A RADIATION SENSITIVE ADHESIVE SYSTEM FOR FUNCTIONALLY GRADED COMPOSITE JOINTS

Adhesively bonded composite joints can help reduce weight in structures and avoid material damage from fastener holes, but stress concentrations formed at the edges of the adhesive bond line are a main cause of failure. Stress concentrations within the adhesive can be reduced by lowering the stiffness at these edges and increasing the stiffness in the center of the joint. This may be achieved using a dual-cure adhesive system, where conventional curing is first used to bond a lap joint, after which high energy radiation is applied to the joint to induce additional crosslinking in specific regions. Anhydride-cured epoxy resins have been formulated to include a radiation sensitizer enabling the desired cure behavior. Tensile testing was performed on cured systems containing varying levels of radiation sensitizer in order to evaluate its effects on young’s modulus as a function of radiation dose.

Etctn 10388: A phase I trial of triapine and lutetium Lu 177 dotatate in well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs).

TPS4660 Background: Radiolabeled somatostatin analogues provide a means of delivering targeted radiation with a high therapeutic index to NETs that express somatostatin receptors (SSTRs). Radiolabeled somatostatin analogue Lutetium Lu 177 Dotatate (Lutathera) is a beta-emitting radionuclide, recently FDA approved for use in SSTR positive gastroenteropancreatic neuroendocrine tumors (GEPNETS) in the US based on the NETTER-1 Phase III trial. Despite favorable PFS and safety profile, the drug has limited cytoreductive capability with a 17% ORR. We hypothesize that addition of an effective radiation sensitizer could help improve antitumor activity of Lutathera. Ribonucleotide reductase (RNR) is the only enzyme responsible for conversion of ribonucleoside diphosphate to deoxyribonucleotide diphosphate (dNDP), the key building blocks for DNA synthesis. Radiation is a potent inducer of DNA double-strand breaks (DSBs), and RNR is the rate-limiting enzyme in the repair of DNA in this setting. Triapine is an inhibitor of RNR. This study will test the hypothesis that radiation sensitizer triapine can be safely combined with peptide receptor radionuclide therapy and ultimately may improve antitumor activity of Lutetium Lu 177 Dotatate. Methods: This study is an investigator initiated, NCI sponsored, multicenter phase 1 trial of triapine and Lutetium Lu 177 Dotatate in well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumor (GEP-NETs) after the failure of at least one line of prior systemic cancer treatment. A total of 29 patients will be enrolled in the dose escalation with help of Bayesian optimal interval design (BOIN) and dose expansion cohorts. The study will be open through the NCI ETCTN (National Cancer Institute Experimental Therapeutics Clinical Trials Network) program. Patients will be treated with 177 lutetium dotatate in combination with triapine. Triapine will be administered orally (100 mg once a day starting dose) from D1-14 with each dose of PRRT [200 mCi]. Primary endpoint is to evaluate recommended phase II dose (RP2D). Secondary endpoints are to evaluate safety, pharmacokinetics, and clinical activity (ORR and PFS). We are also evaluating NETEST, a novel blood based test that evaluates levels of 51 neuroendocrine tumor gene transcripts. In addition, the study will correlate clinical outcome with baseline somatostatin receptor density, somatic tumor mutations and germline mutations. Clinical trial information: 04234568 .

Study of efficacy and tolerability of paclitaxel and carboplatin as a concurrent chemotherapeutic radiation sensitizer regimen in patients of esophageal cancer: Prospective observational study from tertiary center in northern India.

