Long-term outcomes among localized prostate cancer survivors: prospective predictors for return-to-work three years after cancer rehabilitation.

PURPOSE: This study aimed at (1) investigating the work status of men treated by radical prostatectomy due to diagnosis of localized prostate cancer (LPCa) three years after having attended a cancer rehabilitation program and (2) identifying prospective risk factors for not working at this time point. METHODS: In a longitudinal, questionnaire-based multicenter study, 519 working-age LPCa survivors reported on their work status 12 and 36 months following rehabilitation. Chi-square tests/t tests and multivariable logistic regression analysis were used to identify prospective factors associated with not working at 36 months follow-up. RESULTS: Nearly three quarter of LPCa survivors (N = 377, 73%) worked 3 years after post-acute rehabilitation. Most participants (N = 365, 71%) showed continuous return-to-work (RTW) patterns as they worked both 1 and 3 years following rehabilitation. Multivariable regression analysis revealed older age, low or middle socio-economic status as well as resigned and unambitious work behavior and fatigue at the time of attending the rehabilitation program to be prospective factors for not working at 36 months follow-up. Low socio-economic status [Odds ratio (OR) 4.81, 95% confidence interval (CI) 2.07-11.16] and unambitious work behavior [OR 4.48, 95% CI 2.16-9.31] were the strongest predictors. CONCLUSION: Long-term work retention is a realistic goal among LPCa survivors. The results contribute to the identification of at-risk LPCa survivors early in the RTW process. Special attention should be paid to social inequality. Further, interventions related to the management of fatigue and work-related coping styles could improve long-term RTW, as these were relevant, but potentially modifiable factors impeding work retention.

Identifying Expectations of Delayed Return to Work in Patients with Prostate Cancer at the Beginning of a Cancer Rehabilitation Program.

Purpose To investigate factors associated with expectations of delayed return to work (RTW) in patients with prostate cancer recently admitted to a cancer rehabilitation program. Methods In this multicenter study, data about expected time until RTW and potential correlates (personal, medical, psychosocial and work-related factors) were obtained from 822 employed cancer rehabilitation participants at the beginning of the program. Participants expecting early RTW (≤ 3 months) and delayed RTW (> 3 months) were compared. Hierarchical multivariate logistic regression was applied to study which factors are associated with expecting delayed RTW. Results In total, 171 cancer rehabilitation participants (21%) expected delayed RTW. Group comparison showed education, type of occupation, income, number of comorbid conditions, tumor stage according to the staging system of the Union for International Cancer Control (UICC), anxiety and depression, quality-of-life functioning scales, urinary and treatment-related symptoms, duration of sick leave, subjective work ability, perceived ability to return to the former job, intention to apply for a disability pension, effort-reward-imbalance and occupational stress to be associated in bivariate analysis with participants' expectations. Multivariate analysis revealed UICC tumor stage III (compared to stages I/II, OR 2.36), lower subjective work ability (OR 0.82), perceived inability to return to the former job (OR 1.88) and intention to apply for a disability pension (OR 1.94) to increase the likelihood of expecting delayed RTW. Conclusions Negative or non-beneficial RTW expectations, which are related to self-perception and behavioral intention, seem to be key factors for expecting delayed RTW. Interventions to early identify and adjust such expectations might empower cancer rehabilitation participants to develop appropriate expectations for work recovery.

Return to work in prostate cancer survivors - findings from a prospective study on occupational reintegration following a cancer rehabilitation program.

