Consensus conference: implementing treatment recommendations on yttrium-90 immunotherapy in clinical practice - report of a European workshop

Radiolabelled immunotherapy is a significant step forward in the treatment of non-Hodgkin's lymphoma (NHL), with preliminary data suggesting long remissions in some patients. 90Y-ibritumomab tiuxetan is the only therapy approved for use after rituximab failure and is currently indicated in the EU for the treatment of adults with rituximab-relapsed or refractory CD20-positive follicular B-cell NHL. However, retrospective analyses confirm better responses when 90Y-ibritumomab tiuxetan is used earlier in the disease course. An expert panel of oncologists, haematologists and nuclear medicine physicians met at an European workshop to discuss proposed therapeutic algorithms for follicular lymphoma and the preliminary medical evidence supporting the incorporation of 90Y-ibritumomab tiuxetan as an early therapeutic option. Phase II data indicate that 90Y-ibritumomab tiuxetan either alone as primary therapy or as consolidation therapy following induction chemotherapy with or without rituximab achieves high response rates in follicular lymphoma, with complete remission rates of 62-80%. Phase III data are warranted, but based on preliminary observations the expert panel recommended incorporation of radiolabelled immunotherapy into national lymphoma treatment algorithms across Europe. This approach would maximise the therapeutic potential of this agent by encouraging its use early in the disease course of follicular lymphomas.     

Brain tumor tropism of transplanted human neural stem cells is induced by vascular endothelial growth factor

The transplantation of neural stem cells (NSCs) offers a new potential therapeutic approach as a cell-based delivery system for gene therapy in brain tumors. This is based on the unique capacity of NSCs to migrate throughout the brain and to target invading tumor cells. However, the signals controlling the targeted migration of transplanted NSCs are poorly defined. We analyzed the in vitro and in vivo effects of angiogenic growth factors and protein extracts from surgical specimens of brain tumor patients on NSC migration. Here, we demonstrate that vascular endothelial growth factor (VEGF) is able to induce a long-range attraction of transplanted human NSCs from distant sites in the adult brain. Our results indicate that tumor-upregulated VEGF and angiogenic-activated microvasculature are relevant guidance signals for NSC tropism toward brain tumors.     

Enhanced TRAIL-mediated apoptosis in prostate cancer cells by the bioactive compounds neobavaisoflavone and psoralidin isolated from Psoralea corylifolia

Numerous compounds detected in medical plants and dietary components or supplements possess chemopreventive, antitumor and immunomodulatory properties. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an important endogenous anticancer factor that induces apoptosis selectively in cancer cells. However, some tumor cells are resistant to TRAIL-mediated apoptosis. Naturally occurring agents could sensitize TRAIL-resistant cancer cells and augment their apoptotic activity.We examined the cytotoxic and apoptotic effects of neobavaisoflavone and psoralidin in combination with TRAIL on LNCaP prostate cancer cells. The cytotoxicity was evaluated by MTT and LDH assays. The apoptosis was detected using Annexin V-FITC by flow cytometry and fluorescence microscopy. The LNCaP cells were shown to be resistant to TRAIL-induced apoptosis. Our study demonstrated that neobavaisoflavone and psoralidin sensitized TRAIL-resistant cells and markedly augmented TRAIL-mediated apoptosis and cytotoxicity in prostate cancer cells. Cotreatment of LNCaP cells with 100 ng/ml TRAIL and 50 μM neobavaisoflavone or 50 μM psoralidin increased the percentage of the apoptotic cells to 77.5±0.5% or 64.4±0.5%, respectively. The data indicate the potential role of the bioactive compounds isolated from the medicinal plant Psoralea corylifolia (neobavaisoflavone and psoralidin) in prostate cancer chemoprevention through enhancement of TRAIL-mediated apoptosis.     

