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Background To report on our institutional experience using Proton stereotactic body radiation therapy (SBRT) for patients with liver metastases. Methods All patients with liver metastases treated with Proton SBRT between September 2012 and December 2017 were retrospectively analyzed. Local control (LC) and overall survival (OS) were estimated using the Kaplan-Meier method calculated from the time of completion of Proton SBRT. LC was defined according to Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1). Toxicity was graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Results Forty-six patients with 81 lesions were treated with Proton SBRT. The median age was 65.5 years old (range, 33-86 years) and the median follow up was 15 months (range, 1-54 months). The median size of the gross tumor volume (GTV) was 2.5 cm (range, 0.7-8.9 cm). Two or more lesions were treated in 56.5% of patients, with one patient receiving treatment to a total of five lesions. There were 37 lesions treated with a biologically effective dose (BED) ≤60, 9 lesions with a BED of 61-80, 22 lesions with a BED of 81-100, and 13 lesions with a BED >100. The 1-year and 2-year LC for all lesions was 92.5% (95% CI, 82.7% to 96.8%). The grade 1 and grade 2 toxicity rates were 37% and 6.5%, respectively. There were no grade 3 or higher toxicities and no cases of radiation-induced liver disease (RILD). Conclusions Proton SBRT for the treatment of liver metastases has promising LC rates with the ability to safely treat multiple liver metastases. Accrual continues for our phase II trial treating liver metastases with Proton SBRT to 60 GyE (Gray equivalent) in 3 fractions.

Purpose: To determine whether a hypofractionated proton therapy regimen will control early-stage disease and maintain low rates of side effects similar to results obtained using standard-fraction proton therapy at our institution. Materials and Methods: A cohort of 146 patients with low-risk prostate cancer according to National Comprehensive Cancer Network guidelines (Gleason score Results: The median follow-up time was 42 months (range, 3–96 months). Acute grade 2 urinary toxicity occurred in 16% (20/120) of the patients; acute grade 2 or higher gastrointestinal toxicity was seen in 1.7% (2/120). At 9 months, 1 patient had late grade 3 urinary toxicity, which resolved by 12 months; no grade 3 gastrointestinal toxicities occurred. The 3-year biochemical survival rate was 99.3% (144/145). The median time to PSA nadir was 30 months. Conclusion: Hypofractionated proton therapy of 60 Gy in 20 fractions was safe and effective for patients with low-risk prostate cancer.

BACKGROUND: A phase I trial to determine the maximum tolerated dose (MTD) of Proton stereotactic body radiation therapy (SBRT) for liver metastases in anticipation of a subsequent phase II study. METHODS: An institutional IRB approved phase I clinical trial was conducted. Eligible patients had 1–3 liver metastases measuring less than 5 cm, and no metastases location within 2 cm of the GI tract. Dose escalation was conducted with three dose cohorts. The low, intermediate, and high dose cohorts were planned to receive 36, 48, and 60 respectively to the internal target volume (ITV) in 3 fractions. At least 700 mL of normal liver had to receive

Purpose/Objective(s) Given its unique properties, proton beam radiation therapy has the ability to reduce dose to at-risk organs. Proton's Bragg peak gives sharp distal dose fall off, which results in little or no dose beyond this region. As such, ipsilateral head and neck radiation with protons can spare the contralateral side to a greater extent than photon-based radiation, potentially causing reduced acute toxicity. Materials/Methods Eighty-six patients (59 protons and 27 intensity modulated radiation therapy [IMRT]) who received primary or adjuvant ipsilateral head and neck radiation were retrospectively reviewed. Patients received radiation to one side and this must have included at least the parotid region in the treatment field. Primary disease site was major salivary gland in 40, cutaneous in 23, tonsil in 19 and other in 4 patients. Passive scatter proton therapy was delivered with 1-3 fields daily. Median dose delivered was 66 cobalt gray equivalent with protons and 60 gray with IMRT. Results No grade 4 or greater acute mucositis was present in either group. Median acute mucositis was grade 1 for protons and 2 for IMRT. Grade 0, 1, 2 or 3 acute mucositis toxicity was present in 28 (47%), 11 (19%), 17 (29%) and 3 patients (5%) respectively with proton treatment and present in 7 (26%), 3 (11%), 12 (44%) and 5 patients (19%) respectively with IMRT (P = 0.053). Percutaneous endoscopic gastrostomy (PEG) tube was placed during radiation treatment for 1 patient (2%) with protons and 4 patients (15%) for IMRT (P = 0.032). Two patients in the proton group had a PEG tube placed prior to starting radiation and one patient in the IMRT group refused PEG tube placement despite treating physician recommendation. No grade 4 or greater acute radiation dermatitis was experienced by patients in either group. Median acute radiation dermatitis was grade 2 for protons and 2 for IMRT. Grade 0, 1, 2 or 3 toxicity was present in 0 (0%), 7 (12%), 47 (80%) and 4 patients (7%) respectively with proton treatment and present in 0 (0%), 5 (19%), 20 (74%) and 2 patients (7%) respectively with IMRT (P = 0.718). The majority of patients in both treatment groups completed treatment with ≤ 5 days of missed fractions (86.4% with protons, 85.1% with IMRT). Median number of missed treatment days was 2 in both groups. Conclusion Ipsilateral radiation therapy is well tolerated with IMRT and proton based radiation therapy. Fewer patients underwent PEG tube placement in the proton cohort, however these results should be further validated with prospective patient-toxicity centered studies.

