Combined targeted therapies represent novel therapeutic approaches simultaneously acting on several specific molecular pathways in cancer. Patients not harboring driver mutations may benefit from such therapies, but identifying predictive biomarkers is paramount for proper patient selection. The phase II clinical trial SAKK 19/05 studied the safety and efficacy of combined first-line treatment with bevacizumab and erlotinib in unselected patients with NSCLC. Blood samples were taken in 43 non-squamous NSCLC patients at baseline and 24 h after the beginning of initiation of the combined bevacizumab/erlotinib targeted therapy. Messenger RNA was extracted and hybridized on Affymetrix GeneChip Human Exon 1.0 ST arrays. The early change in gene expression was investigated using dually constrained correspondence analysis. Validation of the prognostic value of our biomarkers was done using the online survival analysis software in NSCLC (KM-Plotter). The predictive value of the identified biomarkers was done on a targeted gene approach. Blood gene expression variations measured 24 h after initiation of targeted therapy indicate a direct effect on genes that belong to the KEGG pathway "Pathways in cancer". More specifically, a significant down-regulation was found in genes that are part of the cytokine-cytokine receptor interaction (IGF1R, IGF2R), MPAK signaling pathway (DAPK2, PLD1, MMP9), and mTOR signaling pathway (BIRC3). Although the magnitude of change over 24 h was not predicting patient's outcome, the level of gene expression at baseline and 24 h of ILR1, FLT3, PLD1, BIRC3, and IGF1R was predictive of the tumor shrinkage at week 12, and time-to-progression under targeted therapy, independent of EGFR mutational status. These findings were independently validated using the KM-Plotter webtool. Blood gene expression levels at baseline and 24 h after the initiation of bevacizumab/erlotinib provide potential novel biomarkers of the response to combined targeted therapy in advanced NSCLC.

Erlotinib is approved for patients with pretreated advanced NSCLC based on a 2-months overall survival (OS) improvement against placebo. Recently, 2 out of 3 prospective clinical studies showed a statistical trend for superior survival in patients with pretreated advanced NSCLC receiving chemotherapy versus erlotinib. We collected data of all patients with advanced NSCLC since the approval of erlotinib in 2005. Data included systemic treatment, prognostic covariates such as age, gender, presence of CNS metastases, smoking status, ECOG performance status, radiological response and survival. Primary study endpoint was OS, secondary study endpoint progression-free survival (PFS). We used Kaplan–Meier statistics, multivariate Cox regression and propensity score matching. The study had a power of 87% to detect a survival superiority of 30%. From 827 patients, we excluded 171 patients for potential curative treatment, 189 for treatment outside our hospital, 204 for <2 lines of palliative treatment, 28 with EGFR-mutations and 6 with EML-ALK translocations. The final analysis included 108 chemotherapy patients and 121 patients receiving erlotinib in second (85 patients), third (27) or further-line (9). Women and never smokers were significantly overrepresented in the erlotinib group. OS was similar in erlotinib and chemotherapy patients, both from start of first-line (15.1 vs. 13.8 months, HR = 0.95, P = 0.70) and from start of second-line treatment (7.8 vs. 5.0 months, HR = 0.78, P = 0.08). Survival remained similar after adjustment for known prognostic factors. PFS was not different between groups, neither in first-, second- or third-line. EGFR genotyping was not done in 145 patients with squamous-cell histology, and was unknown in 27 out of 84 patients with non squamous-cell histology; all remaining patients were carriers of EGFR wildtype. No radiological response or long-term stabilization was found in patients under treatment with erlotinib, suggesting a low probability for the presence of EGFR mutations. We found chemotherapy not to be superior to erlotinib in pretreated patients with advanced NSCLC.

