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We examined the potential of cricket farming as an innovative solution to improving household nutrition in Laos, where edible insects are already part of traditional diets. We conducted research with a total of 40 rural households in Central Laos, in which small-scale cricket farming was introduced to 20 intervention households. Nutritional situation and changes of all households and cricket production and consumption of the intervention households were assessed. Malnutrition was prevalent amongst the study population and we found indications for dietary inadequacies. Despite fluctuating harvest results and some production failures, most intervention households successfully produced and harvested crickets over five production cycles. Cricket farming was not only appreciated by the project participants, but also spread to non-project households. 70% of the total cricket harvest were used for own consumption and crickets were eaten by all family members, including small children and women, in amounts that improved nutritional adequacy during the brief period following harvest. To increase the nutritional impact, production has to be stabilised and adapted to provide a more continuous supply of crickets over the year.

Epidemiology Vulvar cancer can be classified into two groups according to predisposing factors: the first type correlates with a HPV infection and occurs mostly in younger patients. The second group is not HPV associated and occurs often in elderly women without neoplastic epithelial disorders. Histology Squamous cell carcinoma (SCC) is the most common malignant tumor of the vulva (95%). Clinical features Pruritus is the most common and long-lasting reported symptom of vulvar cancer, followed by vulvar bleeding, discharge, dysuria, and pain. Therapy The gold standard for even a small invasive carcinoma of the vulva was historically radical vulvectomy with removal of the tumor with a wide margin followed by an en bloc resection of the inguinal and often the pelvic lymph nodes. Currently, a more individualized and less radical treatment is suggested: a radical wide local excision is possible in the case of localized lesions (T1). A sentinel lymph node (SLN) biopsy may be performed to reduce wound complications and lymphedema. Prognosis The survival of patients with vulvar cancer is good when convenient therapy is arranged quickly after initial diagnosis. Inguinal and/or femoral node involvement is the most significant prognostic factor for survival.

Background: Imatinib is a tyrosine kinase inhibitor of BCR-ABL, ABL, PDGFR-α and -β, KIT, and DDR. In solid tumors, it inhibits proliferation and invasiveness and facilitates higher intratumoral cytotoxic drug concentrations. Vinorelbine has good tolerability and efficacy in metastatic breast cancer (MBC). This study evaluates the safety and efficacy of imatinib and vinorelbine in combination. Methods: In a prospective, open-label, phase I/II trial, 400 mg imatinib p.o. daily (corrected from 600 mg) was combined with an escalating dose of vinorelbine i.v. weekly in four dose levels of 10, 15, 20, and 25 mg/m2 (each n ≥ 5) to treat patients with MBC (expressing PDGFR-α and/or -β, and/or KIT). The last patient of each level was treated for >28 days, before enrolment for the next dose level started. Study endpoints were feasibility and tolerability, incidence of hematological and nonhematological toxicity, and clinical efficacy (data cutoff: November 18, 2011). A total of 33 patients have been enrolled, and all dose levels have been fully recruited. One patient is still on study medication. A translational subprotocol is ongoing. Results: All 33 included patients are evaluable for safety (32 within the ITT population). Eleven patients were excluded early from the study (progressive disease, toxicity, and withdrawal of consent). Twenty-two patients participated in the study for >28 days (‘ITT >28'). Within the ITT population, the response rate [complete response (CR) and partial response (PR)] was 9.4% (n = 3), the clinical benefit rate (CBR; CR+PR+stable disease) 50% (n = 16), and the median time to progression (TTP) 155 days. A total of 21.3% of the patients were on study medication for >6 months, and 15.2% for >12 months (mean 140 days, range 15-643). Within ‘ITT >28', the response rate was 13.6%, CBR 72.7%, and median TTP 176 days. The response was independent of the receptor status (PDGFR-α, -β, and KIT). Toxicities were as follows (safety population): 21.6% severe leukopenia, 9.1% severe neutropenia (with 1 febrile neutropenia), 1 case of bowel perforation, 36% diarrhea (3% severe), 84.8% nausea (severe 15.2%), 48.5% vomiting (severe 9.1%), 27.3% infections (severe 6.1%), 12.1% peripheral neuropathy (severe 9.1%), and 36.4% dyspnea (3% severe). Four patients on trial died (nondrug-related). Conclusion: The combination of imatinib and vinorelbine in MBC appeared to be feasible and tolerable. A CBR of 50% (ITT) in pretreated patients suggests that this combination may be active. Although toxicities were frequent, they appeared to be manageable.

Aromatase inhibitors (AI) have improved the treatment of oestrogen receptor positive (ER+) breast cancer. Despite the efficacy of these agents over 40% of patients relapse with endocrine resistant disease. Here we describe an in vitro model of acquired resistance to long-term oestrogen deprivation (LTED). The LTED cells retain expression of the ER and appear hypersensitive to oestrogen as a result of altered kinase activity. Furthermore analysis of temporal changes in gene expression during the acquisition of resistance highlight growth factor receptor pathways as key mediators of this adaptive process.

