Testing the new ICRU 62 'Planning Organ at Risk Volume' concept for the rectum.

BACKGROUND AND PURPOSE: To study the impact of the new ICRU 62 'Planning organ at Risk Volume' (PRV) concept on the relationship between rectum dose-volume histogram (DVH) data and toxicity. PATIENTS AND METHODS: The acute gastro-intestinal (GI) RTOG toxicity in 127 prostate cancer patients prescribed a total dose of 70 Gy with conformal irradiation to either the prostate, the prostate and seminal vesicles or the whole pelvis (initial 50 Gy only) were analysed. DVHs were derived for the rectum only and for rectum extended with six PRV margin sets (narrow/intermediate/wide; anterior/anterior and posterior). The data was analysed using permutation tests, logistic regression and effective uniform dose (EUD) calculations. RESULTS: Acute Grade 2 GI toxicity was seen in 22 of 127 cases (17%). Permutation tests showed that the difference between DVHs for patients with and without Grade 2 effects was significant, both for rectum only and rectum PRVs (P-value range: 0.02-0.04), with generally lower P-values for the PRVs. In the logistic regression, the fractional DVH variables (i.e. volumes) were significantly related to toxicity, with approximately 2-3 times as many significant dose levels for the PRVs as for rectum only. E.g. with wide anterior and posterior margins (16 and 11 mm, respectively) the relation was significant at 26 different dose levels (6-7, 13-14, 35-43, 60-71 and 73 Gy), compared to nine levels (38-40, 43-44 and 71-74 Gy) for rectum only. EUDs were significantly different for patients with and without Grade 2 effects both for rectum only and the PRVs (95% confidence interval for EUD increase with Grade 2 effects: 0.1-3.1 Gy). CONCLUSIONS: All statistical methods applied indicated a small, but definite difference in DVH parameters between patients with versus those without Grade 2 effects. The difference was most pronounced when margins of 16 mm anterior and 11 mm posterior were applied.     

Renal necrosis and DNA damage caused by selectively deuterated and methylated analogs of 1,2-dibromo-3-chloropropane in the rat

Selectively deuterated and methylated analogs of the nematocide 1,2-dibromo-3-chloropropane (DBCP) were compared to DBCP in causing acute renal damage in rats. All of the six deuterated analogs tested at 340 mumol/kg, including the perdeutero compound, failed to significantly alter the kidney necrosis observed at 48 hr compared to DBCP. Furthermore, when the perdeutero analog was administered at several doses (42.5, 85, 170, and 340 mumol/kg), it caused kidney damage that was not significantly different than that caused by an equivalent molar dose of nondeuterated DBCP. Of the five methylated analogs tested at 170 and 340 mumol/kg, only C3-methyl-DBCP and 1,2-dibromo-4-chlorobutane caused nephrotoxicity. The C2-methyl-, C1-dimethyl-, and C2-methyl-DBCP analogs failed to cause renal necrosis determined 48 hr after dosing. In distribution studies DBCP, perdeutero-DBCP, and all the methylated analogs were found to concentrate in the kidney approximately 25 times relative to plasma 1 hr after administration. DBCP at doses of 4.3 mumol/kg and higher caused DNA damage in the kidney as early as 10 min after administration, as measured by alkaline elution of DNA from isolated kidney nuclear preparations. Perdeuteration did not decrease the DNA damaging effect of DBCP. The ability of the methylated DBCP analogs to induce renal DNA damage correlated with their necrogenic potential. Experiments using pretreatments that are known to decrease the nephrotoxicity caused by glutathione and cysteine conjugates of several halogenated alkenes were conducted to examine the effect of these pretreatments on DBCP-induced nephrotoxicity. Probenecid, L-(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (AT-125) and aminooxyacetic acid did not significantly alter renal necrosis or DNA damage induced by DBCP. Based on the absence of any significant isotope effects with the predeutero-DBCP analog, it appears that breaking of a carbon-hydrogen bond is not the rate-limiting step in DBCP-induced nephrotoxicity. Studies with the methylated DBCP analogs indicate that a vicinal dibromo ethyl group must minimally be present for nephrotoxic potential. Furthermore, it seems unlikely that metabolism by renal cysteine conjugate beta-lyase is rate-limiting for DBCP nephrotoxicity.     

