Recurrence of Urothelial Carcinoma of the Bladder: A Role for Insulin-Like Growth Factor-II Loss of Imprinting and Cytoplasmic E-Cadherin Immunolocalization

Purpose:This study documents the frequency of insulin-like growth factor-II (IGF-II) loss of imprinting (LOI) in a series of 87 bladder tissues. E-cadherin (CDH1) immunolocalization was also investigated due to the known redistribution of this adherence protein to the cytoplasm following exogenous exposure to IGF-II.
Experimental Design: Informative IGF-II cases were identified following DNA-PCR amplification and subsequent sequencing of the transcribable ApaI RFLP in exon 9 of IGF-II. Similar approaches using primer-specific cDNA templates identified the imprinting status of IGF-II in these informative cases. CDH1cellular localization was assessed on a tissue microarray platform of 114 urothelial carcinoma of the bladder (UCB) cases (70 pTanoninvasive and 44 pT1laminapropria invasive) using the commercially available Novocastra antibody.
Results: IGF-IILOI was evident in 7 of17 (41%) UCB tumors and 4 of11 (36%) tumor-associated normal urothelial samples.Two of four pT1grade 3 tumors, the subject of much debate concerning their suitability for radical cystectomy, showed LOI at the IGF-II locus. In those tumors showing IGF-II LOI, 4 of 7 (57%) displayed concomitant CDH1cytoplasmic staining. In contrast, only 3 of 10 (30%) IGF-IImaintenance ofimprinting tumorshad concomitant CDH1cytoplasmiclocalization. UCB cell lines displaying cytoplasmic CDH1immunolocalization expressed significantly higher levels of IGF-II (CAL29, HT1376, and RT112) compared with RT4, a cell line displaying crisp membranous CDH1staining. Finally, cytoplasmic CDH1staining was an independent predictor of a shorter time to recurrence independent of tumor grade and stage.
Conclusions: We suggest that CDH1 cytoplasmic immunolocalization as a result of increased IGF-II levels identifies those nonmuscle invasive presentations most likely to recur and therefore might benefit from more radical nonconserving bladder surgery

Randomized Phase II trial of nintedanib, afatinib and sequential combination in castration-resistant prostate cancer

AIMS: The aim of this article was to evaluate afatinib (BIBW 2992), an ErbB family blocker, and nintedanib (BIBF 1120), a triple angiokinase inhibitor, in castration-resistant prostate cancer patients.

PATIENTS & METHODS: Patients were randomized to receive nintedanib (250 mg twice daily), afatinib (40 mg once daily [q.d.]), or alternating sequential 7-day nintedanib (250 mg twice daily) and afatinib (70 mg q.d. [Combi70]), which was reduced to 40 mg q.d. (Combi40) due to adverse events. The primary end point was progression-free rate at 12 weeks.

RESULTS: Of the 85 patients treated 46, 20, 16 and three received nintedanib, afatinib, Combi40 and Combi70, respectively. At 12 weeks, the progression-free rate was 26% (seven out of 27 patients) for nintedanib, and 0% for afatinib and Combi40 groups. Two patients had a ≥50% decline in PSA (nintedanib and the Combi40 groups). The most common drug-related adverse events were diarrhea, nausea, vomiting and lethargy.

CONCLUSION: Nintedanib and/or afatinib demonstrated limited anti-tumor activity in unselected advanced castration-resistant prostate cancer patients.

A phase I/II trial of vorinostat in combination with 5-fluorouracil in patients with metastatic colorectal cancer who previously failed 5-FU-based chemotherapy

PURPOSE: We conducted a phase I/II clinical trial to determine the safety and feasibility of combining vorinostat with 5-fluorouracil (5-FU) in patients with metastatic colorectal cancer (mCRC) and elevated intratumoral thymidylate synthase (TS).

METHODS: Patients with mCRC who had failed all standard therapeutic options were eligible. Intratumoral TS mRNA expression and peripheral blood mononuclear cell (PBMC) histone acetylation were measured before and after 6 consecutive days of vorinostat treatment at 400 mg PO daily. 5-FU/LV were given on days 6 and 7 and repeated every 2 weeks, along with continuous daily vorinostat. Dose escalation occurred in cohorts of three to six patients.

