Prognostic Factors for Elderly Patients Treated with Stereotactic Body Radiation Therapy for Pancreatic Adenocarcinoma

Introduction: Pancreatic ductal adenocarcinoma (PDAC) commonly presents later in life with a median age at diagnosis of 70 years. Unfortunately, elderly patients are significantly underrepresented in clinical trials. Stereotactic body radiation therapy (SBRT) is a promising treatment modality in this population as it has demonstrated excellent local control with minimal toxicity. We aimed to determine prognostic factors associated with outcomes in elderly patients treated with SBRT. Materials and Methods: Elderly patients older than 70 treated with SBRT for PDAC at our institution, from 2004 to 2014 were included. Our primary endpoints included overall survival (OS) and local-progression-free survival (LPFS). Secondary endpoints included regional-progression-free survival (RPFS), distant-progression-free-survival (DPFS) and radiation toxicity. Endpoints were analyzed with the Kaplan-Meier method. The association of these survival endpoints with risk factors was studied with Cox proportional hazards models. Results: We identified 145 patients with 146 lesions of pancreatic adenocarcinoma with a median age at diagnosis of 79 (range, 70.1–90.3). SBRT was delivered to a median dose of 36 Gy (IQR 24–36). Surgical resection was performed on 33.8% of the total patients. Median follow-up was 12.3 months (IQR 6.0–23.3 months) and the median survival for the entire cohort 14.0 months with a 2-year OS of 27%. Multivariate analysis (MVA) demonstrated surgery [p ≤ 0.0001, HR 0.29 (95% CI, 0.16–0.51)] and post-SBRT CA19-9 [p = 0.009, HR 1.0004 (95% CI, 1.0002–1.0005)] significantly associated with overall survival. Recurrent lesions [p = 0.0069, HR 5.1 (95% CI, 1.56–16.64)] and post-SBRT CA19-9 levels [p = 0.0107, HR 1.0005 (95% CI, 1.0001–1.0008)] were significantly associated with local control on MVA. For the entire cohort, 4.1% experienced acute grade 2+ toxicity, and 2% experienced late grade 2+ toxicity at 2 years. Conclusion: This review demonstrates prognostic factors in elderly patients with PDAC treated with SBRT. We identified surgical resection and post-SBRT CA 19-9 as predictive of overall survival in this population. Additionally, we show low acute and late toxicity following SBRT in elderly patients

Initial Results of a Prospective Study of Adjuvant Pancreatic Stereotactic Body Radiation Therapy for Close or Positive Margins

Purpose: Patients with close or positive margins after surgery for pancreatic carcinoma are at a high risk for recurrence. Stereotactic body radiation therapy (SBRT) allows for safe dose escalation with great conformity and short duration of treatment. Herein, we report the initial results of a prospective observational study that evaluated the efficacy and safety of this treatment option. Methods and Materials: Patients eligible for the study had pathologically proven T1-4N0-1M0 pancreatic adenocarcinoma with a positive margin (≤ 1 mm) or a close margin defined as \u3c 2.5 mm. Patients were treated with either neoadjuvant or adjuvant chemotherapy, if eligible for systemic therapy. All patients received 36 Gy in 3 fractions to the close or positive margin site. Results: From February 2013 to January 2018, 50 patients were enrolled with 49 patients treated on protocol and included in the analysis. The median age was 71 years. The median clinical target volume was 11.3 cc and median planning target volume 22.0 cc. The median overall survival was 23.7 months (95% confidence interval, 13.6-33.8). Local progression-free survival at 1 and 2 years was 85% and 77%, respectively. Regional progression-free survival at 1 and 2 years was 73% and 73%, respectively. Distant metastases-free survival was 57% and 49% at 1 and 2 years, respectively. Grade 3+ radiation toxicity was only 4.1% and occurred in 2 patients. Conclusions: Adjuvant pancreatic SBRT was shown to be a safe and feasible treatment option for patients with high-risk pancreatic adenocarcinoma and close or positive margins. This is the first prospective study of SBRT in high-risk postoperative pancreatic cancer. Our results yielded significant local and regional control with low rates of acute toxicity. This technique does not interrupt the administration of systemically dosed multiagent chemotherapy and can be safely interdigitated between cycles because SBRT is only 1 week of treatment

Definitions of disease burden across the spectrum of metastatic castration-sensitive prostate cancer: comparison by disease outcomes and genomics

