Daily Fractions Research Articles

METRIC Modeli ve Google Earth Engine Flux ile Hesaplanan Günlük Bitki Su Tüketimi ve Referans Bitki Su Tüketimi Fraksiyonu Değerlerinin Karşılaştırılması

Evapotranspirasyonun (ET) hassas bir biçimde belirlenmesi su kaynakları yönetiminde oldukça önemlidir. Son yıllarda ET’nin uzaktan algılama teknikleri yardımıyla belirlenmesinde çeşitli modeller geliştirilmiştir. Bu modeller arasında Evapotranspirasyon Haritalamasında Yüksek Çözünürlük ve İçsel Kalibrasyon Modeli (METRIC) en yaygın kullanılanlardan biridir. METRIC modelinde içsel kalibrasyon amacıyla ET’nin potansiyel seviyede ve ET’nin sıfır olduğu iki ekstrem koşulu temsilen seçimler yapılması gerekmektedir. Bu seçimleri hem uzaktan algılama hem de ET üzerine deneyimli kişilerin yapması gerekmektedir. Ancak bu durum METRIC modelinin kullanımını kısıtlamaktadır. Oluşan bu boşluğun doldurulması için Google Earth Engine platformunda Earth Engine Evapotranspiration Flux (EEFlux) uygulaması geliştirilmiştir. Bu uygulamayla METRIC modeli otomatik olarak kalibre edilmektedir. Bu çalışmanın amacı elle METRIC modeli ile EEFlux modelinden elde edilen günlük ET (ETd) ve Referans ET fraksiyonu (ETrF) değerlerinin karşılaştırılmasıdır. Çalışma Amasya ili Merzifon ilçesinde yer alan Uzunyazı, Çayırözü ve Yeşilören köylerindeki arpa, ayçiçeği, buğday, mısır, şeker pancarı, patates ve soğan yetiştiriciliği yapılan tarım alanlarında gerçekleştirilmiştir. Araştırmada üç farklı tarihe ait Landsat 8 uydu görüntüleri kullanılmıştır. Çalışmadan elde edilen sonuçlara göre METRIC ve EEFLUX ile hesaplanan ETd değerleri uyumlu olmasına rağmen (R2=0,87), genel olarak EEFlux-ETd değerleri METRIC-ETd değerlerinden daha düşük gerçekleşmiştir (RMSE=2,5 mm gün-1 ve MAE=2,38 mm gün-1). ETrF değerleri ise ETd değerlerine benzer uyumla hesaplanmıştır (R2=0,88, RMSE=0,11 ve MAE=0,09). Buna göre EEFLUX ve METRIC ile hesaplanan ETd ve ETrF değerleri arasında belirli farklılıklar olmasına rağmen, EEFLUX ile oldukça hızlı, yerel iklim verileri ve deneyimli bir kullanıcı ihtiyacı olmadan ETd değerleri belirlenebilmektedir.

Pencil-beam scanning proton therapy for the treatment of glomus jugulare tumours.

Glomus jugulare tumours (GJT) are benign tumours that arise locally and destructively in the base of the skull and can be successfully treated with radiotherapy. Patients have a long-life expectancy and the late effects of radiotherapy can be serious. Proton radiotherapy reduces doses to critical organs and can reduce late side effects of radiotherapy. The aim of this study was to report feasibility and early clinical results of 12 patients treated using proton therapy. Between December 2013 and June 2019, 12 patients (pts) with GJT (median volume 20.4 cm3 ; range 8.5-41 cm3 ) were treated with intensity modulated proton therapy (IMPT). Median dose was 54 GyE (Gray Equivalents) (50-60 GyE) with daily fractions of 2 GyE. Twelve patients were analysed with a median follow-up time of 42.2 months (11.3-86.7). Feasibility, dosimetric parameters, acute and late toxicity and local effect on tumour were evaluated in this retrospective study. All patients finished treatment without interruption, with excellent dosimetric parameters and mild acute toxicity. Stabilisation of tumour size was detected on MRI in all patients. No changes in symptoms were observed in comparison with pre-treatment conditions. No late effects of radiotherapy were observed. Pencil-beam scanning proton radiotherapy is highly feasible in the treatment of large GJT with mild acute toxicity and promising short-term results. Longer follow-up and larger patient cohorts are required to further identify the role of pencil-beam scanning (PBS) for this indication.

Pilot study evaluating the tolerability of a 3Gy × 10 daily fraction 3D-conformal palliative radiation therapy protocol plus toceranib for the treatment of measurable carcinomas in the dog.

