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Background: The role of systemic tumor immune environment (STIE) is unclear in hepatocellular carcinoma (HCC). This study aimed to exam the cells in the STIE, their changes after transarterial chemoembolisation (TACE), stereotactic body radiotherapy (SBRT), and immunotherapy (IO) and explore their significance in the treatment response of patients with unresectable HCC. Methods: This is a prospective biomarker study of patients with unresectable HCC. The treatment was sequential TACE, SBRT (27.5–40 Gy/5 fractions), and IO. The treatment response was assessed according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) by magnetic resonance imaging (MRI) after 6 months of treatment. Longitudinal data of STIE cells was extracted from laboratory results of complete blood cell counts, including leukocytes, lymphocytes, neutrophils, monocytes, eosinophils, basophils, and platelets. Peripheral blood samples were collected at baseline and after TACE, SBRT, and IO for T-lymphocyte subtyping by flow cytometry. Generalized estimation equation was employed for longitudinal analyses. Results: A total of 35 patients with unresectable HCC were enrolled: 23 patients in the exploratory cohort and 12 in the validation cohort. STIE circulating cells, especially lymphocytes, were heterogenous at baseline and changed differentially after TACE, SBRT, and IO in both cohorts. SBRT caused the greatest reduction of 0.7 × 109/L (95 % CI: 0.3 × 109/L–1.0 × 109/L, P < 0.001) in lymphocytes; less reduction was associated with significantly better treatment response. The analysis of T-lymphocyte lineage revealed that the baseline levels of CD4+ T cells (P = 0.010), type 1 T helper (Th1) cells (P = 0.007), and Th1/Th17 ratios (P = 0.001) were significantly higher in responders, while regulatory T (Treg) cells (P = 0.002), Th17 cells (P = 0.047), and Th2/Th1 ratios (P = 0.028) were significantly higher in non-responders. After treatment with TACE, SBRT and IO, T-lymphocyte lineage also changed differentially. More reductions were observed in CD25+CD8+ T cells and CD127+CD8+ T cells after SBRT in non-responders, while increases in natural killer T (NKT) cells after SBRT (10.4% vs. 3.4 %, P = 0.001) and increases in the lymphocyte counts were noted during IO in responders. Conclusions: STIE cells are significant for treatment response, can be reshaped differentially after TACE, SBRT, and IO. The most significant changes of T-lymphocyte lineage are SBRT associated modulations in CD25+CD8+ T cells, CD127+CD8+ T cells, and NKT cells, which also have significant effects on the ultimate treatment response after TACE-SBRT-IO (ClinicalTrails.gov identifier: GCOG0001/NCT05061342).

Introduction: Anti-programmed cell death 1 (PD-1) immunotherapy is the standard of care for metastatic NSCLC but many tumors develop resistance. We hypothesized that combining a T-cell agonist such as varlilumab (anti-CD27 antibody) with checkpoint inhibition may be synergistic and this synergy may be potentiated further by using targeted radiation (RT). Methods: We conducted an open-label, single-center, phase I trial (NCT04081688) to determine the safety and clinical benefit of the atezolizumab and varlilumab in combination with palliative RT in patients with advanced or metastatic NSCLC with progression on prior programmed cell death ligand 1therapy. On day 1 of each 21-day cycle, patients received varlilumab followed by atezolizumab on day 2. RT to a lung lesion was administered between cycle 1 and cycle 2. Results: A total of 15 patients were enrolled (one patient did not start treatment). The median age was 64 years; 10 patients were female. Eight patients (57%) had at least one treatment-related adverse event (AE) and 7 (50%) had at least one grade III or worse treatment-related AE. There was only one grade III immune-related AE requiring steroids (1 diarrhea and colitis); there were no treatment-related deaths. Of the 12 patients evaluable for efficacy, three patients had stable disease (2 with stable disease > 4 mo) and the clinical benefit rate was 25%. The median progression-free survival was two months and the median overall survival was 6.4 months. Conclusions: Varlilumab in combination with atezolizumab and RT was safe and well tolerated; no additional signal was identified for toxicity. Clinical activity for the combination was modest with 25% of patients with stable disease as the best response.

