Current concept of transurethral resection of bladder cancer: from re-transurethral resection of bladder cancer to en-bloc resection.

PURPOSE OF REVIEW: Transurethral resection of bladder cancer (TURB) is the critical step in the management of nonmuscle invasive bladder cancer (NMIBC). This review presents new improvements in the strategy and technique of TURB as well as in technological developments used for tumour visualization and removal. RECENT FINDINGS: The goal of TURB is to perform complete resection of NMIBC. Tumor visualization during procedure can be improved by enhanced optical technologies. Fluorescence-guided photodynamic diagnosis (PDD) and narrow-band imaging (NBI) used during TURB can improve tumour detection and potentially reduce recurrence rate, their influence on progression, however, remains controversial. TURB can be performed using monopolar or bipolar electrocautery without significant differences in results or safety. To overcome limitations of traditional TURB, the technique of en-bloc resection was introduced to improve the quality of tumour removal. In selected cases, an early re-resection (re-TURB) within 2-6 weeks after initial procedure is recommended. SUMMARY: TURB is a fundamental step in diagnosis and treatment of NMIBC. Urologists should be aware of promising innovations including new imaging and surgical techniques and their potential benefits. Hopefully, new technologies and performance of TURB bring improved outcomes, which can alter the indication criteria for re-TURB.

Intermittent Versus Continuous Androgen Deprivation Therapy in Patients with Relapsing or Locally Advanced Prostate Cancer: A Phase 3b Randomised Study (ICELAND).

BACKGROUND: Intermittent androgen deprivation (IAD) has received increasing attention; however, the current literature is still limited, especially in nonmetastatic prostate cancer (PCa), and the relative efficacy and safety benefits of IAD versus continuous androgen deprivation (CAD) remain unclear. OBJECTIVE: To add to the knowledge base regarding efficacy and potential benefits, including reduced side effects and improved quality of life (QoL), of IAD versus CAD in patients with nonmetastatic relapsing or locally advanced PCa. DESIGN, SETTING, AND PARTICIPANTS: A 42-mo phase 3b open-label randomised study in 933 patients from 20 European countries. INTERVENTION: Following a 6-mo induction with leuprorelin acetate (Eligard) 22.5mg 3-mo depot, patients were randomised to CAD or IAD with leuprorelin for 36 mo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary end point was time to prostate-specific antigen (PSA) progression while receiving luteinising hormone-releasing hormone agonist, defined as three consecutive increasing PSA values ≥ 4 ng/ml ≥ 2 wk apart. Secondary end points included PSA progression-free survival (PFS), overall survival (OS), testosterone levels, performance status, and QoL. RESULTS AND LIMITATIONS: A total of 933 patients entered the induction phase; 701 were randomised. The median number of injections administered after randomisation was 12 (range: 1-12) for the CAD group and 3 (range: 1-10) for the IAD group. There were no statistically significant or clinically relevant differences between the groups for time to PSA progression, PSA PFS, OS, mean PSA levels over time, or QoL. A similar number of adverse events was observed in each group; the most common were hot flushes and hypertension. Study limitations include the open-label design and absence of formal testosterone recovery assessment. CONCLUSIONS: IAD and CAD demonstrated similar efficacy, tolerability, and QoL in men with nonmetastatic PCa. The principal benefit of IAD compared with CAD is a potential cost reduction with comparable OS rates. There are no apparent QoL benefits. PATIENT SUMMARY: This randomised trial showed that both intermittent and continuous hormone therapy had similar efficacy, tolerability, and quality-of-life profiles in patients with relapsing M0 or locally advanced prostate cancer. Intermittent therapy may be a valid option for selected patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00378690.

In vitro culturing of viable circulating tumor cells of urinary bladder cancer.

OBJECTIVE: Approximately one third of patients diagnosed with muscle-invasive urinary bladder cancer (UBC) have undetected metastases at the time of treatment of the primary tumor. Currently there are no reliable specific serum markers for monitoring and evaluating risk profiles of urothelial cancers. Several studies suggest that detection of circulating tumor cells (CTCs) may correlate with the disease status and prognosis at baseline and early in the treatment of cancers. In this study a new way of isolation and in vitro cultivation of CTCs of urinary bladder cancer was introduced. MATERIALS AND METHODS: Peripheral blood (PB) samples from 53 patients who had undergone urological procedure were evaluated using the MetaCell device (MetaCell s.r.o., Ostrava, Czech Republic). The patients enrolled in the study were both oncological patients with UBC and non-oncological patients with inflammation (14 patients). The sensitivity and quantification of CTCs were evaluated. The separated CTCs were cultured in vitro. RESULTS: 39 patients with confirmed UBC were enrolled in the study. CTCs were detected in 25 (64%) patients, and most of these patients had between 6 and 10 cells. The separated CTCs were successfully cultured in vitro. CONCLUSION: CTCs were detected in a higher percentage of patients than in other studies. This paper describes the first successful culturing of human UBC cells. The MetaCell approach used in this study enabled the capture of viable intact virgin CTCs (virgin CTC) suitable for next in vitro culturing, single cell analysis or drug testing.