Objective: Many patients with ovarian cancer disease relapse within 6 months after adjuvant chemotherapy, with a limited prognosis. Epigenetic modifications have been shown to play an important role in tumor development and formation. Therefore, global analysis of DNA methylation patterns might reveal specific CpG sites that correlate with progression-free interval (PFI) after therapy. Methods: Twenty samples of advanced ovarian cancer with a predominantly serous papillary histological subtype were subjected to DNA methylation profiling. Illumina HumanMethylation27 BeadChip technology was used for simultaneous analysis of 27,578 CpG sites in >14,000 genes. Results: Differential DNA methylation of various cytosines correlated with PFI. However, this becomes only significant by classification according to PFI with a cutoff of >28 months. Longer survival was associated with hypomethylation at specific CpG sites (e.g. GREB1, TGIF and TOB1) and hypermethylation in other genes (e.g. TMCO5, PTPRN and GUCY2C). Gene ontology analysis revealed that differentially methylated genes were significantly overrepresented in the categories telomere organization, mesoderm development and immune regulation. Conclusion: Epigenetic modifications at specific CpG sites correlate with PFI in ovarian cancer. Therefore, such analysis might be of prognostic value.

Breast cancer treatment has experienced several changes in the past decades due to the discovery of specific prognostic and predictive biomarkers that enable the application of more individualized therapies to different molecular subgroups. These subgroups show specific differences regarding biological clinical behavior. In addition to the classical clinical prognostic factors of breast cancer, established molecular biomarkers such as estrogen receptor and progesterone receptor have played a significant role in the selection of patients benefiting from endocrine therapy for many years. More recently, the human epidermal growth factor receptor 2 (HER2) has been validated to be not only a prognostic factor, but also a predictor of response to HER2 targeting therapy. The shift toward an earlier diagnosis of breast cancer due to improved imaging methods and screening programs highlights the need for new factors and combinations of biomarkers to quantify the residual risk of patients and to indicate the potential value of additional treatment strategies. The marker of proliferation Ki67 has recently emerged as an important marker due to several applications in neoadjuvant therapy in addition to its moderate prognostic value. With the introduction of high-throughput technologies, numerous multigene signatures have been identified that aim to outperform traditional markers: current prospective clinical trials are seeking evidence for their definitive role in breast cancer. There exist many more factors and approaches that have the potential to become relevant in the near future including the detection of single disseminating and circulating tumor cells in blood and bone marrow as well as of circulating cell-free DNA and microRNA. Careful randomized prospective testing and comparison with existing established factors will be required to select those emerging markers that offer substantial cost-effective benefit and thereby justify their routine use for breast cancer therapy decision-making.

Cyclo-oxygenase 2 (COX-2) is implicated in the regulation of aromatase transcription in malignant breast tissue and has been considered as a potential target for tissue specific aromatase suppression. We initiated a randomised controlled pre-surgical study of celecoxib versus no treatment in women with primary breast cancer to determine the effects of COX-2 inhibition on markers of biological response. Postmenopausal women (50-80 years of age) with stage I or II, primary breast cancer, were randomised 2:1 to receive 400 mg/day celecoxib or no treatment for 14 days prior to surgery. A core biopsy was obtained pre- and post-treatment. Paired baseline and endpoint biopsies were analysed for Ki67, apoptosis, COX-2, CD31, estrogen receptor (ER) and progesterone receptor (PgR). Comparisons between the treatment groups were conducted using the Mann-Whitney test with a two-sided 5% significance. Of the 25 patients treated, 23 had evaluable data and 19 (83%) were ER positive. Overall the geometric mean change in Ki67, the primary end point, relative to baseline in the celecoxib arm was -16.6% (P = 0.056). The change in the no-treatment group was -8.1% (P = 0.24). There was no statistically significant difference in the change between the two groups. Celecoxib did not significantly affect apoptosis, COX-2, ER or PgR expression. There is only modest evidence for a biological effect of celecoxib in primary breast cancer. However, the trend towards a reduction in Ki67 in ER-positive breast cancer warrants further investigations in a larger cohort of patients.

Introduction Imatinib mesylate is a tyrosine kinase receptor inhibitor targeted against PDGFR α and β, c-kit and bcr-abl. These receptors regulate cellular processes such as proliferation, differentiation, and survival. This study was performed to evaluate the effects of imatinib on breast cancer cell lines with respect to the activity of PDGFR β and Akt: a downstream modulator of cell growth and survival. Methods Expression of imatinib targets was analyzed with reverse transciptase PCR and immunoblotting assays in the breast cell lines MDA MB 231, MCF 7, ZR 75-1, and T 47-D. Changes on receptor expression and phosphorylation status under imatinib were evaluated using drug concentrations of 2 to 10 μM. The anti-proliferative and pro-apoptotic effects of imatinib alone and in combination with vinorelbine were investigated with an MTT and TUNEL assay. Results Imatinib inhibited growth and induced apoptosis of all cell lines examined. This effect was increased when combined with vinorelbine. A dose-dependent inhibitory effect on the phosphorylation of PDGFR β and Akt was detected. Conclusions The growth inhibitory effect of imatinib on breast cell lines may be caused by inhibiting the activity of the tyrosine kinases PDGFR β and Akt. Imatinib is a promising novel drug for targeted therapy of breast cancer patients.

Purpose: Nilotinib is a selective tyrosine kinase inhibitor of c-Kit, Abl and platelet-derived growth factor receptor-α/β. To evaluate nilotinib's potential use as a treatment of human ovarian cancer, we tested nilotinib's preclinical activity in ovarian cancer cell lines with different tyrosine kinase expression patterns. Methods: The effects of nilotinib on ovarian cancer cell growth were studied alone and in combination with carboplatin and paclitaxel. Proapoptotic and antimigratory effects were examined using TUNEL and migration assays. Results: Nilotinib alone and in combination with carboplatin and paclitaxel significantly inhibited cell growth in PDGFR-α-positive ovarian cancer cell lines. The combination of nilotinib with carboplatin and paclitaxel showed synergistic effects on cell proliferation. Nilotinib treatment led to the inhibition of cell migration alone and in combination with carboplatin and paclitaxel. Apoptosis induction occurred in response to nilotinib that increased in combination with carboplatin. Conclusions: Nilotinib may be a feasible targeted therapy option for the treatment of ovarian cancer.