Oncological outcomes are improving in gastrointestinal cancer with advancements in systemic therapies, and there is notable potential in combining immunotherapy and radiation therapy (RT) to allow for further improvements. Various preclinical and early phase II studies have shown promising synergy with immunotherapy and RT in gastrointestinal cancer. A few recent phase III studies have shown improved survival with the addition of immunotherapy to standard treatment for gastrointestinal cancer. The timing, duration, sequencing, and integration with other anti-cancer treatments are still areas of ongoing research. We have reviewed the published and ongoing studies of the combinations of immunotherapy and RT in gastrointestinal cancers.

Abstract Modulation of autophagy, specifically its inhibition, stands to transform the capacity to effectively treat a broad range of cancers. However, the clinical efficacy of autophagy inhibitors has been inconsistent. To delineate clinical and epidemiological features associated with autophagy inhibition and a positive oncological clinical response, a retrospective analysis of patients is conducted treated with hydroxychloroquine, a known autophagy inhibitor. A direct correlation between smoking status and inhibition of autophagy with hydroxychloroquine is identified. Recognizing that smoking is associated with elevated circulating levels of carbon monoxide (CO), it is hypothesized that supplemental CO can amplify autophagy inhibition. A novel, gas‐entrapping material containing CO in a pre‐clinical model is applied and demonstrated that CO can dramatically increase the cytotoxicity of autophagy inhibitors and significantly inhibit the growth of tumors when used in combination. These data support the notion that safe, therapeutic levels of CO can markedly enhance the efficacy of autophagy inhibitors, opening a promising new frontier in the quest to improve cancer therapies.

Background and purpose: Prior studies have examined associations of cardiovascular substructure dose with overall survival (OS) or cardiac events after chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC). Herein, we investigate an alternative endpoint, death without cancer progression (DWP), which is potentially more specific than OS and more sensitive than cardiac events for understanding CRT toxicity. Materials and methods: We retrospectively reviewed records of 187 patients with locally advanced or oligometastatic NSCLC treated with definitive CRT from 2008 to 2016 at a single institution. Dosimetric parameters to the heart, lung, and ten cardiovascular substructures were extracted. Charlson Comorbidity Index (CCI), excluding NSCLC diagnosis, was used to stratify patients into CCI low (0–2; n = 66), CCI intermediate (3–4; n = 78), and CCI high (≥5; n = 43) groups. Primary endpoint was DWP, modeled with competing risk regression. Secondary endpoints included OS. An external cohort consisted of 140 patients from another institution. Results: Median follow-up was 7.3 years for survivors. Death occurred in 143 patients (76.5 %), including death after progression in 118 (63.1 %) and DWP in 25 (13.4 %). On multivariable analysis, increasing CCI stratum and mean heart dose were associated with DWP. For mean heart dose ≥ 10 Gy vs

Abstract Background Recent studies have shown that bone morphogenetic protein receptor 2 (BMPR2) regulates cell survival signaling events in cancer cells independent of the BMP type 1 receptor (BMPR1) or the Smad-1/5 transcription factor. Mutations in BMPR2 trafficking proteins leads to overactive BMP signaling, which leads to neurological diseases caused by BMPR2 stabilization of the microtubules. It is not known whether BMPR2 regulates the microtubules in cancer cells and what effect this has on cell survival. It is also not known whether alterations in BMPR2 trafficking effects activity and response to BMPR2 inhibitors. Methods We utilized BMPR2 siRNA and the BMP receptor inhibitors JL5 and Ym155, which decrease BMPR2 signaling and cause its mislocalization to the cytoplasm. Using the JL5 resistant MDA-MD-468 cell line and sensitive lung cancer cell lines, we examined the effects of BMPR2 inhibition on BMPR2 mislocalization to the cytoplasm, microtubule destabilization, lysosome activation and cell survival. Results We show that the inhibition of BMPR2 destabilizes the microtubules. Destabilization of the microtubules leads to the activation of the lysosomes. Activated lysosomes further decreases BMPR2 signaling by causing it to mislocalizated to the cytoplasm and/or lysosome for degradation. Inhibition of the lysosomes with chloroquine attenuates BMPR2 trafficking to the lysosome and cell death induced by BMPR2 inhibitors. Furthermore, in MDA-MD-468 cells that are resistant to JL5 induced cell death, BMPR2 was predominately located in the cytoplasm. BMPR2 failed to localize to the cytoplasm and/or lysosome following treatment with JL5 and did not destabilize the microtubules or activate the lysosomes. Conclusions These studies reveal that the inhibition of BMPR2 destabilizes the microtubules promoting cell death of cancer cells that involves the activation of the lysosomes. Resistance to small molecules targeting BMPR2 may occur if the BMPR2 is localized predominantly to the cytoplasm and/or fails to localize to the lysosome for degradation. Video Abstract

