Search

There is no definitive evidence on the extent of SARS-CoV-2’s effect on the retina. This study aims to determine if the natural history of SARS-CoV-2 infection affects tomographic findings in the retina of patients with COVID-19 pneumonia. This is a prospective cohort study of patients hospitalized with COVID-19 pneumonia. The patients underwent ophthalmological explorations and optical coherence tomography during the acute phase of the infection and at a follow-up 12 weeks later. The primary outcomes were the central retinal thickness and central choroidal thickness, which were compared longitudinally and with non-COVID-19 historical controls. No statistically relevant differences were observed in the longitudinal analysis of the thickness of the central retina (p = 0.056), central choroid (p = 0.99), retinal nerve fiber layer (p = 0.21), or ganglion cell layer (p = 0.32). Patients with acute COVID-19 pneumonia showed significantly greater central retinal thickness than non-COVID controls (p = 0.006). In conclusion, tomographic measures of the retina and choroid are not influenced by the phase of COVID-19 infection and remain stable during 12 weeks. The central retinal thickness may increase in the acute phase of COVID-19 pneumonia, but more epidemiological studies using optical coherence tomography in the early stages of the disease are needed.

Purpose: Lurbinectedin suppresses the oncogenic transcription factor EWS-FLI1 through relocalization to the nucleolus, and delays tumor growth in mice bearing Ewing sarcoma xenografts. On the basis of this rationale, lurbinectedin was evaluated in patients with relapsed Ewing sarcoma. Patients and Methods: This open-label, single-arm, Basket phase II trial included a cohort of 28 treated adult patients with confirmed Ewing sarcoma, measurable disease as per Response Evaluation Criteria In Solid Tumors (RECIST) v.1.1, Eastern Cooperative Oncology Group performance status ≤2, adequate organ function, no central nervous system metastasis, and pretreated with ≤2 chemotherapy lines for metastatic/recurrent disease. Patients received lurbinectedin 3.2 mg/m2 as a 1-hour infusion every 3 weeks. Primary endpoint was overall response rate (ORR) as per RECIST v.1.1. Secondary endpoints included time-to-event parameters and safety profile. Results: ORR was 14.3% [95% confidence interval (CI), 4.0%–32.7%], with median duration of response of 4.2 months (95% CI, 2.9–5.5 months). Median progression-free survival was 2.7 months (95% CI, 1.4–4.3 months), clinical benefit rate was 39.3%, and disease control rate was 57.1%. With 39% censoring, median overall survival was 12.0 months (95% CI, 8.5–18.5 months). Most common grade 3/4 adverse events were neutropenia (57%), anemia, thrombocytopenia, and treatment-related febrile neutropenia (14% each). No deaths or discontinuations were due to toxicity. Conclusions: Lurbinectedin was active in the treatment of relapsed Ewing sarcoma and had a manageable safety profile. Lurbinectedin could represent a valuable addition to therapies for Ewing sarcoma, and is currently being evaluated in combination with irinotecan in advanced Ewing sarcoma in a phase Ib/II trial.

Supplementary Figure S1; Supplementary Tables S1-S2.

Purpose: Two phase I dose-escalation studies were conducted to determine the maximum tolerated dose (MTD) and safety profile of the G2 checkpoint abrogator CBP501, as a single agent and in combination with cisplatin.Experimental Design: Patients with advanced solid tumors were treated with CBP501 alone (D1/D8/D15, q4w, from 0.9 mg/m2), or with cisplatin (both on D1, q3w, from 3.6 mg/m2 CBP501, 50 mg/m2 cisplatin). Dose escalation proceeded if dose-limiting toxicity (DLT) was observed in 1 or less of 3 to 6 patients; CBP501 dose increments were implemented according to the incidence of toxicity. MTD was determined from DLTs occurring during the first two cycles.Results: In the combination study, the DLT was a histamine-release syndrome (HRS) occurring 10 to 60 minutes after initiating infusion that was attenuated by prophylaxis comprising dexamethasone, diphenhydramine, ranitidine, and loratadine. The MTD was 25 mg/m2 CBP501 and 75 mg/m2 cisplatin, with two patients at the highest dose (36.4 mg/m2 CBP501, 75 mg/m2 cisplatin) experiencing grade 3 HRS. The only DLT with monotherapy was transient G3 rise of troponin in one patient. Grade 3 to 4 treatment–related events were rare. Promising activity was observed with CBP501/cisplatin, mainly in ovarian and mesothelioma patients who had previously progressed on platinum-containing regimens. Among ovarian cancer patients, low expression of DNA repair proteins was associated with partial response or stable disease.Conclusions: CBP501 is well tolerated in patients as monotherapy and with cisplatin. At the recommended phase II dose (RP2D), the combination is feasible and HRS manageable with prophylaxis. Evidence of antitumor activity was observed in platinum-resistant patients. Clin Cancer Res; 17(10); 3431–42. ©2011 AACR.