Proton radiotherapy has seen an increasing role in the treatment of hepatocellular carcinoma (HCC). Historically, external beam radiotherapy has played a very limited role in HCC due to a high incidence of toxicity to surrounding normal structures. The ability to deliver a high dose of radiation to the tumor is a key factor in improving outcomes in HCC. Advances in photon radiotherapy have improved dose conformity and allowed dose escalation to the tumor. However, despite these advances there is still a large volume of normal liver that receives a considerable radiation dose during treatment. Proton beams do not have an exit dose along the beam path once they enter the body. The inherent physical attributes of proton radiotherapy offer a way to maximize tumor control via dose escalation while avoiding excessive radiation to the remaining liver, thus increasing biological effectiveness. In this review we discuss the physical attributes and rationale for proton radiotherapy in HCC. We also review recent literature regarding clinical outcomes of using proton radiotherapy for the treatment of HCC.

While the last 30 years chronicles an extensive effort to understand the damage to DNA caused by reactive oxygen species (ROS), little research has examined the chemical damage to the histone proteins found in chromatin. Hypochlorous acid (HOCl), the primary product of activated neutrophils, is known to damage both DNA and proteins. This article describes the use of mass spectrometry to quantitate the formation of 3-chlorotyrosine and 3,5-dichlorotyrosine, stable and unique markers of protein damage caused by HOCl, in the core histone proteins. Our results indicate that up to 25% of the tyrosine in histone proteins become chlorinated by excess HOCl. We also observe significant formation of 3-chlorotyrosine and 3,5-dichlorotyrosine at low HOCl concentrations and short reaction times. We use mass spectrometry to identify the tyrosine residues on each histone protein that are chlorinated based on the observation of chlorine-containing peptides following protease digestion of histone proteins exposed to HOCl. The tyrosine residues preferentially chlorinated by HOCl are generally within three residues of a lysine or histidine residue, further implicating the initial formation of chloramines in the efficient chlorination of tyrosine residues. The methods and results described here should further our understanding of how HOCl produced at sites of inflammation might damage chromatin.

Perturbations in cytosine methylation signals are observed in the majority of human tumors; however, it is as yet unknown how methylation patterns become altered. Epigenetic changes can result in the activation of transforming genes as well as in the silencing of tumor suppressor genes. We report that methyl-CpG-binding proteins (MBPs), specific for methyl-CpG dinucleotides, bind with high affinity to halogenated pyrimidine lesions, previously shown to result from peroxidase-mediated inflammatory processes. Emerging data suggest that the initial binding of MBPs to methyl-CpG sequences may be a seeding event that recruits chromatin-modifying enzymes and DNA methyltransferase, initiating a cascade of events that result in gene silencing. MBD4, a protein with both methyl-binding and glycosylase activity demonstrated repair activity against a series of 5-substituted pyrimidines, with the greatest efficiency against 5-chlorouracil, but undetectable activity against 5-chlorocytosine. The data presented here suggest that halogenated pyrimidine damage products can potentially accumulate and mimic endogenous methylation signals.