HNSCC pts often need a PEG during their disease. While PEG is studied in depth for locally advanced disease, this is not the case for r/mHNSCC, where therapeutic PEG it supposed to compensate for impaired swallowing, aspiration and to improve the patient's nutrition status with a potential positive effect on outcome. We retrospectively analyzed patients with r/mHNSCC referred for palliative systemic treatment between 2005 and 2015. Patients, disease and treatment characteristics were assessed, including the presence of PEG at the start of 1st-line systemic therapy. Known prognostic factors according to Argiris et al were assessed and considered for analysis. Correlation between survival and PEG status was calculated using Kaplan-Meier method and multivariate Cox regression models. We included 110pts in our analysis. 100pts received first-line therapy. Forty-two patients (42%) had a PEG at the time of palliative 1st-line systemic treatment. Mean age was 61years (range 38-85). 84% of pts were male and 16% female. 80% had an ECOG PS of 0 or 1. Oropharynx, oral cavity, larynx and hypopharynx were the primary cancer sites in 29, 26, 20 and 16% respectively, with 9% other sites. Median survival from start of 1st line systemic treatment was 8.0months (95% CI, 6.5-12.0months). ECOG PS was the strongest prognostic factor in our cohort (HR = 2.55, p < 0.001). Overall survival was 4.5months (95% CI, 6.1-11.7months) for pts with PEG and 11.5months (95% CI, 10.9-16.9months) without PEG (adjusted HR = 1.98, P = 0.11). Survival from first occurrence of distant metastases was significantly lower in PEG carriers as compared to patients without a PEG (7.5 v 15.5 months, adjusted HR = 2.60, P < 0.001). The presence of PEG feeding tubes in patients with r/mHNSCC is an independent negative prognostic factor. Currently applied prognostic factors could be insufficient for an adequate adjusted multivariate analysis in r/mHNSCC. Presence or placement of PEG does not seem to prolong survival in this advanced patient population. These data is hypothesis generating. The impact can be important and outweigh other survival benefits due to systemic therapy.

Background: Recurrent triple-negative breast cancer (TNBC) is a condition of high unmet medical need, due to its aggressive biology, fast development of drug resistance, and lack of molecular targets. Until now, chemotherapy remains the standard of care for advanced TNBC, with a poor median overall survival. Recently, pharmacological aggravation of endoplasmic reticulum stress (ERS) has become an attractive strategy not only for multiple myeloma, but also for solid malignancies. Methods: We determined the cytotoxic activity of proteasome inhibitors (bortezomib, bzb; carfilzomib, cfz) alone and in combination with the two HIV protease inhibitors nelfinavir (nel) and lopinavir (lop) in three different TNBC cell lines (BT 549, MDA-MB 231, MDA-MB 468). To assess cytotoxicity, the 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTS) assay was applied. Results: Both proteasome inhibitors moderately reduced cell survival in all TNBC cell lines at clinically relevant concentrations (125 nM) when applied alone (21%–44%). At increased concentrations (1 uM), the irreversible proteasome inhibitor cfz exhibited even higher cytotoxicity (>80%) than bzb (>60%) in all tested cell lines. Importantly, combinations with HIV protease inhibitors yielded significantly enhanced cytotoxicity and mostly synergistic responses in all cell lines compared with either proteasome (table: cytotoxic effects of mono and combination experiments) or HIV protease inhibitors alone. Moreover, preliminary data using combinations with other HIV protease inhibitors showed similar cytotoxic effects. Conclusions: Drug combinations of the irreversible proteasome inhibitor carfilzomib and HIV protease inhibitors such as lopinavir or nelfinavir resulted in substantial cytotoxicity in preclinical models of TNBC. The concept of pharmacological aggravation of ERS is promising in patients with TNBC, and a respective phase1B-2 clinical study is in early planning.Tabled 1Bzb/-Bzb/NelBzb/LopCfz/-Cfz/NelCfz/LopMDA-MB 46827 +/- 890 +/- 284 +/- 121 +/- 788 +/- 284 +/- 4MDA-MB 23136 +/- 887 +/- 585 +/- 0.241 +/- 287 +/- 485 +/- 4BT54923 +/- 392 +/- 180 +/- 0.244 +/- 392 +/- 185 +/- 4(% cell death +/- SD) Open table in a new tab (% cell death +/- SD) Disclosure: All authors have declared no conflicts of interest.

