LIG1 syndrome mutations remodel a cooperative network of ligand binding interactions to compromise ligation efficiency.

Human DNA ligase I (LIG1) is the main replicative ligase and it also seals DNA breaks to complete DNA repair and recombination pathways. Immune compromised patients harbor hypomorphic LIG1 alleles encoding substitutions of conserved arginine residues, R771W and R641L, that compromise LIG1 activity through poorly defined mechanisms. To understand the molecular basis of LIG1 syndrome mutations, we determined high resolution X-ray structures and performed systematic biochemical characterization of LIG1 mutants using steady-state and pre-steady state kinetic approaches. Our results unveil a cooperative network of plastic DNA-LIG1 interactions that connect DNA substrate engagement with productive binding of Mg2+ cofactors for catalysis. LIG1 syndrome mutations destabilize this network, compromising Mg2+ binding affinity, decreasing ligation efficiency, and leading to elevated abortive ligation that may underlie the disease pathology. These findings provide novel insights into the fundamental mechanism by which DNA ligases engage with a nicked DNA substrate, and they suggest that disease pathology of LIG1 syndrome could be modulated by Mg2+ levels.

Pharmacogenomics in Papua New Guineans: unique profiles and implications for enhancing drug efficacy while improving drug safety.

Papua New Guinea (PNG) can be roughly divided into highland, coastal and island peoples with significant mitochondrial DNA differentiation reflecting early and recent distinct migrations from Africa and East Asia, respectively. Infectious diseases such as tuberculosis, malaria and HIV severely impact on the health of its peoples for which drug therapy is the major treatment and pharmacogenetics has clinical relevance for many of these drugs. Although there is generally little information about known single nucleotide polymorphisms in the population, in some instances, their frequencies have been shown to be higher than anywhere worldwide. For example, CYP2B6*6 is over 50%, and CYP2C19*2 and *3 are over 40 and 25%, respectively. Conversely, CYP2A6*9, 2B6*2, *3, *4 and *18, and 2C8*3 appear to be much lower than in Whites. CYP2D6 known variants are unclear, and for phase II enzymes, only UGT2B7 and UGT1A9 data are available, with variant frequencies either slightly lower than or similar to Whites. Although almost all PNG people tested are rapid acetylators, but which variant(s) define this phenotype is not known. For HLA-B*13:01, HLA-B*35:05 and HLA-C*04:01, the frequencies show some regioselectivity, but the clinical implications with respect to adverse drug reactions are not known. There are minimal phenotype data for the CYPs and nothing is known about drug transporter or receptor genetics. Determination of genetic variants that are rare in Whites or Asians but common in PNG people is a topic of both scientific and clinical importance, and further research needs to be carried out. Optimizing the safety and efficacy of infectious disease drug therapy through pharmacogenetic studies that have translation potential is a priority.

Single-fraction radiation retreatment for bone metastases: role of a rapid access clinic.

OBJECTIVES: This study investigates retreatment rates in single-fraction radiation therapy (SFRT) for painful bone metastasis in patients with limited life expectancy. We compared retreatment-free survival (RFS) in patients from a rapid access bone metastases clinic (RABC) and non-RABC patients, identifying factors associated with retreatment. METHODS: In this observational study, we analysed RABC patients who received SFRT between April 2018 and November 2019, using non-RABC SFRT patients as a comparison group. Patients with prior or perioperative radiation therapy (RT) were excluded. The primary endpoint was same-site and any-site retreatment with RT or surgery. Patient characteristics were compared using χ2 and Student's t-tests, with RFS estimates based on a multistate model considering death as a competing risk using Aalen-Johansen estimates. RESULTS: We identified 151 patients (79 RABC, 72 non-RABC) with 225 treatments (102 RABC, 123 non-RABC) meeting eligibility criteria. Of the 22 (10.8%) same-site retreatments, 5 (22.7%) received surgery, 14 (63.6%) received RT and 3 (13.6%) received both RT and surgery. We found no significant differences in any-site RFS (p=0.97) or same-site RFS (p=0.11). CONCLUSIONS: RFS is high and similar comparable in the RABC and non-RABC cohorts. Retreatment rates are low, even in patients with low Eastern Cooperative Oncology Group scores.