Circulating tumor cells in localized prostate cancer: isolation, cultivation in vitro and relationship to T-stage and Gleason score.

The most promising near-term application of circulating tumor cells (CTCs) monitoring relates to the development of targeted cancer therapies, and the need to tailor such treatments to individual tumor characteristics. A high number of new innovative technologies to improve methods for detecting CTCs, with extraordinarily high sensitivity, have recently been presented. The identification and characterization of CTCs require extremely sensitive and specific methods that are able to isolate CTCs with the possibility of cultivation and downstream analysis of in vitro culture of separated CTCs. In this original research paper, we demonstrate that it is possible to isolate human CTCs from a patient with prostate cancer, with subsequent cultivation and proliferation in vitro. We show that the use of a filtration device implemented by MetaCell® can fulfil all the requirements mentioned above. Fifty-five patients with localized prostate cancer have so far been enrolled into the study. CTCs were detected in the blood samples of 28 (52%) out of the 55 patients. We report successful isolation of CTCs from patients with prostate cancer, capturing cells with a proliferative capacity in 18 (64.3%) out of the 28 CTC-positive patients. Direct correlation with Gleason score and T stage was not proven. The cells, captured by a size-based filtration approach, remain in a good state, unaffected by any antibodies or lysing solutions. During the filtration process, no interactions occurred between antibodies and antigens on the surface of CTCs. This biological interaction is specific for immunomagnetic methods. The MetaCell device provides the possibility of reaching virgin CTCs suitable for subsequent cultivation or single-cell analysis. This aspect will have an important impact on the future design of clinical trials testing new drugs against targets expressed on metastatic cancer cells. In addition to measurement of CTC counts, future trials with targeted therapies should also include the assessment of the specific therapeutic target on CTCs.

Precursors and formation of pyrithione and other pyridyl-containing sulfur compounds in drumstick onion, Allium stipitatum.

Two novel, structurally unusual cysteine derivatives were isolated from the bulbs of Allium stipitatum (Allium subg. Melanocrommyum) and shown to be S-(2-pyridyl)cysteine N-oxide and S-(2-pyridyl)glutathione N-oxide. The former compound is the first example of a naturally occurring alliinase substrate that contains an N-oxide functionality instead of the S-oxide group. In addition, S-methylcysteine S-oxide (methiin) and S-(methylthiomethyl)cysteine 4-oxide (marasmin) were found in the bulbs. Presented data suggest that the previously reported identification of S-(2-pyridyl)cysteine S-oxide was most likely erroneous. The alliinase-mediated formation of pyridyl-containing compounds following disruption of A. stipitatum bulbs was studied by a combination of HPLC-MS, HPLC-PDA, DART-MS, and NMR techniques. It was found that no pyridyl-containing thiosulfinates are present in homogenized bulbs in detectable quantities. Instead, various pyridine N-oxide derivatives are formed, including N-hydroxypyridine-2(1H)-thione (pyrithione), 2-(methyldithio)pyridine N-oxide, 2-[(methylthio)methyldithio]pyridine N-oxide, di(2-pyridyl) disulfide N-oxide, and di(2-pyridyl) disulfide N,N'-dioxide. This represents the first report of pyrithione formation as a natural product.

Allium discoloration: the precursor and formation of the red pigment in giant onion (Allium giganteum Regel) and some other subgenus Melanocrommyum species.