BACKGROUND: Several definitions have attempted to stratify metastatic castrate-sensitive prostate cancer (mCSPC) into low and high-volume states. However, at this time, comparison of these definitions is limited. Here we aim to compare definitions of metastatic volume in mCSPC with respect to clinical outcomes and mutational profiles. METHODS: We performed a retrospective review of patients with biochemically recurrent or mCSPC whose tumors underwent somatic targeted sequencing. 294 patients were included with median follow-up of 58.3 months. Patients were classified into low and high-volume disease per CHAARTED, STAMPEDE, and two numeric (≤3 and ≤5) definitions. Endpoints including radiographic progression-free survival (rPFS), time to development of castration resistance (tdCRPC), and overall survival (OS) were evaluated with Kaplan-Meier survival curves and log-rank test. The incidence of driver mutations between definitions were compared. RESULTS: Median OS and tdCRPC were shorter for high-volume than low-volume disease for all four definitions. In the majority of patients (84.7%) metastatic volume classification did not change across all four definitions. High volume disease was significantly associated with worse OS for all four definitions (CHAARTED: HR 2.89; p < 0.01, STAMPEDE: HR 3.82; p < 0.01, numeric ≤3: HR 4.67; p < 0.01, numeric ≤5: HR 3.76; p < 0.01) however, were similar for high (p = 0.95) and low volume (p = 0.79) disease across all four definitions. Those with discordant classification tended to have more aggressive clinical behavior and mutational profiles. Patients with low-volume disease and TP53 mutation experienced a more aggressive course with rPFS more closely mirroring high-volume disease. CONCLUSIONS: The spectrum of mCSPC was confirmed across four different metastatic definitions for clinical endpoints and genetics. All definitions were generally similar in classification of patients, outcomes, and genetic makeup. Given these findings, the simplicity of numerical definitions might be preferred, especially when integrating metastasis directed therapy. Incorporation of tumor genetics may allow further refinement of current metastatic definitions

Streaming birefringence as a hydrodynamic research tool

An optical system capable of providing precise pointwise measurements of streaming birefringence (SBR) was used to explore the flow of dilute solutions of tobacco mosaic virus between rotating eccentric cylinders. The local relationship between the observed optical anisotropy and the rate of strain tensor calculated from the theoretical solution for the particular flow field was studied. The relationship is apparently in accord with the conclusions of the orientation theory for a sufficiently dilute solution of rigid macromolecules in generalized two-dimensional flow. The general problem of using streaming birefringence of colloidal solutions to visualize two-dimensional laminar flows is considered. The conclusion is reached that a clear and unambiguous kinematic interpretation of SBR in such fluids is possible only for a restricted class of flows. If the flow is such that the angle between the streamline and the principal rate of strain axes is not less than 35°, then to a good approximation SBR can give the magnitude and direction of the principal strain rates. This information, it is shown, is sufficient to permit calculation of the entire velocity field if the velocity is known on all boundaries. In the most general flow situations, SBR of colloidal solutions cannot indicate the orientation of the rate of strain tensor. SBR in certain birefringent pure liquids may yield the necessary information even in the most general flows. These pure liquids hold promise of being valuable flow visualization agents

Enzymatic C(sp³)‑H Amination: P450-Catalyzed Conversion of Carbonazidates into Oxazolidinones

Cytochrome P450 enzymes can effectively promote the activation and cyclization of carbonazidate substrates to yield oxazolidinones via an intramolecular nitrene C–H insertion reaction. Investigation of the substrate scope shows that while benzylic/allylic C–H bonds are most readily aminated by these biocatalysts, stronger, secondary C–H bonds are also accessible to functionalization. Leveraging this “non-native” reactivity and assisted by fingerprint-based predictions, improved active-site variants of the bacterial P450 CYP102A1 could be identified to mediate the aminofunctionalization of two terpene natural products with high regio- and stereoselectivity. Mechanistic studies and KIE experiments show that the C–H activation step in these reactions is rate-limiting and proceeds in a stepwise manner, namely, via hydrogen atom abstraction followed by radical recombination. This study expands the reactivity scope of P450-based catalysts in the context of nitrene transfer transformations and provides first-time insights into the mechanism of P450-catalyzed C–H amination reactions

Применение метода акустической эмиссии при исследовании сверления композиционных материалов

Исследованы тенденции использования композиционных материалов в машиностроении. Описаны результаты экспериментальных исследований по сверлению заготовок из стеклопластика с измерением сигналов акустической эмиссии. Приведены результаты анализа качества обработанных отверстий и полученных сигналов акустической эмиссии.Досліджено тенденції використання композиційних матеріалів у машинобудуванні.Описано результати експериментальних досліджень зі свердління заготовок зі склопластика з вимірюванням сигналів акустичної емісії. Наведено результати аналізу якості оброблених отворів і отриманих сигналів акустичної емісії.In this article we have studied the trends in the use of composite materials in engineering, describes the results on the drilling of workpieces of fiberglass with the measurement of acoustic emission signals. Given the qualities of the analysis of the results obtained and processed holes acoustic emission signal

Table_6_Prognostic Factors for Elderly Patients Treated With Stereotactic Body Radiation Therapy for Pancreatic Adenocarcinoma.docx

