A PI3K gene expression signature predicts for recurrence in early-stage non-small cell lung cancer treated with stereotactic body radiation therapy.

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.

Oncogenic KRAS drives radioresistance through upregulation of NRF2-53BP1-mediated non-homologous end-joining repair.

KRAS-activating mutations are oncogenic drivers and are correlated with radioresistance of multiple cancers, including colorectal cancer, but the underlying precise molecular mechanisms remain elusive. Herein we model the radiosensitivity of isogenic HCT116 and SW48 colorectal cancer cell lines bearing wild-type or various mutant KRAS isoforms. We demonstrate that KRAS mutations indeed lead to radioresistance accompanied by reduced radiotherapy-induced mitotic catastrophe and an accelerated release from G2/M arrest. Moreover, KRAS mutations result in increased DNA damage response and upregulation of 53BP1 with associated increased non-homologous end-joining (NHEJ) repair. Remarkably, KRAS mutations lead to activation of NRF2 antioxidant signaling to increase 53BP1 gene transcription. Furthermore, genetic silencing or pharmacological inhibition of KRAS, NRF2 or 53BP1 attenuates KRAS mutation-induced radioresistance, especially in G1 phase cells. These findings reveal an important role for a KRAS-induced NRF2-53BP1 axis in the DNA repair and survival of KRAS-mutant tumor cells after radiotherapy, and indicate that targeting NRF2, 53BP1 or NHEJ may represent novel strategies to selectively abrogate KRAS mutation-mediated radioresistance.

Comparison of baseline drifts using three reflector blocks versus using a single reflector block for the calibration of wall-mounted Respiratory Gating for Scanner (RGSC) camera integrated with a CT.

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.

First-line gemcitabine plus nab-paclitaxel versus FOLFIRINOX for metastatic pancreatic cancer in a real-world population.

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.

Pancreatic cancer that has spread to other parts of the body cannot be cured and patients usually have a limited time to live after diagnosis. It is therefore important to choose an effective treatment while minimizing the side effects of chemotherapy and maintaining patients' quality of life. Initial chemotherapy regimens include a combination of gemcitabine plus nab-paclitaxel (G/nab-P) or 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX). While some studies have found that patients treated with FOLFIRINOX may live longer, they also experience more side effects. This single-center study showed that patients treated with modified G/nab-P and FOLFIRINOX regimens had similar survival outcomes but FOLFIRINOX was associated with increased toxicities.

Comparison of intrafractional motion with two frameless immobilization systems in surface-guided intracranial stereotactic radiosurgery.

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.

Disparate Use of Chemoradiation in Elderly Patients With Localized Anal Cancer.

BACKGROUND: The incidence of squamous cell carcinoma of the anus (SCCA) is increasing, particularly among the elderly (age ≥65 years). We sought to compare patterns of care for the treatment of SCCA in elderly versus nonelderly patients. METHODS: Data for patients with stages I-III SCCA diagnosed from 2004 through 2015 were obtained from the National Cancer Database. Patients were categorized as having received standard-of-care (SOC) chemoradiation (CRT) with multiagent chemotherapy, non-SOC therapy, palliative therapy, or no treatment. Differences in treatment groups were tested using the chi-square test. We used logistic regression to identify predictors of SOC CRT and multiagent versus single-agent chemotherapy in patients receiving CRT. Propensity score matching was used to compare overall survival (OS) in elderly patients receiving multiagent versus single-agent chemotherapy for those receiving CRT. RESULTS: We identified 9,156 elderly and 17,640 nonelderly patients. A lower proportion of elderly versus nonelderly patients (54.5% vs 65.0%; P<.0001) received SOC CRT than other treatments or no treatment. In multivariate analysis, elderly patients were 38% less likely than nonelderly patients to receive SOC CRT (odds ratio, 0.62; 95% CI, 0.58-0.65; P<.0001). A higher proportion of the elderly were treated with single-agent versus multiagent chemotherapy (16.9% vs 11.8%; P<.0001), which resulted in a >1.5-fold increase in the likelihood of elderly patients receiving single-agent chemotherapy (odds ratio, 1.52; 95% CI, 1.39-1.66) in multivariate analysis. After propensity score matching, 3-year OS was higher in elderly patients who received CRT with multiagent versus single-agent chemotherapy (77.1% vs 67.5%; hazard ratio, 0.78; 95% CI, 0.68-0.89; P=.0002). CONCLUSIONS: In this comprehensive study of patients with stages I-III SCCA, elderly patients were less likely than nonelderly patients to receive SOC CRT. The low proportion of elderly patients receiving SOC CRT with multiagent chemotherapy for localized anal cancer suggests that the optimal treatment approach for this vulnerable population remains undefined.

