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Breast carcinoma with neuroendocrine differentiation, also known as neuroendocrine breast carcinoma (NEBC), includes a heterogeneous group of rare tumors, which account for 2–5% of all invasive breast carcinomas. Because of their low incidence, most of the current limited knowledge of these tumors derives from anecdotal case reports or small retrospective series. The diagnosis of NEBC is based on the presence of morphological features similar to gastrointestinal and lung NETs and neuroendocrine markers. NEBCs are usually hormone receptors positive and HER2 negative, but despite this luminal phenotype, most recent studies suggested that NEBC could be associated with worse prognosis compared to invasive breast cancer without neuroendocrine differentiation. Due to its rarity and lack of randomized data, there is little evidence to guide the choice of treatment, so NEBC is currently treated as any invasive breast carcinoma not-otherwise specified. Recently, attempts to molecularly characterize NEBC have been made, in order to provide new targets for a more personalized treatment of this uncommon entity.

New therapies for advanced adrenocortical carcinoma (ACC) are urgently needed, as the majority of the patients experience a rapid and inexorable progression despite surgery and adjuvant mitotane. In vitro data suggest that somatostatin receptors (SSTRs) and mTOR pathway might represent reasonable targets for novel therapies, being involved in functionality and growth of ACC cells. However, in vitro analysis of combination treatments targeting both mTOR and SSTR as compared to mitotane are poorly explored in ACC. This study aimed to investigate in vitro the effects on cell growth of pasireotide, everolimus, and mitotane, alone or combined, in the two ACC cell lines H295R and SW13 (mitotane sensitive and resistant, respectively). Moreover, the tissue expression of mTOR pathway molecules and SSTR (types 1-5) was assessed in 58 ACCs. In both cell lines, only everolimus induced a significant inhibition of cell growth. Conversely, the combinations among mitotane, pasireotide, and everolimus produced antagonistic effects on mitotane-induced growth inhibition on H295R cell line. A heterogeneous profile of mTOR-related molecules and SSTR expression was observed in ACC samples, being the mTOR pathway found activated in approximately 30% of cases. In conclusion, our data suggest caution in designing combinations of mitotane with other drugs potentially active in ACC, such as mTOR inhibitors or somatostatin analogs.

Implantation and maintenance of a permanent cardiac pacing system in children remains challenging due to small patient size, congenital heart defects and somatic growth. We are developing a novel epicardial micropacemaker for children that can be implanted on the epicardium within the pericardial space via a minimally-invasive technique. The key design configurations include a novel open-coiled lead in which living tissue replaces the usual polymeric support for the coiled conductor. To better understand and be able to predict the behavior of the implanted lead, we performed a radiographic image-based modeling study on a chronic animal test. We report a pilot study in which two mechanical dummy pacemakers with epicardial leads were implanted into an adult pig model via a minimally invasive approach. Fluoroscopy was obtained on the animal on Post-Operative Days #9, #35 and #56 (necropsy). We then constructed an analytic model to estimate the in vivo stress conditions on the open-coil lead based on the analysis of orthogonal biplane radiographic images. We obtained geometric deformation data of the implanted lead including elongation magnitudes and bending radii from sequenced films of cardiac motion cycles. The lead stress distribution was investigated on each film frame and the point of maximum stress (Mean Stress = 531.4 MPa; Alternating Stress = ± 216.4 MPa) was consistently where one of the leads exited the pericardial space, a deployment that we expected to be unfavorable. These results suggest the modeling approach can provide a basis for further design optimization. More animal tests and modeling will be needed to validate whether the novel lead design could meet the requirements to withstand ~200 million cardiac motion cycles over 5 years.

Introduction LY2603618 is a selective inhibitor of checkpoint kinase 1 (CHK1) protein kinase, a key regulator of the DNA damage checkpoint, and is predicted to enhance the effects of antimetabolites, such as pemetrexed. This phase II trial assessed the overall response rate, safety, and pharmacokinetics (PK) of LY2603618 and pemetrexed in patients with non-small cell lung cancer (NSCLC). Methods In this open-label, single-arm trial, patients with advanced or metastatic NSCLC progressing after a prior first-line treatment regimen (not containing pemetrexed) and Eastern Cooperative Oncology Group performance status ≤2 received pemetrexed (500 mg/m(2), day 1) and LY2603618 (150 mg/m(2), day 2) every 21 days until disease progression. Safety was assessed using Common Terminology Criteria for Adverse Events v3.0. Serial blood samples were collected for PK analysis after LY2603618 and pemetrexed administration. Expression of p53, as measured by immunohistochemistry and genetic variant analysis, was assessed as a predictive biomarker of response. Results Fifty-five patients were enrolled in the study. No patients experienced a complete response; a partial response was observed in 5 patients (9.1 %; 90 % CI, 3.7-18.2) and stable disease in 20 patients (36.4 %). The median progression-free survival was 2.3 months (range, 0-27.1). Safety and PK of LY2603618 in combination with pemetrexed were favorable. No association between p53 status and response was observed. Conclusions There was no significant clinical activity of LY2603618 and pemetrexed combination therapy in patients with advanced NSCLC. The results were comparable with historical pemetrexed single-agent data, with similar safety and PK profiles being observed.

