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Background Outcomes after definitive chemoradiation for squamous cell carcinoma are generally favorable. However, biomarkers to further yield prognostic information are desired. Treatment-related lymphopenia as well as an elevated baseline neutrophil-lymphocyte ratio have been associated with worse survival in several cancer types. We evaluated absolute lymphocyte count and neutrophil-lymphocyte ratio at baseline and at treatment-related nadir in patients with anal cancer for associations with oncologic endpoints. Methods We conducted a retrospective analysis of 428 consecutive patients with non-metastatic anal cancer treated with definitive, intensity-modulated radiation therapy-based chemoradiation. We analyzed absolute neutrophil and lymphocyte counts at several timepoints: pretreatment, weekly during treatment, and in the six weeks following treatment completion. Neutrophil-lymphocyte ratio was calculated at baseline and treatment-related nadir. We estimated oncologic endpoints using life tables and compared them using the log-rank test. We conducted univariate and multivariable time-to-event analyses using Cox proportional hazards. Results Median absolute lymphocyte count at baseline and nadir were 1.80 [interquartile range (IQR), 1.45-2.32] k/µL and 0.26 (IQR, 0.18-0.36) k/µL, respectively, and 31% developed treatment-related grade 4 lymphopenia. Median neutrophil-lymphocyte ratio at baseline and nadir were 2.34 (IQR, 1.68-3.30) and 8.80 (IQR, 5.86-12.68), respectively. Estimates of overall survival, local failure-free survival, distant metastasis-free survival (DMFS), and freedom from colostomy at 5 years were 87%, 86%, 82%, and 88%, respectively. Baseline and nadir absolute lymphocyte count were not associated with selected outcomes on univariate analysis. On multivariable analysis, factors independently associated with death included T3-T4 disease, HIV-positive status, treatment break, and baseline neutrophil-lymphocyte ratio >3. Baseline neutrophil-lymphocyte ratio showed a trend toward association with distant progression or death (P=0.07). The 5-year overall survival estimates for patients with baseline neutrophil-lymphocyte ratios ≤3 and >3 were 92.3% and 80.6%, respectively. Conclusions Lymphopenia during and after chemoradiation for anal cancer is common but does not appear to be associated with worse survival, recurrence, or metastases. However, elevated baseline neutrophil-lymphocyte ratio was independently associated with overall survival, local recurrence-free survival, and DMFS. Further studies are needed to determine the clinical utility of baseline neutrophil-lymphocyte ratio to guide treatment and follow-up.

Patients with gastrointestinal (GI) cancer frequently experience unplanned hospitalizations, but predictive tools to identify high-risk patients are lacking. We developed a machine learning model to identify high-risk patients.In the study, 1341 consecutive patients undergoing GI (abdominal or pelvic) radiation treatment (RT) from March 2016 to July 2018 (derivation) and July 2018 to January 2019 (validation) were assessed for unplanned hospitalizations within 30 days of finishing RT. In the derivation cohort of 663 abdominal and 427 pelvic RT patients, a machine learning approach derived random forest, gradient boosted decision tree, and logistic regression models to predict 30-day unplanned hospitalizations. Model performance was assessed using area under the receiver operating characteristic curve (AUC) and prospectively validated in 161 abdominal and 90 pelvic RT patients using Mann-Whitney rank-sum test. Highest quintile of risk for hospitalization was defined as "high-risk" and the remainder "low-risk." Hospitalizations for high- versus low-risk patients were compared using Pearson's χOverall, 13% and 11% of patients receiving abdominal and pelvic RT experienced 30-day unplanned hospitalization. In the derivation phase, gradient boosted decision tree cross-validation yielded AUC = 0.823 (abdominal patients) and random forest yielded AUC = 0.776 (pelvic patients). In the validation phase, these models yielded AUC = 0.749 and 0.764, respectively (P.001 and P = .002). Validation models discriminated high- versus low-risk patients: in abdominal RT patients, frequency of hospitalization was 39% versus 9% in high- versus low-risk groups (P.001) and 6-month survival was 67% versus 92% (P = .001). In pelvic RT patients, frequency of hospitalization was 33% versus 8% (P = .002) and survival was 86% versus 92% (P = .15) in high- versus low-risk patients.In patients with GI cancer undergoing RT as part of multimodality treatment, machine learning models for 30-day unplanned hospitalization discriminated high- versus low-risk patients. Future applications will test utility of models to prompt interventions to decrease hospitalizations and adverse outcomes.

Hepatocellular carcinoma (HCC) is the most common liver cancer and one of the leading causes of cancer-related deaths in the world. Multiple immunotherapeutic approaches have been investigated to date, and immunotherapy has become the new standard of care therapy in HCC. However, the current role of immunotherapy in HCC remains non-curative. Given this context, a high priority for oncology is understanding the biomarkers that predict clinical response to immunotherapy, have the potential to improve patient selection to maximize the clinical benefit, and spare unnecessary toxicity. In this review, we summarize the key predictive and prognostic biomarkers investigated in immunotherapy clinical trials in HCC and the emerging biomarkers to serve as a roadmap for future clinical trials. Biomarkers from tumoral tissues including PDL-1 expression, tissue infiltrating lymphocytes, tumor mutational burden (TMB) and specific immune signatures, and from peripheral blood including neutrophil-to-lymphocytes ratio, platelet-to-lymphocytes ratio, circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and specific cytokines, along with gut microbiota are among the studied biomarkers to date in the HCC era. More integrative approaches, including mathematical biomarkers to predict immunotherapy outcomes, are yet to be studied in HCC.

Background The clinical utility of a blood-based biomarker in squamous cell carcinoma of the anus (SCCA) is unknown. We analyzed carcinoembryonic antigen (CEA), a commonly employed assay for patients with colorectal adenocarcinoma, as a serum biomarker for patients with biopsy-proven SCCA. Materials and methods Medical records from 219 patients with biopsy-proven SCCA at the University of Texas MD Anderson Cancer Center were reviewed under an IRB-approved protocol from 2013 to 2020 to assess for correlations between CEA levels and corresponding clinical and pathologic characteristics. Results The mean CEA among subgroups by clinical status at the time of presentation to our institution was highest among those patients with metastatic SCCA to visceral organs (M-V, 20.7 ng/mL), however this finding was not statistically significant by ANOVA (p = .74). By clinical subgroup, the percentage of patients with an abnormally elevated CEA was highest in those patients with metastatic disease to lymph nodes (M-L, 41.2%) followed by recurrent/unresectable SCCA (36.8%), and metastatic SCCA to visceral organs (M-V, 35.2%), and was statistically significant between groups (Fisher's exact test p = .02). Using RECIST criteria for tumor progression and disease response, the mean change in CEA for patients with progression was an increase in 19 ng/mL, compared to a change of -7.3 ng/mL in those with disease response (p = .004). We likewise assessed whether CEA levels were associated with survival outcomes for all patients with metastatic SCCA, and found no correlation between CEA and likelihood for survival in a ROC analysis (multivariate, age-adjusted analysis for CEA cutoff of 8, HR = 1.01, 95% CI 0.52-1.96). Conclusions Despite interesting patterns of abnormally high CEA in SCCA patients with advanced disease, and correlation of increased CEA with disease progression (and conversely decreased CEA with disease response), CEA is not associated with survival outcomes in SCCA, and is not a clinically relevant biomarker in this disease.