Neoadjuvant therapy versus surgery first for ampullary carcinoma: A propensity score-matched analysis of the NCDB.

BACKGROUND: The role of neoadjuvant therapy (NT) for ampullary carcinoma (AC) has not been clearly established. METHODS: Patients who underwent pancreatoduodenectomy for AC between 2004 and 2016 were identified in the National Cancer Database. Overall survival (OS) was compared between those who received NT before resection and those who underwent surgery first (SF). Propensity score matching (PSM) was performed using age, pathologic T and N stage, and tumor differentiation. RESULTS: Among 8688 patients with AC, 175 (2.0%) received NT before surgery. While patients who received NT were younger (p = .022) and more likely to have nodal metastasis (43.3% vs. 35.1%, p < .001), there was no difference in OS on univariate (43 vs. 33 months; hazard ratio [HR]: 1.10, 95% confidence interval [CI]: 0.88-1.37, p = .401) or multivariate (HR: 1.09, 95% CI: 0.88-1.36, p = .416) analysis between groups. After PSM, there remained no difference in OS between NT or SF groups on univariate (37 vs. 32 months; HR: 1.20, 95% CI: 0.87-1.64, p = .350) or multivariate (HR: 0.99, 95% CI: 0.71-1.38, p = .943) analysis. CONCLUSION: NT followed by surgery was not associated with improved survival outcomes compared with SF among patients with localized AC. While NT is an acceptable alternative for patients with advanced disease, SF should remain the standard of care.

The oncogenic potential of a mutant TP53 gene explored in two spontaneous lung cancer mice models.

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.

Contemporary Understandings of Cardiovascular Disease After Cancer Radiotherapy: a Focus on Ischemic Heart Disease.

PURPOSE OF REVIEW: Radiation-induced cardiovascular disease, including coronary artery disease, is a well-known sequela of radiation therapy and represents a significant source of morbidity and mortality for cancer survivors. This review examines current literature and guidelines to care for this growing population of cancer survivors. RECENT FINDINGS: The development of radiation-induced ischemic heart disease following radiation can lead even to early cardiotoxicities, inclusive of coronary artery disease, which limit cancer treatment outcomes. These coronary lesions tend to be diffuse, complex, and proximal. Early detection with multimodality imaging and targeted intervention is required to minimize these risks. Early awareness, detection, and management of radiation-induced cardiovascular disease are paramount as cancer survivorship continues to grow.

WWOX, the FRA16D gene: A target of and a contributor to genomic instability.

WWOX is one of the largest human genes spanning over 1.11 Mbp in length at chr16q23.1-q23.2 and containing FRA16D, the second most common chromosomal fragile site. FRA16D is a hot spot of genomic instability, prone to breakage and for causing germline and somatic copy number variations (CNVs). Consequentially WWOX is frequent target for deletions in cancer. Esophageal, stomach, colon, bladder, ovarian, and uterine cancers are those most commonly affected by WWOX deep focal deletions. WWOX deletions significantly correlate with various clinicopathological features in esophageal carcinoma. WWOX is also a common target for translocations in multiple myeloma. By mapping R-loop (RNA:DNA hybrid) forming sequences (RFLS) we observe this to be a consistent feature aligning with germline and somatic CNV break points at the edges and core of FRA16D spanning from introns 5 to 8 of WWOX. Germline CNV polymorphisms affecting WWOX are extremely common in humans across different ethnic groups. Importantly, structural variants datasets allowed us to identify a specific hot spot for germline duplications and deletions within intron 5 of WWOX coinciding with the 5' edge of the FRA16D core and various RFLS. Recently, multiple pathogenic CNVs spanning WWOX have been identified associated with neurological conditions such as autism spectrum disorder, infantile epileptic encephalopathies, and other developmental anomalies. Loss of WWOX function has recently been associated with DNA damage repair abnormalities, increased genomic instability, and resistance to chemoradiotherapy. The described observations place WWOX both as a target of and a contributor to genomic instability. Both of these aspects will be discussed in this review.

Pathologic complete response following neoadjuvant therapy for pancreatic ductal adenocarcinoma: defining the incidence, predictors, and outcomes.

