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Recent progress in targeting KRAS G12C has provided both insight and inspiration for targeting alternative KRAS mutants. In this study, we evaluated the mechanism of action and anti-tumor efficacy of MRTX1133, a potent, selective and non-covalent KRAS G12D inhibitor. MRTX1133 demonstrated a high-affinity interaction with GDP-loaded KRAS G12D with K D and IC 50 values of ~0.2 pM and <2 nM, respectively, and ~700-fold selectivity for binding to KRAS G12D as compared to KRAS WT . MRTX1133 also demonstrated potent inhibition of activated KRAS G12D based on biochemical and co-crystal structural analyses. MRTX1133 inhibited ERK1/2 phosphorylation and cell viability in KRAS G12D -mutant cell lines, with median IC 50 values of ~5 nM, and demonstrated >1,000-fold selectivity compared to KRAS WT cell lines. MRTX1133 exhibited dose-dependent inhibition of KRAS-mediated signal transduction and marked tumor regression (≥30%) in a subset of KRAS G12D -mutant cell-line-derived and patient-derived xenograft models, including eight of 11 (73%) pancreatic ductal adenocarcinoma (PDAC) models. Pharmacological and CRISPR-based screens demonstrated that co-targeting KRAS G12D with putative feedback or bypass pathways, including EGFR or PI3Kα, led to enhanced anti-tumor activity. Together, these data indicate the feasibility of selectively targeting KRAS mutants with non-covalent, high-affinity small molecules and illustrate the therapeutic susceptibility and broad dependence of KRAS G12D mutation-positive tumors on mutant KRAS for tumor cell growth and survival. A potent and selective inhibitor of KRAS G12D , the most common mutant form of the KRAS oncoprotein, has anti-tumor efficacy in multiple pre-clinical cancer models, opening the possibility to therapeutically target this highly prevalent oncogenic driver.

Since manual detection of brain metastases (BMs) is time consuming, studies have been conducted to automate this process using deep learning. The purpose of this study was to conduct a systematic review and meta-analysis of the performance of deep learning models that use magnetic resonance imaging (MRI) to detect BMs in cancer patients. A systematic search of MEDLINE, EMBASE, and Web of Science was conducted until 30 September 2022. Inclusion criteria were: patients with BMs; deep learning using MRI images was applied to detect the BMs; sufficient data were present in terms of detective performance; original research articles. Exclusion criteria were: reviews, letters, guidelines, editorials, or errata; case reports or series with less than 20 patients; studies with overlapping cohorts; insufficient data in terms of detective performance; machine learning was used to detect BMs; articles not written in English. Quality Assessment of Diagnostic Accuracy Studies-2 and Checklist for Artificial Intelligence in Medical Imaging was used to assess the quality. Finally, 24 eligible studies were identified for the quantitative analysis. The pooled proportion of patient-wise and lesion-wise detectability was 89%. Articles should adhere to the checklists more strictly. Deep learning algorithms effectively detect BMs. Pooled analysis of false positive rates could not be estimated due to reporting differences.

Background Spine stereotactic body radiation therapy (SBRT) uses highly conformal dose distributions and sharp dose gradients to cover targets in proximity to the spinal cord or cauda equina, which requires precise patient positioning and immobilization to deliver safe treatments. Aims Given some limitations with the BodyFIX system in our practice, we sought to evaluate the accuracy and efficiency of the Klarity SBRT patient immobilization system in comparison to the BodyFIX system. Methods Twenty‐three patients with 26 metastatic spinal lesions (78 fractions) were enrolled in this prospective observational study with one of two systems – BodyFIX (n = 11) or Klarity (n = 12). All patients were initially set up to external marks and positioned to match bony anatomy on ExacTrac images. Table corrections given by ExacTrac during setup and intrafractional monitoring and deviations from pre‐ and posttreatment CBCT images were analyzed. Results For initial setup accuracy, the Klarity system showed larger differences between initial skin mark alignment and the first bony alignment on ExacTrac than BodyFIX, especially in the vertical (mean [SD] of 5.7 mm [4.1 mm] for Klarity vs. 1.9 mm [1.7 mm] for BodyFIX, p‐value < 0.01) and lateral (5.4 mm [5.1 mm] for Klarity vs. 3.2 mm [3.2 mm] for BodyFIX, p‐value 0.02) directions. For set‐up stability, no significant differences (all p‐values > 0.05) were observed in the maximum magnitude of positional deviations between the two systems. For setup efficiency, Klarity system achieved desired bony alignment with similar number of setup images and similar setup time (14.4 min vs. 15.8 min, p‐value = 0.41). For geometric uncertainty, systematic and random errors were found to be slightly less with Klarity than with BodyFIX based on an analytical calculation. Conclusion With image‐guided correction of initial alignment by external marks, the Klarity system can provide accurate and efficient patient immobilization. It can be a promising alternative to the BodyFIX system for spine SBRT while providing potential workflow benefits depending on one's practice environment.