The Patient's perspective on radiation therapy for anal cancer: Evaluation of expectations and stigma.

BACKGROUND: Little is known regarding anal cancer patients' perspectives on undergoing radiation therapy. Additionally, the stigma surrounding anal cancer diagnosis warrants a better understanding of the barriers to complete disclosure in patient-healthcare team interactions. METHODS: Included patients had squamous cell carcinoma of the anus treated with definitive chemoradiation (CRT) from 2009 to 2018. Survey questions were adapted from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire and Discrimination and Stigma Scale. RESULTS: A total of 46 anal cancer patients who underwent CRT were surveyed, of which 72% responded. 73% of respondents indicated little to no pre-treatment knowledge of CRT. 70% reported overall short-term effects as worse than expected, most commonly with bowel habits (82%), energy (73%), and interest in sexual activity (64%). 39% reported overall long-term effects to be worse than expected, most commonly with changes to bowel habits (73%), sexual function (67%), and interest in sexual activity (58%). However, 94% agreed they were better off after treatment. Regarding stigma, a subset reported hiding their diagnosis (12%, 24%) and side effects (24%, 30%) from friends/family or work colleagues, respectively, and 15% indicating they stopped having close relationships due to concerns over stigma. CONCLUSIONS: Although patients' perceptions of the severity of short-term CRT side effects were worse than expectations, the vast majority agreed they were better off after treatment. Targeted counseling on common concerns may improve the anal cancer treatment experience. A notable subset reported stigma associated with treatment, warranting further evaluation to understand the impact on the patient experience.

The patient's perspective on radiation for rectal cancer: Initial expectations versus actual experience.

BACKGROUND: The aim of this study was to compare patient perceptions of radiotherapy (RT) before and after treatment to better inform future patients and providers. METHODS: Seventy-eight consecutive patients with rectal adenocarcinoma treated with neo- or adjuvant chemoradiation, surgical resection, and adjuvant chemotherapy from 2009 to 2018 and who were without recurrence were included. Patients were surveyed ≥6 months after ileostomy reversal or ≥3 months after adjuvant chemotherapy. The survey assessed patients' baseline knowledge and fears of RT, how their short- and long-term side effects compared with initial expectations, and how their experiences compared for each modality (RT, surgery, and chemotherapy). RESULTS: Forty patient-responses were received. Before treatment, 70% of patients indicated little to no knowledge of RT, though 43% reported hearing frightening stories about RT. The most commonly top-ranked fears included organ damage (26%), skin burns (14%), and inability to carry out normal daily activities (10%). Eighty percent reported short-term effects of RT to be less than or as expected, with urinary changes (93%), abdominal discomfort (90%), and anxiety (88%) most commonly rated as less than or as expected. 85% reported long-term effects to be less than or as expected, with pain (95%), changes to the appearance of the treated area (85%), and dissatisfaction with body image (80%) most commonly rated as less than or as expected. Surgery was most commonly rated as the most difficult treatment (50%) and most responsible for long-term effects (55%). RT was least commonly rated as the most difficult treatment (13%), and chemotherapy was least commonly rated as most responsible for long-term effects (13%). CONCLUSIONS: The majority of patients indicated short- and long-term side effects of RT for rectal cancer to be better than initial expectations. In the context of trimodality therapy, patients reported RT to be the least difficult of the treatments.

Radiographic response to neoadjuvant therapy in pleural mesothelioma should serve as a guide for patient selection for cytoreductive operations.

