[Tyrosine kinase inhibitor-associated choroidopathy]. / Tyrosinkinaseinhibitor-assoziierte Choroidopathie.

A 66-year-old male patient presented to the ophthalmology department with bilateral blurred vision, which had persisted for 1 week. Due to a pulmonary melanoma metastasis, the patient received a combination treatment with dabrafenib and trametinib. At the first presentation visual acuity was 1.2 on the right and 1.0 on the left. A normotensive intraocular pressure was measured in both eyes. Fundoscopy showed bilateral white, areolar alterations in the choroid and choroid folds and in the left eye a bullous choroidal detachment. Bilateral neurosensory detachment and subretinal fluid were found in optical coherence tomography (OCT). After reduction of the local treatment for pressure reduction and under local and systemic anti-inflammatory treatment, the choroidal swelling was progressive, the visual acuity dropped to 0.5 in the right and to 0.1 in the left eye. A significant regression of the findings occurred only after pausing the treatment with trametinib. Visual acuity rose to 1.0 (left) and 0.8 (right). The OCT showed a dry macula on the right and a small amount of residual subretinal fluid in the left eye.

Publisher Correction: Imaging the square of the correlated two-electron wave function of a hydrogen molecule.

The original version of this Article contained an error in the fifth sentence of the first paragraph of the 'Application on H2' section of the Results, which incorrectly read 'The role of electron correlation is quite apparent in this presentation: Fig. 1a is empty for the uncorrelated Hartree-Fock wave function, since projection of the latter wave function onto the 2pσu orbital is exactly zero, while this is not the case for the fully correlated wave function (Fig. 1d); also, Fig. 1b, c for the uncorrelated description are identical, while Fig. 1e, f for the correlated case are significantly different.' The correct version replaces 'Fig. 1e, f' with 'Fig. 2e and f'.

Imaging the square of the correlated two-electron wave function of a hydrogen molecule.

The toolbox for imaging molecules is well-equipped today. Some techniques visualize the geometrical structure, others the electron density or electron orbitals. Molecules are many-body systems for which the correlation between the constituents is decisive and the spatial and the momentum distribution of one electron depends on those of the other electrons and the nuclei. Such correlations have escaped direct observation by imaging techniques so far. Here, we implement an imaging scheme which visualizes correlations between electrons by coincident detection of the reaction fragments after high energy photofragmentation. With this technique, we examine the H2 two-electron wave function in which electron-electron correlation beyond the mean-field level is prominent. We visualize the dependence of the wave function on the internuclear distance. High energy photoelectrons are shown to be a powerful tool for molecular imaging. Our study paves the way for future time resolved correlation imaging at FELs and laser based X-ray sources.

Two-Particle Interference of Electron Pairs on a Molecular Level.

We investigate the photodouble ionization of H_{2} molecules with 400 eV photons. We find that the emitted electrons do not show any sign of two-center interference fringes in their angular emission distributions if considered separately. In contrast, the quasiparticle consisting of both electrons (i.e., the "dielectron") does. The work highlights the fact that nonlocal effects are embedded everywhere in nature where many-particle processes are involved.

Delocalization of a Vacancy across Two Neon Atoms Bound by the van der Waals Force.

We experimentally study 2p photoionization of neon dimers (Ne_{2}) at a photon energy of hν=36.56 eV. By postselection of ionization events which lead to a dissociation into Ne^{+}+Ne we obtain the photoelectron angular emission distribution in the molecular frame. This distribution is symmetric with respect to the direction of the charged vs neutral fragment. It shows an inverted Cohen-Fano double slit interference pattern of two spherical waves emitted coherently but with opposite phases from the two atoms of the dimer.

Evolution of interatomic Coulombic decay in the time domain.

During the past 15 years a novel decay mechanism of excited atoms has been discovered and investigated. This so-called interatomic Coulombic decay (ICD) involves the chemical environment of the electronically excited atom: the excitation energy is transferred (in many cases over long distances) to a neighbor of the initially excited particle usually ionizing that neighbor. It turned out that ICD is a very common decay route in nature as it occurs across van der Waals and hydrogen bonds. The time evolution of ICD is predicted to be highly complex, as its efficiency strongly depends on the distance of the atoms involved and this distance typically changes during the decay. Here we present the first direct measurement of the temporal evolution of ICD using a novel experimental approach.