Purpose In the last three decades, Synchrotron Microbeam Radiation Therapy (S-MRT) has been shown to achieve both good tumour control and normal tissue sparing in a range of pre-clinical animal models. However, the use of S-MRT for the treatment of lung tumours has not yet been investigated. This study is the first to evaluate the therapeutic efficacy of S-MRT for the treatment of lung carcinoma, using a new syngeneic and orthotopic mouse model. Methods and materials Lewis Lung carcinoma-bearing mice were irradiated with two cross-fired arrays of S-MRT or Synchrotron Broad-Beam (S-BB) radiotherapy. S-MRT consisted of 17 microbeams with a width of 50 µm and centre-to-centre spacing of 400 µm. Each microbeam delivered a peak entrance dose of 400 Gy while S-BB delivered a homogeneous entrance dose of 5.16 Gy (corresponding to the S-MRT valley dose). Results Both treatments prolonged the survival of mice relative to the untreated controls (CTR). However, mice in the S-MRT group developed severe pulmonary oedema around the irradiated carcinomas and did not have improved survival relative to the S-BB group. Subsequent post-mortem examination of tumour size revealed that the mice in the S-MRT group had notably smaller tumour volume compared to the S-BB group, despite the presence of oedema. Mice that were sham-implanted did not display any decline in health following S-MRT, experiencing only mild and transient oedema between 4 days and 3 months post-irradiation which disappeared after 4 months. Finally, a parallel study investigating the lungs of healthy mice showed the complete absence of radiation-induced pulmonary fibrosis 6 months after S-MRT. Conclusions S-MRT is a promising tool for the treatment of lung carcinoma, reducing tumour size compared to mice treated with S-BB and sparing healthy lungs from pulmonary fibrosis. Future experiments should focus on optimising S-MRT parameters to minimise pulmonary oedema and maximise the therapeutic ratio.

Objective The randomized phase 3 CORAIL trial evaluated whether lurbinectedin improved progression-free survival (PFS) compared to pegylated liposomal doxorubicin (PLD) or topotecan in patients with platinum-resistant ovarian cancer. Methods Patients were randomly assigned (1:1) to lurbinectedin 3.2 mg/m2 1-h i.v. infusion q3wk (experimental arm), versus PLD 50 mg/m2 1-h i.v. infusion q4wk or topotecan 1.50 mg/m2 30-min i.v. infusion Days 1–5 q3wk (control arm). Stratification factors were PS (0 vs. ≥1), prior PFI (1–3 months vs. >3 months), and prior chemotherapy lines (1–2 vs. 3). The primary endpoint was PFS by Independent Review Committee in all randomized patients. This study was registered with ClinicalTrials.gov , NCT02421588 . Results 442 patients were randomized: 221 in lurbinectedin arm and 221 in control arm (127 PLD and 94 topotecan). With a median follow-up of 25.6 months, median PFS was 3.5 months (95% CI, 2.1–3.7) in the lurbinectedin arm and 3.6 months (95% CI, 2.7–3.8) in the control arm (stratified log-rank p = 0.6294; HR = 1.057). Grade ≥ 3 treatment-related adverse events (AEs) were most frequent in the control arm: 64.8% vs. 47.9% (p = 0.0005), mainly due to hematological toxicities. The most common grade ≥ 3 AEs were: fatigue (7.3% of patients) and nausea (5.9%) with lurbinectedin; mucosal inflammation (8.5%) and fatigue (8.0%) in the control arm. Conclusions The primary endpoint of improvement in PFS was not met. Lurbinectedin showed similar antitumor efficacy and was better tolerated than current standard of care in patients with platinum-resistant ovarian cancer.

International audience; Purpose: Radiation therapy is an important treatment component for patients with lung cancer. However, the survival time gained with clinical radiation therapy techniques is relatively short. Data from preclinical experiments suggest that synchrotron microbeam radiation therapy could be much better suited to control malignant brain tumors than current clinical concepts of radiation therapy. Even at peak doses of several hundred gray, the extent of functional deficits is low. Methods and Materials: We have developed the first mouse model to study the effects of microbeam irradiation in lung tissue. Results: Up to peak doses of 400 Gy, no acute adverse effects were seen. Conclusion: This model is well suited to explore the potential of microbeam radiation therapy in the treatment of lung cancer and the response of normal lung tissue and organs at risk. (C) 2021 The Authors. Published by Elsevier Inc.