BACKGROUND: Neoadjuvant therapy (NT) is increasingly utilized for patients with pancreatic ductal adenocarcinoma (PDAC) but the nationwide incidence and long-term prognosis of a pathologic complete response (pCR) remains poorly understood. METHODS: Patients with localized PDAC and known cT and pT stage who received NT prior to pancreatectomy from 2004 to 2016 were identified using the National Cancer Database. The clinicopathologic characteristics and long-term outcomes of patients who did and did not experience a pCR were compared. RESULTS: Among 7,902 patients who underwent NT prior to pancreatectomy, 244 (3.1%) experienced a pCR while 7,658 (96.9%) did not. On multivariable regression, longer duration of NT (OR 1.20, 95% CI 1.14-1.27 per month) and use of preoperative radiation (OR 9.98, 95% CI 3.05-32.71) were independently associated with a pCR. Median overall survival (OS) was longer among patients who experienced a pCR (77 vs 26 months, p < 0.001). On multivariate analysis, pCR was the strongest predictor of improved OS (HR 0.43, 95%CI 0.32-0.58, p < 0.001). CONCLUSION: A pCR following NT for PDAC occurs infrequently but is associated with significantly improved OS. Better predictors of response and more effective preoperative regimens should be aggressively sought.

National Cancer Institute (NCI) state of the science: Targeted radiosensitizers in colorectal cancer.

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.

Design of a prospective, multicenter, global, cohort study of electromagnetic navigation bronchoscopy.

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.

Initial testing (stage 1) of the tubulin binding agent nanoparticle albumin-bound (nab) paclitaxel (Abraxane(®)) by the Pediatric Preclinical Testing Program (PPTP).

BACKGROUND: Nanoparticle albumin-bound paclitaxel (nab-paclitaxel, Abraxane(®)) is FDA approved for the treatment of several adult cancers. Antimitotic agents are essential components for curative therapy of pediatric solid tumors, although taxanes have shown limited activity. Because of the novel formulation, nab-paclitaxel was evaluated against a limited series of Pediatric Preclinical Testing Program (PPTP) solid tumors. PROCEDURES: Nab-paclitaxel was tested against a limited subset of PPTP solid tumor xenograft models at a dose of 50 mg/kg using a q4d × 3 schedule intravenously. RESULTS: Nab-paclitaxel was well tolerated in vivo, producing maximum weight loss of approximately 10% with recovery to baseline weight in the week following the third dose. All 20 xenograft models tested were considered evaluable for efficacy. Nab-paclitaxel induced statistically significant differences in event-free survival (EFS) distribution compared to control in 19 of 20 (95%) of the solid tumors. Objective responses were observed in 12 of 20 (60%) solid tumor xenografts. Complete responses (CR) or maintained CR were observed in 5 of 8 Ewing sarcoma models and 6 of 8 rhabdomyosarcomas. There were no objective regressions in either neuroblastoma (n = 2) or osteosarcoma (n = 2) xenograft panels. At the dose tested, systemic exposures of nab-paclitaxel in mice were somewhat greater than those tolerated in humans. CONCLUSIONS: The high level of activity observed against the rhabdomyosarcoma and Ewing sarcoma PPTP preclinical models makes nab-paclitaxel an interesting agent to consider for pediatric evaluation.

Grade 5 Radiation Necrosis After Whole-Brain Radiation Therapy.

Whole-brain radiation treatment is often considered for patients with leptomeningeal disease. There are limited reports of the development of radiation necrosis after whole-brain radiation treatment and fewer associating the presence of germline mutations with risk. We present a case report to highlight the need for consideration of radiosensitizing mutations when recommending radiation therapy.

Improved Targeting and Safety of Doxorubicin through a Novel Albumin Binding Prodrug Approach.

Human serum albumin (HSA) improves the pharmacokinetic profile of drugs attached to it, making it an attractive carrier with proven clinical success. In our previous studies, we have shown that Caveolin-1 (Cav-1) and caveolae-mediated endocytosis play important roles in the uptake of HSA and albumin-bound drugs. Doxorubicin is an FDA-approved chemotherapeutic agent that is effective against multiple cancers, but its clinical applicability has been hampered by its high toxicity levels. In this study, a doxorubicin-prodrug was developed that could independently and avidly bind HSA in circulation, called IPBA-Dox. We first developed and characterized IPBA-Dox and confirmed that it can bind albumin in vitro while retaining a potent cytotoxic effect. We then verified that it efficiently binds to HSA in circulation, leading to an improvement in the pharmacokinetic profile of the drug. In addition, we tested our prodrug for Cav-1 selectivity and found that it preferentially affects cells that express relatively higher levels of Cav-1 in vitro and in vivo. Moreover, we found that our compound was well tolerated in vivo at concentrations at which doxorubicin was lethal. Altogether, we have developed a doxorubicin-prodrug that can successfully bind HSA, retaining a strong cytotoxic effect that preferentially targets Cav-1 positive cells while improving the general tolerability of the drug.