RESULTS: Ten patients were enrolled. Three dose levels were explored in the phase I portion of the study. Two dose-limiting toxicities (DLTs) were observed at the starting dose level, which resulted in dose de-escalation to levels -1 and -2. Given the occurrence of two DLTs at each of the dose levels, we were unable to establish a maximum tolerated dose (MTD). Two patients achieved significant disease stabilization for 4 and 6 months. Grade 3 and 4 toxicities included fatigue, thrombocytopenia and mucositis. Intratumoral TS downregulation > or = 50% was observed in one patient only. Acetylation of histone 3 was observed in PBMCs following vorinostat treatment.

CONCLUSIONS: The study failed to establish a MTD and was terminated. The presence of PBMC histone acetylation indicates biological activity of vorinostat, however, consistent reductions in intratumoral TS mRNA were not observed. Alternate vorinostat dose-scheduling may alleviate the toxicity and achieve optimal TS downregulation.

Systematic approach to the quantitative voltammetric analysis of the Fe III /Fe II component of the [α 2 -Fe(OH 2 )P 2 W 17 O 61 ] 7-/8- reduction process in buffered and unbuffered aqueous media

The one-electron reduction of [α2-FeIII(OH2)P2W17O61]7- at a glassy carbon electrode was investigated using cyclic and rotating-disk-electrode voltammetry in buffered and unbuffered aqueous solutions over the pH range 3.45−7.50 with an ionic strength of approximately 0.6 M maintained. The behavior is well-described by a square-scheme mechanism P + e- ↔ Q (E10/ = −0.275 V, k10/ = 0.008 cm s-1, and α1 = 1/2), PH+ + e- ↔ QH+ (E20/ = −0.036 V, k20/ = 0.014 cm s-1, and α2 = 1/2), PH+ ↔ P + H+ (KP = 3.02 × 10-6 M), and QH+ ↔ Q + H+ (KQ = 2.35 × 10-10 M), where P, Q, PH+, and QH+ correspond to [α2-FeIII(OH)P2W17O61]8-, [α2-FeII(OH)P2W17O61]9-, [α2-FeIII(OH2)P2W17O61]7-, and [α2-FeII(OH2)P2W17O61]8-, respectively; E10‘ and E20‘ are the formal potentials, k10‘ and k20‘ are the formal (standard) rate constants, and KP and KQ are the acid dissociation constants for the relevant reactions. The analysis for the buffered media is based on the approach of Laviron who demonstrated that a square scheme with fully reversible protonations, reversible or quasi reversible electron transfers with the assumption that α1 = α2, can be well-described by the behavior of a simple redox couple, ox + e- ↔ red, whose formal potential, Eapp0‘, and standard rate constant, kapp0‘, are straightforwardly derived functions of pH, as are the values of E10‘, k10‘, E20‘, k20‘, and KP (only three of the four thermodynamic parameters in a square scheme can be specified). It was assumed that αapp = 1/2, and the simulation program DigiSim was used to determine the values of Eapp0‘ and kapp0‘, which are required to describe the cyclic voltammograms obtained in buffered media in the pH range from 3.45 to 7.52 (buffer-related reactions which effect general acid−base catalysis are included in the simulations). DigiSim simulations of cyclic voltammograms obtained in unbuffered media yielded the values of E10‘ and k10‘; KQ was then directly computed from thermodynamic constraints. These simulations included additional reactions between the redox species and H2O. The value of the diffusion coefficient of the [α2-FeIII(OH2)P2W17O61]7-, 2.92 × 10-6 cm2 s-1, was determined using DigiSim simulations of voltammograms at a rotating disk electrode in buffered and unbuffered media at pH 3.45. The diffusion coefficients of all redox species were assumed to be identical. When the pH is greater than 6, instability of P (i.e., [α2-FeIII(OH)P2W17O61]8-) led to the loss of the reactant and precluded lengthy experimentation.

