[Radiotherapy in node-positive prostate cancer]. / Strahlentherapie beim nodal-positiven Prostatakarzinom.

BACKGROUND: There are numerous randomized trials to guide the management of patients with localized (and metastatic) prostate cancer, but only a few (mostly retrospective) studies have specifically addressed node-positive patients. Therefore, there is uncertainty regarding optimal treatment in this situation. Current guidelines recommend long-term androgen deprivation therapy (ADT) alone or radiotherapy plus long-term ADT as treatment options. OBJECTIVES: This overview summarizes the existing literature on the use of radiotherapy for node-positive prostate cancer as definitive treatment and as adjuvant or salvage therapy after radical prostatectomy. In this context, we also discuss several PET tracers in the imaging evaluation of patients with biochemical recurrence of prostate cancer after radical prostatectomy. As for definitive treatment, retrospective studies suggest that ADT plus radiotherapy improves overall survival compared with ADT alone. These studies also consistently demonstrated that many patients with node-positive prostate cancer can achieve long-term survival - and are likely curable - with aggressive therapy. RESULTS: The beneficial impact of adjuvant radiotherapy on survival in patients with pN1 prostate cancer seems to be highly influenced by tumor characteristics. Men with ≤ 2 positive lymph nodes in the presence of intermediate- to high-grade disease, or positive margins, and those with 3 or 4 positive lymph nodes are the ideal candidates for adjuvant radiotherapy (plus long-term ADT) after surgery. CONCLUSION: There is a need for randomized trials to further examine the potential role of radiotherapy as either definitive or adjuvant treatment, for patients with node-positive prostate cancer.

[Adjuvant vs. salvage radiotherapy after radical prostatectomy]. / Adjuvante vs. Salvage-Strahlentherapie nach radikaler Prostatektomie.

BACKGROUND: After radical prostatectomy (RP) the pre-RP PSA value, Gleason Score, pT-stage, state of seminal vesicles and state of surgical margins are key indicators for the risk of biochemical or clinical recurrence. Depending on the tumour stage, 50-70% of the high-risk patients suffer biochemical progression. The treatment options in these circumstances are adjuvant radiotherapy (ART, for an undetectable PSA) or salvage radiotherapy (SRT, for persisting PSA or PSA re-rising above detection limits). Data from ongoing randomised trials that compare ART and SRT directly have not yet been published. METHOD: A search in PubMed for ART and SRT after RP for prostate cancer was undertaken to compare the results of the 2 treatment approaches. RESULTS: 3 randomised phase-III studies have shown a nearly 20% advantage in terms of biochemical progression after ART (60-64 Gy) compared with a wait-and-see strategy. The largest effect was seen in patients with pT3 prostate cancer with positive surgical margins. According to the German S3-guidelines, SRT with at least 66 Gy can be offered to patients with a post-RP persisting PSA or a PSA re-rising above detection limits. 30-70% of these patients re-achieve an undetectable PSA. Thus, there is a second option for curative treatment. Due to the lower total dose, ART seems to be connected with fewer late complications than SRT. SRT, on the other hand, reduces the risk of potential interactions with post-RP complications and of overtreatment. There is a controversial discussion about the inclusion of the pelvic lymph nodes in the treatment volume, the additional application of anti-androgens and the total dose of both ART and SRT. CONCLUSIONS: The comparison of SRT after PSA progression with ART at a PSA below the detection limits cannot yet be judged conclusively. The indication for ART depends on the associated risk factors. However, regarding freedom from biochemical progression, it is backed up by high level evidence. If SRT is applied for biochemical progression, then it should be initiated early, i. e., at the lowest PSA possible.

Modelling the growth of plants with a uniform growth logistics.

BACKGROUND AND AIMS: The increment model has previously been used to describe the growth of plants in general. Here, we examine how the same logistics enables the development of different superstructures. METHODS: Data from the literature are analyzed with the increment model. Increments are growth-invariant molecular clusters, treated as heuristic particles. This approach formulates the law of mass action for multi-component systems, describing the general properties of superstructures which are optimized via relaxation processes. RESULTS: The daily growth patterns of hypocotyls can be reproduced implying predetermined growth invariant model parameters. In various species, the coordinated formation and death of fine roots are modeled successfully. Their biphasic annual growth follows distinct morphological programs but both use the same logistics. In tropical forests, distributions of the diameter in breast height of trees of different species adhere to the same pattern. Beyond structural fluctuations, competition and cooperation within and between the species may drive optimization. CONCLUSION: All superstructures of plants examined so far could be reproduced with our approach. With genetically encoded growth-invariant model parameters (interaction with the environment included) perfect morphological development runs embedded in the uniform logistics of the increment model.

Radiotherapy after radical prostatectomy: immediate or early delayed?

