Synthesis of α-L-rhamnosyl ceramide and evaluation of its binding with anti-rhamnose antibodies.

An α-L-rhamnosyl ceramide (1, α-L-RhaCer) has been prepared that was recognized by anti-L-rhamnose (anti-Rha) antibodies. During these studies we explored the use of an α-L-rhamnosyl thioglycoside and a trichloroacetimidate as a glycosyl donors. Subsequently, the acceptors desired for glycosylation, 3-O-benzoylazidosphingosine or 3-O-alloxycarbonylsphingosine, were prepared from D-xylose. The thioglycoside donor, 2,3,4-tri-O-acetyl-1-(4-tolyl)thio-α-L-rhamnopyranoside, and the trichloroacetimidate donor, 2,3,4-tri-O-acetyl-1-(2,2,2-trichloroethanimidate)-α-L-rhamnopyranoside, were synthesized in 50% and 78% yield overall, respectively. The synthesis of the glycosylation acceptor employed an addition-fragmentation olefination that was successfully carried out in 53% yield. With the successful synthesis of key intermediates, α-L-RhaCer (1) was prepared without any insurmountable obstacles. Anti-Rha antibodies were prepared in BALB/c mice by immunizing them with rhamnose-ovalbumin (Rha-Ova) with Sigma Adjuvant System (SAS) and the anti-L-Rha antibodies were isolated from the blood sera. Liposomes and EL4 tumor cells were used as model systems to demonstrate the ability of 1 to insert into a lipid bilayer. The interaction of the liposomes or the EL4 cells with α-L-RhaCer (1) and anti-Rha antibodies were investigated by fluorescence microscopy and flow cytometry, respectively, to confirm the ability of glycolipid 1 to be displayed on the tumor cell surface as well as the ability to be recognized by anti-Rha antibodies.

Functional liver-image guided hepatic therapy (FLIGHT): A technique to maximize hepatic functional reserve.

INTRODUCTION: Radiation planning approaches for liver radiation often do not consider the regional variation that can exist in liver function. This study dosimetrically compares functional liver image-guided hepatic therapy (FLIGHT) to standard stereotactic body radiation therapy (SBRT) plans. In the FLIGHT plans, functional data from hepatobiliary iminodiacetic acid (HIDA) single photon emission computed tomography (SPECT) scans serve as a road map to guide beam arrangement. While meeting the same target volume coverage, plans are optimized to reduce dose to high-functioning liver. MATERIALS AND METHODS: The study included 10 patients with hepatocellular carcinoma (HCC) with baseline HIDA SPECT imaging. Standard SBRT plans which did not systematically incorporate these scans had previously been completed on all 10 plans. Retrospectively, FLIGHT plans were created based on the use of contours of relative liver function from the HIDA SPECT as avoidance structures. Resulting dose to each relative functional liver structure was examined and compared qualitatively and using Wilcoxin rank-sum tests. Target coverage, doses to organs at risk (OARs), conformity index (CI), and gradient index (GI) were also evaluated. RESULTS: While maintaining the same target coverage, FLIGHT plans reduced the mean dose to the high functioning liver by a median of 3.0 Gy (range 0.7 to 4.6 Gy), which represented a 31.4% mean reduction compared to standard planning. FLIGHT plans reduced the volume of high functioning liver receiving 15 Gy by a mean of 59.3 cc (range 7 to 170 cc), for a mean reduction of 41.9%. The mean dose to areas of liver function defined by 25% to 100% and 50% to 100% maximum was reduced with FLIGHT from 10.5 Gy to 8.5 Gy and from 10.5 Gy to 7.5 Gy, respectively (p < 0.005 for both comparisons). The FLIGHT plans' mean CI and GI did not differ significantly from the standard plans' (p = 0.721 and 0.169, respectively). CONCLUSION: FLIGHT SBRT allows for field design and plan optimization individualized to a patient's baseline regional liver function to maximize hepatic functional reserve. This personalized approach is achieved without compromising target coverage or OAR sparing.

A Case Report of an Early Response to Definitive Chemoradiation for Esophageal Carcinoma Cuniculatum.

This case report describes a 63-year-old female with a locally advanced esophageal carcinoma cuniculatum treated with definitive chemoradiation who had a rapid and early response. This case is illustrative of an aggressive behavior with rapid response and rapid recurrence. The cases of esophageal carcinoma cuniculatum as well as the closely related clinical entity of verrucous carcinoma are reviewed suggesting good clinical outcomes after definitive therapy with chemoradiation and/or surgery.

Radioluminescent nanoparticles for radiation-controlled release of drugs.