BACKGROUND: This prospective multicentre-study aimed to analyze return to work (RTW) among prostate cancer survivors 12 months after having attended a cancer rehabilitation program and to identify risk factors for no and late RTW. METHODS: Seven hundred eleven employed prostate cancer survivors treated with radical prostatectomy completed validated self-rating questionnaires at the beginning, the end, and 12 months post rehabilitation. Disease-related data was obtained from physicians and medical records. Work status and time until RTW were assessed at 12-months follow-up. Data were analyzed by univariate analyses (t-tests, chi-square-tests) and multivariate logistic regression models (OR with 95% CI). RESULTS: The RTW rate at 12-months follow-up was 87% and the median time until RTW was 56 days. Univariate analyses revealed significant group differences in baseline personal characteristics and health status, psychosocial well-being and work-related factors between survivors who had vs. had not returned to work. Patients' perceptions of not being able to work (OR 3.671) and feeling incapable to return to the former job (OR 3.162) were the strongest predictors for not having returned to work at 12-months follow-up. Being diagnosed with UICC tumor stage III (OR 2.946) and patients' perceptions of not being able to work (OR 4.502) were the strongest predictors for late RTW (≥ 8 weeks). CONCLUSIONS: A high proportion of prostate cancer survivors return to work after a cancer rehabilitation program. However, results indicate the necessity to early identify survivors with low RTW motivation and unfavorable work-related perceptions who may benefit from intensified occupational support during cancer rehabilitation.

Outcomes across the return-to-work process in PC survivors attending a rehabilitation measure-results from a prospective study.

PURPOSE: Approximately 60% of patients are able to work following a cancer diagnosis. The return-to-work (RTW) process after disability can be conceptualized as a multi-phase construct. This study investigated RTW outcomes throughout the RTW process among survivors of prostate cancer (PC) attending a cancer rehabilitation measure. METHODS: The study was based on a sample of 837 employed PC survivors enrolled in a longitudinal multicenter study. Data was collected at the beginning of the rehabilitation measure, at the end and at 12-month follow-up by means of self-report questionnaires. We compared outcomes with regard to age (<60 and ≥60 years) and socio-economic status (SES; lower, middle, higher) using t tests or univariate ANOVA for metrical and chi-square test or Fisher's exact test for categorical variables. RESULTS: In the off-work phase, most survivors reported positive expectations regarding future work, including responsiveness of their work environment. Nevertheless, one fourth intended to apply for a disability pension. At 12-month follow-up, the RTW rate was 87% and 62% when applying more conservative criteria of RTW. Among survivors who had returned to work, most reported stability of the work situation. Survivors with lower SES showed least favorable outcomes throughout the RTW process, while older age was less consistently of negative impact. CONCLUSIONS: Survivors reported many favorable RTW outcomes, but low SES might be a barrier at various stages of the RTW process. Thus, special attention must be paid to the role of social inequalities during rehabilitation and work reintegration to help survivors managing the RTW process.

Psychosocial and physical outcomes of in- and outpatient rehabilitation in prostate cancer patients treated with radical prostatectomy.

PURPOSE: A radical prostatectomy might lead to an impaired quality of life. Aim of the study was to analyse the impact of inpatient and outpatient rehabilitation on psychosocial and physical outcomes in patients after surgery. METHODS: Six hundred nineteen inpatients and 95 outpatients, treated for localized prostate cancer by prostatectomy, completed the Hospital Anxiety and Depression Scale (HADS) and two quality-of-life questionnaires (EORTC QLQ-C30 and EORTC QLQ-PR25) at the beginning and end of rehabilitation as well as 12 months after rehabilitation. Data were analysed by using t-tests, chi(2) - tests and analyses of variance with repeated measures. RESULTS: Compared to a population sample, patients reported a significantly worse quality of life (EORTC QLQ-C30) and more anxiety (HADS) at the beginning of rehabilitation. Physical, role and social functioning increased significantly over time for in- and outpatients. Patients still reported lower emotional functioning (EORTC QLQ-C30), anxiety (HADS) and prostate cancer-specific physical symptoms (EORTC QLQ-PR25) 1 year after rehabilitation, although symptom levels decreased significantly over time. The setting did not have an independent significant effect in the multivariate model. CONCLUSIONS: In- and outpatients reported an increased quality of life 1 year after rehabilitation with respect to their physical constitution and their reintegration into social life. Nonetheless, both groups still struggled with problems due to surgery. The results indicated that both settings seem to be supportive in the recovery process but that patients seem to require additional support with aftercare for treating surgery-related problems as well as emotional discomfort.

