Thyroid cancer and endocrine disruptive chemicals: a case-control study on per-fluoroalkyl substances and other persistent organic pollutants.

Objective: The aim was to evaluate the possible association between some endocrine disruptive chemicals and thyroid cancer (TC) in an Italian case-control cohort. Methods: We enrolled 112 TC patients and 112 sex- and age-matched controls without known thyroid diseases. Per- and poly-fluoroalkyl substances (PFAS), poly-chlorinated biphenyls (PCBs), and dichlorodiphenyltrichloroethane (4,4'-DDT and 4,4'-DDE) were measured in the serum by liquid or gas chromatography-mass spectrometry. Unconditional logistic regression, Bayesan kernel machine regression and weighted quantile sum models were used to estimate the association between TC and pollutants' levels, considered individually or as mixture. BRAFV600E mutation was assessed by standard methods. Results: The detection of perfluorodecanoic acid (PFDA) was positively correlated to TC (OR = 2.03, 95% CI: 1.10-3.75, P = 0.02), while a negative association was found with perfluorohexanesulfonic acid (PFHxS) levels (OR = 0.63, 95% CI: 0.41-0.98, P = 0.04). Moreover, perfluorononanoic acid (PFNA) was positively associated with the presence of thyroiditis, while PFHxS and perfluorooctane sulfonic acid (PFOS) with higher levels of presurgical thyroid-stimulating hormone (TSH). PFHxS, PFOS, PFNA, and PFDA were correlated with less aggressive TC, while poly-chlorinated biphenyls (PCB-105 and PCB-118) with larger and more aggressive tumors. Statistical models showed a negative association between pollutants' mixture and TC. BRAF V600E mutations were associated with PCB-153, PCB-138, and PCB-180. Conclusion: Our study suggests, for the first time in a case-control population, that exposure to some PFAS and PCBs associates with TC and some clinical and molecular features. On the contrary, an inverse correlation was found with both PFHxS and pollutants' mixture, likely due to a potential reverse causality.

Efficacy and safety of a 3-in-1 antiaging night facial serum containing melatonin, bakuchiol, and ascorbyl tetraisopalmitate through clinical and histological analysis.

BACKGROUND: Changes induced by intrinsic and extrinsic photoaging result in signs of skin aging including altered pigmentation and wrinkles. A 3-in-1 night facial serum (NFS) was developed to treat skin aging by antioxidative and retinoid-like mechanisms. OBJECTIVE: To determine the clinical and histological effects of the 3-in-1 NFS on signs of skin aging, clinically and histologically. METHODS & MATERIALS: Twenty-four subjects applied serum nightly for 12 weeks, and 12 subjects continued an extension study to 24 weeks. Clinical assessment of skin quality was performed by dermatologists. Skin biopsy was performed at 12 weeks to assess histological changes. RESULTS: There was a global aesthetic improvement over the duration of the study: +1.21 points at 12 weeks; +1.25 at 24 weeks. Skin texture, pigmentation, erythema, skin tone, complexion, lines, and wrinkles all significantly improved (P < .05). There was also a significant reduction in photodamage, hyperpigmentation, and wrinkle scores, most notably horizontal forehead expression lines, and marionette lines (P < .05 for all). Dermal and epidermal thickness increased without reaching statistical significance. CONCLUSION: The 3-in-1 NFS had clinically and statistically significant effects on signs of skin aging after 12 weeks, which became more pronounced after 24 weeks.

Maternal serum levels of perfluoroalkyl substances in early pregnancy and offspring birth weight.

BACKGROUND: Perfluoroalkyl substances (PFASs) are widespread, bioaccumulating, and persistent and show placental transfer. Emerging research indicates associations between prenatal exposure and low birth weight. The aim of this study was to assess the associations between first trimester exposure to PFASs and birth weight (BW) in the Swedish Environmental, Longitudinal, Mother and child, Asthma and allergy (SELMA) study and examine whether associations differ between girls and boys. METHODS: Eight PFASs were analyzed in maternal serum (median: 10 weeks of pregnancy). Associations between prenatal PFAS exposure and birth outcomes with BW, BW for gestational age, and birth small for gestational age (SGA) were assessed in 1533 infants, adjusted for potential confounders and stratified by sex. RESULTS: Increased maternal perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUnDA) were associated with lower BW, lower BW for gestational age, and SGA birth. Associations were significant only in girls, where prenatal exposure in the upper quartile was associated with a 93-142-g lower BW when compared with that of the lowest quartile exposure. The associations were not mediated by effects on gestational age. CONCLUSIONS: We found associations between prenatal exposure for five different PFASs and birth weight, with more pronounced associations in girls than in boys.