Osteoarthritis (OA) is a degenerative disorder resulting from loss of joint cartilage and underlying bone. Sports injuries are considered disorders of the musculoskeletal system or concussions that are generally caused during sportive activities such as football

Summary Background Few options exist for treatment of patients with small-cell lung cancer (SCLC) after failure of first-line therapy. Lurbinectedin is a selective inhibitor of oncogenic transcription. In this phase 2 study, we evaluated the acti and safety of lurbinectedin in patients with SCLC after failure of platinum-based chemotherapy. Methods In this single-arm, open-label, phase 2 basket trial, we recruited patients from 26 hospitals in six European countries and the USA. Adults (aged ≥18 years) with a pathologically proven diagnosis of SCLC, Eastern Cooperative Oncology Group performance status of 2 or lower, measurable disease as per Response Criteria in Solid Tumors (RECIST) version 1.1, absence of brain metastasis, adequate organ function, and pre-treated with only one previous chemotherapy-containing line of treatment (minimum 3 weeks before study initiation) were eligible. Treatment consisted of 3·2 mg/m2 lurbinectedin administered as a 1-h intravenous infusion every 3 weeks until disease progression or unacceptable toxicity. The primary outcome was the proportion of patients with an overall response (complete or partial response) as assessed by the investigators according to RECIST 1.1. All treated patients were analysed for activity and safety. This study is ongoing and is registered with ClinicalTrials.gov , NCT02454972 . Findings Between Oct 16, 2015, and Jan 15, 2019, 105 patients were enrolled and treated with lurbinectedin. Median follow-up was 17·1 months (IQR 6·5–25·3). Overall response by investigator assessment was seen in 37 patients (35·2%; 95% CI 26·2–45·2). The most common grade 3–4 adverse events (irrespective of causality) were haematological abnormalities—namely, anaemia (in nine [9%] patients), leucopenia (30 [29%]), neutropenia (48 [46%]), and thrombocytopenia (seven [7%]). Serious treatment-related adverse events occurred in 11 (10%) patients, of which neutropenia and febrile neutropenia were the most common (five [5%] patients for each). No treatment-related deaths were reported. Interpretation Lurbinectedin was active as second-line therapy for SCLC in terms of overall response and had an acceptable and manageable safety profile. Lurbinectedin could represent a potential new treatment for patients with SCLC, who have few options especially in the event of a relapse, and is being investigated in combination with doxorubicin as second-line therapy in a randomised phase 3 trial. Funding Pharma Mar.

Radiation therapy (RT) is a vital component of multimodal cancer treatment, and its immunomodulatory effects are a major focus of current therapeutic strategies. Macrophages are some of the first cells recruited to sites of radiation-induced injury where they can aid in tissue repair, propagate radiation-induced fibrogenesis and influence tumour dynamics. Microbeam radiation therapy (MRT) is a unique, spatially fractionated radiation modality that has demonstrated exceptional tumour control and reduction in normal tissue toxicity, including fibrosis. We conducted a morphological analysis of MRT-irradiated normal liver, lung and skin tissues as well as lung and melanoma tumours. MRT induced distinct patterns of DNA damage, reflecting the geometry of the microbeam array. Macrophages infiltrated these regions of peak dose deposition at variable timepoints post-irradiation depending on the tissue type. In normal liver and lung tissue, macrophages clearly demarcated the beam path by 48 h and 7 days post-irradiation, respectively. This was not reflected, however, in normal skin tissue, despite clear DNA damage marking the beam path. Persistent DNA damage was observed in MRT-irradiated lung carcinoma, with an accompanying geometry-specific influx of mixed M1/M2-like macrophage populations. These data indicate the unique potential of MRT as a tool to induce a remarkable accumulation of macrophages in an organ/tissue-specific manner. Further characterization of these macrophage populations is warranted to identify their organ-specific roles in normal tissue sparing and anti-tumour responses.

FLASH radiotherapy (FLASH-RT) and spatially fractionated radiation therapy (SFRT) are two new therapeutical strategies that use non-standard dose delivery methods to reduce normal tissue toxicity and increase the therapeutic index. Although likely based on different mechanisms, both FLASH-RT and SFRT have shown to elicit radiobiological effects that significantly differ from those induced by conventional radiotherapy. With the therapeutic potential having been established separately for each technique, the combination of FLASH-RT and SFRT could therefore represent a winning alliance. In this review, we discuss the state of the art, advantages and current limitations, potential synergies, and where a combination of these two techniques could be implemented today or in the near future.