Background: Malignant pleural mesothelioma (MPM) is associated with poor prognosis despite advances in multimodal therapeutic strategies. While patients with resectable disease may benefit from added survival with oncologic resection, patient selection for mesothelioma operations often relies on both objective and subjective evaluation metrics. We sought to evaluate factors associated with improved overall survival (OS) in patients with mesothelioma who underwent macroscopic complete resection (MCR). Methods: Patients with MPM who received neoadjuvant therapy and underwent MCR were identified in a prospectively maintained departmental database. Clinicopathologic, blood-based, and radiographic variables were collected and included in a Cox regression analysis (CRA). Response to neoadjuvant therapy was characterized by a change in tumor thickness from pretherapy to preoperative scans using the modified RECIST criteria. Results: In this study, 99 patients met the inclusion criteria. The median age of the included patients was 64.7 years, who were predominantly men, had smoking and asbestos exposure, and who received neoadjuvant therapy. The median change in tumor thickness following neoadjuvant therapy was -16.5% (interquartile range of -49.7% to +14.2%). CRA demonstrated reduced OS associated with non-epithelioid histology [hazard ratio (HR): 3.06, 95% confidence interval (CI): 1.62-5.78, p < 0.001] and a response to neoadjuvant therapy inferior to the median (HR: 2.70, CI: 1.55-4.72, p < 0.001). Patients who responded poorly (below median) to neoadjuvant therapy had lower median survival (15.8 months compared to 38.2 months, p < 0.001). Conclusion: Poor response to neoadjuvant therapy in patients with MPM is associated with poor outcomes even following maximum surgical cytoreduction and should warrant a patient-centered discussion regarding goals of care and may therefore help guide further therapeutic decisions.

Efficacy and clinicogenomic correlates of response to immune checkpoint inhibitors alone or with chemotherapy in non-small cell lung cancer.

The role of combination chemotherapy with immune checkpoint inhibitors (ICI) (ICI-chemo) over ICI monotherapy (ICI-mono) in non-small cell lung cancer (NSCLC) remains underexplored. In this retrospective study of 1133 NSCLC patients, treatment with ICI-mono vs ICI-chemo associate with higher rates of early progression, but similar long-term progression-free and overall survival. Sequential vs concurrent ICI and chemotherapy have similar long-term survival, suggesting no synergism from combination therapy. Integrative modeling identified PD-L1, disease burden (Stage IVb; liver metastases), and STK11 and JAK2 alterations as features associate with a higher likelihood of early progression on ICI-mono. CDKN2A alterations associate with worse long-term outcomes in ICI-chemo patients. These results are validated in independent external (n = 89) and internal (n = 393) cohorts. This real-world study suggests that ICI-chemo may protect against early progression but does not influence overall survival, and nominates features that identify those patients at risk for early progression who may maximally benefit from ICI-chemo.

Predicting benefit from immune checkpoint inhibitors in patients with non-small-cell lung cancer by CT-based ensemble deep learning: a retrospective study.

BACKGROUND: Only around 20-30% of patients with non-small-cell lung cancer (NCSLC) have durable benefit from immune-checkpoint inhibitors. Although tissue-based biomarkers (eg, PD-L1) are limited by suboptimal performance, tissue availability, and tumour heterogeneity, radiographic images might holistically capture the underlying cancer biology. We aimed to investigate the application of deep learning on chest CT scans to derive an imaging signature of response to immune checkpoint inhibitors and evaluate its added value in the clinical context. METHODS: In this retrospective modelling study, 976 patients with metastatic, EGFR/ALK negative NSCLC treated with immune checkpoint inhibitors at MD Anderson and Stanford were enrolled from Jan 1, 2014, to Feb 29, 2020. We built and tested an ensemble deep learning model on pretreatment CTs (Deep-CT) to predict overall survival and progression-free survival after treatment with immune checkpoint inhibitors. We also evaluated the added predictive value of the Deep-CT model in the context of existing clinicopathological and radiological metrics. FINDINGS: Our Deep-CT model demonstrated robust stratification of patient survival of the MD Anderson testing set, which was validated in the external Stanford set. The performance of the Deep-CT model remained significant on subgroup analyses stratified by PD-L1, histology, age, sex, and race. In univariate analysis, Deep-CT outperformed the conventional risk factors, including histology, smoking status, and PD-L1 expression, and remained an independent predictor after multivariate adjustment. Integrating the Deep-CT model with conventional risk factors demonstrated significantly improved prediction performance, with overall survival C-index increases from 0·70 (clinical model) to 0·75 (composite model) during testing. On the other hand, the deep learning risk scores correlated with some radiomics features, but radiomics alone could not reach the performance level of deep learning, indicating that the deep learning model effectively captured additional imaging patterns beyond known radiomics features. INTERPRETATION: This proof-of-concept study shows that automated profiling of radiographic scans through deep learning can provide orthogonal information independent of existing clinicopathological biomarkers, bringing the goal of precision immunotherapy for patients with NSCLC closer. FUNDING: National Institutes of Health, Mark Foundation Damon Runyon Foundation Physician Scientist Award, MD Anderson Strategic Initiative Development Program, MD Anderson Lung Moon Shot Program, Andrea Mugnaini, and Edward L C Smith.

