Excellent results of screening for subsequent breast cancers in long-term survivors of childhood Hodgkin's lymphoma-Results of a population-based study.

Introduction: Subsequent breast cancer (SBC) represents a major complication in childhood cancer survivors and screening for SBC in survivors after incidental irradiation of breasts is recommended. In this article, we report the results and discuss benefits of SBC screening in female pts treated for Hodgkin's lymphoma (HL) in Slovenia in a period of 45 years. Methods: Between 1966 and 2010, 117 females were treated for HL under the age of 19 in Slovenia. One hundred five of them survived for 5 years and were included in our study. They were 3-18 (med. 15) years old at diagnosis and followed for 6-52 (med. 28) years. Eighty-three percent of them had chest RT with a median dose of 30 Gy. Ninety-seven (92%) of 105 pts were regularly followed according to the international guidelines including yearly screening mammography/breast MRI in those who received chest RT. Results: We diagnosed 10 SBCs in eight pts 14-39 (med. 24) years after diagnosis at the age of 28-52 (med. 42) years. At 40 years of follow-up, cumulative incidence of SBCs in females who got chest RT was 15.2%. Seven of eight patients (with 9 SBCs) got chest RT with 24-80 (med. 36) Gy at the age of 12 to 18 (median 17) years. Two patients in this group got bilateral SBC. One patient got invasive SBC after being treated with ChT containing high-dose of anthracyclines without chest RT at the age of 13. All eight invasive SBCs were invasive ductal cancers, HER2 receptors negative, all but one with positive hormonal receptors. Six invasive cancers were of stage T1N0, one T1N1mi, only one, diagnosed before era of screening, was of T2N1. None of 8 pts died of SBC. Conclusion: After introduction of regular breast screening in our female patients, who received chest RT in childhood, all SBCs were of early stage and no patients died of SBC. Survivors of pediatric HL should be informed about the risk of late sequelae of treatment for HL, including SBC. Regular follow-up with breast cancer screening and breast self-examination is of vital importance in those treated with chest RT.

Cognitive functioning is prognostic in patients with IDH1-wild type and MGMT-unmethylated high-grade gliomas.

AIM: To investigate the prognostic factors of survival in patients with high-grade gliomas without isocitrate dehydrogenase-1 (IDH) mutation and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. METHODS: The study enrolled Slovenian patients with high-grade gliomas. Postoperatively, they completed a battery of neuropsychological tests. Demographics and clinical data were collected. The results of cognitive tests were converted to standardized scores and dichotomized based on impairment. A univariate Cox proportional hazard regression model was used to determine clinical predictors, and a multivariate Cox model was used to determine the prognostic value of cognitive test results. Kaplan-Meier curves were constructed, and survival was compared with the log rank test. RESULTS: The study enrolled 49 patients with IDH wild-type, MGMT-unmethylated high-grade gliomas. The median time to progression was 9.92 months (7.25, 12.59) and the overall median survival was 12.19 months (8.95, 15.4). Age and the extent of surgery were significant prognostic factors for survival. After controlling for these factors, cognitive functioning in the domain of verbal fluency remained a significant predictor of survival outcomes. CONCLUSION: Cognitive functioning in the domain of verbal fluency was associated with overall survival independently of age and the extent of surgery. Cognitive functioning could be an important stratifying tool in this group of patients lacking other predictors.

ESTRO ACROP and SIOPE recommendations for myeloablative Total Body Irradiation in children.