The use of radiation therapy in conjunction with small molecule inhibitors is an appealing treatment combination for non-resectable carcinomas, which tend to be locally invasive with variable risk of locoregional metastasis. This prospective, pilot study aimed to evaluate the tolerability and adverse event profile of concurrent toceranib and palliative-intent radiation therapy (PRT) in dogs with measurable carcinoma and to secondarily evaluate short-term measurable tumor response. Fifteen dogs with measurable carcinoma received toceranib and 3D-conformal PRT in 3Gy/fraction for 10 daily fractions. Adverse events were graded using standard schemes and tolerability was followed via quality-of-life questionnaires during the 12-week treatment period. Thirteen dogs (87%) experienced acute radiation toxicity, graded as severe in three dogs. All dogs experienced toceranib toxicity, graded as severe in one dog. Seven dogs (47%) completed the 12-week study protocol; four were withdrawn due to toxicity and/or associated poor quality of life and four developed progressive disease. Based on these preliminary results, this 3D-conformal chemoradiation protocol should be considered with caution and only with proper owner education on potential toxicity. More conformal treatment planning techniques or alternative protocols should be investigated for improved tolerability.

Detecting Streamflow in Dryland Rivers Using CubeSats.

Determining the flow regime of non‐perennial rivers is critical in hydrology. In this study, we developed a new approach using CubeSat imagery to detect streamflow presence using differences in surface reflectance for areas within and outside of a river reach. We calibrated the approach with streamflow records in the Hassayampa River of Arizona over 3 years (2019–2021), finding good agreement in the annual fractions of flowing days at stream gages (R 2 = 0.82, p < 0.0001). Subsequently, annual fractions of flowing days were derived at 90 m intervals along the Hassayampa River, finding that 12% of reaches were classified as intermittent, with the remaining as ephemeral. Using a Hovmöller diagram, streamflow presence was visualized in unprecedented spatiotemporal detail, allowing estimates of daily fraction of flowing channel and annual fractions of flowing days. This new tool opens avenues for detecting streamflow and studying hydrological and biogeochemical processes dependent on water presence in drylands.

Efficacy of Thymosin α1 in Management of Radiation Pneumonitis in Patients With Locally Advanced Non-Small Cell Lung Cancer Treated With Concurrent Chemoradiotherapy: A Phase 2 Clinical Trial (GASTO-1043)

To evaluate the efficacy of thymosin α1 in management of radiation pneumonitis (RP) in patients with locally advanced non-small cell lung cancer (LANSCLC) treated with concurrent chemoradiotherapy (CCRT). This phase 2, single-arm trial enrolled patients with unresectable LANSCLC of 18 to 75 years' old and an Eastern Cooperative Oncology Group performance status of 0 to 1. Eligible patients received definitive CCRT and weekly thymosin α1 from the start of CCRT until 2 months after CCRT. Patients were administered 51 Gy in 17 daily fractions or 40 Gy in 10 daily fractions in the first course followed by a re-evaluation and those patients without disease progression had an adaptive plan of 15 Gy in 5 daily fractions or 24 Gy in 6 daily fractions as a boost. Concurrent chemotherapy consisted of weekly docetaxel (25 mg/m2) and nedaplatin (25 mg/m2) during radiation therapy. The primary endpoint was the incidence of Grade (G) ≥2 RP. Secondary endpoints included the incidence of late pulmonary fibrosis, total lymphocyte count (TLC), serum C-reactive protein (CRP) levels, and the composition of gut microbiota. TLC and CRP data were collected at baseline, 2 to 3 weeks during CCRT, the end of CCRT, 2 and 6 months after CCRT. Fecal samples were collected at baseline and the end of CCRT. Patients treated with CCRT but without thymosin α1 intervention during the same period were selected as the control group by the propensity score matching method. Sixty-nine patients were enrolled in the study, and another 69 patients were selected as the control group. The incidence of G≥2 RP was lower in the study group compared with control cases (36.2% vs 53.6%, P=.040). G1 late pulmonary fibrosis occurred in 2 (3.7%) patients of the control group compared with no event in the study group (P=.243). Compared with the control group, the incidence of G3 to G4 lymphopenia (19.1% vs 62.1%, P < .001) was lower, and the median TLC nadir (0.51 k/µL vs 0.30 k/µL, P < .001) was higher in the study group. The proportion of patients with maximum CRP ≥100 mg/L was lower in the study group (13.8% vs 29.7% P=.029). The diversity and community composition of the gut microbiota were not significantly different between the 2 groups. Administration of thymosin α1 during and after CCRT was associated with significant reductions in G≥2 RP and G3 to G4 lymphopenia in patients with LANSCLC compared with historic controls.

A Phase 1 Trial of Highly Conformal, Hypofractionated Postprostatectomy Radiation Therapy

