Identifying pre-habilitation targets for the mitigation of long-term side effects of chemotherapy in patients with early breast cancer.

BACKGROUND: Pre-treatment characteristics of women with early breast cancer that are associated with persistent fatigue or suboptimal health-related quality of life (HRQOL) post-chemotherapy need to be identified as potential targets for pre-habilitation. PATIENTS AND METHODS: Ancillary analysis of previously collected data from patients with newly diagnosed Stage I-III breast cancer scheduled to receive chemotherapy. The objective was to identify baseline (pre-chemotherapy) variables associated with meaningful deteriorations in fatigue and other measures of HRQOL from pre-treatment to 6 months after chemotherapy completion. Percentages are reported along with unadjusted and adjusted relative risks. RESULTS: In a sample of 249 women post-chemotherapy, 32% reported worsening fatigue (FACIT-F), 35% worsening Physical Well-Being (PWB), 16% worsening Functional Well-Being (FWB), 8% worsening Emotional Well-Being (EWB), and 30% worsening Social Well-Being (SWB). In multivariable (MV) analysis, variables that were significant in univariate analysis - Black race, high BMI, and baseline poorer EWB - remained significant for worsening post-chemotherapy fatigue (FACIT-F). In MV analysis that included race, education, falls, and baseline EWB, Black race and a positive falls history remained significant for worsening PWB. In MV analysis inclusive of race, Short Physical Performance Battery (SPPB) and FWB, lower SPPB and FWB remained significant predictors of worsening FWB. In MV analysis that included baseline Mental Health Index-Anxiety, EWB and SWB, a higher SWB and lower EWB remained significant for worsening SWB. CONCLUSION: Pre-chemotherapy characteristics in women with early-stage breast cancer that are associated with increased fatigue and reduced HRQOL post-treatment could be used to identify patients who may benefit from pre-habilitation interventions.

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.

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 exposure to formaldehyde induced down-regulation of SPO11 in rats.

Objective: Formaldehyde, a ubiquitous environmental contaminant, has long been suspected of causing male reproductive injury, but the underlying molecular mechanism remains largely unknown. SPO11 is a meiosis-related gene, whose absence can cause spermatogenesis arrest. Materials and methods: The present study aimed to explore the role of SPO11 in male reproductive injury induced by long-term formaldehyde exposure, so as to further understand the molecular mechanism of formaldehyde-induced male reproductive toxicity. Adult male Sprague-Dawley rats (n = 24, 245 ± 22 g) were randomly divided into four groups of six (n = 6) and were exposed to formaldehyde gas at doses of 0 (control), 0.5, 2.46 and 5 mg/m3, respectively, via inhalation for 8 consecutive weeks. Results and dissussion: The expression levels of SPO11 were detected in testicular tissues by real-time quantitative polymerase chain reaction, immunofluorescence, and Western blot. The results indicated that the expression of SPO11 was inhibited by formaldehyde exposure in a dose-dependent manner. Furthermore, the histopathological results showed that testicular seminiferous tubules were atrophied, spermatogenic cells were decreased and the lumina were oligozoospermic in the 2.46 and 5 mg/m3 formaldehyde exposure groups. Combined with the morphometric results, we found that the downregulated expression levels of SPO11 were consistent with the changes of testicular seminiferous tubule diameter and seminiferous epithelium height in testicular tissue, suggesting that SPO11 might be one of the main targets of formaldehyde reproductive toxicity. Conclusions: In conclusion, our findings indicated that SPO11 might be related to male reproductive injuries induced by long-term formaldehyde exposure.

Zn concentration decline and apical endpoints recovery of earthworms (E. andrei) after removal from an acidic soil spiked with coated ZnO nanoparticles.