HDR brachytherapy combined with interstitial hyperthermia in locally advanced cervical cancer patients initially treated with concomitant radiochemotherapy – a phase III study

Background and purpose

The aim of this randomised trial was to investigate whether hyperthermia (HT) combined with interstitial brachytherapy (ISBT) has any influence on local control (LC), disease-free survival (DFS), or acute and late side effects in patients with advanced cervical cancer.

Materials and methods

After radiochemotherapy, consecutive patients with cervical cancer (FIGO stage II–III) were randomly assigned to two treatment groups, either ISBT alone or ISBT combined with interstitial hyperthermia (ISHT). A total of 205 patients were included in the statistical analysis. Once a week, HT, at a temperature above 42.5 °C, was administered for 45 min before and during the HDR BT.

Results

The median follow-up time was 45 months (range 3–72 months). An effect of hyperthermia was not detected for disease-free survival (DFS) (log-rank test: p = 0.178) or for local control (LC) (p = 0.991). According to Cox’s analysis, HT did not significantly influence failure or interactions with potential prognostic factors for LC or DFS. Statistical differences were not observed for the distribution of early and late complications between the HT and non HT groups.

Conclusions

ISHT is well-tolerated and does not affect treatment-related early or late complications. Improvements in DFS and LC were not observed following the addition of ISHT to ISBT.     

Serum levels of IGF-I and IGFBP-3 in patients with lung cancer during chemotherapy

The aim of this study was to assess serum levels of insulin-like growth factors (IGF-I and IGFBP-3) in patients with lung cancer during chemotherapy. The study included 38 patients (33 males and 5 females; mean age 59.8) diagnosed histologically with lung cancer. Twenty-five patients (65%) had non-small cell lung cancer (NSCLC) and 13 patients (35%) had small cell lung cancer (SCLC). Squamous cell carcinoma was established in 30% (11 patients) of all patients with NSCLC, adenocarcinoma in 13% (5 patients), and non-small cell cancer in 36% (9 patients). The control group consisted of 10 healthy volunteers. Peripheral blood samples were taken before and after four cycles of chemotherapy. IGF-I and IGFBP-3 levels were assessed by ELISA method. Serum levels of IGF-I measured before chemotherapy were significantly higher in both NSCLC and SCLC groups in comparison with controls. No significant differences were observed in serum IGF-I levels before and after four cycles of chemotherapy. The levels were still high after chemotherapy in patients with NSCLC and SCLC. Serum levels of IGFBP-3 were markedly lower in patients with NSCLC both before and after treatment compared to controls. No significant differences were found in patients with NSCLC before and after cytoreduction treatment. Prior to treatment, serum IGFBP-3 levels were significantly lower in patients with SCLC in comparison with controls. After cytoreduction treatment, the levels were decreased when compared to controls but without statistical significance. In conclusion, both before and after chemotherapy serum levels of IGF-I were significantly higher, whereas IGFBP-3 levels were lower in patients with NSCLC and SCLC compared to controls. Chemotherapy had no influence on the serum levels of IGF-I and IGFBP-3. Neither a histological type of NSCLC nor clinical staging had any effect on the serum levels of IGF-I and IGFBP-3.     

KIF1A and EDNRB are differentially methylated in primary HNSCC and salivary rinses

Silencing of tumor suppressor genes plays a vital role in head and neck carcinogenesis. In this study, we aimed to evaluate to the utility of aberrant promoter hypermethylation for detection in a panel of 10 genes (KIF1A, EDNRB, CDH4, TERT, CD44, NISCH, PAK3, VGF, MAL and FKBP4) in head and neck squamous cell carcinoma (HNSCC) via a candidate gene approach. We investigated methylation of the gene promoters by bisulfite modification and quantitative methylation‐specific PCR (Q‐MSP) in a preliminary study of a limited cohort of salivary rinses from healthy subjects (n = 61) and patients with HNSCC (n = 33). The methylation status of 2 selected genes (EDNRB and KIF1A) were then analyzed in 15 normal mucosa samples from a healthy population, 101 HNSCC tumors and the corresponding salivary rinses from 71 out of the 101 HNSCC patients were collected before treatment. The promoter regions of CDH4, TERT, VGF, MAL, FKBP4, NISCH and PAK3 were methylated in normal salivary rinses while no methylation of CD44 was observed in either normal salivary rinses or tumor samples. However, KIF1A and EDNRB were methylated in 98 and 97% of primary HNSCC tissues respectively and were only methylated in 2 and 6.6% of normal salivary rinses. In addition, KIF1A and EDNRB were methylated in 38 and 67.6% of salivary rinses from HNSCC patients, respectively. Promoter hypermethylation of KIF1A and EDNRB is a frequent event in primary HNSCC, and these genes are preferentially methylated in salivary rinses from HNSCC patients. KIF1A and EDNRB are potential biomarkers for HNSCC detection.     

