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Introduction: Increasingly, early‐stage non–small cell lung cancer (NSCLC) is treated with stereotactic body radiation therapy (SBRT). Although treatment is generally effective, a small subset of tumors will recur because of radioresistance. Preclinical studies suggested PI3K‐AKT‐mTOR activation mediates radioresistance. This study sought to validate this finding in tumor samples from patients who underwent SBRT for NSCLC. Methods: Patients with T1‐3N0 NSCLC treated with SBRT at our institution were included. Total RNA of formalin‐fixed paraffin‐embedded tumor biopsy specimens (pretherapy) was isolated and analyzed using the Clariom D assay. Risk scores from a PI3K activity signature and four published NSCLC signatures were generated and dichotomized by the median. Kaplan–Meier curves and Cox regressions were used to analyze their association with recurrence and overall survival (OS). The PI3K signature was also tested in a data set of resected NSCLC for additional validation. Results: A total of 92 patients were included, with a median follow‐up of 18.3 months for living patients. There was no association of any of the four published gene expression signatures with recurrence or OS. However, high PI3K risk score was associated with higher local recurrence (hazard ratio [HR], 11.72; 95% CI, 1.40–98.0; p =.023) and worse disease‐free survival (DFS) (HR, 3.98; 95% CI, 1.57–10.09; p =.0035), but not OS (p =.49), regional recurrence (p =.15), or distant recurrence (p =.85). In the resected NSCLC data set (n = 361), high PI3K risk score was associated with decreased OS (log‐rank p =.013) but not DFS (p = 0.54). Conclusions: This study validates that higher PI3K activity, measured by gene expression, is associated with local recurrence and worse DFS in early‐stage NSCLC patients treated with SBRT. This may be useful in prognostication and/or tailoring treatment, and merits further validation. In this single‐institution study of 92 patients with T1‐3 non–small cell lung cancer treated with stereotactic body radiation therapy, it was found that high PI3K activity, measured by gene expression using pretreatment biopsy specimens, was associated with worse local recurrence and disease‐free survival. [ABSTRACT FROM AUTHOR]

Background: The calibration of the Respiratory Gating for SCanner (RGSC) system is critical to achieve better and more stable accuracy. The current procedure for a wall‐mounted RGSC system has a relatively large residual error. Purpose: To compare the baseline drifts in the image acquisition of DIBH using three reflector blocks versus using a single reflector block in the calibration of a wall‐mounted RGSC camera system. Materials and methods: Varian provides a calibration plate with three rows of calibration points: each row is separated by 15 cm longitudinally and by 10 cm laterally. In Varian's single‐block calibration method, the reflector block was first placed on the center point of the calibration plate and aligned with the scanner isocenter. The calibration took a picture of the block, then placed the block on the other eight points sequentially. In the proposed three‐block method, we placed three reflector blocks on the center row, with the center block aligned with the isocenter, and we took a picture of the center block by manually blocking the other two blocks in calibration. By moving the couch longitudinally in or out 15 cm, the calibration goes through all nine points. Monte Carlo simulation was done using Matlab to analyze the calibration matrix eigenvalue characteristics. Results: For a typical scan length of 40 cm of DIBH, the residual baseline drift in simulated DIBH is 0.02 ± 0.03 versus 0.30 ± 0.12 cm for three‐block calibration and single‐block calibration, respectively. To achieve 0.5 mm tolerance for the eigenvalue, the laser and reflector box should be within ±3 mm uncertainties based on the eigenvalue simulation. Conclusion: Three‐block calibration method effectively removes baseline drift caused by couch movement in DIBH/4D CT scan for the wall‐mounted camera while the single‐block calibration method still has significant residual baseline drift. [ABSTRACT FROM AUTHOR]

Simple Summary: Genetic information is seldom incorporated in formulating radiation treatment recommendations for patients with cancer, even though genetic information is now well established to be prognostic and predictive of cancer outcomes and response to systemic therapy. With the increasing accessibility to and use of genetic testing, tumor, and germline genetic data have the potential to inform clinical decisions by improving the efficacy of radiation treatment and ensuring the safety of treatment delivery. This review summarizes the biological underpinning of "radio-sensitizing genes", discusses the clinical basis and evidence for identifying genetic mutations as radiation response biomarkers, and proposes future directions for research as well as clinical implementation. Radiation treatment (RT) is a mainstay treatment for many types of cancer. Recommendations for RT and the radiation plan are individualized to each patient, taking into consideration the patient's tumor pathology, staging, anatomy, and other clinical characteristics. Information on germline mutations and somatic tumor mutations is at present rarely used to guide specific clinical decisions in RT. Many genes, such as ATM, and BRCA1/2, have been identified in the laboratory to confer radiation sensitivity. However, our understanding of the clinical significance of mutations in these genes remains limited and, as individual mutations in such genes can be rare, their impact on tumor response and toxicity remains unclear. Current guidelines, including those from the National Comprehensive Cancer Network (NCCN), provide limited guidance on how genetic results should be integrated into RT recommendations. With an increasing understanding of the molecular underpinning of radiation response, genomically-guided RT can inform decisions surrounding RT dose, volume, concurrent therapies, and even omission to further improve oncologic outcomes and reduce risks of toxicities. Here, we review existing evidence from laboratory, pre-clinical, and clinical studies with regard to how genetic alterations may affect radiosensitivity. We also summarize recent data from clinical trials and explore potential future directions to utilize genetic data to support clinical decision-making in developing a pathway toward personalized RT. [ABSTRACT FROM AUTHOR]