RAS-RAF-miR-296-3p signaling axis increases Rad18 expression to augment radioresistance in pancreatic and thyroid cancers.

Oncogenic RAS and RAF signaling has been implicated in contributing to radioresistance in pancreatic and thyroid cancers. In this study, we sought to better clarify molecular mechanisms contributing to this effect. We discovered that miRNA 296-3p (miR-296-3p) is significantly correlated with radiosensitivity in a panel of pancreatic cancer cells, and miR-296-3p is highly expressed in normal cells, but low in cancer cell lines. Elevated expression of miR-296-3p increases radiosensitization while decreasing the expression of the DNA repair enzyme RAD18 in both pancreatic and thyroid cancer cells. RAD18 is overexpressed in both pancreatic and thyroid tumors compared to matched normal controls, and high expression of RAD18 in tumors is associated with poor prognostic features. Modulating the expression of mutant KRAS in pancreatic cancer cells or mutant BRAF in thyroid cancer cells demonstrates a tight regulation of RAD18 expression in both cancer types. Depletion of RAD18 results in DNA damage and radiation-induced cell death. Importantly, RAD18 depletion in combination with radiotherapy results in marked and sustained tumor regression in KRAS mutant pancreatic cancer orthotopic tumors and BRAF mutant thyroid heterotopic tumors. Overall, our findings identify a novel coordinated RAS/RAF-miR-296-3p-RAD18 signaling network in pancreatic and thyroid cancer cells, which leads to enhanced radioresistance.

Consideration of Metastasis-Directed Therapy for Patients With Metastatic Colorectal Cancer: Expert Survey and Systematic Review.

BACKGROUND: A survey of medical oncologists (MOs), radiation oncologists (ROs), and surgical oncologists (SOs) who are experts in the management of patients with metastatic colorectal cancer (mCRC) was conducted to identify factors used to consider metastasis-directed therapy (MDT). MATERIALS AND METHODS: An online survey to assess clinical factors when weighing MDT in patients with mCRC was developed based on systematic review of the literature and integrated with clinical vignettes. Supporting evidence from the systematic review was included to aid in answering questions. RESULTS: Among 75 experts on mCRC invited, 47 (response rate 62.7%) chose to participate including 16 MOs, 16 ROs, and 15 SOs. Most experts would not consider MDT in patients with 3 lesions in both the liver and lung regardless of distribution or timing of metastatic disease diagnosis (6 vs. 36 months after definitive treatment). Similarly, for patients with retroperitoneal lymph node and lung and liver involvement, most experts would not offer MDT regardless of timing of metastatic disease diagnosis. In general, SOs were willing to consider MDT in patients with more advanced disease, ROs were more willing to offer treatment regardless of metastatic site location, and MOs were the least likely to consider MDT. CONCLUSIONS: Among experts caring for patients with mCRC, significant variation was noted among MOs, ROs, and SOs in the distribution and volume of metastatic disease for which MDT would be considered. This variability highlights differing opinions on management of these patients and underscores the need for well-designed prospective randomized trials to characterize the risks and potential benefits of MDT.

The Society of Thoracic Surgeons/American Society for Radiation Oncology Updated Clinical Practice Guidelines on Multimodality Therapy for Locally Advanced Cancer of the Esophagus or Gastroesophageal Junction.

Outcomes for patients with esophageal cancer have improved over the last decade with the implementation of multimodality therapy. There are currently no comprehensive guidelines addressing multidisciplinary management of esophageal cancer that have incorporated the input of surgeons, radiation oncologists, and medical oncologists. To address the need for multidisciplinary input in the management of esophageal cancer and to meet current best practices for clinical practice guidelines, the current guidelines were created as a collaboration between The Society of Thoracic Surgeons (STS), American Society for Radiation Oncology (ASTRO), and the American Society of Clinical Oncology (ASCO). Physician representatives chose 8 key clinical questions pertinent to the care of patients with locally advanced, resectable thoracic esophageal cancer (excluding cervical location). A comprehensive literature review was performed identifying 227 articles that met the inclusion criteria covering the use of induction chemotherapy, chemotherapy vs chemoradiotherapy before surgery, optimal radiation dose, the value of esophagectomy, timing of esophagectomy, the approach and extent of lymphadenectomy, the use of minimally invasive esophagectomy, and the value of adjuvant therapy after resection. The relevant data were reviewed and voted on by the panel with 80% of the authors, with 75% agreement on class and level of evidence. These data were then complied into the guidelines document.