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Amplification of 11q13 is found in approximately 15% of breast cancers. Cyclin D1 (CCND1) has been reported to be the 'driver' of this amplicon, however, multiple genes map to the smallest region of amplification of 11q13. Out of these genes, cortactin (CTTN) has been shown to be consistently overexpressed at the mRNA level in tumours harbouring 11q13 amplification. The aims of this study are to define whether CTTN is consistently co-amplified with the main core of the 11q13 amplicon, whether it is consistently overexpressed when amplified and to determine correlations between CTTN amplification and overexpression with clinicopathological features of breast cancers and survival of breast cancer patients. CTTN and CCND1 chromogenic in situ hybridisation (CISH) probes and a validated monoclonal antibody against CTTN were applied to a tissue microarray of a cohort of breast cancers from patients treated with anthracycline-based chemotherapy. CTTN and CCND1 amplifications were found in 12.3 and 12.4% of cases, respectively. All cases harbouring CTTN amplification also displayed CCND1 amplification. High expression of CTTN was found in 10.8% of cases and was associated with CTTN amplification, expression of 'basal' markers and topoisomerase IIα. Exploratory subgroup analysis of tumours devoid of 11q13 amplification revealed that high expression of CTTN in the absence of CTTN gene amplification was associated with lymph node negative disease, lack of hormone receptors and FOXA1, expression of 'basal' markers, high Ki-67 indices, p53 nuclear expression, and basal-like and triple negative phenotypes. CTTN expression and CTTN gene amplification were not associated with disease-, metastasis-free and overall survival. In conclusion, CTTN is consistently co-amplified with CCND1 and expressed at higher levels in breast cancers harbouring 11q13 amplification, suggesting that CTTN may also constitute one of the drivers of this amplicon. CTTN expression is not associated with the outcome of breast cancer patients treated with anthracycline-based chemotherapy.

PPM1D (protein phosphatase magnesium-dependent 1δ) maps to the 17q23.2 amplicon and is amplified in ∼8% of breast cancers. The PPM1D gene encodes a serine threonine phosphatase, which is involved in the regulation of several tumour suppressor pathways, including the p53 pathway. Along with others, we have recently shown that PPM1D is one of the drivers of the 17q23.2 amplicon and a promising therapeutic target. Here we investigate whether PPM1D is overexpressed when amplified in breast cancers and the correlations between PPM1D overexpression and amplification with clinicopathological features and survival of breast cancer patients from a cohort of 245 patients with invasive breast cancer treated with therapeutic surgery followed by adjuvant anthracycline-based chemotherapy. mRNA was extracted from representative sections of tumours containing >50% of tumour cells and subjected to TaqMan quantitative real-time PCR using primers for PPM1D and for two housekeeping genes. PPM1D overexpression was defined as the top quartile of expression levels. Chromogenic in situ hybridization with in-house-generated probes for PPM1D was performed. Amplification was defined as >50% of cancer cells with >5 signals per nucleus/large gene clusters. PPM1D overexpression and amplification were found in 25 and 6% of breast cancers, respectively. All cases harbouring PPM1D amplification displayed PPM1D overexpression. PPM1D overexpression was inversely correlated with expression of TOP2A, EGFR and cytokeratins 5/6 and 17. PPM1D amplification was significantly associated with HER2 overexpression, and HER2, TOP2A and CCND1 amplification. No association between PPM1D gene amplification and PPM1D mRNA overexpression with survival was observed. In conclusion, PPM1D is consistently overexpressed when amplified; however, PPM1D overexpression is more pervasive than gene amplification. PPM1D overexpression and amplification are associated with tumours displaying luminal or HER2 phenotypes. Co-amplification of PPM1D and HER2/TOP2A and CCND1 are not random events and may suggest the presence of a 'firestorm' genetic profile.

Breast cancer is the leading cancer type diagnosed among women in Western countries. Despite great advances in cancer therapies, many of these patients develop non-curable metastases. The objective of cancer treatment in the metastatic setting is mainly to control symptoms and to prolong survival. The selection of the optimal chemotherapeutic regimen is affected by performance status, tumour biology, site and extent of the disease and the exposure to prior therapies. Recent developments in new kinds of cancer drugs have contributed not only to immense progress in clinical outcomes but also to dramatically increased treatment-related health costs. Cost-effectiveness analysis is a type of economic evaluation that compares costs and health outcomes of alternative intervention strategies in a systematic way. In this review, a systematic literature search was performed and the evidence on the cost effectiveness of conventional chemotherapy and targeted therapy for metastatic breast cancer was explored. Cost-effectiveness/-utility analysis of treatment regimens for metastatic breast cancer were identified using literature and reference searches (MEDLINE). Published reports on conventional and targeted cancer therapies were scrutinized and incremental cost-effectiveness ratios (ICERs) were abstracted. Furthermore, the quality of reporting, as well as methodological and modeling issues, were extensively discussed. From full-text article reviews, six cost-effectiveness analyses on conventional therapies and seven studies on targeted therapies were included. Eight analyses were conducted in European countries, three in the US and two in Canada. The economic models were primarily (69%) based on clinical trial data. Results from sensitivity analyses and study perspectives were reported by all studies. Discount rates were mentioned in five articles (39%). The methods of reporting costs and effects varied considerably, as did trial design across conventional chemotherapies, which made it difficult to compare those analyses. The pharmacoeconomic studies came to different conclusions. The actual clinical evidence does not suggest one conventional chemotherapy regimen as superior. Studies on cytotoxic agents showed mainly favourable cost-effectiveness ratios. Targeted therapies indicated both favourable and non-favourable ratios. Currently, trastuzumab is the only antibody-based targeted therapy that is established in the clinic for the metastatic setting.