PURPOSE: With increased adoption of next-generation sequencing, tailored therapy on the basis of molecular status is being delivered for patients with early-stage resectable non–small-cell lung cancer (NSCLC). The purpose of this narrative review was to focus on recent developments of targeted therapies in the adjuvant and neoadjuvant/adjuvant setting for early-stage disease. METHODS: A systematic search of the MEDLINE/PubMed database was performed, focusing on studies published within the past 10 years. Our search queried "early-stage NSCLC (AND) tyrosine kinase inhibitor (TKI; OR) epidermal growth factor receptor (EGFR; OR) anaplastic lymphoma kinase (ALK)" and was limited only to prospective and ongoing studies. RESULTS: Most studies examining the benefit of targeted therapies in early-stage resectable NSCLC have been for EGFR-TKIs in the adjuvant setting. Currently, only one study, the ADAURA trial of adjuvant osimertinib, has demonstrated an overall survival benefit with the use of an EGFR-TKI in the adjuvant setting. Future work to build on the success of the ADAURA trial is focused on determining the optimal duration of targeted therapies and using biomarkers, such as circulating tumor DNA, to risk-stratify patients and guide maintenance targeted therapy duration. CONCLUSION: The results of several ongoing studies are eagerly awaited regarding the use of targeted therapies in the neoadjuvant/adjuvant setting and for more uncommon or rare mutations such as ALK , ROS proto-oncogene 1, rearranged during transfection, mesenchymal-epithelial transition factor, and B-Raf proto-oncogene V600E. The treatment landscape for early-stage NSCLC harboring actionable mutations is likely to shift dramatically in the upcoming decade. [ABSTRACT FROM AUTHOR]

Background: The RefleXion X1 is a novel radiotherapy delivery system on a ring gantry equipped with fan‐beam kV‐CT and PET imaging subsystems. The day‐to‐day scanning variability of radiomics features must be evaluated before any attempt to utilize radiomics features. Purpose: This study aims to characterize the repeatability and reproducibility of radiomic features produced by the RefleXion X1 kV‐CT. Materials and Methods: The Credence Cartridge Radiomics (CCR) phantom includes six cartridges of varied materials. It was scanned 10 times on the RefleXion X1 kVCT imaging subsystem over a 3‐month period using the two most frequently used scanning protocols (BMS and BMF). Fifty‐five radiomic features were extracted for each ROI on each CT scan and analyzed using LifeX software. The coefficient of variation (COV) was computed to evaluate the repeatability. Intraclass correlation coefficient (ICC) and concordance correlation coefficient (CCC) were used to evaluate the repeatability and reproducibility of the scanned images using 0.9 as the threshold. This process is repeated on a GE PET‐CT scanner using several built‐in protocols as a comparison. Results: On average, 87% of the features on both scan protocols on the RefleXion X1 kVCT imaging subsystem can be considered repeatable as they met COV < 10% criteria. On GE PET‐CT, this number is similar at 86%. When we tighten the criteria to COV <5%, the RefleXion X1 kVCT imaging subsystem showed much better repeatability with 81% of features on average whereas GE PET‐CT showed only 73.5% on average. About 91% and 89% of the features with ICC > 0.9 respectively for BMS and BMF protocols on RefleXion X1. On the other hand, the percentage of features with ICC > 0.9 on GE PET‐CT ranges from 67% to 82%. The RefleXion X1 kVCT imaging subsystem showed excellent intra‐scanner reproducibility between the scanning protocols much better than the GE PET CT scanner. For the inter‐scanner reproducibility, the percentage of features with CCC > 0.9 ranged from 49% to 80%. between X1 and GE PET‐CT scanning protocols. Conclusions: Clinically useful CT radiomic features produced by the RefleXion X1 kVCT imaging subsystem are reproducible and stable over time, demonstrating its utility as a quantitative imaging platform. [ABSTRACT FROM AUTHOR]

Simple Summary: Magnetic resonance-guided radiotherapy (MRgRT) is an emerging radiotherapy technology combining real-time magnetic resonance imaging and radiation delivery. By administering radiation with a linear accelerator with built in low-field or high-field MRI, practitioners have a greater ability to align to the target for daily set-up, precisely track the motion of and thereby target or avoid tissues and adapt to inter-treatment daily changes. This decreased uncertainty has implications for facilitating smaller, less-toxic treatment margins, potentially allowing delivery of higher dose radiotherapy that will lead to better control of tumors. The technology has already found success in treating breast, prostate, pancreatic, liver, lung, and limited metastatic cancers, in addition to non-oncologic indications such as cardiac ablation. The present narrative review aims to describe the current and future state of MRgRT technology and research. Magnetic resonance-guided radiotherapy (MRgRT) represents a promising new image guidance technology for radiation treatment delivery combining an onboard MRI scanner with radiation delivery technology. By enabling real-time low-field or high-field MRI acquisition, it facilitates improved soft tissue delineation, adaptive treatment, and motion management. Now that MRgRT has been available for nearly a decade, research has shown the technology can be used to effectively shrink treatment margins to either decrease toxicity (in breast, prostate cancer, and pancreatic cancer) or facilitate dose-escalation and improved oncologic outcomes (in pancreatic and liver cancer), as well as enabling indications that require clear soft tissue delineation and gating (lung and cardiac ablation). In doing so, the use of MRgRT has the potential to significantly improve the outcomes and quality of life of the patients it treats. The present narrative review aims to describe the rationale for MRgRT, the current and forthcoming state of technology, existing studies, and future directions for the advancement of MRgRT, including associated challenges. [ABSTRACT FROM AUTHOR]