The fate of isoprene inhaled by rats: comparison to butadiene

Isoprene (2-methyl-1,3-butadiene), a volatile monomer occurring in the natural environment and used in the manufacture of elastomers, is a close chemical relative of the animal carcinogen 1,3-butadiene. To obtain toxicokinetic data for inhaled isoprene, male F344 rats were exposed in groups of 30 to 14C-labeled isoprene vapor at four concentrations from 8 to 8200 ppm. The percentage of the inhaled isoprene that was metabolized decreased with increasing exposure concentration. The percentage of the total metabolites (that is, non-isoprene-retained 14C) excreted in urine and feces or expired was determined as a function of vapor concentration. About 75% of the total metabolites was excreted in urine. This was independent of inhaled isoprene concentration. After exposure to 8200 ppm, a larger percentage of the metabolites was excreted in feces than after exposure to lower concentrations. Using vacuum line techniques, blood metabolite concentrations were determined as functions of both vapor concentration and exposure duration. At one exposure concentration (1480 ppm) metabolites were measured in the nose, lungs, liver, kidney, and fat, as well as in blood. A mutagenic metabolite, isoprene diepoxide, was tentatively identified in all tissues examined. Between 0.0018 and 0.031% of the inhaled 14C label was tentatively identified as this metabolite in blood. The relative amount of the metabolites present in blood was highest for low concentrations of inhaled isoprene and for shorter exposure durations. Body fat appeared to be a reservoir for both isoprene metabolites and isoprene itself. The appearance of metabolites in the respiratory tract after short exposure durations together with low blood concentrations of isoprene indicated that substantial metabolism of inhaled isoprene in the respiratory tract may occur.     

Physiological instability is linked to mortality in primary central nervous system lymphoma: A case–control fMRI study

Primary central nervous system lymphoma (PCNSL) is an aggressive brain disease where lymphocytes invade along perivascular spaces of arteries and veins. The invasion markedly changes (peri)vascular structures but its effect on physiological brain pulsations has not been previously studied. Using physiological magnetic resonance encephalography (MREG_BOLD) scanning, this study aims to quantify the extent to which (peri)vascular PCNSL involvement alters the stability of physiological brain pulsations mediated by cerebral vasculature. Clinical implications and relevance were explored. In this study, 21 PCNSL patients (median 67y; 38% females) and 30 healthy age‐matched controls (median 63y; 73% females) were scanned for MREG_BOLD signal during 2018–2021. Motion effects were removed. Voxel‐by‐voxel Coefficient of Variation (CV) maps of MREG_BOLD signal was calculated to examine the stability of physiological brain pulsations. Group‐level differences in CV were examined using nonparametric covariate‐adjusted tests. Subject‐level CV alterations were examined against control population Z‐score maps wherein clusters of increased CV values were detected. Spatial distributions of clusters and findings from routine clinical neuroimaging were compared [contrast‐enhanced, diffusion‐weighted, fluid‐attenuated inversion recovery (FLAIR) data]. Whole‐brain mean CV was linked to short‐term mortality with 100% sensitivity and 100% specificity, as all deceased patients revealed higher values (n = 5, median 0.055) than surviving patients (n = 16, median 0.028) (p < .0001). After adjusting for medication, head motion, and age, patients revealed higher CV values (group median 0.035) than healthy controls (group median 0.024) around arterial territories (p ≤ .001). Abnormal clusters (median 1.10 × 10⁵mm³) extended spatially beyond FLAIR lesions (median 0.62 × 10⁵mm³) with differences in volumes (p = .0055).     

Distribution of single wall carbon nanotubes in the Xenopus laevis embryo after microinjection

Single wall carbon nanotubes (SWCNTs) are advanced materials with the potential for a myriad of diverse applications, including biological technologies and large‐scale usage with the potential for environmental impacts. SWCNTs have been exposed to developing organisms to determine their effects on embryogenesis, and results have been inconsistent arising, in part, from differing material quality, dispersion status, material size, impurity from catalysts and stability. For this study, we utilized highly purified SWCNT samples with short, uniform lengths (145 ± 17 nm) well dispersed in solution. To test high exposure doses, we microinjected > 500 µg ml^–1 SWCNT concentrations into the well‐established embryogenesis model, Xenopus laevis, and determined embryo compatibility and subcellular localization during development. SWCNTs localized within cellular progeny of the microinjected cells, but were heterogeneously distributed throughout the target‐injected tissue. Co‐registering unique Raman spectral intensity of SWCNTs with images of fluorescently labeled subcellular compartments demonstrated that even at regions of highest SWCNT concentration, there were no gross alterations to subcellular microstructures, including filamentous actin, endoplasmic reticulum and vesicles. Furthermore, SWCNTs did not aggregate and localized to the perinuclear subcellular region. Combined, these results suggest that purified and dispersed SWCNTs are not toxic to X. laevis animal cap ectoderm and may be suitable candidate materials for biological applications. Copyright © 2015 John Wiley & Sons, Ltd.     