Pancreatic ductal adenocarcinoma (PDAC) is almost uniformly fatal and characterized by early metastasis. Oncogenic KRAS mutations prevail in 95% of PDAC tumors and co-occur with genetic alterations in the TP53 tumor suppressor in nearly 70% of patients. Most TP53 alterations are missense mutations that exhibit gain-of-function phenotypes that include increased invasiveness and metastasis, yet the extent of direct cooperation between KRAS effectors and mutant p53 remains largely undefined. We show that oncogenic KRAS effectors activate CREB1 to allow physical interactions with mutant p53 that hyperactivate multiple prometastatic transcriptional networks. Specifically, mutant p53 and CREB1 upregulate the prometastatic, pioneer transcription factor FOXA1, activating its transcriptional network while promoting WNT/β-catenin signaling, together driving PDAC metastasis. Pharmacologic CREB1 inhibition dramatically reduced FOXA1 and β-catenin expression and dampened PDAC metastasis, identifying a new therapeutic strategy to disrupt cooperation between oncogenic KRAS and mutant p53 to mitigate metastasis. Significance: Oncogenic KRAS and mutant p53 are the most commonly mutated oncogene and tumor suppressor gene in human cancers, yet direct interactions between these genetic drivers remain undefined. We identified a cooperative node between oncogenic KRAS effectors and mutant p53 that can be therapeutically targeted to undermine cooperation and mitigate metastasis. This article is highlighted in the In This Issue feature, p. 1861

Brian De,1,* Sweet Ping Ng,1,2,* Amy Y Liu,1 Santiago Avila,1 Randa Tao,3 Emma B Holliday,1 Zachary Brownlee,4 Ahmed Kaseb,5 Sunyoung Lee,3 Kanwal Raghav,5 Jean-Nicolas Vauthey,6 Bruce D Minsky,1 Joseph M Herman,1 Prajnan Das,1 Grace L Smith,1 Cullen M Taniguchi,1 Sunil Krishnan,7 Christopher H Crane,8 Clemens Grassberger,9 Theodore S Hong,9 Steven H Lin,1 Albert C Koong,1 Radhe Mohan,1 Eugene J Koay1 1Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Department of Radiation Oncology, Austin Health, Melbourne, Victoria, Australia; 3Department of Radiation Oncology, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, USA; 4Department of Radiation Oncology, Tufts Medical Center, Boston, MA, USA; 5Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 6Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 7Department of Radiation Oncology, Mayo Clinic Jacksonville, Jacksonville, FL, USA; 8Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 9Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA*These authors contributed equally to this workCorrespondence: Eugene J KoayMD Anderson Cancer Center, Department of Radiation Oncology, 1400 Pressler St. Unit 1422, Houston, TX, 77030, USATel + 1 713-563-2381Fax +1 713-563-2331Email EKoay@mdanderson.orgBackground: The immune system plays a crucial role in cancer surveillance. Previous studies have shown that lymphopenia associated with radiotherapy (RT) portends a poor prognosis. We sought to differentiate the effects of proton and photon RT on changes in absolute lymphocyte count (ALC) for patients with hepatocellular carcinoma (HCC).Patients and Methods: Patients with HCC treated with definitive RT from 2006 to 2016 were studied. Serial ALCs were graded according to CTCAE v4.0. Overall survival (OS), disease-free survival, and distant metastasis-free survival were analyzed using the Kaplan–Meier method. Univariableand multivariable Cox-proportional hazards analyses were used to identify predictors of OS. A cohort analysis matched for treatment volume was performed to investigate differences in ALC dynamics between photon and proton therapy.Results: Of 143 patients identified, the median age was 66 (range, 19– 90) years. The treatment modality was photon in 103 (72%) and proton in 40 (28%). Median follow-up was 17 months (95% confidence interval, 13– 25 months). The median time to ALC nadir after initiation of RT was 17 days with a median relative decrease of 67%. Those who received proton RT had a higher median ALC nadir (0.41 vs 0.32 k/μL, p=0.002) and longer median OS (33 vs 13 months, p=0.002) than those who received photon RT. Matched cohort analyses revealed a larger low-dose liver volume in the photon group, which correlated with lower ALC. On multivariable Cox analysis, Grade 3 or higher lymphopenia prior to or after RT, portal venous tumor thrombus, larger planning target volumes, Child-Pugh (CP) Class B, and increased CP score after RT were associated with a higher risk of death, whereas the use of proton therapy was associated with lower risk.Conclusion: Grade 3 or higherlymphopenia may be associated with poorer outcomes in patients receiving RT for HCC. Protons may mitigate lymphopenia compared with photons, potentially due to reduced dose exposure of sites of lymphopoiesis.Keywords: lymphocyte count, circulating lymphocytes, splenic dose, liver dose, overall survival

Highlights • PDSA methodology was used to implement a pancreas SBRT in an academic satellite network. • Oncologic outcomes were favorable with no serious adverse events. • This technical note provides groundwork for safe establishment of SBRT pancreas programs., Background With increasing interest in stereotactic body radiotherapy (SBRT) for unresectable pancreatic cancer, quality improvement (QI) initiatives to develop integrated clinical workflows are crucial to ensure quality assurance (QA) when introducing this challenging technique into radiation practices. Materials/Methods: In 2017, we used the Plan, Do, Study, Act (PDSA) QI methodology to implement a new pancreas SBRT program in an integrated community radiation oncology satellite. A unified integrated information technology infrastructure was used to virtually integrate the planned workflow into the community radiation oncology satellite network (P – Plan/D – Do). This workflow included multiple prospective quality assurance (QA) measures including multidisciplinary evaluation, prospective scrutiny of radiation target delineation, prospective radiation plan evaluation, and monitoring of patient outcomes. Institutional review board approval was obtained to retrospectively study and report outcomes of patients treated in this program (S – Study). Results: There were 12 consecutive patients identified who were treated in this program from 2017 to 2020 with a median follow-up of 27 months. The median survival was 13 months, median local failure free survival was 12 months and median progression free survival was 6 months from SBRT. There were no acute or late Common Terminology Criteria for Adverse Effects (CTCAE) version 5 toxicities ≥ Grade 3. Conclusion: We report the successful implementation of a community pancreas SBRT program involving multiple prospective QA measures, providing the groundwork to safely expand access to pancreas SBRT in our community satellite network (A – Act).