Oncogenic mutations (such as in KRAS) can dysregulate transcription and replication, leading to transcription-replication conflicts (TRCs). Here, we demonstrate that TRCs are enriched in human pancreatic ductal adenocarcinoma (PDAC) compared to other common solid tumors or normal cells. Several orthogonal approaches demonstrated that TRCs are oncogene dependent. A small interfering RNA (siRNA) screen identified several factors in the base-excision repair (BER) pathway as main regulators of TRCs in PDAC cells. Inhibitors of BER pathway (methoxyamine and CRT) enhanced TRCs. Mechanistically, BER pathway inhibition severely altered RNA polymerase II (RNAPII) and R-loop dynamics at nascent DNA, causing RNAPII trapping and contributing to enhanced TRCs. The ensuing DNA damage activated the ATR-Chk1 pathway. Co-treatment with ATR inhibitor (VX970) and BER inhibitor (methoxyamine) at clinically relevant doses synergistically enhanced DNA damage and reduced cell proliferation in PDAC cells. The study provides mechanistic insights into the regulation of TRCs in PDAC by the BER pathway, which has biologic and therapeutic implications. [Display omitted] • Human PDAC demonstrates high levels of TRCs driven by oncogenic KRAS • Base-excision repair (BER) pathway regulates TRCs in PDAC cells • BER inhibition causes DNA damage by impacting RNAPII and R-loop dynamics at TRCs • BER and ATR inhibition cause synergistic toxicity in PDAC cells Meng et al. characterize transcription-replication conflicts (TRCs) as a key adaptive dependency of oncogenic KRAS in human PDAC. Their work uncovers the base-excision repair (BER) pathway as a key regulator of TRCs. Inhibition of the BER pathway altered transcription dynamics and activated ATR checkpoint. Co-inhibition of the BER and ATR pathway produced lethal DNA damage. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic cancers are highly aggressive tumors that carry a poor prognosis. With recent advances in radiation therapy techniques and systemic therapy, there is hope that the treatment landscape for pancreatic cancers will improve in the near future. This review summarizes radiation dose escalation strategies to improve outcomes in locally advanced pancreatic cancer as well as novel neoadjuvant therapy strategies to improve outcomes in resectable and borderline resectable pancreatic cancers. This review aims to summarize the recent advances in radiation oncology for pancreatic cancer. A systematic search of the MEDLINE/PubMed database and Clinicaltrials.gov was performed, focusing on studies published within the last 10 years. Our search queried "locally advanced pancreatic cancer [AND] stereotactic body radiation therapy (SBRT) [OR] hypofractionation [OR] magnetic resonance guidance radiation therapy (MRgRT) [OR] proton" and "borderline resectable pancreatic cancer [AND] neoadjuvant radiation" and was limited only to prospective and retrospective studies and metanalyses. For locally advanced pancreatic cancers (LAPC), retrospective evidence supports the notion of radiation dose escalation to improve overall survival (OS). Novel methods for increasing the dose to high risk areas while avoiding dose to organs at risk (OARs) include SBRT or ablative hypofractionation using a simultaneous integrated boost (SIB) technique, MRgRT, or charged particle therapy. The use of molecularly targeted agents with radiation to improve radiosensitization has also shown promise in several prospective studies. For resectable and borderline resectable pancreatic cancers (RPC and BRPC), several randomized trials are currently underway to study whether current neoadjuvant regimens using radiation may be improved with the use of the multi-drug regimen FOLFIRINOX or immune checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

Simple Summary: Most patients with EGFR-mutated NSCLC who receive treatment with targeted therapy will eventually develop resistance, meaning the therapy will lose its efficacy. Prior studies have shown a benefit to continuing to treat patients on TKI therapy despite limited progression of one or more sites of metastatic disease in EGFR-mutated NSCLC. Based on the data reviewed here, the use of radiation therapy to sites of disease progression is both efficacious and carries a low risk for side effects, with the added benefit of allowing patients to continue on TKI therapy. Tyrosine kinase inhibitor (TKI) therapy is the recommended first-line treatment for metastatic non-small-cell lung cancer (NSCLC) positive for epidermal growth factor receptor (EGFR) gene mutation. However, most individuals treated with TKI therapy for EGFR-mutant NSCLC will develop tumor resistance to TKI therapy. Therapeutic strategies to overcome TKI resistance are the topic of several ongoing clinical trials. One potential strategy, which has been explored in numerous trials, is the treatment of progressive sites of disease with stereotactic body radiation treatment (SBRT) or stereotactic radiosurgery (SRS). We sought to review the literature pertaining to the use of local ablative radiation therapy in the setting of acquired resistance to TKI therapy and to discuss stereotactic radiation therapy as a strategy to overcome TKI resistance. [ABSTRACT FROM AUTHOR]