BACKGROUND AND PURPOSE: Myeloablative Total Body Irradiation (TBI) is an important modality in conditioning for allogeneic hematopoietic stem cell transplantation (HSCT), especially in children with high-risk acute lymphoblastic leukemia (ALL). TBI practices are heterogeneous and institution-specific. Since TBI is associated with multiple late adverse effects, recommendations may help to standardize practices and improve the outcome versus toxicity ratio for children. MATERIAL AND METHODS: The European Society for Paediatric Oncology (SIOPE) Radiotherapy TBI Working Group together with ESTRO experts conducted a literature search and evaluation regarding myeloablative TBI techniques and toxicities in children. Findings were discussed in bimonthly virtual meetings and consensus recommendations were established. RESULTS: Myeloablative TBI in HSCT conditioning is mostly performed for high-risk ALL patients or patients with recurring hematologic malignancies. TBI is discouraged in children <3-4 years old because of increased toxicity risk. Publications regarding TBI are mostly retrospective studies with level III-IV evidence. Preferential TBI dose in children is 12-14.4 Gy in 1.6-2 Gy fractions b.i.d. Dose reduction should be considered for the lungs to <8 Gy, for the kidneys to ≤10 Gy, and for the lenses to <12 Gy, for dose rates ≥6 cGy/min. Highly conformal techniques i.e. TomoTherapy and VMAT TBI or Total Marrow (and/or Lymphoid) Irradiation as implemented in several centers, improve dose homogeneity and organ sparing, and should be evaluated in studies. CONCLUSIONS: These ESTRO ACROP SIOPE recommendations provide expert consensus for conventional and highly conformal myeloablative TBI in children, as well as a supporting literature overview of TBI techniques and toxicities.

Screening colonoscopy according to guidelines in long-term survivors of childhood cancer-results of a population-based study.

PURPOSE: To report on findings in screening colonoscopies in long-term survivors of childhood cancer treated with abdominopelvic irradiation (RT). METHODS: Screening colonoscopies were introduced at the Slovenian outpatient follow-up clinic in 2015, according to the Children's Oncology Group guidelines. In January 2019, 54 patients who received abdominopelvic irradiation for Hodgkin disease, Wilms tumour or dysgerminoma at the age of 0-16 between 1968 and 1995 were eligible for screening colonoscopy, and until December 2019, twenty-eight asymptomatic patients have undergone this examination. RESULTS: Patients were 1-16 (median 13) years old at cancer diagnosis and had colonoscopy 24-47 (median 36) years after diagnosis. They received abdominopelvic irradiation with the dose 16-46 (median 30) Gy. Adenomatous lesions were found in 18 patients (64%) and advanced adenomatous lesions in one-third. Patients who received abdominopelvic RT with a dose below 30 Gy had 75% incidence of adenomatous lesions and in those who received a dose of 30 Gy or more the incidence was 60%. Alkylating agents did not have impact on this incidence. CONCLUSIONS: In this first population-based study of screening colonoscopies in asymptomatic survivors of childhood cancer, we provided new evidence for 64% incidence of adenomatous lesions after abdominopelvic RT with the dose above or below 30 Gy. IMPLICATIONS FOR CANCER SURVIVORS: Screening colonoscopies are of vital importance in patients treated with abdominal RT in childhood.

Probabilistic risk assessment for milk in dark chocolate, cookies and other baked goods with PAL sold in Canada.

The risk of having an allergic reaction in milk-allergic individuals consuming products with precautionary allergen labelling (PAL) for milk has been rarely studied in products such as dark chocolate, cookies, and other baked goods. A probabilistic risk assessment model was developed to estimate potential risks. Milk occurrence and contamination levels were reported in a previous article from our group. Dose-response curves for milk were constructed using values (n = 1078) from published double-blind placebo-controlled food challenges. Canadian consumption data was extracted from a national survey, and a homemade survey involving food-allergic Canadians. Milk eliciting doses (ED) were 0.23 (ED01), 1.34 (ED05), 3.42 (ED10), and 16.3 (ED25) mg of milk protein (Log-Normal distribution). Average exposures, per eating occasion, were 24 mg (dark chocolate), 3.9 mg (baked goods), and 0.20 mg (cookies) of milk proteins. The estimated risk of having a milk-induced allergic reaction by consuming foods with PAL for milk was higher for dark chocolate (16%; 15,881/100,000) than baked goods (3.8%; 3802/100,000) or cookies (0.6%; 646/100,000) in milk-allergic Canadians. Dark chocolate, cookies, and baked goods with PAL for milk, should be avoided by milk-allergic Canadians (consuming or not products with PAL) to prevent allergic reactions.

Towards homogenization of total body irradiation practices in pediatric patients across SIOPE affiliated centers. A survey by the SIOPE radiation oncology working group.