Maternal plasma concentrations of perfluoroalkyl and polyfluoroalkyl substances during pregnancy and anogenital distance in male infants.

STUDY QUESTION: Are maternal plasma concentrations of perfluoroalkyl and polyfluoroalkyl substances (PFASs) during pregnancy associated with anogenital distance (AGD) in male infants at birth, 6, and 12 months of age? SUMMARY ANSWER: Higher maternal plasma concentrations of some PFASs were associated with shorter AGD in male infants at birth and 6 months of age. WHAT IS KNOWN ALREADY: Two animal studies have found that exposure to PFASs was associated with shorter AGD in male rat fetuses and wild male minks. There is only one human study on the topic that did not identify consistent patterns between maternal serum concentrations of PFASs during pregnancy and AGD in male infants. STUDY DESIGN, SIZE, DURATION: In the prospective cohort study, a total of 1292 eligible pregnant women were recruited at 12-16 weeks of gestation between April and December 2012 at the Maternal and Child Health Hospital of Minhang district in Shanghai, China. At delivery, 667 male singletons were born. They were then followed up at birth (n = 439) and at 6 (n = 411) and 12 months (n = 376) of age when anopenile distance (AGDAP) and anoscrotal distance (AGDAS) were measured. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 500 male infants who had both maternal plasma concentrations of PFASs and at least one AGD measurement of at three time points were included in the present study. Multiple linear regression models were used to evaluate the potential linear associations between maternal concentrations of PFASs and AGD. MAIN RESULTS AND THE ROLE OF CHANCE: Maternal plasma concentrations (ln-transformed) of perfluorooctane sulfonate (PFOS), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUdA) were inversely associated with AGDAS or AGDAP at birth (AGDAS: per ln unit increase in PFAS concentrations: ß (95% CI): -0.65 (-1.27 to -0.02) mm for PFOS; -0.58 (-1.11 to -0.06) mm for PFDA; and -0.57 (-1.09 to -0.06) mm for PFUdA; AGDAP: per ln unit increase in PFAS concentrations: ß (95% CI): -0.63 (-1.24 to -0.01) mm for PFDA and - 0.76 (-1.36 to -0.16) mm for PFUdA). At 6 months of age, per unit increase in maternal ln concentrations of PFOS and perfluorotridecanoic acid (PFTrDA), AGDAS decreased on average by -2.21 (95% CI: -4.28 to -0.14) and -1.11 (95% CI: -2.17 to -0.06) mm, respectively. Additionally, ln-transformed perfluorooctanoic acid (PFOA) showed nonsignificant but inverse associations with both AGDAS and AGDAP at 6 months of age. We found no significant associations between ln-transformed maternal concentrations of PFASs and either AGDAS or AGDAP at 12 months of age. However, significantly inverse association of ln-transformed PFOA with AGDAP was observed in male infants who never or shortly breastfed (<3 months) at 12 months of age. LIMITATIONS, REASONS FOR CAUTION: AGD measurements were performed by different examiners at each follow-up visit, and the intra-examiner variation was not assessed, which might cause intra-rater and inter-rater measurement errors. Additionally, our study may have selection bias since a considerable number of participants withdrew from the cohort although the differences in demographic characteristics were not statistically significant between included mother-infant pairs and those excluded. No statistical correction was made for multiple comparisons. WIDER IMPLICATIONS OF THE FINDINGS: Our findings may have important implications for the early development of genital health in male infants since PFASs can be detected in almost all pregnant women and infants worldwide. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by grants from the National Key Research and Development program of China (2018YFC1002801 and 2016YFC1000505), the Science and Technology Commission of Shanghai Municipality (16ZR1430100), the National Natural Science Foundation of China (81428011), and the Innovation-Oriented Science and Technology Grant from National Health Commission Key Laboratory of Reproduction Regulation (CX2017-06). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Immunotoxic and hepatotoxic effects of perfluoro-n-decanoic acid (PFDA) on female Harlan Sprague-Dawley rats and B6C3F1/N mice when administered by oral gavage for 28 days.