Purpose Synchrotron microbeam radiation therapy (MRT) is a method that spatially distributes the x-ray beam into several microbeams of very high dose (peak dose), regularly separated by low-dose intervals (valley dose). MRT selectively spares normal tissues, relative to conventional (uniform broad beam [BB]) radiation therapy. Methods and Materials To evaluate the effect of MRT on radioresistant melanoma, B16-F10 murine melanomas were implanted into mice ears. Tumors were either treated with MRT (407.6 Gy peak; 6.2 Gy valley dose) or uniform BB irradiation (6.2 Gy). Results MRT induced significantly longer tumor regrowth delay than did BB irradiation. A significant 24% reduction in blood vessel perfusion was observed 5 days after MRT, and the cell proliferation index was significantly lower in melanomas treated by MRT compared with BB. MRT provoked a greater induction of senescence in melanoma cells. Bio-Plex analyses revealed enhanced concentration of monocyte-attracting chemokines in the MRT group: MCP-1 at D5, MIP-1α, MIP-1β, IL12p40, and RANTES at D9. This was associated with leukocytic infiltration at D9 after MRT, attributed mainly to CD8 T cells, natural killer cells, and macrophages. Conclusions In light of its potential to disrupt blood vessels that promote infiltration of the tumor by immune cells and its induction of senescence, MRT could be a new therapeutic approach for radioresistant melanoma.

Melanoma is the deadliest type of skin cancer, due to its invasiveness and limited treatment efficacy. The main therapy for primary melanoma and solitary organ metastases is wide excision. Adjuvant therapy, such as chemotherapy and targeted therapies are mainly used for disseminated disease. Radiotherapy (RT) is a powerful treatment option used in more than 50% of cancer patients, however, conventional RT alone is unable to eradicate melanoma. Its general radioresistance is attributed to overexpression of repair genes in combination with cascades of biochemical repair mechanisms. A novel sophisticated technique based on synchrotron-generated, spatially fractionated RT, called Microbeam Radiation Therapy (MRT), has been shown to overcome these treatment limitations by allowing increased dose delivery. With MRT, a collimator subdivides the homogeneous radiation field into an array of co-planar, high-dose microbeams that are tens of micrometres wide and spaced a few hundred micrometres apart. Different preclinical models demonstrated that MRT has the potential to completely ablate tumours, or significantly improve tumour control while dramatically reducing normal tissue toxicity. Here, we discuss the role of conventional RT-induced immunity and the potential for MRT to enhance local and systemic anti-tumour immune responses. Comparative gene expression analysis from preclinical tumour models indicated a specific gene signature for an ‘MRT-induced immune effect’. This focused review highlights the potential of MRT to overcome the inherent radioresistance of melanoma which could be further enhanced for future clinical use with combined treatment strategies, in particular, immunotherapy.

The authors wish to make the following corrections to this paper [...]

Background: Microbeam Radiation Therapy (MRT) is an innovative approach in radiation oncology where a collimator subdivides the homogeneous radiation field into an array of co-planar, high-dose beams which are tens of micrometres wide and separated by a few hundred micrometres. Objective: This scoping review was conducted to map the available evidence and provide a comprehensive overview of the similarities, differences, and outcomes of all experiments that have employed animal models in MRT. Methods: We considered articles that employed animal models for the purpose of studying the effects of MRT. We searched in seven databases for published and unpublished literature. Two independent reviewers screened citations for inclusion. Data extraction was done by three reviewers. Results: After screening 5688 citations and 159 full-text papers, 95 articles were included, of which 72 were experimental articles. Here we present the animal models and pre-clinical radiation parameters employed in the existing MRT literature according to their use in cancer treatment, non-neoplastic diseases, or normal tissue studies. Conclusions: The study of MRT is concentrated in brain-related diseases performed mostly in rat models. An appropriate comparison between MRT and conventional radiotherapy (instead of synchrotron broad beam) is needed. Recommendations are provided for future studies involving MRT.

Introduction: The National Comprehensive Cancer Network guidelines recommend re-challenge with the first-line treatment for relapsed small cell lung cancer (SCLC) with chemotherapy-free interval (CTFI)≥180 days. A phase II study (NCT02454972) showed remarkable antitumor activity in SCLC patients treated with lurbinectedin 3.2 mg/m2 1 -h intravenous infusion every 3 weeks as second-line therapy. We report results for the pre-planned subset of patients with CTFI ≥ 180 days. Material and Methods: Twenty patients aged ≥18 years with pathologically proven SCLC diagnosis, pretreated with only one prior platinum-containing line, no CNS metastases, and with CTFI ≥ 180 days were evaluated. The primary efficacy endpoint was the overall response rate (ORR) assessed by the Investigators according to RECIST v1.1. Results: ORR was 60.0 % (95 %CI, 36.1−86.9), with a median duration of response of 5.5 months (95 %CI, 2.9−11.2) and disease control rate of 95.0 % (95 %CI, 75.1−99.9). Median progression-free survival was 4.6 months (95 %CI, 2.6−7.3). With a censoring of 55.0 %, the median overall survival was 16.2 months (95 %CI, 9.6-upper level not reached). Of note, 60.9 % and 27.1 % of patients were alive at 1 and 2 years, respectively. The most common grade 3/4 adverse events and laboratory abnormalities were hematological disorders (neutropenia, 55.0 %; anemia; 10.0 % thrombocytopenia, 10.0 %), fatigue (10.0 %) and increased liver function tests (GGT, 10 %; ALT and AP, 5.0 % each). No febrile neutropenia was reported. Conclusion: Lurbinectedin is an effective treatment for platinum-sensitive relapsed SCLC, especially in patients with CTFI ≥ 180 days, with acceptable safety and tolerability. These encouraging results suggest that lurbinectedin can be another valuable therapeutic option rather than platinum re-challenge., SCOPUS: ar.j, info:eu-repo/semantics/published