Evaluate utility of dual energy CT iodine material density images to identify preoperatively nodal positivity in pancreatic cancer patients who underwent neoadjuvant therapy. This IRB approved retrospective study evaluated 62 patients between 2012 and 2016 with proven pancreatic ductal adenocarcinoma, who underwent neoadjuvant therapy, tumor resection and both baseline and preoperative assessment with pancreatic multiphasic rapid switching dual energy CT. Three radiologists in consensus identified on imaging nodes > 0.5 cm in short axis, evaluated nodal morphology, size and on each phase density in HU, and concentrations on iodine material density images normalized to the aorta. Of 62 patients, 33 were N0, 20 N1, and 9 N2. Total of 145 lymph nodes were evaluated, with average number of nodes per anatomic site ranging from 1.3 (body tumors) to 5 (uncinate) versus average of 24 and 30 nodes recovered respectively at surgery. Most (N = 44) were pancreatic head tumors. For all patients, regardless of site of primary tumor, the minimum measured iodine value of all of a patient’s measured nodes taken as a group on preoperative studies, as normalized to the aorta, was significant at P = 0.041 value in differentiating N0 from N1/2 and ROC analysis showed an AUC of 0.67. With a cutoff of 0.2857, sensitivity was 0.78 and specificity was 0.58, with values

A large proportion of patients with cancer are unresponsive to treatment with immune checkpoint blockade and other immunotherapies. Here, we report a mathematical model of the time course of tumour responses to immune checkpoint inhibitors. The model takes into account intrinsic tumour growth rates, the rates of immune activation and of tumour-immune cell interactions, and the efficacy of immune-mediated tumour killing. For 124 patients, four cancer types and two immunotherapy agents, the model reliably described the immune responses and final tumour burden across all different cancers and drug combinations examined. In validation cohorts from four clinical trials of checkpoint inhibitors (with a total of 177 patients), the model accurately stratified the patients according to reduced or increased long-term tumour burden. We also provide model-derived quantitative measures of treatment sensitivity for specific drug-cancer combinations. The model can be used to predict responses to therapy and to quantify specific drug-cancer sensitivities in individual patients.

ObjectivesTumor size measurement is critical for accurate tumor staging in patients with pancreatic ductal adenocarcinoma (PDAC). However, accurate tumor size measurement is challenging in patients who received neoadjuvant therapy before resection, due to treatment-induced fibrosis and tumor invasion beyond the grossly identified tumor area. In this study, we evaluated the correlation between the tumor size and tumor volume measured on post-therapy computed tomography (CT) scans and the pathological measurement. Also, we investigated the correlation between these measurements and clinicopathological parameters and survival.Materials and methodsRetrospectively, we evaluated 343 patients with PDAC who received neoadjuvant therapy, followed by pancreaticoduodenectomy and had pre-operative pancreatic protocol CT imaging. We measured the longest tumor diameter (RadL) and the radiological tumor volume (RadV) on the post-therapy CT scan, then we categorized RadL into four radiologic tumor stages (RTS) based on the current AJCC staging (8th edition) protocol and RadV based on the median. Pearson correlation or Spearman's coefficient (δ), T-test and ANOVA was used to test the correlation between the radiological and pathological measurement. Chi-square analysis was used to test the correlation with the tumor pathological response, lymph-node metastasis and margin status and Kaplan-Meier and Cox-proportional hazard for survival analysis. P-value < 0.05 was considered significant.ResultsAs a continuous variable, RadL showed a positive linear correlation with the post-therapy pathologic tumor size in the overall patient population (Pearson correlation coefficient: 0.72, P&nbsp

Background Detection of cystic lesions of the pancreas has outpaced our ability to stratify low-grade cystic lesions from those at greater risk for pancreatic cancer, raising a concern for overtreatment. Methods We developed a Markov decision model to determine the cost-effectiveness of guideline-based management for asymptomatic pancreatic cysts. Incremental costs per quality-adjusted life year gained and survival were calculated for current management guidelines. A sensitivity analysis estimated the effect on cost-effectiveness and mortality if overtreatment of low-grade cysts is avoided, and the sensitivity and specificity thresholds required of methods of cyst stratification to improve costs expended. Results “Surveillance” using current management guidelines had an incremental cost-effectiveness ratio of $171,143/quality adjusted life year compared with no surveillance or operative treatment (“do nothing”). An incremental cost-effectiveness ratio for surveillance decreases to $80,707/quality adjusted life year if the operative overtreatment of low-grade cysts was avoided. Assuming a societal willingness-to-pay of $100,000/quality adjusted life year, the diagnostic specificity for high-risk cysts must be >67% for surveillance to be preferred over surgery and “do nothing.” Changes in sensitivity alone cannot make surveillance cost-effective. Most importantly, survival in surveillance is worse than “do nothing” for 3 years after cyst diagnosis, although long-term survival is improved. The disadvantage is eliminated when overtreatment of low-grade cysts is avoided. Conclusion Current management of pancreatic cystic lesions is not cost-effective and may increase mortality owing to overtreatment of low-grade cysts. The specificity for risk stratification for high-risk cysts must be greater than 67% to make surveillance cost-effective.

The critical roles of oxygen homeostasis in metabolism are indisputable and hypoxic responses are correlated with the pathogenesis of gastrointestinal, pulmonary, renal diseases and cancers. Evaluating tissue hypoxia to predict treatment outcome is challenging, however, due to the lack of rapid, accurate and non-invasive methods. Hypoxia enhances prolyl-4-hydroxylase α1 (P4HA1) expression, which can convert bradykinin (BK) to hydroxyprolyl-BK (Hyp-BK), leading us to hypothesize that circulating Hyp-BK/BK ratios may reflect tissue hypoxia and predict treatment outcomes. Direct quantification of Hyp-BK peptides in serum or plasma by conventional MALDI-TOF MS analysis is technically challenging. In our study, a nanopore-based fractionation and enrichment protocol was utilized to allow the simple workflow for circulating Hyp-BK/BK analysis. Hypoxia is linked to poor prognosis due to its role in promoting pancreatic cancer progression and metastasis. Here we show that P4HA1 expression was increased in pancreatic tumors versus adjacent tissue, associated with poor survival, and corresponded with tumor expression of the hypoxia inducible factor 1α (HIF-1α) and carbonic anhydrase 9 (CA9). Hypoxia-induced P4HA1 expression and BK conversion to Hyp-BK were found to be HIF-1α dependent, pre-treatment serum Hyp-BK/BK ratios corresponded with tissue HIF-1α and P4HA1 expression, and high Hyp-BK/BK levels corresponded with poor response to therapy. These results suggest that pre-treatment circulating Hyp-BK/BK ratios may have value as a non-invasive, surrogate indicator of tissue hypoxia and tumor responses to therapy.

The role and sequencing of short-course radiation therapy (SCRT) in the preoperative management of locally advanced rectal cancer is unclear. This study of 39 patients compares outcomes between those who had surgery within 14 days after finishing SCRT and those who were delayed. Our data show similar outcomes between these groups, suggesting SCRT is well-tolerated regardless of sequence. BACKGROUND: The role of neoadjuvant short-course radiation therapy (SCRT) in treating rectal adenocarcinoma is a topic of ongoing debate. Growing interest in total neoadjuvant therapy has spurred discussion on the optimal sequence of preoperative SCRT and chemotherapy. PATIENTS AND METHODS: All patients receiving SCRT (5 Gy × 5 fractions) were identified. Details about preoperative treatments, radiation toxicities, and postoperative complications were collected. Patients were divided into 2 groups: those who underwent surgery within 14 days of completing SCRT and those with a longer delay. Outcomes compared included extent of pathologic response, margin-negative resection rate, acute radiation toxicities, and postoperative complications. RESULTS: Fifty-seven patients with locally advanced or metastatic rectal cancer received SCRT between 2008 and 2018. Thirty-nine of 57 patients underwent definitive pelvic surgery with total mesorectal excision. There were no significant differences in tumor downstaging, radial margin status, or percent tumor viability between patients with immediate surgery versus delayed surgery. The delay group had higher rates of nodal downstaging (64.7% vs. 18.2%; P = .003). There were no differences in total or grade 3+ gastrointestinal radiation toxicity, postoperative complications, reoperation, readmission, and mortality between the 2 groups. CONCLUSIONS: Though not yet common in the United States, SCRT has compared favorably with long course chemoradiation in multiple trials. Moreover, it is associated with greater efficiency and less disruption to chemotherapy. Our data show similar response and toxicity outcomes between the immediate and delay groups, suggesting SCRT is well-tolerated regardless of treatment sequence. Recently completed prospective trials may reveal the optimal preoperative treatment sequence.

