Theranostic applications of pair-production for enhancing radiation therapy.

Purpose/Objective(s): To enhance radiotherapy by utilizing pair-production, the probability of which increases with X-ray energy and atomic Z number. Introducing high Z metals during 18MV irradiation should result in increased cell killing compared to 18MV irradiation without metal or 6MV with/without metal. This effect will be due to increased pair-production near high Z nuclei which increases locally absorbed radiation dose. This effect requires metal, preferably nontoxic, to be present during irradiation and will be measured in vitro with clonogenic survival assays. Purpose/Objective(s): Clonogenic survival assays were carried out using A549 human lung cancer cells. Tissue culture plates were irradiated with 2Gy of either 6MV or 18MV photons with or without metal drugs (100 uM sodium phosphotungstate hydrate, 4ug/ml cisplain, and 12ug/ml carboplatin) present during radiotherapy. Metal drugs were introduced to culture media 2 hours prior to irradiation and left in place during irradiation. The media was replaced immediately after irradiation with metal-free media. Calibrated output factors were used to ensure the same absorbed dose between the two beam energies under identical experimental setup conditions. Results: Mean plating efficiency was determined to be 41% on average for A549. Incubating cells in 100uM tungsten for 4 hours without irradiation produced no significant toxicity (\u3e95% survival). In the absence of metal drug, the 2Gy 6MV and 18MV plates showed similar survival (64% vs 67%). When tungsten compound was introduced, the 6MV plate again showed 66% survival, however the 18MV plate showed 34% survival, approximately double cell killing. These experiments were repeated at 4, 6, and 8Gy to generate cell survival curves and the radiation sensitization enhancement ratio (SER) was found to be approximately 1.5. The tungsten 18MV survival curve shows a minimal shoulder region compared to the 6MV with/without tungsten and 18MV without tungsten curves, suggesting inhibition of sublethal damage repair. The 2Gy 6MV vs 18MV clonogenic survival studies were carried out for 4ug/ml cisplatin and 12ug/ml carboplatin which similarly showed approximately 40% enhancement of cell killing for both drugs at 18MV compared to 6MV. Conclusion: Cells treated with 18MV irradiation in the presence of 100uM sodium phosphotungstate hydrate showed approximately 50% less cell survival at 2, 4, 6, and 8Gy compared to 6MV with/without metal and 18MV without metal. Cisplatin and carboplatin show similar radiosensitization at 18MV yielding 40% more cell killing than 6MV. This effect is due to pair-production leading to increased photon-matter interaction and requires metal to be present at time of irradiation. The survival curves at 2, 4, 6, and 8Gy show loss of initial shoulder region suggesting impaired sublethal damage repair or increased effective LET. The generation of 511keV annihilation photons in situ may allow tumor imaging and dose measurement via PET technology. Confirmatory in vivo studies are planned

Thlaspi montanum L. (BR0000010535356)

Belgium Herbarium image of Meise Botanic Garden

Solitary ovarian plasmacytoma A case report and review of literature

•A patient with rare solitary ovarian plasmacytoma is reported •Diagnostic work-up is mandatory to rule out ovarian involvement as part of multiple myeloma. •After complete surgical resection, the prognosis appears to be very favorable

Effects of Cancer Treatment on the Education and Cognition of South Florida Pediatric Cancer Survivors

Purpose As pediatric cancer survival rates have exponentially increased in the past decade, with the vast majority surviving five years or more, the long-term impacts of treatment on the quality of survivorship must be explored. This study examines the effects of pediatric cancer treatment regimens on education outcomes among a demographically diverse regional population. The primary objective is to identify potential factors that may impact the educational and cognitive quality of life in this population.  Methods Four hundred sixty-eight pediatric oncology patients diagnosed at age <20 between January 1990 - August 2019 and treated for cancer with radiation therapy at a large public or a multi-center private hospital in South Florida were identified. A novel survey available in English and Spanish was electronically distributed at least three times to each patient from August 2020 - July 2021 via email, phone call, and text message. Variables relating to demographics, treatment, cognitive impairment, and school re-entry were collected through the survey and electronic medical record review. Descriptive statistical analysis was performed.  Results Of the patients, 10.5% responded to the survey (26 male, 21 female, two unidentified sex). The mean age was 8.9 years old (range 0-20) at diagnosis, 24.0 years old (range 8-39) at the time of survey completion, and 55.1% self-identified as Hispanic. Nearly one-quarter of respondents (22.4%) were unable to correctly identify the treatment modalities they received; Hispanic self-identifying patients were 1.75 times more likely than non-Hispanic patients to incorrectly report the treatment modalities received. One-quarter (26.5%) of respondents reported long-term cognitive deficits post-treatment, of which, over three-quarters (76.9%) identified as Hispanic.  Conclusion This study illuminates patients' perspectives on their long-term cognitive impacts after pediatric cancer treatment. Given the diverse study population, ethnic disparities in post-treatment survivorship were explored. A substantial subset of Hispanic participants was unable to correctly identify their treatment regimen, and a disproportionately large group of Hispanic patients experienced cognitive long-term cognitive deficits, suggesting that ethnic disparities play a critical role in post-treatment survivorship. Further research on prioritizing educational intervention during and after treatment is essential to improving both the quality and equity of survivorship among pediatric oncology patients