Aim: To compare the overall survival (OS) among patients who received first-line modified gemcitabine plus nab-paclitaxel (G/nab-P) or 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (mFOLFIRINOX) for metastatic pancreatic cancer. Methods: A single-center, retrospective, real-world study was conducted. Results: The median OS was 9.4 months versus 7.5 months in the mFOLFIRINOX and modified G/Nab-P groups, respectively (p = 0.16). An exploratory subgroup analysis excluding patients who received one infusion and had an Eastern Cooperative Oncology Group performance score of 2 demonstrated similar OS of 11.3 months and 8.9 months, respectively. Median progression-free survival and time-to-treatment failure were not significantly different. Higher rates of adverse events were noted with mFOLFIRINOX. Conclusion: mFOLFIRINOX did not significantly prolong OS compared with modified G/nab-P and was associated with increased toxicities. [ABSTRACT FROM AUTHOR]

Purpose/objectives: The aim of this study is to compare intrafractional motion using two commercial non‐invasive immobilization systems for linac‐based intracranial stereotactic radiosurgery (SRS) under guidance with a surface‐guided radiotherapy (SGRT) system. Materials/methods: Twenty‐one patients who received intracranial SRS were retrospectively selected. Ten patients were immobilized with a vacuum fixation biteplate system, while 11 patients were immobilized with an open‐face mask system. A setup margin of 1 mm was used in treatment planning. Real‐time surface motion data in 37 treatment fractions using the vacuum fixation system and 44 fractions using the open‐face mask were recorded by an SGRT system. Variances of intrafractional motion along three translational directions and three rotational directions were compared between the two immobilization techniques with Levene's tests. Intrafractional motion variation over time during treatments was also evaluated. Results: Using the vacuum fixation system, the average and standard deviations of the shifts were 0.01 ± 0.18 mm, ‐0.06 ± 0.30 mm, and 0.02 ± 0.26 mm in the anterior–posterior (AP), superior–inferior (SI), and left–right (LR) directions, and ‐0.02 ± 0.19°, ‐0.01 ± 0.13°, and 0.01 ± 0.13° for rotations in yaw, roll, and pitch, respectively; using the open‐face mask system, the average and standard deviations of the shifts were ‐0.06 ± 0.20 mm, ‐0.02 ± 0.35 mm, and 0.01 ± 0.40 mm in the AP, SI, and LR directions, and were 0.05 ± 0.23°, 0.02 ± 0.21°, and 0.00 ± 0.16° for rotations in yaw, roll, and pitch, respectively. There was a significant increase in intrafractional motion variance over time during treatments. Conclusion: Patients with the vacuum fixation system had significantly smaller intrafractional motion variation compared to those with the open‐face mask system. Using intrafractional motion techniques such as surface imaging system is recommended to minimize dose deviation due to intrafractional motion. The increase in intrafractional motion over time indicates clinical benefits with shorter treatment time. [ABSTRACT FROM AUTHOR]

Background: In patients with stage III melanoma, the use of adjuvant radiation therapy (RT) after lymph node dissection (LND) may be currently considered in selected high-risk patients to improve tumor control. Melanomas harbor BRAF mutations (BRAF+) in 40-50% of cases, the majority of which are on the V600E residue. This study sought to compare the clinical outcomes after RT between patients with BRAF+ and BRAF- melanoma.Methods: This was a retrospective review of 105 Stage III melanoma patients treated at our institution with LND followed by adjuvant RT from 2006 to 2019. BRAF mutational status was determined on the primary skin or nodal tissue samples from all patients. We compared characteristics of the BRAF+ and BRAF- groups using Fisher's exact test and Wilcoxon rank sum test and performed univariate and multivariate analysis using Kaplan-Meier estimates, log-rank tests, and Cox proportional hazards modeling with the clinical outcomes of local-regional lymph node control, distant metastasis-free survival (DMFS), recurrence-free survival (RFS), and overall survival (OS).Results: Fifty-three (50%) patients harbored a BRAF mutation (92%, pV600E). BRAF+ patients were younger and had primary tumors more commonly found in the trunk vs head and neck compared to BRAF- patients (p < 0.05). The 5 year local-regional control in the BRAF + patients was 60% compared to 81% in the BRAF- patients (HR 4.5, 95% CI 1.3-15.5, p = 0.02). There were no significant differences in 5-year DMFS, RFS, and OS rates between the two BRAF patient groups. The presence of 4 or more positive LNs remained a significant prognostic factor for local-regional lymph node control, RFS, and OS in multivariate analysis.Conclusions: Stage III melanoma patients with BRAF mutation treated with adjuvant RT had > 4 times increased risk of local recurrence or regional lymph node recurrence. These results could be useful for adjuvant RT consideration in lymph node positive melanoma patients and supports other data that BRAF mutation confers radiation resistance. [ABSTRACT FROM AUTHOR]