ZnO nanoparticles (ZnO-NPs) can reach soil in both deliberate and non-deliberate ways, which leads to contamination. Notwithstanding knowledge about ZnO-NPs impacts on earthworms inhabiting these soils is limited and gaps appear in the recovery of damaged functions after their migration to unpolluted environments. To estimate these impacts, earthworms (Eisenia andrei) were exposed to different concentrations of coated ZnO-NPs (20, 250, 500, 1000 mgZnkg-1) in an acidic agricultural soil (pH 5.4) for 28 days. Subsequently, earthworms were placed in the same unpolluted soil to study the depletion of Zn accumulated and the recovery potential of the affected functions for another 28-day period.In the exposure phase, ecotoxicological responses were dose-dependent. Mortality and growth were affected at 500 and 1000 mg kg- 1, and the reproduction was impaired from 250 mgZnkg- 1 compared to control (54% fecundity and 80% fertility reduction). Zn uptake increased with coated ZnO-NPs in soil but it did not exceed 163 mgZnkg- 1 earthworm. During the recovery period, the Zn in earthworms were similar to the control regardless of the initially Zn accumulated. Reproduction parameters returned to the control values in the animals pre-exposed to 250 mgZnkg- 1 as coated ZnO-NP. In the earthworms preexposed to the two highest doses, growth and fertility were stimulated compared to the control when placed in clean soil, but not fecundity. However, the total hatchlings number did not reach the control figures after 28 days, but probably would for in longer times, which would be key for maintaining earthworm populations.

Long-term sexual functioning in germ-cell tumor survivors.

BACKGROUND: Survivors of germ-cell tumors (GCT) may suffer from long-term adverse consequences. Our study was conducted to assess a long-term sexual functioning in GCT survivors. METHODS: GCT survivors (N = 170) from the National Cancer Institute in Slovakia completed a Sexual Function Questionnaire that was modified from PROMIS Sexual Function and Satisfaction Questionnaire 9-year median follow up (range 5-32) as a primary exploratory aim. Study groups consisted of 17 survivors (10%) who had active surveillance (AS, controls), and 153 (90%) survivors who received treatment beyond orchiectomy (Tx), including cisplatin-based chemotherapy (CT, N = 132; 78%), radiotherapy to the retroperitoneal lymph nodes (RT, N = 12; 7%) or both (CTRT, N = 9; 5%). RESULTS: In univariate analysis, treatment of any type resulted in difficulty to maintain erection during sexual intercourse compared to patients treated with AS (P = 0.04). Survivors who received CTRT had lower ability to achieve orgasm during sexual activities (P = 0.04) and they reported disappointment with their overall quality of sex life (P = 0.002). The number of attempts to initiate sexual intercourse did not differ. Sexual relationships caused none or mild anxiety and the desire to be sexually active was higher after CTRT (P = 0.05). Multivariable analysis confirmed that orgasmic dysfunction after ≥400 mg/m2 of cisplatin and issues in maintaining erection after Tx were independent of retroperitoneal lymph-node dissection (P = 0.03 and P = 0.04, respectively). Survivors were disappointed with the quality of sex life and had stronger desire to be sexually active independent of age, (P = 0.01 and P = 0.05, respectively). CONCLUSIONS: This study identified an impairment in sexual function may represent an issue for long-term GCT survivors. Treatment with chemotherapy plus radiotherapy were associated with disappointment and stronger sexual desire, while a higher cumulative dose of cisplatin may be responsible for orgasmic dysfunction.

Comprehensive assessments and related interventions to enhance the long-term outcomes of child, adolescent and young adult cancer survivors - presentation of the CARE for CAYA-Program study protocol and associated literature review.