Background Radiotherapy (RT) can be used for tumor downstaging and as a bridge to transplantation in hepatocellular carcinoma (HCC), but its effect on surgical complications is unknown. Therefore, we investigated post-transplant mortality and acute readmission rates in HCC with and without preoperative RT using the National Cancer Database (NCDB). Methods After exclusion, 11,091 transplant patients were analyzed, 165 of whom received RT prior to transplant. Multivariable binomial logistic regression analysis identified characteristics associated with use of RT, and factors associated with increased 30/90-day mortality and 30-day readmission, following propensity matching. Results Although RT (median 40 Gy in 5 fractions) was more often delivered to larger tumors and advanced stages, it resulted in 59% downstaging rate, 39% pathologic complete response rate, and a median of 4 additional months to transplantation. Crude 30/90-day mortality rates were both 1.2% with preoperative RT, compared to 2.7% and 4.4% without. The 30-day readmission rate was 5.5% with RT and 10.7% without it. Propensity matched analysis demonstrated no statistical differences in 30/90-day mortality and a lower 30-day readmission rate with preoperative RT. Age >58, stage III disease, lack of transarterial chemoembolization, and shorter time to transplant independently predicted higher 90-day mortality. Conclusion Preoperative RT for HCC did not increase postoperative mortality or length of stay following liver transplant.

Purpose: Preoperative chemoradiation is being currently evaluated in 2 randomized international trials. However, chemoradiation for gastric cancer can be associated with relatively high rates of acute toxicity. We compared rates of toxicity, toxicity-related events, and oncologic outcomes in patients treated with intensity modulated radiation therapy (IMRT) and those treated with 3-dimensional conformal radiation therapy (3DCRT). Methods and Materials: We retrospectively reviewed records of 202 patients with consecutive gastric cancer treated with preoperative intent radiation therapy at our institution from 1998 to 2018. Patients with gastroesophageal junction involvement and those with metastatic disease were excluded. Eighty-two patients received 3DCRT, and 120 patients received IMRT. The median radiation dose was 45 Gy, and 99% received concurrent chemotherapy. Results: There were no significant differences between the 3DCRT and IMRT groups regarding sex, race, histology, tumor location, histology, or nodal stage. The rate of grade 3 to 4 acute toxicity was significantly lower in patients treated with IMRT compared with 3DCRT (49% vs 70%, P = .004). The composite rate of toxicity-related events (hospitalization, feeding tube use, intravenous rehydration, or radiation therapy breaks) was also significantly lower in patients treated with IMRT compared with 3DCRT (56% vs 85%, P

Background The incidence and magnitude of indicators of radiographic response of pancreatic cancer to systemic chemotherapy and (chemo)radiation administered prior to anticipated pancreatectomy are unclear. Methods Sequential computed tomography scans of 226 patients with localized pancreatic cancer who received chemotherapy consisting of 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX) or gemcitabine and nanoparticle albumin-bound paclitaxel (GA) with or without (chemo)radiation and who subsequently underwent surgery with curative intent from January 2010 to December 2018 at The University of Texas MD Anderson Cancer Center and Verona University Hospital were re-reviewed and compared. Results Overall, 141 patients (62%) received FOLFIRINOX, 70 (31%) received GA, and 15 (7%) received both; 164 patients (73%) received preoperative (chemo)radiation following chemotherapy and prior to surgery; and 151 (67%), 70 (31%), and 5 (2%) patients had Response Evaluation Criteria in Solid Tumors (RECIST) stable disease, partial response, and progressive disease, respectively. The tumors of 29% of patients with borderline resectable or locally advanced cancer were downstaged after preoperative therapy. Radiographic downstaging was more common with chemotherapy than with (chemo)radiation (24% vs. 6%; p = 0.04), and the median tumor volume loss after chemotherapy was significantly greater than that after (chemo)radiation (28% vs. 17%; p Conclusions Less than one-third of patients treated with FOLFIRINOX or GA with or without (chemo)radiation experienced either RECIST partial response or radiographic downstaging prior to surgery. The incidence of tumor downstaging was higher and the magnitude of tumor volume loss was greater following chemotherapy than after (chemo)radiation.

Purpose Deformable image registration (DIR) of longitudinal liver cancer computed tomographic (CT) images can be challenging owing to anatomic changes caused by radiation therapy (RT) or disease progression. We propose a workflow for the DIR of longitudinal contrast-enhanced CT scans of liver cancer based on a biomechanical model of the liver driven by boundary conditions on the liver surface and centerline of an autosegmentation of the vasculature. Methods and Materials Pre- and post-RT CT scans acquired with a median gap of 112 (32-217) days for 28 patients who underwent RT for intrahepatic cholangiocarcinoma were retrospectively analyzed. For each patient, 5 corresponding anatomic landmarks in pre- and post-RT scans were identified in the liver by a clinical expert for evaluation of the accuracy of different DIR strategies. The first strategy corresponded to the use of a biomechanical model-based DIR method with boundary conditions specified on the liver surface (BM_DIR). The second strategy corresponded to the use of an expansion of BM_DIR consisting of the auto-segmentation of the liver vasculature to determine additional boundary conditions in the biomechanical model (BM_DIR_VBC). The 2 strategies were also compared with an intensity-based DIR strategy using a Demons algorithms. Results The group mean target registration errors were 12.4 ± 7.5, 7.7 ± 3.7 and 4.4 ± 2.5 mm, for the Demons, BM_DIR and BM_DIR_VBC, respectively. Conclusions In regard to the large and complex deformation observed in this study and the achieved accuracy of 4.4 mm, the proposed BM_DIR_VBC method might reveal itself as a valuable tool in future studies on the relationship between delivered dose and treatment outcome.

We have previously shown that ablative radiotherapy (A-RT) with a biologically effective dose (BED10) ≥ 80.5 Gy for patients with unresectable intrahepatic cholangiocarcinoma (ICC) is associated with longer survival. Despite recent large-scale sequencing efforts in ICC, outcomes following RT based on genetic alterations have not been described. We reviewed records of 156 consecutive patients treated with A-RT for unresectable ICC from 2008 to 2020. For 114 patients (73%), next-generation sequencing provided molecular profiles. The overall survival (OS), local control (LC), and distant metastasis-free survival (DMFS) were estimated using the Kaplan–Meier method. Univariate and multivariable Cox analyses were used to determine the associations with the outcomes. The median tumor size was 7.3 (range: 2.2–18.2) cm. The portal vein thrombus (PVT) was present in 10%. The RT median BED10 was 98 Gy (range: 81–144 Gy). The median (95% confidence interval) follow-up was 58 (42–104) months from diagnosis and 39 (33–74) months from RT. The median OS was 32 (29–35) months after diagnosis and 20 (16–24) months after RT. The one-year OS, LC, and intrahepatic DMFS were 73% (65–80%), 81% (73–87%), and 34% (26–42%). The most common mutations were in IDH1 (25%), TP53 (22%), ARID1A (19%), and FGFR2 (13%). Upon multivariable analysis, the factors associated with death included worse performance status, larger tumor, metastatic disease, higher CA 19-9, PVT, satellitosis, and IDH1 and PIK3CA mutations. TP53 mutation was associated with local failure. Further investigation into the prognostic value of individual mutations and combinations thereof is warranted.