<p>Introduction: Pancreatic ductal adenocarcinoma (PDAC) commonly presents later in life with a median age at diagnosis of 70 years. Unfortunately, elderly patients are significantly underrepresented in clinical trials. Stereotactic body radiation therapy (SBRT) is a promising treatment modality in this population as it has demonstrated excellent local control with minimal toxicity. We aimed to determine prognostic factors associated with outcomes in elderly patients treated with SBRT.</p><p>Materials and Methods: Elderly patients older than 70 treated with SBRT for PDAC at our institution, from 2004 to 2014 were included. Our primary endpoints included overall survival (OS) and local-progression-free survival (LPFS). Secondary endpoints included regional-progression-free survival (RPFS), distant-progression-free-survival (DPFS) and radiation toxicity. Endpoints were analyzed with the Kaplan-Meier method. The association of these survival endpoints with risk factors was studied with Cox proportional hazards models.</p><p>Results: We identified 145 patients with 146 lesions of pancreatic adenocarcinoma with a median age at diagnosis of 79 (range, 70.1–90.3). SBRT was delivered to a median dose of 36 Gy (IQR 24–36). Surgical resection was performed on 33.8% of the total patients. Median follow-up was 12.3 months (IQR 6.0–23.3 months) and the median survival for the entire cohort 14.0 months with a 2-year OS of 27%. Multivariate analysis (MVA) demonstrated surgery [p ≤ 0.0001, HR 0.29 (95% CI, 0.16–0.51)] and post-SBRT CA19-9 [p = 0.009, HR 1.0004 (95% CI, 1.0002–1.0005)] significantly associated with overall survival. Recurrent lesions [p = 0.0069, HR 5.1 (95% CI, 1.56–16.64)] and post-SBRT CA19-9 levels [p = 0.0107, HR 1.0005 (95% CI, 1.0001–1.0008)] were significantly associated with local control on MVA. For the entire cohort, 4.1% experienced acute grade 2+ toxicity, and 2% experienced late grade 2+ toxicity at 2 years.</p><p>Conclusion: This review demonstrates prognostic factors in elderly patients with PDAC treated with SBRT. We identified surgical resection and post-SBRT CA 19-9 as predictive of overall survival in this population. Additionally, we show low acute and late toxicity following SBRT in elderly patients.</p

One- vs. Three-Fraction Pancreatic Stereotactic Body Radiation Therapy for Pancreatic Carcinoma: Single Institution Retrospective Review

Background/introductionEarly reports of stereotactic body radiation therapy (SBRT) for pancreatic ductal adenocarcinoma (PDAC) used single fraction, but eventually shifted to multifraction regimens. We conducted a single institution review of our patients treated with single- or multifraction SBRT to determine whether any outcome differences existed.Methods and materialsPatients treated with SBRT in any setting for PDAC at our facility were included, from 2004 to 2014. Overall survival (OS), local control (LC), regional control (RC), distant metastasis (DM), and late grade 3 or greater radiation toxicities from the time of SBRT were calculated using Kaplan–Meier estimation to either the date of last follow-up/death or local/regional/distant failure.ResultsWe identified 289 patients (291 lesions) with pathologically confirmed PDAC. Median age was 69 (range, 33–90) years. Median gross tumor volume was 12.3 (8.6–21.3) cm3 and planning target volume 17.9 (12–27) cm3. Single fraction was used in 90 (30.9%) and multifraction in 201 (69.1%) lesions. At a median follow-up of 17.3 months (IQR 10.1–29.3 months), the median survival for the entire cohort 17.8 months with a 2-year OS of 35.3%. Univariate analysis showed multifraction schemes to have a higher 2-year OS 30.5% vs. 37.5% (p = 0.019), it did not hold significance on MVA. Multifractionation schemes were found to have a higher LC on MVA (HR = 0.53, 95% CI, 0.33–0.85, p = 0.009). At 2 years, late grade 3+ toxicity was 2.5%. Post-SBRT CA19-9 was found on MVA to be a prognostic factor for OS (HR = 1.01, 95% CI, 1.01–1.01, p = 0.009), RC (HR = 1.01, 95% CI 1.01–1.01, p = 0.02), and DM (HR = 1.01, 95% CI, 1.01–1.01, p = 0.001).ConclusionOur single institution retrospective review is the largest to date comparing single and multifraction SBRT and the first to show multifraction regimen SBRT to have a higher LC than single fractionation. Additionally, we show low rates of severe late toxicity with SBRT

Variable Clinical Expression in Patients with Mosaicism for KCNQ2 Mutations

International audienceMutations in the KCNQ2 gene, encoding a potassium channel subunit, were reported in patients presenting epileptic phenotypes of varying severity. Patients affected by benign familial neonatal epilepsy (BFNE) are at the milder end of the spectrum, they are affected by early onset epilepsy but their subsequent neurological development is usually normal. Mutations causing BFNE are often inherited from affected parents. Early infantile epileptic encephalopathy type 7 (EIEE7) is at the other end of the severity spectrum and, although EIEE7 patients have early onset epilepsy too, their neurological development is impaired and they will present motor and intellectual deficiency. EIEE7 mutations occur de novo. Electrophysiological experiments suggested a correlation between the type of mutation and the severity of the disease but intra and interfamilial heterogeneity exist. Here, we describe the identification of KCNQ2 mutation carriers who had children affected with a severe epileptic phenotype, and found that these individuals were mosaic for the KCNQ2 mutation. These findings have important consequences for genetic counseling and indicate that neurological development can be normal in the presence of somatic mosaicism for a KCNQ2 mutation