BACKGROUND: Improved, multimodal treatment strategies have been shown to increase cure rates in cancer patients. Those who survive cancer as a child, adolescent or young adult (CAYA), are at a higher risk for therapy-, or disease-related, late or long-term effects. The CARE for CAYA-Program has been developed to comprehensively assess any potential future problems, to offer need-based preventative interventions and thus to improve long-term outcomes in this particularly vulnerable population. METHODS: The trial is designed as an adaptive trial with an annual comprehensive assessment followed by needs stratified, modular interventions, currently including physical activity, nutrition and psycho-oncology, all aimed at improving the lifestyle and/or the psychosocial situation of the patients. Patients, aged 15-39 years old, with a prior cancer diagnosis, who have completed tumour therapy and are in follow-up care, and who are tumour free, will be included. At baseline (and subsequently on an annual basis) the current medical and psychosocial situation and lifestyle of the participants will be assessed using a survey compiled of various validated questionnaires (e.g. EORTC QLQ C30, NCCN distress thermometer, PHQ-4, BSA, nutrition protocol) and objective parameters (e.g. BMI, WHR, co-morbidities like hyperlipidaemia, hypertension, diabetes), followed by basic care (psychological and lifestyle consultation). Depending on their needs, CAYAs will be allocated to preventative interventions in the above-mentioned modules over a 12-month period. After 1 year, the assessment will be repeated, and further interventions may be applied as needed. During the initial trial phase, the efficacy of this approach will be compared to standard care (waiting list with intervention in the following year) in a randomized study. During this phase, 530 CAYAs will be included and 320 eligible CAYAs who are willing to participate in the interventions will be randomly allocated to an intervention. Overall, 1500 CAYAs will be included and assessed. The programme is financed by the innovation fund of the German Federal Joint Committee and will be conducted at 14 German sites. Recruitment began in January 2018. DISCUSSION: CAYAs are at high risk for long-term sequelae. Providing structured interventions to improve lifestyle and psychological situation may counteract against these risk factors. The programme serves to establish uniform regular comprehensive assessments and need-based interventions to improve long-term outcome in CAYA survivors. TRIAL REGISTRATION: Registered at the German Clinical Trial Register (ID: DRKS00012504, registration date: 19th January 2018).

Efficacy, long-term toxicity, and mechanistic studies of gold nanorods photothermal therapy of cancer in xenograft mice.

Gold nanorods (AuNRs)-assisted plasmonic photothermal therapy (AuNRs-PPTT) is a promising strategy for combating cancer in which AuNRs absorb near-infrared light and convert it into heat, causing cell death mainly by apoptosis and/or necrosis. Developing a valid PPTT that induces cancer cell apoptosis and avoids necrosis in vivo and exploring its molecular mechanism of action is of great importance. Furthermore, assessment of the long-term fate of the AuNRs after treatment is critical for clinical use. We first optimized the size, surface modification [rifampicin (RF) conjugation], and concentration (2.5 nM) of AuNRs and the PPTT laser power (2 W/cm2) to achieve maximal induction of apoptosis. Second, we studied the potential mechanism of action of AuNRs-PPTT using quantitative proteomic analysis in mouse tumor tissues. Several death pathways were identified, mainly involving apoptosis and cell death by releasing neutrophil extracellular traps (NETs) (NETosis), which were more obvious upon PPTT using RF-conjugated AuNRs (AuNRs@RF) than with polyethylene glycol thiol-conjugated AuNRs. Cytochrome c and p53-related apoptosis mechanisms were identified as contributing to the enhanced effect of PPTT with AuNRs@RF. Furthermore, Pin1 and IL18-related signaling contributed to the observed perturbation of the NETosis pathway by PPTT with AuNRs@RF. Third, we report a 15-month toxicity study that showed no long-term toxicity of AuNRs in vivo. Together, these data demonstrate that our AuNRs-PPTT platform is effective and safe for cancer therapy in mouse models. These findings provide a strong framework for the translation of PPTT to the clinic.

Responses of Harmonia axyridis (Coleoptera: Coccinellidae) to sulfoxaflor exposure.