Although the development of effective combined chemoradiation regimens for esophageal cancers has resulted in statistically significant survival benefits, the majority of patients treated with curative intent develop locoregional and/or distant relapse. Further improvements in disease control and survival will require the development of individualized therapy based on the knowledge of host and tumor genomics and potentially harnessing the host immune system. Although there are a number of gene targets that are amplified and proteins that are overexpressed in esophageal cancers, attempts to target several of these have not proven successful in unselected patients. Herein, we review our current state of knowledge regarding the molecular pathways implicated in esophageal carcinoma, and the available agents for targeting these pathways that may rationally be combined with standard chemoradiation, with the hope that this commentary will guide future efforts of novel combinations of therapy. [ABSTRACT FROM AUTHOR]

Accurate and complete DNA replication and separation are essential for genetic information inheritance and organism maintenance. Errors in DNA duplication are the main source of genetic instability. Understanding DNA duplication regulation is the key to elucidate the mechanisms and find treatment strategies for human genetic disorders, especially cancer. The mechanistic target of rapamycin (mTOR) is a central regulator of cell growth and proliferation by integrating and processing extracellular and intracellular signals to monitor the well-being of cell physiology. mTOR signaling dysregulation is associated with many human diseases including cancer and diabetes. Emerging evidence has demonstrated that mTOR signaling plays a key role in DNA duplication. We herein review the current knowledge of mTOR signaling in the regulation of DNA replication origin licensing, replication fork progression, and stabilization. [ABSTRACT FROM AUTHOR]

It has long been recognized that defects in cell cycle checkpoint and DNA repair pathways give rise to genomic instability, tumor heterogeneity, and metastasis. Despite this knowledge, the transcription factor-mediated gene expression programs that enable survival and proliferation in the face of enormous replication stress and DNA damage have remained elusive. Using robust omics data from two independent studies, we provide evidence that a large cohort of lung adenocarcinomas exhibit significant genome instability and overexpress the DNA damage responsive transcription factor MYB proto-oncogene like 2 (MYBL2). Across two studies, elevated MYBL2 expression was a robust marker of poor overall survival and disease-free survival outcomes, regardless of disease stage. Clinically, elevated MYBL2 expression identified patients with aggressive early onset disease, increased lymph node involvement, and increased incidence of distant metastases. Analysis of genomic sequencing data demonstrated that MYBL2 High lung adenocarcinomas had elevated somatic mutation burden, widespread chromosomal alterations, and alterations in single-strand DNA break repair pathways. In this study, we provide evidence that impaired single-strand break repair, combined with a loss of cell cycle regulators TP53 and RB1, give rise to MYBL2-mediated transcriptional programs. Omics data supports a model wherein tumors with significant genomic instability upregulate MYBL2 to drive genes that control replication stress responses, promote error-prone DNA repair, and antagonize faithful homologous recombination repair. Our study supports the use of checkpoint kinase 1 (CHK1) pharmacological inhibitors, in targeted MYBL2 High patient cohorts, as a future therapy to improve lung adenocarcinoma patient outcomes. [ABSTRACT FROM AUTHOR]

Objectives: Neutrophil–lymphocyte ratio (NLR) has been associated with mortality in non-small cell lung cancer (NSCLC), but its association with recurrence in locally advanced NSCLC (LA-NSCLC), specifically, is less established. We hypothesized pre- and posttreatment NLR would be associated with recurrence and mortality. Methods: We studied the association of pretreatment NLR (pre-NLR) and posttreatment NLR at 1 (post-NLR1) and 3 months (post-NLR3) with outcomes in patients with LA-NSCLC treated with chemoradiation. Pre-NLR was dichotomized by 5, an a priori cutoff previously shown to be prognostic in LA-NSCLC. Post-NLR1 and post-NLR3 were dichotomized by their medians. Results: We identified 135 patients treated with chemoradiation for LA-NSCLC between 2007 and 2016. Median follow-up for living patients was 61.1 months. On multivariable analysis, pre-NLR ≥ 5 was associated with worse overall survival (HR = 1.82; 95% CI 1.15 – 2.88; p = 0.011), but not with any recurrence, locoregional recurrence, or distant recurrence. Post-NLR1 ≥ 6.3 was not associated with recurrence or survival. Post-NLR3 ≥ 6.6 was associated with worse overall survival (HR = 3.27; 95% CI 2.01– 5.31; p < 0.001), any recurrence (HR = 2.50; 95% CI 1.53 – 4.08; p < 0.001), locoregional recurrence (HR = 2.50; 95% CI 1.40 – 4.46; p = 0.002), and distant recurrence (HR = 2.53; 95% CI 1.49 – 4.30; p < 0.001). Conclusion: Pretreatment NLR is associated with worse overall survival and posttreatment NLR is associated with worse survival and recurrence. These findings should be validated independently and prospectively studied. [ABSTRACT FROM AUTHOR]