PurposeThis phase 1 trial aimed to identify the maximally tolerated hypofractionated dose schedule for postoperative radiation therapy (PORT) after radical prostatectomy. Secondary objectives included biochemical control and quality of life (QoL) measures. Methods and MaterialsPatients were treated on 1 of 3 dose levels (DLs): 56.4 Gy in 20 fractions (DL1), 51.2 Gy in 15 fractions (DL2), and 44.2 Gy in 10 fractions (DL3). Treatment was delivered to the prostate bed without pelvic nodal irradiation. Dose escalation followed a standard 3 + 3 design with an expansion for 6 additional patients at the maximally tolerated hypofractionated dose schedule. Acute dose-limiting toxicity (DLT) was defined as grade 3 toxicity lasting >4 days within 21 days of PORT completion; late DLT was defined as grade 4 gastrointestinal (GI) or genitourinary (GU) toxicity. ResultsBetween January 2018 and August 2019, 15 patients underwent radiation treatment: 3 on DL1, 3 on DL2, and 9 on DL3. The median follow-up was 24 months. There were no DLTs, and the maximally tolerated hypofractionated dose schedule was identified as DL3. Two of the 15 patients (13.3%) experienced biochemical failure (prostate-specific antigen >0.1). Ten of 15 patients (67%) had grade 2+ acute toxicities, consisting of transient GI toxicities. Three patients experienced late grade 2+ GI toxicity, and 5 patients experienced late grade 2+ GU toxicity. Late grade 3 GU toxicity occurred in 2 patients. There were no grade 4+ acute or late toxicities. There were no significant differences in GI measures of QoL, however, there was an increase in GU symptoms and corresponding decrease in GU QoL between 12 and 24 months. ConclusionsThe maximum tolerated hypofractionated dose schedule for hypofractionated PORT to the prostate bed was determined to be 44.2 Gy in 10 daily fractions. The most frequent clinically significant toxicities were late grade 2+ GU toxicities, which corresponded to a worsening of late GU QoL.

Feasibility and Short-Term Toxicity of a Consecutively Delivered Five Fraction Stereotactic Body Radiation Therapy Regimen in Early-Stage Breast Cancer Patients Receiving Partial Breast Irradiation.

BackgroundFor appropriately selected patients with early-stage breast cancer (ESBC), accelerated partial breast irradiation (APBI) yields equivalent rates of ipsilateral breast tumor recurrence with mixed results in patient-rated cosmesis compared with whole-breast radiotherapy depending on the technique utilized. When utilizing external beam radiotherapy for APBI, techniques to reduce target margins and overall treatment volume are potentially important to decrease rates of long-term adverse cosmesis. Stereotactic body radiotherapy (SBRT) is a promising technique to deliver APBI because of its increased accuracy and sparing of uninvolved breast tissue. We report the initial results of a prospective clinical trial investigating feasibility, safety, and cosmetic outcomes of a daily five-fraction SBRT regimen for APBI.MethodsTwenty-three patients with ESBC after lumpectomy who met APBI suitability were enrolled. During lumpectomy, a bioabsorbable three-dimensional fixed array tissue marker (BioZorb™, Hologic, Marlborough, MA) was placed for enhanced visualization of the cavity boundaries. Clinical target volume (CTV) was defined as the delineable cavity plus a 1-cm isotropic expansion followed by a 3-mm isotropic planning target volume (PTV) expansion. Patients received 30 Gy delivered in five planned consecutive daily fractions in either prone or supine positioning depending on individual anatomy. Two patients completed the five-fraction treatments in 9-day interval and 11-day interval due to external circumstances. A maximum PTV of 124cc was allowed to minimize incidence of fat necrosis. Plans utilized 10-MV flattening filter–free beams delivered on a Varian Edge linear accelerator. Local control, toxicity, and nurse/patient-scored cosmesis at pre-treatment baseline, 1 month post-treatment, and at subsequent 6-month intervals were recorded.ResultsTwenty-three patients were accrued at the time of submission with median follow-up of 6 months. No patients experienced grade ≥3 acute toxicity. Of the 10 events reported probably related to SBRT, nine were grade 1 (n = 9/10, 90%). There was no evidence of difference, deterioration, or change in patient or nurse-scored cosmesis from baseline to 1 and 6 months post-treatment. One patient developed nodal failure shortly after APBI.ConclusionsAlthough longer follow-up is needed to assess long-term toxicity and local control, this study demonstrated a five-fraction SBRT regimen delivered over consecutive days is a safe, efficient, well-tolerated, and cosmetically favorable means of delivering APBI in suitable women.Clinical Trial Registrationhttps://www.clinicaltrials.gov/ct2/show/NCT03643861, NCT03643861.

64-Year-Old Woman With Aphasia and Troponin Elevation

64-Year-Old Woman With Aphasia and Troponin Elevation

Abstract 207: MET inhibition enhances the effect of radiation in MET mutated non-small cell lung cancer brain metastasis patient derived xenografts