The antineoplastic activity of HDAC inhibitors is an unquestionable property of these compounds, but recent studies in tumor cells have revealed the potential of HDAC inhibitors (e.g., suberoylanilide hydroxamic acid SAHA, valproic acid VPA) to cause acquisition of HDAC inhibitor resistance. We report that trichostatin A (TSA), an HDAC inhibitor structurally related to SAHA, causes the acquisition of multidrug resistance transporter-independent and irreversible 3-fold resistance to TSA in MLH1-deficient (absent MLH1 protein expression) but not in MLH1-proficient (expressing MLH1 protein) HCT116 colon tumor cells. This MLH1-deficient subline selected for TSA resistance by stepwise exposures to increasing TSA concentrations exhibited failure in the accumulation of acetylated histones, in p21 induction, and in apoptosis activation. These are cellular responses normally seen in tumor cells treated with HDAC inhibitors. Whereas the absence of acetyl-histone accumulation did not correlate with altered HDAC activity, the absence of apoptosis correlated with reduced expression of (pro-apoptotic) Bax. This TSA-resistant subline was cross-resistant to SAHA and VPA but not to 'classic' non-HDAC inhibitor-type anticancer agents such as docetaxel and doxorubicin. These herein presented results expand on a previous study reporting HDAC inhibitor resistance acquisition by SAHA which was independent of the MLH1 expression status. Taken together, the present study identifies TSA, besides SAHA and VPA, as another potential causative of HDAC inhibitor resistance acquisition specifically in MLH1-deficient HCT116 colon tumor cells, and it reveals a possible function of MLH1 protein in protecting colon tumor cells from resistance acquisition by TSA.

The addition of bevacizumab to weekly paclitaxel as primary chemotherapy for HER-2 negative metastatic breast cancer (MBC) prolongs progression-free survival without a substantial increase of toxicity. A Markov cohort simulation was used to follow the clinical course of typical patients with MBC. Information on response rates and major adverse effects was derived, and transition probabilities were estimated, based on the results of the E2100 clinical trial. Direct costs were assessed from the perspective of the Swiss health system. The addition of bevacizumab to weekly paclitaxel is estimated to cost an additional 40,369euro and to yield a gain of 0.22 quality-adjusted life years (QALYs), resulting in an incremental cost-effectiveness ratio of 189,427euro/QALY gained. Probabilistic sensitivity analysis showed that the willingness-to-pay threshold of 60,000euro was never reached. The addition of bevacizumab to paclitaxel in MBC patients is expensive given the clinical benefit in terms of QALYs gained.

Background: One strategy to reduce the consumption of resources associated to specific procedures is to utilize clinical pathways, in which surgical care is standardized and preset by determination of perioperative in-hospital processes. The aim of this prospective study was to establish the impact of clinical pathways on costs, complication rates, and nursing activities., Method: Data was prospectively collected for 171 consecutive patients undergoing laparoscopic cholecystectomy (n = 50), open herniorrhaphy (n = 56), and laparoscopic Roux-en-Y gastric bypass (n = 65)., Results: Clinical pathways reduced the postoperative hospital stay by 28% from a mean of 6.1 to 4.4 days (p < 0.001), while the 30-day readmission rate remained unchanged (0.5% vs. 0.45%). Total mean costs per case were reduced by 25% from euro 6,390 to euro 4,800 (p < 0.001). Costs for diagnostic tests were reduced by 33% (p < 0.001). Nursing hours decreased, reducing nursing costs by 24% from euro 1,810 to euro 1,374 (p < 0.001). A trend was noted for lower postoperative complication rates in the clinical pathway group (7% vs. 14%, p = 0.07)., Conclusions: This study demonstrates clinically and economically relevant benefits for the utilization of clinical pathways with a reduction in use of all resource types, without any negative impact on the rate of complications or re-hospitalization.