Background: Lung cancer is the number one cancer killer worldwide. A major drawback in the lung cancer treatment field is the lack of realistic mouse models that replicate the complexity of human malignancy and immune contexture within the tumor microenvironment. Such models are urgently needed. Mutations of the tumor protein p53 are among the most common alterations in human lung cancers.Methods: Previously, we developed a line of lung cancer mouse model where mutant human TP53-273H is expressed in a lung specific manner in FVB/N background. To investigate whether the human TP53 mutant has a similar oncogenic potential when it is expressed in another strain of mouse, we crossed the FVB/N-SPC-TP53-273H mice to A/J strain and created A/J-SPC-TP53-273H transgenic mice. We then compared lung tumor formation between A/J-SPC-TP53-273H and FVB/N-SPC-TP53-273H.Results: We found the TP53-273H mutant gene has a similar oncogenic potential in lung tumor formation in both mice strains, although A/J strain mice have been found to be a highly susceptible strain in terms of carcinogen-induced lung cancer. Both transgenic lines survived more than 18 months and developed age related lung adenocarcinomas. With micro CT imaging, we found the FVB-SPC-TP53-273H mice survived more than 8 weeks after initial detection of lung cancer, providing a sufficient window for evaluating new anti-cancer agents.Conclusions: Oncogenic potential of the most common genetic mutation, TP53-273H, in human lung cancer is unique when it is expressed in different strains of mice. Our mouse models are useful tools for testing novel immune checkpoint inhibitors or other therapeutic strategies in the treatment of lung cancer. [ABSTRACT FROM AUTHOR]

We conducted an institutional study to compare the clinical and pathological efficacy between the neoadjuvant therapy (NAT)‐modified FOLFIRINOX (mFOLF) vs nanoparticle albumin–bound paclitaxel plus gemcitabine (nab‐P/G) for borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC) patients who completed resection. The study retrospectively enrolled patients with pathologically confirmed BRPC or LAPC from 2010 to 2018 at our institution. The survival rates were determined by the Kaplan‐Meier method and log‐rank test was used to test differences. Cox's proportional hazard model was used to assess survival with respect to covariates. Seventy‐two patients who completed at least two cycles of neoadjuvant chemotherapy and surgical resection were included, with 52 (72.2%) patients receiving mFOLF and 20 (27.8%) receiving nab‐P/G. Patients treated with mFOLF had statistically higher rates of RECIST 1.1 partial or complete response (16/52 vs 1/20, P =.028). Additionally, mFOLF patients had greater pathological tumor size reduction, fewer positive lymph nodes, and higher treatment response grade compared to the nab‐P/G patients (all P <.05). The median overall survival was 33.3 months vs 27.1 months (P =.105), and distant metastasis‒free survival (DMFS) was 21.3 months vs 14.6 months (P =.042) in the mFOLF vs nab‐P/G groups, respectively. On multivariate analysis, mFOLF (hazard ratio, 0.428; 95% confidence interval [CI], 0.186‐0.987) and abnormal postoperative CA 19‐9 (hazard ratio, 2.47; 95% CI, 1.06‐5.76) were associated with DMFS. Among patients with BRPC and LAPC who complete surgical resection, neoadjuvant mFOLF was associated with improved pathological and clinical outcomes compared with nab‐P/G. [ABSTRACT FROM AUTHOR]

Primary small cell carcinoma of the breast (SCCB) is a rare tumor subtype comprising <0.1% of all breast carcinomas. Here we present a case of thyroid transcription factor-1 (TTF-1) positive SCCB that recurred within 3 years of diagnosis in the lung and lymph nodes. Given the small number of cases, no clear guidelines exist on the appropriate management of patients with these aggressive tumors. We present a case study and review the current literature to highlight the knowledge gaps and needs of patients with these rare tumors. A 50-year-old premenopausal woman with no family history, presented with a palpable right breast mass. Biopsy was consistent with primary SCCB that was poorly differentiated, positive for synaptophysin and chromogranin and TTF-1 and presence of ductal carcinoma in situ component showing neuroendocrine differentiation. Imaging with PET, CT, and MRI brain excluded any other sites of primary disease. She underwent a right lumpectomy with axillary lymph node dissection and was treated with adjuvant cisplatin-based chemotherapy and concurrent radiation therapy. Thirty-four months later, routine scans showed a new right lower-lobe lung nodule and an enlarged sub-carinal node that was proven to be poorly differentiated neuroendocrine cancer. This case report sheds light on a rarely described disease and provides a comprehensive approach to diagnosis and management. Primary SCCB is an extremely rare, aggressive form of breast cancer that is molecularly and histologically similar to SCLC. However, a review of the literature highlights recent mutational analyses that show important differences between these two cancer types, including an increase in PIK3CA mutations in primary SCCB. Further studies, including genomic analyses are needed to better define this malignancy and to develop a standard treatment. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy worldwide and a leading cause of death worldwide. Its incidence continues to increase in the US due to hepatitis C infection and nonalcoholic steatohepatitis. Liver transplantation and resection remain the best therapeutic options for cure, but these are limited by the shortage of available organs for transplantation, diagnosis at advanced stage, and underlying chronic liver disease found in most patients with HCC. Immune checkpoint inhibitors (ICIs) have been shown to be an evolving novel treatment option in certain advanced solid tumors and have been recently approved for inoperable, advanced, and metastatic HCC. Unfortunately, a large cohort of patients with HCC fail to respond to immunotherapy. In this review, we discuss the ICIs currently approved for HCC treatment and their various mechanisms of action. We will highlight current understanding of mechanism of resistance and limitations to ICIs. Finally, we will describe emerging biomarkers of response to ICIs and address future direction on overcoming resistance to immune checkpoint therapy. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) represents a major public health problem as the second leading cause of cancer-related mortality in the United States. Of an estimated 140,000 newly diagnosed CRC cases in 2018, roughly one-third of these patients will have a primary tumor located in the distal large bowel or rectum. The current standard-of-care approach includes curative-intent surgery, often after preoperative (neoadjuvant) radiotherapy (RT), to increase rates of tumor down-staging, clinical and pathologic response, as well as improving surgical resection quality. However, despite advancements in surgical techniques, as well as sharpened precision of dosimetry offered by contemporary RT delivery platforms, the oncology community continues to face challenges related to disease relapse. Ongoing investigations are aimed at testing novel radiosensitizing agents and treatments that might exploit the systemic antitumor effects of RT using immunotherapies. If successful, these treatments may usher in a new curative paradigm for rectal cancers, such that surgical interventions may be avoided. Importantly, this disease offers an opportunity to correlate matched paired biopsies, radiographic response, and molecular mechanisms of treatment sensitivity and resistance with clinical outcomes. Herein, the authors highlight the available evidence from preclinical models and early-phase studies, with an emphasis on promising developmental therapeutics undergoing prospective validation in larger scale clinical trials. This review by the National Cancer Institute's Radiation Research Program Colorectal Cancer Working Group provides an updated, comprehensive examination of the continuously evolving state of the science regarding radiosensitizer drug development in the curative treatment of CRC. [ABSTRACT FROM AUTHOR]