The precursor of the orange-red pigment formed upon wounding the bulbs of Allium giganteum (Allium subg. Melanocrommyum) was isolated and shown to be S-(2-pyrrolyl)cysteine S-oxide. In addition, two other pyrrolylsulfinyl derivatives were found in an extract from the bulbs, namely, 3-(2-pyrrolylsulfinyl)lactic acid and S-(3-pyrrolyl)cysteine S-oxide. Contrary to a previous report, the latter compound was shown not to serve as the precursor of the pigment, being in fact only an artifact formed during isolation. The formation of pyrrolyl-containing compounds following disruption of A. giganteum bulbs was studied by a combination of LC-MS, LC-NMR and DART-MS. It was found that S-(2-pyrrolyl)cysteine S-oxide is cleaved by a C-S lyase (alliinase) to yield 2-pyrrolesulfenic acid. Two molecules of the latter compound give rise to highly reactive S-(2-pyrrolyl) 2-pyrrolethiosulfinate which in turn converts into red 2,2'-epidithio-3,3'-dipyrrole (dipyrrolo[2,3-d:2',3'-e]-1,2-dithiin). Several other pyrrolyl-containing compounds were detected in A. giganteum for the first time, including S-methyl 2-pyrrolethiosulfinate, S-(2-pyrrolyl) methanethiosulfinate, di(2-pyrrolyl) disulfide, and S-(2-pyrrolyl) 2-pyrrolethiosulfonate. It can be concluded that the formation of the orange-red pigment in Allium subg. Melanocrommyum species, despite sharing several analogous features, is of a different nature than the pink discoloration of onion (A. cepa).

Applications of direct analysis in real time-mass spectrometry (DART-MS) in Allium chemistry. (Z)-butanethial S-oxide and 1-butenyl thiosulfinates and their S-(E)-1-butenylcysteine S-oxide precursor from Allium siculum.

Lachrymatory (Z)-butanethial S-oxide along with several 1-butenyl thiosulfinates was detected by DART mass spectrometry upon cutting Allium siculum , a popular ornamental Allium species used in some cultures as a spice. (Z)-Butanethial S-oxide isolated from the plant was shown to be identical to a synthetic sample. Its likely precursor, (R(S),R(C),E)-S-(1-butenyl)cysteine S-oxide (homoisoalliin), was isolated from homogenates of A. siculum, and a closely related species Allium tripedale , and fully characterized. Through use of LC-MS, a series of related gamma-glutamyl derivatives were tentatively identified in A. siculum and A. tripedale homogenates, including gamma-glutamyl-(E)-S-(1-butenyl)cysteine and its S-oxide, gamma-glutamyl-S-butylcysteine and its S-oxide, and gamma-glutamyl-S-methylcysteine and its S-oxide. Because compounds containing the 1-butenyl group have not been previously identified in genus Allium species, this work extends the range of known Allium sulfur compounds. The general applicability of DART mass spectrometry in identifying naturally occurring, thermally fragile thial S-oxides and thiosulfinates is illustrated with onion, Allium cepa , as well as a plant from a different genus, Petiveria alliacea .

29Si-13C spin-spin couplings over Si-O-Carom link.

29Si-13C couplings were measured in para substituted silylated phenols, X--C6H4--O--SiR1R2R3 (X = NO2, CF3, Cl, F, H, CH3, CH3O). The SiR1R2R3 silyl groups included trimethylsilyl (Si(CH3)3, TMS), tert-butyldimethylsilyl (Si(CH3)2C(CH3)3, TBDMS), dimethylsilyl (SiH(CH3)2, DMS), and tert- butyldiphenylsilyl (Si(C6H5)2C(CH3)3, TBDPS). Previously developed (Si,C,Si)gHMQC methods and narrow 29Si lines allowed the determination of coupling constants over up to five bonds. Besides the number of intervening bonds between the silicon and carbon atoms, all the measurable couplings depend also on the nature of the substituents on the silicon. The two- and three-bond couplings are not affected by ring substitution in the para position. These properties render the 29Si-13C couplings suitable for line assignment in the spectra of silylated polyphenols. The experimental results are in reasonable agreement with theoretical calculations. The calculations show, in agreement with the data reported in the literature for couplings between other nuclei, that the two-bond and three-bond couplings, which are of similar magnitudes, are of opposite signs. If the signs of these geminal and vicinal couplings could be determined experimentally, they would greatly facilitate the line assignment. The four- and five-bond couplings are affected by the substituent X in a nontrivial manner.

Characterization of polyphenols from plant materials through their silylation and 29Si NMR spectroscopy-line assignment through 29Si, 13C spin-spin couplings.

The lines in (29)Si NMR spectra of silylated polyphenols and some other compounds are difficult to assign owing to the absence of couplings with protons outside the silyl group. The assignment can be derived through small (n)J((29)Si, (13)C) couplings (n > 1). Using a previously described method for measurements of these couplings, the assignment procedure is demonstrated here on three examples of trimethylsilylated phenols: 7-hydroxyflavone, ferulic acid, and quercetin. In some cases the procedure can be used to identify carbon atoms to which the siloxy groups are attached.