The 11th St. Gallen consensus meeting on the primary treatment of early breast cancer put a special emphasis on a tailored approach for patient subgroups, and by the selection of targetted treatments according to tumour biology. Sentinel node procedure was considered as the standard in invasive breast cancer with no clinical evidence of lymph node involvement. Concerning ductal carcinoma in situ (DCIS), the panellists voted for adjuvant radiotherapy to be considered standard for excised DCIS, but irradiation might be avoided in the elderly and in patients with low-grade DCIS. Accelerated whole breast radiotherapy was considered an acceptable optional after tumour excision, especially in patients above the age of 60 years. Furthermore, the panel supported validated multigene assays to be considered as an additional tool for choosing chemotherapy in endocrine-responsive disease. Concerning endocrine treatment, the panellists preferred upfront endocrine therapy with an aromatase inhibitor on the basis of the updated results of BIG 1-98, especially for cases with high risk of early recurrence. Changing the aromatase inhibitor to tamoxifen after 2 years of treatment was accepted as a treatment option. Finally, dose-dense doxorubicin/cyclophosphamide chemotherapy followed by paclitaxel, and docetaxel/cyclophosphamide were added to the group of standard adjuvant regimens.

A liquid chromatography-tandem mass spectrometric assay for the determination of uracil, 5,6-dihydrouracil and beta-ureidopropionic acid in urine was developed to measure the activities of enzymes involved in pyrimidine breakdown. The assay was required to investigate the relation between the uracil-dihydrouracil ratio and toxicities observed after treatment with fluoropyrimidines drugs. After addition of stable isotopically labelled internal standards, the analytes were isolated from a 100-microl urine sample using liquid-liquid extraction with ethyl acetate-2-propanol. Compounds were separated on an Atlantis dC18 column, using ammonium acetate-formic acid in water as the eluent. The eluate was totally led into an electrospray interface with positive ionisation and the analytes were quantified using triple quadrupole mass spectrometry. The assay was validated in the range 1.6-1600 microM, using both, artificial urine and pooled urine as matrices. Intra-day precisions were < or = 8% and inter-day precisions were < or = 10%. Accuracies between 91 and 108% were found. The analytes were chemically stable under all relevant conditions and the assay was successfully applied in two clinical studies of cancer patients treated with 5-fluorouracil or capecitabine.

This contribution addresses both the general mid-infrared (MIR) properties of Cu2O and induced absorption due to intraexcitonic 1s -> 2p transitions under simultaneous cw laser excitation. After an overview of the current state of knowledge and remaining open questions concerning excitons in Cu2O we will first discuss several absorption bands in the spectral range between approximately 100 and 150 meV in terms of multiphonon and biphonon features. The second, more extensive part will concern a pump-probe experiment in the limit of low densities of 1s excitons where we investigated intraexcitonic transitions appearing in the MIR spectral range as well. We find a signal which can be clearly assigned to a 1s para -> 2p para transition and present various data depending on excitation conditions and sample temperature. Applying the results of detailed theoretical considerations we can estimate the density and lifetime of the 1s para-exciton and at least speculate about its dispersion.

In a cw differential absorption experiment, we examined infrared transitions of excitons in Cu2O. We find a clear transition which is assigned to induced 1s para→2p para absorption. Line shape and intensity of induced absorption are analysed as a function of temperature and excitation conditions.

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This contribution consists of several parts. In a first part we discuss transport measurements of excitons in Cu2O, their detection by spatially and temporally resolved pump-and-probe beam spectroscopy and by field ionization in a Schottky barrier; in the next one we report on transitions from the 1s para to the 2p para exciton state observed in visible pump-IR probe spectroscopy and finally we discuss qualitatively a phase diagram for bulk semiconductors including excitonic Bose–Einstein condensation and the transition to an electron–hole plasma.

