Beyond Front-Line Therapy for Unresectable Gastroesophageal Adenocarcinoma: Are There Differences in Subsequent Therapy Sequencing?

Background: Platinum + fluoropyrimidine is standard front-line therapy for unresectable gastroesophageal adenocarcinoma (GA). Subsequent therapy recommendations are ramucirumab + paclitaxel (RAM/PAC), taxane, irinotecan, or trifluridine-tipiracil. RAM/PAC is the preferred 2nd line choice; however, patients can have a contraindication due to cumulative neuropathy. Our study assessed varied sequencing of second-line and third-line therapies comparing RAM/PAC followed by fluoropyrimidine + irinotecan (FOLFIRI/CAPEIRI) vs the opposite sequence. Methods: We retrospectively analyzed metastatic GA patients who received at least 3 lines of therapy. Two cohorts were studied. Group A: RAM/PAC second-line with FOLFIRI/CAPIRI third-line or Group B: FOLFIRI/CAPEIRI second-line followed by RAM/PAC. Primary outcome was overall survival (OS). Results: 94 patients were available for analysis (51 pts Group A: 43 pts Group B). No difference was observed in median OS from the start of second-line therapy (Group A =10.5 months vs. Group B = 11.1 months, p=0.97) or median OS from metastatic disease diagnosis (Group A = 19.8 months vs Group B = 19.4 months, p=0.73). Conclusions: Our study, examining a practical issue of how to sequence 2nd and 3rd line therapies, documents that one sequence versus the other does not compromise patient outcomes and overall our patients had an outstanding OS of beyond 19 months when they receive 3rd line therapy.

Radiomic Based Machine learning Performance for a Three Class Problem in Neuro-oncology: Time to Test the Waters?

Prior radiomics studies have focused on two-class brain tumor classification, which limits generalizability. The performance of radiomics in differentiating the three most common malignant brain tumors (glioblastoma (GBM), primary central nervous system lymphoma (PCNSL), and metastatic disease) is assessed; factors affecting the model performance and usefulness of a single sequence versus multiparametric MRI (MP-MRI) remain largely unaddressed. This retrospective study included 253 patients (120 metastatic (lung and brain), 40 PCNSL, and 93 GBM). Radiomic features were extracted for whole a tumor mask (enhancing plus necrotic) and an edema mask (first pipeline), as well as for separate enhancing and necrotic and edema masks (second pipeline). Model performance was evaluated using MP-MRI, individual sequences, and the T1 contrast enhanced (T1-CE) sequence without the edema mask across 45 model/feature selection combinations. The second pipeline showed significantly high performance across all combinations (Brier score: 0.311–0.325). GBRM fit using the full feature set from the T1-CE sequence was the best model. The majority of the top models were built using a full feature set and inbuilt feature selection. No significant difference was seen between the top-performing models for MP-MRI (AUC 0.910) and T1-CE sequence with (AUC 0.908) and without edema masks (AUC 0.894). T1-CE is the single best sequence with comparable performance to that of multiparametric MRI (MP-MRI). Model performance varies based on tumor subregion and the combination of model/feature selection methods.

How Does Hypodontia Compare in Nonsyndromic Pierre Robin Sequence Versus Isolated Cleft Palate and Isolated Cleft Lip?

Objective: To assess the prevalence and patterns of hypodontia in nonsyndromic Pierre Robin sequence (PRS) and compare it with hypodontia in nonsyndromic isolated cleft palates and isolated cleft lips. Design: Retrospective cohort study. Setting: Alder Hey Children’s Hospital, United Kingdom. Patients: Patients with nonsyndromic PRS (group 1), isolated cleft palate (group 2), and isolated cleft lip (group 3). Main Outcome Measures: Hypodontia in the permanent dentition assessed from orthopantomographs. Results: A total of 154 patients were included. Group 1 had the highest incidence of hypodontia with 47% having at least one tooth congenitally absent. Groups 2 and 3 had reduced rates of hypodontia with 27% and 19% of the groups missing teeth, respectively; 93% of cases of hypodontia in group 1 involved the absence of at least one second premolar. Of these patients, there was found to be bilateral agenesis of second premolars in 50% of cases. Conclusions: Patients with PRS and cleft palates are more likely to have hypodontia than those with isolated cleft palates or unilateral cleft lips. Patients with PRS have more severe hypodontia than those with isolated cleft palates or unilateral cleft lips. Bilateral agenesis of lower second premolars is a commonly seen pattern among patients with PRS. In this large UK study, a similar prevalence and pattern of hypodontia to other nonsyndromic PRS populations worldwide has been demonstrated.

