10-yr Results of Moderately Hypofractionated Postoperative Radiotherapy for Prostate Cancer Focused on Treatment Related Toxicity.

INTRODUCTION: To retrospectively report long term outcomes following postoperative hypofractionated radiotherapy (RT) for prostate cancer, emphasizing treatment related toxicity. MATERIAL AND METHODS: Patients for whom adjuvant or salvage RT was indicated after prostatectomy were treated with a course of moderate hypofractionation consisting in the delivery of 62.5 Gy in 25 fractions (2.5 Gy per fraction) on the prostate bed in 5 consecutive weeks (EQD21.5 = 70 Gy) by means of 3D-CRT in most of them. Androgen deprivation therapy (ADT) was allowed at physician's discretion. Patients were evaluated for urinary and rectal complications according to the Common Terminology Criteria for Adverse Events v4 (CTCAE v.4). Overall survival (OS), biochemical recurrence free survival (bRFS), and metastasis-free survival (MFS) were estimated using the Kaplan-Meier method. RESULTS: One hundred and ten patients with a median age of 67 years (range 51-78) were enrolled. The majority of them (82%) had adverse pathologic features only, while 31 (28%) had early biochemical relapse. Median PSA level before RT was 0.12 ng/mL (range 0-9 ng/mL). Median time from surgery was 4 months (range 1-136 months). Twenty-eight patients (25.4%) also received ADT. At a median follow up of 103 months (range 19-138 months), late Grade 3 and Grade 4 rectal toxicity were 0.9% (1 case of hematochezia) and 0.9% (1 case of fistula), respectively, while late Grade 3 GU side effects (urethral stenosis) occurred in 9 cases (8%). No late Grade 4 events were observed, respectively. Ten-year OS, b-RFS and MFS were 77.3% (95%CI: 82.1%-72.5%), 53.3% (95%CI: 59.9%-47.6%), and 76.7% (95%CI: 81.2%-72.2%), respectively. CONCLUSION: Our study provides long term data that a shortened course of postoperative RT is as safe and effective as a long course of conventionally fractionated RT and would improve patients' convenience and significantly reduce RT department workloads.

Toxicity study of compound granules of Hedyotis diffusa: Acute toxicity and long-term toxicity.

ETHNOPHARMACOLOGICAL RELEVANCE: The clinical efficacy of the hospital preparation compound granules of Hedyotis diffusa (CGHD), which is composed of Hedyotis diffusa Willd, Smilax china L., Solanum lyratum Thunb., has accumulated a good reputation over the past decades. However, because it is a hospital preparation, few researchers have paid attention to it, resulting in a lack of systematic basic research studies. Thus, it is not clear whether there are safety concerns that restrict its clinical application, and toxicological evaluation of CGHD is needed. AIM OF THE STUDY: The aim of this study was to evaluate the safety of CGHD by conducting acute toxicity and long-term toxicity experiments, with the objective of providing evidence for its clinical safety and a theoretical foundation for its clinical application. MATERIALS AND METHODS: KM mice were selected for the acute toxicity experiment and were administered water or CGHD-E 3 times within 24 h. The reactions of the animals to CGHD treatment were observed and recorded within 1 h after administration and then once a day for 14 consecutive days. SD rats were selected to conduct the long-term toxicity experiment. The drug-treated groups were administered different doses of CGHD-E, which were equivalent to 10 times, 20 times and 50 times the clinical dose in humans. The rats were administered the drug for 28 consecutive days. After 28 days, the animals were sacrificed, and routine blood tests, blood coagulation function analysis, liver and kidney function tests, and glycolipid metabolism related tests were conducted. The major organs of the rats were collected to calculate organ coefficients and perform hematoxylin-eosin (HE) staining. RESULTS: In the CGHD-E acute toxicity experiment, the drug-treated groups did not show adverse reactions or poisoning symptoms, and the maximum tolerated dose of CGHD-E in mice was greater than 45.072 g/kg. In the long-term toxicity experiment, drug-treated rats generally exhibited a good condition, but continuous administration decreased on body weight and food intake, especially in male rats. Coagulation function alterations and the impact on the liver during long-term drug administration were also assessed, which should be emphasized in clinical applications. No significant toxic effects were observed according to routine blood tests or test of liver and kidney function, glucose and lipid metabolism, or ion metabolism. CONCLUSIONS: The results of this study showed that CGHD was nontoxic or had low toxicity, providing not only a scientific basis for its clinical application, determining the appropriate clinical dose and monitoring clinical toxicity but also theoretical support for subsequent clinical drug trials.

