We present an exquisite 30 minute cadence Kepler (K2) light curve of the Type Ia supernova (SN Ia) 2018oh (ASASSN-18bt), starting weeks before explosion, covering the moment of explosion and the ...subsequent rise, and continuing past peak brightness. These data are supplemented by multi-color Panoramic Survey Telescope (Pan-STARRS1) and Rapid Response System 1 and Cerro Tololo Inter-American Observatory 4 m Dark Energy Camera (CTIO 4-m DECam) observations obtained within hours of explosion. The K2 light curve has an unusual two-component shape, where the flux rises with a steep linear gradient for the first few days, followed by a quadratic rise as seen for typical supernovae (SNe) Ia. This "flux excess" relative to canonical SN Ia behavior is confirmed in our i-band light curve, and furthermore, SN 2018oh is especially blue during the early epochs. The flux excess peaks 2.14 0.04 days after explosion, has a FWHM of 3.12 0.04 days, a blackbody temperature of K, a peak luminosity of , and a total integrated energy of . We compare SN 2018oh to several models that may provide additional heating at early times, including collision with a companion and a shallow concentration of radioactive nickel. While all of these models generally reproduce the early K2 light curve shape, we slightly favor a companion interaction, at a distance of ∼ based on our early color measurements, although the exact distance depends on the uncertain viewing angle. Additional confirmation of a companion interaction in future modeling and observations of SN 2018oh would provide strong support for a single-degenerate progenitor system.
While previous studies have reported on the prognostic value of total plasma cell-free deoxyribonucleic acid (cfDNA) in lung cancers, few have prospectively evaluated its predictive value for ...systemic therapy response.
We conducted a prospective study to evaluate the association between changes in total cfDNA and radiologic response to systemic therapy in patients with stage IIIB/IV non-small-cell lung cancers (NSCLCs). Paired blood collections for cfDNA and computed tomography (CT) assessments by RECIST v1.0 were performed at baseline and 6–12 weeks after therapy initiation. Total cfDNA levels were measured in plasma using quantitative real-time polymerase chain reaction. Associations between changes in cfDNA and radiologic response, progression-free survival (PFS), and overall survival (OS) were measured using Kruskal–Wallis and Kaplan–Meier estimates.
A total of 103 patients completed paired cfDNA and CT response assessments. Systemic therapy administered included cytotoxic chemotherapy in 57% (59/103), molecularly targeted therapy in 17% (17/103), and combination therapy in 26% (27/103). Median change in cfDNA from baseline to response assessment did not significantly differ by radiologic response categories of progression of disease, stable disease and partial response (P = 0.10). However, using radiologic response as continuous variable, there was a weak positive correlation between change in radiologic response and change in cfDNA (Spearman's correlation coefficient 0.21, P = 0.03). Baseline cfDNA levels were not associated with PFS hazard ratio (HR) = 1.06, 95% confidence interval (CI) 0.93–1.20, P = 0.41 or OS (HR = 1.04, 95% CI 0.93–1.17, P = 0.51), neither were changes in cfDNA.
In this large prospective study, changes in total cfDNA over time did not significantly predict radiologic response from systemic therapy in patients with advanced NSCLC. Pretreatment levels of total cfDNA were not prognostic of survival. Total cfDNA level is not a highly specific predictive biomarker and future investigations in cfDNA should focus on tumor-specific genomic alterations using expanded capabilities of next-generation sequencing.
The primary objective of this phase I trial was to determine the maximum-tolerated dose of radiation that could be delivered to the primary tumor concurrent with full-dose gemcitabine in patients ...with advanced pancreatic cancer.
Thirty seven patients with unresectable (n = 34) or incompletely resected pancreatic cancer (n = 3) were treated. Gemcitabine was administered as a 30-minute intravenous infusion at a dose of 1,000 mg/m(2) on days 1, 8, and 15 of a 28-day cycle. Radiation therapy was initiated on day 1 and directed at the primary tumor alone, without prophylactic nodal coverage. The starting radiation dose was 24 Gy in 1.6-Gy fractions. Escalation was achieved by increasing the fraction size in increments of 0.2 Gy, keeping the duration of radiation constant at 3 weeks. A second cycle of gemcitabine alone was intended after a 1-week rest.