Background: Synchrotron Microbeam Radiotherapy (MRT) significantly improves local tumour control with minimal normal tissue toxicity. MRT delivers orthovoltage X-rays at an ultra-high &ldquo, FLASH&rdquo, dose rate in spatially fractionated beams, typically only few tens of micrometres wide. One of the biggest challenges in translating MRT to the clinic is its use of high peak doses, of around 300&ndash, 600 Gy, which can currently only be delivered by synchrotron facilities. Therefore, in an effort to improve the translation of MRT to the clinic, this work studied whether the temporal fractionation of traditional MRT into several sessions with lower, more clinically feasible, peak doses could still maintain local tumour control. Methods: Two groups of twelve C57Bl/6J female mice harbouring B16-F10 melanomas in their ears were treated with microbeams of 50 &micro, m in width spaced by 200 &micro, m from their centres. The treatment modality was either (i) a single MRT session of 401.23 Gy peak dose (7.40 Gy valley dose, i.e., dose between beams), or (ii) three MRT sessions of 133.41 Gy peak dose (2.46 Gy valley dose) delivered over 3 days in different anatomical planes, which intersected at 45 degrees. The mean dose rate was 12,750 Gy/s, with exposure times between 34.2 and 11.4 ms, respectively. Results: Temporally fractionated MRT ablated 50% of B16-F10 mouse melanomas, preventing organ metastases and local tumour recurrence for 18 months. In the rest of the animals, the median survival increased by 2.5-fold in comparison to the single MRT session and by 4.1-fold with respect to untreated mice. Conclusions: Temporally fractionating MRT with lower peak doses not only maintained tumour control, but also increased the efficacy of this technique. These results demonstrate that the solution to making MRT more clinically feasible is to irradiate with several fractions of intersecting arrays with lower peak doses. This provides alternatives to synchrotron sources where future microbeam radiotherapy could be delivered with less intense radiation sources.

Purpose This multicenter phase II trial evaluated lurbinectedin (PM01183), a selective inhibitor of active transcription of protein-coding genes, in patients with metastatic breast cancer. A unicenter translational substudy assessed potential mechanisms of lurbinectedin resistance. Patients and Methods Two arms were evaluated according to germline BRCA1/2 status: BRCA1/2 mutated (arm A; n = 54) and unselected ( BRCA1/2 wild-type or unknown status; arm B; n = 35). Lurbinectedin starting dose was a 7-mg flat dose and later, 3.5 mg/m2 in arm A. The primary end point was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST). The translational substudy of resistance mechanisms included exome sequencing (n = 13) and in vivo experiments with patient-derived xenografts (n = 11) from BRCA1/2-mutated tumors. Results ORR was 41% (95% CI, 28% to 55%) in arm A and 9% (95% CI, 2% to 24%) in arm B. In arm A, median progression-free survival was 4.6 months (95% CI, 3.0 to 6.0 months), and median overall survival was 20.0 months (95% CI, 11.8 to 26.6 months). Patients with BRCA2 mutations showed an ORR of 61%, median progression-free survival of 5.9 months, and median overall survival of 26.6 months. The safety profile improved with lurbinectedin dose adjustment to body surface area. The most common nonhematologic adverse events seen at 3.5 mg/m2 were nausea (74%; grade 3, 5%) and fatigue (74%; grade 3, 21%). Neutropenia was the most common severe hematologic adverse event (grade 3, 47%; grade 4, 10%). Exome sequencing showed mutations in genes related to the nucleotide excision repair pathway in four of seven tumors at primary or acquired resistance and in one patient with short-term stable disease. In vivo, sensitivity to cisplatin and lurbinectedin was evidenced in lurbinectedin-resistant (one of two) and cisplatin-resistant (two of three) patient-derived xenografts. Conclusion Lurbinectedin showed noteworthy activity in patients with BRCA1/2 mutations. Response and survival was notable in those with BRCA2 mutations. Additional clinical development in this subset of patients with metastatic breast cancer is warranted.