Abstract Background Increased risk of a second primary malignancy (SPM) before or after diagnosis of anal squamous cell carcinoma (ASCC) has been reported in a previous single‐institution study. We hypothesize that patients diagnosed with ASCC are at increased risk for developing SPMs before or after the diagnosis of ASCC. The primary objective of this study was to identify the diagnoses of cancer most likely to occur as SPMs before or after ASCC. Methods This work employs the Surveillance, Epidemiology, and End Results (SEER) Program registry data to conduct a US‐population‐based study of patients diagnosed with ASCC between 1975 and 2016. In patients diagnosed with ASCC, we evaluated the risk of SPMs and the risk of developing ASCC as an SPM after another cancer using standardized incidence ratios (SIR) for all SPMs by calculating the ratio of observed events in the ASCC cohort compared to expected (O/E) events in a matched reference cohort of the general population. Results A total of 7,594 patients with primary ASCC were included. Patients with ASCC were at increased risk of the diagnosis of an SPM (SIR = 1.45), particularly cancers of the lung, vulva, oropharynx, or colon. Patients with ASCC had an increased rate of previous malignancy (SIR = 1.23), especially Kaposi sarcoma or vulvar cancer. Overall elevated incidence of SPMs was unrelated to prior radiation treatment. Radiation treatment was associated with increased risk for SPMs in the female genital system but appeared protective against prostate cancer as SPMs. Conclusions Our findings support increased surveillance and screening for second malignancies in patients with these diagnoses, as patients with ASCC are often either survivors of a prior cancer diagnosis or are at increased risk of developing later malignancies.

Purpose: Margin-negative (R0) resection is the only potentially curative treatment for patients with pancreatic ductal adenocarcinoma (PDAC). Pre-operative multi-agent chemotherapy alone (MAC) or MAC followed by pre-operative radiotherapy (MAC + RT) may be used to improve resectability and potentially survival. However, the optimal pre-operative regimen is unknown. Methods: Patients with non-metastatic PDAC from 2006 to 2016 who received pre-operative MAC or MAC + RT before oncologic resection were identified in the National Cancer Database. Univariable and multivariable (MVA) associates with R0 resection were identified with logistic regression, and survival was analyzed secondarily with the Kaplan Meier method and Cox regression analysis. Results: 4,599 patients were identified (MAC: 3,109, MAC + RT: 1,490). Compared to those receiving MAC, patients receiving MAC + RT were more likely to have cT3-4 disease (76% vs 64%, p

Background: Neoadjuvant therapy (NAT) for T1/T2 pancreatic adenocarcinoma (PDAC) prior to pancreaticoduodenectomy remains controversial. We compared positive margin rates in patients with clinical T1&T2 tumors who did and did not receive NAT. Methods: The National Cancer Database (NCDB) found clinical T1&T2 PDAC patients who underwent pancreaticoduodenectomy from 2004 to 2014. Univariate and multivariate regression determined factors associated with a positive margin and survival. Results: 9795 patients underwent surgery for clinical T1 or T2 pancreatic head adenocarcinoma. 8472 patients had data regarding use of neoadjuvant and adjuvant therapies; of which, 774 (9.1%) received NAT and 435 (5.1%) received both chemotherapy and radiation therapy. NAT was found to lower positive margin rates from 21.8 to 15.5% (p

Although rectal cancer comprises up to one-third of colorectal cancer cases and several prognosis nomograms have been established for colon cancer, statistical tools for predicting long-term survival in rectal cancer are lacking. In addition, previous prognostic studies did not include much imaging findings, qualitatively or quantitatively. Therefore, we include multiparametric MRI information from both radiologists’ readings and quantitative radiomics signatures to construct a prognostic model that allows 5-year overall survival (OS) prediction for advance-staged rectal cancer patients. The result suggested that the model combined with quantitative imaging findings might outperform that of conventional TNM staging or other clinical prognostic factors. It was noteworthy that the identified radiomics signature consisted of three from dynamic contrast-enhanced (DCE)-MRI, four from anatomical MRI, and one from functional diffusion-weighted imaging (DWI). This highlighted the importance of multiparametric MRI to address the issue of long-term survival estimation in rectal cancer. Additionally, the constructed radiomics signature demonstrated value to the conventional prognostic factors in predicting 5-year OS for stage II–III rectal cancer. The presented nomogram also provides a practical example of individualized prognosis estimation and may potentially impact treatment strategies.

