is the most recent agent approved by the US Food and Drug Administration in combination with trastuzumab and docetaxel for the treatment of patients with HER2+ metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. This approval has been based on data from a phase III Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) study. The antitumor activity with the significant reduction in the risk of progression or death, as reflected upon the increase of 6.1 months in median progression-free survival, indicates that pertuzumab may provide an avenue for achieving additional benefit for patients with HER2+. Moreover, pertuzumab seems to have a putative role in the management of patients with HER2 who are resistant to trastuzumab. The promising role of pertuzumab in the neoadjuvant and adjuvant settings remains to be further investigated and established in the future. © 2013 Elsevier Inc. All rights reserved.

Pregnancy-associated breast cancer (PABC) is defined as breast cancer occurring anytime during gestation, lactation or within one year after delivery. The optimal management of pregnant women with breast cancer is challenging and not well established; the main concern is the effect of the drugs on the developing fetus and long-term complications after in utero exposure to anti-cancer drugs. Surgical resection is the mainstay of treatment for early breast cancer diagnosed during pregnancy. Modified radical mastectomy is standard of care in first trimester, whereas breast-conserving surgery (lumpectomy with lymph node dissection) can be performed preferably in the second and third trimester. Of note, breast-conserving surgery is not contraindicated per se during the first trimester, but owing to the potential impact of delaying radiotherapy. Radiation therapy is not favored during pregnancy. Moreover, tamoxifen is contraindicated during pregnancy; the agent has been associated with birth defects in up to 20% of exposures. Chemotherapy is generally contraindicated during the first trimester because of the possible damage to organogenesis. Anthracyclines-based regimens are the most widely used is breast cancer treatment and were been shown to be associated with favourable safety profile when administered during pregnancy. As for taxanes, more limited data is available. The use of trastuzumab is contraindicated during pregnancy, given the apparent risk of oligo- and/or anhydramnios as well as the unknown long-term sequelae on the fetus. It is obvious that, diagnosis of breast cancer during pregnancy adds complexity to cancer treatment recommendations. In all cases, a multidisciplinary therapeutic approach among obstetricians, gynaecologists, surgical oncologists, radiation oncologists, medical oncologists, pediatricians and hematologists is clearly warranted © Pioneer Bioscience Publishing Company.

Objective: Cervical cancer is the most common solid carcinoma diagnosed during pregnancy; obviously, pregnancy adds complexity to treatment recommendations. We synthesized all available data and evaluated the efficacy and safety of the administration of platinum derivatives during pregnancy in cervical cancer. Data Sources: Eligible articles were identified by a search of MEDLINE and ClinicalTrials.gov databases for the period up to September 7, 2012; the algorithm comprised a predefined combination of the terms cervical, cancer, cisplatin, carboplatin, and pregnancy. Methods of Study Selection:: Two investigators, working independently, searched the literature and extracted data from all studies that examined the efficacy and safety of platinum derivatives administered during pregnancy in cervical cancer. All cases in which therapeutic abortion was scheduled were excluded. Moreover, quantitative synthesis of the published articles was performed. Tabulation, Integration, And Results: Overall, 24 studies (48 pregnancies, 48 newborns [one twin pregnancy and one miscarriage]) were eligible. In relation to cisplatin, 47 pregnancies were identified, whereas regarding carboplatin administration, only one pregnancy was retrieved. Cisplatin was administered either as monotherapy or combined with bleomycin, 5-fluorouracil, paclitaxel, vincristine, and bleomycin, whereas carboplatin was given in combination with paclitaxel. In most cases (67.4%), a completely healthy neonate was born; all children were healthy with a median follow-up of 12.5 months. The mean delivery weight of newborns was 2,213 g. Complete and partial response was achieved in 10% and 63.4% of patients with cervical cancer, respectively, whereas stabilization and progression of the disease occurred in 23.3% and 3.3% of women in the case group. In the majority of women in the case group, chemotherapy was well tolerated. The median progression-free survival was 48.5 months. Conclusion: Cisplatin may play a significant role in the management of patients with cervical cancer during the second and third trimesters. © 2013 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins.