The Effect of Health Insurance on Pediatric Cancer Survival: An Analysis of Children Evaluated for Radiation Therapy in Diverse Multicenter Health Systems

BACKGROUNDUnderstanding the role of health insurance in cancer survival in a diverse population of pediatric radiation oncology patients could help to identify patients at risk of adverse outcomes. MATERIALS AND METHODSData were collected from cancer patients evaluated for radiation therapy, age <19, diagnosed from January 1990 to August 2019. Predictors of recurrence-free survival (RFS) and overall survival (OS) were analyzed by univariable and multivariable Cox regression. Variables included health insurance, diagnosis type, sex, race/ethnicity, and socioeconomic status deprivation index. RESULTSThe study included 459 patients with a median diagnosis age of 9 years. Demographic breakdown was 49.5% Hispanic, 27.2% non-Hispanic White, and 20.7% non-Hispanic Black. There were 203 recurrences and 86 deaths observed over a median follow-up of 2.4 years. Five-year RFS was 59.8% (95% CI, 51.6, 67.0) versus 36.5% (95% CI, 26.6, 46.6), and 5-year OS was 87.5% (95% CI, 80.9, 91.9) versus 71.0% (95% CI, 60.3, 79.3) in private pay insurance versus Medicaid/Medicare, respectively. Multivariable showed Medicaid/Medicare patients experienced a 54% higher risk of recurrence (hazard ratio: 1.54, 95% CI, 1.08, 2.20) and 79% higher risk of death (hazard ratio: 1.79, 95% CI, 1.02, 3.14) than privately insured patients. CONCLUSIONSSignificant disadvantages in RFS and OS were identified in radiation oncology patients with Medicaid/Medicare insurance, even after adjusting for clinical and demographic variables

Omission of Staging Bone Marrow Biopsy Does Not Affect Outcomes in Patients with Stage I Extranodal Marginal Zone Lymphoma (EMZL) Treated with Radiation Therapy

INTRODUCTION: Patients with stage I localized extranodal marginal zone lymphoma (EMZL) treated with radiation therapy (RT) have excellent outcomes. Negative bone marrow (BM) biopsy at diagnosis is key to confirm early stage disease. However, BM biopsy is not performed in some patients for various reasons such as comorbidities, patient refusal or physician decision. The aim of this study was to assess the effects of BM status (negative vs. not done) on disease recurrence/progression and survival in EMZL patients presenting with otherwise localized disease by imaging and treated with RT. METHODS: From January 1995 to January 2019, we identified 188 patients with stage I EMZL treated with frontline RT at the University of Miami Health Care System. All patients had biopsy proven EMZL and scans (CT, MRI, and/or PET-CT) at the time of diagnosis. Medical records were reviewed and pertinent information gathered. Relapse/progression was subclassified based on disease location: inside, outside, or inside and outside of the radiation field (RF). The competing risk method and the Gray's test were used in analysis of incidence rates of type of relapse/progression and lymphoma-specific death. The Kaplan-Meier method and the log-rank test were used in analyses of progression-free survival (PFS) and overall survival (OS). RESULTS: Among 188 patients included in this study, 104 (55.3%) were ≤60 years and 135 (71.8%) 60 years (26, 65%). Radiation doses broadly varied but most patients (176, 93.6%) received ≥30 Gy. 183 patients (97.3%) achieved complete response (CR) following RT with 2 (1.1%) achieving partial response (PR), 2 (1.1%) stable disease and 1 (0.5%) demonstrating disease progression. Among 176 patients receiving ≥30 Gy RT, 173 (98.2%) achieved CR. With a median follow-up of 6.2 years (range 0.3-22.3 years) the 10 years-PFS was 64.4% (95%CI:54.9%-72.5%). No difference in PFS was observed by location of disease or BM biopsy (negative vs. not done). Patients treated with ≥30Gy had statistically significantly longer PFS compared to patients treated with <30Gy, whether or not BM biopsy was done. There were 52 progression events, including 5 inside RF (4 relapses/1 progression), 6 inside & outside (5 relapses/1 progression), 25 outside alone (24 relapses/1 progression), and 16 non-lymphoma deaths. Taking into account non-lymphoma death as a competing risk, the 5-year incidence of lymphoma relapse/progression was 2.9% (95%CI:1.1-6.3%) inside RF, 3.4% (95%CI:1.2-7.3%) inside & outside RF and 9.8% (5.8-15.0%) outside RF. Importantly, there was no higher cumulative incidence of each type of relapse/progression relative to RF (inside p=0.2490, inside & outside p=0.1617, and outside alone p=0.3070) in patients without vs. negative staging BM biopsy. There were 23 deaths, 7 attributed to lymphoma. The 10-year OS was 83.3% (95%CI:75.0-89.0%), and there was no difference in OS by EMZL location. Patients without staging BM biopsy had shorter OS (p=0.0062). However, when lymphoma-specific death was analyzed (non-lymphoma death as competing risk) the estimated 10-year cumulative incidence of lymphoma-specific death was 5.3% (2.3%-10.2%) and there was a non-statistically significant difference between patients with and without staging BM biopsy (p=0.5201). The cumulative 10-years incidence of non-lymphoma specific death (lymphoma death as competing risk) was 11.4% (95% CI:6.3%-18.2%). There was a statistically significant difference by BM biopsy status (p=0.0107), with patients without staging BM biopsy having higher incidence of non-lymphoma death compared to negative BM biopsy patients (10-yr rate 26.7% vs 7.9%, respectively), likely due to coexistent comorbidities. CONCLUSION: In this large cohort of patients with stage I EMZL treated with RT we demonstrate for the first time that omission of BM biopsy at diagnosis does not affect lymphoma-specific survival or the incidence of disease relapse/progression overall or by relapse location type, suggesting that diagnostic BM biopsy may not be necessary. Disclosures Alderuccio: Foundation Medicine: Other: Immediate family member; Inovio Pharmaceuticals: Other: Immediate family member; Targeted Oncology: Honoraria; Agios: Other: Immediate family member; Puma Biotechnology: Other: Immediate family member; OncLive: Consultancy. Lossos:NIH: Research Funding; Janssen Scientific: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees

Long-Term Outcome of Conjunctival Extranodal Marginal Zone Lymphoma: A Large Single-Institution Analysis

Abstract Background The most common subtype of B-cell lymphomas presenting in the conjunctiva is extranodal marginal zone lymphoma (EMZL), accounting for ~80% of cases. Most patients (pts) present with localized disease, and radiation therapy (RT) is the preferred treatment strategy. We aimed to retrospectively analyze our single-institution experience to provide further insight into the characteristics and long-term outcomes of conjunctival EMZL. Methods We evaluated 72 pts diagnosed with conjunctival EMZL between 01/1995 and 12/2020 at the University of Miami. Pts' characteristics included age, sex, TNM-AJCC ocular lymphoma and Ann Arbor staging systems, MALT-IPI score, treatment (RT, chemotherapy, rituximab), and treatment response (complete response (CR), partial response, stable disease, progression of disease). Primary endpoints were progression-free survival (PFS) and overall survival (OS), estimated using the Kaplan-Meier method, and compared using the log rank test and the univariable Cox regression analysis. We also performed a competing risk univariable analysis (UVA) assessing predictors of cumulative incidence of relapse/progression, with death without relapse as a competing risk, using the Fine and Gray regression analysis. Results Among all 72 pts, mean age was 59.9 yrs (7-93) with 38 (52.8%) being >60 yrs old, 46 (63.9%) were female, 56 (77.8%) had unilateral conjunctival disease, localized disease (T1N0M0 and Ann Arbor stage I) was present in 63 (87.5%), 6 (8.3%) had disseminated disease with more than 1 extranodal site involved, and 29 (40.3%) had a MALT-IPI of 1 or 2. After biopsy and surgical removal, 65 (90.2%) received additional treatment, while 6 (8.3%) were followed only, and in one case therapy information was not available . RT was the most common treatment (53 pts [73.6%], with 46 [86.8%] of those treated with ≥ 30 Gy). In two of these patients RT was combined with chemotherapy. Other treated pts received immunochemotherapy (12 [16.7%], including rituximab in 8). Five pts with stage II-IV disease received systemic therapy. CR was achieved in 63 (87.5%) after first line treatment, and no high-grade lymphoma transformation was seen. With a median follow up of 6.67 yrs (0.56-24.13), there were 14 relapses (19.4%). Among 53 pts treated with RT there were 8 relapses (15.1%), only one (1.9%) within the RT field. There were 23 progression events (31.9%, 14 relapses and 9 deaths without documented relapse), and a total of 14 deaths (19.4%). Mean PFS and OS were 6.69 yrs (0.49-20.37, SD 4.95) and 7.81 yrs (0.56-24.13, SD 5.40), respectively. The 10-yr PFS and OS were 68.4% (95%CI 52.8, 79.8%) and 89.4% (95%CI 77.4, 95.2%), respectively. Variables associated with shorter PFS in UVA Cox model were age > 60 yrs (HR=2.93, 95%CI 1.08, 7.95; p=0.035), high MALT-IPI (1-2) (HR=2.42, 95%CI 1.01, 5.78; p=0.048), and use of chemotherapy only (HR=2.73, 95%CI 1.13, 6.56; p=0.025). Variables associated with shorter OS included age >60 yrs (HR=9.07, 95%CI 1.17, 70.26; p=0.035) and high MALT-IPI (HR=6.19, 95%CI 1.35, 28.33; p=0.019). CR after frontline therapy was associated with longer PFS (HR=0.13, 95%CI 0.04, 0.45; p=0.001) but not OS. PFS of MALT-IPI 0 vs 1-2 was significantly longer (p=0.042), with 10-yr PFS 80.9% (95%CI 63.4%, 90.6%) vs 55.6% (95%CI 32.1%, 73.8%). Similarly, longer OS was observed in MALT-IPI 0 pts (p=0.0077; 10-yr OS 95.2% [95%CI 82.2%, 98.8%] vs 80.6% [95%CI 55.6%, 92.4%]) (Figure). A subset UVA Cox analysis of patients with Ann Arbor stage I showed longer PFS associated with CR after frontline therapy (HR 0.15, 95%CI 0.04, 0.58; p=0.006) with no significant association with age >60 yrs, high MALT-IPI or use of chemotherapy. Variables associated with shorter OS were age >60 yrs (HR 8.01, 95%CI 1.00, 63.98; p=0.05) and high MALT-IPI (HR 13.41, 95%CI 1.67, 107.99; p=0.015), similarly to the primary analysis. On univariable Fine and Gray regression models with death without relapse/progression as a competing risk, RT (SHR=0.33, 95%CI 0.12, 0.96; p=0.041) and CR-post frontline therapy (SHR=0.11, 95%CI 0.03, 0.36; p<0.001) were associated with lower risk of relapse. Conversely, chemotherapy (SHR=3.47, 95%CI 1.20, 10.0; p=0.022) was associated with higher risk of relapse. Conclusion Patients with conjunctival EMZL exhibit excellent long-term survival, and RT remains the most effective frontline therapy. MALT-IPI appropriately identifies patients at risk for treatment failure. Figure 1 Figure 1. Disclosures Alderuccio: ADC Therapeutics: Consultancy, Research Funding; Oncinfo / OncLive: Honoraria; Puma Biotechnology: Other: Family member; Inovio Pharmaceuticals: Other: Family member; Agios Pharmaceuticals: Other: Family member; Forma Therapeutics: Other: Family member. Lossos: Lymphoma Research Foundation: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; NCI: Research Funding; Stanford University: Patents & Royalties; Verastem: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; NIH grants: Research Funding; University of Miami: Current Employment