Zielgerichtete Medikamente fuhren zu einer Kostensteigerung der Brustkrebstherapie. Es gibt nur wenige Untersuchungen in Deutschland zur Kosteneffizienz dieser Substanzen. Die zitierten Studien aus verschiedenen Industrienationen, deren Gesundheitssysteme z. T. sehr unterschiedlich sind, konnen der Orientierung dienen, sind jedoch nicht direkt auf die deutsche Situation ubertragbar. Trastuzumab ist heute Teil der adjuvanten Standardtherapie bei einer HER-2/neu-Uberexpression. Eine Schweizer Analyse hat in dieser Indikation eine Kosteneffizienz gezeigt, besonders fur Follow-up-Perioden >10 Jahre. Fur HER-2/neu-positive metastasierte Mammakarzinome (MBC) unterstellte eine franzosische Untersuchung fur Trastuzumab ebenfalls kosteneffizient zu sein. In einer englischen Bewertung des National Institute for Health and Clinical Excellence wurde Lapatinib, das auch gegen HER-2/neu gerichtet ist, in Kombination mit Capecitabine bei MBC als nicht kosteneffizient eingeschatzt. Auch eine Schweizer Bewertung von Bevacizumab in Kombination mit Paclitaxel bei MBC ergab keine Kosteneffizienz. In Deutschland fehlt es an orientierenden Empfehlungen zur Kosteneffizienz neuer zielgerichteter Substanzen. Da auch hier die Ressourcen im Gesundheitswesen limitiert sind, ware eine intensive gesellschaftliche Diskussion daruber dringend notwendig.

We have found that the platelet-derived growth factor receptor (PDGFR)/Abl signaling pathway is up-regulated as a determinant of the acquisition of resistance to estrogen deprivation in vitro. We aimed to determine its clinical relevance in aromatase inhibitor (AI)-resistant breast cancer. We identified a cohort of 45 patients with estrogen receptor-positive breast cancer who had been treated with an AI, subsequently relapsed and had biopsy material available from both the presentation and post-AI recurrent lesion. PDGFR alpha, PDGFR beta and Abl expression was assessed in formalin-fixed paraffin-embedded sections. Tumor protein expression of PDGFR alpha (1.39-fold, P = 0.0065), PDGFR beta (4.32-fold, P = 0.006) and Abl (1.8-fold, P = 0.001) was increased at the point of relapse. Tumor and stromal expression of PDGFR alpha as well as PDGFR beta was significantly correlated in pre-treatment and relapse samples. High post-treatment tumor and stromal PDGFR beta levels were associated with a short time to treatment failure (TTF). Expression of PDGFR alpha in relapsing tumor specimens was correlated with Abl expression and Ki67 levels. Furthermore, changes in Abl correlated significantly with changes in ER expression. These clinical data support a role for enhanced PDGF/Abl signaling in AI-resistant disease and provide a rationale for targeting the pathway in endocrine-resistant breast cancer.

Introduction The majority of breast tumors at primary diagnosis are estrogen receptor positive (ER+). Estrogen (E) mediates its effects by binding to the ER. Therapies targeting the estrogenic stimulation of tumor growth reduce mortality from ER+ breast cancer. However, resistance remains a major clinical problem. Methods To identify molecular mechanisms associated with resistance to E-deprivation, we assessed the temporal changes in global gene expression during adaptation to long-term culture of MCF7 human breast cancer cells in the absence of estradiol (E2), long term estrogen deprived (LTED), that leads to recovery of proliferative status and models resistance to an aromatase inhibitor (AI). The expression levels of proteins were determined by western blotting. Proliferation assays were carried out using the dual platelet derived growth factor receptor (PDGFR)/Abelson tyrosine kinase (Abl) inhibitor nilotinib. Luciferase reporter assays were used to determine effects on ER-mediated transactivation. Changes in recruitment of cofactors to the gene regulated by estrogen in breast cancer 1 (GREB1) promoter were determined by chromatin immunoprecipitation (ChIP). Gene expression data were derived from 81 postmenopausal women with ER+ BC pre-treatment and at two-weeks post-treatment with single agent anastrozole in a neoadjuvant trial. Results The PDGF/Abl canonical pathway was significantly elevated as early as one week post E-deprivation (P = 1.94 E-04) and this became the top adaptive pathway at the point of proliferative recovery (P = 1.15 E-07). Both PDGFRβ and Abl protein levels were elevated in the LTED cells compared to wild type (wt)-MCF7 cells. The PDGF/Abl tyrosine kinase inhibitor nilotinib, suppressed proliferation in LTED cells in the presence or absence of E. Nilotinib also suppressed ER-mediated transcription by destabilizing the ER and reducing recruitment of amplified in breast cancer-1 (AIB1) and the CREB binding protein (CBP) to the promoter of the E-responsive gene GREB1. High PDGFRβ in primary ER+ breast cancer of 81 patients prior to neoadjuvant treatment with an AI was associated with poorer antiproliferative response. Additionally PDGFRβ expression increased after two weeks of AI therapy (1.25 fold, P = 0.003). Conclusions These preclinical and clinical data indicate that the PDGF/Abl signaling pathway merits clinical evaluation as a therapeutic target with endocrine therapy in ER+ breast cancer.