A photocurrent signal and its temporal dependence on the excitation conditions observed in a Cu/Cu2O Schottky barrier after pulsed illumination of the Cu2O crystal has been used to claim excitonic super-fluidity and Bose-Einstein condensation. See, e.g., E. Benson, E. Fortin, and A. Mysyrowicz [phys. stat. sot. (b) 191, 345 (1995)]. C. Klingshirn, T. Fleck, and M. Jorger [phys. stat. sot. (b) 234, 23 (2002)] showed that a similar behaviour can be expected also from detector saturation which is very likely for the excitation conditions used in the above work. In the above comment [phys. stat. sot. (b) 239, 257 (2003)], these arguments have been rejected, based on new experiments under resonant exciton creation. In this response we show that the excitation conditions used in these new experiments do not allow to question the statements in favour of detector saturation, but raise some additional questions. (C) 2003 WILEY-VCH Veriag GmbH & Co. KGaA, Weinheim.

In a differential absorption experiment the induced infrared transitions from the excitonic 1s to the 2p levels in Cu2O have been investigated. Intermediate densities of 1s excitons were created by cw-laser excitation while the interexcitonic 1s to 2p transitions were probed simultaneously, using Fourier spectroscopy. Our data give evidence for a surprisingly large splitting of the 2p level (approximate to 3.7 meV) the origin of which is a matter of speculation. An analysis of lineshape and width of the transitions results in a ratio of the effective masses m(1s)/m(2p) which deviates from the literature value. (C) 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The possibility of Bose-Einstein condensation of excitons in semiconductors and/or their superfluid transport are long-standing, still controversially discussed problems. In a recent series of experiments by E. Fortin and coworkers [1-3] [phys. stat. sol. (b) 191, 345 (1995); Phys. Rev. Lett. 77, 896 (1996); and Proc. Internat. Conf, Exciton Processes in Condensed Matter, World Scientific, Singapore 2000, respectively], (para-)excitons in Cu2O have been detected electrically by their field ionization in a Schottky barrier. We analyze the electric field in the Schottky barrier and its screening by the holes remaining after field ionization and find serious screening and saturation effects of this Schottky-barrier exciton detector under the excitation conditions of the experiment. These findings make a reinterpretation of the data very likely.

Differential absorption spectroscopy shows a characteristic dependence on the density of 1s excitons in Cu2O at low temperature. The relation between absorption change and 1s exciton density is established and calibrated using one- and two-photon excitation. The calibrated density evaluation is applied to exciton transport measurements in a quasi-one-dimensional sample geometry. A numerical simulation of the transport yields extremely long exciton lifetimes of up to 3 ms. The Auger recombination of excitons is almost negligible, contrary to previous estimates. A deviation of the transport characteristics from the diffusive regime was not observed.

In cubic CdS/ZnSe type-II heterostructures collective excitations have been studied using infrared spectroscopy. The CdS/ZnSe structures were grown by solid-source molecular-beam epitaxy on semi-insulating GaAs substrates. Highly n-type-doped multiple-quantum-well and superlattice samples show strong intersubband and interminiband absorption in the midinfrared. The validity of the polarization selection rule is verified experimentally. The CdS/ZnSe conduction band offset is determined using a combination of interband and intersubband spectroscopy. Measured transition energies agree well to model calculations if many-body effects and band nonparabolicity are included. Intensity-dependent pump and probe measurements on doped and undoped samples reveal a fast increase of the photoinduced absorption signal at low pump intensities. At high pump intensities the absorption signal saturates. This behavior is explained by the existence of a subgroup of long-lived photogenerated electron-hole pairs. An observed redshift of the photoinduced interminiband transitions is explained by filling of the lowest miniband. The effective electron mass of cubic CdS is determined from thick films using infrared reflection spectroscopy.