Abstract Objective: The MET receptor is mutated in 3-4% and amplified in 1-6% of patients with non-small cell lung cancer. The most common MET mutation is in exon 14, which results in deletion of the intracellular juxtamembrane domain of the receptor, leading to enhanced signaling. Mutation at Asp-1000 in the juxtamembrane region has also been reported and can lead to inhibition of apoptosis and cell proliferation. MET is involved in multiple pathways associated with radiation response. Therefore, we investigated the effects of inhibiting MET in combination with radiation in two preclinical non-small cell lung cancer (NSCLC) brain metastasis patient derived xenograft (PDX) models. Methods: Surgically obtained tissue was implanted subcutaneously into immunodeficient mice. Histology and DNA loci were compared between original tumor and PDX. DNA sequencing was performed on tumors for mutation analysis. In vivo growth responses to the MET inhibitor capmatinib or savolitinib with and without radiation were assessed. Radiation was delivered in 10 daily fractions of 2 Gy. Drug was administered by oral gavage daily 1 hour prior to radiation at a dose of 2.5 mg/kg for savaolitnib or 20 mg/kg for capmatinib for 10 days. Immunohistochemistry (IHC) was performed to evaluate MET signaling and proliferation. Results: PDXs were successfully established from two patients with MET mutated NSCLC brain metastases: a lung adenocarcinoma with a MET exon 14 skipping mutation and a lung sarcomatoid carcinoma with adenocarcinoma component with an Asp-1000 frameshift mutation. Morphologically, strong retention of cytoarchitectural features was observed between original patient tumors and PDXs. Short tandem repeat analysis confirmed 100% matching of alleles between patient tumors and PDXs. DNA sequencing confirmed METex14 and MET Asp-1000 frameshift mutation. In the METex14 PDX, savolitinib alone significantly inhibited tumor growth with a growth inhibition value of 46% (p&amp;lt;0.01). Combination of savolitinib and radiation significantly delayed growth compared to vehicle control, savolitinib alone or radiation alone (p&amp;lt;0.001). The absolute growth delay was 42.4 days for savolitinib plus radiation treatment compared to 9.3 days for savolitinib alone and 28.2 days for irradiation. In the MET Asp-1000 PDX, capmatinib and radiation significantly delayed growth compared the other treatment arms (p&amp;lt;0.01). IHC demonstrated inhibition of phospho-MET and pS6 and a decrease in Ki67 with MET inhibition. Conclusion: Inhibition of MET enhanced the effect of radiation in our two preclinical in vivo MET mutated NSCLC brain metastasis models. Additional studies are currently underway evaluating the mechanisms of radiation sensitization and the efficacy of this combination in MET amplified PDX models. Citation Format: Kwangok P. Nickel, Shrey Ramesh, Saahil Javeri, Nitin Somasundaram, Nan Sethakorn, Randall J. Kimple, Andrew M. Baschnagel. MET inhibition enhances the effect of radiation in MET mutated non-small cell lung cancer brain metastasis patient derived xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 207.

Role of Radiation in the treatment of Cushing Disease.

In Cushing disease (CD), radiation therapy (RT) is mostly used in the adjuvant setting in patients who have failed transsphenoidal surgery or have recurrent CD. Stereotactic radiotherapy (SRT) is administered as either single or several sessions, and the most commonly used modalities include photon source (Gamma Knife, CyberKnife, and LINAC) or heavy particles (protons). In multicenter studies, Gamma Knife SRT can lead to biochemical control in 80%, with medial time to remission approximately 15 mos, and 70% recurrence free at 10 years. Conventional RT (CRT) consists of administration of small daily fractions over six weeks, with cumulative dose of 45-50Gy. Biochemical control is achieved in up to 64% of patients with CRT. Choice of radiation modality includes convenience for patients (SRT is more convenient) and proximity to critical structures. Both forms of RT can result in hypopituitarism. RT remains an important modality for the treatment of patients with CD.

A randomized phase II study of anlotinib combined with STUPP versus STUPP alone in patients with newly diagnosed glioblastoma (GBM).

TPS2079 Background: Postoperative with radiotherapy, and concomitant and up to 6 cycles of maintenance temozolomide (TMZ) chemotherapy (STUPP regimen) is now the standard treatment for newly diagnosed GBM, while the effectiveness is limited. Anlotinib is a novel, multi-kinase inhibitor against both tumor angiogenesis and tumor cell proliferation with encouraging findings in preclinical GBM models. Our previous single-arm study (NCT04119674) showed that the addition of anlotinb to STUPP exhibited promising progression-free survival (PFS) in patients with GBM. Therefore, a phase II trial was designed to assessed the efficacy and safety of anlotinib with the STUPP regimen. Methods: This is a multicenter, randomized, controlled, phase II superiority trial. Approximately 150 patients will be randomly assigned 1:1 to receive TMZ-based radiochemotherapy with anlotinib or TMZ-based radiochemotherapy with placebo. All patients will receive radiotherapy (fractionated focal irradiation in daily fractions of 1.8–2.0 Gy given 5 days per week for 6 weeks, for a total of 54–60 Gy) concurrently with TMZ (75 mg/m2 QD) and anlotinib (10 mg QD, d1–14/3wks) or placebo. Anlotinib or placebo is administrated during the 28-day treatment break. Adjuvant therapy start four weeks after radiotherapy completion, including six cycles of TMZ (150–200mg/m2, d1–5/4wks) and eight cycles of anlotinib (10 mg QD, d1–14/3wks) or placebo. Patients who complete adjuvant therapy are administrated anlotinib or placebo continuously until the disease progressed or unacceptable toxic effects developed. Eligibility criteria include histologically confirmed newly diagnosed GBM and a World Health Organization (WHO) performance status ≤ 2. Additional inclusion criteria include patients between 18 and 75 years old with adequate wound healing of craniotomy or biopsy; adequate hematologic, hepatic, and renal function; acceptable blood coagulation levels; and the stable or decreasing usage of glucocorticoid doses within 5 days before randomization. Exclusion criteria include potentially fatal intracranial hemorrhage on magnetic resonance imaging (MRI); tumors located only in the brainstem; prior chemotherapy or radiotherapy administered for GBM; and IDH1/2 mutation. The primary objective of this study is to compare PFS accessed by Independent Review Committee in patients receiving anlotinib in addition to standard treatment with patients receiving standard treatment only. Secondary endpoints include overall survival (OS), PFS accessed by investigators, overall response rate (ORR), severity and frequency of AEs (CTCAE V5.0), and quality of life (QOL). The disease control rate (DCR) and duration of response (DOR) will also be explored. Clinical trial information: NCT04959500. Research Sponsor: Chia Tai Tianqing Pharmaceutical Group Co., Ltd .