Poly- and perfluoroalkyl substances (PFAS) are chemically and thermally stable, hydrophobic, lipophobic compounds used in stain repellants and water and oil surfactants, and associated with immunosuppression and peroxisome proliferator activity. Perfluoro-n-decanoic acid (PFDA, (CF3(CF2)8COOH), a fluorinated straight chain fatty acid compound, is reported to induce thymic atrophy and reversible bone marrow hypocellularity in rodent models. The objective of this study was to assess potential immunotoxicity of PFDA, due to its structural similarity to other immunosuppressive PFASs. Female Harlan Sprague-Dawley rats were exposed to 0-2.0 mg PFDA/kg by oral gavage daily for 28 d. Female B6C3F1/N mice were exposed once/week to 0-5.0 mg PFDA/kg by gavage for 4 weeks. Animals were evaluated for effects on immune cell populations in spleen and bone marrow, and innate, humoral-, and cell-mediated immunity. Mice were also evaluated for resistance to Influenza virus. Treatment-related hepatocyte necrosis and hepatomegaly were observed in rats treated with 0.5 mg PFDA/kg/d. In mice, hepatomegaly (26-89%) was observed following exposure to ≥0.625 mg PFDA/kg/week, while splenic atrophy (20%) was observed at 5.0 mg PFDA/kg/week. At 5.0 mg PFDA/kg/week, total spleen cells, and Ig + and NK + cells were decreased (17.6-27%). At ≥ 1.25 mg PFDA/kg/week the numbers of splenic CD3+, CD4+, CD8+, and Mac3+ cells were decreased (10.5-39%). No changes were observed in leukocyte subpopulations in PFDA-exposed rats. Phagocytosis by fixed-tissue macrophages was decreased in liver (specific activity, 24-39%) at ≥0.25 mg PFDA/kg/d in rats. PFDA-induced effects on humoral- and cell-mediated immunity, host resistance, and bone marrow progenitor cells were limited. These data suggest that exposure to PFDA may induce adverse effects in rat liver in a manner consistent with the PFAS class, and may also alter the balance of immune cell populations in lymphoid tissues in mice.

Novel Application of Time-Spatial Labeling Inversion Pulse Magnetic Resonance Imaging for Diagnosis of External Hydrocephalus.

BACKGROUND: Although a subdural fluid collection frequently is observed, diagnostic methods that differentiate between the subdural collection caused by external hydrocephalus and that caused by subdural hygroma have not been established. Here, we report a case of external hydrocephalus caused by Gliadel-induced eosinophilic meningitis that has been previously reported in only 1 case and can be diagnosed by time-spatial labeling inversion pulse magnetic resonance imaging (time-SLIP MRI). CASE DESCRIPTION: A tumor located in the left temporal was detected incidentally in an 81-year-old man by examination of a head injury. The tumor was surgically resected and diagnosed as a high-grade glioma during the surgery; Gliadel wafers subsequently were implanted. Three weeks after the resection, the patient showed disturbed consciousness, and computed tomography revealed a subdural fluid collection. The out-flow of cerebrospinal through the resection cavity was detected by time-SLIP MRI. Cerebrospinal tests indicated high white blood cell counts and high protein levels, with more than 90% of the white blood cell count comprising eosinophils. Therefore, we suspected that the subdural fluid collection was caused by external hydrocephalus because of Gliadel-induced eosinophilic meningitis. We surgically removed the Gliadel wafers and subsequently performed a surgery to insert a ventriculoperitoneal shunt. Histologic examination indicated eosinophilic accumulation around the Gliadel wafers. The patient's symptoms improved after the insertion of a ventriculoperitoneal shunt. CONCLUSIONS: In the present case, time-SLIP MRI was a useful and noninvasive method for diagnosing external hydrocephalus which was caused by eosinophilic meningitis because of Gliadel-induced eosinophilic meningitis.