Gamma radiation represents a potential health risk to aquatic and terrestrial biota, due to its ability to ionize atoms and molecules in living tissues. The effects of exposure to 60Co gamma radiation in zebrafish (Danio rerio) were studied during two sensitive life stages: gametogenesis (F0: 53 and 8.7mGy/h for 27 days, total doses 31 and 5.2Gy) and embryogenesis (9.6mGy/h for 65h; total dose 0.62Gy). Progeny of F0 exposed to 53mGy/h showed 100% mortality occurring at the gastrulation stage corresponding to 8h post fertilization (hpf). Control and F0 fish exposed to 8.7mGy/h were used to create four lines in the first filial generation (F1): control, G line (irradiated during parental gametogenesis), E line (irradiated during embryogenesis) and GE line (irradiated during parental gametogenesis and embryogenesis). A statistically significant cumulative mortality of GE larva (9.3%) compared to controls was found at 96 hpf. E line embryos hatched significantly earlier compared to controls, G and GE (48-72 hpf). The deformity frequency was higher in G and GE, but not E line compared to controls at 72 hpf. One month after parental irradiation, the formation of reactive oxygen species (ROS) was increased in the G line, but did not significantly differ from controls one year after parental irradiation, while at the same time point it was significantly increased in the directly exposed E and GE lines from 60 to 120 hpf. Lipid peroxidation (LPO) was significantly increased in the G line one year after parental irradiation, while significant increase in DNA damage was detected in both the G and GE compared to controls and E line at 72 hpf. Radiation-induced bystander effects, triggered by culture media from tissue explants and observed as influx of Ca2+ ions through the cellular membrane of the reporter cells, were significantly increased in 72 hpf G line progeny one month after irradiation of the parents. One year after parental irradiation, the bystander effects were increased in the E line compared to controls, but not in progeny of irradiated parents (G and GE lines). Overall, this study showed that irradiation of parents can result in multigenerational oxidative stress and genomic instability in irradiated (GE) and non-irradiated (G) progeny of irradiated parents, including increases in ROS formation, LPO, DNA damage and bystander effects. The results therefore highlight the necessity for multi- and transgenerational studies to assess the environmental impact of gamma radiation.

3078 Background: PM14 is a new chemical entity that forms DNA adducts which specifically inhibit RNA synthesis and block active transcription of protein-coding genes. Antitumor activity has been demonstrated in vitro in several cell lines (e.g. lung, kidney, prostate), and in vivo in mice bearing xenografted human-derived tumors (soft tissue sarcoma, small cell lung cancer, ovarian, gastric, breast and renal cancer). Methods: Open-label, dose-escalating, phase I trial of PM14 administered as a 3-hour infusion i.v. every 3 weeks (q3wk) in patients (pts) with advanced solid tumors, adequate organ function and ECOG PS score of 0-1. Two schedules were explored: Schedule A (Day 1 [D1], Day 8 [D8]) and Schedule B (D1). Results: 37 pts were treated (Schedule A/B: 28/9 pts). Baseline characteristics of pts (A/B): median age 56/47 years; male 57%/56%; ECOG PS 0: 57%/56%; median of prior lines (range): 3 (1-8)/4 (1-10). Most common tumor types (A + B): STS (n=7 pts), ovarian (n=6), pancreatic (n=4), prostate cancer (n=3). The maximum tolerated dose was 4.5 mg/m2 for A (dose-limiting toxicities [DLTs]: D8 omission due to lack of recovery of lab parameters for re-treatment [n=2 pts]) and 5.6 mg/m2 (DLTs: G4 febrile neutropenia [n=1], G4 transaminase increase [n=1]) for B. The recommended dose (RD) was 3.0 mg/m2 on D1,D8 (A), and 4.5 mg/m2 on D1 (B). No DLTs were present at the RDs. Most common toxicities were hematological abnormalities and transaminase increase. Main toxicities at the RDs are shown below. Antitumor activity comprised stable disease ≥4 months in 7 heavily pretreated pts (6 in A; 1 in B) at all dose levels. Linear pharmacokinetics were observed for PM14 at tested doses (0.25-5.6 mg/m²), with geometric mean (CV%) total plasma clearance 5.9 L/h (88%), volume of distribution 128 L (81%) and median (range) terminal half-life 15.9 h (7.5-34.3 h). Less than 1.6% of administered dose was recovered in urine. Conclusions: RDs were determined for two PM14 schedules in pts with advanced solid tumors. At the RDs, PM14 is well tolerated and has a manageable safety profile. An expansion phase in specific tumor types, with an optional Bayesian continual reassessment method for RD fine-tuning, is ongoing with both schedules.[Table: see text]