BACKGROUND: Biochemical recurrence after radical prostatectomy (RP) is associated with risk indicators, including Gleason score, preoperative PSA level, tumor stage, seminal vesicle invasion, and positive surgical margins. The 5-year biochemical progression rate among predisposed patients is as high as 50-70%. Post-RP treatment options include adjuvant radiotherapy (ART, for men with undetectable PSA) or salvage radiotherapy (SRT, for PSA persisting or re-rising above detection threshold). Presently, there are no published randomized trials evaluating ART vs. SRT directly. METHODS: Published data on ART and SRT were reviewed to allow a comparison of the two treatment approaches. RESULTS: Three randomized phase III trials demonstrated an almost 20% absolute benefit for biochemical progression-free survival after ART (60-64 Gy) compared to a "wait and see" policy. The greatest benefit was achieved in patients with positive margins and pT3 tumors. SRT can be offered to patients with elevated PSA after RP. In 30-70% of SRT patients, PSA will decrease to an undetectable level, thus giving a second curative chance. The rate of side effects for both treatments is comparably low. The role of irradiation of pelvic lymph nodes and the additional use of hormone therapy and radiation dose are discussed. CONCLUSION: It remains unclear whether early SRT initiated after PSA failure is equivalent to ART. Where SRT is indicated, it should be started as early as possible.

On the structure-bounded growth processes in plant populations.

If growing cells in plants are considered to be composed of increments (ICs) an extended version of the law of mass action can be formulated. It evidences that growth of plants runs optimal if the reaction-entropy term (entropy times the absolute temperature) matches the contact energy of ICs. Since these energies are small, thermal molecular movements facilitate via relaxation the removal of structure disturbances. Stem diameter distributions exhibit extra fluctuations likely to be caused by permanent constraints. Since the signal-response system enables in principle perfect optimization only within finite-sized cell ensembles, plants comprising relatively large cell numbers form a network of size-limited subsystems. The maximal number of these constituents depends both on genetic and environmental factors. Accounting for logistical structure-dynamics interrelations, equations can be formulated to describe the bimodal growth curves of very different plants. The reproduction of the S-bended growth curves verifies that the relaxation modes with a broad structure-controlled distribution freeze successively until finally growth is fully blocked thus bringing about "continuous solidification".

Absence of inflammatory response from upper airway epithelial cells after X irradiation.

Radiotherapy of head and neck tumors causes adverse reactions in normal tissue, especially mucositis. The dose- and time-dependent response of upper airway cells to X radiation should be analyzed in terms of the pro-inflammatory potential. Immortalized BEAS-2B lung epithelial cells were treated with 2, 5 and 8 Gy. Out of 1232 genes, those that were transcribed differentially after 2, 6 and 24 h were assigned to biological themes according to the Gene Ontology Consortium. Enrichment of differentially regulated gene clusters was determined with GOTree ( http://bioinfo.vanderbilt.edu/gotm ). Eleven cytokines were measured in culture supernatants. The cell cycle response up to 24 h and induction of apoptosis up to 4 days after exposure were determined by flow cytometry. A significant dose- and time-dependent gene activation was observed for the categories response to DNA damage, oxidative stress, cell cycle arrest and cell death/apoptosis but not for immune/inflammatory response. This correlated with functional G(2) arrest and apoptosis. Pro-inflammatory cytokines accumulated in supernatants of control cells but not of X-irradiated cells. The complex gene expression pattern of X-irradiated airway epithelial cells is accompanied by cell cycle arrest and induction of apoptosis. In vivo, this may impair the epithelial barrier. mRNA and protein expression suggest at most an indirect contribution of epithelial cells to early radiogenic mucositis.

The general growth logistics of cell populations.

An increment model based on thermodynamics lays bare that the cell size distributions of archaea, prokaryotes and eukaryotes are optimized and belong to the same universal class. Yet, when a cell absorbs mass or signals are processed, these conditions are disturbed. Relaxation re-installs ideal growth conditions via an exponential process with a rate that slows down with the cell size. In a growing ensemble, a distribution of relaxation modes comes in existence, exactly defined by the universal cell size distribution. The discovery of nano-mechanic acoustic activities in cells led us to assume that in a growing ensemble acoustic signals may contribute significantly to the transmission of essential information about growth-induced disturbances to all cells, initiating that way coordinated relaxation. The frequency increases with the cell number shortening the period between successive signals. The completion of rearrangements occurring at a constant rate is thus progressively impaired, until cellular growth stops, totally. Due to this phenomenon, the so-called "relaxation-frequency-dispersion" cell colonies should exhibit a maximum cell number. In populations with large cell numbers, subsystems, behaving similar-like colonies, should form network-like patterns. Based on these ideas, we formulate equations that describe the growth curves of all cell types, verifying that way the general nature of the growth logistics.