Excellent Outcomes in Children, Adolescents, and Young Adults with Ovarian Germ Cell Tumors Treated by Either Reduced- or Standard-Dose Bleomycin.

To investigate the outcomes of children, adolescents, and young adults (AYAs) with malignant ovarian germ cell tumors (MOGCTs), we analyzed the data of 61 patients aged ≤39 years diagnosed with MOGCT between 2006 and 2022. Among 59 patients who received chemotherapy after initial diagnosis, 57 received BEP (standard dose of bleomycin with 30 units per week, n = 13) or bEP (reduced dose of bleomycin with 15 units/m2 on day 1, n = 44). The 5-year overall survival (OS) and event-free survival (EFS) rates were 98.3% and 84.9%, respectively. Reduced bleomycin dose did not adversely affect survival. Normalization of tumor markers within 3 months after surgery was significantly associated with better EFS (p < 0.01). Of the 59 surviving patients, 8 experienced surgery-related menopause, while 49 demonstrated menstrual recovery. After completion of chemotherapy, there was no significant difference in pulmonary function regarding bleomycin dose, and no overt nephrotoxicity. Approximately 60% and 25% of survivors experienced peripheral neuropathy at the end of chemotherapy and after 1 year, respectively (p < 0.01). Children and AYAs with MOGCT have favorable survival rates with minimal long-term toxicity, which are not influenced by a reduced bleomycin dose. Rapid normalization of tumor markers is associated with improved outcomes.

Effects of profenofos on the growth, reproduction, behavior, and gene transcription of Daphnia magna.

Profenofos (PFF) is an organophosphorus pesticide frequently detected in surface waters, soil habitats, and even biota. Some studies have demonstrated the potential risks of PFF to aquatic organisms. However, most of these studies were focused on its acute rather than chronic impacts, and the subjects are usually large vertebrates. Here, we treated D. magna (< 24 h) with PFF at doses of 0, 0.07, 0.28, and 1.12 mg/L for 21 days to study its long-term toxic impacts. Exposure to PFF largely decreased the survival rate and inhibited the growth and reproduction of D. magna. Then, PCR arrays were used to evaluate the changes in the expression of 13 genes related to growth, reproduction, and swimming behavior. The results revealed that the expression of several genes was dramatically changed by exposure to each dose of PFF, which might be responsible for the observed toxic effects of PFF. In summary, our findings imply that long-term PFF exposure can be highly hazardous to the growth, development, and reproduction of D. magna.

Tandem versus single haematopoietic stem cell transplant and BV maintenance in relapsed/refractory Hodgkin lymphoma: A matched cohort analysis from the LYSA.

Autologous hematopoietic stem cell transplant (ASCT) is the standard curative treatment for patients with high-risk relapsed/refractory Hodgkin lymphoma (R/R HL). The AETHERA study showed survival gain with Brentuximab Vedotin (BV) maintenance after ASCT in BV-naive patients, which was recently confirmed in the retrospective AMAHRELIS cohort, including a majority of BV-exposed patients. However, this approach has not been compared to intensive tandem auto/auto or auto/allo transplant strategies, which were used before BV approval. Here, we matched BV maintenance (AMAHRELIS) and tandem SCT (HR2009) cohorts, and observed that BV maintenance was associated with better survival outcome in patients with HR R/R HL.

A study of long-term toxicity of multiple mixtures with hormetic effects by the characteristic parameter σ2(k∙ECx) and stepwise method.

A previous study found that the characteristic parameter σ2(k∙ECx) (the concentration ECx and slope k of the concentrationresponse curve (CRC) at the effect x %) can predict the acute combined toxicity of multiple mixtures with S-shaped CRCs. In this paper, the competence of σ2(k∙ECx) to predict the long-term toxicity of multiple mixtures with J-shaped CRCs was explored using the Aliivibrio fischeri as the test organism. The combined toxicity was evaluated by the independent action (IA) model and the effect ratio (ERx) model. The stepwise method was used to divide J-shaped CRC into ML and MR (SL and SR). The results showed that the σ2(k∙ECx) and ERx of each segment was in good agreement with the exponential function. A new type of mixture was added to the original type A and type B, whose rules of interaction were opposite to those of type B (named opposite B, OB). This paper improves the understanding and analysis of the J-shaped CRCs in environmental risk assessment.