Adverse and long-term protective effects following oil-adjuvanted vaccination against Aeromonas salmonicida in rainbow trout.

Prophylactic measures against Aeromonas salmonicida subsp. salmonicida, the causative agent of furunculosis, have been an active field of research for decades, with studies mainly focused on Atlantic salmon (Salmo salar). In the present study we have examined the protective and adverse effects of mineral oil-adjuvanted injection vaccines on rainbow trout (Oncorhynchus mykiss). A commercial vaccine and an experimental auto vaccine, as well as their respective adjuvant formulations alone were used to evaluate their individual effects, both prior to and during an experimental waterborne infection challenge. Macro- and microscopic examination revealed signs of vaccine-induced adverse effects from 10 weeks to 14 months post vaccination. Both vaccines induced statistically significant protection during the experimental challenge (P=0.018 for both vaccines), as well as significantly elevated levels of specific circulating antibodies prior to and during the experimental challenge when compared to an unvaccinated control group. During the early, critical time points of the infection, both vaccines appeared to protect against pathological changes to the liver and spleen, which provides a probable explanation for the reduced mortality seen in the vaccinated groups. A significant correlation was found between the level of A. salmonicida-specific antibodies measured prior to challenge and the endpoint survival of each group after the experimental infection, and furthermore, the levels of these antibodies remained elevated for at least 14 months post vaccination.

Long-lasting protection induced by bath vaccination against Aeromonas salmonicida subsp. salmonicida in rainbow trout.

For decades Aeromonas salmonicida subsp. salmonicida (from here referred to as A. salmonicida) has been recognized as the causative agent of typical furunculosis. This disease has had a major impact on aquaculture worldwide, making it a target for international research, particularly within the field of immunoprohylaxis. Initial studies attempted vaccination via oral route and immersion. However, these vaccination methods proved insufficient when compared to intraperitoneally (i.p.) injected vaccines. The focus of vaccine research regarding A. salmonicida shifted towards the i.p.-injected vaccines during the 1980's and -90's, resulting in oil-adjuvanted vaccines providing high levels of protection over longer periods of time. The majority of this research has been conducted using salmon, while rainbow trout, which is also a commercially important species, has played a much less central role. In this study, we have examined the effect of a bath vaccination using an experimental A. salmonicida bacterin. Rainbow trout were vaccinated by a 5 min bath in a formalin-inactivated bacterin. Half of these fish was booster vaccinated using 50% of the initial vaccine dose 10 weeks post primary immunization. Along with an un-vaccinated control group, the fish were challenged by waterborne infection 24 weeks post primary immunization. Both vaccinated groups showed a significantly increased survival (>93% survival) compared to a 70% survival in the un-vaccinated control group (P = 0.005 and P = 0.019 for single and dual immunizations, respectively). When comparing the survival of the single and dual immunization groups, there was no significant difference (P = 0.531). ELISA showed no significant induction of specific circulating antibodies in either vaccinated group. These results are interesting with regard to the protective mechanisms, seen in the light of previous results obtained using bath as well as i.p. vaccination against furunculosis in salmonid fishes.

Association between Yersinia ruckeri infection, cytokine expression and survival in rainbow trout (Oncorhynchus mykiss).