BACKGROUND AND PURPOSE: To reduce relapse risk, Total Body Irradiation (TBI) is part of conditioning regimens for hematopoietic stem cell transplantation (HSCT) in pediatric acute leukemia. The study purpose was to evaluate clinical practices regarding TBI, such as fractionation, organ shielding and delivery techniques, among SIOPE affiliated radiotherapy centers. METHODS: An electronic survey was sent out to 233 SIOPE affiliated centers, containing 57 questions about clinical practice of TBI. Surveys could be answered anonymously. RESULTS: From over 25 countries, 82 responses were collected. For TBI-performing centers, 40/48 irradiated ≤10 pediatric patients annually (range: 1-2 to >25). Most indications concerned acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). Four different fractionation schedules were used, of which 12 Gy in 6 fractions was applied in 91% for ALL and 86% for AML. Dose reduction to the lungs, mostly to a mean dose of 8-10 Gy, was applied by 28/33 centers for ALL and 19/21 centers for AML, in contrast to much less applied dose reduction to the kidneys (7/33 ALL and 7/21 AML), thyroid (2/33 ALL and 2/21 AML), liver (4/33 ALL and 3/21 AML) and lenses (4/33 ALL and 4/21 AML). Conventional TBI techniques were used by 24/29 responding centers, while 5/29 used advanced optimized planning techniques. CONCLUSION: Across SIOPE, there is a high level of uniformity in fractionation and use of lung shielding. Practices vary regarding other organs-at-risk shielding and implementation of advanced techniques. A SIOPE radiotherapy working group will be established to define international guidelines for pediatric TBI.

Surgery results in low relapse and progression rates in extramedullary plasmacytoma of the head and neck: A case cohort and review of the literature.

Extramedullary plasmacytoma of the head and neck is a rare indolent neoplasm. Radiotherapy is often the preferred treatment option with excellent local control and survival. The risk of local recurrence or transformation to multiple myeloma is 10-30%. In our case-cohort, thorough, sensitive initial evaluation for disseminated clonal disease and the incorporation of surgery led to excellent results with no recurrences or systemic progression.

Worldwide contamination of food-crops with mycotoxins: Validity of the widely cited 'FAO estimate' of 25.

Prior to 1985 the Food and Agriculture Organization (FAO) estimated global food crop contamination with mycotoxins to be 25%. The origin of this statement is largely unknown. To assess the rationale for it, the relevant literature was reviewed and data of around 500,000 analyses from the European Food Safety Authority and large global survey for aflatoxins, fumonisins, deoxynivalenol, T-2 and HT-2 toxins, zearalenone and ochratoxin A in cereals and nuts were examined. Using different thresholds, i.e. limit of detection, the lower and upper regulatory limits of European Union (EU) legislation and Codex Alimentarius standards, the mycotoxin occurrence was estimated. Impact of different aspects on uncertainty of the occurrence estimates presented in literature and related to our results are critically discussed. Current mycotoxin occurrence above the EU and Codex limits appears to confirm the FAO 25% estimate, while this figure greatly underestimates the occurrence above the detectable levels (up to 60-80%). The high occurrence is likely explained by a combination of the improved sensitivity of analytical methods and impact of climate change. It is of immense importance that the detectable levels are not overlooked as through diets, humans are exposed to mycotoxin mixtures which can induce combined adverse health effects.

Portable Infrared Laser Spectroscopy for On-site Mycotoxin Analysis.

Mycotoxins are toxic secondary metabolites of fungi that spoil food, and severely impact human health (e.g., causing cancer). Therefore, the rapid determination of mycotoxin contamination including deoxynivalenol and aflatoxin B1 in food and feed samples is of prime interest for commodity importers and processors. While chromatography-based techniques are well established in laboratory environments, only very few (i.e., mostly immunochemical) techniques exist enabling direct on-site analysis for traders and manufacturers. In this study, we present MYCOSPEC - an innovative approach for spectroscopic mycotoxin contamination analysis at EU regulatory limits for the first time utilizing mid-infrared tunable quantum cascade laser (QCL) spectroscopy. This analysis technique facilitates on-site mycotoxin analysis by combining QCL technology with GaAs/AlGaAs thin-film waveguides. Multivariate data mining strategies (i.e., principal component analysis) enabled the classification of deoxynivalenol-contaminated maize and wheat samples, and of aflatoxin B1 affected peanuts at EU regulatory limits of 1250 µg kg-1 and 8 µg kg-1, respectively.

Novel aerosol analysis approach for characterization of nanoparticulate matter in snow.