Vibrationally resolved decay width of interatomic Coulombic decay in HeNe.

We investigate the ionization of HeNe from below the He 1s3p excitation to the He ionization threshold. We observe HeNe+ ions with an enhancement by more than a factor of 60 when the He side couples resonantly to the radiation field. These ions are an experimental proof of a two-center resonant photoionization mechanism predicted by Najjari et al. [Phys. Rev. Lett. 105, 153002 (2010)]. Furthermore, our data provide electronic and vibrational state resolved decay widths of interatomic Coulombic decay in HeNe dimers. We find that the interatomic Coulombic decay lifetime strongly increases with increasing vibrational state.

Impact of quality of life parameters and coping strategies on postchemotherapy nausea and vomiting.

To assess whether prechemotherapy quality of life (QoL) factors and certain coping strategies are associated with postchemotherapy nausea and vomiting (PCNV). A total of 43 chemotherapy-naïve patients scheduled to receive anti-emetic prophylaxis were enrolled in this study. QoL parameters were measured by a modified EORTC Quality of Life Questionnaire (QLQ-30). In addition, questions regarding active or passive coping strategies were asked 1 day before chemotherapy. Prechemotherapy QoL factors, coping strategies as well as other patient, disease and treatment variables were compared between the groups of patients with or without PCNV. The univariate analysis identified four QoL parameters, 'tiredness', 'impairment of daily life by pain', 'sensation of abdominal pressure and fullness' and 'impairment of social activities' as associated with PCNV. No association was found between coping strategies and PCNV. In the multivariate analysis, the factors 'impairment of social activities' and 'sensation of abdominal pressure and fullness' remained significant. Specific pretreatment QoL parameters are associated with the risk to develop PCNV. Thus, in addition to other established risk factors for PCNV, patients should be screened for these QoL factors in order to improve the control of PCNV and facilitate the selection of appropriate, individualised anti-emetic prophylaxes.

Impact of cytokine- and FasL-induced apoptosis in the beta-cell line NIT-1.

Cytokine- and FasL-induced pathways contribute to beta-cell death in type 1 diabetes. It remains unclear, however, whether pro-apoptotic cyto-kines or FasL have more apoptotic impact. Cytokine- and FasL-induced apoptosis were simulated using IL-1beta/IFN-gamma, Super-FasLigand and the beta-cell line NIT-1. The role of caspases was addressed using the general caspase inhibitor ZVAD. Exposure to IL-1beta/IFN-gamma induced NIT-1 cell death. FasL augmented cytokine-induced cell death accompanied by increased caspase-3 activation, DNA fragmentation, and chromatin condensation. However, FasL mediated comparable effects on the mitochondrial transmembrane potential (Deltapsi (m)) and nitrite in cytokine- and untreated cells. The cytokine-induced sequence of apoptotic events was (1) Fas, nitrite, (2) Deltapsi (m), (3) DNA fragmentation, cell death, and (4) chromatin condensation. In the presence of FasL, cell death and chromatin condensation appeared earlier implicating a compression of the apoptotic time course. General caspase inhibition using ZVAD prevented cell death, Deltapsi (m), and DNA fragmentation; however, Fas expression and nitrite were increased. In conclusion, cytokines account for the major part of cell death induced by the simultaneously action of FasL + IL-1beta/IFN-gamma. Caspases are of central importance for beta-cell death.

HPLC-ESI-MS/MS determination of zuclopenthixol in a fatal intoxication during psychiatric therapy.

The first non-suicidal fatality due to intramuscular administration of Cisordinol (zuclopenthixol, ZPT) is described. A new, rapid, and sensitive method for the determination of ZPT in postmortem specimens has been developed. High performance liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) was employed for drug confirmation and quantitation. Sample clean up was performed using a simple liquid-liquid extraction procedure. The postmortem concentration of ZPT in heart blood was 0.68 microg/ml. Furthermore, zotepine, carbamazepine, and chlorprotixene were detected in body fluids. The proposed method enables the unambiguous identification and quantitation of ZPT and other neuroleptic drugs in clinical and forensic specimens.