Skeletal muscle (1) H MRSI before and after prolonged exercise. II. visibility of free carnitine

Carnitine (Car) buffers excess acetyl-CoA through the formation of acetylCar (AcCar). AcCar's acetyl group (AG-AcCar) gives rise to a peak at 2.13 ppm in ¹H MR spectra of skeletal muscle, whereas the trimethylammonium (TMA) groups of both, AcCar and Car, are thought to contribute to the TMA peak at 3.23 ppm. Surprisingly, in previous studies both resonances, AG-AcCar and TMA, increased after exercise. The aim of this study was to assess if the exercise-related TMA increase correlated with AcCar production. Magnetic resonance spectroscopic imaging (pulse repetition time/echo time = 1200/35 ms) was performed before and after prolonged exercise in the lower leg and thigh of eight runners and eight cyclists, respectively. TMA and AG-AcCar increased after exercise (P < 0.001). TMA's increase correlated with the AG-AcCar increase (R² = 0.73, P < 0.001, lower leg; R² = 0.28, P < 0.001, thigh). The correlation of ΔTMA with ΔAG-AcCar suggests that the TMA increase is due to AcCar formation. As total Car (Car + AcCar) remains unchanged with exercise, these findings suggest that the contribution of free Car to the TMA peak is limited and, therefore, is partly invisible in muscle ¹H MR spectra. This indicates that the biochemically relevant cytosolic content of free Car is considerably lower than the overall concentration determined by radioisotopic assays, a potentially important result with respect to regulation of substrate oxidation.

Palliative in-patient cancer treatment in an anthroposophic hospital: II. Quality of life during and after stationary treatment, and subjective treatment benefits

BACKGROUND: There is an increasing demand for comprehensive forms of palliative cancer care, meeting physical as well as emotional, cognitive, spiritual and social needs. Therapy programs of anthroposophic hospitals are aimed at improving health and quality of life (QoL) at these levels. However, data on the influence of these programs on QoL of patients with advanced cancer are scarce. PATIENTS AND METHODS: 144 in-patients with advanced epithelial cancers were treated at the anthroposophic Lukas Klinik, Arlesheim, Switzerland. QoL was assessed upon admission, discharge and after 4 months, using 20 functional scales from the questionnaires EORTC QLQ-C30, HADS and SELT-M. Statistical testing was performed with the Wilcoxon signed rank test. At month 4, subjectively perceived benefits from anthroposophic medicine (AM) and conventional cancer therapy (CCT) were assessed by telephone. OBJECTIVE: The aim was to provide an account of global, physical, emotional, cognitive-spiritual and social QoL developments in advanced cancer patients, during and after in-patient AM treatment, and to investigate subjective benefits from AM and CCT. RESULTS: QoL improvements were observed in all 20 dimensions (12 significant). Compared to related studies, improvements were fairly high. At month 4, QoL scores had decreased but were still above baseline in all 20 dimensions. Both AM and CCT were perceived as beneficial. CONCLUSION: Our data provide evidence that in-patient therapy at an anthroposophic hospital can lead to significant QoL improvements, especially in emotional, but also global, physical, cognitive-spiritual and social aspects. Benefits of AM were experienced on the physical, emotional, cognitive- spiritual and social level. Benefits of CCT were tumor-focused.

S9511: a Southwest Oncology Group phase II study of trimetrexate, 5-fluorouracil, and leucovorin in unresectable or metastatic adenocarcinoma of the stomach.

OBJECTIVE: The primary objective of this trial was to evaluate the response rate for trimetrexate in conjunction with 5-FU and leucovorin (LV) (= TFL) in the treatment of advanced gastric cancer in a phase II, cooperative group setting. METHODS: Patients with locally advanced, unresectable, or metastatic adenocarcinoma of the stomach received trimetrexate 110 mg/m IV over 60 minutes day 1, followed by 5-FU 500 mg/m IV bolus and LV 200 mg/m IV over 60 minutes day 2, followed by oral LV 15 mg every 6 hours x 7 doses, all weekly for 6 weeks followed by 2 weeks of rest, continued until progression. RESULTS: Characteristics for 37 eligible patients: median age 63 (range: 23-83); male/female: 69% of 31%; performance status 0/1/2 15/20/1. The confirmed response rate was 19%, and median overall survival was 6 months. Two patients died as a result of therapy, 1 because of infection without significant neutropenia, and 1 due to perforation of a responding gastric lesion. Seventy-two percent experienced grades 3 and 4 toxicity, most commonly diarrhea, fatigue, and lymphopenia. CONCLUSIONS: This regimen achieves response rates comparable to other 5-FU-based regimens, when used in treatment of incurable gastric cancer. Toxicity appears manageable.