A Novel Mechanism of High Dose Radiation Sensitization by Metformin

Introduction: Metformin, the most widely used treatment for diabetes, is lethal to cancer cells and increases in toxicity when used in combination with radiation. In addition to various molecular and metabolic mechanisms that have been previously proposed, the studies presented provide evidence of an additional, novel mechanism of sensitization following high dose radiotherapy; the magnitude of sensitization depends on the microenvironmental levels of glucose and oxygen which are in turn affected by high dose radiation. Methods: Cancer cells (A549 and MCF7) were studied in vitro under various controlled conditions. Endpoints included clonogenic cell survival and ROS expression measured by DHE and DCFDA. CD1 nu/nu athymic mice implanted with A549 cells received metformin alone (200 mg/kg, i.p.), radiation alone (15 Gy) or a combination of metformin and radiation; the effect of treatment sequence on efficacy was assessed by tumor growth delay and histology. In a separate set of experiments, tumor blood flow was measured using a tracer clearance technique using SPECT after the administration of metformin alone, radiation alone and the combined treatment. Results: In vivo, metformin provided equally effective tumor growth delay when given 24 h after radiation as when given 1 h or 4 h before radiation, an observation not previously reported and, in fact, unexpected based on published scientific literature. When drug followed radiation, the tumors were histologically characterized by massive cellular necrosis. In vitro, cancer cells when glucose depleted and/or hypoxic were preferentially killed by metformin, in a drug dose dependent manner. A549 cells exposed to 5.0 mM of metformin was reduced seven fold in survival when in a glucose deprived as compared to a low-glucose medium (0 vs. 1.0 g/L). Finally, using a SPECT detector to follow the washout of a radioactive tracer, it was shown that a high single dose of radiosurgery (15 Gy) could dramatically inhibit blood flow and presumably diminish glucose and oxygen. Discussion: Insight into the best timing of drug and radiation administration is gained through an understanding of the mechanisms of interaction. A new mechanism of metformin sensitization by high dose radiation is proposed based on the blood flow, glucose and oxygen