Radiation Oncology Program Directors' Attitudes Toward Twenty-Seven Discrete Palliative Care Skills.

Background: We evaluated radiation oncology residency program directors' attitudes toward discrete palliative care skills in effort to determine which skills should be prioritized in radiation oncology resident training. Design: We identified 93 U.S. radiation oncology residency program directors and sent them a survey through e-mail. The survey assessed views of 27 discrete palliative care skills in eight domains and was adapted from the American Society of Clinical Oncology/American Academy of Hospice and Palliative Medicine Guidance Statement defining high-quality primary palliative care in medical oncology. Using a nine-point scale, respondents rated each skill on three constructs: (1) importance to high-quality cancer care, (2) relevance of the skill to radiation oncology practice, and (3) importance to radiation oncology residency education. Skills were categorized as "Include" (median score ≥7 for all constructs), "Exclude" (median score ≤3 for all constructs), or "Uncertain" (all other skills) using a composite score of all constructs. Results: Twenty-nine program directors (response rate 31%) completed the survey. Of the 27 skills, 100% were rated as highly important to high-quality cancer care, 70% were rated as highly relevant to radiation oncology practice, and 81% were rated as highly important to resident education (median score ≥7). Using the composite score, 70% of skills were categorized as "Include." The domains of Caregiver Support (100%), End-of-Life Care (66%), and Spiritual/Cultural Assessment and Management (33%) had the highest proportions of skills rated as "Uncertain." Conclusions: The surveyed radiation oncology residency program directors generally value palliative care skills within radiation oncology.

Discovery and Structural Basis of the Selectivity of Potent Cyclic Peptide Inhibitors of MAGE-A4.

MAGE proteins are cancer testis antigens (CTAs) that are characterized by highly conserved MAGE homology domains (MHDs) and are increasingly being found to play pivotal roles in promoting aggressive cancer types. MAGE-A4, in particular, increases DNA damage tolerance and chemoresistance in a variety of cancers by stabilizing the E3-ligase RAD18 and promoting trans-lesion synthesis (TLS). Inhibition of the MAGE-A4:RAD18 axis could sensitize cancer cells to chemotherapeutics like platinating agents. We use an mRNA display of thioether cyclized peptides to identify a series of potent and highly selective macrocyclic inhibitors of the MAGE-A4:RAD18 interaction. Co-crystal structure indicates that these inhibitors bind in a pocket that is conserved across MHDs but take advantage of A4-specific residues to achieve high isoform selectivity. Cumulatively, our data represent the first reported inhibitor of the MAGE-A4:RAD18 interaction and establish biochemical tools and structural insights for the future development of MAGE-A4-targeted cellular probes.

Treatment-related pulmonary adverse events induced by chemoradiation and Durvalumab affect survival in locally advanced non-small cell lung cancer.