Stationary cell size distributions and mean protein chain length distributions of Archaea, Bacteria and Eukaryotes described with an increment model in terms of irreversible thermodynamics.

In terms of an increment model irreversible thermodynamics allows to formulate general relations of stationary cell size distributions observed in growing colonies. The treatment is based on the following key postulates: i) The growth dynamics covers a broad spectrum of fast and slow processes. ii) Slow processes are considered to install structural patterns that operate in short periods as temporary stationary states of reference in the sense of irreversible thermodynamics. iii) Distortion during growth is balanced out via the many fast processes until an optimized stationary state is achieved. The relation deduced identifies the numerous different stationary patterns as equivalents, predicting that they should fall on one master curve. Stationary cell size distributions of different cell types, like Hyperphilic archaea, E. coli (Prokaryotes) and S. cerevisiae (Eukaryotes), altogether taken from the literature, are in fact consistently described. As demanded by the model they agree together with the same master curve. Considering the "protein factories" as subsystems of cells the mean protein chain length distributions deduced from completely sequenced genomes should be optimized. In fact, the mean course can be described with analogous relations as used above. Moreover, the master curve fits well to the patterns of different species of Archaea, Bacteria and Eukaryotes. General consequences are discussed.

Cell cycle and growth response of CHO cells to X-irradiation: threshold-free repair at low doses.

PURPOSE: To test the hypothesis of a threshold for induced repair of DNA damage (IR) and, secondarily, of hyperradiosensitivity (HRS) to low-dose X-irradiation. METHODS AND MATERIALS: Exponentially growing Chinese hamster ovary cells (CHO) were X-irradiated with doses from 0.2 to 8 Gy. Survival data were established by conventional colony-forming assay and flow-cytometric population counting. The early cell cycle response to radiation was studied based on DNA-profiles and bromodeoxyuridine pulse-labeling experiments. RESULTS: Colony-forming data were consistent with HRS. However, these data were of low statistic significance. Population counting provided highly reproducible survival curves that were in perfect accord with the linear-quadratic (LQ) model. The dominant cell cycle reaction was a dose-dependent delay of G2 M and late S-phase. CONCLUSION: There was no evidence for a threshold of IR and for low-dose HRS in X-irradiated CHO cells. It is suggested that DNA damage repair activity is constitutively expressed during S-phase and is additionally induced in a dose-dependent and threshold-free manner in late S-phase and G2. The resulting survival is precisely described by the LQ model.

Summary of well water sampling in California to detect pesticide residues resulting from nonpoint-source applications.

This report summarizes well sampling protocols, data collection procedures, and analytical results for the presence of pesticides in ground water developed by the California Department of Pesticide Regulation (DPR). Specific well sampling protocols were developed to meet regulatory mandates of the Pesticide Contamination Prevention Act (PCPA) of 1986 and to provide further understanding of the agronomic, chemical, and geographic factors that contribute to movement of residues to ground water. The well sampling data have formed the basis for the DPR's regulatory decisions. For example, a sampling protocol, the Four-Section Survey, was developed to determine if reported detections were caused by nonpoint-source agricultural applications, a determination that can initiate formal review and subsequent regulation of a pesticide. Selection of sampling sites, which are primarily rural domestic wells, was initially based on pesticide use and cropping patterns. Recently, soil and depth-to-ground water data have been added to identify areas where a higher frequency of detection is expected. In accordance with the PCPA, the DPR maintains a database for all pesticide well sampling in California with submission required by all state agencies and with invitations for submission extended to all local and federal agencies or other entities. To date, residues for 16 active ingredients and breakdown products have been detected in California ground water as a result of legal agricultural use. Regulations have been adopted for all detected parent active ingredients, and they have been developed regardless of the level of detection.

Comparative analysis of apoptosis in HL60 detected by annexin-V and fluorescein-diacetate.

BACKGROUND: Our aim was to compare and evaluate apoptosis formation as detected by propidium-iodide (PI)/annexin-V or PI/fluorescein-diacetate (FDA) as dose-response parameters in a human promyelocytic leukemia cell line, HL60. METHODS: In exponentially growing HL60 cells, apoptosis was induced by ionizing radiation, hyperthermia, topotecan, and cytosine beta-D-arabinofuranoside. At 4 consecutive days following induction, apoptosis was detected by double-labelling, either with PI/annexin-V or PI/FDA. Forward and side scatter, red (PI), and green (FDA or annexin-V) fluorescence were measured by flow cytometry. RESULTS: While light scatter discriminated between morphologically damaged and undamaged cells, fluorescence differentiated vital, apoptotic, and dead cells. Equal proportions of these three subpopulations were detected by both staining techniques. Occasionally, early and mature apoptoses were identified as distinct clusters. During the 4-day observation period, no pronounced maxima of the apoptotic fractions were obtained with either treatment modality. The gradual increases usually showed a delay of 1-2 days. CONCLUSIONS: FDA and annexin-V are equally suitable for detecting apoptosis. Separation improves with time after induction, indicating that, with respect to test specificity, mature apoptoses are superior to early stages. However, the sensitivity towards low rates of apoptosis after weak induction appears limited with both staining procedures.