Chemotherapy-Induced Neutropenia and Febrile Neutropenia in the US: A Beast of Burden That Needs to Be Tamed?

Neutropenia and febrile neutropenia (FN) are common complications of myelosuppressive chemotherapy. This review provides an up-to-date assessment of the patient and cost burden of chemotherapy-induced neutropenia/FN in the US, and summarizes recommendations for FN prophylaxis, including the interim guidance that was recommended during the coronavirus disease 2019 (COVID-19) pandemic. This review indicates that neutropenia/FN place a significant burden on patients in terms of hospitalizations and mortality. Most patients with neutropenia/FN presenting to the emergency department will be hospitalized, with an average length of stay of 6, 8, and 10 days for elderly, pediatric, and adult patients, respectively. Reported in-hospital mortality rates for neutropenia/FN range from 0.4% to 3.0% for pediatric patients with cancer, 2.6% to 7.0% for adults with solid tumors, and 7.4% for adults with hematologic malignancies. Neutropenia/FN also place a significant cost burden on US healthcare systems, with average costs per neutropenia/FN hospitalization estimated to be up to $40 000 for adult patients and $65 000 for pediatric patients. Evidence-based guidelines recommend prophylactic granulocyte colony-stimulating factors (G-CSFs), which have been shown to reduce FN incidence while improving chemotherapy dose delivery. Availability of biosimilars may improve costs of care. Efforts to decrease hospitalizations by optimizing outpatient care could reduce the burden of neutropenia/FN; this was particularly pertinent during the COVID-19 pandemic since avoidance of hospitalization was needed to reduce exposure to the virus, and resulted in the adaptation of recommendations to prevent FN, which expanded the indications for G-CSF and/or lowered the threshold of use to >10% risk of FN.     

A cerebral glioma model for experimental therapy andin vivo invasion studies in syngeneic BD IX rats

Anin vivo glioma model was developed in syngeneic BD IX rats. The BT₄An tumor was derived from serialin vivo passages of the BT₄A tumor, originally induced from transformed fetal rat brain cells after transplacental exposure to ethylnitrosourea. The cell line was characterized for the presence of neuroglial differentiation markers, chromosome content and cell cycle distribution as determined by flowcytometry. A standardized method for i.c. tumor induction was developed, and the tumors were investigated by light and electron microscopy and for evidence of blood-brain barrier disruption. Tumor cell ability for phagocytosis was studied, as this property may be important for the invasion pattern of the tumors. We conclude that the model seems suitable for bothin vivo therapy and invasion studies. The tumor had 100% tumor take, yielded a predictable symptom-free life span after inoculation, had a characteristic histological picture of an aggressive glioma, and the blood-brain barrier within the tumor was in part disrupted. Compared to the parent cell line, there was loss of neuroglial differentiation markers, the chromosomal distribution was changed, and the ability for phagocytosis was practically lost.     

Altruistic acting caused by a touching hand: neural underpinnings of the Midas touch effect

Giving and receiving touch are some of the most important social stimuli we exchange in daily life. By touching someone, we can communicate various types of information. Previous studies have also demonstrated that interpersonal touch may affect our altruistic behavior. A classic study showed that customers give bigger tips when they are lightly touched by a waitress, which has been called the Midas touch effect. Numerous studies reported similar effects of touch on different kinds of helping or prosocial behaviors. Here, we aim to examine the neural underpinnings of this effect by employing a functional magnetic resonance imaging approach. While lying in the scanner, participants played different rounds of the dictator game, a measure of prosocial behavior. Before each round, participants were touched (or not touched in the control condition) by an experimenter. We found that touching the hand increased the likeliness to behave prosocial (but not the general liking of control stimuli), thereby confirming the Midas touch effect. The effect was predicted by activity in the primary somatosensory cortex, indicating that the somatosensory cortex here plays a causal role in prosocial behavior. We conclude that the tactile modality in social life may be much more important than previously thought.