Background: Fiducial markers (FMs) help direct stereotactic body radiation therapy (SBRT) and localization for surgical resection in lung cancer management. We report the safety, accuracy, and practice patterns of FM placement utilizing electromagnetic navigation bronchoscopy (ENB). Methods: NAVIGATE is a global, prospective, multicenter, observational cohort study of ENB using the superDimension™ navigation system. This prospectively collected subgroup analysis presents the patient demographics, procedural characteristics, and 1-month outcomes in patients undergoing ENB-guided FM placement. Follow up through 24 months is ongoing. Results: Two-hundred fifty-eight patients from 21 centers in the United States were included. General anesthesia was used in 68.2%. Lesion location was confirmed by radial endobronchial ultrasound in 34.5% of procedures. The median ENB procedure time was 31.0 min. Concurrent lung lesion biopsy was conducted in 82.6% (213/258) of patients. A mean of 2.2 ± 1.7 FMs (median 1.0 FMs) were placed per patient and 99.2% were accurately positioned based on subjective operator assessment. Follow-up imaging showed that 94.1% (239/254) of markers remained in place. The procedure-related pneumothorax rate was 5.4% (14/258) overall and 3.1% (8/258) grade ⩾ 2 based on the Common Terminology Criteria for Adverse Events scale. The procedure-related grade ⩾ 4 respiratory failure rate was 1.6% (4/258). There were no bronchopulmonary hemorrhages. Conclusion: ENB is an accurate and versatile tool to place FMs for SBRT and localization for surgical resection with low complication rates. The ability to perform a biopsy safely in the same procedure can also increase efficiency. The impact of practice pattern variations on therapeutic effectiveness requires further study. Trial registration: ClinicalTrials.gov identifier: NCT02410837. [ABSTRACT FROM AUTHOR]

Purpose: To test the hypothesis that increasing radiation dose to the thoracic marrow (TM) contributes to the development of hematologic toxicities (HT) in esophageal cancer (EC) patients receiving chemoradiation therapy (CRT). Methods: We identified EC cases treated with curative intent CRT at our institution from 2007 to 2016. The TM was contoured as the union of the vertebral bodies (VB) from T1-L1, the ribs from T1-L1, and the sternum. The TM-mean dose and the TM volume receiving at least 5–50 Gy (V5-V50) were collected. Grade ≥ 3 HT (HT3+) was the primary endpoint. Normal tissue complication probability (NTCP) was evaluated using the Lyman-Kutcher-Burman (LKB) model. Logistic regression was used to test associations between HT3+ and dosimetric parameters. Odds ratios (OR) and 95% confidence intervals (CI) are reported with p < 0.05 considered significant. Receiver operating characteristics analysis was used to determine optimal cut points. Results: We identified 137 EC cases, and most received concurrent carboplatin/paclitaxel (N = 83). Median radiation dose was 50.4 Gy (IQR = 50.4–50.4 Gy). The rate of HT3+ was 39.4%. Optimization of the LKB model yielded the results n = 0.70, m = 0.67, and TD50 = 20.1 Gy. The TM-V30 was most strongly associated with HT3+ and on multivariate analysis, patients with TM-V30 ≥ 14% had a 5.7-fold (95% CI 2.42–14.54, p < 0.001) increased odds of HT3+ in the entire cohort and a 4-fold (95% CI 1.54–11.11, p = 0.006) increased odds of HT3+ in the carboplatin/paclitaxel cohort compared to patients with TM-V30 < 14%. Radiation dose to the VB and rib sub-sites of the TM were also associated with HT3+, particularly VB-V40. Conclusion: We found that increasing TM radiation dose was associated with HT3+ in EC patients treated with CRT. Radiation dose to the VB and rib sub-sites were also associated with HT3+. These findings suggest that limiting radiation dose to the TM (or its sub-sites) may be sufficient to decrease HT3+, but further prospective evaluation of these results is needed. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 68-year-old man who history of noncreative hepatitis B, hepatitis C, alcohol abuse and intact liver function treated with sorafenib. The article discusses radiation therapy for hepatocellular carcinoma, ionizing radiation generating reactive oxygen species and DNA damage.