Oxidative Stress in Long-Term Exposure to Multi-Walled Carbon Nanotubes in Male Rats.

Multi-walled carbon nanotubes (MWCNTs) serve as nanoparticles due to their size, and for that reason, when in contact with the biological system, they can have toxic effects. One of the main mechanisms responsible for nanotoxicity is oxidative stress resulting from the production of intracellular reactive oxygen species (ROS). Therefore, oxidative stress biomarkers are important tools for assessing MWCNTs toxicity. The aim of this study was to evaluate the oxidative stress of multi-walled carbon nanotubes in male rats. Our animal model studies of MWCNTs (diameter ~15-30 nm, length ~15-20 µm) include measurement of oxidative stress parameters in the body fluid and tissues of animals after long-term exposure. Rattus Norvegicus/Wistar male rats were administrated a single injection to the knee joint at three concentrations: 0.03 mg/mL, 0.25 mg/mL, and 0.5 mg/mL. The rats were euthanized 12 and 18 months post-exposure by drawing blood from the heart, and their liver and kidney tissues were removed. To evaluate toxicity, the enzymatic activity of total protein (TP), reduced glutathione (GSH), glutathione S-transferase (GST), thiobarbituric acid reactive substances (TBARS), Trolox equivalent antioxidant capacity (TEAC), nitric oxide (NO), and catalase (CAT) was measured and histopathological examination was conducted. Results in rat livers showed that TEAC level was decreased in rats receiving nanotubes at higher concentrations. Results in kidneys report that the level of NO showed higher concentration after long exposure, and results in animal serums showed lower levels of GSH in rats exposed to nanotubes at higher concentrations. The 18-month exposure also resulted in a statistically significant increase in GST activity in the group of rats exposed to nanotubes at higher concentrations compared to animals receiving MWCNTs at lower concentrations and compared to the control group. Therefore, an analysis of oxidative stress parameters can be a key indicator of the toxic potential of multi-walled carbon nanotubes.

Late effects and treatment related morbidity associated with treatment of neuroblastoma patients in a tertiary paediatric centre.

BACKGROUND: Survival of neuroblastoma patients has improved over recent decades, but chronic health issues and treatment related late effects cause significant morbidity in survivors. AIMS: We aimed to describe late effects and long-term toxicity in neuroblastoma patients treated at a tertiary, paediatric institution in Australia. METHODS & RESULTS: Patients with neuroblastoma treated primarily at The Children's hospital at Westmead were eligible for inclusion. Retrospective analysis of 65 (45 with high-risk and 20 with non-high-risk disease) neuroblastoma patients were performed via medical record review. Approximately 60% of patients were >5 years from diagnosis and termed the "full effects cohort" who had a range of medical and psychosocial late effects analysed through descriptive means. The remaining 26 patients who had not yet reached 5 years post treatment had audiometry analysis only. Of the 65 patients, 72% were alive at last follow-up. The median length of follow-up was 7 years from diagnosis amongst survivors. Therapy was according to contemporary protocols for neuroblastoma and ranged from standard cytotoxic therapies to intensive multimodal regimens and/or experimental therapy depending on risk group/relapse status. Of the 39 full effects cohort, 85% suffered from at least one late effect. Late effects were common in the endocrine, dental and audiometry domains with 38%, 49% and 72% of patients affected in these areas, respectively. Neuro-cognitive domains were also notably affected with 46% of patients suffering a deficit. Two thirds of survivors were disease free at last follow-up. CONCLUSION: Survivors of high-risk neuroblastoma suffer from a range of chronic illnesses, which lead to morbidity and affect quality of life of survivors.

Environmental Hazards of Nanobiomaterials (Hydroxyapatite-Based NMs)-A Case Study with Folsomia candida-Effects from Long Term Exposure.