The Selective Personalized Radio-immunotherapy for Locally Advanced NSCLC Trial (SPRINT): Initial results.

8510 Background: Standard therapy for unresectable locally advanced non-small cell lung cancer (LA-NSCLC) is concurrent chemoradiotherapy followed by adjuvant durvalumab. We performed a prospective trial testing sequential pembrolizumab and risk-adapted radiotherapy without chemotherapy for biomarker-selected LA-NSCLC patients. Methods: Patients with stage III NSCLC or unresectable stage II NSCLC, ECOG performance status 0-1, and no contraindications to protocol-specified therapy were eligible for this trial. Subjects with PD-L1 tumor proportion score (TPS) ≥ 50% underwent baseline FDG-PET/CT, received three cycles of induction pembrolizumab (200 mg, every 21 days), underwent restaging FDG-PET/CT, received risk-adapted thoracic radiotherapy (55 Gy delivered to tumors or lymph nodes with metabolic tumor volume exceeding 20 cc and 48 Gy delivered to smaller lesions, all in 20 daily fractions), and then received up to 13 cycles of additional pembrolizumab. The primary study endpoint was one-year progression-free survival (PFS). Here we report response rates following induction pembrolizumab, PFS and overall survival (OS) rates, and adverse event rates (CTCAE v. 4.03). Results: Twenty-five subjects with PD-L1 TPS ≥ 50% from three institutions were enrolled between August 2018 and November 2021. Median age was 71 (interquartile range [IQR] 62 to 77). One subject had stage II disease, 13 had stage IIIA disease, nine had stage IIIB disease, and two had stage IIIC disease. Median PD-L1 TPS was 75% (IQR 60 to 80%). Two subjects (8%) developed disease progression during induction pembrolizumab, and two subjects discontinued pembrolizumab after one infusion due to immune-related adverse events. Using RECIST 1.1 criteria, 12 subjects (48%) exhibited a partial (n = 11) or complete (n = 1) response following induction pembrolizumab on CT. Using PERCIST criteria, 12 subjects (48%) exhibited a partial response following induction pembrolizumab on PET. Four subjects had responses on PET but not on CT, and four had responses on CT but not on PET. With a median follow-up duration of 13 months, the actuarial 1-year PFS rate is 74%, and the actuarial 1-year OS rate is 95%. Grade 3 adverse events have been limited to single cases of anemia, arthritis, diarrhea, esophagitis, and pneumonitis, and no grade 4-5 adverse events have occurred. Exploratory analyses suggest that response to induction pembrolizumab on PET predicts efficacy of this treatment approach, with a 1-year PFS rate of 100% for responders, compared to 61% for non-responders (logrank p = 0.007). Conclusions: Treatment with pembrolizumab and risk-adapted radiotherapy is a promising treatment approach for LA-NSCLC patients with PD-L1 TPS ≥ 50%. Response on PET following induction pembrolizumab may be useful for identifying patients who can be treated successfully without chemotherapy. Clinical trial information: NCT03523702.

Successful management of Australian patients with extensive skin field cancerization (ESFC) with widefield volumetric arc radiation therapy (VMAT): Report with 12-month follow-up.

9582 Background: Non-melanomatous skin cancer (NMSC) diagnoses are associated with a high risk of developing new skin cancers in adjacent areas. Patients with extensive skin field cancerization (ESFC) have large areas (generally ≥50cm2) of compromised skin characterized by pre-cancerous actinic keratoses often requiring repeated interventions. Lesion-directed therapies have excellent cure rates, but therapies targeting a wider region have limited durability, including topical agents such as 5-flurouracil. The development of volumetric modulated arc radiation therapy (VMAT) to precisely target large, curved skin surfaces has generated interest in its application to ESFC. This is a report on the efficacy, safety, and cosmetic outcomes of VMAT in the management of patients with ESFC at facilities across five Australian states. Methods: Sixty-three ESFC zones on 60 patients were prescribed widefield VMAT and prospectively enrolled in the National (Australian) Dermatology Radiation Oncology Registry (NDROR). Over 80% of patients had received up to 4 prior non-radiotherapy interventions. Fields included lower and upper limb, face, scalp, or trunk regions. Total widefield VMAT RT doses ranged from 45-50 Gy delivered in 25-30 daily fractions across 5-7 weeks. 3-, 6-, and 12-month follow-up assessments rated the percentage of disease clearance, cosmesis using the Lovett’s scale, and toxicity based on CTCAE. Results: At 12-month follow-up, 97% of treated zones had achieved and maintained clinical success, defined as &gt; 90% field clearance. Five percent of patients exhibited recurrence of original disease, whereas 10% of patients developed a new actinic keratosis or NMSC. Cosmesis was rated as excellent or good in 98% of patients. Most patients exhibited grade 1-2 radiation-induced dermatitis during therapy, which resolved by 3-month follow-up. Grade 3 dermatitis at end of treatment was exhibited in 7% of the patients, which also resolved. Eight percent of patients discontinued treatment due to acute toxicities. The most common persistent toxicity at 12-month follow-up was localized grade 1 xerosis (dryness) at 43% and/or alopecia at 33%. Conclusions: Widefield VMAT achieved very promising clinical success in patients with ESFC for whom other therapies had failed. VMAT yielded favorable cosmetic outcomes, and treatment-related toxicity was manageable and transient in most patients. While additional follow up is necessary, these results demonstrate that widefield VMAT may be an excellent option for some patients with increasingly unmanageable presentations of ESFC.