Eosinophilic meningitis triggered by implanted Gliadel wafers: case report.

Although carmustine (Gliadel) wafers improve local tumor control and extend the overall survival in patients with malignant glioma, adverse effects have been documented. The authors report the first case of eosinophilic meningitis triggered by the placement of Gliadel wafers. A 61-year-old man with a history of alimentary allergy and glioblastoma in the right frontal lobe underwent resection followed by the implantation of Gliadel wafers. Three weeks later he suffered the sudden onset of headache, vomiting, and progressive consciousness disturbance. Computed tomography revealed enlargement of the ventricular system and subdural space on the side of the tumor. His CSF leukocyte count increased up to 3990 cells/mm3; 95% of the cells were eosinophilic granulocytes (EGs), suggesting eosinophilic meningitis. Laboratory examination showed the patient to have various elevated allergy indicators. The administration of corticosteroids failed to improve his condition. Despite the insertion of a lumbar drain his symptoms failed to improve. He underwent a second surgical intervention to remove the Gliadel wafers. Histologically, EGs had assembled around the wafers. Eosinophilic infiltrate was present in the brain parenchyma around small vessels. After ventriculoperitoneal shunting his course was favorable. A drug lymphocyte stimulation test against the Gliadel wafers failed to demonstrate a positive reaction; polifeprosan, the wafer matrix without 1,3-bis(2-chloroethyl)-1-nitrosourea, yielded a positive reaction. These findings strongly suggest that although extremely rare, polifeprosan (the wafer matrix) can elicit an allergic reaction. When eosinophilic meningitis is suspected after the implantation of Gliadel wafers, their immediate removal should be considered.

Gliadel wafer implantation combined with standard radiotherapy and concurrent followed by adjuvant temozolomide for treatment of newly diagnosed high-grade glioma: a systematic literature review.

Since 2003, only two chemotherapeutic agents, evaluated in phase III trials, have been approved by the US Food and Drug Administration for treatment of newly diagnosed high-grade glioma (HGG): Gliadel wafers (intracranially implanted local chemotherapy) and temozolomide (TMZ) (systemic chemotherapy). Neither agent is curative, but each has been shown to improve median overall survival (OS) compared to radiotherapy (RT) alone. To date, no phase III trial has tested these agents when used in sequential combination; however, a number of smaller trials have reported favorable results. We performed a systematic literature review to evaluate the combination of Gliadel wafers with standard RT (60 Gy) plus concurrent and adjuvant TMZ (RT/TMZ) for newly diagnosed HGG. A literature search was conducted for the period of January 1995 to September 2015. Data were extracted and categorized, and means and ranges were determined. A total of 11 publications met criteria, three prospective trials and eight retrospective studies, representing 411 patients who received Gliadel plus standard RT/TMZ. Patients were similar in age, gender, and performance status. The weighted mean of median OS was 18.2 months (ten trials, n = 379, range 12.7 to 21.3 months), and the weighted mean of median progression-free survival was 9.7 months (seven trials, n = 287, range 7 to 12.9 months). The most commonly reported grade 3 and 4 adverse events were myelosuppression (10.22 %), neurologic deficit (7.8 %), and healing abnormalities (4.3 %). Adverse events reflected the distinct independent safety profiles of Gliadel wafers and RT/TMZ, with little evidence of enhanced toxicity from their use in sequential combination. In the 11 identified trials, an increased benefit from sequentially combining Gliadel wafers with RT/TMZ was strongly suggested. Median OS tended to be improved by 3 to 4 months beyond that observed for Gliadel wafers or TMZ when used alone in the respective phase III trials. Larger prospective trials of Gliadel plus RT/TMZ are warranted.

Safety concerns over the use of intestinal permeation enhancers: A mini-review.