Hydroxyapatite (HA) is a calcium phosphate used in many fields, including biomedical applications. In particular, ion-doped HA nanomaterials (nHA) are developed for their increased bioactivity, particularly in the fields of regenerative medicine and nanomedicine. In this study, we assessed the ecotoxicological impact of five nHA materials: a synthesized calcium hydroxyapatite (CaP-HA), superparamagnetic iron-doped hydroxyapatite (Fe-HA), titanium-doped hydroxyapatite (Ti-HA), alginate/titanium-doped hydroxyapatite hybrid composite (Ti-HA-Alg), and a commercial HA. The soil ecotoxicology model species Folsomia candida (Collembola) was used, and besides the standard reproduction test (28 days), an extension to the standard for one more generation was performed (56 days). Assessed endpoints included the standard survival and reproduction, and additionally, growth. Exposure via the standard (28 days) did not cause toxicity, but reproduction increased in commercial HA (significantly at 320 mg HA/kg) whereas via the extension (56 days) it decreased in all tested concentrations. Juveniles' size (56 days) was reduced in all tested nHA materials, except commercial HA. nHA materials seem to trigger a compromise between reproduction and growth. Long-term effects could not be predicted based on the standard shorter exposure; hence, the testing of at least two generations (56 days) is recommended to assess the toxicity of nanomaterials, particularly in F. candida. Further, we found that the inclusion of size as additional endpoint is highly relevant.

Preclinical safety evaluation of Macleaya Cordata extract: A re-assessment of general toxicity and genotoxicity properties in rodents.

Macleaya cordata extract (MCE) is widely used for its diverse pharmacological actions and beneficial effects on farm animals. Modern pharmacological studies have shown that it has anti-inflammatory, anti-cancer, and anti-bacterial activities, and is gradually becoming a long-term additive veterinary drug used to improve animal intestinal health and growth performance. Although some evidence points to the DNA mutagenic potential of sanguinarine (SAN), a major component of MCE, there is a lack of sufficient basic toxicological information on the oral route, posing a potential safety risk for human consumption of food of animal origin. In this study, we assessed the acute oral toxicity, repeated 90-day oral toxicity and 180-day chronic toxicity of MCE in rats and mice and re-evaluated the genotoxicity of MCE using a standard combined in vivo and ex vivo assay. In the oral acute toxicity test, the LD50 for MCE in rats and mice was 1,564.55 mg/kg (95% confidence interval 1,386.97-1,764.95 mg/kg) and 1,024.33 mg/kg (95% confidence interval 964.27-1,087.30 mg/kg), respectively. The dose range tested had no significant effect on hematology, clinical chemistry, and histopathological findings in rodents in the long-term toxicity assessment. The results of the bacterial reverse mutation, sperm abnormality and micronucleus test showed negative results and lack of mutagenicity and teratogenicity; the results of the rat teratogenicity test showed no significant reproductive or embryotoxicity. The results indicate that MCE was safe in the dose range tested in this preclinical safety assessment. This study provides data to support the further development of maximum residue limits (MRLs) for MCE.

Correlation analysis of single- and multigenerational endpoints in Daphnia magna toxicity tests: A case-study using TiO2 nanoparticles.

Multigenerational toxicity tests provide more sensitive measures of population-level effects than conventional single-generation tests. Particularly for stressors which exhibit slow uptake rates (e.g. nanomaterials), multigenerational tests may also provide a more realistic representation of natural exposure scenarios. To date, the inherently high costs and labor intensity have however limited the use of multigenerational toxicity tests and thereby their incorporation in environmental risk assessment. The aim of the present study was therefore to determine to what extent short(er) term endpoints which are conventionally measured in Daphnia magna toxicity tests hold predictive capacity towards reproduction measured over longer timescales, including multiple generations. To assess this, a case-study was performed in which effects of TiO2 nanoparticles (0, 0.02, 0.2, 2 and 5 mg L-1) on D. magna life-history traits were assessed over five generations. Additionally, it was determined whether offspring derived from exposed parents exhibited sustained adverse effects when rearing them in clean (non-exposed) media after each generation of exposure. The present study showed that although various life-history traits correlate with the total reproductive output in the same- and subsequent generation under non-exposed conditions, these correlations were decoupled in presence of exposure to nTiO2. In addition, it was found that nTiO2 can induce adverse effects on population relevant endpoints at concentrations 1-2 orders of magnitude lower than previously found (i.e. 0.02 mg L-1), and close to the range of concentrations occurring in natural freshwater ecosystems.

Long-term effects of lithium and lithium-microplastic mixtures on the model species Daphnia magna: Toxicological interactions and implications to 'One Health'.