Background A strong dose-volume relationship exists between the amount of small bowel receiving low- to intermediate-doses of radiation and the rates of acute, severe gastrointestinal toxicity, principally diarrhea. There is considerable interest in the application of highly conformal treatment approaches, such as intensity-modulated radiation therapy (IMRT), to reduce dose to adjacent organs-at-risk in the treatment of carcinoma of the rectum. Therefore, we performed a comprehensive dosimetric evaluation of IMRT compared to 3-dimensional conformal radiation therapy (3DCRT) in standard, preoperative treatment for rectal cancer. Methods Using RTOG consensus anorectal contouring guidelines, treatment volumes were generated for ten patients treated preoperatively at our institution for rectal carcinoma, with IMRT plans compared to plans derived from classic anatomic landmarks, as well as 3DCRT plans treating the RTOG consensus volume. The patients were all T3, were node-negative (N = 1) or node-positive (N = 9), and were planned to a total dose of 45-Gy. Pairwise comparisons were made between IMRT and 3DCRT plans with respect to dose-volume histogram parameters. Results IMRT plans had superior PTV coverage, dose homogeneity, and conformality in treatment of the gross disease and at-risk nodal volume, in comparison to 3DCRT. Additionally, in comparison to the 3DCRT plans, IMRT achieved a concomitant reduction in doses to the bowel (small bowel mean dose: 18.6-Gy IMRT versus 25.2-Gy 3DCRT; p = 0.005), bladder (V 40Gy : 56.8% IMRT versus 75.4% 3DCRT; p = 0.005), pelvic bones (V 40Gy : 47.0% IMRT versus 56.9% 3DCRT; p = 0.005), and femoral heads (V 40Gy : 3.4% IMRT versus 9.1% 3DCRT; p = 0.005), with an improvement in absolute volumes of small bowel receiving dose levels known to induce clinically-relevant acute toxicity (small bowel V 15Gy : 138-cc IMRT versus 157-cc 3DCRT; p = 0.005). We found that the IMRT treatment volumes were typically larger than that covered by classic bony landmark-derived fields, without incurring penalty with respect to adjacent organs-at-risk. Conclusions For rectal carcinoma, IMRT, compared to 3DCRT, yielded plans superior with respect to target coverage, homogeneity, and conformality, while lowering dose to adjacent organs-at-risk. This is achieved despite treating larger volumes, raising the possibility of a clinically-relevant improvement in the therapeutic ratio through the use of IMRT with a belly-board apparatus.

With improvements in survival for patients with metastatic cancer, long-term local control of brain metastases has become an increasingly important clinical priority. While consensus guidelines recommend surgery followed by stereotactic radiosurgery (SRS) for lesions >3 cm, smaller lesions (≤3 cm) treated with SRS alone elicit variable responses. To determine factors influencing this variable response to SRS, we analyzed outcomes of brain metastases ≤3 cm diameter in patients with no prior systemic therapy treated with frame-based single-fraction SRS. Following SRS, 259 out of 1733 (15%) treated lesions demonstrated MRI findings concerning for local treatment failure (LTF), of which 202 /1733 (12%) demonstrated LTF and 54/1733 (3%) had an adverse radiation effect. Multivariate analysis demonstrated tumor size (>1.5 cm) and melanoma histology were associated with higher LTF rates. Our results demonstrate that brain metastases ≤3 cm are not uniformly responsive to SRS and suggest that prospective studies to evaluate the effect of SRS alone or in combination with surgery on brain metastases ≤3 cm matched by tumor size and histology are warranted. These studies will help establish multi-disciplinary treatment guidelines that improve local control while minimizing radiation necrosis during treatment of brain metastasis ≤3 cm. Current guidelines recommend stereotactic radiosurgery for brain metastasis measuring less than 3 cm but there is significant variability in outcomes following treatment. This study shows that in treatment naïve brain metastasis less than 3 cm, intrinsic biological differences across multiple histologies may influence response to stereotactic radiosurgery.