The new Cobas Core CMV IGM and IgG enzyme immunoassays (Roche Diagnostic Systems, Basle, Switzerland) were evaluated for their ability to detect cytomegalovirus (CMV)-specific IgM and IgG antibodies. Therefore, both were compared with some other commercially available and already established serological tests used in the laboratory diagnosis of CMV infection. These included the Abbott IMx CMV IgM and IgG assays, the Abbott CMV-M EIA, the Gull CMV IgM and IgG immunofluorescence tests, the medac CMV-IgM-ELA, and the Enzygnost anti-cytomegalovirus assay (Behringwerke). A total of 572 serum samples of various categories were examined and the results showed high concordances between all methods, ranging from 84.5% to 94.9%.. In a follow-up on renal transplant patients, the times of first detection of seroconversions were compared. Since a high overall agreement between the Cobas Core CMV IgM and IgG enzyme immunoassays and the other test systems were observed, these new assays represent useful and reliable tools for clinical CMV diagnosis.

Objectives Endometriosis is a common gynaecological disease with clinical symptoms such as chronic pain, infertility and intra-abdominal adhesions. Different theories on the pathogenesis of endometriosis and especially its aggressive subtype with infiltrative growth have been discussed. The objective of this study is to evaluate differences in proliferation and invasive properties of invasive colorectal endometriosis, superficial peritoneal endometriosis and endometrial carcinoma (G1 and G2). Study design Paraffin embedded tissues of peritoneal endometriosis, endometriosis of the intestine and endometrial carcinoma from 97 patients were stained immunohistochemically to assess differences in expression patterns of matrix metalloproteinases (MMP-2, MMP-9) as markers of invasion and the marker of proliferation PCNA. MMP expression was evaluated using the Immuno Reactive Score (IRS) (combining positive cell ratio and staining intensity) and PCNA expression was assessed as the percentage of positively stained cells in representative areas. Results MMP-2, MMP-9 and PCNA showed differential expression patterns in the different tissues examined. MMP-2 and PCNA expression was stronger in invasive colorectal endometriosis than in superficial peritoneal endometriosis ( p =0.0394). MMP-9, however, was more frequently expressed in peritoneal endometriosis (59.1%) than in colorectal endometriosis (44.4%). This result did not reach statistical significance. When colorectal endometriosis was compared to low grade endometrial carcinoma, proliferation detected by PCNA was significantly higher in endometriosis ( p =0.0008). MMP-2 and MMP-9 showed higher expression in endometrial carcinoma than in endometriosis. Conclusions There are obvious differences in expression patterns of MMP-2, MMP-9 and PCNA in different stages of endometriosis and in endometrial cancer. These markers can be helpful to evaluate aggressiveness and invasiveness of endometriosis in different localizations. The results obtained could be of relevance for a better understanding of the pathogenesis of endometriosis and the development of an individual therapy concept.

BMC cancer 10(412), (2010). doi:10.1186/1471-2407-10-412, Published by BioMed Central, London

In advanced ovarian cancers (OCs), p53 mutations are frequently observed. The objective of this study was to explore the value of the p53 mutational status, using four different techniques, in advanced OC patients as a predictive marker for responsiveness to platinum-based chemotherapy. One hundred and four, mostly serous papillary OC specimens were analyzed, of which all received a platinum containing chemotherapy after optimal cyto-reductive surgery. To verify the p53 mutational status, immunohistochemical staining with monoclonal antibodies, functional yeast assay (FASAY), single-strand conformation polymorphism analysis (SSCP) and genomic sequencing was performed in parallel. Out of ten OC patients [2 low malignant potential (LMP)/8 G1] only two had a mutant p53, whereas eight showed a wild-type p53. 40 out of 63 (G2/3) patients with G2/3 OC showed mutant p53 and 23 patients showed a wild-type pattern. p53 status was significantly different between these two groups (LMP/G1 vs. G2/3) (P = 0.015). A progressive disease after chemotherapy completion was noted in 35.6% of the patients (26 out of 73); in 69.2%, a mutated p53 and in 30.8%, a wild-type p53 was found. Nine (12.3%) patients showed a complete response at the end of the first-line chemotherapy. Out of these nine patients five had a mutated and four a wild-type p53. A partial response was observed in nine (12.3%) patients of whom four had a mutated p53. With respect to response to first-line chemotherapy (six cycles of platinum containing regimen), the p53 status was not predictive; no statistical significance regarding the p53 mutational status was observed when the two extreme groups PD versus PR/CR were compared (P > 0.05). In this study, the p53 mutational status was not predictive for responsiveness to platinum-based chemotherapy; but p53 was significantly more frequently mutated in poorly differentiated OCs.

Leiomyomatosis peritonealis disseminata (LPD) is a rare disease occurring as intraabdominal benign tumors. The underlying mechanism of LPD development in premenopausal females is still unknown, but high levels of estrogen and progesterone seem to play a major role. We present a case of a 29-year-old gravida 1, 22 6/7 weeks of gestation with symptoms of an acute abdomen. Abdominal ultrasound and MRI showed intraabdominal masses of uncertain origin most likely to be an extreme example of pseudomyxoma peritonei. Explorative laparotomy was performed, and histopathological analysis revealed benign tumors classified as leiomyomatosis. A cesarean section was performed due to increasing abdominal pain and excessive elevated inflammatory serum parameters. Postpartum, a spontaneous regression of the LPD was marked. LPD is a rare disease of young women. Excessive hormonal exposure seems to play a major role. Diagnosis is often difficult and a histopathological analysis is needed.