Lung cancer treatment is constantly evolving due to technological advances in the delivery of radiation therapy. Adaptive radiation therapy (ART) allows for modification of a treatment plan with the goal of improving the dose distribution to the patient due to anatomic or physiologic deviations from the initial simulation. The implementation of ART for lung cancer is widely varied with limited consensus on who to adapt, when to adapt, how to adapt, and what the actual benefits of adaptation are. ART for lung cancer presents significant challenges due to the nature of the moving target, tumor shrinkage, and complex dose accumulation because of plan adaptation. This article presents an overview of the current state of the field in ART for lung cancer, specifically, probing topics of: patient selection for the greatest benefit from adaptation, models which predict who and when to adapt plans, best timing for plan adaptation, optimized workflows for implementing ART including alternatives to re-simulation, the best radiation techniques for ART including magnetic resonance guided treatment, algorithms and quality assurance, and challenges and techniques for dose reconstruction. To date, the clinical workflow burden of ART is one of the major reasons limiting its widespread acceptance. However, the growing body of evidence demonstrates overwhelming support for reduced toxicity while improving tumor dose coverage by adapting plans mid-treatment, but this is offset by the limited knowledge about tumor control. Progress made in predictive modeling of on-treatment tumor shrinkage and toxicity, optimizing the timing of adaptation of the plan during the course of treatment, creating optimal workflows to minimize staffing burden, and utilizing deformable image registration represent ways the field is moving toward a more uniform implementation of ART.

Background: We aim to assess the prognostic ability of three common lymph node–based staging algorithms, namely, the number of positive lymph nodes (pN), the lymph node ratio (LNR), and log odds of positive lymph nodes (LODDS) in patients with esophageal squamous cell carcinoma (ESCC). Methods: A total of 3902 ESCC patients treated at 10 Chinese institutions between 2003 and 2013 were included, along with 2465 patients from the Surveillance, Epidemiology, and End Results (SEER) database. The prognostic ability of the aforementioned algorithms was evaluated using time-dependent receiver operating characteristic (tdROC) curves, R 2 , Harrell’s concordance index (C-index), and the likelihood ratio chi-square score. The primary outcomes included cancer-specific survival (CSS), overall survival (OS), and CSS with a competing risk of death by non-ESCC causes. Results: LODDS had better prognostic performance than pN or LNR in both continuous and stratified patterns. In the multicenter cohort, the multivariate analysis showed that the model based on LODDS classification was superior to the others in predictive accuracy and discriminatory capacity. Two nomograms integrating LODDS classification and other clinicopathological risk factors associated with OS as well as cancer-specific mortality were constructed and validated in the SEER database. Finally, a novel TN LODDS classification which incorporates the LODDS classification was built and categorized patients in to three new stages. Conclusion: Among the three lymph node–based staging algorithms, LODDS demonstrated the highest discriminative capacity and prognostic accuracy for ESCC patients. The nomograms and novel TN LODDS classification based on LODDS classification could serve as precise evaluation tools to assist clinicians in estimating the survival time of individual patients and improving clinical outcomes postoperatively in the future.