Intestinal permeation enhancers (PEs) are key components in ∼12 oral peptide formulations in clinical trials for a range of molecules, primarily insulin and glucagon-like-peptide 1 (GLP-1) analogs. The main PEs comprise medium chain fatty acid-based systems (sodium caprate, sodium caprylate, and N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC)), bile salts, acyl carnitines, and EDTA. Their mechanism of action is complex with subtle differences between the different molecules. With the exception of SNAC and EDTA, most PEs fluidize the plasma membrane causing plasma membrane perturbation, as well as enzymatic and intracellular mediator changes that lead to alteration of intestinal epithelial tight junction protein expression. The question arises as to whether PEs can cause irreversible epithelial damage and tight junction openings sufficient to permit co-absorption of payloads with bystander pathogens, lipopolysaccharides and its fragment, or exo- and endotoxins that may be associated with sepsis, inflammation and autoimmune conditions. Most PEs seem to cause membrane perturbation to varying extents that is rapidly reversible, and overall evidence of pathogen co-absorption is generally lacking. It is unknown however, whether the intestinal epithelial damage-repair cycle is sustained during repeat-dosing regimens for chronic therapy.

Prenatal Exposure to Perfluorinated Compounds Affects Birth Weight Through GSTM1 Polymorphism.

OBJECTIVE: The aim of this study was to investigate the effect of genetic polymorphisms on the association of prenatal exposure to perfluorinated compounds (PFCs) with birth weight. METHODS: We analyzed the level of eight PFCs in cord blood and two genetic polymorphisms in maternal blood of 268 subjects. RESULTS: Concentrations of perfluorooctanoic acid, perfluorooctane sulfonate, perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUnDA) showed significant association with a decrease in birth weight (P < 0.05). In mothers with glutathione S-transferase M1 (GSTM1) null genotype, concentrations of PFNA, PFDA, and PFUnDA showed significantly negative association with birth weight (P < 0.05). CONCLUSION: Our findings indicated that GSTM1 polymorphism might affect the association between exposure to PFCs and birth weight, suggesting the effect of genetic susceptibility on the relationship between prenatal PFCs exposure and birth outcomes.

[Risk Factors for Adverse Events after Implantation of BCNU Wafers in High-grade Gliomas].

BACKGROUND: In Japan, patients with malignant glioma have been treated with BCNU wafers (Gliadel®) since January 2013. Several adverse events(AEs)associated with implantation of BCNU wafers, including cerebral edema or cyst formation, are recognized. Here, we report a retrospective review of the experience with implantation of BCNU wafers in our institutions and our findings regarding the risk factors for the AEs. METHODS: We reviewed the records of patients with malignant glioma who were implanted with BCNU wafers between April 2013 and September 2014. Their AEs were examined clinically and radiologically and evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) grading. For investigating the association between risk factors and incidence of AEs, histological diagnosis, extent of resection, and period of BCNU wafers implantation surgery were selected as possible risk factors. RESULTS: Twenty-one patients were included in this investigation. There were no associations among incidence of AEs and histological diagnosis or extent of tumor resection. However, regarding the period of BCNU wafers implantation, additional resection for newly diagnosed tumors and resection for recurrent tumors tended to increase the rate and severity of AEs, especially cerebral edema, compared to primary resection. CONCLUSION: In cases of BCNU wafers implantation, the incidence and degree of AEs might increase if additional resection for newly diagnosed tumors or resection for recurrent tumors is performed. Our investigation revealed that AEs associated with implantation of BCNU wafers tend to occur in the repeated glioma surgery.

The role of Gliadel wafers in the treatment of newly diagnosed GBM: a meta-analysis.

BACKGROUND: Standard treatment for high-grade glioma (HGG) includes surgery followed by radiotherapy and/or chemotherapy. Insertion of carmustine wafers into the resection cavity as a treatment for malignant glioma is currently a controversial topic among neurosurgeons. Our meta-analysis focused on whether carmustine wafer treatment could significantly benefit the survival of patients with newly diagnosed glioblastoma multiforme (GBM). METHOD: We searched the PubMed and Web of Science databases without any restrictions on language using the keywords "Gliadel wafers", "carmustine wafers", "BCNU wafers", or "interstitial chemotherapy" in newly diagnosed GBM for the period from January 1990 to March 2015. Randomized controlled trials (RCTs) and cohort studies/clinical trials that compared treatments designed with and without carmustine wafers and which reported overall survival or hazard ratio (HR) or survival curves were included in this study. Moreover, the statistical analysis was conducted by the STATA 12.0 software. RESULTS: Six studies including two RCTs and four cohort studies, enrolling a total of 513 patients (223 with and 290 without carmustine wafers), matched the selection criteria. Carmustine wafers showed a strong advantage when pooling all the included studies (HR = 0.63, 95% confidence interval (CI) = 0.49-0.81; P = 0.019). However, the two RCTs did not show a statistical increase in survival in the group with carmustine wafer compared to the group without it (HR = 0.51, 95% CI = 0.18-1.41; P = 0.426), while the cohort studies demonstrated a significant survival increase (HR = 0.59, 95% CI = 0.44-0.79; P < 0.0001). CONCLUSION: Carmustine-impregnated wafers play a significant role in improving survival when used for patients with newly diagnosed GBM. More studies should be designed for newly diagnosed GBM in the future.