Imatinib is a small molecule inhibiting the tyrosine kinases bcr-abl, c-kit, PDGFR-alpha and PDGFR-beta. Investigations were performed to screen ovarian cancer cell lines and tumor samples for target receptor expression. Effects of Imatinib on cell proliferation and apoptosis induction were measured with and without additional cytotoxic agents.Expression patterns of abl, c-kit, PDGFR-alpha and PDGFR-beta (Imatinib targets) were studied in 5 cell lines and 111 tissue arrays by PCR and immunohistochemistry. Proliferation assays were performed with single agent Imatinib or combined with Paclitaxel and Carboplatin. Apoptosis was measured by DNA fragmentation.All cell lines expressed abl and PDGFR-beta. C-kit was only expressed in 2/5 cell lines and PDGFR-alpha in 4/5. Imatinib reduced cell growth and lead to pro-apoptotic changes. Combination of Carboplatin, Paclitaxel and Imatinib showed synergistic activity.Our results suggest that Imatinib may be useful for the specific treatment of ovarian cancer as an add-on to conventional chemotherapy.

• Many different materials are available for augmentation mentoplasty. However, the optimal implant material for chin implantation has yet to be found. During the past several years, a number of experienced surgeons have turned to the use of Mersilene mesh. Mersilene mesh is a nonabsorbable Dacron polyester fiber that can be conformed easily into layers to achieve tailored dimensions and shape. At the McCollough Plastic Surgery Clinic PA, Birmingham, Ala, 277 patients over a 10-year period underwent chin augmentation with Mersilene mesh implants. The material provides excellent tensile strength, durability, and surgical adaptability. The overall complication rate was 3.2% (nine patients); infection rate, 2.5% (seven patients); and removal secondary to infection, 1.7% (five patients). Based on this 10-year experience, Mersilene mesh remains our material of choice for chin augmentation. (Arch Otolaryngol Head Neck Surg. 1990;116:1154-1158)

e13503 Background: Imatinib is a tyrosine kinase inhibitor of bcr-abl, PDGF-R, SCF, c-Kit and abl. In solid tumors it inhibits proliferation and facilitates higher intratumoral cytotoxic drug concentrations. Vinorelbine has good tolerability and efficacy in MBC. This study evaluates the combination of imatinib and vinorelbine. Methods: In aprospective open-label, phase I/II trial 400 mg imatinib p.o. daily (amended from 600 mg) was combined with an escalating dose of vinorelbine i.v. weekly in four dose levels with 10, 15, 20, 25 mg/m² (each n ≥ 5) for pats. with MBC (which express PDGF-R-α and/or -β and/or c-kit). The last pat. of a level was treated > 28 days, before enrolment for the next dose level started. Study endpoints were feasibility and tolerability, incidence of hematological and non-hematological toxicity and clinical efficacy (data cut: 18/11/2011). A translational subprotocol is ongoing. 33 pats. have been enrolled; all dose levels have been fully recruited. 1 patient is still on study medication. Results: 32 pats. are evaluable (ITT population). 11 pats. went off study early (progressive disease, toxicity and withdrawal of consent). 22 pats. were on study >28 days (“ITT>28”). Within the ITT population the response rate (complete (CR) and partial response (PR)) was 9.4% (n=3), the clinical benefit rate CBR (CR+PR+stable disease) 50% (n=16), median time to progression (TTP) 155 days. 21.3% were on study medication >6 months, 15.2% > 12 months (mean 133 days, 15-617 days). Within “ITT>28,” the response rate was 13.6%, CBR 72.7% and median TTP 176 days. Toxicities (ITT population): 21.6% severe leukopenia, 9.1% severe neutropenia (with 1 febrile neutropenia), 1 case of bowel perforation, 36% diarrhea (3% severe), 84.8% nausea (severe 15.2%), 48.5% vomiting (severe 9.1%), 27.3% infections (severe 6.1%), 12.1% periph. neuropathy (severe 9.1%) and 36.4% dyspnea (3% severe). 1 patient on study medication died (non drug related). Conclusions: The combination of imatinib and vinorelbine in MBC appeared to be feasible and tolerable. A CBR of 50% (ITT) in pre-treated pats. proves the efficacy of this combination. Although toxicities were frequent, they appeared to be manageable.

Background Imatinib mesylate is a tyrosine kinase inhibitor which originally had been developed to block pathognomonic bcr-abl oncoprotein in chronic myeloic leukemia. It is also an inhibitor of the receptor tyrosine kinases of platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit, and ab1. Therefore it also inhibits PDGF- and SCF-mediated cellular events, as tumor cell proliferation in solid tumors. Additionally, inhibition of PDGF- b-receptor relieves tumor hypertension in solid tumors and thereby helps to deliver higher concentrations of cytotoxic drugs into the tumor cell. Vinorelbine is a semisynthetic vincaalcaloid with antitumor activity. As a single agent and as a combination partner of other cytotoxic drugs, it has proven good tolerability and high effectiveness in treatment of patients with metastatic breast cancer (MBC). This study was designed to evaluate the feasability of the combination of imatinib mesylate and the cytotoxic drug of vinorelbine in different concentrations in patients with advanced and MBC. Study design: This is a prospective open-label, single arm phase I/II study combining 400 mg Imatinib Mesylate p.o. daily (amended from 600 mg) with an escalating dose of vinorelbine i.v. weekly for patients with locally advanced or metastatic breast cancer. Patients must have tumors expressing PDGF-receptor-α and/or -β and/or c-kit and have received pretreatment with an anthracyclin containing regimen. Main study endpoints are feasibility and tolerability of this novel combination. In addition to the total toxicity and the incidences of hematological and non-hematological toxicity of grade 3 and 4, the clinical activity together with the clinical response rate and the time to disease progression will be evaluated.The quality of life is examined during the whole course of treatment. Recruitment started for level one with 10 mg/m2 vinorelbine and proceeds to the next higher levels 15, 20 and 25 mg/m2. Each dose level will be filled with at least five patients. Patients of one dose level will be followed for a minimum of 28 days during therapy, before enrolment of patients for the next dose level can start. For translational research multiple skin biopsies will be taken (skin wounding assays). When feasible tumor-biopsies are taken before and during therapy. Expression of tyrosine kinase receptors (c-kit and PDGF-receptor) will be correlated with treatment response. Present accrual and target accrual: 33 patients have been enrolled into the study. Dose levels I-III have been fully recruited. In dose level IV two patients with visceral metastasis are ongoing on study medication. Safety and clinical data will be available after the last patient discontinues study treatment. Information on the study protocol, the translational subprotocol and details on c-kit and PDGF-receptor expression analysis will be presented at the meeting. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT3-01-02.