Abstract Purpose To develop a novel approach to accurately verify patient set up in proton radiotherapy, especially for the verification of the nozzle – body surface air gap and source-to-skin distance (SSD), the consistency and accuracy of which is extremely important in proton treatment. Methods Patient body surfaces can be captured and monitored with the optical surface imaging system during radiation treatment for improved intrafraction accuracy. An in-house software package was developed to reconstruct the patient body surface in the treatment position from the optical surface imaging reference capture and to calculate the corresponding nozzle – body surface air gap and SSD. To validate this method, a mannequin was scanned on a CT simulator and proton plans were generated for a Mevion S250 Proton machine with 20 gantry/couch angle combinations, as well as two different snout sizes, in the Varian Eclipse Treatment Planning Systems (TPS). The surface generated in the TPS from the CT scan was imported into the optical imaging system as an RT Structure for the purpose of validating and establishing a benchmark for ground truth comparison. The optical imaging surface reference capture was acquired at the treatment setup position after orthogonal kV imaging to confirm the positioning. The air gaps and SSDs calculated with the developed method from the surface captured at the treatment setup position (VRT surface) and the CT based surface imported from the TPS were compared to those calculated in TPS. The same approach was also applied to 14 clinical treatment fields for 10 patients to further validate the methodology. Results The air gaps and SSDs calculated from our program agreed well with the corresponding values derived from the TPS. For the phantom results, using the CT surface, the absolute differences in the air gap were 0.45 mm ± 0.33 mm for the small snout, and 0.51 mm ± 0.49 mm for the large snout, and the absolute differences in SSD were 0.68 mm ± 0.42 mm regardless of snout size. Using the VRT surface, the absolute differences in air gap were 1.17 mm ± 1.17 mm and 2.1 mm ± 3.09 mm for the small and large snouts, respectively, and the absolute differences in SSD were 0.81 mm ± 0.45 mm. Similarly, for patient data, using the CT surface, the absolute differences in air gap were 0.42 mm ± 0.49 mm, and the absolute differences in SSD were 1.92 mm ± 1.4 mm. Using the VRT surface, the absolute differences in the air gap were 2.35 mm ± 2.3 mm, and the absolute differences in SSD were 2.7 mm ± 2.17 mm. Conclusion These results showed the feasibility and robustness of using an optical surface imaging approach to conveniently determine the air gap and SSD in proton treatment, providing an accurate and efficient way to confirm the target depth at treatment.

Purpose: We examined long-term clinical outcomes among patients with synchronous oligometastatic non-small cell lung cancer (NSCLC) treated at our institution with definitive thoracic chemoradiation therapy (CRT) and local therapy to all oligometastatic lesions. Methods and Materials: A retrospective review identified 38 patients with synchronous oligometastatic NSCLC (≤3 metastatic lesions) who were treated with definitive CRT to the primary tumor and regional lymph nodes between 1999 and 2017 at our institution. Of the 38 patients, 27 patients (71%) received induction chemotherapy, all of whom responded or stabilized with initial systemic therapy before consideration of CRT. Most patients received chemotherapy concurrently with radiation therapy (n = 32; 84%) and local therapy to the metastatic disease site(s) (n = 34; 89%). We assessed patterns of progression or failure, overall survival (OS), progression-free survival (PFS), and toxicities. Results: The median follow-up duration was 54.9 months. Most patients (84%) presented with N2 to N3 disease. The brain or central nervous system was the most common site of disease progression and occurred in 16 of 28 patients (57%) experiencing any progression and 10 of 16 patients (63%) who initially presented with brain oligometastases. Median OS was 21.1 months (95% confidence interval [CI], 15.6-49.0 months), and median PFS 9.7 months (95% CI, 8.2-14.4 months). The 1-, 2-, and 4-year OS rates were 75.7%, 45.0%, and 33.7%, respectively. On multivariate analysis, both locoregional progression (hazard ratio: 5.8; 95% CI, 2.2-15.0; P = .0003) and distant progression (hazard ratio: 6.0; 95% CI, 2.3-15.4; P = .0002), when treated as time-dependent covariates, were associated with inferior OS. Grade ≥3 esophagitis occurred in 9% and grade ≥3 pneumonitis in 5% of patients with evaluable data. Conclusions: Patients with synchronous oligometastatic NSCLC and a high regional nodal burden treated with definitive thoracic CRT experienced favorable survival outcomes and low toxicity. At our institution, treating oligometastatic disease with CRT after systemic therapy is incorporated into the treatment plan from the onset of therapy, and we monitor the neuraxis closely for progression during and after treatment. Future research should focus on novel treatment combinations, such as immunotherapy or targeted systemic therapy as appropriate to further improve tumor control and survival.