Bone complications of metastatic disease, including skeletal-related events (SREs), impair patients' functioning and quality of life. In a randomized, phase 3 trial of 1,776 patients with metastases from solid tumors (except breast or prostate) or multiple myeloma, denosumab was non-inferior to zoledronic acid (ZA) in delaying or preventing SREs. This ad hoc analysis reports outcomes in the subgroup of 1,597 patients with solid tumors, excluding patients with multiple myeloma. Patients received monthly subcutaneous denosumab 120 mg or intravenous ZA 4 mg, adjusted for creatinine clearance, with calcium and vitamin D supplementation recommended. Endpoints included times to first on-study SRE, first-and-subsequent SREs, and pain worsening. Denosumab significantly delayed time to first on-study SRE compared with ZA (HR, 0.81; 95 % CI, 0.68–0.96) and time to first-and-subsequent SREs (RR, 0.85; 95 % CI, 0.72–1.00). Denosumab also significantly delayed time to development of moderate or severe pain (HR, 0.81; 95 % CI, 0.66–1.00), pain worsening (HR, 0.83; 95 % CI, 0.71–0.97), and worsening pain interference in patients with no/mild baseline pain (HR, 0.77; 95 % CI, 0.61–0.96). Adverse event rates were 96 % in both groups. Grade 3 or 4 hypocalcemia, mostly without clinical sequelae, was more frequent in denosumab-treated patients (denosumab 4 %, ZA 2 %). Osteonecrosis of the jaw occurred infrequently (denosumab 0.8 %, ZA 1.1 %). Denosumab was more effective in delaying or preventing SREs in patients with bone metastases from solid tumors and also prevented pain progression compared to ZA in this ad hoc analysis.

Bronchioloalveolar carcinoma (BAC) is a subtype of adenocarcinoma with unique epidemiology, pathology, clinical features, radiographic presentation, and natural history compared with other non-small cell lung cancer (NSCLC) subtypes. According to criteria of the revised 2004 World Health Organization classification it accounts for only 5% of all cases of NSCLC. BAC cases are mostly represented by females and non-smokers and are diagnosed at a younger age. Patients with resected BAC have prolonged survival and a lower recurrence rate after surgical resection than other NSCLC subtypes. In advanced BAC cytotoxic chemotherapy seems as effective as in other NSCLC, although studies on pure BAC are based on small numbers of patients and mainly tested paclitaxel based regimens on preclinical activity on cell lines. A higher than expected response rate to the epidermal growth factor (EGFR) tyrosine kinase inhibitors gefitinib and erlotinib was recorded in BAC or in adenocarcinomas with BAC features compared with other NSCLC subtypes, mainly due to a higher rate of never-smoking patients. In fact, these agents demonstrated activity in the first-line setting especially in patients harboring EGFR mutations. The role of molecular predictors of response and survival such as EGFR gene amplification or EGFR mutations is an open field of research in fine-tuning BAC management. New drugs are being tested in advanced BAC, while more prospective data must be collected on predictive and prognostic factors.

High precision U–Pb geochronology of rutile from quartz–carbonate–white mica–rutile veins that are hosted within eclogite and schist of the Monte Rosa nappe, western Alps, Italy, indicate that the Monte Rosa nappe was at eclogite-facies metamorphic conditions at 42.6 ± 0.6 Ma. The sample area [Indren glacier, Furgg zone; Dal Piaz (2001) Geology of the Monte Rosa massif: historical review and personal comments. SMPM] consists of eclogite boudins that are exposed inside a south-plunging overturned synform within micaceous schist. Associated with the eclogite and schist are quartz–carbonate–white mica–rutile veins that formed in tension cracks in the eclogite and along the contact between eclogite and surrounding schist. Intrusion of the veins at about 42.6 Ma occurred at eclogite-facies metamorphic conditions (480–570°C, >1.3–1.4 GPa) based on textural relations, oxygen isotope thermometry, and geothermobarometry. The timing of eclogite-facies metamorphism in the Monte Rosa nappe determined in this study is identical to that of the Gran Paradiso nappe [Meffan-Main et al. (2004) J Metamorphic Geol 22:261–281], confirming that these two units have shared the same Alpine metamorphic history. Furthermore, the Gran Paradiso and Monte Rosa nappes underwent eclogite-facies metamorphism within the same time interval as the structurally overlying Zermatt-Saas ophiolite [∼50–40 Ma; e.g., Amato et al. (1999) Earth Planet Sci Lett 171:425–438; Mayer et al. (1999) Eur Union Geosci 10:809 (abstract); Lapen et al. (2003) Earth Planet Sci Lett 215:57–72]. The nearly identical P–T–t histories of the Gran Paradiso, Monte Rosa, and Zermatt-Saas units suggest that these units shared a common Alpine tectonic and metamorphic history. The close spatial and temporal associations between high pressure (HP) ophiolite and continental crust during Alpine orogeny indicates that the HP internal basement nappes in the western Alps may have played a key role in exhumation and preservation of the ophiolitic rocks through buoyancy-driven uplift. Coupling of oceanic and continental crust may therefore be critical in preventing permanent loss of oceanic crust to the mantle.