Two of six assessable patients experienced dose-limiting toxicity at the final planned dose level of the trial (42 Gy in 2.8-Gy fractions), one with grade 4 vomiting and one with gastric/duodenal ulceration. Two additional patients at this dose level experienced late gastrointestinal toxicity that required surgical management.
The final dose investigated (42 Gy) is not recommended for further study considering the occurrence of both acute and late toxicity. However, a phase II trial of this novel gemcitabine-based chemoradiotherapy approach, at a radiation dose of 36 Gy in 2.4-Gy fractions, is recommended on the basis of tolerance, patterns of failure, and survival data.
Previous studies have examined the relationship between specific nutrient and food intakes with limited markers of either inflammation or oxidant status. The objective of this study was to determine ...if an increase in combined self-reported fruit and vegetable (F&V) intake in a community setting was associated with improved multiple markers of inflammatory and oxidant status. A community group (N = 1000, age 18-85 years, 61% female) gave two fasted blood samples separated by 12 weeks. Blood inflammatory biomarkers included total leukocytes (WBC), plasma C-reactive protein (CRP), interleukin-6 (IL-6), IL-10, tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1, and granulocyte colony stimulating factor. Measured oxidant status markers were ferric reducing ability of plasma (FRAP), oxygen radical absorbance capacity (ORAC) and plasma F₂-isoprostanes. The relation of markers across categories of F&V intake was examined. In analyses controlling for other important dietary and lifestyle factors, IL-6 and TNF-α were significantly lower across categories of increasing F&V intakes (p < 0.008). FRAP and ORAC were significantly higher (p < 0.0001 and p = 0.047 respectively) while F(2)-isoprostanes was significantly lower (p < 0.0001) across F&V categories. In a community study, several markers of both inflammation and oxidant status were associated in a putatively salutary direction by higher intake of combined F&V, supporting current guidelines suggesting increased F&V consumption for the prevention of chronic diseases.
To describe the dose-volume tolerance for radiation-induced liver disease (RILD) using the Lyman-Kutcher-Burman (LKB) normal tissue complication probability (NTCP) model.
A total of 203 patients ...treated with conformal liver radiotherapy and concurrent hepatic arterial chemotherapy were prospectively followed for RILD. Normal liver dose-volume histograms and RILD status for these patients were used as input data for determination of LKB model parameters. A complication was defined as Radiation Therapy Oncology Group Grade 3 or higher RILD < o r =4 months after completion of radiotherapy. A maximal likelihood analysis yielded best estimates for the LKB NTCP model parameters for the liver for the entire patient population. A multivariate analysis of the potential factors associated with RILD was also completed, and refined LKB model parameters were obtained for patient subgroups with different risks of RILD.
Of 203 patients treated with focal liver irradiation, 19 developed RILD. The LKB NTCP model fit the complication data for the entire group. The "n" parameter was larger than previously described, suggesting a strong volume effect for RILD and a correlation of NTCP with the mean liver dose. No cases of RILD were observed when the mean liver dose was <31 Gy. Multivariate analysis demonstrated that in addition to NTCP and the mean liver dose, a primary hepatobiliary cancer diagnosis (vs. liver metastases), bromodeoxyuridine hepatic artery chemotherapy (vs. fluorodeoxyuridine chemotherapy), and male gender were associated with RILD. For 169 patients treated with fluorodeoxyuridine, the refined LKB model parameters were n = 0.97, m = 0.12, tolerance dose for 50% complication risk for whole organ irradiated uniformly TD50(1) = 45.8 Gy for patients with liver metastases, and TD50(1) = 39.8 Gy for patients with primary hepatobiliary cancer.
These data demonstrate that the liver exhibits a large volume effect for RILD, suggesting that the mean liver dose may be useful in ranking radiation plans. The inclusion of clinical factors, especially the diagnosis of primary hepatobiliary cancer vs. liver metastases, improves the estimation of NTCP over that obtained solely by the use of dose-volume data. These findings should facilitate the application of focal liver irradiation in future clinical trials.
Radiosensitizing Nucleosides McGinn, Cornelius J.; Shewach, Donna S.; Lawrence, Theodore S.