Estimates of alcohol use and clinical treatment needs among homosexually active men and women in the U.S. population.

Concerns about dysfunctional alcohol use among lesbians and gay men are longstanding. The authors examined alcohol use patterns and treatment utilization among adults interviewed in the 1996 National Household Survey on Drug Abuse. Sexually active respondents were classified into 2 groups: those with at least 1 same-gender sexual partner (n = 194) in the year prior to interview and those with only opposite-gender sexual partners (n = 9,714). The authors compared these 2 groups separately by gender. For men, normative alcohol use patterns or morbidity did not differ significantly between the 2 groups. However, homosexually active women reported using alcohol more frequently and in greater amounts and experienced greater alcohol-related morbidity than exclusively heterosexually active women. Findings suggest higher risk for alcohol-related problems among lesbians as compared with other women, perhaps because of a more common pattern of moderate alcohol consumption.

The role of insulin-like growth factor I and its receptor in cell growth, transformation, apoptosis, and chemoresistance in solid tumors.

Insulin-like growth factor I (IGF-I) exerts pleiotropic effects on mammalian cells via stimulation of its receptor (IGF-IR), a receptor tyrosine kinase. In vivo, IGF-I acts both as a local tissue growth factor and as a circulating hormone. In oncological research, IGF-I has received increased attention as the activated IGF-I/IGF-IR system displays mitogeneic, transforming, and anti-apoptotic properties in various cell types by stimulating distinct intracellular signaling pathways. Recent data suggest that the anti-apoptotic effect of IGF-I may mediate decreased sensitivity to chemotherapeutic drugs in vitro and in vivo. Thus, targeting the IGF-I/IGF-IR system could serve as an approach to overcome clinical drug resistance in certain tumors.

[Diagnostic and therapeutic management of the superior vena cava syndrome]. / Diagnostisches und therapeutisches Management der oberen Einflussstauung.

BACKGROUND: Superior vena cava syndrome (SVCS) is the clinical expression of obstruction of blood flow through the superior caval vein. In more than 80% of patients this complication is due to a malignant tumor, and in 60% of cases the first symptom of this tumor. DIAGNOSIS AND TREATMENT: If the clinical course of SVCS represents an absolute emergency, irradiation may have to be started immediately, even before the histologic diagnosis is established. Alternatively, expandable metallic stents have been used with considerable success for treatment of vena caval obstruction since patients respond immediately after stent implantation. For diagnosis, a chest X-ray and a CT scan should be performed. Chemotherapy is the treatment of choice for high-grade lymphomas, germ cell tumors and small-cell lung cancer since this modality is more effective than radiotherapy (response rate: 80%). For less chemotherapy responsive tumors radiotherapy is the primary treatment. Successful experience with thrombolytic agents is limited to treatment of catheter-induced SVCS, in contrast, only 20% of patients respond to thrombolytic therapy in the absence of a central catheter. Surgical resection of SVCS associated tumors has not improved survival rates and should be avoided.

Autologous transplantation of urothelium into demucosalized gastrointestinal segments: evidence for epithelialization and differentiation of in vitro expanded and transplanted urothelial cells.

