Purpose: Over the past decade, high-dose methotrexate has emerged as the single most effective agent in the initial treatment of primary nervous system lymphoma. However, the majority of patients who respond initially to treatment relapse. The optimal management of these patients has not been determined. We performed a multicenter, retrospective study of high-dose methotrexate in patients with relapsed central nervous system lymphoma.Experimental Design: Patients with relapsed disease were eligible if they achieved a complete response to initial treatment with methotrexate-based chemotherapy or received methotrexate after gross total resection or interstitial radiation. All of the patients were retreated with a regimen containing high-dose methotrexate (>3 g/m 2 ). Results: Twenty-two patients with a median age of 58 years were included in the study. Overall response rates were 91% to first salvage (20 of 22 patients) and 100% to second salvage (4 of 4 patients). Median survival was 61.9 months after first relapse (95% confidence interval, 42.1-ؕ) and 91.9 months overall (95% confidence interval, 47.2-ؕ). Toxicity was primarily hematologic with 10 episodes of grade 3 or 4 toxicity during 566 cycles of chemotherapy.Conclusions: These results indicate that high-dose methotrexate remains effective for relapsed central nervous system lymphoma in patients who initially respond to methotrexate and raise the possibility of deferring more toxic salvage regimens in this select group of patients.

Purpose To report dosimetry and early toxicity data in breast cancer patients treated with postoperative proton radiation therapy. Methods and Materials From March 2013 to April 2014, 30 patients with nonmetastatic breast cancer and no history of prior radiation were treated with proton therapy at a single proton center. Patient characteristics and dosimetry were obtained through chart review. Patients were seen weekly while on treatment, at 1 month after radiation therapy completion, and at 3- to 6-month intervals thereafter. Toxicity was scored using Common Terminology Criteria for Adverse Events version 4.0. Frequencies of toxicities were tabulated. Results Median dose delivered was 50.4 Gy (relative biological equivalent [RBE]) in 5 weeks. Target volumes included the breast/chest wall and regional lymph nodes including the internal mammary lymph nodes (in 93%). No patients required a treatment break. Among patients with >3 months of follow-up (n = 28), grade 2 dermatitis occurred in 20 patients (71.4%), with 8 (28.6%) experiencing moist desquamation. Grade 2 esophagitis occurred in 8 patients (28.6%). Grade 3 reconstructive complications occurred in 1 patient. The median planning target volume V95 was 96.43% (range, 79.39%-99.60%). The median mean heart dose was 0.88 Gy (RBE) [range, 0.01–3.20 Gy (RBE)] for all patients, and 1.00 Gy (RBE) among patients with left-sided tumors. The median V20 of the ipsilateral lung was 16.50% (range, 6.1%–30.3%). The median contralateral lung V5 was 0.34% (range, 0%–5.30%). The median maximal point dose to the esophagus was 45.65 Gy (RBE) [range, 0–65.4 Gy (RBE)]. The median contralateral breast mean dose was 0.29 Gy (RBE) [range, 0.03–3.50 Gy (RBE)]. Conclusions Postoperative proton therapy is well tolerated, with acceptable rates of skin toxicity. Proton therapy favorably spares normal tissue without compromising target coverage. Further follow-up is necessary to assess for clinical outcomes and cardiopulmonary toxicities.

In South Koreans, more severe myopia was associated with greater odds of glaucoma as defined by ISGEO criteria.

Purpose. Some patients with nonmalignant systemic diseases, like collagen vascular disease (CVD), hypertension, diabetes mellitus, and inflammatory bowel disease (IBD), tolerate radiation therapy poorly. Although the mechanisms of each of these disease processes are different, they share a common microvessel pathology that is potentially exacerbated by radiotherapy. This article reviews and evaluates available data examining the effects of these benign disease processes on radiation tolerance.Methods. We conducted a thorough review of the Anglo-American medical literature from 1960 to 2001 on the effects of radiotherapy on CVD, hypertension, diabetes mellitus, and IBD.Results. Fifteen studies were identified that examined the effects of radiation therapy for cancer in patients with CVDs. Thirteen of 15 studies documented greater occurrences of acute and late toxicities (range 7%-100%). Higher rates of complications were noted especially for nonrheumatoid arthritis CVDs. Nine studies evaluated the effects of hypertension and diabetes on radiation tolerance. All nine studies documented higher rates of late toxicities than in a "control" group (range 34%-100%). When patients had both diabetes and hypertension, the risk of late toxicities was even higher. Six studies examined radiation tolerance of patients with IBD irradiated to the abdomen and pelvis. Five of these six studies showed greater occurrences of acute and late toxicities for patients with IBD, even with precautionary measures like reduced fraction size and volume and patient immobilization (13%-29%).Conclusion. The majority of published studies documented lower radiation tolerance for patients who have CVD, diabetes mellitus, hypertension, and IBD. This may reflect a publication bias, as the majority of these studies are retrospective with small numbers of patients and use different scoring scales for complications. These factors may contribute to an overestimation of true radiationinduced morbidity. Although the paucity of data makes precise estimates difficult, a subset of patients, in particular, those with active CVD, IBD, or a combination of uncontrolled hypertension with type I diabetes, is likely to be at higher risk. Future prospective trials need to document these disease entities when reporting treatmentrelated complications and also must monitor toxicities associated with quiescent versus active IBD and CVD, type I versus type II diabetes, and levels of hypertension (controlled versus uncontrolled) matched for radiationspecific treatment sites, field size, fractionation, and total dose.