JNCI : Journal of the National Cancer Institute,
09/1996, Letnik:
88, Številka:
17
Journal Article
Recenzirano
Odprti dostop
Chemotherapeutic drugs that perturb nucleotide metabolism have the potential to produce substantial sensitization of tumor cells to radiation treatment. The process is called radiosensitization, and ...the agents that induce it are called radiosensitizers. The clinical effectiveness of fluoropyrimidines as radiosensitizers has been proven in multiple randomized trials. Thymidine analogues and hydroxyurea also appear to produce clinically relevant increases in radiation sensitivity. Recent laboratory investigations have identified difluorodeoxycytidine (gemcitabine) and fludarabine as promising agents to use in combination with radiation. Until recently, little was known about how the biochemical changes caused by these drugs produced radiosensitization. However, advances in related fields, such as cell cycle checkpoint control, have permitted the development of a hypothesis that may explain the relative tumor selectivity of fluoropyrimidine-mediated radiosensitization. In addition, recent findings suggest that the rational manipulation of drug administration schedules and the use of combinations of radiosensitizers have the potential to improve the efficacy of the currently used agents and to establish the benefit of new ones. J Natl Cancer Inst 1996;88:1193–1203
Purpose: To evaluate the intrafraction and interfraction reproducibility of liver immobilization using active breathing control (ABC).
Methods and Materials: Patients with unresectable intrahepatic ...tumors who could comfortably hold their breath for at least 20 s were treated with focal liver radiation using ABC for liver immobilization. Fluoroscopy was used to measure any potential motion during ABC breath holds. Preceding each radiotherapy fraction, with the patient setup in the nominal treatment position using ABC, orthogonal radiographs were taken using room-mounted diagnostic X-ray tubes and a digital imager. The radiographs were compared to reference images using a 2D alignment tool. The treatment table was moved to produce acceptable setup, and repeat orthogonal verification images were obtained. The positions of the diaphragm and the liver (assessed by localization of implanted radiopaque intra-arterial microcoils) relative to the skeleton were subsequently analyzed. The intrafraction reproducibility (from repeat radiographs obtained within the time period of one fraction before treatment) and interfraction reproducibility (from comparisons of the first radiograph for each treatment with a reference radiograph) of the diaphragm and the hepatic microcoil positions relative to the skeleton with repeat breath holds using ABC were then measured. Caudal-cranial (CC), anterior-posterior (AP), and medial-lateral (ML) reproducibility of the hepatic microcoils relative to the skeleton were also determined from three-dimensional alignment of repeat CT scans obtained in the treatment position.
Results: A total of 262 fractions of radiation were delivered using ABC breath holds in 8 patients. No motion of the diaphragm or hepatic microcoils was observed on fluoroscopy during ABC breath holds. From analyses of 158 sets of positioning radiographs, the average intrafraction CC reproducibility (σ) of the diaphragm and hepatic microcoil position relative to the skeleton using ABC repeat breath holds was 2.5 mm (range 1.8–3.7 mm) and 2.3 mm (range 1.2–3.7 mm) respectively. However, based on 262 sets of positioning radiographs, the average interfraction CC reproducibility (σ) of the diaphragm and hepatic microcoils was 4.4 mm (range 3.0–6.1 mm) and 4.3 mm (range 3.1–5.7 mm), indicating a change of diaphragm and microcoil position relative to the skeleton over the course of treatment with repeat breath holds at the same phase of the respiratory cycle. The average population absolute intrafraction CC offset in diaphragm and microcoil position relative to skeleton was 2.4 mm and 2.1 mm respectively; the average absolute interfraction CC offset was 5.2 mm. Analyses of repeat CT scans demonstrated that the average intrafraction excursion of the hepatic microcoils relative to the skeleton in the CC, AP, and ML directions was 1.9 mm, 0.6 mm, and 0.6 mm respectively and the average interfraction CC, AP, and ML excursion of the hepatic microcoils was 6.6 mm, 3.2 mm, and 3.3 mm respectively.
Conclusion: Radiotherapy using ABC for patients with intrahepatic cancer is feasible, with good intrafraction reproducibility of liver position using ABC. However, the interfraction reproducibility of organ position with ABC suggests the need for daily on-line imaging and repositioning if treatment margins smaller than those required for free breathing are a goal.