The immune response against bacterial pathogens has been widely studied in teleosts and it is evident that survival chances differ significantly within a host population. Identification of indicators for susceptibility and responsiveness will improve our understanding of this host-pathogen interaction. The present work shows that the transcripts of cytokine genes in blood cells sampled three days post-infection was significantly higher in fish which obtained a high bacteriemia and died at later time points when compared to both non-infected control fish and infected fish that survived the infection. Rainbow trout were infected by bath challenge in a bacterial suspension (LD(60) dose, 1.8 × 10(9) CFU/ml Yersiniaruckeri for 1 h) and subsequently transferred to individual aquaria for 30 days of observation. Blood samples were analyzed for presence of Y. ruckeri both by culture and quantitative RT real-time PCR (qRT-PCR) and transcript levels of 28 genes encoding molecules which are important in the immune response. The transcript levels of a number of central cytokines, chemokines and cytokine receptors (IL-1ß, IL-6, IL-8, IL-10, TNF-α, IL-receptor II) were significantly increased in infected fish that died later. In addition, a significantly higher amount of Y. ruckeri was found in the blood of the fish that died when compared to survivors. The study indicates that highly susceptible trout obtain an early heavy septicemia infection, which elicits a high up-regulation of the transcript of pro-inflammatory cytokines. Thus, less susceptible fish are protected by other factors and contract merely a weak non-lethal infection eliciting no or a weak cytokine response.

A randomized phase II trial of efficacy and safety of the immunotherapy ALECSAT as an adjunct to radiotherapy and temozolomide for newly diagnosed glioblastoma.

BACKGROUND: There is an urgent need for effective treatments against glioblastoma (GBM). In this trial, we investigated the efficacy and safety of an adoptive cell-based immunotherapy. METHODS: Patients with newly diagnosed GBM were recruited at 4 study sites in Sweden. The patients were randomized 1:2 to receive either radiotherapy (RT), 60 Gy/30 fractions, with concomitant and adjuvant temozolomide (TMZ) only, or RT and TMZ with the addition of Autologous Lymphoid Effector Cells Specific Against Tumor (ALECSAT) in an open-label phase II trial. The primary endpoint was investigator-assessed progression-free survival (PFS). The secondary endpoints were survival and safety of ALECSAT. RESULTS: Sixty-two patients were randomized to either standard of care (SOC) with RT and TMZ alone (n = 22) or SOC with ALECSAT (n = 40). Median age was 57 years (range 38-69), 95% of the patients were in good performance status (WHO 0-1). There was no significant difference between the study arms (SOC vs ALECSAT + SOC) in PFS (7.9 vs 7.8 months; hazard ratio [HR] 1.28; 95% confidence interval [CI] 0.70-2.36; P = .42) or in median overall survival (OS) (18.3 vs 19.2 months; HR 1.16, 95% CI 0.58-2.31; P = .67). The treatment groups were balanced in terms of serious adverse events (52.4% vs 52.5%), but adverse events ≥grade 3 were more common in the experimental arm (81.0% vs 92.5%). CONCLUSION: Addition of ALECSAT immunotherapy to standard treatment with radiochemotherapy was well tolerated but did not improve PFS or OS for patients with newly diagnosed GBM.

Does a Train-the-Trainer Approach for Enhancing Healthcare Professionals' Skills in Patient Education during Inpatient Medical Rehabilitation Improve Patient Outcomes?

This study is aimed at identifying the impact of a team-based train-the-trainer program (TTT-P) to enhance healthcare professional (HCP) skills in patient education during medical rehabilitation. Focusing on patient-reported outcomes, a prospective, sequential two-cohort study was conducted in the fields of psychosomatic and oncological rehabilitation. Two hundred fifteen patients were evaluated before (Cohort 1) and 196 post implementation of TTT-P (Cohort 2). Patients of both cohorts completed validated questionnaires on self-management (heiQ®), general self-efficacy (GSE scale), and quality of life (WHOQOL-Bref) at the beginning, at the end, and at the 6-month follow-up to analyze short- and intermediate-term effects. Analyses were conducted separately for the psychosomatic and oncological setting. Results showed that TTT-P had no impact on patient outcomes in both rehabilitation settings. Patients did report positive outcomes as a result of the whole inpatient rehabilitation programs, though effects at follow-up were mostly small to medium size. Concerning self-management competencies, cancer patients gained less benefit during rehabilitation than psychosomatic patients. In conclusion, TTT-P did not result in measurable improvements at the patient level, likely because of the limited nature of the intervention. However, these populations of rehabilitants took benefit from participating in a multimodal rehabilitation program, of which patient education is one part.