PURPOSE: Our study established a technique for in vitro expansion and subsequent transplantation of autologous urothelial cells into vascularized seromuscular segments from stomach and colon in sheep. The proof of proliferation and differentiation of the transplanted urothelium in the absence of resident urothelium is considered to be a prerequisite for use of this technique in bladder augmentation. MATERIALS AND METHODS: Autologous sheep urothelial cells were expanded in vitro and grown on collagen membranes for sheet grafting. Using a vital stain, viability and confluency status of the urothelial graft were determined before transplantation into demucosalized segments isolated from the sheep stomach and colon gastrointestinal pouches. The gastrointestinal segments were sewn up and remained in the abdomen as small pouches stiched to the abdominal wall. Take and differentiation of transplanted cells within the pouch were assessed two and three weeks later using histological and immunohistological means. RESULTS: Urothelial cells grew well on collagen membranes. A confluency status > 40% and co-culturing with 3T3 feeder cells favored successful transplantation. Two weeks after transplantation a multilayered urothelial-like epithelium was found to line the lumen of the pouch. The epithelium was characterized by a distinct urothelium-typical distribution of basal and luminal keratins and the expression of the umbrella cell-specific marker uroplakin III. Moreover, the epithelium had an underlying basal lamina which focally contained collagen type IV. CONCLUSIONS: The data indicate that in vitro expanded urothelial cells are capable of epithelializing demucosalized gastrointestinal segments forming a genuine, differentiated "neo" urothelium.

A phase I/II study of sequential, dose-escalated, high dose ifosfamide plus doxorubicin with peripheral blood stem cell support for the treatment of patients with advanced soft tissue sarcomas.

BACKGROUND: This Phase I/II study investigates increasingly high doses of ifosfamide combined with full dose doxorubicin chemotherapy supported with peripheral blood stem cells (PBSC) and granulocyte-colony stimulating factor (G-CSF) in patients with metastatic soft tissue sarcoma (STS). METHODS: Patients with histologically proven metastatic or advanced adult STS without prior treatment received doxorubicin, 75 mg/m2, on Day 1 followed by 4-day continuous infusion of ifosfamide at 5 consecutive dose levels starting with 8 g/m2 and escalating to 16 g/m2 in increments of 2 g/m2. Three patients per dose level and a maximum of 5 treatment cycles per level at 3-week intervals were planned. Each cycle was followed by G-CSF and retransfusion of PBSC. PBSC separation was performed prior to chemotherapy by steady state mobilization with G-CSF. RESULTS: Eighteen patients (median age, 45 years, range, 25-57 years) were included, with 4, 3, 4, 4, and 3 patients assigned to Levels 1-5, respectively. Metastatic sites included the lungs in 12 patients (67%), lymph nodes in 8 patients (44%), and the liver in 5 patients (28%). Nine patients (50%) achieved objective responses with 4 complete responses (22%) and 5 partial responses (28%). Lung metastases and a histology of synovial sarcoma or malignant fibrous histiocytoma were favorable features for response to therapy. The median survival for all patients was 13+ months (range, 3-19+ months). Hematotoxicity was manageable and treatment could be administered at a median interval of 24 days. One case of World Health Organization Grade 3 neurotoxicity occurred. Nephrotoxicity was dose-limiting, with 1 patient in Level 4 (WHO Grade 2) and 2 patients in Level 5 (WHO Grade 3). CONCLUSIONS: Multiple cycles of dose-intensive therapy with doxorubicin and high dose ifosfamide can be administered safely with PBSC support. Nephrotoxicity is dose-limiting for ifosfamide at total doses of 16 g/m2. Multiple cycles of high dose chemotherapy at short treatment intervals using ifosfamide at a dose of 14 g/m2 should be investigated further in a neoadjuvant setting in patients with STS.

[Management of endocrine pancreatic tumors]. / Management endokriner Pankreastumoren.

A Medline based literature research was undertaken to review the available information on endocrine pancreatic tumors until 1/95. The current diagnostic and therapeutic strategies in the management of this tumor will be summarized.

Failure of orally administered dipyridamole to enhance the antineoplastic activity of fluorouracil in combination with leucovorin in patients with advanced colorectal cancer: a prospective randomized trial.