Aim: To determine the relevance of PDGF/Abl signaling pathway as a therapeutic target in endocrine resistance in vitro and in vivo. Rationale: Targeting estrogenic stimulation reduces mortality from ER-positive (ER+) breast cancer (BC) but resistance remains a major clinical problem. To identify the molecular mechanisms associated with resistance to estrogen-deprivation, we previously assessed the temporal changes in gene expression during adaptation to long-term culture of MCF7 human breast cancer cells in the absence of estradiol (E2) (LTED), modeling resistance to an aromatase inhibitor (AI). Platelet-derived growth factor (PDGF)/Abl signaling was the top adaptive pathway at the point of resistance (p=1.15 E-07), but there is limited evidence for it playing a role clinically. Methods: Gene expression data from postmenopausal women with ER+ BC at pre-treatment and at 2-week on-treatment with neoadjuvant anastrozole were interrogated. Immunohistochemical staining using antibodies against PDGFRα, β and Abl was assessed in paired clinical specimen of 45 patients who had received an AI and presented progressive disease. Proliferation assays, immunoblots and ChIP assays were carried out using either the PDGFR/Abl inhibitor nilotinib or siRNA knockdowns in LTED and wild-type MCF7 cells. Results: In vitro: PDGFRβ and Abl expression and phosphorylation were elevated in LTED cells. Cell proliferation was decreased in LTED cells by siRNA knock-down of either PDGFRβ (50% p High post-treatment tumor and stromal PDGFRβ levels were associated with a short time to treatment failure (TTF) (T: Rs −0.284, p=0.066; S: Rs −0.307, p=0.046). Expression of PDGFRα in relapsing tumor specimens was correlated with Abl expression (Rs 0.342, p=0.027) and Ki67 levels (Rs 0.39, p=0.01). Furthermore, changes in Abl correlated significantly with changes in ER expression (Rs 0.307, p=0.048). Discussion: These in vitro and clinical data support a biological interaction between PDGF/Abl and ER-signaling and suggest that the PDGF signaling pathway warrants clinical evaluation as a therapeutic target in endocrine resistant breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-01-01.

e15526 Background: Nilotinib, a multi-target tyrosine kinase inhibitor (TKI), was tested for the treatment of human ovarian cancer (target-receptors: c-Kit, abl, PDGFR α/β). Ovarian epithelial aden...

e13657 Background: In the need to optimize breast cancer therapies, constantly new targeted agents are examined for their potential clinical use. In a broad range of solid and haematological cancer...

The majority of breast tumours at primary diagnosis are estrogen receptor positive (ER). Estrogen (E) mediates its effects by binding to the ER. E-bound ER associates classically with estrogen response elements (EREs) on target genes controlling proliferation and cell survival. ER's ability to regulate gene transcription is also influenced by the activity of co-regulatory proteins such as AIB1. Therapies targeting the estrogenic stimulation of tumour growth have been a major success in reducing mortality from ER-positive breast cancer. However, resistance remains a major clinical problem. To identify the molecular mechanisms associated with resistance to E-deprivation, we assessed the temporal changes in gene expression during adaptation to long-term culture of MCF7 human breast cancer cells in the absence of E2 (LTED), modelling resistance to an aromatase inhibitor (AI). Analyses of canonical signalling pathways showed that platelet-derived growth factor (PDGF)/Abl was significantly elevated as early as one-week post E-deprivation (p=1.94 E-04). Of note this became the top adaptive pathway at the point of resistance (p=1.15 E-07). Clinical data from 88 patients treated with an AI in the neoadjuvant setting, showed increases in PDGFRβ and PDGF expression after two weeks (1.25 fold, p=0.003 and 1.43 fold, p=4.4E-06). Low PDGFRβ at pre-treatment was associated with a better response. Assessment of the level of protein expression and activation status in a panel of cell lines modelling both endocrine sensitive and resistant breast cancer showed PDGFRβ was elevated in both LTED and tamoxifen resistant MCF7 cells (TAMR) compared to wt-MCF7. Moreover, the level of receptor phosphorylation was increased in the resistant cell lines. PDGFRβ expression was also evident in SKBR3 (ER-/ERBB2+) but not in BT474 (ER+/ERBB2+) cells. Of note both LTED and TAMR cells were sensitive to the inhibitory effect of the PDGFR/Abl tyrosine kinase inhibitor nilotinib, in the presence or absence of E. In contrast wt-MCF7 cells showed limited sensitivity in the presence of E. Both SKBR3 and BT474 cells were insensitive. These data suggested that PDGFRβ was associated with the endocrine resistant phenotype. Assessment using ER/ERE linked reporter assays showed nilotinib suppressed ER-mediated transcription and inhibited expression of two endogenous E-regulated genes TFF1 and PGR. Chromatin immunoprecipitation indicated that nilotinib reduced the recruitment of AIB1 and CBP to the TFF1 promoter. Furthermore we were able to demonstrate that nilotinib in combination with tamoxifen resensitised TAMR cells to the inhibitory effect of tamoxifen. These data for the first time reveal cross talk between ER and PDGF/Abl, strongly suggesting that the PDGF signalling pathway merits clinical evaluation as a therapeutic target in endocrine resistant breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2920.