ChemoTherapy aNd chemoradioTherapy for adenocarcinoma of the OESophagus and esophagogastric junction with oligometastases: Protocol of the TNT-OES-1 trial

BackgroundFLOT and CROSS are effective neoadjuvant regimens for esophageal cancer patients. Chemotherapy (FLOT) is aimed to have merely a systemic effect whereas neoadjuvant chemoradiotherapy (CROSS) achieves good locoregional response with clinically complete response (cCR) rates up to 33% [1]. The aim of the present study is to assess safety and feasibility of dual therapy (FLOT-CROSS) in patients with oligometastases. MethodsThis phase-II single-center, single-arm, intervention study includes patients with oligometastatic adenocarcinoma of the esophagus or esophagogastric junction. Patients will be treated with four biweekly cycles of FLOT, consisting of intravenous fluorouracil (2600 mg/m2), leucovorin (200 mg/m2), oxaliplatin (85 mg/m2) and docetaxel (50 mg/m2). Response evaluation by CT-scan will be performed 4–6 weeks after completion of FLOT. In case of regression or stable disease according to RECIST criteria (v.1.1), patients will receive additional CROSS, consisting of five weekly cycles of intravenous carboplatin (AUC 2) and paclitaxel (50 mg/m2), with concurrent 41.4 Gy radiotherapy, in 23 daily fractions of 1.8 Gy [2]. Response evaluation by endoscopy with biopsies, endoscopic ultrasonography and CT-scan will be performed 4–6 weeks after completion of CROSS. Primary endpoint is tolerability of FLOT-CROSS, defined as the proportion of patients who complete the full regimen. Secondary endpoints include disease control rate, objective response rate, overall survival and progression-free survival. In total, 20 patients will be included. DiscussionIf patients are able to complete and tolerate FLOT-CROSS, this regimen should be tested in a phase-III trial and as neoadjuvant treatment in patients with locally advanced non-metastatic esophageal or junctional adenocarcinoma.

Early Drug-Induced Liver Injury Risk Screening: “Free,” as Good as It Gets

Abstract For all the promise of and need for clinical drug-induced liver injury (DILI) risk screening systems, demonstrating the predictive value of these systems versus readily available physicochemical properties and inherent dosing information has not been thoroughly evaluated. Therefore, we utilized a systematic approach to evaluate the predictive value of in vitro safety assays including bile salt export pump transporter inhibition and cytotoxicity in HepG2 and transformed human liver epithelial along with physicochemical properties. We also evaluated the predictive value of in vitro ADME assays including hepatic partition coefficient (Kp) and its unbound counterpart because they provide insight on hepatic accumulation potential. The datasets comprised of 569 marketed drugs with FDA DILIrank annotation (most vs less/none), dose and physicochemical information, 384 drugs with Kp and plasma protein binding data, and 279 drugs with safety assay data. For each dataset and combination of input parameters, we developed random forest machine learning models and measured model performance using the receiver operator characteristic area under the curve (ROC AUC). The median ROC AUC across the various data and parameters sets ranged from 0.67 to 0.77 with little evidence of additive predictivity when including safety or ADME assay data. Subsequent machine learning models consistently demonstrated daily dose, fraction sp3 or ionization, and cLogP/D inputs produced the best, simplest model for predicting clinical DILI risk with an ROC AUC of 0.75. This systematic framework should be used for future assay predictive value assessments and highlights the need for continued improvements to clinical DILI risk annotation.

Lung Inflammation Predictors in Combined Immune Checkpoint-Inhibitor and Radiation Therapy-Proof-of-Concept Animal Study.