PURPOSE: We compared treatment-related pulmonary adverse events (TRPAE), progression-free survival (PFS), and overall survival (OS) among locally advanced non-small cell lung cancer (NSCLC) patients who received concurrent chemoradiotherapy (CRT) versus CRT followed by immune check point inhibitor (ICI) immunotherapy (CRTI). MATERIALS AND METHODS: TRPAE was defined as any pulmonary events as defined in CTCAE v.5 occurring within 12 months after completion of radiotherapy. Outcomes were compared between CRT and CTRI by Cox proportional hazard regression and Kaplan-Meier analyses. We also assessed if TRPAE-induced discontinuation of ICI affected survival. RESULTS: We analyzed 326 patients treated between July 2010 and November 2019; 195 patients received CRT and 131 received CRTI. The incidences of severe grade ≥ 3 TRPAE were similar between the two groups, however, symptomatic TRPAE was almost doubled in CRTI group (65.7 % CTRI vs 35.9 % CRT, P < 0.0001). The rates of 4-year OS and PFS were 54.5 % vs 36.7 % (P = 0.0003) and 43.8 % vs 35.8 % (P = 0.038) in CRT + Durvalumab and CRT group, respectively. Receipt of ICI Durvalumab was associated with better 4-year OS (HR 0.53, 95 % CI 0.36-0.78, P = 0.001) and PFS (HR 0.55, 95 % CI 0.38-0.80, P = 0.002). Patients who discontinued ICI because of TRPAE had worse 4-year OS (P = 0.001) and higher rates of distant metastasis (P = 0.003) than those who completed planned ICI after developing TRPAE. CONCLUSION: CRT followed by adjuvant ICI led to improved 4-year OS and PFS consistent with published data. CRTI was associated with higher incidence of grade ≥ 2 TRPAE in both high and low mean lung dose groups without significant difference in grade ≥ 3 TRPAE. Discontinuation of ICI due to TRPAE was associated with poorer OS and distant disease control than completing ICI as planned after developing TRPAE.

Association of Driver Oncogene Variations With Outcomes in Patients With Locally Advanced Non-Small Cell Lung Cancer Treated With Chemoradiation and Consolidative Durvalumab.

Importance: Consolidative durvalumab after definitive chemoradiation for unresectable locally advanced non-small cell lung cancer (NSCLC) can significantly improve progression-free survival (PFS) and overall survival (OS), as shown in the PACIFIC trial. However, whether patients with driver variations derive equal benefit from this regimen remains unclear. Objectives: To compare outcomes of patients with locally advanced NSCLC with and without driver variations treated with the PACIFIC regimen. Design, Setting, and Participants: This cohort study examined 104 patients with unresectable locally advanced NSCLC with mutational profiling treated at a tertiary cancer center with definitive chemoradiation and consolidative durvalumab from June 2017 through May 2020. Patients with recurrent disease or those receiving postoperative therapy were excluded. Outcomes were analyzed with Kaplan-Meier and multivariate regression analyses. Exposures: Patients were grouped according to the presence of non-KRAS driver variations (EGFR exon 19 deletion, EGFR exon 20 insertion, EGFR exon 21 mutation [L858R], ERBB2 exon 20 insertion, EML4-ALK fusion, MET exon 14 skipping, NTRK2 fusion), KRAS driver variations, or no driver variations. Main Outcomes and Measures: The primary outcomes were PFS, OS, and second progression-free survival (PFS2) times. Results: The 104 patients had a median (IQR) age of 65.1 (9.8) years, with 55 females (53%) and 85 former or current smokers (88%). There were 43 patients (41%) with driver variations with a median PFS time of 8.4 months vs 40.1 months for patients without driver variations (hazard ratio [HR], 2.75; 95% CI, 1.64-4.62; log-rank P < .001). Both patients with non-KRAS and KRAS driver variations had worse PFS. No difference in OS was found between patients with and without driver variations (log rank P = .24). Among the 63 patients who developed progressive disease, those with non-KRAS driver variations had a median PFS2 time of 13.7 months vs 4.4 months for all other patients (HR, 0.37; 95% CI, 0.21-0.64; log-rank P = .001). Rates of overall grade 2 toxic effects or higher did not differ by driver mutation status. Conclusions and Relevance: In this cohort study, driver variations in patients with unresectable locally advanced NSCLC were associated with significantly shorter PFS time after definitive chemoradiation and consolidative durvalumab. These findings suggest the need to consider additional or alternative treatment options to the PACIFIC regimen for patients with driver variations.

Extrapleural Pneumonectomy Versus Pleurectomy/Decortication for Malignant Pleural Mesothelioma.