Background:Checkpoint inhibitor therapy of cancer has led to markedly improved survival of a subset of patients in multiple solid malignant tumor types, yet the factors driving these clinical responses or lack thereof are not known. We have developed a mechanistic mathematical model for better understanding these factors and their relations in order to predict treatment outcome and optimize personal treatment strategies.Methods:Here, we present a translational mathematical model dependent on three key parameters for describing efficacy of checkpoint inhibitors in human cancer: tumor growth rate (α), tumor-immune infiltration (Λ), and immunotherapy-mediated amplification of anti-tumor response (µ). The model was calibrated by fitting it to a compiled clinical tumor response dataset (n = 189 patients) obtained from published anti-PD-1 and anti-PD-L1 clinical trials, and then validated on an additional validation cohort (n = 64 patients) obtained from our in-house clinical trials.Results:The derived parameters Λ and µ were both significantly different between responding versus nonresponding patients. Of note, our model appropriately classified response in 81.4% of patients by using only tumor volume measurements and within 2 months of treatment initiation in a retrospective analysis. The model reliably predicted clinical response to the PD-1/PD-L1 class of checkpoint inhibitors across multiple solid malignant tumor types. Comparison of model parameters to immunohistochemical measurement of PD-L1 and CD8+ T cells confirmed robust relationships between model parameters and their underlying biology.Conclusions:These results have demonstrated reliable methods to inform model parameters directly from biopsy samples, which are conveniently obtainable as early as the start of treatment. Together, these suggest that the model parameters may serve as early and robust biomarkers of the efficacy of checkpoint inhibitor therapy on an individualized per-patient basis.Funding:We gratefully acknowledge support from the Andrew Sabin Family Fellowship, Center for Radiation Oncology Research, Sheikh Ahmed Center for Pancreatic Cancer Research, GE Healthcare, Philips Healthcare, and institutional funds from the University of Texas M.D. Anderson Cancer Center. We have also received Cancer Center Support Grants from the National Cancer Institute (P30CA016672 to the University of Texas M.D. Anderson Cancer Center and P30CA072720 the Rutgers Cancer Institute of New Jersey). This research has also been supported in part by grants from the National Science Foundation Grant DMS-1930583 (ZW, VC), the National Institutes of Health (NIH) 1R01CA253865 (ZW, VC), 1U01CA196403 (ZW, VC), 1U01CA213759 (ZW, VC), 1R01CA226537 (ZW, RP, WA, VC), 1R01CA222007 (ZW, VC), U54CA210181 (ZW, VC), and the University of Texas System STARS Award (VC). BC acknowledges support through the SER Cymru II Programme, funded by the European Commission through the Horizon 2020 Marie Skłodowska-Curie Actions (MSCA) COFUND scheme and the Welsh European Funding Office (WEFO) under the European Regional Development Fund (ERDF). EK has also received support from the Project Purple, NIH (U54CA210181, U01CA200468, and U01CA196403), and the Pancreatic Cancer Action Network (16-65-SING). MF was supported through NIH/NCI center grant U54CA210181, R01CA222959, DoD Breast Cancer Research Breakthrough Level IV Award W81XWH-17-1-0389, and the Ernest Cockrell Jr. Presidential Distinguished Chair at Houston Methodist Research Institute. RP and WA received serial research awards from AngelWorks, the Gillson-Longenbaugh Foundation, and the Marcus Foundation. This work was also supported in part by grants from the National Cancer Institute to SHC (R01CA109322, R01CA127483, R01CA208703, and U54CA210181 CITO pilot grant) and to PYP (R01CA140243, R01CA188610, and U54CA210181 CITO pilot grant). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Purpose Patients with pancreatic cancer often receive radiation therapy before undergoing surgical resection. We compared the clinical outcomes differences between stereotactic body radiation therapy (SBRT) and 3-dimensional (3D)/intensity-modulated radiation therapy (IMRT). Methods and Materials We retrospectively collected data from the University of Texas MD Anderson Cancer Center. Patients with borderline resectable/potentially resectable or locally advanced pancreatic cancer receiving neoadjuvant SBRT (median, 36.0 Gy/5fx), 3D conformal radiation (median, 50.4 Gy/28 fx) or IMRT (median, 50.4 Gy/28 fx) were included. Overall survival (OS) and progression-free survival were analyzed using Cox regression. Results In total, 104 patients were included in our study. Fifty-seven patients (54.8%) were treated with SBRT, and 47 patients (45.2%) were treated with 3D/IMRT. Patients in the SBRT group were slightly older (median age: 70.3 vs 62.7 in the 3D/IMRT group). Both groups had similar proportions of patients with locally advanced pancreatic cancer (SBRT: 30, 52.6%; 3D/IMRT: 24, 51.1%). All patients were treated with chemotherapy. Patients in the SBRT group underwent more surgical resection compared with the 3D/IMRT group (38.6% vs 23.4%, respectively). At a median follow-up of 22 months, a total of 60 patients (57.7%) died: 25 (25/57, 43.9%) in the SBRT group, and 35 (35/47, 74.5%) in the 3D/IMRT group. Median OS was slightly higher in the SBRT group (29.6 months vs 24.1 months in the 3D/IMRT group). On multivariable Cox regression, the choice of radiation therapy technique was not associated with differences in OS (adjusted hazard ratios [aHR] = 0.5; 95% confidence interval [CI], 0.2%-1.3%, P = .18). Moreover, patients that underwent surgical resection had better OS (aHR = 0.3, 95% CI, 0.1%-0.8%, P = .01). Furthermore, progression-free survival was also similar between patients treated with SBRT and those treated with 3D/IMRT (aHR = 0.9, 95% CI, 0.5%-1.8%, P = .81) Conclusions SBRT was associated with similar clinical outcomes compared with conventional radiation techniques, despite being delivered over a shorter period of time which would spare patients prolonged treatment burden. Future prospective data are still needed to better assess the role of SBRT in patients with pancreatic cancer.