Purpose/ObjectivesDespite its widespread availability, the use of kilovoltage (kV) image guidance is often related to factors such as perceived adequacy of clinical patient setup and individual practice patterns. We sought to determine whether kV image guidance in the treatment of painful bone metastases would improve therapeutic efficacy.Materials/MethodsUnder an Institutional Review Board approved protocol, hospital records of 164 patients having received radiation therapy to 257 individual painful osseous metastases were retrospectively reviewed. Marginal logistic regression analyses using the generalized estimating equation (GEE) approach were used to investigate potential associations between pain reduction and several patient, disease, and treatment related variables. Correlation of kV image guidance with pain reduction was analyzed by univariate and multivariate GEE logistic regression analysis.ResultsMedian time to pain reduction was 3 days (range 0~109 days) from the start of radiation therapy. Pain reduction ≥ 50% was noted in 196 (77%) metastatic lesions with 136 (53%) demonstrating complete pain relief. Patients with metastatic lesions from non-small cell lung cancer experienced less pain relief (p = 0.007). Disease extension outside of bone was a negative predictor for pain reduction (p = 0.02). On univariate and multivariate logistic regression, kV image guidance demonstrated a statistically significant correlation with improved pain control in cases involving treatment of the lower extremities (p = 0.03) and those with fewer treatment fractions (p = 0.01), particularly in the setting of extra-osseous disease extension (p = 0.003).ConclusionsKilovoltage image guidance in the treatment of painful bone metastases may offer greater pain control through improved patient setup, particularly for patients with tumors of the lower extremities, extraosseous disease extension, and fewer treatment fractions.

Purpose: Although the association of marital status with outcomes for patients with cancer has been widely studied, the mechanisms underpinning the protective effect of marriage are still not fully understood. The social support that marriage imparts is often discussed as an explanation for why patients with cancer who are married have better outcomes. Social support has been difficult to objectively quantify. Accompaniment of the patient at physician visits may be more meaningful than marital status itself. This study investigated the effect of caregiver presence at physician visits on treatment tolerance and outcome in patients undergoing chemoradiation therapy (CRT) for esophageal cancer. Methods and Materials: Patients who received a diagnosis of esophageal cancer who underwent CRT from January 1, 2005, to January 1, 2016, as part of their curative-intent management were retrospectively reviewed. Data collected included the patients’ marital status, caregiver presence at each physician visit, baseline performance status, serum albumin values and leukocyte values throughout treatment, patient weight values throughout treatment, tumor response to therapy, and overall survival. Patients were divided into 2 groups based on frequency of caregiver presence at physician visits (

Purpose: This study aimed to evaluate whether the coronavirus disease of 2019 (COVID-19) pandemic resulted in treatment delays in patients scheduled for or undergoing brachytherapy. Methods and Materials: A retrospective cohort study was conducted across 4 affiliated sites after local institutional review board approval. The eligibility criteria were defined as all patients with cancer whose treatment plan included brachytherapy during the COVID-19 pandemic from February 24, 2020 to June 30, 2020. Treatment delays, cancellations, alterations of fractionation regimens, and treatment paradigm changes were evaluated. Results: A total of 47 patients were eligible for the analysis. Median patient age at the time of treatment was 62 years (interquartile range, 56-70 years). Endometrial, cervical, and prostate cancers were the most common sites included in this analysis. Three patients (6.4%) with cervical cancer were diagnosed with COVID-19 during the course of their treatment. Interruptions of external beam radiation therapy (EBRT), cancellations of EBRT, cancellations of brachytherapy, and treatment delays due to COVID occurred in 5 (10.6%), 3 (6.4%), 8 (17%), and 9 (19%) patients, respectively. The mean and median number of days delayed for patients who experienced treatment interruptions were 16.3 days (standard deviation: 13.9 days) and 14 days (interquartile range, 5.75-23.75 days), respectively. For patients with cervical cancer, the mean and median overall treatment times defined as the time from the start of EBRT to the end of brachytherapy were 56 and 49 days, respectively. Conclusions: Despite the challenges the health care system faced during the pandemic, most patients with cancer were safely treated with minor treatment delays and interruptions. Long-term follow up is needed to assess the impact of COVID-19 and treatment interruptions on oncologic outcomes.