BACKGROUND: Whether extrapleural pneumonectomy (EPP) or extended pleurectomy/decortication (P/D) is the optimal resection for malignant pleural mesothelioma remains controversial. We therefore compared perioperative outcomes and long-term survival of patients who underwent EPP versus P/D. METHODS: Patients with the diagnosis of malignant pleural mesothelioma who underwent either EPP or P/D from 2000 to 2019 were identified from our departmental database. Propensity score matching was performed to minimize potential confounders for EPP or P/D. Survival analysis was performed by the Kaplan-Meier method and Cox multivariable analysis. RESULTS: Of 282 patients, 187 (66%) underwent EPP and 95 (34%) P/D. Even with propensity score matching, perioperative mortality was significantly higher for EPP than for P/D (11% vs 0%; P = .031); when adjusted for perioperative mortality, median overall survival between EPP and P/D was 15 versus 22 months, respectively (P = .276). Cox multivariable analysis for the matched cohort identified epithelioid histology (hazard ratio [HR], 0.56; P = .029), macroscopic complete resection (HR, 0.41; P = .004), adjuvant radiation therapy (HR, 0.57; P = .019), and more recent operative years (HR, 0.93; P = .011)-but not P/D-to be associated with better survival. Asbestos exposure (HR, 2.35; P = .003) and pathologic nodal disease (HR, 1.61; P = .048) were associated with worse survival. CONCLUSIONS: In a multimodality treatment setting, P/D and EPP had comparable long-term oncologic outcomes, although P/D had much lower perioperative mortality. The goal of surgical cytoreduction should be macroscopic complete resection achieved by the safest operation a patient can tolerate.

High-fidelity DNA ligation enforces accurate Okazaki fragment maturation during DNA replication.

DNA ligase 1 (LIG1, Cdc9 in yeast) finalizes eukaryotic nuclear DNA replication by sealing Okazaki fragments using DNA end-joining reactions that strongly discriminate against incorrectly paired DNA substrates. Whether intrinsic ligation fidelity contributes to the accuracy of replication of the nuclear genome is unknown. Here, we show that an engineered low-fidelity LIG1Cdc9 variant confers a novel mutator phenotype in yeast typified by the accumulation of single base insertion mutations in homonucleotide runs. The rate at which these additions are generated increases upon concomitant inactivation of DNA mismatch repair, or by inactivation of the Fen1Rad27 Okazaki fragment maturation (OFM) nuclease. Biochemical and structural data establish that LIG1Cdc9 normally avoids erroneous ligation of DNA polymerase slippage products, and this protection is compromised by mutation of a LIG1Cdc9 high-fidelity metal binding site. Collectively, our data indicate that high-fidelity DNA ligation is required to prevent insertion mutations, and that this may be particularly critical following strand displacement synthesis during the completion of OFM.

Simulated consult and treatment exercise improves radiation oncology trainee confidence and knowledge.

Malignant epidural spinal cord compression (MESCC) represents the most common indication for emergent radiotherapy. First-year residents must quickly gain competence in managing this condition prior to taking call for the department. We sought to develop a hybrid didactic/simulation exercise to assist first-year radiation oncology residents in developing a skillset relevant to treating a MESCC case in an emergency situation. This was a prospective, qualitative survey study conducted at the University of California, Los Angeles, during the years 2014-2016. Following an introductory lecture during orientation for academic years 2014-2016, residents completed a simulated consultation on a patient with suspected MESCC. Subsequently, they worked with radiation therapists to complete the clinical treatment procedure (including field placement and manual calculation of monitor units needed to deliver the prescribed dose) to a phantom placed on a linear accelerator. Residents were then surveyed about whether the exercise increased confidence in their ability to successfully complete a consult, and urgent treatment if needed, for MESCC. All residents agreed or strongly agreed that this exercise had improved this ability, and all agreed or strongly agreed that the exercise was valuable and should be retained in the curriculum. Simulated consultation and treatment of MESCC provides new residents with increased confidence and knowledge regarding this relatively common indication for emergent radiation.

Use of Multi-Site Radiation Therapy for Systemic Disease Control.