Tropospheric aerosols are involved in several key atmospheric processes: from ice nucleation, cloud formation, and precipitation to weather and climate. The impact of aerosols on these atmospheric processes depends on the chemical and physical characteristics of aerosol particles, and these characteristics are still largely uncertain. In this study, we developed a system for processing and aerosolization of melted snow in particle-free air, coupled with a real-time measurement of aerosol size distributions. The newly developed technique involves bringing snow-borne particles into an airborne state, which enables application of high-resolution aerosol analysis and sampling techniques. This novel analytical approach was compared to a variety of complementary existing analytical methods as applied for characterization of snow samples from remote sites in Alert (Canada) and Barrow (USA), as well as urban Montreal (Canada). The dry aerosol measurements indicated a higher abundance of particles of all sizes, and the 30 nm size dominated in aerosol size distributions for the Montreal samples, closely followed by Barrow, with about 30% fewer 30 nm particles, and about four times lower 30 nm particle abundance in Alert samples, where 15 nm particles were most abundant instead. The aerosolization technique, used together with nanoparticle tracking analysis and electron microscopy, allowed measurement of a wide size range of snow-borne particles in various environmental snow samples. Here, we discuss the application of the new technique to achieve better physicochemical understanding of atmospheric and snow processes. The results showed high sensitivity and reduction of particle aggregation, as well as the ability to measure a high-resolution snow-borne particle size distribution, including nanoparticulate matter in the range of 10 to 100 nm.

Co-Occurrence of Regulated, Masked and Emerging Mycotoxins and Secondary Metabolites in Finished Feed and Maize-An Extensive Survey.

Global trade of agricultural commodities (e.g., animal feed) requires monitoring for fungal toxins. Also, little is known about masked and emerging toxins and metabolites. 1926 samples from 52 countries were analysed for toxins and metabolites. Of 162 compounds detected, up to 68 metabolites were found in a single sample. A subset of 1113 finished feed, maize and maize silage samples containing 57 compounds from 2012 to 2015 from 44 countries was investigated using liquid chromatography and mass spectrometry. Deoxynivalenol (DON), zearalenone (ZEN) and fumonisins showed large increases of annual medians in Europe. Within a region, distinct trends were observed, suggesting importance of local meteorology and cultivars. In 2015, median DON concentrations increased to 1400 µ g·kg - 1 in Austria, but were stable in Germany at 350 µ g·kg - 1 . In 2014, enniatins occurred at median concentrations of 250 µ g·kg - 1 in Europe, at levels similar to DON and ZEN. The latter were frequently correlated with DON-3-glucoside and ZEN-14-sulfate. Co-occurrence of regulated toxins was frequent with e.g., enniatins, and moniliformin. Correlation was observed between DON and DON-3-glucoside and with beauvericin. Results indicate that considerably more than 25% of agricultural commodities could be contaminated with mycotoxins as suggested by FAO, although this is at least partly due to the lower limits of detection in the current survey. Observed contamination percentages ranged from 7.1 to 79% for B trichothecenes and 88% for ZEN.

A novel chemometric classification for FTIR spectra of mycotoxin-contaminated maize and peanuts at regulatory limits.

The rapid identification of mycotoxins such as deoxynivalenol and aflatoxin B1 in agricultural commodities is an ongoing concern for food importers and processors. While sophisticated chromatography-based methods are well established for regulatory testing by food safety authorities, few techniques exist to provide a rapid assessment for traders. This study advances the development of a mid-infrared spectroscopic method, recording spectra with little sample preparation. Spectral data were classified using a bootstrap-aggregated (bagged) decision tree method, evaluating the protein and carbohydrate absorption regions of the spectrum. The method was able to classify 79% of 110 maize samples at the European Union regulatory limit for deoxynivalenol of 1750 µg kg-1 and, for the first time, 77% of 92 peanut samples at 8 µg kg-1 of aflatoxin B1. A subset model revealed a dependency on variety and type of fungal infection. The employed CRC and SBL maize varieties could be pooled in the model with a reduction of classification accuracy from 90% to 79%. Samples infected with Fusarium verticillioides were removed, leaving samples infected with F. graminearum and F. culmorum in the dataset improving classification accuracy from 73% to 79%. A 500 µg kg-1 classification threshold for deoxynivalenol in maize performed even better with 85% accuracy. This is assumed to be due to a larger number of samples around the threshold increasing representativity. Comparison with established principal component analysis classification, which consistently showed overlapping clusters, confirmed the superior performance of bagged decision tree classification.