Pharmacodynamic analysis of recombinant human erythropoietin effect on reticulocyte production rate and age distribution in healthy subjects

OBJECTIVE: To evaluate the effect of recombinant human erythropoietin (rHuEPO) on the reticulocyte production rate and age distribution in healthy subjects. METHODS: Extensive pharmacokinetic and pharmacodynamic data collected from 88 subjects who received a single subcutaneous dose of rHuEPO (dose range 20-160 kIU) were analysed. Four nonlinear mixed-effects models were evaluated to describe the time course of the percentage of reticulocytes and their age distribution in relation to rHuEPO pharmacokinetics. Model A accounted for stimulation of the production of progenitor cells in bone marrow, and model B implemented shortening of differentiation and maturation times of early progenitors in bone marrow. Model C was the combination of models A and B, and model D was the combination of model A with an increase in the maturation times of the circulating reticulocytes. Model evaluation was performed using goodness-of-fit plots, a nonparametric bootstrap and a posterior predictive check. RESULTS: Model D was selected as the best model, and evidenced accurate and precise estimation of model parameters and prediction of the time course of the percentage of reticulocytes. At baseline, the estimated circulating reticulocyte maturation time was 2.6 days, whereas the lifespan of the precursors in the bone marrow was about 5 days. The rHuEPO potency for the stimulatory effect (7.61 IU/L) was higher than that for the increase in reticulocyte maturation times (56.3 IU/L). There was a significant 1- to 2-day lag time in the reticulocyte response. The effect of rHuEPO on the reticulocyte age distribution consisted of a transient increase in the reticulocyte maturation time from baseline up to 6-7 days, occurring 1 day after administration. The dose-dependent amplitude of the changes in the age distribution lasted for 12-14 days. The model-predicted peak increase in the reticulocyte release rate ranged from 140% to 160% of the baseline value and was maximal on days 7-8 following rHuEPO administration. CONCLUSIONS: A semiphysiological model quantifying the effect of rHuEPO on the reticulocyte production rate and age distribution was developed. The validated model predicts that rHuEPO increases the reticulocyte production rate and modifies the reticulocyte age distribution in a dose-dependent manner.     

Basic pharmacodynamic models for agents that alter the lifespan distribution of natural cells

A new class of basic indirect pharmacodynamic models for agents that alter the loss of natural cells based on a lifespan concept are presented. The lifespan indirect response (LIDR) models assume that cells (R) are produced at a constant rate (k(in)), survive during a certain duration T(R), and finally are lost. The rate of cell loss is equal to the production rate but is delayed by T(R). A therapeutic agent can increase or decrease the baseline cell lifespan to a new cell lifespan, T(D), by temporally changing the proportion of cells belonging to the two modes of the lifespan distribution. Therefore, the change of lifespan at time t is described according to the Hill function, H(C(t)), with capacity (E(max)) and sensitivity (EC(50)), and the pharmacokinetic function C(t). A one-compartment cell model was examined through simulations to describe the role of pharmacokinetics, pharmacodynamics and cell properties for the cases where the drug increases (T(D) > T(R)) or decreases (T(D) < T(R)) the cell lifespan. The area under the effect curve (AUCE) and explicit solutions of LIDR models for large doses were derived. The applicability of the model was further illustrated using the effects of recombinant human erythropoietin (rHuEPO) on reticulocytes. The cases of both stimulation of the proliferation of bone marrow progenitor cells and the increase of reticulocyte lifespans were used to describe mean data from healthy subjects who received single subcutaneous doses of rHuEPO ranging from 20 to 160 kIU. rHuEPO is about 4.5-fold less potent in increasing reticulocyte survival than in stimulating the precursor production. A maximum increase of 4.1 days in the mean reticulocyte lifespan was estimated and the effect duration on the lifespan distribution was dose dependent. LIDR models share similar properties with basic indirect response models describing drug stimulation or inhibition of the response loss rate with the exception of the presence of a lag time and a dose independent peak time. The current concept can be applied to describe the pharmacodynamic effects of agents affecting survival of hematopoietic cell populations yielding realistic physiological parameters.     