Metastatic cancer is a heterogeneous entity, some of which could benefit from local consolidative radiation therapy (RT). Although randomized evidence is growing in support of using RT for oligometastatic disease, a highly active area of investigation relates to whether RT could benefit patients with polymetastatic disease. This article highlights the preclinical and clinical rationale for using RT for polymetastatic disease, proposes an exploratory framework for selecting patients best suited for these types of treatments, and briefly reviews potential challenges. The goal of this hypothesis-generating review is to address personalized multimodality systemic treatment for patients with metastatic cancer. The rationale for using high-dose RT is primarily for local control and immune activation in either oligometastatic or polymetastatic disease. However, the primary application of low-dose RT is to activate distinct antitumor immune pathways and modulate the tumor stroma in efforts to better facilitate T cell infiltration. We explore clinical cases involving high- and low-dose RT to demonstrate the potential efficacy of such treatment. We then group patients by extent of disease burden to implement high- and/or low-dose RT. Patients with low-volume disease may receive high-dose RT to all sites as part of an oligometastatic paradigm. Subjects with high-volume disease (for whom standard of care remains palliative RT only) could be treated with a combination of high-dose RT to a few sites for immune activation, while receiving low-dose RT to several remaining lesions to enhance systemic responses from high-dose RT and immunotherapy. We further discuss how emerging but speculative concepts such as immune function may be integrated into this approach and examine therapies currently under investigation that may help address immune deficiencies. The review concludes by addressing challenges in using RT for polymetastatic disease, such as concerns about treatment planning workflows, treatment times, dose constraints for multiple-isocenter treatments, and economic considerations.

High-dose irradiation in combination with non-ablative low-dose radiation to treat metastatic disease after progression on immunotherapy: Results of a phase II trial.

AIM: To report early findings from a phase II trial of high-dose radiotherapy (HD-RT) with or without low-dose RT (LD-RT) for metastatic cancer. METHODS: Eligible patients had metastatic disease that progressed on immunotherapy within 6 months. Patients were given either HD-RT (20-70 Gy total; 3-12.5 Gy/f), or HD-RT + LD-RT (0.5-2 Gy/f up to 1-10 Gy total) to separate lesions, with continued immunotherapy. Radiographic response was assessed per RECIST 1.1 and Immune-Related Response Criteria (irRC). Primary endpoints: (1) 4-month disease control (DCR, complete/partial response [CR/PR] or stable disease [SD]) or an overall response (ORR, CR/PR) at any point in ≥10% of patients, per RECIST 1.1; (2) dose-limiting toxicity within 3 months not exceeding 30%. Secondary endpoint was lesion-specific response. RESULTS: Seventy-four patients (NSCLC, n = 38; melanoma n = 21) were analyzed (39 HD-RT and 35 HD-RT + LD-RT). The median follow-up time was 13.6 months. The primary endpoint was met for 72 evaluable patients, with a 4-month DCR of 42% (47% [16/34] vs. 37% [14/38] in HD-RT + LD-RT vs. HD-RT, P = 0.38), and 19% ORR at any time (26% [9/34] vs. 13% [5/38] in HD-RT + LD-RT vs. HD-RT, P = 0.27). Three patients had toxicity ≥grade 3. LD-RT lesion response (53%) was improved compared to nonirradiated lesions in HD-RT + LD-RT (23%, P = 0.002) and HD-RT (11%, P < 0.001). T- and NK cell infiltration was enhanced in lesions treated with LD-RT. CONCLUSIONS: HD-RT plus LD-RT safely improved lesion-specific response in patients with immune resistant solid tumors by promoting infiltration of effector immune cells into the tumor microenvironment.

Irradiation of the potential cancer stem cell niches in the adult brain improves progression-free survival of patients with malignant glioma.