Environmental contamination with lithium (Li) and microplastics (MP) has been steadily increasing and this trend is expected to continue in the future. Many freshwater ecosystems, which are crucial to reach the United Nations Sustainable Development Goals, are particularly vulnerable to Li and MP contamination, and other pressures. The long-term effects of Li, either alone or combined with MP (Li-MP mixtures), were investigated using the freshwater zooplankton micro-crustacean Daphnia magna as model species. In the laboratory, D. magna females were exposed for 21 days to water concentrations of Li (0.02, 0.04, 0.08 mg/L) or Li-MP mixtures (0.02 Li + 0.04 MP, 0.04 Li + 0.09 MP mg/L, 0.08 Li + 0.19 MP mg/L). In the range of concentrations tested, Li and Li-MP mixtures caused parental mortality, and decreased the somatic growth (up to 20% and 40% reduction, respectively) and the reproductive success (up to 93% and 90% reduction, respectively). The 21-day EC50s of Li and Li-MP mixtures on D. magna reproduction were 0.039 mg/L and 0.039 Li + 0.086 MP mg/L, respectively. Under exposure to the highest concentration of Li (0.08 mg/L) and Li-MP mixtures (0.08 Li + 0.19 MP mg/L), the mean of D. magna population growth rate was reduced by 67% and 58%, respectively. Based on the population growth rate and using data from a bioassay testing the same concentrations of MP alone and carried simultaneously, the toxicological interaction between Li and MP was antagonism under exposure to the lowest and the highest concentrations of Li-MP mixtures, and synergism under exposure to the medium concentration of Li-MP mixtures. These findings highlight the need of further investigating the combined effects of contaminants, and the threat of long-term environmental contamination with Li and MP to freshwater zooplankton, biodiversity, ecosystem services and 'One Health'.

hUC-MSCs: evaluation of acute and long-term routine toxicity testing in mice and rats.

Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) are present in human umbilical connective tissue and can differentiate into various cell types. Our previous studies have proved that hUC-MSCs do not lead to allergies and tumorigenesis. In the present study, the acute and long-term toxicity of hUC-MSCs in mice and rats was evaluated. The acute toxicity of hUC-MSCs was assessed in 8-week-old mice receiving two caudal intravenous (i.v.) injections of hUC-MSCs at the maximum tolerated dose of 1.5 × 107 cells/kg with an interval of 8 h and the observation period sustained for 14 days. For the long-term toxicity evaluation, rats were randomly divided into control, low-dose (3.0 × 105 cells/kg), mid-dose (1.5 × 106 cells/kg), and high-dose (7.5 × 106 cells/kg) groups, which were treated with hUC-MSCs via a caudal i.v. injection every 3 days for 90 days. Weight and food intake evaluation was performed for all rats for 2 weeks after the hUC-MSC administration. The animals were then sacrificed for hematological, blood biochemical, and pathological analyses, as well as organ index determination. We observed no obvious acute toxicity of hUC-MSCs in mice at the maximum tolerated dose. Long-term toxicity tests in rats showed no significant differences between HUC-MSC-treated and control groups in the following parameters: body weight, hematological and blood biochemical parameters, and histopathologic changes in the heart, liver, kidneys, and lungs. This study provides evidence of the safety of i.v. hUC-MSCs infusion for future clinical therapies.

Acute and long-term effects of VX in rat brain cell aggregate culture.

The contact poison VX (O-ethyl S-(2-diisopropylaminoethyl) methylphosphonothioate) is a chemical warfare agent that is one of the most toxic organophosphorus compounds known. Its primary mechanism of toxic action is through the inhibition of acetylcholinesterase and resultant respiratory paralysis. The majority of work on VX has thus concentrated on its potent anticholinesterase activity and acute toxicity, with few studies investigating potential long-term effects. In this report we describe the effects of VX in aggregating rat brain cell cultures out to 28 days post-exposure. Cholinesterase activity was rapidly inhibited (60 min IC50 = 0.73 +/- 0.27 nM), but recovered towards baseline values over the next four weeks. Apoptotic cell death, as measured using caspase-3 activity was evident only at 100 µM concentrations. Cell type specific enzymatic markers (glutamine synthase, choline acetyltransferase and 2',3'-cyclic nucleotide 3'-phosphodiesterase) showed no significant changes. Total Akt levels were unchanged, while an increased phosphorylation of this protein was noted only at the highest VX concentration on the first day post-exposure. In contrast, significant and delayed (28 days post-exposure) decreases were noted in vascular endothelial growth factor (VEGF) levels, a protein whose reduced levels are known to contribute to neurodegenerative disorders. These observations may indicate that the long-term effects noted in some survivors of nerve agent intoxication may be due to VX-induced declines in brain VEGF levels.