Volatile organic compounds in Arctic snow: concentrations and implications for atmospheric processes.

The role of volatile organic compounds (VOC) in the snowpack for atmospheric oxidation, gas-particle transfer and aerosol formation remains poorly understood, partly due to a lack of methodology and unavailable data. We deployed solid phase micro-extraction (SPME) gas chromatography with flame ionization detection for measurement of halogenated, aromatic and oxygenated VOC in the snow pack in Alert, NU, Canada, a High Arctic site. Maximum concentrations in snow were 39 ± 6 µg L(-1) (styrene), indicating a potential VOC contribution to atmospheric oxidation and aerosol formation. Concurrently sampled air had concentrations of up to 1.0 ± 0.3 ng L(-1) (trichloroethene). Back trajectory data showed a change of air mass source region during a depletion event of several VOC in snow (e.g., trichloroethene and benzene). Snow profiles showed an enrichment of most compounds close to the surface. During a second study in Barrow, AK, USA VOC were quantified in snow and frost flowers in the Montreal lab. In Barrow work was carried out as part of the extensive OASIS (Ocean-Atmosphere-Sea Ice-Snowpack) field campaign. Maximum VOC concentrations were up to 1.3 ± 0.1 µg L(-1) (acetophenone). Bromoform in frost flowers averaged 0.19 ± 0.04 µg L(-1), indicating the potential to contribute to bromine generation through photolysis.

Microbial and "de novo" transformation of dicarboxylic acids by three airborne fungi.

Micro-organisms and organic compounds of biogenic or anthropogenic origins are important constituents of atmospheric aerosols, which are involved in atmospheric processes and climate change. In order to investigate the role of fungi and their metabolisation activity, we collected airborne fungi using a biosampler in an urban location of Montreal, Quebec, Canada (45 degrees 28' N, 73 degrees 45' E). After isolation on Sabouraud dextrose agar, we exposed isolated colonies to dicarboxylic acids (C(2)-C(7)), a major group of organic aerosols and monitored their growth. Depending on the acid, total fungi numbers varied from 35 (oxalic acid) to 180 CFU/mL (glutaric acid). Transformation kinetics of malonic acid, presumably the most abundant dicarboxylic acid, at concentrations of 0.25 and 1.00 mM for isolated airborne fungi belonging to the genera Aspergillus, Penicillium, Eupenicillium, and Thysanophora with the fastest transformation rate are presented. The initial concentration was halved within 4.5 and 11.4 days. Other collected fungi did not show a significant degradation and the malonic acid concentration remained unchanged (0.25 and 1.00 mM) within 20 days. Degradation of acid with formation of metabolites was followed using high performance liquid chromatography-ultraviolet detection (HPLC/UV) and gas chromatography-mass spectrometry (GC/MS), as well as monitoring of (13)C labelled malonic acid degradation with solid-state nuclear magnetic resonance spectroscopy (NMR). Using GC/MS we identified two processes driving chemical modifications of organic aerosol solutions: (I) formation of metabolites within several days, and (II) rapid release (< or =2 min) of organic molecules from fungal species upon the insertion of taxa in organic aerosol solutions. Metabolites included aromatic compounds and alcohols (e.g. trimethylbenzene and butanol). Potential atmospheric implications of our results are discussed.

Optimisation of a sample preparation procedure for the screening of fungal infection and assessment of deoxynivalenol content in maize using mid-infrared attenuated total reflection spectroscopy.

A sample preparation procedure for the determination of deoxynivalenol (DON) using attenuated total reflection mid-infrared spectroscopy is presented. Repeatable spectra were obtained from samples featuring a narrow particle size distribution. Samples were ground with a centrifugal mill and analysed with an analytical sieve shaker. Particle sizes of <100, 100-250, 250-500, 500-710 and 710-1000 microm were obtained. Repeatability, classification and quantification abilities for DON were compared with non-sieved samples. The 100-250 microm fraction showed the best repeatability. The relative standard deviation of spectral measurements improved from 20 to 4.4% and 100% of sieved samples were correctly classified compared with 79% of non-sieved samples. The DON level in analysed fractions was a good estimate of overall toxin content.