Erratum: "Evaluation of repeatability and reproducibility of radiomic features produced by the fan-beam kV-CT on a novel ring gantry-based PET/CT linear accelerator" https://10.1002/mp.16399 In Ketcherside et al., 1 the COI disclosure statement missed disclosing three authors who are from commercial companies, thus the COI disclosure statement is corrected. CONFLICT OF INTEREST STATEMENT David Leung, Andrew Sundquist, and Calvin Huntzinger are employed by Reflexion Medical. [Extracted from the article]

Purpose of Review: Three-dimensional conformal radiation therapy (3DCRT) has been the standard technique in the treatment of rectal cancer. The use of new radiation treatment technologies such as intensity-modulated radiation therapy (IMRT), proton therapy (PT), stereotactic body radiation therapy (SBRT), and brachytherapy (BT) has been increasing over the past 10 years. This review will highlight the advantages and drawbacks of these techniques. Recent Findings: IMRT, PT, SBRT, and BT achieve a higher target coverage conformity and a higher organ at risk sparing and enable dose escalation compared to 3DCRT. Some studies suggest a reduction in gastrointestinal and hematologic toxicities and an increase in the complete pathologic response rate; however, the clinical benefit of these techniques remains controversial. Summary: The results of these new techniques seem encouraging despite conclusive data. Further trials are required to establish their role in rectal cancer. [ABSTRACT FROM AUTHOR]

Background: Electromagnetic navigation bronchoscopy (ENB) procedures allow physicians to access peripheral lung lesions beyond the reach of conventional bronchoscopy. However, published research is primarily limited to small, single-center studies using previous-generation ENB software. The impact of user experience, patient factors, and lesion/procedural characteristics remains largely unexplored in a large, multicenter study. Methods/design: NAVIGATE (Clinical Evaluation of superDimension™ Navigation System for Electromagnetic Navigation Bronchoscopy) is a prospective, multicenter, global, cohort study. The study aims to enroll up to 2,500 consecutive subjects presenting for evaluation of lung lesions utilizing the ENB procedure at up to 75 clinical sites in the United States, Europe, and Asia. Subjects will be assessed at baseline, at the time of procedure, and at 1, 12, and 24 months post-procedure. The pre-test probability of malignancy will be determined for peripheral lung nodules. Endpoints include procedure-related adverse events, including pneumothorax, bronchopulmonary hemorrhage, and respiratory failure, as well as quality of life, and subject satisfaction. Diagnostic yield and accuracy, repeat biopsy rate, tissue adequacy for genetic testing, and stage at diagnosis will be reported for biopsy procedures. Complementary technologies, such as fluoroscopy and endobronchial ultrasound, will be explored. Success rates of fiducial marker placement, dye marking, and lymph node biopsies will be captured when applicable. Subgroup analyses based on geography, demographics, investigator experience, and lesion and procedure characteristics are planned. Discussion: Study enrollment began in April 2015. As of February 19, 2016, 500 subjects had been enrolled at 23 clinical sites with enrollment ongoing. NAVIGATE will be the largest prospective, multicenter clinical study on ENB procedures to date and will provide real-world experience data on the utility of the ENB procedure in a broad range of clinical scenarios. Trial Registration: ClinicalTrials.gov NCT02410837 . Registered 31 March 2015. [ABSTRACT FROM AUTHOR]

Purpose: Analyze inter-fraction volumetric changes of lung tumors treated with stereotactic body radiation therapy (SBRT) and determine if the volume changes during treatment can be predicted and thus considered in treatment planning. Methods and Materials: Kilo-voltage cone-beam CT (kV-CBCT) images obtained immediately prior to each fraction were used to monitor inter-fraction volumetric changes of 15 consecutive patients (18 lung nodules) treated with lung SBRT at our institution (45–54 Gy in 3–5 fractions) in the year of 2011–2012. Spearman's (ρ) correlation and Spearman's partial correlation analysis was performed with respect to patient/tumor and treatment characteristics. Multiple hypothesis correction was performed using False Discovery Rate (FDR) and q-values were reported. Results: All tumors studied experienced volume change during treatment. Tumor increased in volume by an average of 15% and regressed by an average of 11%. The overall volume increase during treatment is contained within the planning target volume (PTV) for all tumors. Larger tumors increased in volume more than smaller tumors during treatment (q = 0.0029). The volume increase on CBCT was correlated to the treatment planning gross target volume (GTV) as well as internal target volumes (ITV) (q = 0.0085 and q = 0.0039 respectively) and could be predicted for tumors with a GTV less than 22 mL. The volume increase was correlated to the integral dose (ID) in the ITV at every fraction (q = 0.0049). The peak inter-fraction volume occurred at an earlier fraction in younger patients (q = 0.0122). Conclusions: We introduced a new analysis method to follow inter-fraction tumor volume changes and determined that the observed changes during lung SBRT treatment are correlated to the initial tumor volume, integral dose (ID), and patient age. Furthermore, the volume increase during treatment of tumors less than 22mL can be predicted during treatment planning. The volume increase remained significantly less than the overall PTV expansion, and radiation re-planning was therefore not required for the purpose of tumor control. The presence of the studied correlations suggests that the observed volumetric changes may reflect some underlying biologic process rather than random fluctuations. [ABSTRACT FROM AUTHOR]