Background: Optimal patient selection for radiotherapy in pancreatic ductal adenocarcinoma (PDAC) is unestablished. Molecular profiling may select patients at high risk for locoregional recurrence (LRR) who would benefit from radiation. Methods: We included resectable pancreatic cancer (R-PDAC) patients, divided into training and validation cohorts, treated among three institutions with surgery and adjuvant chemotherapy, and borderline resectable or locally advanced pancreatic cancer (BR/LA-PDAC) patients treated with chemotherapy with or without radiation at the primary study institution. We isolated RNA from R-PDAC surgical specimens. Using NanoString, we identified miRNAs differentially expressed between normal and malignant pancreatic tissue. ElasticNet regression identified two miRNAs most predictive of LRR in the training cohort, miR-181b/d and miR-575, which were used to generate a risk score (RS). We evaluated the association of the median-dichotomized RS with recurrence and overall survival (OS). Results: We identified 183 R-PDAC and 77 BR/LA-PDAC patients with median follow up of 37 months treated between 2001 and 2014. On multivariable analysis of the R-PDAC training cohort (n = 90), RS was associated with worse LRR (HR = 1.34, 95%CI 1.27–11.38, p = 0.017) and OS (HR = 2.89, 95%CI 1.10–4.76, p = 0.027). In the R-PDAC validation cohort, RS was associated with worse LRR (HR = 2.39, 95%CI 1.03–5.54, p = 0.042), but not OS (p = 0.087). For BR/LA-PDAC, RS was associated with worse LRR (HR = 2.71, 95%CI 1.14–6.48, p = 0.025), DR (HR = 1.93, 95%CI 1.10–3.38, p = 0.022), and OS (HR = 1.97, 95%CI 1.17–3.34, p = 0.011). Additionally, after stratifying by RS and receipt of radiation in BR/LA-PDAC patients, high RS patients who did not receive radiation had worse LRR (p = 0.018), DR (p = 0.006), and OS (p &lt, 0.001) compared to patients with either low RS or patients who received radiation, irrespective of RS. Conclusions: RS predicted worse LRR and OS in R-PDAC and worse LRR, DR, and OS in BR/LA-PDAC. This may select patients who would benefit from radiation and should be validated prospectively.

Objective We sought to determine whether postoperative chemotherapy after preoperative therapy and pancreatectomy for pancreatic ductal adenocarcinoma (PDAC) prolongs survival. Background Data to support administering postoperative chemotherapy to patients who received preoperative therapy are lacking. Methods All patients with PDAC who underwent pancreatectomy after preoperative therapy between 2010 and July 2017 at The University of Texas MD Anderson Cancer Center were identified. To control for selection bias, patients who received postoperative therapy and patients who did not were matched by propensity scores based on factors associated with the use of postoperative chemotherapy. Results Among 245 patients treated with a median of 4 cycles of preoperative treatment and pancreatectomy, 155 (63%) initiated postoperative chemotherapy and 90 (37%) did not. Patients who received postoperative therapy had a higher median cancer antigen 19-9 level before surgery, larger median tumor diameter, higher rate of extrapancreatic invasion, and lower rate of pathologic major response. The propensity-matched cohort comprised 122 patients: 61 who received postoperative chemotherapy and 61 who did not. The median overall survival (OS) and recurrence free survival (RFS) for patients who received postoperative therapy were 42 and 17 months, respectively, versus 32 and 12 months for patients who did not (OS: P = 0.06; RFS: P = 0.04). Postoperative therapy was marginally associated with a longer OS (hazard ratio 0.55, 95% confidence interval 0.29-1.01; P = 0.05) and significantly associated with a longer RFS (hazard ratio 0.55, 95% confidence interval 0.29-0.96; P = 0.04). Conclusions Despite being administered more frequently to patients with poor prognostic factors, postoperative chemotherapy after preoperative therapy and pancreatectomy for PDAC was of clinical benefit.

PURPOSE Effective preoperative regimens and biomarkers for pancreatic ductal adenocarcinoma (PDAC) are lacking. We prospectively evaluated fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX)-based treatment and imaging-based biomarkers for borderline resectable PDAC. METHODS Eligible patients had treatment-naïve, histology-confirmed PDAC and one or more high-risk features: mesenteric vessel involvement, CA 19-9 level of 500 mg/dL or greater, and indeterminate metastatic lesions. Patients received modified FOLFIRINOX and chemoradiation before anticipated pancreatectomy. Tumors were classified on baseline computed tomography as high delta (well-defined interface with parenchyma) or low delta (ill-defined interface). We designated computed tomography interface response after therapy as type I (remained or became well defined) or type II (became ill defined). The study had 80% power to differentiate a 60% from 40% resection rate (α = .10). Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method, and subgroups were compared using log-rank tests. RESULTS Thirty-three patients initiated therapy; 45% underwent pancreatectomy. The median OS was 24 months (95% CI, 16.2 to 29.6 months). For patients who did and did not undergo pancreatectomy, the median OS was 42 months (95% CI, 17.7 months to not estimable) and 14 months (95% CI, 9.0 to 24.8 months), respectively. Patients with high-delta tumors had lower 3-year PFS (4% v 40%) and 3-year OS rates (20% v 60%) than those with low-delta tumors (both P < .05). Patients with type II interface responses had lower 3-year PFS (0% v 29%) and 3-year OS rates (16% v 47%) than those with type I responses (both P < .001). CONCLUSION Preoperative FOLFIRINOX followed by chemoradiation for high-risk borderline resectable PDAC was associated with a resection rate of 45% and median OS of approximately 2 years. Our imaging-based biomarker validation indicates that personalized treatment may be achieved using these biomarkers at baseline and post-treatment.

PURPOSE: Currently, radiologists use tumor-to-normal tissue contrast across multiphase computed tomography (MPCT) for lesion detection. Here, we developed a novel voxel-based enhancement pattern mapping (EPM) technique and investigated its ability to improve contrast-to-noise ratios (CNRs) in a phantom study and in patients with hepatobiliary cancers. METHODS: The EPM algorithm is based on the root mean square deviation between each voxel and a normal liver enhancement model using patient-specific (EPM-PA) or population data (EPM-PO). We created a phantom consisting of liver tissue and tumors with distinct enhancement signals under varying tumor sizes, motion, and noise. We also retrospectively evaluated 89 patients with hepatobiliary cancers who underwent active breath-hold MPCT between 2016 and 2017. MPCT phases were registered using a three-dimensional deformable image registration algorithm. For the patient study, CNRs of tumor to adjacent tissue across MPCT phases, EPM-PA and EPM-PO were measured and compared. RESULTS: EPM resulted in statistically significant CNR improvement (P < 0.05) for tumor sizes down to 3 mm, but the CNR improvement was significantly affected by tumor motion and image noise. Eighty-two of 89 hepatobiliary cases showed CNR improvement with EPM (PA or PO) over grayscale MPCT, by an average factor of 1.4, 1.6, and 1.5 for cholangiocarcinoma, hepatocellular carcinoma, and colorectal liver metastasis, respectively (P < 0.05 for all). CONCLUSIONS: EPM increases CNR compared with grayscale MPCT for primary and secondary hepatobiliary cancers. This new visualization method derived from MPCT datasets may have applications for early cancer detection, radiomic characterization, tumor treatment response, and segmentation. IMPLICATIONS FOR PATIENT CARE: We developed a voxel-wise enhancement pattern mapping (EPM) technique to improve the contrast-to-noise ratio (CNR) of multiphase CT. The improvement in CNR was observed in datasets of patients with cholangiocarcinoma, hepatocellular carcinoma, and colorectal liver metastasis. EPM has the potential to be clinically useful for cancers with regard to early detection, radiomic characterization, response, and segmentation.