Determination of a wide range of volatile and semivolatile organic compounds in snow by use of solid-phase micro-extraction (SPME).

Quantification and transformation of organic compounds are pivotal in understanding atmospheric processes, because such compounds contribute to the oxidative capacity of the atmosphere and drive climate change. It has recently been recognized that chemical reactions in snow play a role in the production or destruction of photolabile volatile organic compounds (VOC). We present an environmentally friendly method for determination of VOC and semi-VOC in snow collected at three sites-remote, urban, and (sub-)arctic. A solid-phase micro-extraction (SPME) procedure was developed and (semi-)VOC were identified by gas chromatography with mass spectrometric detection (GC-MS). A broad spectrum of (semi-)VOC was found in snow samples, including aldehydes, and aromatic and halogenated compounds. Quantification was performed for 12 aromatic and/or oxygenated compounds frequently observed in snow by use of neat standard solutions. The concentrations detected were between 0.12 (styrene and ethylbenzene) and 316 microg L(-1) (toluene) and limits of detection varied between 0.11 (styrene) and 1.93 microg L(-1) (benzaldehyde). These results indicate that the SPME technique presented is a broad but selective, versatile, solvent-free, ecological, economical, and facile method of analysis for (semi-)VOC in natural snow samples.

A comparative study of mid-infrared diffuse reflection (DR) and attenuated total reflection (ATR) spectroscopy for the detection of fungal infection on RWA2-corn.

An investigation into the rapid detection of mycotoxin-producing fungi on corn by two mid-infrared spectroscopic techniques was undertaken. Corn samples from a single genotype (RWA2, blanks, and contaminated with Fusarium graminearum) were ground, sieved and, after appropriate sample preparation, subjected to mid-infrared spectroscopy using two different accessories (diffuse reflection and attenuated total reflection). The measured spectra were evaluated with principal component analysis (PCA) and the blank and contaminated samples were classified by cluster analysis. Reference data for fungal metabolites were obtained with conventional methods. After extraction and clean-up, each sample was analyzed for the toxin deoxynivalenol (DON) by gas chromatography with electron capture detection (GC-ECD) and ergosterol (a parameter for the total fungal biomass) by high-performance liquid chromatography with diode array detection (HPLC-DAD). The concentration ranges for contaminated samples were 880-3600 microg/kg for ergosterol and 300-2600 microg/kg for DON. Classification efficiency was 100% for ATR spectra. DR spectra did not show as obvious a clustering of contaminated and blank samples. Results and trends were also observed in single spectra plots. Quantification using a PLS1 regression algorithm showed good correlation with DON reference data, but a rather high standard error of prediction (SEP) with 600 microg/kg (DR) and 490 microg/kg (ATR), respectively, for ergosterol. Comparing measurement procedures and results showed advantages for the ATR technique, mainly owing to its ease of use and the easier interpretation of results that were better with respect to classification and quantification.

Development of a method for the determination of Fusarium fungi on corn using mid-infrared spectroscopy with attenuated total reflection and chemometrics.

A novel method, which enables the determination of fungal infection with Fusarium graminearum on corn within minutes, is presented. The ground sample was sieved and the particle size fraction between >250 and 100 microm was used for mid-infrared/attenuated total reflection (ATR) measurements. The sample was pressed onto the ATR crystal, and reproducible pressure was applied. After the spectra were recorded, they were subjected to principle component analysis (PCA) and classified using cluster analysis. Observed changes in the spectra reflected changes in protein, carbohydrate, and lipid contents. Ergosterol (for the total fungal biomass) and the toxin deoxynivalenol (DON; a secondary metabolite) of Fusarium fungi served as reference parameters, because of their relevance for the examination of corn based food and feed. The repeatability was highly improved by sieving prior to recording the spectra, resulting in a better clustering in PCA score/score plots. The developed method enabled the separation of samples with a toxin content of as low as 310 microg/kg from noncontaminated (blank) samples. Investigated concentration ranges were 880-3600 microg/kg for ergosterol and 310-2596 microg/kg for DON. The percentage of correctly classified samples was up to 100% for individual samples compared with a number of blank samples.