Harmonia axyridis is an important predator of several pest species and is part of many Integrated Pest Management (IPM) programs. To assess the risks of pesticide application to H. axyridis, we studied the effects of sulfoxaflor on H. axyridis larvae. At 72 h after treatment, the acute toxicity LR50 was 311.9476 g a. i. ha-1 by the residual contact method. This result indicated low-contact toxicity against second-instar H. axyridis larvae. The LR50 of the F1 generation decreased from 69.96 to 36.41 g a. i. ha-1 in a long-term toxicity test. The daily hazard quotient (HQ) for H. axyridis larvae lowered the safety threshold value in the first 5 d. However, the HQ values were greater than 2 during days 6-18 after sulfoxaflor treatments. We determined the No Observed Effect Application Rates of sulfoxaflor on the survival (<11.25 g a. i. ha-1), duration of larval and pupal stages (45 g a. i. ha-1), adult stage (90 g a. i. ha-1), total pre-oviposition period, adult pre-oviposition period (45 g a. i. ha-1), and reproduction (11.25 g a. i. ha-1). Pupation, adult emergence, and eggs counts of H. axyridis were reduced after sulfoxaflor treatments. The predation ability and population demography parameters were significantly impaired by higher application rates. At 90 g a. i. ha-1 or less, sulfoxaflor was slightly harmful to H. axyridis but a rate of 180 g a. i. ha-1 was moderately harmful. These results demonstrated that sulfoxaflor is harmful to H. axyridis when applied at high application rates.

Nonclinical Safety Assessment of a Long-Acting Recombinant PEGylated Factor Eight (BAY 94-9027) With a 60 kDa PEG.

BAY 94-9027 (Jivi) is a site-specifically PEGylated human B-domain-deleted (BDD) recombinant factor VIII (FVIII), with a 60 kDa branched PEG molecule attached. The nonclinical safety of BAY 94-9027 was evaluated in a toxicology program that included 2 weeks intravenous (IV) toxicity studies in rats and rabbits, a juvenile toxicity study in rats as well as a 26-week chronic study in rats. Doses of 75, 750, or 2250 IU/kg given every other day for 2 weeks did not elicit any findings related to BAY 94-9027. Specifically, no thrombus formation or histological changes such as cellular vacuolation were seen. In the chronic toxicity study, 40, 400, and 1200 IU/kg of BAY 94-9027 given twice weekly did not induce adverse effects related to BAY 94-9027, and no tissue vacuolation was observed. There was no PEG detected in choroid plexus or other areas of the brain, cerebrospinal fluid or in spleen or kidneys. These results were supported by toxicity studies in rats and rabbits treated with PEG 60 kDa attached to the maleimide linker (PEG-60-Mal-Cys). No findings related to PEG-60-Mal-Cys were seen. These results demonstrate the safety of BAY 94-9027 for long-term use.

Effects of aged ZnO NPs and soil type on Zn availability, accumulation and toxicity to pea and beet in a greenhouse experiment.

Most studies have assessed the toxicity of pristine NPs to plants without considering the likely changes that these NPs will undergo during their residence time in the soil. In this study, we assessed the effects of ZnO NPs (3, 20, and 225 mg Zn kg-1 soil) aged for a year in soil and after a previous crop on the Zn availability in soil, leaf accumulation and toxicity to green pea (Pisum sativum L.) and beet root (Beta vulgaris L). The effects were compared to bulk ZnO and ZnSO4 in two agricultural soils with different pH under greenhouse conditions. The Zn concentration in the plant leaf was 6-12-fold higher in acidic than in calcareous soil that could explain the different effects on plants caused by Zn applications depending on soil type. Thus, in acidic soil, ZnO NPs promoted ROS generation in both plant species with increases from 47% to 130%, increased the MDA content in pea up to 58 ±â€¯8% in plant exposed to ZnSO4 at 225 mg Zn kg-1 soil and altered the ratio of photosynthetic pigments in beet between 12% and 41%, suggesting distressed chloroplast constituents. In calcareous soil, the changes seemed to be related to the supply of Zn in Zn deficient soils, whose principal effect was the 20-65% decrease of ROS levels in treated plants. The available and leaf Zn concentrations did not differ among Zn sources. Likewise, ZnO NPs showed comparable toxic or stimulatory effects to ZnO bulk and Zn salt, with some exceptions where Zn ion showed the highest phytotoxicity and effectiveness as a micronutrient. According to our results, we cannot affirm that NPs pose a higher potential environmental risk than their bulk counterparts after one-year of residence time in soil.