Survival outcomes and safety of carmustine wafers in the treatment of high-grade gliomas: a meta-analysis.

Carmustine wafers (CW; Gliadel(®) wafers) are approved to treat newly-diagnosed high-grade glioma (HGG) and recurrent glioblastoma. Widespread use has been limited for several reasons, including concern that their use may preclude enrollment in subsequent clinical trials due to uncertainty about confounding of results and potential toxicities. This meta-analysis estimated survival following treatment with CW for HGG. A literature search identified relevant studies. Overall survival (OS), median survival, and adverse events (AEs) were summarized. Analysis of variance evaluated effects of treatment (CW vs non-CW) and diagnosis (new vs recurrent) on median survival. The analysis included 62 publications, which reported data for 60 studies (CW: n = 3,162; non-CW: n = 1,736). For newly-diagnosed HGG, 1-year OS was 67 % with CW and 48 % without; 2-year OS was 26 and 15 %, respectively; median survival was 16.4 ± 21.6 months and 13.1 ± 29.9 months, respectively. For recurrent HGG, 1-year OS was 37 % with CW and 34 % without; 2-year OS was 15 and 12 %, respectively; median survival was 9.7 ± 20.9 months and 8.6 ± 22.6 months, respectively. Effects of treatment (longer median survival with CW than without; P = 0.043) and diagnosis (longer median survival for newly-diagnosed HGG than recurrent; P < 0.001) on median survival were significant, with no significant treatment-by-diagnosis interaction (P = 0.620). The most common AE associated with wafer removal was surgical site infection (SSI); the most common AEs for repeat surgery were mass effect, SSI, hydrocephalus, cysts in resection cavity, acute hematoma, wound healing complications, and brain necrosis. These data may be useful in the context of utilizing CW in HGG management, and in designing future clinical trials to allow CW-treated patients to participate in experimental protocols.

A multicenter phase I/II study of the BCNU implant (Gliadel(®) Wafer) for Japanese patients with malignant gliomas.

Carmustine (BCNU) implants (Gliadel(®) Wafer, Eisai Inc., New Jersey, USA) for the treatment of malignant gliomas (MGs) were shown to enhance overall survival in comparison to placebo in controlled clinical trials in the United States and Europe. A prospective, multicenter phase I/II study involving Japanese patients with MGs was performed to evaluate the efficacy, safety, and pharmacokinetics of BCNU implants. The study enrolled 16 patients with newly diagnosed MGs and 8 patients with recurrent MGs. After the insertion of BCNU implants (8 sheets maximum, 61.6 mg BCNU) into the removal cavity, various chemotherapies (including temozolomide) and radiotherapies were applied. After placement, overall and progression-free survival rates and whole blood BCNU levels were evaluated. In patients with newly diagnosed MGs, the overall survival rates at 12 months and 24 months were 100.0% and 68.8%, and the progression-free survival rate at 12 months was 62.5%. In patients with recurrent MGs, the progression-free survival rate at 6 months was 37.5%. There were no grade 4 or higher adverse events noted due to BCNU implants, and grade 3 events were observed in 5 of 24 patients (20.8%). Whole blood BCNU levels reached a peak of 19.4 ng/mL approximately 3 hours after insertion, which was lower than 1/600 of the peak BCNU level recorded after intravenous injections. These levels decreased to less than the detection limit (2.00 ng/mL) after 24 hours. The results of this study involving Japanese patients are comparable to those of previous studies in the United States and Europe.