BackgroundUp to 20% of patients with non-small cell lung cancer (NSCLC) develop brain metastasis (BM), for which the current standard of care is radiation therapy with or without surgery. There are no prospective data on the safety of stereotactic radiosurgery (SRS) concurrent with immune checkpoint inhibitor therapy for BM. This is the safety cohort of the phase I/II investigator-initiated trial of SRS with nivolumab and ipilimumab for patients with BM from NSCLC.Patients and methodsThis single-institution study included patients with NSCLC with active BM amenable to SRS. Brain SRS and systemic therapy with nivolumab and ipilimumab were delivered concurrently (within 7 days). The endpoints were safety and 4-month intracranial progression-free survival (PFS).ResultsThirteen patients were enrolled in the safety cohort, 10 of whom were evaluable for dose-limiting toxicities (DLTs). Median follow-up was 23 months (range 9.7–24.3 months). The median interval between systemic therapy and radiation therapy was 3 days. Only one patient had a DLT; hence, predefined stopping criteria were not met. In addition to the patient with DLT, three patients had treatment-related grade ≥3 adverse events, including elevated liver function tests, fatigue, nausea, adrenal insufficiency, and myocarditis. One patient had a confirmed influenza infection 7 months after initiation of protocol treatment (outside the DLT assessment window), leading to pneumonia and subsequent death from hemophagocytic lymphohistiocytosis. The estimated 4-month intracranial PFS rate was 70.7%.ConclusionConcurrent brain SRS with nivolumab/ipilimumab was safe for patients with active NSCLC BM. Preliminary analyses of treatment efficacy were encouraging for intracranial treatment response.

Purpose We investigated the feasibility of thoracic spine stereotactic body radiotherapy (SBRT) using the Elekta Unity magnetic resonance‐guided linear accelerator (MRL) in patients who received prior radiotherapy. We hypothesized that Monaco treatment plans can improve the gross tumor volume minimum dose (GTVmin) with spinal cord preservation and maintain consistent plan quality during daily adaptation. Methods Pinnacle clinical plans for 10 patients who underwent thoracic spine SBRT (after prior radiotherapy) were regenerated in the Monaco treatment planning system for the Elekta Unity MRL using 9 and 13 intensity‐modulated radiotherapy (IMRT) beams. Monaco adapt‐to‐position (ATP) and adapt‐to‐shape (ATS) workflow plans were generated using magnetic resonance imaging with a simulated daily positional setup deviation, and these adaptive plans were compared with Monaco reference plans. Plan quality measures included target coverage, Paddick conformity index, gradient index, homogeneity index, spinal cord D0.01cc, esophagus D0.01cc, lung V10, and skin D0.01cc. Results GTVmin values from the Monaco 9‐beam and 13‐beam plans were significantly higher than those from Pinnacle plans (p < 0.01) with similar spinal cord dose. Spinal cord D0.01cc, esophagus D0.01cc, and lung V10 did not statistically differ among the three plans. The electron‐return effect did not induce remarkable dose effects around the lungs or skin. While in the ATP workflow, a large increase in GTVmin was observed at the cost of a 10%–50% increase in spinal cord D0.01cc, in the ATS workflow, the spinal cord dose increase was maintained within 3% of the reference plan. Conclusion These findings show that MRL plans for thoracic spine SBRT are safe and feasible, allowing tumor dose escalation with spinal cord preservation and consistent daily plan adaptation using the ATS workflow. Careful plan review of hot spots and lung dose is necessary for safe MRL‐based treatment.

Purpose To develop an automated workflow for rectal cancer three‐dimensional conformal radiotherapy (3DCRT) treatment planning that combines deep learning (DL) aperture predictions and forward‐planning algorithms. Methods We designed an algorithm to automate the clinical workflow for 3DCRT planning with field aperture creations and field‐in‐field (FIF) planning. DL models (DeepLabV3+ architecture) were trained, validated, and tested on 555 patients to automatically generate aperture shapes for primary (posterior–anterior [PA] and opposed laterals) and boost fields. Network inputs were digitally reconstructed radiographs, gross tumor volume (GTV), and nodal GTV. A physician scored each aperture for 20 patients on a 5‐point scale (>3 is acceptable). A planning algorithm was then developed to create a homogeneous dose using a combination of wedges and subfields. The algorithm iteratively identifies a hotspot volume, creates a subfield, calculates dose, and optimizes beam weight all without user intervention. The algorithm was tested on 20 patients using clinical apertures with varying wedge angles and definitions of hotspots, and the resulting plans were scored by a physician. The end‐to‐end workflow was tested and scored by a physician on another 39 patients. Results The predicted apertures had Dice scores of 0.95, 0.94, and 0.90 for PA, laterals, and boost fields, respectively. Overall, 100%, 95%, and 87.5% of the PA, laterals, and boost apertures were scored as clinically acceptable, respectively. At least one auto‐plan was clinically acceptable for all patients. Wedged and non‐wedged plans were clinically acceptable for 85% and 50% of patients, respectively. The hotspot dose percentage was reduced from 121% (σ = 14%) to 109% (σ = 5%) of prescription dose for all plans. The integrated end‐to‐end workflow of automatically generated apertures and optimized FIF planning gave clinically acceptable plans for 38/39 (97%) of patients. Conclusion We have successfully automated the clinical workflow for generating radiotherapy plans for rectal cancer for our institution.