e16526 Background: Neo-adjuvant chemotherapy followed by surgery is the standard of care in non metastatic oesophageal cancers. After the overall survival benefit observed in Cross trial, Paclitaxel and Carboplatin based neo-adjuvant chemoradiation has become the preferred treatment modality. There is paucity of data of its efficacy and tolerability in Indian patients. So this prospective study was done to assess the same. Methods: We enrolled 64 patients aged 18-75 years with histologically confirmed, potentially resectable squamous-cell carcinoma of the esophagus or esophagogastric junction from Aug 2017 to Jan 2019. On days 1, 8, 15, 22, and 29, carboplatin AUC 2 and paclitaxel 50 mg/m2 intravenously and a total radiation dose of 41.4 Gy was given in 23 fractions of 1.8 Gy each by external-beam radiation. Pathological complete response rate, Clinical response based on PET-CT scan and tolerability of paclitaxel and carboplatin as a concurrent chemotherapeutic radiation sensitizer regimen was studied. Results: 23 out 64 patients underwent surgery while others were either lost to follow up or they refused for surgery. Of these 23, 87.5% could complete all 5 planned cycles of chemotherapy. Complete pathological response was found in 73.9% patients. Statistically significant correlation was found between pathological and PET-CT based response (p-0.044). 4 patients showed distant progression on PET-CT based evaluation after neoadjuvant chemo radiotherapy before surgery. The most common major hematologic toxic effects were leukopenia (14%) and neutropenia (12.5%). Febrile neutropenia and grade 3 anemia was observed 2 and 4 patients respectively. The most common major non-hematologic toxic effects were vomiting (4.6%), nausea (3.1%), bronchoesophageal fistula(3.1%). Post operative mortality was seen in 1(4.3%) patient. Grade 3 pulmonary complications, atrial fibrillation and anastomotic leak was observed in 1 patient each. Conclusions: Concurrent chemoradiotherpy with weekly paclitaxel and caboplatin is well tolerated in Indian patients. High complete resection rate and PCR rate can be achieved with this regime with manageable adverse effect profile. Response evaluation with PET-CT after completion of preoperative therapy has correlation with pathological complete response.

Antitumor efficacy of M3814 as a radiation sensitizer in neuroendocrine tumor (NET) preclinical models.

e15699 Background: Recent FDA approval of peptide receptor radiotherapy paved the way for radiation-based treatment for gastroenteropancreatic neuroendocrine tumors (GEPNETs). M-3814, a DNA-dependent Protein Kinase Inhibitor (DNA-PKi), is known to potentiate the effects of radiation therapy in various solid tumor in vivo models. Currently there is no data evaluating anti-tumor efficacy of DNA-PK inhibitors in preclinical NET models. M-3814 inhibits DNA damage repair mechanism; antitumor efficacy of M-3814 in NETs is unknown. Methods: The efficacy of M-3814 in combination with radiation therapy (XRT) was evaluated in QGP-1 (pancreatic NET cell line) mouse model. Mice were injected with QGP-1 cells (5 mice) in 100 µL of PBS into the flank of mice with a 27-gauge needle. When tumor volumes reached average ~200 mm3, tumors were excised, separated into equal size tumor pieces and implanted subcutaneously into athymic nude mice. Next, mice were randomized into 4 groups for treatment with either placebo (n = 5), M-3814 (n = 5) alone (100 mg/Kg body weight (BW), XRT (n = 5) alone or in combination with M-3814 (n = 5). Treatment started when palpable tumors were established (200 mm3). Mice received M-3814 by gavage 30 minute prior to radiation therapy and irradiated with 4 daily doses of XRT at 2Gy per dose. Results: XRT and XRT+M-3814 treatment significantly decreased tumor size compared to control group. Combination treatment resulted in marked anti-tumor activity compared to both control group and XRT group. Tumors treated with XRT+M-3814 were also visibly less vascular. (Images will be provided in the poster). M-3814 alone had no effect on tumor growth as expected. Similar mouse weight changes were observed in both XRT and XRT+M-3814 treatment groups. Conclusions: M-3814 is a potent radiation sensitizer in preclinical neuroendocrine models. Strong antitumor activity was observed in QGP-1 xenograft model with marked reduction of tumor growth. Our enthusiasm for current project is driven not only by its inherent scientific importance, but also by its translational potential and the possibility to provide a more effective and less toxic radiation based treatment regimen for neuroendocrine tumors. [Table: see text]