Leptomeningeal carcinomatosis (MC) represents an uncommon, but devasting manifestation of metastatic breast cancer. This is the first systematic review/pooled analysis to synthesize all available data evaluating the efficacy and safety of intrathecal (IT) administration of trastuzumab for the treatment of MC in HER2-positive breast cancer patients. This study was performed in accordance with the PRISMA guidelines. A total of 13 articles (17 patients) were eligible. The mean age of patients at IT trastuzumab administration was 48.2 years (SD 8.4, range 38-66). The mean total dose was 399.8 mg (SD 325.4, range 35-1,110 mg). IT trastuzumab alone or as part of combination therapies seemed to be safe; no serious adverse events were reported in 88.2 % of cases. In 68.8 % of cases, a significant clinical improvement was observed, while stabilization or progression of the disease was noticed in 31.2 % of cases. Cerebrospinal fluid (CSF) response was noted in 66.7 % of cases. The median overall survival was 13.5 months, whereas the median central nervous system progression-free survival (CNS-PFS) was 7.5 months. In 23.5 % of cases, IT trastuzumab was administered beyond CNS progression with a response noticed in 75 % of cases and a CNS-PFS of 9.4 months. The cumulative dose of IT trastuzumab given was 1,040 mg (SD 697.9, median 1,215, range 55-1,675). The protective effect of prior radio- or neurosurgery upon CNS-PFS was sizeable but did not reach formal statistical significance (HR 0.28, 95 % CI 0.06-1.37). Clinical improvement (HR 0.14, 95 % CI 0.02-0.91) and CSF response (HR 0.09, 95 % CI 0.01-0.89) were associated with longer CNS-PFS. IT trastuzumab administration seems to represent a safe and in some cases effective option for the treatment of HER2-positive breast cancer patients with leptomeningeal involvement. However, clinical trials are urgently needed to establish the definite role of IT trastuzumab in HER2-positive metastatic breast cancer patients with MC. © 2013 Springer Science+Business Media New York.

Background:Data regarding the safety and effectiveness of aromatase inhibitors (AIs) as monotherapy or combined with gonadotropin-releasing hormone (GnRH) analogue in male breast cancer are scarce. Methods: In this retrospective chart review, cases of male breast cancer patients treated with AIs with or without a GnRH analogue were evaluated. Results: Twenty-three men were included into this case series. Aromatase inhibitors in combination with or without a GnRH analogue were given as first-line therapy in 60.9% and as second-line therapy in 39.1% of patients, respectively. All patients had visceral metastases, whereas in five of them bone lesions coexisted. In all cases AIs were tolerated well, and no case of grade 3 and 4 adverse events was reported. A partial response was observed in 26.1% of patients and stable disease in 56.5%. Median overall survival (OS) was 39 months and median progression-free survival (PFS) was 13 months. Regarding OS and PFS, no significant effects of GnRH analogue co-administration or type of AI were noted.Conclusion:Our study shows that AIs with or without GnRH analogues may represent an effective and safe treatment option for hormone-receptor positive, pretreated, metastatic, male breast cancer patients. © 2013 Cancer Research UK. All rights reserved.

Pancreatic cancer is the fourth leading cause of cancer-related death. Most patients present with an advanced stage of disease that has a dismal outcome, with a median survival of approximately 6 months. Evidently, there is a clear need for the development of new agents with novel mechanisms of action in this disease. A number of biological agents modulating different signal transduction pathways are currently in clinical development, inhibiting angiogenesis and targeting epidermal growth factor receptor, cell cycle, matrix metalloproteinases, cyclooxygenase-2, mammalian target of rapamycin, or proteasome. This is the first systematic review of the literature to synthesize all available data coming from trials and evaluate the efficacy and safety of molecular targeted drugs in unresectable and metastatic pancreatic cancer. However, it should be stressed that although multiple agents have been tested, only 9 phase 3 trials have been conducted and one agent (erlotinib) has been approved by the Food and Drug Administration for use in clinical practice. As knowledge accumulates on the molecular mechanisms underlying carcinogenesis in the pancreas, the anticipated development and assessment of molecularly targeted agents may offer a promising perspective for a disease which, to date, remains incurable. Copyright © 2013 by Lippincott Williams & Wilkins.

Objective: Ovarian cancer in pregnancy is uncommon; however, this diagnosis adds complexity to cancer treatment recommendations. This is the first systematic review to synthesize all available data and evaluate the efficacy and safety of taxanes during pregnancy in ovarian cancer. Methods: This systematic review was performed in accordance with PRISMA guidelines. All studies that examined the efficacy and safety of taxanes administered during pregnancy in ovarian cancer, regardless of sample size, were considered eligible. Results: Overall, 8 articles (11 pregnancies, 12 newborns) were retrieved for paclitaxel and 1 for docetaxel (1 pregnancy, 1 newborn). In 92.31% of cases a healthy child was born, with a median follow-up of 20 months. The mean weight of the babies at delivery was 2,381 g. One study providing follow-up until the 11th year of age reported a case of attention deficit disorder. In 6 out of 8 case reports providing survival data, the mother was alive and disease free at the end of follow-up (ranging from 9.75 to 45 months). Conclusion: Taxanes may play a significant role in the treatment of ovarian cancer patients during the 2nd and 3rd trimesters. Before that, the risk of abortion or congenital anomalies is increased. Copyright © 2012 S. Karger AG, Basel.