The Turkish Empire in Europe, Asia, and Africa: dividid into all its governments, together with the other territories that are tributary to it, as also the dominions of ye Emperor of Marocco [sic] according to the newest and most exact observations

by H. Moll.

The Elector's guide. Addressed to the freeholders of the county of York.

No. I. The "Catholic question".--No. II. The general state of the country banks and paper money; Death of Alexander, emperor of Russia; State of parties in the kingdom; A letter to Fountayne Wilson, esq.; Duncombe and the treadmill; Poetry and miscellanies.--No. III. A letter to the Duke of York; Auri sacra fames; or, Sturdy beggars: a county job; Church Methodism; A Protestant confessor; His Majesty's speech to Parliament; Miscellanies, and poetry.--No. IV. A letter to Daniel Sykes, esq. on West Indian slavery; Catholic and Protestant; The last man; Confidence in banks; Hints to electors; The proceedings in Parliament, &c., &c., &c.--No. V. An address to the suffering people of England; Slavery; A letter to Sir John Bayley, knt,; Banks; The Protestant champion; Poetry, &c., &c.--No. VI. A charge of His Grace the Archbishop of York to the clergy of the diocese; A secret; A good action.--No. VII. Observations upon county representation; A full account of the county meeting, &c., &c.

History of Frederick the Second, emperor of the Romans. From chronicles and documents published within the last ten years.

Mode of access: Internet.

Posthumous works of Frederic II, King of Prussia.

"Translated from the French by Thomas Holcroft."

Multi-centre Phase II trial of the polyamine synthesis inhibitor SAM486A (CGP48664) in patients with metastatic melanoma

Purpose: To determine the activity and tolerability of SAM496A, an inhibitor of S-adenosylmethionine decarboxylase (SAMDC), in patients with metastatic melanoma who had not received prior chemotherapy. Selected patients were offered participation in two sub-studies examining early changes in tumor metabolism with FDG-PET and changes in tumor polyamine content. Patients and methods: Fifteen patients with measurable metastatic melanoma, normal cardiac function, and no known CNS metastases were eligible and received SAM486A by 1-hour IV infusion daily for 5 days every 3 weeks. Response was assessed by SWOG criteria. Results: No patient had a confirmed partial response. Fatigue/lethargy, myalgia and neutropenia were the main toxicities but no febrile neutropenia or grade 4 non-hematological toxicity occurred. Five patients had PET scans pre-treatment and on days 8-12 of cycle 1. No patient had reduction of tumor metabolism. Serial biopsy in one patient showed alterations in polyamines consistent with SAMDC inhibition. Conclusions: Using the present dose and schedule of administration, SAM486A does not have significant therapeutic potential in patients with metastatic melanoma.

Evaluation of piezoelectric PVDF polymers for use in space environments. II. Effects of atomic oxygen and vacuum UV exposure

The effects of atomic oxygen (AO) and vacuum UV radiation simulating low Earth orbit conditions on two commercially available piezoelectric polymer films, poly(vinylidene fluoride) (PVDF) and poly(vinylidene fluoride-trifluoroethylene) P(VDF-TrFE), have been studied. Surface erosion and pattern development are significant for both polymers. Erosion yields were determined as 2.8 � 10�24 cm3/atom for PVDF and 2.5 � 10�24 cm3/atom for P(VDF-TrFE). The piezoelectric properties of the residual material of both polymers were largely unchanged after exposure, although a slight shift in the Curie transition of the P(VDF-TrFE) was observed. A lightly cross-linked network was formed in the copolymer presumably because of penetrating vacuum ultraviolet (VUV) radiation, while the homopolymer remained uncross-linked. These differences were attributed to varying degrees of crystallinity and potentially greater absorption, and hence damage, of VUV radiation in P(VDFTrFE) compared with PVDF.