Osteochondroma in long-term survivors of high-risk neuroblastoma.

BACKGROUND: Osteochondromas are benign bony protrusions that can be spontaneous or associated with radiotherapy (RT). Current treatment of high-risk neuroblastoma includes dose-intensive chemotherapy, local RT, an anti-GD2 monoclonal antibody (MoAb), and isotretinoin. Late effects are emerging. METHODS: The authors examined osteochondromas in 362 patients who were aged <10 years when diagnosed with neuroblastoma, had received a MoAb plus isotretinoin since 2000, and had survived >24 months from the time of the first dose of the MoAb. The incidence rate of osteochondroma was determined using the competing risks approach, in which the primary event was osteochondroma calculated from the date of neuroblastoma diagnosis and the competing event was death without osteochondroma. RESULTS: A total of 21 osteochondroma cases were found among 14 patients who were aged 5.7 to 15.3 years (median, 10.4 years) and 3.1 to 11.2 years (median, 8.2 years) from the time of neuroblastoma diagnosis. The cumulative incidence rate was 0.6% at 5 years and 4.9% at 10 years from the neuroblastoma diagnosis. Nine osteochondromas were revealed incidentally during assessments of neuroblastoma disease status or bone age. Thirteen osteochondromas were detected outside RT portals and had characteristics of spontaneous forms. Complications were limited to pain necessitating surgical resection in 3 patients, but follow-up was short at 0.3 to 7.7 years (median, 3.5 years). CONCLUSIONS: Osteochondromas in long-term survivors of neuroblastoma should be expected because these benign growths can be related to RT and these patients undergo radiologic studies over years, are monitored for late toxicities through and beyond adolescence, and receive special attention (because of concerns about disease recurrence) if they develop a bony protuberance. A pathogenic role for chemotherapy, anti-GD2 MoAbs, or isotretinoin remains speculative.

Long-term exposure to circulating platinum is associated with late effects of treatment in testicular cancer survivors.

BACKGROUND: The success of cisplatin-based (Platinol, Bristol-Myers Squibb Company, New York, NY, USA) chemotherapy for testicular cancer comes at the price of long-term and late effects related to healthy tissue damage. We assessed and modelled serum platinum (Pt) decay after chemotherapy and determined relationships between long-term circulating Pt levels and known late effects. PATIENTS AND METHODS: In 99 testicular cancer survivors, treated with cisplatin-based chemotherapy, serum and 24-h urine samples were collected during follow-up (1-13 years after treatment). To build a population pharmacokinetic model, measured Pt data were simultaneously analysed, together with cisplatin dose, age, weight and height using the NONMEM software. Based on this model, area under the curve between 1 and 3 years after treatment (Pt AUC1-3 years) was calculated for each patient. Predicted long-term Pt exposure was related to renal function and to late effects of treatment assessed median 9 (3-15) years after chemotherapy. RESULTS: Decay of Pt was best described by a two-compartment model. Mean terminal T1/2 was 3.7 (range 2.5-5.2) years. Pt AUC1-3 years correlated with cumulative cisplatin dose, and creatinine clearance before and 1 year after treatment. Patients with paraesthesia had higher Pt AUC1-3 years (30.9 versus 27.0 µg/l month) compared with those without paraesthesia (P = 0.021). Patients with hypogonadism, elevated LDL-cholesterol levels or hypertension also had higher Pt AUC1-3 years. CONCLUSIONS: Renal function before and after cisplatin treatment is an important determinant of long-term Pt exposure. Known long-term effects of testicular cancer treatment, such as paraesthesia, hypogonadism, hypercholesterolaemia and hypertension, are associated with long-term circulating Pt exposure.