Out-of-field effects are of considerable interest in radiotherapy. The mechanisms are poorly understood but are thought to involve signaling processes, which induce responses in non-targeted cells and tissues. The immune response is thought to play a role. The goal of this research was to study the induction of abscopal effects in the bladders of NU-Foxn1 mice after irradiating their brains using Pencil Beam (PB) or microbeam (MRT) irradiation at the European Synchrotron Radiation Facility (ESRF) in Grenoble, France. Athymic nude mice injected with F98 glioma cells into their right cerebral hemisphere 7 d earlier were treated with either MRT or PB. After recovery times of 2, 12, and 48 h, the urinary bladders were extracted and cultured as tissue explants for 24 h. The growth medium containing the potential signaling factors was harvested, filtered, and transferred to HaCaT reporter cells to assess their clonogenic survival and calcium signaling potential. The results show that in the tumor-free mice, both treatment modalities produce strong bystander/abscopal signals using the clonogenic reporter assay; however, the calcium data do not support a calcium channel mediated mechanism. The presence of a tumor reduces or reverses the effect. PB produced significantly stronger effects in the bladders of tumor-bearing animals. The authors conclude that immunocompromised mice produce signals, which can alter the response of unirradiated reporter cells; however, a novel mechanism appears to be involved.

Over the past several years, investigations in both low-dose hyper-radiosensitivity and increased radioresistance have been a focus of radiation oncology and biology research, since both conditions occur primarily in tumor cell lines. There has been significant progress in elucidating their signaling pathways, however uncertainties exist when they are studied together with radiation-induced bystander effects. Therefore, the aim of this work was to further investigate this relationship using the T98G glioma and HaCaT cell lines. T98G glioma cells have demonstrated a strong transition from hyper-radiosensitivity to induced radioresistance, and HaCaT cells do not show low-dose hypersensitivity. Both cell lines were paired using a mix-and-match protocol, which involved growing nonirradiated cells in culture media from irradiated cells and covering all possible combinations between them. The end points analyzed were clonogenic cell survival and live calcium measurements through the cellular membrane. Our data demonstrated that T98G cells produced bystander signals that decreased the survival of both reporter T98G and HaCaT cells. The bystander effect occurred only when T98G cells were exposed to doses below 1 Gy, which was corroborated by the induction of calcium fluxes. However, when bystander signals originated from HaCaT cells, the survival fraction increased in reporter T98G cells while it decreased in HaCaT cells. Moreover, the corresponding calcium data showed no calcium fluxes in T98G cells, while HaCaT cells displayed a biphasic calcium profile. In conclusion, our findings indicate a possible link between low-dose hyper-radiosensitivity and bystander effects. This relationship varies depending on which cell line functions as the source of bystander signals. This further suggests that the bystander mechanisms are more complex than previously expected and caution should be taken when extrapolating bystander results across all cell lines and all radiation doses.

3635 Background: Lurbinectedin (L), an inhibitor of active transcription, has shown activity in second-line (2L) small cell lung cancer (SCLC) (ASCO 2019). Topotecan (T) is the only approved drug in 2L SCLC and is also used in platinum resistant ovarian cancer (PROC). Methods: This pooled safety analysis includes data from 554 patients (pts) treated with L at 3.2 mg/m2 Day 1 q3wk 1-h (no primary prophylaxis with G-CSF required): 335 with selected solid tumors (9 indications, including 105 pts with SCLC) from a phase II Basket study and 219 with PROC in the phase III CORAIL study. An indirect exploratory comparison (pooled data from CORAIL + Basket) and a direct comparison (data from CORAIL) of L vs. T are presented. Results: Most common adverse events with L were grade 1/2 fatigue, nausea and vomiting. Treatment-related (L/T): dose reductions: 22.9/48.3%, delays: 25.8/52.9%, grade ≥3 serious adverse events (SAEs): 15.0/32.2%, discontinuations: 3.2/5.7%, deaths: 1.3/1.5%, G-CSF use: 23.8/70.1%, and transfusions: 15.9/52.9%. Conclusions: Lurbinectedin has a predictable and manageable safety profile. A significant safety advantage was observed when lurbinectedin was compared with topotecan in the CORAIL trial in terms of hematological toxicities. With the limitations of indirect comparisons, in the pooled safety analysis, fewer lurbinectedin-treated pts had severe hematological toxicities, SAEs, dose adjustments, treatment discontinuations and use of supportive treatments than topotecan-treated pts. Clinical trial information: NCT02421588 and NCT02454972 . [Table: see text]

Purpose: This review follows the development of microbeam technology from the early days of single cell irradiations, to investigations of specific cellular mechanisms and to the development of new treatment modalities in vivo. A number of microbeam applications are discussed with a focus on preclinical modalities and translation towards clinical application.Conclusions: The development of radiation microbeams has been a valuable tool for the exploration of fundamental radiobiological response mechanisms. The strength of micro-irradiation techniques lies in their ability to deliver precise doses of radiation to selected individual cells in vitro or even to target subcellular organelles. These abilities have led to the development of a range of microbeam facilities around the world allowing the delivery of precisely defined beams of charged particles, X-rays, or electrons.In addition, microbeams have acted as mechanistic probes to dissect the underlying molecular events of the DNA damage response following highly localised dose deposition. Further advances in very precise beam delivery have also enabled the transition towards new and exciting therapeutic modalities developed at synchrotrons to deliver radiotherapy using plane parallel microbeams, in Microbeam Radiotherapy (MRT).