Tirapazamine (3-amino-1,2,4-benzotriazine-1,4-dioxide) is a promising hypoxia-selective cytotoxin that has shown significant activity in advanced clinical trials in combination with radiotherapy and cisplatin. The current study aimed to advance our understanding of tirapazamine-induced lesions and the pathways involved in their repair. We show that homologous recombination plays a critical role in repair of tirapazamine-induced damage because cells defective in homologous recombination proteins XRCC2, XRCC3, Rad51D, BRCA1, or BRCA2 are particularly sensitive to tirapazamine. Consistent with the involvement of homologous recombination repair, we observed extensive sister chromatid exchanges after treatment with tirapazamine. We also show that the nonhomologous end-joining pathway, which predominantly deals with frank double-strand breaks (DSB), is not involved in the repair of tirapazamine-induced DSBs. In addition, we show that tirapazamine preferentially kills mutants both with defects in XPF/ERCC1 (but not in other nucleotide excision repair factors) and with defects in base excision repair. Tirapazamine also induces DNA-protein cross-links, which include stable DNA-topoisomerase I cleavable complexes. We further show that ;H2AX, an indicator of DNA DSBs, is induced preferentially in cells in the S phase of the cell cycle. These observations lead us to an overall model of tirapazamine damage in which DNA single-strand breaks, base damage, and DNA-protein cross-links (including topoisomerase I and II cleavable complexes) produce stalling and collapse of replication forks, the resolution of which results in DSB intermediates, requiring homologous recombination and XPF/ERCC1 for their repair. [Cancer Res 2008;68(1):257-65]

IntroductionCell supplementation to the herniated or degenerated intervertebral disc (IVD) is a potential strategy to promote tissue regeneration and slow disc pathology. Human umbilical cord mesenchymal stromal cells (HUCMSCs) – originating from the Wharton’s jelly – remain an attractive candidate for such endeavors with their ability to differentiate into multiple lineages. Previously, mesenchymal stem cells (MSCs) have been studied as a potential source for disc tissue regeneration. However, no studies have demonstrated that MSCs can regenerate matrix with unique characteristics matching that of immature nucleus pulposus (NP) tissues of the IVD. In our prior work, immature NP cells were found to express specific laminin isoforms and laminin-binding receptors that may serve as phenotypic markers for evaluating MSC differentiation to NP-like cells. The goal of this study is to evaluate these markers and matrix synthesis for HUCMSCs cultured in a laminin-rich pseudo-three-dimensional culture system.MethodsHUCMSCs were seeded on top of Transwell inserts pre-coated with Matrigel™, which contained mainly laminin-111. Cells were cultured under hypoxia environment with three differentiation conditions: NP differentiation media (containing 2.5% Matrigel™ solution to provide for a pseudo-three-dimensional laminin culture system) with no serum, or the same media supplemented with either insulin-like growth factor-1 (IGF-1) or transforming growth factor-β1 (TGF-β1). Cell clustering behavior, matrix production and the expression of NP-specific laminin and laminin-receptors were evaluated at days 1, 7, 13 and 21 of culture.ResultsData show that a pseudo-three-dimensional culture condition (laminin-1 rich) promoted HUCMSC differentiation under no serum conditions. Starting at day 1, HUCMSCs demonstrated a cell clustering morphology similar to that of immature NP cells in situ and that observed for primary immature NP cells within the similar laminin-rich culture system (prior study). Differentiated HUCMSCs under all conditions were found to contain glycosaminoglycan, expressed extracellular matrix proteins of collagen II and laminin α5, and laminin receptors (integrin α3 and β4 subunits). However, neither growth factor treatment generated distinct differences in NP-like phenotype for HUCMSC as compared with no-serum conditions.ConclusionsHUCMSCs have the potential to differentiate into cells sharing features with immature NP cells in a laminin-rich culture environment and may be useful for IVD cellular therapy.

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Thyroid eye disease is an auto-immune mediated orbitopathy which can cause dysthyroid compressive optic neuropathy. Traditional management of active thyroid eye disease includes temporizing high-dose steroids, orbital radiation and surgical decompression, which each possess significant limitations and/or side effects. Teprotumumab is an IGF-IR inhibitor recently FDA-approved for active thyroid eye disease. The authors report reversal of bilateral dysthyroid compressive optic neuropathy managed medically utilizing teprotumumab.