Impact of imidacloprid on life-cycle development of Coccinella septempunctata in laboratory microcosms.

Long-term effects of a single application of imidacloprid on ladybird beetle, Coccinella septempunctata L., were studied in indoor laboratory microcosms, starting with the 2nd instar larvae of C. septempunctata but covering the full life cycle. The microcosms comprised enclosures containing a pot with soil planted with broad bean plants and black bean aphid, Aphis craccivora Koch, as food. Exposure doses (0.85-13.66g a.i. ha(-1)) in the long-term microcosm experiment were based on a preliminary short-term (72h) toxicity test with 2nd instar larvae. The measurement endpoints used to calculate NOERs (No Observed Effect application Rates) included development time, hatching, pupation, adult emergence, survival and number of eggs produced. Furthermore, for these endpoints ER50 (application rate causing 50 percent effect) and LR50 (application rate causing 50 percent mortality) values were calculated when possible. The single imidacloprid application affected survival (lowest LR50 4.07g a.i. ha(-1); NOER 3.42g a.i. ha(-1)), egg production (ER50 26.63g a.i. ha(-1)) and egg hatching (NOER 6.83g a.i. ha(-1)). Statistically significant treatment-related effects on the whole development duration, pupation and adult emergence could not be demonstrated (NOER≥13.66g a.i. ha(-1)). The lowest L(E)R50 values and NOERs derived from the laboratory microcosm test with C. septempunctata are lower than the reported field application rates of imidacloprid (15-60g a.i. ha(-1)) in cotton cultivation in China, suggesting potential risks to beneficial arthropods.

Multi-biomarker assessment of chronic toxicity induced by the chemical warfare agent adamsite in Danio rerio.

Several hundred thousand tons of chemical warfare agents (CWAs) were disposed of at sea, leading to environmental contamination. Among the most toxic and persistent CWAs is adamsite; however, the ecotoxicological data on this compound is limited. Presented research focuses on the long-term effects of adamsite on fish. A 28-day exposure study was conducted, evaluating the impact of adamsite on life history parameters (body length, body mass, growth rate), tissue accumulation, and the expression/activity of detoxification-related enzymes in the model fish species, Danio rerio. Results indicate that chronic adamsite exposure significantly reduces body length, weight, and growth rate of fish at trace concentrations (0.20 and 0.25 µg × L-1). Adamsite-related compounds accumulate in fish muscle tissues, increasing by approximately 4 µg per gram (dry weight) for every microgram of adamsite per litre of water during chronic exposure. The mRNA expression and activity of detoxification-related enzymes were elevated in the gills of fish, indicating oxidative stress. This study highlights the severe chronic toxicity of adamsite, which could not be anticipated based on acute toxicity. It underscores the need for comprehensive long-term toxicity assays for CWAs and emphasizes the potential ecological and health risks posed by adamsite, necessitating more stringent risk assessments.

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.

[Primary retroperitoneal lymph node dissection in testicular germ cell cancer in clinical stage IIA/B-renaissance of an established treatment?] / Die primäre retroperitoneale Lymphadenektomie beim testikulären Keimzelltumor im klinischen Stadium IIA/B ­ Renaissance einer etablierten Therapie?