Background Immune checkpoint inhibitors (ICIs) improve survival outcomes in metastatic melanoma and non-small cell lung cancer (NSCLC). Preclinical evidence suggests that overexpression of cyclo-oxygenase-2 (COX2) in tumors facilitates immune evasion through prostaglandin E2 production and that COX inhibition synergizes with ICIs to promote antitumor T-cell activation. This study investigates whether concurrent COX inhibitor (COXi) use during ICI treatment compared with ICI alone is associated with improved time-to-progression (TTP), objective response rate (ORR) and overall survival (OS) in patients with metastatic melanoma and NSCLC.Methods We retrospectively reviewed 90 metastatic melanoma and 37 metastatic NSCLC patients, treated with ICI between 2011 and 2019. Differences in TTP and OS by ICI+COXi versus ICI alone were compared using Kaplan-Meier and Cox regression. Interaction between ICI+COXi versus ICI alone and pretreatment neutrophil–lymphocyte ratio (NLR) was examined. Independent radiology review per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 was performed.Results For patients with melanoma, median TTP was significantly prolonged in ICI+COXi versus ICI alone (245 vs 100.5 days, p=0.002). On multivariate analysis, ICI+COXi associated with increased TTP (HR 0.36, 95% CI 0.2 to 0.66, p=0.001), adjusted for age, pretreatment NLR, and gender. For NSCLC patients, ICI+COXi also associated with increased TTP compared with ICI alone on multivariate analysis (HR 0.45; 95% CI 0.21 to 0.97; p=0.042) adjusted for age. ORR at 6 months was significantly higher in patients who received ICI+COXi compared with ICI alone in both melanoma (58.6% vs 19.2%, p=0.0005) and NSCLC (73.7% vs 33.3%, p=0.036) cohorts. In the melanoma cohort, high pretreatment NLR (>5) associated with decreased TTP (HR 3.21, 95% CI 1.64 to 6.3; p=0.0007); however, ICI+COXi significantly associated with increased TTP in high NLR (>5) patients (HR 0.08, 95% CI 0.03 to 0.25), but not in low NLR (≤5) patients (HR 0.65, 95% CI 0.32 to 1.32). Similar outcomes were found in an adjusted melanoma cohort after RECIST review.Conclusions Our study suggests that COXi use concurrently with ICI significantly associated with longer TTP and improved ORR at 6 months in patients with metastatic melanoma and NSCLC compared with ICI alone. Furthermore, COXi use appears to reverse the negative prognostic effect of a high NLR by prolonging TTP in patients with melanoma.

Abstract Background The principle aim of this study is to incorporate 4DCT ventilation imaging into functional treatment planning that preserves high-functioning lung with both double scattering and scanning beam techniques in proton therapy. Methods Eight patients with locally advanced non-small-cell lung cancer were included in this study. Deformable image registration was performed for each patient on their planning 4DCTs and the resultant displacement vector field with Jacobian analysis was used to identify the high-, medium- and low-functional lung regions. Five plans were designed for each patient: a regular photon IMRT vs. anatomic proton plans without consideration of functional ventilation information using double scattering proton therapy (DSPT) and intensity modulated proton therapy (IMPT) vs. functional proton plans with avoidance of high-functional lung using both DSPT and IMPT. Dosimetric parameters were compared in terms of tumor coverage, plan heterogeneity, and avoidance of normal tissues. Results Our results showed that both DSPT and IMPT plans gave superior dose advantage to photon IMRTs in sparing low dose regions of the total lung in terms of V5 (volume receiving 5Gy). The functional DSPT only showed marginal benefit in sparing high-functioning lung in terms of V5 or V20 (volume receiving 20Gy) compared to anatomical plans. Yet, the functional planning in IMPT delivery, can further reduce the low dose in high-functioning lung without degrading the PTV dosimetric coverages, compared to anatomical proton planning. Although the doses to some critical organs might increase during functional planning, the necessary constraints were all met. Conclusions Incorporating 4DCT ventilation imaging into functional proton therapy is feasible. The functional proton plans, in intensity modulated proton delivery, are effective to further preserve high-functioning lung regions without degrading the PTV coverage.