The present work demonstrates a novel concept for intratumoral chemo-radio combination therapy for locally advanced solid tumors. For some locally advanced tumors, chemoradiation is currently standard of care. This combination treatment can cause acute and long term toxicity that can limit its use in older patients or those with multiple medical comorbidities. Intratumoral chemotherapy has the potential to address the problem of systemic toxicity that conventional chemotherapy suffers, and may, in our view, be a better strategy for treating certain locally advanced tumors. The present study proposes how intratumoral chemoradiation can be best implemented. The enabling concept is the use of a new chemotherapeutic formulation in which chemotherapy drugs (e.g., paclitaxel (PTX)) are co-encapsulated with radioluminecsnt nanoparticles (e.g., CaWO4 (CWO) nanoparticles (NPs)) within protective capsules formed by biocompatible/biodegradable polymers (e.g., poly(ethylene glycol)-poly(lactic acid) or PEG-PLA). This drug-loaded polymer-encapsulated radioluminescent nanoparticle system can be locally injected in solution form into the patient's tumor before the patient receives normal radiotherapy (e.g., 30-40 fractions of 2-3 Gy daily X-ray dose delivered over several weeks for locally advanced head and neck tumors). Under X-ray irradiation, the radioluminescent nanoparticles produce UV-A light that has a radio-sensitizing effect. These co-encapsulated radioluminescent nanoparticles also enable radiation-triggered release of chemo drugs from the polymer coating layer. The non-toxic nature (absence of dark toxicity) of this drug-loaded polymer-encapsulated radioluminescent nanoparticle ("PEG-PLA/CWO/PTX") formulation was confirmed by the MTT assay in cancer cell cultures. A clonogenic cell survival assay confirmed that these drug-loaded polymer-encapsulated radioluminescent nanoparticles significantly enhance the cancer cell killing effect of radiation therapy. In vivo study validated the efficacy of PEG-PLA/CWO/PTX-based intratumoral chemo-radio therapy in mouse tumor xenografts (in terms of tumor response and mouse survival). Results of a small-scale NP biodistribution (BD) study demonstrate that PEG-PLA/CWO/PTX NPs remained at the tumor sites for a long period of time (> 1 month) following direct intratumoral administration. A multi-compartmental pharmacokinetic model (with rate constants estimated from in vitro experiments) predicts that this radiation-controlled drug release technology enables significant improvements in the level and duration of drug availability within the tumor (throughout the typical length of radiation treatment, i.e., > 1 month) over conventional delivery systems (e.g., PEG-PLA micelles with no co-encapsulated CaWO4, or an organic liquid, e.g., a 50:50 mixture of Cremophor EL and ethanol, as in Taxol), while it is capable of maintaining the systemic level of the chemo drug far below the toxic threshold limit over the entire treatment period. This technology thus has the potential to offer a new therapeutic option that has not previously been available for patients excluded from conventional chemoradiation protocols.

Effects of Proton Center Closure on Pediatric Case Volume and Resident Education at an Academic Cancer Center.

PURPOSE: To analyze effects of closure of an academic proton treatment center (PTC) on pediatric case volume, distribution, and resident education. METHODS AND MATERIALS: This was a review of 412 consecutive pediatric (age ≤18 years) cases treated at a single institution from 2012 to 2016. Residents' Accreditation Council for Graduate Medical Education case logs for the same years were also analyzed. Characteristics of the patient population and resident case volumes before and after closure of the PTC are reported. RESULTS: Overall pediatric new starts declined by approximately 50%, from 35 to 70 per 6 months in 2012 to 2014 to 22 to 30 per 6 months in 2015 to 2016. Central nervous system (CNS) case volume declined sharply, from 121 patients treated in 2012 to 2015 to 18 patients in 2015 to 2016. In 2012 to 2014 our institution treated 36, 24, and 17 patients for medulloblastoma/intracranial primitive neuroectodermal tumor, ependymoma, and low-grade glioma, respectively, compared with 0, 1, and 1 patient(s) in 2015 to 2016. Forty-nine patients were treated with craniospinal radiation (CSI) from 2012 to 2014, whereas only 2 patients underwent CSI between 2015 and 2016. Hematologic malignancy patient volume and use of total body irradiation remained relatively stable. Patients treated when the PTC was open were significantly younger (9.1 vs 10.7 years, P=.010) and their radiation courses were longer (35.4 vs 20.9 days, P<.0001) than those treated after its closure. Resident case logs showed only a small decline in total pediatric cases, because the percentage of pediatric cases covered by residents increased after PTC closure; however, residents logged fewer CNS cases after PTC closure versus before. CONCLUSIONS: Overall pediatric case volume decreased after PTC closure, as did the number of patients treated for potentially curable CNS tumors. Our findings raise important questions regarding resident training in pediatric radiation oncology as these cases become increasingly concentrated at specialized centers.

Functional liver image guided hepatic therapy (FLIGHT) with hepatobiliary iminodiacetic acid (HIDA) scans.

PURPOSE: Hepatobiliary iminodiacetic acid (HIDA) scans provide global and regional assessments of liver function that can serve as a road map for functional avoidance in stereotactic body radiation therapy (SBRT) planning. Functional liver image guided hepatic therapy (FLIGHT), an innovative planning technique, is described and compared with standard planning using functional dose-volume histograms. Thresholds predicting for decompensation during follow up are evaluated. METHODS AND MATERIALS: We studied 17 patients who underwent HIDA scans before SBRT. All SBRT cases were replanned using FLIGHT. The following dosimetric endpoints were compared for FLIGHT versus standard SBRT planning: functional residual capacity <15 Gy (FRC15HIDA), mean liver dose (MLD), equivalent uniform dose (EUD), and functional EUD (FEUD). Receiver operating characteristics curves were used to evaluate whether baseline HIDA values, standard cirrhosis scoring, and/or dosimetric data predicted clinical decompensation. RESULTS: Compared with standard planning, FLIGHT significantly improved FRC15HIDA (mean improvement: 5.3%) as well as MLD, EUD, and FEUD (P < .05). Considerable interindividual variations in the extent of benefit were noted. Decompensation during follow-up was associated with baseline global HIDA <2.915%/min/m2, FRC15HIDA <2.11%/min/m2, and MELD ≥11 (P < .05). CONCLUSIONS: FLIGHT with HIDA-based parameters may complement blood chemistry-based assessments of liver function and facilitate individualized, adaptive liver SBRT planning.