Innate immune response in rainbow trout (Oncorhynchus mykiss) against primary and secondary infections with Yersinia ruckeri O1.

Response mechanisms in teleosts against bacterial pathogens have been widely studied following injection procedures applying preparations of killed bacteria. In contrast, investigations on immune reactions in fish which have survived a primary infection and subsequently have been challenged are few or lacking. However, knowledge on these factors during infection and re-infection could provide the basis for development of improved vaccines. The innate immune response in rainbow trout (Oncorhynchus mykiss) against Yersinia ruckeri O1 has been studied following a primary intra-peritoneal injection with 5 x 10(5) CFU Y. ruckeri, and after bacterial clearance a secondary infection 35 days later. The number of pathogens in the liver was measured with a Y. ruckeri specific 16S ribosomal RNA quantitative real-time RT-PCR (q-PCR) during the course of infection. The bacterial counts peaked on day 3 during the primary infection and were significantly lower during the re-infection. Re-challenged fish showed a highly increased survival when compared to the naïve fish receiving a primary infection indicating development of adaptive immunity in the fish against this bacterial pathogen. We investigated the gene expression of innate immune factors in the liver during infections in order to elucidate molecules involved in survival of hosts before adaptive immunity was mounted. Transcription of mRNA was measured in liver samples taken 8 h, 1, 3, 7, 14 and 28 d post-infection using q-PCR. The investigation focused on genes encoding toll-like receptor 5 (TLR5), the pro-inflammatory cytokines IL-1beta, IL-6 and TNF-alpha, the acute phase proteins (APPs) serum amyloid protein a (SAA), trout C polysaccharide binding protein, a CRP/SAP like pentraxin, precerebellin, transferrin, hepcidin and finally the complement factors C3, C5 and factor B. Infection elicited significantly increased gene expression of all the cytokines (IL-6 > 1000-fold), some acute phase proteins (SAA > 3000-fold) and down-regulation of complement factors (C3, C5 and factor B). SAA expression was significantly earlier activated during the re-infection when compared to the primary infection. The pattern of gene activation suggested that the innate response was based on pathogen binding to toll-like receptors, production of cytokines and subsequent release of APPs. In general, both the innate immune response and the amount of Y. ruckeri measured in the liver during the re-infection was much lower compared to the first infection, probably reflecting development of adaptive immunity.

Response of rainbow trout (Oncorhynchus mykiss) in skin and fin tissue during infection with a variant of Gyrodactylus salaris (Monogenea: Gyrodactylidae).

Response mechanisms of rainbow trout Oncorhynchus mykiss (Walbaum), experimentally infected with a Danish strain of Gyrodactylus salaris Malmberg, 1957 were investigated using molecular tools (qPCR) and immunohistochemistry. Expression of ten immune-relevant genes and reactivity with five different antibodies in the epidermis of skin and fin tissue were analysed in susceptible but responding rainbow trout. Rainbow trout were susceptible with regard to the parasite strain which initially colonised fins but relocated to the body region as infection progressed. The ten investigated genes encoding the cytokines IL-1beta, TNF-alpha, IFN-gamma, IL-10 and markers for adaptive immune activity, such as CD-4, CD-8, TCR-alpha, IgM, IgT and MHC II, were not found significantly regulated during the course of infection although IFN-gamma showed a slight up-regulation. Immunohistochemical analyses showed positive reactivity with antibodies against CD3, B-lymphocytes, neutrophilic granulocytes and collectin but not with mAb against IgM. No staining differences between infected and non-infected skin and fin tissue were detected.