Background: Metastatic breast cancer (MBC) is a clinically heterogeneous disease in which selective approaches are needed to identify patients (pts) who will benefit the most from available therapies and avoid unnecessary toxicities. Lurbinectedin (PM01183) is a new anticancer drug that binds to the DNA minor groove inducing double-strand breaks and blocking transcription. It has significant in vitro and in vivo antitumor activity, particularly in breast cancer models. PM01183 is more active against homologous recombination-deficient cell lines. Hence, MBC pts with deleterious germline BRCA mutations might be more sensitive to PM01183 than those with sporadic tumors. PM1183 activity was shown in different tumor types in clinical trials, especially in pts with platinum-resistant ovarian cancer (objective response rate [ORR]: 30%). Methods: MBC pts < 75-years-old with ductal or lobular carcinoma pretreated with ≤ 3 chemotherapy regimens for MBC, measurable disease per RECIST v1.1, performance status (PS) ≤1 and adequate major organ function are being treated with PM01183 7.0 mg flat dose i.v. every 3 weeks. The primary aim is to evaluate the clinical efficacy of PM01183 in two cohorts of MBC pts: cohort A: BRCA+ (known germline BRCA1/2 mutation) and cohort B: unselected (BRCA1/2 wild type or unknown mutation status). The primary endpoint is confirmed ORR by RECIST v1.1. A futility analysis was planned when 20 and 30 pts were recruited in cohort A and B, respectively. If at least 4 pts in cohort A and 3 pts in cohort B, achieve a response, recruitment in that cohort will continue up to 53 and 64 total pts, respectively. Results: As of June 2014, 56 pts had been enrolled. Cohort A/B (n: 21/35): Median age 40/52-years-old; Cohort A(%)/B(%): PS 0: 48/66; >2 metastatic sites: 58/40; most common sites of metastasis: lymph node 79/33, liver 48/60 and bone 42/48; triple negative: 57/46; hormonal receptor +: 38/49; prior anthracyclines: 95/91, taxanes: 100/94, platinum: 52/26, PARPi: 29/0; cohort A: BRCA 1/2 (%): 52/48. Cohort A-BRCA 1/2+ (n=21)Cohort B-unselected (n=35)Median cycles (range)4 (1-20)3 (1-14)Best overall response(n= 17 evaluable)(n= 34 evaluable)CR1 (6%)0PR6 (35%)3 (9%)SD6 (35%)16 (47%)PD4 (24%)15 (44%)ORR (95%CI)41% (18-67%)9% (1.9-23.7%)Median duration of response Monts (95%CI)5.0 (0.1-12.8)3.3 (1.4-5.1) In an exploratory analysis, ORR in cohort A was higher in PARPi naïve pts: 64% (7/11 pts). Grade (G) 3-4 related adverse events occurred in >5% pts were myelosuppression (neutropenia 69%, febrile neutropenia 7%, thrombocytopenia 14%); G3 fatigue 7%, transient transaminase increase 19% (G4: 2%), nausea 6% and dyspnea 6% (3 pts, 2 of them due to pneumonitis). One patient with massive liver involvement and impaired function died on C1D4 due to multiorgan failure possibly related to the study drug. Conclusions: PM01183 has promising activity in pretreated MBC pts with BRCA mutation. Safety profile appears to be mostly predictable and with non-cumulative toxicity. Treatment-related neutropenia was manageable with G-CSF and/or dose reduction. After futility analysis, targeted activity has been met in cohort A (BRCA+), and recruitment will continue up to 53 evaluable BRCA+ pts. Citation Format: Judit Balmaña, Cristina Cruz, Judy Garber, Jose A Perez Fidalgo, Ana Lluch, Nadine Tung, Silvia Antolin, Cristian Fernandez, Carmen Kahatt, Sergio Szyldergemajn, Arturo Soto Matos, Sonia Extremera, Jose Baselga, Steven J Isakoff. Lurbinectedin (PM01183) activity in BRCA1/2-associated or unselected metastatic breast cancer. Interim results of an ongoing phase II trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-13-01.