Achieving NIR Light-Mediated Tumor-Specific Fenton Reaction-Assisted Oncotherapy by Using Magnetic Nanoclusters.

As an emerging strategy for oncotherapy, Fenton chemistry can efficiently improve the conversion from endogenous H2O2 into highly toxic ·OH in the whole high-performance therapeutic process. Although promising, the efficiency of Fenton reaction in tumor regions is highly limited by the inefficient delivery of Fenton reagents and the restrictive conditions of tumor microenvironment. One promising strategy against the above limitations is to specifically increase the temperature around the tumor regions. In this study, a novel NIR light-mediated tumor-specific nanoplatform based on magnetic iron oxide nanoclusters (MNCs) was rationally designed and well developed for photothermally enhanced Fenton reaction-assisted oncotherapy. MNCs could accumulate into the tumor regions with the help of an external magnet field to enable T2-weighted magnetic resonance (MR) imaging of tumors and MR imaging-guided combined antitumor therapy. Our well-prepared MNCs also revealed excellent photothermal effect upon a NIR light irradiation, promising their further important role as a photothermal therapy (PTT) agent. More importantly, heat induced by the PTT of MNCs could accelerate the release of Fe from MNCs and enhance the efficiency of Fenton reaction under H2O2-enriched acidic tumor microenvironment. Results based on long-term toxicity investigations demonstrated the overall safety of MNCs after intravenous injection. This work therefore introduced a novel nanoplatform based on MNCs that exerted a great antitumor effect via photothermally enhanced tumor-specific Fenton chemistry.

The Burden of Survivorship on Hematological Patients-Long-Term Analysis of Toxicities after Total Body Irradiation and Allogeneic Stem Cell Transplantation.

Total body irradiation is an effective conditioning modality before autologous or allogeneic stem cell transplantation. With the whole body being the radiation target volume, a diverse spectrum of toxicities has been reported. This fact prompted us to investigate the long-term sequelae of this treatment concept in a large patient cohort. Overall, 322 patients with acute leukemia or myelodysplastic syndrome with a minimum follow-up of one year were included (the median follow-up in this study was 68 months). Pulmonary, cardiac, ocular, neurological and renal toxicities were observed in 23.9%, 14.0%, 23.6%, 23.9% and 20.2% of all patients, respectively. The majority of these side effects were grades 1 and 2 (64.9-89.2% of all toxicities in the respective categories). The use of 12 Gray total body irradiation resulted in a significant increase in ocular toxicities (p = 0.013) and severe mucositis (p < 0.001). Renal toxicities were influenced by the age at transplantation (relative risk: 1.06, p < 0.001) and disease entity. In summary, total body irradiation triggers a multifaceted, but manageable, toxicity profile. Except for ocular toxicities and mucositis, a 12 Gray regimen did not lead to an increase in long-term side effects.

Toxicity of clothianidin to common Eastern North American fireflies.

BACKGROUND: Previous research suggests that fireflies (Coleoptera: Lampyridae) are susceptible to commonly used insecticides. In the United States, there has been a rapid and widespread adoption of neonicotinoid insecticides, predominantly used as seed coatings on large-acreage crops like corn, soy, and cotton. Neonicotinoid insecticides are persistent in soil yet mobile in water, so they have potential to contaminate firefly habitats both in and adjacent to application sites. As a result, fireflies may be at high risk of exposure to neonicotinoids, possibly jeopardizing this already at-risk group of charismatic insects. METHODS: To assess the sensitivity of fireflies to neonicotinoids, we exposed larvae of Photuris versicolor complex and Photinus pyralis to multiple levels of clothianidin-treated soil and monitored feeding behavior, protective soil chamber formation, intoxication, and mortality. RESULTS: Pt. versicolor and Pn. pyralis larvae exhibited long-term intoxication and mortality at concentrations above 1,000 ng g-1 soil (1 ppm). Under sub-lethal clothianidin exposure, firefly larvae fed less and spent less time in protective soil chambers, two behavioral changes that could decrease larval survival in the wild. DISCUSSION: Both firefly species demonstrated sub-lethal responses in the lab to clothianidin exposure at field-realistic concentrations, although Pt. versicolor and Pn. pyralis appeared to tolerate higher clothianidin exposure relative to other soil invertebrates and beetle species. While these two firefly species, which are relatively widespread in North America, appear somewhat tolerant of neonicotinoid exposure in a laboratory setting, further work is needed to extend this conclusion to wild populations, especially in rare or declining taxa.

