Effects of dietary phenethyl isothiocyanate, ellagic acid, sulindac and calcium on the induction and progression of N-nitrosomethylbenzylamine-induced esophageal carcinogenesis in rats

The potential inhibitory effects of phenethyl isothiocyanate(PEITC), ellagic acid (EA), sulindac and supplemental dietarycalcium (SDC) on N-nitrosomethylbenzylamine (NMBA)-induced esophagealcarcinogenesis were evaluated in rats utilizing an abbreviated(5 week) NMBA treatment protocol which allowed administrationof the putative inhibitors throughout the experiment (i.e. beginning2 weeks prior to NMBA treatment) or following completion ofNMBA dosing only. PEITC at 500 p.p.m. significantly inhibitedtumor incidence and multiplicity when given before and during,but not following, NMBA treatment. Neither sulindac at 125 p.p.m.nor SDC (2% versus 0.5% in control diet) inhibited tumor developmentwhen given during or following NMBA treatment. EA, which wasadministered only following NMBA treatment, significantly reducedthe incidence (66.7% versus 100% in NMBA controls), but notthe multiplicity, of esophageal tumors at the high-dose (4000p.p.m.) level. Together these findings indicate that: (i) PEITCselectively inhibits the induction but not the subsequent progressionof NMBA-induced esophageal tumors; (ii) EA may repress esophagealtumor development when administered following NMBA treatment;(iii) at the doses administered, neither sulindac nor SDC possesssignificant inhibitory activity against NMBA-induced esophagealcarcinogenesis in the rat.     

O6-Methyguanine levels and histopathological changes in the rat esophagus and liver following single and repeated administration of N-nitrosomethylbenzylamin

In this study we investigated the time course of O⁶-methylguanine(O⁶-meGua) levels and concomitant histo-pathological effectsin the rat esophagus and liver following single and repeateds.c administration of the esophagus-specific carcinogen N-nitrosomethylbenzylamine(NMBA). The primary purpose of this study was to determine ifdifferences in the induction and/or persistence of O⁶-meGuamight account for differences in the tumorigenicity of NMBAobserved with treatment regimens of 0.5 mg/kg/ dose, 3 doses/weekfor 5 weeks (a proven tumorigenic regimen) and 1.67 mg/kg/dose,3 doses/week for 2 weeks (an essentially non-tumorigenic regimen).Results of the single dose experiment indicated that enzymaticactivation of NMBA in the rat esophagus was not dose limited,at least at doses up to and including 5.0 mg/kg. Results ofthe repeated dose experiment demonstrated that the non-tumorigenicNMBA regimen produced significantly higher levels of esophagealO⁶meGua compared with the tumorigenic NMBA regimen. During the2 week treatment period of the non-tumorigenic regimen esophagealO⁶-meGua levels decreased progressively, but remained significantlyhigher than in the tumorigenic regimen. In contrast, the relativelylower O⁶-meGua levels of the tumorigenic regimen remained essentiallyunchanged during the course of treatment At 72 h following conclusionof dosing no O⁶-meGua was detected in the esophagi of rats treatedwith either regimen. Microscopic examinations revealed thatthe non-tumorigenic NMBA regimen produced a marked cytotoxiceffect on the esophageal epithelium, while microscopic esophagealchanges observed with the tumorigenic regimen were generallyless severe. In the liver O⁶meGua was detected in only a fewrats and no remarkable microscopic pathology was observed inthis organ. Together these findings indicate that: (i) abbreviatedNMBA treatment induces tumors in the rat esophagus only at levelsthat induce DNA damage without causing extensive cytotoxicity;(ii) the lack of NMBA tumorigenicity in the rat liver may bedue, at least in part, to the rapid and efficient repair ofO⁶-meGua adducts, coupled with the lack of necrosis and compensatorycell division in this organ.     

Immune effector cell–associated neurotoxicity syndrome after chimeric antigen receptor T-cell therapy for lymphoma: predictive biomarkers and clinical outcomes

BackgroundCD19-directed chimeric antigen receptor (CAR) T-cell therapy (CAR-T) has emerged as effective for relapsed/refractory large B-cell lymphoma (R/R LBCL). The neurologic toxicity seen with CAR-T, referred to as immune effector cell–associated neurotoxicity syndrome (ICANS), is poorly understood. To better elucidate the clinical characteristics, treatment outcomes, and correlative biomarkers of ICANS, we review here a single-center analysis of ICANS after CAR T-cell therapy in R/R LBCL.MethodsPatients (n = 45) with R/R LBCL treated with axicabtagene ciloleucel (axi-cel) were identified. Data regarding treatment course, clinical outcomes, and correlative studies were collected. Patients were monitored and graded for ICANS via CARTOX-10 scoring and Common Terminology Criteria for Adverse Events (CTCAE) v4.03 criteria, respectively.ResultsTwenty-five (56%) patients developed ICANS, 18 (72%) of whom had severe (CTCAE grades 3–4) ICANS. Median time to development of ICANS was 5 days (range, 3–11). Elevated pre-infusion (day 0 [D0]) fibrinogen (517 vs 403 mg/dL, upper limit of normal [ULN] 438 mg/dL, P = 0.01) and D0 lactate dehydrogenase (618 vs 506 units/L, ULN 618 units/L, P = 0.04) were associated with ICANS. A larger drop in fibrinogen was associated with ICANS (393 vs 200, P < 0.01). Development of ICANS of any grade had no effect on complete remission (CR), progression-free survival (PFS), or overall survival (OS). Duration and total dose of steroid treatment administered for ICANS did not influence CR, PFS, or OS.ConclusionsICANS after CAR-T with axi-cel for R/R LBCL was seen in about half of patients, the majority of which were high grade. Contrary to previous reports, neither development of ICANS nor its treatment were associated with inferior CR, PFS, or OS. The novel finding of high D0 fibrinogen level can identify patients at higher risk for ICANS.     