Recent studies have shown that reactive chlorine species, derived from myeloperoxidase-mediated inflammation responses, can modify DNA bases, generating 5-chloropyrimidines. The chlorinated adducts could be mutagenic or perturb DNA-protein interactions; however, the biological significance of these adducts is as yet unknown. We report here a method for the synthesis of 5-chlorocytosine- (ClC-) containing oligonucleotides that will be used in subsequent biochemical and biophysical studies to determine the consequences of pyrimidine chlorination. The ClC-phosphoramidite synthon is obtained by chlorination of 2'-deoxyuridine followed by conversion to the O(4)-ethyl analogue. The amino group needed to form the corresponding cytosine derivative is added by displacement of the O(4)-ethyl group during ammonia deprotection. A battery of methods, including mass spectrometry, has been used to characterize oligonucleotides containing ClC. Following oligonucleotide synthesis and deprotection, only trace amounts of the deamination product 5-chlorouracil can be detected by enzymatic cleavage of duplex oligonucleotides with the mispaired uracil glycosylase, MUG. In contrast to previous reports, we find that ClC is more stable in DNA than anticipated. Approximately 20% ClC is lost under standard formic acid hydrolysis conditions (88% formic acid, 140 degrees C, 30 min), while only 5% is recovered as 5-chlorouracil (ClU).

Proton radiotherapy has seen an increasing role in the treatment of hepatocellular carcinoma (HCC). Historically, external beam radiotherapy has played a very limited role in HCC due to a high incidence of toxicity to surrounding normal structures. The ability to deliver a high dose of radiation to the tumor is a key factor in improving outcomes in HCC. Advances in photon radiotherapy have improved dose conformity and allowed dose escalation to the tumor. However, despite these advances there is still a large volume of normal liver that receives a considerable radiation dose during treatment. Proton beams do not have an exit dose along the beam path once they enter the body. The inherent physical attributes of proton radiotherapy offer a way to maximize tumor control via dose escalation while avoiding excessive radiation to the remaining liver, thus increasing biological effectiveness. In this review we discuss the physical attributes and rationale for proton radiotherapy in HCC. We also review recent literature regarding clinical outcomes of using proton radiotherapy for the treatment of HCC.

Inflammation-mediated, neutrophil-derived hypochlorous acid can damage DNA and result in the chlorination damage products 5-chlorocytosine and 5-chlorouracil as well as the oxidation damage products 5-hydroxycytosine and 5-hydroxyuracil. While 5-chlorocytosine could potentially perturb epigenetic signals if formed at a CpG dinucleotide, the remaining products are miscoding and could result in transition mutations. In this article, we have investigated the reaction of hypochlorous acid with an oligonucleotide site-specifically enriched with 15N to probe the reactivity of cytosine at CpG. These experiments demonstrate directly the formation of 5-chlorocytosine at a CpG dinucleotide in duplex DNA. We observe that chlorination relative to oxidation damage is greater at CpG by a factor of approximately two, whereas similar amounts of 5-chlorocytosine and 5-hydroxycytosine are formed at two non-CpG sites examined. The relative amounts of deamination of the cytosine to uracil derivatives are similar at CpG and non-CpG sites. Overall, we observe that the reactivity of cytosine at CpG and non-CpG sites toward hypochlorous acid induced damage is similar (5-chlorocytosine5-hydroxycytosine5-hydroxyuracil5-chlorouracil), with a greater proportion of chlorination damage at CpG sites. These results are in accord with the potential of inflammation-mediated DNA damage to both induce transition mutations and to perturb epigenetic signals.

We report the case of a 39-year-old African-American lady diagnosed with a cutaneous vasculitis manifesting as hyperpigmented areas over the lower extremities. She was ANA and ds-DNA positive and was started on immunosuppressive agents, which were discontinued due to side effects. Over the next 2 months, she developed III, IV, VI, VII, and VIII cranial nerve (CN) palsy on the left side. The patient9s MRI showed abnormal T2 lengthening in the pons, midbrain, and medulla without abnormal enhancement, with a differential diagnosis of thiamine deficiency, vitamin B12 deficiency, multiple sclerosis, and postviral encephalopathy. Her cerebrospinal fluid studies were negative for infections. Her antiphospholipid antibodies and anti-β2-glycoprotein 1 antibodies were strongly positive. She was treated with intravenous thiamine, high-dose corticosteroids with no effect. She was then given rituximab, a CD20 monoclonal antibody, infusions 375 mg/m2 once a week for 4 weeks. The clinical changes involving the IV and VI CN completely resolved in 2 weeks, and there was significant improvement in her III, VII, and VIII CN palsy. The MRI changes resolved completely 2 months after rituximab infusions. Cranial neuropathies occur in 3 to 16% of systemic lupus erythematosus patients and can be due to vascular occlusion, demyelination, vasculitis, or meningitis. There are only two such case reports of multiple cranial nerve involvement secondary to antiphospholipid antibody syndrome-associated demyelination in the foreign language literature and none in English-language journals.