The treatment of gastric cancer requires a multimodal approach to decrease the risk of locoregional and distant recurrence. The optimal timing of chemotherapy, surgery, and radiation therapy continues to be explored in ongoing trials. In the United States, surgical resection is often followed by adjuvant chemoradiation therapy or by a combination of neoadjuvant and adjuvant chemotherapy. Here we report on 4 patients with resected gastric adenocarcinoma who were treated with a combination of these 2 approaches, receiving neoadjuvant chemotherapy followed by adjuvant chemoradiation therapy.

Introduction: Malignant pleural mesothelioma (MPM) is a rare malignancy with a poor prognosis. While treatment with a platinum-based chemotherapy is the standard of care, many patients have rapid progression of disease with a median overall survival of ~12 months. Limited data exist about the genomic alterations associated with MPM and their clinical implications. Methods: We report genomic alterations and clinical data for 17 patients with MPM who had next generation sequencing performed. Overall survival (OS) and progression-free survival (PFS) were analyzed with Kaplan-Meier method. Results: Median age at diagnosis was 70 years (range 55–85), and 47% of the patients were male. The most common genomic alterations in the 17 patients were NF2 (53%), BAP1 (41%), CDKN2A (41%) and TP53 (29%). The median OS was 10.8 months. When stratified by mutational status, patients had better median OS if they had a BAP1 alteration compared to TP53 alteration (median OS 14.5 vs 7.2 months). Median PFS with first-line chemotherapy was 7 months (SD ± 3.3). However, patients with TP53 mutations had worse PFS with chemotherapy with median of only 3.9 months. Tumor mutation burden (TMB) was available for 12 patients and all had low TMB (range 1 to 8.1 mutation/Mb). Median PFS with immunotherapy was poor with at 1.5 months (SD ±0.4) and there was no significant difference in PFS with immunotherapy based on molecular profile. Conclusion: Our study has identified that TP53 confers worse survival and response to platinum chemotherapy compared to BAP1. Overall PDL1 expression and TMB is low in patients with MPM resulting in limited benefit from single agent PD-1/PD-L1 agent.

Purpose: Strong mentorship has been shown to improve mentee productivity, clinical skills, medical knowledge, and career preparation. We conducted a survey to evaluate resident satisfaction with mentorship within their radiation oncology residency programs.Methods and Materials: In January 2019, 126 radiation oncology residents training at programs in the northeastern United States were asked to anonymously complete the validated Munich Evaluation of Mentoring Questionnaire (MEMeQ). Results of residents with a formal mentoring program were compared to those without a formal program.Results: Overall response rate was 42%(n = 53). Participants were 25% post-graduate year two (PGY-2), 21% PGY-3, 26% PGY-4, and 28% PGY-5. Only 38% of residents reported participation in a formal mentoring program, while 62% had no formal program, and 13% reported having no mentor at all. Residents participating in a formal mentoring program reported strikingly higher rates of overall satisfaction with mentoring compared to those who were not (90% vs. 9%, p < 0.001). Overall, 38% of residents were either satisfied/very satisfied with their mentoring experience, while 49% of residents were unsatisfied/very unsatisfied.Conclusion: Residents participating in a formal mentorship program are significantly more likely to be satisfied with their mentoring experience than those who are not. Our results suggest that radiation oncology residency programs should strongly consider implementing formal mentorship programs.

Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide, with a majority of HCC patients not suitable for curative therapies. Approximately 70% of initially diagnosed patients cannot undergo surgical resection or transplantation due to locally advanced disease, poor liver function/underlying cirrhosis, or additional comorbidities. Local therapeutic options for patients with unresectable HCC, who are not suitable for thermal ablation, include transarterial embolization (bland, chemoembolization, radioembolization) and/or external beam radiation therapy (EBRT). Regarding EBRT specifically, technological advancements provide a means for safe and effective radiotherapy delivery in a wide spectrum of HCC patients. In multiple prospective studies, EBRT delivery in a variety of different fractionation schemes or in combination with transcatheter arterial chemoembolization (TACE) demonstrate improved outcomes, particularly with combination therapy. The Barcelona Clinic Liver Cancer classification provides a framework for treatment selection; however, given the growing complexity of treatment strategies, this classification system tends to simplify decision-making. In this review, we discuss the current literature regarding unresectable HCC and propose a modified treatment algorithm that emphasizes the role of radiation therapy for Child-Pugh score A or B patients with ≤3 nodules measuring >3 cm, multinodular disease or portal venous thrombosis.