Purpose: Combined radiotherapy (RT) and immune checkpoint-inhibitor (ICI) therapy can act synergistically to enhance tumor response beyond what either treatment can achieve alone. Alongside the revolutionary impact of ICIs on cancer therapy, life-threatening potential side effects, such as checkpoint-inhibitor-induced (CIP) pneumonitis, remain underreported and unpredictable. In this preclinical study, we hypothesized that routinely collected data such as imaging, blood counts, and blood cytokine levels can be utilized to build a model that predicts lung inflammation associated with combined RT/ICI therapy. Materials and Methods: This proof-of-concept investigational work was performed on Lewis lung carcinoma in a syngeneic murine model. Nineteen mice were used, four as untreated controls and the rest subjected to RT/ICI therapy. Tumors were implanted subcutaneously in both flanks and upon reaching volumes of ~200 mm3 the animals were imaged with both CT and MRI and blood was collected. Quantitative radiomics features were extracted from imaging of both lungs. The animals then received RT to the right flank tumor only with a regimen of three 8 Gy fractions (one fraction per day over 3 days) with PD-1 inhibitor administration delivered intraperitoneally after each daily RT fraction. Tumor volume evolution was followed until tumors reached the maximum size allowed by the Institutional Animal Care and Use Committee (IACUC). The animals were sacrificed, and lung tissues harvested for immunohistochemistry evaluation. Tissue biomarkers of lung inflammation (CD45) were tallied, and binary logistic regression analyses were performed to create models predictive of lung inflammation, incorporating pretreatment CT/MRI radiomics, blood counts, and blood cytokines. Results: The treated animal cohort was dichotomized by the median value of CD45 infiltration in the lungs. Four pretreatment radiomics features (3 CT features and 1 MRI feature) together with pre-treatment neutrophil-to-lymphocyte (NLR) ratio and pre-treatment granulocyte-macrophage colony-stimulating factor (GM-CSF) level correlated with dichotomized CD45 infiltration. Predictive models were created by combining radiomics with NLR and GM-CSF. Receiver operating characteristic (ROC) analyses of two-fold internal cross-validation indicated that the predictive model incorporating MR radiomics had an average area under the curve (AUC) of 0.834, while the model incorporating CT radiomics had an AUC of 0.787. Conclusions: Model building using quantitative imaging data, blood counts, and blood cytokines resulted in lung inflammation prediction models justifying the study hypothesis. The models yielded very-good-to-excellent AUCs of more than 0.78 on internal cross-validation analyses.

Deep Learning for Per-Fraction Automatic Segmentation of Gross Tumor Volume (GTV) and Organs at Risk (OARs) in Adaptive Radiotherapy of Cervical Cancer.

Background/HypothesisMRI-guided online adaptive radiotherapy (MRI-g-OART) improves target coverage and organs-at-risk (OARs) sparing in radiation therapy (RT). For patients with locally advanced cervical cancer (LACC) undergoing RT, changes in bladder and rectal filling contribute to large inter-fraction target volume motion. We hypothesized that deep learning (DL) convolutional neural networks (CNN) can be trained to accurately segment gross tumor volume (GTV) and OARs both in planning and daily fractions’ MRI scans.Materials/MethodsWe utilized planning and daily treatment fraction setup (RT-Fr) MRIs from LACC patients, treated with stereotactic body RT to a dose of 45-54 Gy in 25 fractions. Nine structures were manually contoured. MASK R-CNN network was trained and tested under three scenarios: (i) Leave-one-out (LOO), using the planning images of N- 1 patients for training; (ii) the same network, tested on the RT-Fr MRIs of the “left-out” patient, (iii) including the planning MRI of the “left-out” patient as an additional training sample, and tested on RT-Fr MRIs. The network performance was evaluated using the Dice Similarity Coefficient (DSC) and Hausdorff distances. The association between the structures’ volume and corresponding DSCs was investigated using Pearson’s Correlation Coefficient, r.ResultsMRIs from fifteen LACC patients were analyzed. In the LOO scenario the DSC for Rectum, Femur, and Bladder was >0.8, followed by the GTV, Uterus, Mesorectum and Parametrium (0.6-0.7). The results for Vagina and Sigmoid were suboptimal. The performance of the network was similar for most organs when tested on RT-Fr MRI. Including the planning MRI in the training did not improve the segmentation of the RT-Fr MRI. There was a significant correlation between the average organ volume and the corresponding DSC (r = 0.759, p = 0.018).ConclusionWe have established a robust workflow for training MASK R-CNN to automatically segment GTV and OARs in MRI-g-OART of LACC. Albeit the small number of patients in this pilot project, the network was trained to successfully identify several structures while challenges remain, especially in relatively small organs. With the increase of the LACC cases, the performance of the network will improve. A robust auto-contouring tool would improve workflow efficiency and patient tolerance of the OART process.

Epidemiology and outcomes of ventilator-associated events in critically ill children: Evaluation of three different definitions.