Aromatase inhibitors (AI) have improved the treatment of estrogen receptor positive (ER+) early and advanced breast cancer (BC). However, the efficacy of AIs is limited by disease progression or relapse. No data is available assessing the temporal changes in gene expression during the development of acquired resistance to long-term estrogen deprivation (LTED). To model the adaptive changes associated with resistance to AI therapy, ER+ human BC cells MCF7 were cultured in the absence of estrogen (E). Genome-wide expression analysis using Illumina 48K arrays was performed to assess changes in gene expression during adaptation at 10 time-points up to 40 weeks (wks). Strikingly, the expression of a proliferation metagene showed resistance to E-deprivation occurred as early as 9 wks. Validation by global assessment of gene expression, revealed a stabilisation of the gene signatures after this time-point. Further analyses were restricted to a triangular pairwise comparison: wt MCF7 cells (modelling pre-treatment), 1 wk post E-deprivation (on AI treatment) and at 9 wks (clinical relapse). Comparison of wt MCF7 versus 1 wk showed 2158 genes were down-regulated and 1724 genes were up-regulated (p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4598.

14639 Background: Radiotherapy is commonly used in different stages of breast cancer. It is able to effect intracellular signal transduction leading to inhibition of cell proliferation. Impact of t...

16557 Background: Ovarian cancer is newly diagnosed in∼ 22,000 cases each year in the US. Standard treatment is cyto reductive surgery followed by a platinum based chemotherapy. Some patients do no...

20040 Background: The prognosis of patients with progressed breast cancer remains poor after intensive chemotherapy. Therefore new treatment options such as targeted therapies are needed. Imatinib Mesylate is a tyrosin kinase inhibitor targeting growth receptors like PDGF-R α and β, c-kit. These receptors and their downstream effectors trigger a cascade that regulates multiple cellular processes such as proliferation, differentiation and survival. The activity of the important downstream effector Akt leads to cell survival through inhibition of pro-apoptotic signals. We therefore evaluated the effects of Imatinib on of PDGFR β and Akt activity in breast cancer cell lines in vitro. We previously detected that Imatinib inhibits the growth of the breast cancer cell lines MDA MB 231, MCF 7, ZR 75–1 and T 47-D in vitro. Furthermore Imatinib induces apoptosis in these cell lines. Methods: To investigate effects on receptor activation, cells were stimulated with PDGF BB, the physiological ligand of PDGFR β. Phosphorylation of PDGFR β and Akt was examined after incubation with increasing concentrations of Imatinib by immunohistochemical and western blot assays. Imatinib concentrations from 2 μM to 10 μM were applied. Results: Imatinib Mesylate shows a dose dependent inhibitory effect on PDGFR β phosphorylation, determined by immunohistochemistry and western blot analysis. No changes in the expression pattern occured. The phosphorylation of the tyrosine kinase Akt can also be inhibited by Imatinib in a dose dependent manner. The expression of Akt remains also unchanged. Conclusions: It can be suggested that the growth inhibitory effect of Imatinib Mesylate on breast cancer cell lines is caused by a dose dependent decrease of activation in PDGFR β and Akt. The inhibition of Akt phosphorylation by Imatinib explains the induction of apoptosis. These interesting effects should be further validated in vivo in clinical trials. [Table: see text]

3210 Background: New targeted therapies for solid tumors are currently investigated in pre-clinical and clinical studies. For Imatinib mesylate activities in inhibiting selected tyrosine kinase rec...

3203 Background: In CML Imatinib mesylate is known to reduce cell growth by blocking the pathognomonic brc-abl oncoprotein. In several solid tumors Imatinib inhibits cell-growth by blocking signali...

• The proper management of the clinically negative neck in primary squamous cell carcinomas of the head and neck remains controversial. Although many clinicians believe that elective neck dissection or neck irradiation are equally effective for controlling subclinical disease, previous studies have not directly addressed this question. The charts of 195 patients with advanced primary squamous carcinoma, yet with clinically negative necks, were reviewed. There were no significant differences in the rates of neck cancer recurrence among the elective neck irradiation, dissection, and combined treatment groups. Elective neck irradiation and neck dissection in patients with clinically negative nodes seemed equivalent in their ability to control neck disease. The decision as to which form of therapy is preferable must therefore be based on other criteria. ( Arch Otolaryngol Head Neck Surg 1989;115:691-694)

Studies in man have proposed that individuals with adrenocorticoid insufficiency show a heightened auditory detection threshold. This hyperacuity was shown to be specific for deficits in carbohydrate-active steroids, with threshold levels improved at least 13 dB between 1,000 Hz and 4,000 Hz. These reversible changes in auditory detection have been related to specific influences of glucocorticoids on the metabolism of neural tissue. The present study was designed to examine the hypothesis that glucocorticoid deficiencies cause decreased electrocochleographically measured auditory thresholds with interference in the central conduction of these impulses. A rat model was employed in an attempt to demonstrate the mechanism for a state of increased neural excitability in the absence of carbohydrate-active steroid influence. Electrocochleographic and auditory brain-stem evoked response threshold and latency determinations were made in eight experimental rats. Adrenalectomies were then performed in all animals with postoperative electrocochleographic and auditory brain stem responses being made at 3, 7, and 21 days. Threshold recordings for all experimental animals showed no significant changes following the cessation of glucocorticoid production. Latency measurements revealed impaired central neural transmission of the first and second order neurons. The possible mechanisms for these findings are discussed.