BACKGROUND: Glioblastoma is the most common brain tumor in adults. The mechanisms leading to glioblastoma are not well understood but animal studies support that inactivation of tumor suppressor genes in neural stem cells (NSC) is required and sufficient to induce glial cancers. This suggests that the NSC niches in the brain may harbor cancer stem cells (CSCs), Thus providing novel therapy targets. We hypothesize that higher radiation doses to these NSC niches improve patient survival by eradicating CSCs. METHODS: 55 adult patients with Grade 3 or Grade 4 glial cancer treated with radiotherapy at UCLA between February of 2003 and May of 2009 were included in this retrospective study. Using radiation planning software and patient radiological records, the SVZ and SGL were reconstructed for each of these patients and dosimetry data for these structures was calculated. RESULTS: Using Kaplan-Meier analysis we show that patients whose bilateral subventricular zone (SVZ) received greater than the median SVZ dose (= 43 Gy) had a significant improvement in progression-free survival if compared to patients who received less than the median dose (15.0 vs 7.2 months PFS; P = 0.028). Furthermore, a mean dose >43 Gy to the bilateral SVZ yielded a hazard ratio of 0.73 (P = 0.019). Importantly, similarly analyzing total prescription dose failed to illustrate a statistically significant impact. CONCLUSIONS: Our study leads us to hypothesize that in glioma targeted radiotherapy of the stem cell niches in the adult brain could yield significant benefits over radiotherapy of the primary tumor mass alone and that damage caused by smaller fractions of radiation maybe less efficiently detected by the DNA repair mechanisms in CSCs.

Practical Safety Considerations for Integration of Magnetic Resonance Imaging in Radiation Therapy.

Interest in integrating magnetic resonance imaging (MRI) in radiation therapy (RT) practice has increased dramatically in recent years owing to its unique advantages such as excellent soft tissue contrast and capability of measuring biological properties. Continuous real-time imaging for intrafractional motion tracking without ionizing radiation serves as a particularly attractive feature for applications in RT. Despite its many advantages, the integration of MRI in RT workflows is not straightforward, with many unmet needs. MR safety remains one of the key challenges and concerns in the clinical implementation of MR simulators and MR-guided radiation therapy systems in radiation oncology. Most RT staff are not accustomed to working in an environment with a strong magnetic field. There are specific requirements in RT that are different from diagnostic applications. A large variety of implants and devices used in routine RT practice do not have clear MR safety labels. RT-specific imaging pulse sequences focusing on fast acquisition, high spatial integrity, and continuous, real-time acquisition require additional MR safety testing and evaluation. This article provides an overview of MR safety tailored toward RT staff, followed by discussions on specific requirements and challenges associated with MR safety in the RT environment. Strategies and techniques for developing an MR safety program specific to RT are presented and discussed.

Time-Driven Activity-Based Costing Comparison of CT-Guided Versus MR-Guided SBRT.

PURPOSE: Magnetic resonance-guided radiation therapy (MRgRT) has recently become commercially available, offering the opportunity to accurately image and target moving tumors as compared with computed tomography-guided radiation therapy (CTgRT) systems. However, the costs of delivering care with these 2 modalities remain poorly described. With localized unresectable hepatocellular carcinoma as an example, we were able to use time-driven activity-based costing to determine the cost of treatment on linear accelerators with CTgRT compared with MRgRT. MATERIALS AND METHODS: Process maps, informed via interviews with departmental personnel, were created for each phase of the care cycle. Stereotactic body radiation therapy was delivered at 50 Gy in 5 fractions, either with CTgRT using fiducial placement, deep inspiration breath-hold (DIBH) with real-time position management, and volumetric-modulated arc therapy, or with MRgRT using real-time tumor gating, DIBH, and static-gantry intensity-modulated radiation therapy. RESULTS: Direct clinical costs were $7,306 for CTgRT and $8,622 for MRgRT comprising personnel costs ($3,752 v $3,603), space and equipment costs ($2,912 v $4,769), and materials costs ($642 v $250). Increased MRgRT costs may be mitigated by forgoing CT simulation ($322 saved) or shortening treatment to 3 fractions ($1,815 saved). Conversely, adaptive treatment with MRgRT would result in an increase in cost of $529 per adaptive treatment. CONCLUSION: MRgRT offers real-time image guidance, avoidance of fiducial placement, and ability to use adaptive treatments; however, it is 18% more expensive than CTgRT under baseline assumptions. Future studies that elucidate the magnitude of potential clinical benefits of MRgRT are warranted to clarify the value of using this technology.