Immune-relevant genes expressed in rainbow trout following immunisation with a live vaccine against Ichthyophthirius multifiliis.

Rainbow trout Oncorhynchus mykiss were immunised by intra-peritoneal injection using a live vaccine based on Ichthyophthirius multifiliis (Ich) theronts, which previously has shown protection against white spot disease. Samples were taken pre-vaccination and on Day 1, 7, 21 and 28 post-immunisation (p.i.). Expression of immune relevant genes in the liver, spleen and head kidney was monitored by qPCR. To describe the immune reaction following this immunisation, a series of genes encoding cytokines, complement factors, immunoglobulins and acute phase reactants were studied. Genes encoding acute phase reactants in the liver were up-regulated with serum amyloid A (SAA) as the most pronounced with a 2299-fold increase at 24 h p.i. Hepcidin and pre-cerebellin were also up-regulated in the liver 24 h p.i., by 7- and 4-fold, respectively. Complement factors C3, C5 and factor B (Bf) were up-regulated in the spleen and the head kidney 24 h and 28 d p.i. Genes encoding immunoglobulins were not up-regulated, but a specific low titer IgM response (titer 25) against parasite antigens was detected by a modified ELISA 4 wk p.i.

Temperature-dependent expression of immune-relevant genes in rainbow trout following Yersinia ruckeri vaccination.

The gene expression of immune-relevant genes in rainbow trout Oncorhynchus mykiss following vaccination with a bacterin of Yersinia ruckeri, a bacterial pathogen causing enteric red mouth disease (ERM), was investigated at 5, 15, and 25 degrees C. Rainbow trout were immunized by i.p. injection of a water-based Y. ruckeri (serotype O1) bacterin, and gene expression profiles were compared to control groups injected with phosphate buffered saline (PBS). Blood and tissue samples (spleen and head kidney) were taken for subsequent analysis using solid phase enzyme-linked immunosorbent assay (ELISA) and real-time PCR, respectively. The up-regulation of cytokine genes was generally faster and higher at high water temperature, with major expression at 25 degrees C. The proinflammatory cytokine interleukin (IL)-1beta and interferon (IFN)-gamma were significantly up-regulated in all immunized groups, whereas the cytokine IL-10 was only up-regulated in fish kept at 15 and 25 degrees C. The gene encoding the C5a (anaphylatoxin) receptor was expressed at a significantly increased level in both head kidney and spleen of immunized fish. The secreted immunoglobulin M (IgM)-encoding gene was significantly up-regulated in the head kidney of immunized trout reared at 25 degrees C, and a positive correlation (r = 0.663) was found between gene expression of secreted IgM in the head kidney and Y. ruckeri-specific antibodies in plasma measured by ELISA. However, no regulation of the teleost specific immunoglobulin T (IgT), which was generally expressed at a much lower level than IgM, could be detected. The study indicated that expression of both innate and specific adaptive immune-response genes are highly temperature-dependent in rainbow trout.

Allogeneic hematopoietic cell transplantation (HCT) following reduced-intensity conditioning in patients with acute leukemias.

The majority of patients with acute leukemia enter complete remission following induction therapy, but relapse despite consolidation and maintenance chemotherapy. Allogeneic hematopoietic cell transplantation (HCT) is the most effective consolidation therapy but unfortunately associated with high transplant-related mortality (TRM). In order to decrease TRM but still apply a graft-versus-tumor effect, allogeneic HCT protocols with reduced-intensity conditioning were developed and more than 5000 HCT, of which 1500 for acute leukemia, performed. Detailed information is available on more than 400 patients with acute leukemia. The results, summarized in this article, confirm that reduced-intensity preparative regimens lead to full donor chimerism and to generation of graft-versus-leukemia (GvL) effects with curative potential in older patients (>60 years). Prospective-controlled clinical trials are needed in younger patients to compare results of HCT after reduced-intensity conditioning to those of HCT with conventional conditioning.