Radiomics-Based Differentiation between Glioblastoma, CNS Lymphoma, and Brain Metastases: Comparing Performance across MRI Sequences and Machine Learning Models

Prior radiomics studies have focused on two-class brain tumor classification, which limits generalizability. The performance of radiomics in differentiating the three most common malignant brain tumors (glioblastoma (GBM), primary central nervous system lymphoma (PCNSL), and metastatic disease) is assessed; factors affecting the model performance and usefulness of a single sequence versus multiparametric MRI (MP-MRI) remain largely unaddressed. This retrospective study included 253 patients (120 metastatic (lung and brain), 40 PCNSL, and 93 GBM). Radiomic features were extracted for whole a tumor mask (enhancing plus necrotic) and an edema mask (first pipeline), as well as for separate enhancing and necrotic and edema masks (second pipeline). Model performance was evaluated using MP-MRI, individual sequences, and the T1 contrast enhanced (T1-CE) sequence without the edema mask across 45 model/feature selection combinations. The second pipeline showed significantly high performance across all combinations (Brier score: 0.311–0.325). GBRM fit using the full feature set from the T1-CE sequence was the best model. The majority of the top models were built using a full feature set and inbuilt feature selection. No significant difference was seen between the top-performing models for MP-MRI (AUC 0.910) and T1-CE sequence with (AUC 0.908) and without edema masks (AUC 0.894). T1-CE is the single best sequence with comparable performance to that of multiparametric MRI (MP-MRI). Model performance varies based on tumor subregion and the combination of model/feature selection methods.

Silencing of oncogenic KRAS by mutant-selective small interfering RNA

Oncogenic mutations in the KRAS gene are well-established drivers of cancer. While the recently developed KRASG12C inhibitors offer a targeted KRAS therapy and have shown success in the clinic, KRASG12C represents only 11% of all KRAS mutations. Current therapeutic approaches for all other KRAS mutations are both indirect and non-mutant-selective, largely focusing on inhibition of downstream KRAS effectors such as MAP kinases. Inhibition of KRAS downstream signaling results in a system-wide down-modulation of the respective targets, raising concerns about systemic cell toxicity. Here, we describe a custom short interfering RNA (siRNA) oligonucleotide (EFTX-D1) designed to preferentially bind mRNA of the most commonly occurring KRAS missense mutations in codons 12 and 13. We determined that EFTX-D1 preferentially reduced the mutant KRAS sequence versus wild-type at the levels of both transcription and translation, and reversed oncogenic KRAS-induced morphologic and growth transformation. Furthermore, EFTX-D1 significantly impaired the proliferation of several KRAS mutant cancer cell lines in 2-D as well as 3-D assays. Taken together, our data indicate a novel use of RNA interference (RNAi) to target oncogenic KRAS-driven cancers specifically.

Preliminary Evidence That Motor Planning Is Slower and More Difficult for Children With Autism Spectrum Disorder During Motor Cooperation

Children with autism spectrum disorder (ASD) exhibit impairment in helping someone else with a motor action, which may arise from impairment in selecting and preparing motor responses. Five children with ASD and five typically developing children performed a cooperative motor planning task that required them to reach for, lift, and hand an object (hammer or stick) to a researcher. The response, movement, and grasp time were measured. Children with ASD grasped the object longer on trials where they helped, indicating that the action was planned in sequence versus as a whole (i.e., prior to the onset of movement). The hammer object elicited a quicker response than the stick, suggesting the facilitation of planning by tools with inherent action properties. Finally, the increased helping of children with ASD was not mirrored by changes in the response, movement, or grasp time.