Isothiocyanates and freeze-dried strawberries as inhibitors of esophageal cancer

A group of arylalkyl isothiocyanates were tested for their abilities to inhibit tumorigenicity and DNA methylation induced by the esophageal- specific carcinogen, N-nitrosomethylbenzylamine (NMBA) in the F344 rat esophagus. Phenylpropyl isothiocyanate (PPITC) was more potent than either phenylethyl isothiocyanate (PEITC) or benzyl isothiocyanate (BITC). Phenylbutyl isothiocyanate (PBITC), however, had a lesser inhibitory effect on esophageal tumorigenesis, and phenylhexyl isothiocyanate (PHITC) actually enhanced esophageal tumorigenesis. Thus, the two- and three-carbon isothiocyanates were more effective inhibitors of NMBA-esophageal carcinogenesis than the longer chain isothiocyanates. The effects of the isothiocyanates on tumorigenesis were well correlated as to their effects on DNA adduct formation. The most likely mechanism of inhibition of tumorigenesis by these isothiocyanates is via inhibition of the cytochrome P450 enzymes responsible for the metabolic activation of NMBA in rat esophagus. A freeze-dried strawberry preparation was also evaluated for its ability to inhibit NMBA-esophageal tumorigenesis. It proved to be an effective inhibitor, although not as potent as either PEITC or PPITC. The inhibitory effect of the berries could not be attributed solely to the content of the chemopreventive agent, ellagic acid, in the berries.      

Salvage fractionated stereotactic re-irradiation (FSRT) for patients with recurrent high grade gliomas progressed after bevacizumab treatment

Bevacizumab failure is a major clinical problem in the management of high grade gliomas (HGG), with a median overall survival (OS) of <?4 months. This study evaluated the feasibility and efficacy of fractionated stereotactic re-irradiation (FSRT) for patients progressed after Bevacizumab treatment. Retrospective review was conducted of 36 patients treated with FSRT after progression on bevacizumab. FSRT was most commonly delivered in 3.5 Gy fractions to a total dose of 35 Gy. Survival from initial diagnosis, as well as from recurrence and re-irradiation, were utilized as study endpoints. Univariate and multivariate analysis was performed. The median time from initial bevacizumab treatment to FSRT was 8.5 months. The median plan target volume for FSRT was 27.5 cc. The median OS from FSRT was 4.8 months. FSRT treatment was well tolerated with no grade 3 or higher toxicity. Favorable outcomes were observed in patients with recurrent HGG who received salvage FSRT after bevacizumab failure. The treatment was well tolerated. Prospective study is warranted to further evaluate the efficacy of salvage FSRT for selected patients with recurrent HGG amenable to FSRT, who had failed bevacizumab treatment.     

Clinical experience transitioning from IMRT to VMAT for head and neck cancer

To quantify clinical differences for volumetric modulated arc therapy (VMAT) versus intensity modulated radiation therapy (IMRT) in terms of dosimetric endpoints and planning and delivery time, twenty head and neck cancer patients have been considered for VMAT using Nucletron Oncentra MasterPlan delivered via an Elekta linear accelerator. Differences in planning time between IMRT and VMAT were estimated accounting for both optimization and calculation. The average delivery time per patient was obtained retrospectively using the record and verify software. For the dosimetric comparison, all contoured organs at risk (OARs) and planning target volumes (PTVs) were evaluated. Of the 20 cases considered, 14 had VMAT plans approved. Six VMAT plans were rejected due to unacceptable dose to OARs. In terms of optimization time, there was minimal difference between the two modalities. The dose calculation time was significantly longer for VMAT, 4 minutes per 358 degree arc versus 2 minutes for an entire IMRT plan. The overall delivery time was reduced by 9.2 ± 3.9 minutes for VMAT (51.4 ± 15.6%). For the dosimetric comparison of the 14 clinically acceptable plans, there was almost no statistical difference between the VMAT and IMRT. There was also a reduction in monitor units of approximately 32% from IMRT to VMAT with both modalities demonstrating comparable quality assurance results. VMAT provides comparable coverage of target volumes while sparing OARs for the majority of head and neck cases. In cases where high dose modulation was required for OARs, a clinically acceptable plan was only achievable with IMRT. Due to the long calculation times, VMAT plans can cause delays during planning but marked improvements in delivery time reduce patient treatment times and the risk of intra-fraction motion.