BACKGROUND: The guideline-recommended treatment of choice for clinical stage IIA/B testicular germ cell tumors is chemotherapy with three cycles of PEB/four cycles of PE or, alternatively, radiation for seminomas. Despite their high curative efficacy, both options are associated with significant long-term toxicities. We evaluated the functional and oncological outcomes of primary retroperitoneal lymph node dissection (RPLND) as a therapeutic alternative. PATIENTS AND METHODS: Between 2018 and 2022, 76 patients (n = 34 seminomas, n = 42 nonseminomas) underwent primary RPLND for marker-negative clinical stage IIA/B testicular germ cell cancer. All patients underwent nerve-sparing RPLND with a unilateral or bilateral template dissection and had a follow-up ≥ 3 months. None of the patients received adjuvant chemotherapy. In 24 patients, the serum concentration of miR371a-3p was evaluated preoperatively. Follow-up was performed according to EAU guidelines. RESULTS: Median age and median follow-up were 30.1 (17-62) years and 29.3 (3-72) months, respectively. Mean operation time, blood loss, and duration of hospitalization were 131 (105-195) min, < 150 ml, and 4.5 (3-9) days, respectively. A Clavien-Dindo IIIa complication was experienced by 8 (10.9%) patients. Antegrade ejaculation was preserved in 90.8%. A mean number of 19 (7-68) lymph nodes were dissected. The mean number of positive lymph nodes was 1.1 (1-5), and the mean diameter of positive lymph nodes was 2.4 (0.8-4.6) cm. Eleven (14.5%) patients had stage pN0 (3/34 seminomas, 8/42 nonseminomas). In 24/27 patients (88.9%) miR371 was positive, and it was negative in 4/4 with pN0 and 3/3 (100%) with teratoma. An outfield relapse was experienced by 7 patients (9.2%), who then received salvage chemotherapy. CONCLUSION: Primary RPLND for marker-negative clinical stage IIA/B germ cell tumors results in high cure rates without adjuvant chemotherapy and is associated with a low rate of complications if performed in experienced hands. Therefore, primary RPLND should be included in the management of these patients.

In vivo toxicity test and safety study of Shenfu injection for sepsis treatment.

AIM: This study aimed to evaluate the preclinical safety of Shenfu injection for the treatment of sepsis. Tests were designed and conducted to determine the acute and long-term toxicity of Shenfu injection in rats, based on the recommended indications and dosage for human use. MATERIALS AND METHODS: Rats were administered 22.5 g of raw drug/kg/day via tail vein injection. Toxicity symptoms were monitored for 14 days following the intravenous injection of Shenfu injection, and target organs affected by toxicity were analyzed. To assess long-term toxicity, rats were given 12, 9, or 6 g of raw drug/kg/day by intraperitoneal injection, equivalent to 12, 9, and 6 times the daily clinical dose for adult sepsis patients (3.3 mL of stock solution per 1 g of raw drug/kg/day), for 30 consecutive days. This was followed by a 28-day recovery period after withdrawal of the drug. During the administration and recovery periods, signs of toxicity were observed and compared with those in the control (stromal fluid) group. The aim was to predict potential clinical adverse reactions, including the nature and severity of these reactions, dose-response and time-response relationships, and the reversibility of the effects. Additionally, the study sought to identify the target organs or tissues potentially affected by repeated administration and suggest clinical indicators that should be monitored during the product's use. Furthermore, the safety of co-administration with commonly used chemical medications for the treatment of sepsis was investigated. RESULTS: In the acute toxicity test, administration of the maximum dose of Shenfu injection (75 mL of stock solution/22.5 g of raw drug/kg/day) via tail vein injection resulted in transient symptoms, including piloerection (vertical hair response), weight loss, and reduced food intake. In the long-term toxicity experiments, rats received intraperitoneal injections of 0.3 g/mL (stock solution), 0.225 g/mL, and 0.15 g/mL Shenfu injection per day, which corresponded to 12, 9, and 6 times the daily clinical dose for adults with sepsis. The injections were administered twice daily for 30 days, followed by a 28-day drug withdrawal period for recovery. After 28 days, no significant toxicological changes were observed, apart from a hemodilution effect caused by the excessive volume of the drug and a slight increase in alkaline phosphatase and total bilirubin levels. The effects were reversible upon drug discontinuation. CONCLUSIONS: A single intravenous injection of 22.5 g of raw drug/kg/day and long-term intraperitoneal administration of up to 12 g of raw drug/kg/day are considered safe doses for rats.

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.