The Bio-Persistence of Reversible Inflammatory, Histological Changes and Metabolic Profile Alterations in Rat Livers after Silver/Gold Nanorod Administration.

As a widely applied nanomaterial, silver nanomaterials (AgNMs) have increased public concern about their potential adverse biological effects. However, there are few related researches on the long-term toxicity, especially on the reversibility of AgNMs in vivo. In the current study, this issue was tackled by exploring liver damage after an intravenous injection of silver nanorods with golden cores (Au@AgNRs) and its potential recovery in a relatively long term (8 w). After the administration of Au@AgNRs into rats, Ag was found to be rapidly cleared from blood within 10 min and mainly accumulated in liver as well as spleen until 8 w. All detected parameters almost displayed a two-stage response to Au@AgNRs administration, including biological markers, histological changes and metabolic variations. For the short-term (2 w) responses, some toxicological parameters (hematological changes, cytokines, liver damages etc.) significantly changed compared to control and AuNRs group. However, after a 6-week recovery, all abovementioned changes mostly returned to the normal levels in the Au@AgNRs group. These indicated that after a lengthy period, acute bioeffects elicited by AgNMs could be followed by the adaptive recovery, which will provide a novel and valuable toxicity mechanism of AgNMs for potential biomedical applications of AgNMs.

Late toxicities and recurrences in patients with clinical stage I non-seminomatous germ cell tumours after 1 cycle of adjuvant bleomycin, etoposide and cisplatin versus primary retroperitoneal lymph node dissection - A 13-year follow-up analysis of a phase III trial cohort.

BACKGROUND: One cycle of adjuvant chemotherapy with bleomycin, etoposide and cisplatin (BEP) has shown superiority in recurrence-free survival over retroperitoneal lymph node dissection (RPLND) in patients with clinical stage (CS) I non-seminomatous germ cell tumours (NSGCTs) of the testis in the setting of a phase III trial. We report the recurrences and late toxicities of this study after 13 years of follow-up. METHODS: Questionnaires from 382 patients with CS I NSGCT treated with 1 cycle of adjuvant BEP (arm A) or RPLND + two cycles of adjuvant BEP in cases of pathological stage II disease (arm B) were evaluated regarding recurrences and late toxicity. Overall, information on recurrence status was available in 337 patients, and 170 questionnaires were evaluable for toxicity (arm A: 95; arm B: 75). RESULTS: With a median follow-up of 13.8 years (0-22), 3 patients (1.6%) in arm A and 16 patients (8.4%) in arm B experienced recurrence. The 15-year PFS in arm A/B was 99% (CI 96-100%)/92% (CI 89-99%) (p = 0.0049). The 15-year OS in arm A/B was 93% (CI 87-97%)/93% (CI 86-97%) (p = 0.83). Eight patients (4.2%) in arm A and four patients (2.1%) in arm B showed metachronous secondary testicular cancer (p = 0.26). Five patients (2.6%) in arm A and four patients (2.1%) in arm B developed other malignancies. Toxicities were not significantly different apart from retrograde ejaculation, which occurred more frequently after RPLND (10% versus 24%, p = 0.01). CONCLUSIONS: With long-term observation, one cycle of BEP remains superior to RPLND in preventing recurrence and was tolerated without any clinically relevant long-term toxicities.

[Testicular and penile cancer-survival and quality of life : New guideline and network for second opinions]. / Hodentumor und Peniskarzinom ­ Überleben mit Lebensqualität : Neue Leitlinien und Zweitmeinungsnetzwerk.

Testicular cancer occupies a special position in several respects. Although it belongs to the group of rare tumors, which is why extensive experience in treating this tumor can not be guaranteed, interdisciplinary experts collaboration and the consequent implementation of clinical studies have resulted in standardized treatment recommendations. Because testicular cancer is one of the most curable cancers, long-term toxicity and treatment sequelae are of special importance. In the early stages, toxicity could be reduced by minimizing therapy to the extent possible, but without decreasing treatment success. Nevertheless, treatment is still controversially discussed, especially concerning treatment of stage I disease. Finally particular focus should be paid to non-germinal tumors which are even more rare, but partly also more dangerous. Therefore known facts should be made available for the broad medical community. In penile cancer, which is also a very rare tumor entity, organ-sparing surgery and consequent invasive lymph node staging are mandatory.