Cervical cancer represents the third most common cause of female cancer mortality. Even with the best currently available treatment, a significant proportion of patients will experience recurrence and eventually die. Evidently, there is a clear need for the development of new agents with novel mechanisms of action in this disease. A number of biological agents modulating different signal transduction pathways are currently in clinical development, inhibiting angiogenesis, targeting epidermal growth factor receptor, cell cycle, histone deacetylases, cyclooxygenase-2 (COX-2), or mammalian target of rapamycin (mTOR). This is the first systematic review of the literature to synthesize all available data emerging from trials and evaluate the efficacy and safety of molecularly targeted drugs in cervical cancer. However, it should be stressed that relatively fewer molecularly targeted agents have been tested in cervical cancer in comparison with other cancer types; of note, no related phase 3 trials have been published and consequently no agent has been approved for use in clinical practice. Nevertheless, the promising results of bevacizumab in therapeutic trials for cervical cancer have shown that targeting the VEGF pathway is an attractive therapeutic strategy. As knowledge accumulates on the molecular mechanisms underlying carcinogenesis in the cervix, the anticipated development and assessment of molecularly targeted agents may offer a promising perspective for cervical cancer. © 2012 Elsevier Inc. All rights reserved.

PI3K/AKT/mTOR pathway is a crucial mediator of tumor progression. As the PI3K/Akt pathway is heavily deregulated in breast cancer, the application of mTOR inhibitors in breast cancer patients seems warranted. This is the first systematic review according to PRISMA guidelines to synthesize all available data of mTOR inhibitors in all subcategories of breast cancer. The search strategy retrieved 16 studies evaluating everolimus (1492 patients), seven studies examining temsirolimus (1245 patients), one study evaluating sirolimus (400 patients) and two studies evaluating MKC-1 (60 patients). The Breast Cancer Trials of Oral Everolimus-2 (BOLERO-2) study has marked a turning point in the evaluation of everolimus in the treatment of estrogen receptor positive breast cancer. Given the positive results, everolimus has entered NCCN 2012 guidelines, and its approval of its combination with exemestane by FDA and EMA is imminent. In addition, the promising antitumor activity and long-term disease control further suggest that mTOR inhibition with everolimus may provide an avenue for achieving long-lasting benefit from trastuzumab-based therapy in HER2-positive patients. Regarding temsirolimus, it seems that the agent may play, in the future, a role in the treatment of metastatic breast cancer; importantly, however, there is an unmet need to find its optimal target subpopulation. © 2012 Elsevier Inc. All rights reserved.

BACKGROUND: After breast-conserving surgery, radiotherapy reduces recurrence and breast cancer death, but it may do so more for some groups of women than for others. We describe the absolute magnitude of these reductions according to various prognostic and other patient characteristics, and relate the absolute reduction in 15-year risk of breast cancer death to the absolute reduction in 10-year recurrence risk. METHODS: We undertook a meta-analysis of individual patient data for 10,801 women in 17 randomised trials of radiotherapy versus no radiotherapy after breast-conserving surgery, 8337 of whom had pathologically confirmed node-negative (pN0) or node-positive (pN+) disease. FINDINGS: Overall, radiotherapy reduced the 10-year risk of any (ie, locoregional or distant) first recurrence from 35.0% to 19.3% (absolute reduction 15.7%, 95% CI 13.7-17.7, 2p/=20%), intermediate (10-19%), or lower (, link_to_OA_fulltext

A total of 181 persons aged between 16 and 18 were checked fully audiometrically (conventional and high-frequency audiogram). Dates of history about hereditary hearing damage, own ear diseases, noise exposure during frequent visits to discothecs or usage of Walkman etc. were ascertained by questionnaires. The evaluation of the results was carried out with the help of discrimination analysis allowing a multi-dimensional classification. As a result there could be made a sure discrimination analytic separation in persons with ear diseases during their childhood, when the high frequencies from 10 to 15 kHz were taken in. Thus the damage of the inner ear was to be found mainly on the base of the cochlea. Also in cases of hereditary influence there was to be seen a clear deminution in the high frequency area. The group of persons, who regularly went to discos (more than three times a month) as well as the group often using Walkman revealed a sure separation, when the high frequencies above 8 kHz were considered in the calculation. Altogether there could be seen an early damage more clearly in the high frequency area after ear diseases in childhood as well as a result of sound overloading than in conventional hearing area.

This paper reports on the degree of accuracy of determinations of hearing threshold in the 0.5 to 18 kHz range. As far as possible, these hearing thresholds were compared with those of ISO 389. Furthermore, the study compared determinations of hearing thresholds measured on different days. Reproducibility was very good, particularly of the high-frequency thresholds. The two types of sound transducers used here (a quasi-free field system developed by the authors and a pair of professional headphones) showed an identical transmission of frequencies and good reproducibility of the results of measurements.