The role of Gliadel wafers in the treatment of high-grade gliomas.

Glioblastoma multiforme (GBM) is the most aggressive brain tumor. Standard treatment includes surgery, radiation and chemotherapy. Prognosis is dismal with an average survival of approximately 1 year. Gliadel wafers are one treatment option, working as a source for local chemotherapy delivery. Their use is controversial with questionable survival benefit and potential side effects. We reviewed the literature in an effort to clarify their role in the treatment of high-grade gliomas. A systematic PubMed search was performed using the keywords 'Gliadel', 'carmustine' or 'BCNU wafers' in newly diagnosed high-grade glioma patients. Treatment regimen, and median survival were analyzed. Adverse event ratio was calculated by computing the number of adverse events in a study per patient receiving carmustine wafers. Nineteen studies with 795 patients were included in our review. Survival was 8.7-22.6 months with a mean overall survival (OS) of 16.2 months (control survival is approximately 14 months with surgery and adjuvant chemoradiotherapy). Adverse event ratio using Gliadel wafersin control group. Complication rate was 42.7%. Gliadel wafers may marginally increase survival and local control in newly diagnosed GBM patients but are associated with a high complication rate; therefore, we do not recommend using Gliadel wafers in patients with GBM. Further research may be warranted once a safer alternative to Gliadel wafers has been introduced.

Intestinal absorption of raltitrexed and evaluation of the effects of absorption enhancers.

Raltitrexed (RTX) has shown clinical activity in a variety of advanced solid tumours. Its oral bioavailability is low and its intestinal absorption mechanism is not clear. In the present study, the absorption mechanism of RTX in the small intestine was investigated, and the effects of absorption enhancers and efflux transporter inhibitors were evaluated by in vitro transport studies using the Caco-2 cell model and in situ perfusion experiments in rats. Oral bioavailability of RTX in rats in the presence or absence of enhancers were also investigated. The results of in vitro and in situ experiments indicated that the kinetic model of combined mechanism (active and passive transport) fitted the concentration-time data of RTX best with the highest R2 and lowest SSE (Sum of Squares for Error). The apparent or effective permeability coefficient (P(app) or P(eff)) of RTX remained statistically constant in a certain concentration range, then decreased when the concentration increased. But the decrease trend did not continue with further increase in concentration. And folic acid could competitively inhibit RTX absorption. These results suggested that a combined absorption mechanism for RTX existed. Furthermore, within certain concentration ranges, Carbomer 934P and sodium caprate (Cap-Na) exhibited significant absorption enhancement effects with low toxicity, whereas the enhancement effects of sodium deoxycholate (Deo-Na) were accompanied with acute toxicities. Moreover, probenecid and pantoprazole obviously enhanced RTX absorption, demonstrating that RTX is a substrate of the multidrug resistance protein (MRP) and breast cancer resistance protein (BCRP). A secretion experiment indicated that RTX could be effluxed into the intestines both with bile and by active efflux action. Oral bioavailability of RTX was significantly improved by the investigated absorption enhancers and transporter inhibitors, which is consistent with the in vitro and in situ experiments.

Enhancement by sodium caprate and sodium deoxycholate of the gastrointestinal absorption of berberine chloride in rats.

The aim of the investigation was to compare the effectiveness of two absorption enhancers, sodium caprate (C10) and sodium deoxycholate (SDC), in increasing the bioavailability of a poorly absorbed paracellar flux drug, berberine chloride, across the intestinal mucosae of rats in vivo, together with examination of their effects on mucosal damage. In addition, all four intestinal segments were collected after administration of the enhancers and sodium saline. The results of the bioavailability experiments showed the oral absorption of berberine chloride was poor and both C10 and SDC could significantly improve the very poor absorption of berberine chloride. After co-administration, the area under the plasma concentration-time curve of berberine chloride was increased 41.1-fold by C10 (100 mg/kg) and 35.3-fold by SDC (100 mg/kg) compared with that in the absence of C10 and SDC, respectively. Local toxicity experiment indicated that both enhancers caused no specific damage to the intact intestine. This study demonstrates that C10 and SDC could significantly promote the absorption of berberine chloride from the gastrointestinal tract with few toxic effects, which might be due mainly to relaxing the absorption limitation while inhibiting the efflux transporter of berberine chloride by the enhancers. Besides, this could lead to the development of new drug-enhancers.