PURPOSE: A randomized trial was performed to investigate the ability of the nucleoside transport inhibitor dipyridamole (DP) to enhance the antitumor activity of fluorouracil (5-FU)/leucovorin (folinic acid [FA]). PATIENTS AND METHODS: One hundred eighty-one untreated patients with advanced colorectal cancer were randomized to receive 5-FU 600 mg/m2 plus FA 300 mg/m2 on days 2 to 4 with or without DP 75 mg orally three times daily on days 1 to 5. Cycles were repeated every 3 weeks. Only patients with documented tumor progression before therapy were eligible. 5-FU pharmacokinetics using high-performance liquid chromatography (HPLC) were assessed in 11 nonrandomized patients receiving paired cycles with or without DP. RESULTS: One hundred seventy-four patients were assessable for toxicity and response. There was no significant difference in toxicity, except DP-related headache in 24% of patients. An objective response rate of 15% (one complete response [CR] and 13 partial responses [PRs]) for 5-FU/FA and 13% (two CRs and nine PRs) for 5-FU/FA/DP was observed. The dose-intensity of 5-FU delivered was significantly higher (1.09- to 1.16-fold) for the DP-containing arm. Pharmacokinetic parameters of 5-FU did not differ significantly, except for a prolonged half-life (t1/2) induced by DP. The median time to progression (P = .8) and the median survival time (11.6 months for 5-FU/FA v 9.3 months for 5-FU/FA/DP; P = .14, log-rank test) were not different between treatment arms. CONCLUSION: Orally administered DP did not improve the antineoplastic activity of 5-FU/FA in patients with advanced colorectal cancer when used at this dose and schedule. The observed increase in 5-FU dose-intensity for FU/FA/DP was not clinically relevant.

Cellular heterogeneity in DNA damage and growth inhibition induced by ICI D1694, thymidylate synthase inhibitor, using single cell assays.

Heterogeneity in the response of the HCT-8 (human ileocecal adenocarcinoma) tumor cell line to a new thymidylate synthase inhibitor, ICI D1694, was investigated in terms of induction of DNA single-strand breaks and cytotoxicity, applying the single cell alkaline gel (SCG) electrophoresis assay and the individual colony formation assay (iCFA), respectively. ICI D1694 induced maximal total DNA single-strand breaks 24 hr after a 2-hr drug exposure with incomplete repair by 72 hr. The level of DNA damage was concentration dependent and paralleled cellular growth inhibition in vitro. The proportion of cells with DNA damage and the extent of DNA single-strand breaks increased with drug concentration. At 1 microM ICI D1694 (IC95), a significant level of DNA damage was detected in 58% of the cells; however, 25% of the cells had little or no damage. Using the iCFA system, it was observed that with 1 microM ICI D1694, only 2.6% of the seeded cells maintained a colony growth rate similar to that of the control colonies, and 22% of the cells were growing significantly more slowly. In conclusion, the SCG assay and the iCFA identified subpopulations of cells that were unaffected by ICI D1694. Although these cells represented only a small proportion of the total cell population, this phenomenon of heterogeneity in response to ICI D1694 might limit its therapeutic efficacy.

Down-regulation of c-myc gene expression with induction of high molecular weight DNA fragments by fluorodeoxyuridine.

5-Fluoro-2'-deoxyuridine (FdUrd), a potent inhibitor of thymidylate synthase, induces extensive bulk DNA damage at drug concentrations that produce significant in vitro growth inhibition of human ileocecal carcinoma (HCT-8) cells. Constant- and pulsed-field gel electrophoresis (CFGE and PFGE), to detect size distribution of DNA double-strand breaks and repair kinetics, in parallel with northern and western blot analyses, to quantitate c-myc gene and protein expression, were utilized to analyze drug effects. At 24-hr post in vitro drug treatment, when maximum bulk DNA damage was detected, FdUrd produced a broad range of high molecular weight DNA fragments, clustering between 0.1 and 5.7 megabases in size, and resulted in a decrease in the level of c-myc transcripts and protein with no significant effect on the level of v-myc and H-ras. These effects preceded the observed cellular growth inhibition. Addition of the reduced folate leucovorin potentiated the effects induced by FdUrd, indicating that thymidylate synthase inhibition is an important initial step in drug effect followed by DNA fragmentation and suppression of c-myc expression. Changes in the integrity of the genetic materials and regulatory genes occurred prior to the observed cell growth inhibition by FdUrd, suggesting that these molecular alterations by FdUrd may be associated with subsequent FdUrd-induced cell growth inhibition.