Expression of bone morphogenetic protein 2 in breast cancer cells inhibits hypoxic cell death.

BMP-2 is involved in the fetal and postnatal development of the mammary gland but has also been detected in breast cancer cells. To clarify the biological role of BMP-2 in breast cancer, we used the human breast cancer cell line MCF-7. Incubation with BMP-2 under serum-free conditions induced activation of the mitogen activated protein kinases (MAPKs) ERK1/2 and the basic helix-loop-helix transcription factors Id-1, proteins that can protect from apoptosis. Stably transfected MCF-7 cells overexpressing BMP-2 revealed significantly increased resistance to hypoxia-induced apoptosis compared to empty vector controls. Cytoplasmic BMP-2/4 protein expression was detected in carcinoma cells of 81 samples of invasive breast cancer in contrast to adjacent normal mammary epithelial cells. BMP-2/4 expression did not correlate with common prognostic parameters and was not associated with relapse-free or overall survival. We conclude that BMP-2/4 expression is reactivated in invasive breast cancer and part of an autocrine/paracrine mechanism rescuing malignant cells from hypoxic cell death via activation of the MAPK and Id-1 pathway.

Bone morphogenetic protein 2 (BMP-2) induces in vitro invasion and in vivo hormone independent growth of breast carcinoma cells.

Breast cancer cell lines migrated towards a BMP-2 source depending on BMP-2 concentration. After a short exposure to BMP-2, the cells were able to migrate through matrigel. MCF-7 cells transfected with the BMP-2 gene also showed enhanced migratory properties and high expression of the metastasis-related gene BCSG1. In a xenograft model without estrogen supplementation MCF-7/BMP-2 cells formed tumors. These tumors were characterised by an enhanced vasculature and the formation of chondroid and osseous structures. In conclusion elevated levels of BMP-2 enhance the tumorigenic properties of breast carcinoma cells and drive the cells towards a more aggressive phenotype with estrogen independent growth.

Bone morphogenetic protein 2 (BMP-2) and induction of tumor angiogenesis.

PURPOSE: Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta family and play an important role in the regulation of embryonic vasculogenesis but their role in postnatal angiogenesis remains to be clarified. In this study we investigated a possible role of BMP-2 in the promotion of tumor angiogenesis. METHODS: We studied the effect of BMP-2 on human dermal microvascular endothelial cells (HDMECs) and examined a possible angiogenic activity of BMP-2 with the mouse sponge assay. The effect of BMP-2 overexpression on tumor vascularization was also analyzed in xenografts of human BMP-2 transfected MCF-7 breast cancer cells (MCF-7/BMP2) in mice. RESULTS: BMP receptor activation selectively induced the phosphorylation of p38 mitogen-activated protein kinase (MAPK) in contrast to the ERK1/2 MAP kinases. In keeping with this finding, BMP-2 had no significant effect on endothelial cell proliferation but promoted HDMEC tube formation in the matrigel assay. The transcription factor inhibitor of differentiation 1 (Id1), which is known to play an important role in neovascularization of tumors, was confirmed as a BMP target in HDMECs. Immunohistochemical analysis of sponge sections revealed that BMP-2 induced vascularization and showed an additive enhancement of angiogenesis with VEGF. In the murine breast cancer xenograft model, human MCF-7 cells with stable overexpression of BMP-2 developed vascularized tumors while empty vector control MCF-7 cells failed to form tumors. CONCLUSIONS: We conclude that activation of the BMP pathway by BMP-2 can promote vascularization and might be involved in tumor angiogenesis possibly by stimulating the Id1 and p38 MAPK pathway.

Global 3D imaging of Yersinia ruckeri bacterin uptake in rainbow trout fry.