Pretreatment with xenon protected immature rabbit heart from ischaemia/reperfusion injury by opening of the mitoKATP channel.

BACKGROUND: The noble gas anaesthetic, xenon has previously been shown to protect the adult myocardium from ischaemia/reperfusion (I/R) injury, however its effect on immature myocardium is unclear. The aim of this study was to investigate the effect of xenon on the isolated immature heart. METHODS: Isolated, immature (2-3weeks old) New Zealand rabbit hearts were perfused with Krebs-Henseleit buffer via Langendorff-mode. After 20min of baseline equilibration, hearts were pretreated with 75% xenon, 75% xenon+100µM diazoxide, or 75% xenon+100µM 5-hydroxydecanoate, and then subjected to 1h of global ischaemia and 3h of reperfusion. RESULTS: Pretreatment with 75% xenon significantly improved cardiac function (P<0.01 vs. the I/R group, respectively), limited myocardial infarct size (20.83±2.16%, P<0.01 vs. 35.82±2.14% of the I/R group), reduced cardiac enzyme release (CK-MB, 1.00±0.19IU/L, P<0.01 vs. 0.44±0.14IU/L of the I/R group; LDH, 6.15±1.06IU/L P<0.01 vs. 3.49±0.37IU/L of the I/R group) and decreased apoptosis (6.17±0.56%, P<0.01 vs. 11.31±0.93% of the I/R group). In addition, the mitochondrial structure changes caused by I/R injury were largely prevented by 75% xenon pretreatment (1.37±0.16, P<0.01 vs. 2.32±0.13 of the I/R group). The mitochondrial adenosine triphosphate-sensitive potassium (mitoKATP) channel opener diazoxide did not influence the effect of xenon, but the specific mitoKATP channel blocker 5-hydroxydecanoate completely abolished this effect. CONCLUSIONS: Our study demonstrated that pretreatment with 75% xenon protected immature heart from I/R injury, and this protection was probably mediated by preservation of myocardial mitochondria and opening of mitoKATP channel.

The effects of the NICE Technology Appraisal 121 (gliadel and temozolomide) on survival in high-grade glioma.

OBJECTIVE: The prognosis of high-grade glioma (HGG) is poor with a median survival of about 1 year for glioblastoma. In 2007, NICE published a technology appraisal (TA121) recommending the use of carmustine wafers (Gliadel) and systemic therapy with temozolomide for selected patients with HGG. Outcomes for HGG surgery in the United Kingdom with these combined treatments have not been published. DESIGN: Retrospective audit of consecutive patients in a single unit with carmustine wafer implantation. SUBJECTS: Fifty-nine patients had carmustine wafers implanted at primary surgery, between October 2005 and October 2010 at Wessex Neurological Centre, Southampton, UK. METHODS: Patients were given chemotherapeutic treatments strictly according to NICE TA121. Survival was calculated using Kaplan-Meier method. RESULTS: Fifty-five patients had WHO grade IV tumours and four had grade III. Median age was 61 years. At follow-up, 39 patients had died. Median survival was 15.3 months. Eight patients (13.5%) experienced post-operative complications (including five infections) for which four had the carmustine wafers removed. Forty-seven (80%) patients were treated with radical radiotherapy (55-60 Gy) and six (10%) patients received palliative radiotherapy (30 Gy). Thirty-seven patients (63%) received concomitant temozolomide chemotherapy. In the subset of 37 patients receiving multimodal treatment with radical radiotherapy and concomitant temozolomide, median survival was 15.8 months compared with 7.4 months in those not receiving multimodal treatment. DISCUSSION: Carmustine wafers for primary HGG surgery in accordance with the NICE TA121 were associated with a median survival of 15.3 months; this is improved compared with previously reported randomised trials. Multimodal treatment with carmustine wafers, radical radiotherapy and concomitant temozolomide was associated with improved survival. Increased incidence of infections was observed in cases receiving carmustine wafers.