Differential proliferation dependence of alpha and beta damage in X-irradiated Chinese hamster cells.

PURPOSE: To determine quantitatively the influence of altering proliferation rates on clonal survival of asynchronously growing Chinese hamster (CHO) cells after X-irradiation and to evaluate the related contribution of alpha and beta damage. MATERIAL AND METHODS: Cell cycle distributions at the time of X-irradiation of CHO cells were assessed by flow cytometry. Clonal radiation survival was established by colony forming assay. Survival data were fitted to the linear-quadratic model and analyzed on the basis of the mean inactivation dose, D. RESULTS: Increased S-phases were associated with increased resistance to X-rays. Radiosensitivity as expressed by D differed by a factor of 1.6 between the most sensitive and the most resistant populations. Separately analyzing the alpha and beta coefficients of survival curves revealed that the proliferation dependent effect was correlated only with beta. The major determinant of D was alpha, but its substantial interexperimental variations were independent of the cell cycle. CONCLUSIONS: Due to altering cell cycle distributions, considerable changes of radiosensitivity can occur. They can in part be understood as a consequence of S-phase dependent alterations of DNA damage repair. Reasons for the changes of a damage dependent lethality remain to be discovered by further research.

Stable radiobiological features in a genetically unstable glioblastoma cell line.

In a human glioblastoma (grade IV) cell line, A7, the change in chromosome number, growth characteristics, radiosensitivity and DNA-repair capacity were determined during continuous culture over approximately 1300 generations. The median chromosome number fell from 101 to 85 while a remarkable variability was retained. The net population doubling time shortened from 21 to 16 h but no alterations were detected either in radiosensitivity or DNA-repair capacity, as measured by colony and plasmid-reconstitution assays respectively. Reviewing radiosensitivity data from the literature, it is considered that the relative radioresistance of glioblastomas might be inherited from the normal tissue from which they are derived.

Dose dependence of the cytokinetic and cytotoxic effects of epirubicin in vitro.

CHO cells were exposed in vitro for 1 h to concentrations of 0.1-20 micrograms/ml of the cytostatic drug epirubicin. Population growth, survival fractions, cell-cycle-phase distribution, and BrdU incorporation were analyzed. A fraction of the cells showed a transitory cytostatic reaction at 1 microgram/ml, and greater than 99% of the cells were killed at 10 micrograms/ml. The survival curve was biphasic with a steep slope at concentrations of up to 5 micrograms/ml. Approximately 0.1% of the cells were resistant to higher concentrations of epirubicin. Bivariate DNA/BrdU flow cytometry revealed that the sensitive cells were blocked and probably killed in the G2M phase of the cell cycle.

DNA flow cytometry in the prognosis of primary malignant melanoma.

DNA flow cytometry was carried out on 804 primary melanomas. The data were analyzed with a follow-up of 24-96 months. 57% of the cases were diploid, 32% had one abnormal cell population, and 11% were multiclonal. In 8% of the aneuploid tumors there were cell lines in the hypertetraploid range. A reliable S phase determination was possible in 524 cases. Among these 11% had an S phase exceeding 15%. Using an increased tumor thickness, relapse rate and mortality as criteria of tumor progression, aneuploidy and multiclonality, the occurrence of hypertetraploid cell lines and a high S phase (greater than 15%) proved to be correlated with a poor prognosis.

Sequential DNA flow cytometry in metastatic malignant melanoma.

Sequential flow cytometry was performed on 73 metastatic malignant melanomas, derived from 804 primary tumors. Tumor thickness was confirmed an excellent prognostic parameter in primary melanoma, but did not allow reliable predictions in metastatic disease. Also, aneuploidy and genetic heterogeneity, both common in metastatic melanoma, were equally distributed among patients differing in survival time. However, a remarkable acceleration was observed in the generation of abnormal cell lines in patients dying early of metastatic disease.

[Magnetic resonance imaging in the evaluation in utero of Siamese twins]. / Imagerie par résonance magnétique (IRM) dans le bilan in utero des jumeaux siamois.

The authors report a case of twins conjoined at the umbilicus and diagnosed by ultrasound after 19 weeks of amenorrhoea in whom an assessment in utero was carried out using magnetic resonance imaging after the patient had been curarized. A review of the literature on this very difficult problem of conjoined twins has given us the possibility to assess the diagnostic measures as well as the prognosis of this pathology. In particular we point out the results that can be obtained using MRI in utero during the second and third trimesters of the pregnancy.