Yeast cytosine deaminase (yCD) is a well-characterized prodrug/enzyme system that converts 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU), and has been combined with oncolytic viruses. However, in ...vivo studies of the interactions between 5-FC bioactivation and viral replication have not been previously reported, nor have the kinetics of transgene expression and the pharmacokinetics of 5-FC and 5-FU. We constructed a replication-conditional Herpes simplex virus 1 (HSV-1) expressing yCD and examined cytotoxicity when 5-FC was initiated at different times after viral infection, and observed that earlier 5-FC administration led to greater cytotoxicity than later 5-FC administration in vitro and in vivo. In animal models, 12 days of 5-FC administration was superior to 6 days, but dosing beyond 12 days did not further enhance efficacy. Consistent with the dosing-schedule results, both viral genomic DNA copy number and viral titers were observed to peak on Day 3 after viral injection and gradually decrease thereafter. The virus is replication-conditional and was detected in tumors for as long as 2 weeks after viral injection. The maximum relative extent of yCD conversion of 5-FC to 5-FU in tumors was observed on Day 6 after viral injection and it decreased progressively thereafter. The observation that 5-FU generation within tumors did not lead to appreciable levels of systemic 5-FU (<10 ng ml⁻¹) is important and has not been previously reported. The approaches used in these studies of the relationship between the viral replication kinetics, transgene expression, prodrug administration and anti-tumor efficacy are useful in the design of clinical trials of armed, oncolytic viruses.
Purpose: CT-based models of the patient that do not account for the motion of ventilation may not accurately predict the shape and position of critical abdominal structures. Respiratory gating ...technology for imaging and treatment is not yet widely available. The purpose of the current study is to explore an intermediate step to improve the veracity of the patient model and reduce the treated volume by acquiring the CT data with the patients holding their breath at normal exhale.
Methods and Materials: The ventilatory time courses of diaphragm movement for 15 patients (with no special breathing instructions) were measured using digitized movies from the fluoroscope during simulation. A subsequent clinical protocol was developed for treatment based on exhale CT models. CT scans (typically 3.5-mm slice thickness) were acquired at normal exhale using a spiral scanner. The scan volume was divided into two to three segments, to allow the patient to breathe in between. Margins were placed about intrahepatic target volumes based on the ventilatory excursion inferior to the target, and on only the reproducibility of exhale position superior to the target.
Results: The average patient’s diaphragm remained within 25% of the range of ventilatory excursion from the average exhale position for 42% of the typical breathing cycle, and within 25% of the range from the average inhale position for 15% of the cycle. The reproducibility of exhale position over multiple breathing cycles was 0.9 mm (2σ), as opposed to 2.6 mm for inhale. Combining the variation of exhale position and the uncertainty in diaphragm position from CT slices led to typical margins of 10 mm superior to the target, and 19 mm inferior to the target, compared to margins of 19 mm in both directions under our prior protocol of margins based on free-breathing CT studies. For a typical intrahepatic target, these smaller volumes resulted in a 3.6% reduction in V
eff for the liver. Analysis of portal films shows proper target coverage for patients treated based on exhale modeled plans.
Conclusions: Modeling abdominal treatments at exhale, while not realizing all the gains of gated treatments, provides an immediate reduction in the volume of normal tissue treated, and improved reliability of patient data for NTCP modeling, when compared to current “free breathing” CT models of patients.
To evaluate the response, time to progression, survival, and impact of radiation (RT) dose on survival in patients with intrahepatic malignancies treated on a phase I trial of escalated focal liver ...RT.
From April 1996 to January 1998, 43 patients with unresectable intrahepatic hepatobiliary cancer (HB; 27 patients) and colorectal liver metastases (LM; 16 patients) were treated with high-dose conformal RT. The median tumor size was 10 x 10 x 8 cm. The median RT dose was 58.5 Gy (range, 28.5 to 90 Gy), 1.5 Gy twice daily, with concurrent continuous-infusion hepatic arterial fluorodeoxyuridine (0.2 mg/kg/d) during the first 4 weeks of RT.
The response rate in 25 assessable patients was 68% (16 partial and one complete response). With a median potential follow-up period of 26.5 months, the median times to progression for all tumors, LM, and HB were 6, 8, and 3 months, respectively. The median survival times of all patients, patients with LM, and patients with HB were 16, 18, and 11 months, respectively. On multivariate analyses, escalated RT dose was independently associated with improved progression-free and overall survival. The median survival of patients treated with 70 Gy or more has not yet been reached (16.4+ months), compared with 11.6 months in patients treated with lower RT doses (P =.0003).
The excellent response rate, prolonged intrahepatic control, and improved survival in patients treated with RT doses of 70 Gy or more motivate continuation of dose-escalation studies for patients with intrahepatic malignancies.
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