Undoubtedly, the war on cancer is an expensive endeavour. It is estimated that, where data are available in Europe (e.g. Germany and France), cancer care accounts for a similar proportion of overall health-care expenditure to that in the USA, i.e. approximately 5%. Currently, no society can afford all of the potential cancer treatments for all the patients that could benefit from them. How the required resources should be provided is one of the great on-going debates, and different countries approach this problem in different ways. Additionally, the more we understand about the pathology, pathogenesis, diagnosis and treatment of cancer, the more options are created. Many of these options are new diagnostic tools and more effective treatments. Obviously these innovations, paired with an increasing patient pool, are leading to tremendous health-care expenditures, well surpassing current budgets. Hence, the question arises of how many resources should be devoted to the management of cancers, given that resources are scarce and many other fields and specialities are competing for these resources. This paper addresses the question of whether preventive measures in oncology eventually pay off.

Endometrial cancer is the most common gynecologic malignancy in Switzerland. Nowadays the gold standard for the treatment of endometrial cancer is total abdominal hysterectomy, bilateral salpingo-oophorectomy and in most cases pelvic and para-aortic lymphadenectomy. However, the use of minimally invasive surgical techniques has increased in recent years. Several prospective, randomized trials demonstrate the safety, feasibility and effectiveness of laparoscopy; the impact on survival and disease-free survival is equivalent to that of laparotomy. In future, laparoscopy and maybe robotic surgery could be effective in a selected population. Until then, further large-scale, prospective multicenter studies with longer follow-ups are required to confirm the current data.

Objective: To determine characteristics and clinical course of high-grade anogenital intraepithelial neoplasia (AIN) in human immunodeficiency virus (HIV)-infected women., Study Design: HIV-positive women with biopsy-proven high-grade (II and III) vulvar (VIN), vaginal (VAIN) or perianal intraepithelial neoplasia (PAIN) were identified in the electronic databases of 2 colposcopy clinics., Results: A total of 31 patients were identified from 1992 to 2007, of which 30 had a mean follow-up of 47.7 months (SD = 46.0; range, 2.6-166.2). Of the patients, 77.4% had VIN, 12.9% VAIN and 9.7% PAIN at first diagnosis. Age at diagnosis of IN was 36.2 years (SD +/- 5.2; range, 23.5-47.0). Ninety percent of patients received antiretroviral therapy at first diagnosis of IN; 65% (13 of 20) of patients with a follow-up of > 2 years required a second treatment, and 2 developed invasive vulvar cancer (10%)., Conclusion: AIN among HIV-positive women shows a high relapse rate despite treatment modality used and a substantial invasive potential.

Hormone-receptor-positive cancer is the most common tumor subtype in women with breast cancer. Endocrine treatment in this subgroup is essential for premenopausal as well as postmenopausal patients. Tamoxifen substantially improves disease-free survival and overall survival in combination with chemotherapy or alone in adjuvant therapy. In recent years, a number of large-scale, randomized trials have evaluated the role of the aromatase inhibitors (AI) in postmenopausal women with hormone-receptor-positive breast cancer. These studies tested one of three approaches: (1) an upfront AI, (2) a sequential approach after 2-3 years of tamoxifen and (3) an extended endocrine therapy beyond 5 years. The positive results of these studies have challenged the previous standard of a 5-year course of tamoxifen alone. While the AI have become a standard component of treatment for most postmenopausal women, many questions still remain regarding the optimal endocrine treatment., (Copyright 2008 S. Karger AG, Basel.)

Invasive lobular carcinoma is the second most common histological type of breast cancer and differs from invasive ductal carcinoma also in some clinical features. Multifocal or multicentric as well as contralateral diseases are more frequently found among patients with lobular carcinoma. Tumor size at diagnosis is larger than in patients with ductal carcinoma due to diagnostic challenges associated with lobular histology. For surgical management, breast conserving surgery followed by radiotherapy offers equal local control as mastectomy. Controversy however exists regarding risk for positive margins and subsequent need for second operations. Axillary staging can be safely performed by sentinel node biopsy if lymph nodes are clinically negative, even in multifocal or multicentric disease.

Postoperative enteral nutrition is a widely accepted route of application for nutrition formulas due to a low complication rate, a good acceptance by patients. and a favorable cost-effectiveness. We report three cases of bezoar ileus after early postoperative enteral nutrition, using a fine needle jejunostomy (FNJ) in two cases and a nasoduodenal tube in one case. A male patient who underwent gastric resection for a gastrointestinal stroma tumor and was nourished through an fine needle jejunostomy developed an acute abdomen on the seventh postoperative day. Surgical exploration revealed a mechanical ileus caused by denaturated nutrition formula distal to the catheter tip. The second case, a female patient, underwent gastric resection for a gastric cancer and on the fourth postoperative day developed acute onset of abdominal pain. Intraoperative findings were the same as described in the first case. The third case, a male patient with necrotizing cholecystitis, underwent open cholecystectomy. Postoperative enteral feeding was performed using a nasoduodenal tube. He developed a small bowel obstruction on the 17th postoperative day that was caused by an intraluminal bezoar. In conclusion, bezoar formation represents an underestimated complication of postoperative enteral feeding. Acute onset of abdominal pain and the development of small bowel obstruction are the main clinical symptoms of this severe complication. The pathogenesis of bezoar formation remains unclear.