Introduction Strategies to improve the efficacy of endocrine agents in breast cancer (BC) therapy and to delay the onset of resistance include concomitant targeting of the estrogen receptor alpha (ER) and the mammalian target of rapamycin complex 1 (mTORC1), which regulate cell-cycle progression and are supported by recent clinical results. Methods BC cell lines expressing aromatase (AROM) and modeling endocrine-sensitive (MCF7-AROM1) and human epidermal growth factor receptor 2 (HER2)-dependent de novo resistant disease (BT474-AROM3) and long-term estrogen-deprived (LTED) MCF7 cells that had acquired resistance associated with HER2 overexpression were treated in vitro and as subcutaneous xenografts with everolimus (RAD001-mTORC1 inhibitor), in combination with tamoxifen or letrozole. End points included proliferation, cell-cycle arrest, cell signaling, and effects on ER-mediated transactivation. Results Everolimus caused a concentration-dependent decrease in proliferation in all cell lines, which was associated with reductions in S6 phosphorylation. Everolimus plus letrozole or tamoxifen enhanced the antiproliferative effect and G1-accumulation compared with monotherapy, as well as increased phosphorylation (Ser10) and nuclear accumulation of p27 and pronounced dephosphorylation of Rb. Sensitivity was greatest to everolimus in the LTED cells but was reduced by added estrogen. Increased pAKT occurred in all circumstances with everolimus and, in the BT474 and LTED cells, was associated with increased pHER3. Decreased ER transactivation suggested that the effectiveness of everolimus might be partly related to interrupting cross-talk between growth-factor signaling and ER. In MCF7-AROM1 xenografts, letrozole plus everolimus showed a trend toward enhanced tumor regression, versus the single agents. In BT474-AROM3 xenografts, everolimus alone was equally effective at reducing tumor volume as were the combination therapies. Conclusions The results provide mechanistic support for recent positive clinical data on the combination of everolimus and endocrine therapy, as well as data on potential routes of escape via enhanced HER2/3 signaling. This merits investigation for further improvements in treatment efficacy.

Tympanostomy tube placement has clearly been shown to be an efficacious treatment for recurrent bouts of acute otitis media or chronic otitis media with effusion. However, there are few objective, prospective, randomized studies present in the literature to aid the clinical otolaryngologist with the proper tube choice for middle ear aeration. A prospective, randomized study was undertaken of four commonly used tympanostomy tubes. Shepard Teflon grommet, Armstrong beveled tube, Reuter-Bobbin tube, and Goode T-tube. This study was undertaken to determine which of these tubes had the fewest number of postplacement complications, including otorrhea, plugging, residual perforation, or chronic persistence in the tympanic membrane. Average follow-up was 17 months. The Shepard and Armstrong tubes showed a comparatively low rate of plugging and otorrhea. Both tubes had extrusion times that averaged less than 1 year. The Reuter-Bobbin tube had a much greater rate of plugging, compared to the other tubes. The T-tube had an increased incidence of otorrhea and persistence in the tympanic membrane well beyond 1 year. The T-tube was also the only tube in this study associated with residual perforations.

New strategies in the therapy for malignant diseases depend on a targeted influence on signal transduction pathways that regulate proliferation, cell growth, differentiation, and apoptosis by the activation of serine/threonine kinases. Enzastaurin (LY317615.HCl), a selective inhibitor of protein kinase Cbeta (PKCbeta), is one of these new drugs and causes inhibition of proliferation and induction of apoptosis. Pemetrexed, a multitarget inhibitor of folate pathways, is broadly active in a wide variety of solid tumors. Therefore, the effect of enzastaurin and the combination treatment with pemetrexed was analyzed when applied to the drug-sensitive ovarian cancer cell line HEY and various subclones with drug resistance against cisplatin, etoposide, docetaxel, and paclitaxel, as well as pemetrexed, and gemcitabine. In these novel chemoresistant subclones, the expression of the enzastaurin targets PKCbetaII and glycogen synthase kinase 3beta (GSK3beta) was analyzed. Exposition to enzastaurin showed various inhibitory effects on phosphorylated forms of GSK3beta and the mitogen-activated protein kinase extracellular signal-regulated kinase 1/2. Cell proliferation experiments identified the cell line-specific half-maximal inhibitory concentration values of enzastaurin and a synergistic inhibitory effect by cotreatment with the antifolate pemetrexed. Induction of apoptosis by enzastaurin treatment was investigated by Cell Death Detection ELISA and immunoblot analyses. Simultaneous treatment with pemetrexed resulted in an enhanced inhibition of proliferation and induction of apoptosis even in partial enzastaurin-resistant cells. Therefore, the combinational effect of enzastaurin and pemetrexed can have promise in clinical application to overcome the fast-growing development of resistance to chemotherapy in ovarian cancer.