Highlights • Proton pelvic reirradiation results in lower bone marrow dose compared to photons. • Proton pelvic reirradiation of the pelvis is well tolerated with limited toxicities., Introduction Pelvic reirradiation (re-RT) presents challenges due to concerns for late toxicity to tissues-at-risk including pelvic bone marrow (PBM). We routinely utilize a hyperfractionated, accelerated re-RT for recurrent rectal or anal cancer in the setting of prior radiation. We hypothesized that proton beam radiation (PBR) is uniquely suited to limit doses to pelvic non-target tissues better than photon-based approaches. Materials and methods All patients who received hyperfractionated, accelerated PBR re-RT to the pelvis from 2007 to 2017 were identified. Re-RT was delivered twice daily with a 6 h minimum interfraction interval at 1.5 Gray Relative Biological Effectiveness (Gy(RBE)) per fraction to a total dose of 39–45 Gy(RBE). Concurrent chemotherapy was given to all patients. Comparison photon plans were generated for dosimetric analysis. Dosimetric parameters compared using a matched-pair analysis and the Wilcoxon signed-rank test. Survival analysis was performed Kaplan Meier curves. Results Fifteen patients were identified, with a median prior pelvic RT dose of 50.4 Gy (range 25–80 Gy). Median time between the initial RT and PBRT re-RT was 4.7 years (range 1.0–36.1 years). In comparison to corresponding photon re-RT plans, PBR re-RT plans had lower mean PBM dose, and lower volume of PBM getting 5 Gy, 10 Gy, 20 Gy, and 30 Gy (p

Purpose Ablative radiation therapy is increasingly being used for hepatocellular carcinoma (HCC) resulting in excellent local control rates; however, patients without evidence of disease progression often die from liver failure. The clinical benefit of proton- over photon-based radiation therapy is unclear. We therefore sought to compare clinical outcomes of proton versus photon ablative radiation therapy in patients with unresectable HCC. Methods and Materials This is a single-institution retrospective study of patients treated during 2008 to 2017 with nonmetastatic, unresectable HCC not previously treated with liver-directed radiation therapy and who did not receive further liver-directed radiation therapy within 12 months after completion of index treatment. The primary outcome, overall survival (OS), was assessed using Cox regression. Secondary endpoints included incidence of non–classic radiation-induced liver disease (defined as increase in baseline Child-Pugh score by ≥2 points at 3 months posttreatment), assessed using logistic regression, and locoregional recurrence, assessed using Fine-Gray regression for competing risks. All outcomes were measured from radiation start date. Results The median follow-up was 14 months. Of 133 patients with median age 68 years and 75% male, 49 (37%) were treated with proton radiation therapy. Proton radiation therapy was associated with improved OS (adjusted hazard ratio, 0.47; P = .008; 95% confidence interval [CI], 0.27-0.82). The median OS for proton and photon patients was 31 and 14 months, respectively, and the 24-month OS for proton and photon patients was 59.1% and 28.6%, respectively. Proton radiation therapy was also associated with a decreased risk of non–classic radiation–induced liver disease (odds ratio, 0.26; P = .03; 95% CI, 0.08-0.86). Development of nonclassic RILD at 3 months was associated with worse OS (adjusted hazard ratio, 3.83; P Conclusions Proton radiation therapy was associated with improved survival, which may be driven by decreased incidence of posttreatment liver decompensation. Our findings support prospective investigations comparing proton versus photon ablative radiation therapy for HCC.

OBJECTIVE: We sought to identify potential radiologic and serologic markers of pancreatic tumor response to therapy, using pathologic major response (pMR) as the objective endpoint. BACKGROUND: We previously demonstrated that a pMR to preoperative therapy, defined as detection of

Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer that progresses without any symptom, and oftentimes, it is detected at an advanced stage. The lack of prior symptoms and effective treatments have created a knowledge gap in the management of this lethal disease. This issue can be addressed by developing novel noninvasive imaging-based biomarkers in PDAC. We explored in vivo hyperpolarized (HP) 13C MRS of pyruvate to lactate conversion and ex vivo 1H NMR spectroscopy in a panel of well-annotated patient-derived PDAC xenograft (PDXs) model and investigated the correlation between aberrant glycolytic metabolism and aggressiveness of the tumor. Real-time metabolic imaging data demonstrate the immediate intracellular conversion of HP 13C pyruvate to lactate after intravenous injection interrogating upregulated lactate dehydrogenase (LDH) activity in aggressive PDXs. Total ex vivo lactate measurement by 1H NMR spectroscopy showed a direct correlation with in vivo dynamic pyruvate-to-lactate conversion and demonstrated the potential of dynamic metabolic flux as a biomarker of total lactate concentration and aggressiveness of the tumor. Furthermore, the metabolite concentrations were very distinct among all four tumor types analyzed in this study. Overexpression of LDH-A and hypoxia-inducible factor (HIF-1α) plays a significant role in the conversion kinetics of HP pyruvate-to-lactate in tumors. Collectively, these data identified aberrant metabolic characteristics of pancreatic cancer PDXs and could potentially delineate metabolic targets for therapeutic intervention. Metabolic imaging with HP pyruvate and NMR metabolomics may enable identification and classification of aggressive subtypes of patient-derived xenografts. Translation of this real-time metabolic technique to the clinic may have the potential to improve the management of patients at high risk of developing pancreatic diseases.

When pancreatic cancer cannot be removed surgically, patients frequently experience morbidity and death from progression of their primary tumor. Radiation therapy (RT) cannot yet substitute for an operation because radiation causes fatal bleeding and ulceration of the nearby stomach and intestines before achieving tumor control. There are no FDA-approved medications that prevent or reduce radiation-induced gastrointestinal injury. Here, we overcome this fundamental problem of anatomy and biology with the use of the oral EGLN inhibitor FG-4592, which selectively protects the intestinal tract from radiation toxicity without protecting tumors. A total of 70 KPC mice with autochthonous pancreatic tumors received oral FG-4592 or vehicle control ± ablative RT to a cumulative 75 Gy administered in 15 daily fractions to a limited tumor field. Although ablative RT reduced complications from local tumor progression, fatal gastrointestinal bleeding was observed in 56% of mice that received high-dose RT with vehicle control. However, radiation-induced bleeding was completely ameliorated in mice that received high-dose RT with FG-4592 (0% bleeding, P < 0.0001 compared with vehicle). Furthermore, FG-4592 reduced epithelial apoptosis by half (P = 0.002) and increased intestinal microvessel density by 80% compared with vehicle controls. EGLN inhibition did not stimulate cancer growth, as treatment with FG-4592 alone, or overexpression of HIF2 within KPC tumors independently improved survival. Thus, we provide a proof of concept for the selective protection of the intestinal tract by the EGLN inhibition to enable ablative doses of cytotoxic therapy in unresectable pancreatic cancer by reducing untoward morbidity and death from radiation-induced gastrointestinal bleeding. Significance: Selective protection of the intestinal tract by EGLN inhibition enables potentially definitive doses of radiation therapy. This might allow radiation to be a surgical surrogate for unresectable pancreatic cancer.