Background: In diagnostic pathology, HER2 status is determined in interphase nuclei by fluorescence in situ hybridization (FISH) with probes for the HER2 gene and for the chromosome 17 centromere (CEP17). The latter probe is used as a surrogate for chromosome 17 copies, however chromosome 17 (Chr17) is frequently rearranged. The frequency and type of specific structural Chr17 alterations in breast cancer have been studied by using comparative genomic hybridization and spectral karyotyping, but not fully detailed. Actually, balanced chromosome rearrangements (e.g. translocations or inversions) and low frequency mosaicisms are assessable on metaphases using G-banding karyotype and multicolor FISH (M-FISH) only. Methods: We sought to elucidate the CEP17 and HER2 FISH patterns of interphase nuclei by evaluating Chr17 rearrangements in metaphases of 9 breast cancer cell lines and a primary culture from a triple negative breast carcinoma by using G-banding, FISH and M-FISH. Results: Thirty-nine rearranged chromosomes containing a portion of Chr17 were observed. Chromosomes 8 and 11 were the most frequent partners of Chr17 translocations. The lowest frequency of Chr17 abnormalities was observed in the HER2-negative cell lines, while the highest was observed in the HER2-positive SKBR3 cells. The MDA-MB231 triple negative cell line was the sole to show only non-altered copies of Chr17, while the SKBR3, MDA-MB361 and JIMT-1 HER2-positive cells carried no normal Chr17 copies. True polysomy was observed in MDA-MB231 as the only Chr17 alteration. In BT474 cells polysomy was associated to Chr17 structural alterations. By comparing M-FISH and FISH data, in 8 out of 39 rearranged chromosomes only CEP17 signals were detectable, whereas in 14 rearranged chromosomes HER2 and STARD3 genes were present without CEP17 signals. HER2 and STARD3 always co-localized on the same chromosomes and were always co-amplified, whereas TOP2A also mapped to different derivatives and was co-amplified with HER2 and STARD3 on SKBR3 cells only. Conclusion: The high frequency of complex Chr17 abnormalities suggests that the interpretation of FISH results on interphase nuclei using a dual probe assay to assess gene amplification should be performed 'with caution', given that CEP17 signals are not always indicative of normal unaltered or rearranged copies of Chr17. © 2014 Rondón-Lagos et al.

Can advanced non-small-cell lung cancer be treated with weekly instead of 3-weekly docetaxel?

Rat liver plasma membranes contain F(O)F(1) complexes (ecto-F(O)F(1)) displaying a similar molecular weight to the mitochondrial F(O)F(1) ATP synthase, as evidenced by Blue Native PAGE. Their ATPase activity was stably reduced in short-term extra-hepatic cholestasis. Immunoblotting and immunoprecipitation analyses demonstrated that the reduction in activity was not due to a decreased expression of ecto-F(O)F(1) complexes, but to an increased level of an inhibitory protein, ecto-IF(1), bound to ecto-F(O)F(1). Since cholestasis down regulates the hepatic uptake of HDL-cholesterol, and ecto-F(O)F(1) has been shown to mediate SR-BI-independent hepatic uptake of HDL-cholesterol, these findings provide support to the hypothesis that ecto-F(O)F(1) contributes to the fine control of reverse cholesterol transport, in parallel with SR-BI. No activity change of the mitochondrial F(O)F(1) ATP synthase (m-F(O)F(1)), or any variation of its association with m-IF(1) was observed in cholestasis, indicating that ecto-IF(1) expression level is modulated independently from that of ecto-F(O)F(1), m-IF(1) and m-F(O)F(1).

The role of the integral inner membrane subunit e in self-association of F0F1ATP synthase from bovine heart mitochondria was analyzed by in situ limited proteolysis, blue native PAGE/iterative SDS-PAGE, and LC-MS/MS. Selective degradation of subunit e, without disrupting membrane integrity or ATPase capacity, altered the oligomeric distribution of F 0F1ATP synthase, by eliminating oligomers and reducing dimers in favor of monomers. The stoichiometry of subunit e was determined by a quantitative MS-based proteomics approach, using synthetic isotope-labelled reference peptides IAQL*EEVK, VYGVGSL*ALYEK, and ELAEAQEDTIL*K to quantify the b, γ and e subunits, respectively. Accuracy of the method was demonstrated by confirming the 1:1 stoichiometry of subunits γ and b. Altogether, the results indicate that the integrity of a unique copy of subunit e is essential for self-association of mammalian F0F1ATP synthase. © 2008 Springer Science+Business Media, LLC.