Ventilator-associated pneumonia (VAP) is one of the most common healthcare-associated infections in pediatric intensive care units (PICUs), but its definite diagnosis remains controversial. The CDC Ventilator-Associated Event (VAE) module (validated in adults) constitutes a new approach for VAP surveillance. We described epidemiological characteristics of PICU VAE cases, investigated possible risk factors, and evaluated 3 different sets of diagnostic VAE criteria. This study was conducted in a PICU in a tertiary-care general hospital in northern Greece during 2017-2019. The study included patients aged 35 days-16 years who received mechanical ventilation. From medical records, we retrieved epidemiological data, clinical data, and laboratory characteristics as well as ventilator settings for our analysis. We assessed "oxygen deterioration" for the tier 1 CDC VAE module using 3 sets of diagnostic criteria: (1) CDC adult VAE criteria [increase of daily minimum fraction of inspired oxygen (FiO2) ≥ 0.2 or positive end expiratory pressure (PEEP) ≥ 3 cmH2O for 2 days], (2) the US pediatric VAE criteria [increase of FiO2 ≥ 0.25 or mean airway pressure (MAP) ≥ 4 cmH2O for 2 days], and (3) the European pediatric VAE criteria (increase of FiO2 ≥ 0.2 or PEEP ≥ 2 cmH2O for 1 day or increase of FiO2 ≥ 0.15 and PEEP ≥ 1 cm H2O for 1 day). Among 326 children admitted to the PICU, 301 received mechanical ventilation. The incidence rate according to the CDC adult VAE criteria was 4.7 per 1,000 ventilator days. For the US pediatric VAE criteria the incidence rate was 6 per 1,000 ventilator days. For the European pediatric VAE criteria the incidence rate was 9.7 per 1,000 ventilator days. These results revealed statistically significant correlation of all 3 algorithms with adverse outcomes, including mortality. All VAE algorithms were associated with higher mortality rates. Our findings highlight the need for a unified pediatric VAE definition to improve preventive strategies.

Radiation Therapy for Prostate Cancer Using HYpofractionation Directed by UltraSound (RAPHYDUS): A Brazilian Public Health Care System Study

PurposeThis study evaluated the toxicity associated with a short course dose-escalated hypofractionated radiation therapy (HFRT) using image guided RT with or without androgen suppression therapy in patients with prostate cancer. Methods and MaterialsThis single-center prospective observational study included 132 patients with prostate cancer from 2016 to 2020. Patients received HFRT using image guided RT (84%) with 3-dimensional (91%) or intensity modulated RT (9%). Total prescribed doses were 66 Gy (63%), 63 Gy (12%), and 60 Gy (24%) in 22, 21, or 20 daily fractions depending on organ-at-risk dose constraints. Acute toxicity was scored using Radiation Therapy Oncology Group criteria and the international prostate symptom index. The expanded prostate cancer index composite questionnaire was used to collect quality of life data (ranging from 0-100). ResultsThe study population consisted of 111 patients who completed RT during a period of 3 years. The risk groups were as follows: low risk (12%), intermediate (32%), and high (56%). None of the patients had suspicious lymph nodes. Ninety percent received androgen suppression therapy. Maximum acute genitourinary and gastrointestinal toxicity peaked at grade 3 in 4 of 111 evaluated patients (4%) and at grade 2 in 7 of 111 evaluated patients (8%), respectively. The average international prostate symptom score increased from 4.8 at pretreatment to 14.0 during week 4 and normalized (5.7) 3 months after treatment completion. ConclusionsThe current HFRT dose-escalation trial has demonstrated the feasibility of administering 66 Gy in 22 fractions with low acute gastrointestinal and genitourinary toxicities. Further follow-up will report late toxicities and outcomes.

Lactobacillus reuteri Releasing IL-22 (LR-IL-22) Facilitates Intestinal Radioprotection for Whole-Abdomen Irradiation (WAI) of Ovarian Cancer.

Oral administration (gavage) of a second-generation probiotic, Lactobacillus reuteri (L. reuteri), that releases interleukin-22 (LR-IL-22) at 24 h after total-body irradiation (TBI) mitigates damage to the intestine. We determined that LR-IL-22 also mitigates partial-body irradiation (PBI) and whole-abdomen irradiation (WAI). Irradiation can be an effective treatment for ovarian cancer, but its use is limited by intestinal toxicity. Strategies to mitigate toxicity are important and can revitalize this modality to treat ovarian cancer. In the present studies, we evaluated whether LR-IL-22 facilitates fractionated WAI in female C57BL/6 mice with disseminated ovarian cancer given a single fraction of either 15.75 Gy or 19.75 Gy or 4 daily fractions of 6 Gy or 6.5 Gy. Mice receiving single or multiple administrations of LR-IL-22 during WAI showed improved intestinal barrier integrity (P = 0.0167), reduced levels of radiation-induced intestinal cytokines including KC/CXCL1 (P = 0.002) and IFN-γ (P = 0.0024), and reduced levels of plasma, Eotaxin/CCL11 (P = 0.0088). LR-IL-22 significantly preserved the numbers of Lgr5+GFP+ intestinal stem cells (P = 0.0010) and improved survival (P < 0.0343). Female C57BL/6MUC-1 mice with widespread abdominal syngeneic 2F8cis ovarian cancer that received LR-IL-22 during 6.5 Gy WAI in 4 fractions had reduced tumor burden, less intestinal toxicity, and improved 30-day survival. Furthermore, LR-IL-22 facilitated WAI when added to Paclitaxel and Carboplatin chemotherapy and further increased survival. Oral administration (gavage) of LR-IL-22 is a potentially valuable intestinal radioprotector, which can facilitate therapeutic WAI for widespread intra-abdominal ovarian cancer.