Health and life style-related determinants of survival rate in the male residents of the city of Łódź

Introduction

The article presents a selected part of an analysis of health- and lifestyle-related determinants of the longevity of male residents of the city of ?ód?. The WHO strategy for the European region assumes that the term’ lifestyle’ refers to the way of life based on the association between conditions of life understood in a broad sense and individual patterns of behaviour determined by socio-cultural factors and individual features. On this basis, the aim of this study is to identify the multiple statistical relationships on the mortality of men living in ?ód?, particularly the influence of the following variables on the probability of survival: age, subjective health assessment, nutritional habits, alcohol consumption and tobacco smoking.

Materials and Methods

The study sample (1004 respondents) was selected, and the study was carried out, based on the standards of the CINDI WHO Programme. The investigations included socio-demographic data, health status, lifestyle and anthropometric measurements.

Results

From the results of the first-study performed in Poland of the longevity of men with identified risk factors of cardiovascular diseases, it has been found that: 1) Tobacco smoking has a negative influence on male longevity; 2) Alcohol consumed in moderate amounts favours male longevity; 3) The level of physical activity observed among the studied men was too low to affect longevity; 4) A diet rich in fish and consumption of yellow cheese are positive predictors of longevity, while additional use of table salt at meals and consumption of sweets (cakes) are negative ones.

Conclusions

Risky lifestyles and a reluctance to abandon them are responsible for a shorter lifespan among men in Poland. Reducing this difference between women and men is a real challenge for public health professionals and preventive medicine specialists.     

Gender differentiation of indirect self-destructiveness

Objectives

The objective of this study was to examine the sex (gender) differentiation of indirect self-destructiveness intensity and its manifestations, as well as relationships between indirect self-destructiveness and its manifestations (categories) and the psychological dimensions of masculinity and femininity, also from the point of view of assessing occupational health and safety.

Materials and Methods

A population of 558 individuals (399 females and 159 males) aged 19–25 (mean age: 22.6) was studied. The Polish version of the “Chronic Self-Destructiveness Scale” (CS-DS) by Kelley adapted by Suchańska was used in order to examine indirect self-destructiveness and its manifestations. Gender testing applied the Polish version of the Bem Sex Role Inventory (BSRI) by Bem in its adaptation by Kuczyńska.

Results

Males’ scores are significantly higher than those of females for the majority of CS-DS scales/indices: Indirect Self-Destructiveness (general index), Poor Health Maintenance (A2), Lack of Planfulness (A4), and Helplessness, Passiveness (A5). Moreover, there are statistically significant correlations between CS-DS scales and the masculinity dimension (positive) as well as the femininity dimension (negative).

Conclusions

Masculinity is a factor that may predispose towards indirectly self-destructive behaviors, while femininity is a factor protecting against those. The study results may prove useful in preventing indirectly and directly self-destructive behaviors as well as in therapy work with the individuals who display such tendencies or have made attempts on their own lives, in particular taking into account their being of a specific sex/gender and in the context of work (especially in difficult or dangerous conditions or both).