Yersinia ruckeri is the causative agent of enteric redmouth disease (ERM) in rainbow trout, and the first commercially available fish vaccine was an immersion vaccine against ERM consisting of Y. ruckeri bacterin. The ERM immersion vaccine has been successfully used in aquaculture farming of salmonids for more than 35 years. The gills and the gastrointestinal (GI) tract are believed to be the portals of antigen uptake during waterborne vaccination against ERM; however, the actual sites of bacterin uptake are only partly understood. In order to obtain insight into bacterin uptake during waterborne vaccination, optical projection tomography (OPT) together with immunohistochemistry (IHC) was applied to visualize bacterin uptake and processing in whole rainbow trout fry. Visualization by OPT revealed that the bacterin was initially taken up via gill lamellae from within 30 seconds post vaccination. Later, bacterin uptake was detected on other mucosal surfaces such as skin and olfactory bulb from 5 to 30 minutes post vaccination. The GI tract was found to be filled with a complex of bacterin and mucus at 3 hours post vaccination and the bacterin remained in the GI tract for at least 24 hours. Large amounts of bacterin were present in the blood, and an accumulation of bacterin was found in filtering lymphoid organs such as spleen and trunk kidney where the bacterin accumulates 24 hours post vaccination as demonstrated by OPT and IHC. These results suggest that bacterin is taken up via the gill epithelium in the earliest phases of the bath exposure and from the GI tract in the later phase. The bacterin then enters the blood circulatory system, after which it is filtered by spleen and trunk kidney, before finally accumulating in lymphoid organs where adaptive immunity against ERM is likely to develop.

Chronomodulated chemotherapy in metastatic gastrointestinal cancer combining 5-FU and sodium folinate with oxaliplatin, irinotecan or gemcitabine: the Jena experience in 79 patients.

PURPOSE: To study efficacy and tolerability of chronomodulated (CM)-chemotherapy in patients with metastatic or locally advanced tumors of the GI tract. Furthermore, calcium folinate was replaced by sodium folinate due to better feasibility. PATIENTS AND METHODS: We treated 79 patients with metastatic or locally advanced colorectal cancer ( n=52), cancer of the pancreas/biliary tract ( n=14), and other malignancies ( n=14) with a total of 592 courses of CM-therapy. Out of the total study population 53/79, i.e., 67.1% had received prior chemotherapy. Most of the patients (77.2%) received sodium-folinate-5-FU-oxaliplatin-CM (SOFOX-CM) as first-line chronomodulated therapy, 20.3% received sodium-folinate-5-FU-irinotecan-CM (SOFIRI-CM), and 2.5% ( n=1) received sodium-folinate-5-FU-gemcitabine-CM (SOFGEM-CM). RESULTS: We found a moderate overall toxicity with grade 3-4 neuropathy in 7.46% of patients during a total of 433 courses of SOFOX-CM and grade 3-4 diarrhea in 10.26% of patients after 154 courses of SOFIRI-CM. SOFOX-CM had to be stopped only in one patient due to grade 3-4 sensory neuropathy. CM-therapy led to complete response (CR) in 1.3%, partial response (PR) in 15.2%, stable disease (SD) in 32.9%, and progressive disease (PD) in 44.3% of all patients. For the 26 chemonaive patients remission data were as follows: CR one patient (3.8%), PR four patients (15.4%), SD seven patients (26.9%), PD 12 patients (46.3%), lost to follow-up one patient (3.8%), and too-early-for-analysis one patient (3.8%). The median progression-free-survival (PFS) was 4 months (range, 0-24 months). The median PFS was also 4 months (range, 0-21 months) for those patients receiving SOFOX-CM as first CM-therapy ( n=61), while it was found to be 0 months (range, 0-10 months) for patients ( n=16) receiving SOFIRI-CM as first chronomodulated therapy. CONCLUSIONS: We found CM-therapy to be effective and safe in the treatment of advanced malignancies of the GI tract. Sodium folinate offers superior feasibility and compatibility with cytostatic drugs without drawbacks.