The vast majority of patients with pancreatic ductal adenocarcinoma (PDAC) presents with symptomatic, surgically unresectable disease. While the goal of early detection of PDAC is laudable, and likely to result in significant improvement in overall survival, the relatively low prevalence of PDAC renders general population screening infeasible. The challenges of early detection include identification of at-risk individuals in the general population who would benefit from longitudinal surveillance programs, and appropriate biomarker and imaging-based modalities utilized for PDAC surveillance in such cohorts. In recent years, various subgroups at higher than average risk for PDAC have been identified, including those with familial risk due to germline mutations, a history of pancreatitis, patients with mucinous pancreatic cysts, and elderly patients with new onset diabetes (NOD). The last two categories will be discussed at length in terms of the opportunities and challenges they present for PDAC early detection. We also discuss current and emerging imaging modalities that are critical to identifying early, potentially curable, PDAC in high-risk cohorts on surveillance.

Purpose To evaluate the effect of setup uncertainties including uncertainties between different breath holds (BH) and inter-fractional anatomical changes under CT-guided BH with intensity-modulated proton therapy (IMPT) in patients with liver cancer. Methods and materials This retrospective study considered 17 patients with liver tumors who underwent feedback-guided BH (FGBH) IMRT treatment with daily CT-on-rail imaging. Planning CT images were acquired at simulation using FGBH, and FGBH CT-on-rail images were also acquired prior to each treatment. Selective robust IMPT plans were generated using planning CT and re-calculated on each daily CT-on-rail image. Subsequently, the fractional doses were deformed and accumulated onto the planning CT according to the deformable image registration between daily and planning CTs. The doses to the target and organs at risk (OARs) were compared between IMRT, planned IMPT, and accumulated IMPT doses. Results For IMPT plans, the mean of D98% of CTV for all 17 patients was slightly reduced from the planned dose of 68.90 ± 1.61 Gy to 66.48 ± 1.67 Gy for the accumulated dose. The target coverage could be further improved by adjusting planning techniques. The dose–volume histograms of both planned and accumulated IMPT doses showed better sparing of OARs than that of the IMRT. Conclusions IMPT with FGBH and CT-on-rail guidance is a robust treatment approach for liver tumor cases.

Checkpoint inhibitor therapy of cancer has led to markedly improved survival of a subset of patients in multiple solid malignant tumor types, yet the factors driving these clinical responses or lack thereof are not known. Here we present a translational mathematical model dependent on three key parameters for describing efficacy of checkpoint inhibitors in human cancer: tumor growth rate (α), tumor immune infiltration (Λ), and immunotherapy-mediated amplification of anti-tumor response (µ). The model was validated by fitting it to a compiled clinical tumor response dataset (n = 189 patients) obtained from published anti-PD-1 and anti-PD-L1 clinical trials, and then validated on an additional validation cohort (n = 64 patients) obtained from our in-house clinical trials. The derived parameters Λ and µ were both significantly different between responding versus non-responding patients. Of note, our model appropriately classified response in 81.4% of patients by using only tumor volume measurements and within two months of treatment initiation in a retrospective analysis. The model reliably predicted clinical response to the PD-1/PD-L1 class of checkpoint inhibitors across multiple solid malignant tumor types. Comparison of model parameters to immunohistochemical measurement of PD-L1 and CD8+ T cells confirmed robust relationships between model parameters and their underlying biology, demonstrating reliable methods to inform model parameters directly from biopsy samples, which are conveniently obtainable as early as the start of treatment. Together, these results suggest that the model parameters may serve as early and robust biomarkers of the efficacy of checkpoint inhibitor therapy on an individualized per-patient basis.SIGNIFICANCECheckpoint inhibitors have revolutionized cancer immunotherapy, but only a subset of patients with solid tumors responds clinically. The ability to predict tumor responses a priori or soon after starting therapy would allow for personalized and timely adaptive clinical applications of checkpoint inhibitor- based immunotherapy in patients. By applying a mechanistic mathematical model, we show that checkpoint inhibitor therapeutic effectiveness is accurately predictable in most patients within two months after treatment initiation. Our method may be implemented directly into clinical practice, as it relies on standard-of-care imaging and pathology. If successful in prospective studies, this model will improve selection of cancer patients for checkpoint inhibitor therapy, and perhaps for other forms of humoral- or cell-based immunotherapy.

IntroductionPancreatic adenocarcinoma (PAC) has some of the worst treatment outcomes for any solid tumor. PAC creates substantial difficulty for effective treatment with traditional RT delivery strategies primarily secondary to its location and limited visualization using CT. Several of these challenges are uniquely addressed with MR-guided RT. We sought to summarize and place into context the currently available literature on MR-guided RT specifically for PAC.MethodsA literature search was conducted to identify manuscript publications since September 2014 that specifically used MR-guided RT for the treatment of PAC. Clinical outcomes of these series are summarized, discussed, and placed into the context of the existing pancreatic literature. Multiple international experts were involved to optimally contextualize these publications.ResultsOver 300 manuscripts were reviewed. A total of 6 clinical outcomes publications were identified that have treated patients with PAC using MR guidance. Successes, challenges, and future directions for this technology are evident in these publications. MR-guided RT holds theoretical promise for the treatment of patients with PAC. As with any new technology, immediate or dramatic clinical improvements associated with its use will take time and experience. There remain no prospective trials, currently publications are limited to small retrospective experiences. The current level of evidence for MR guidance in PAC is low and requires significant expansion. Future directions and ongoing studies that are currently open and accruing are identified and reviewed.ConclusionsThe potential promise of MR-guided RT for PAC is highlighted, the challenges associated with this novel therapeutic intervention are also reviewed. Outcomes are very early, and will require continued and long term follow up. MR-guided RT should not be viewed in the same fashion as a novel chemotherapeutic agent for which dosing, administration, and toxicity has been established in earlier phase studies. Instead, it should be viewed as a novel procedural intervention which must be robustly tested, refined and practiced before definitive conclusions on the potential benefits or detriments can be determined. The future of MR-guided RT for PAC is highly promising and the potential implications on PAC are substantial.

BackgroundGlucose-regulated protein 78 (GRP78) plays an essential role in protein folding, transportation, and degradation, thus regulates ER homeostasis and promotes cell survival, proliferation and invasion. GRP78 expression in PDAC patients who received neoadjuvant therapy has not been reported.MethodsThis retrospective study of resected PDAC patients included 125 patients treated with neoadjuvant therapy (NAT) and 140 patients treated with surgery first (SF). The expression of GRP78 was evaluated by immunohistochemistry on tissue microarrays and the results were correlated with clinicopathologic parameters and survival.ResultsGRP78 expression was higher in SF patients compared to NAT patients (P&nbsp

PURPOSE/OBJECTIVE(S) Few studies have long-term follow-up assessing patient-reported outcomes (PROs) after intensity-modulated radiation therapy (IMRT)-based chemoradiation (CRT) for squamous cell carcinoma of the anus (SCCA). There is poor agreement between physician-graded toxicity and PROs regarding quality of life (QOL) in patients with SCCA. Therefore, we surveyed SCCA survivors ≥ 2 years out from CRT with validated PRO instruments assessing bowel, bladder, and sexual function. MATERIALS/METHODS We identified 248 patients with SCCA treated with definitive IMRT-based CRT at a large tertiary cancer center from 2010-2018, who were alive and without recurrence. Patients were asked to complete five PRO instruments: Fecal Incontinence QOL Scale (FIQOL), Low Anterior Resection Syndrome Score (LARS), International Consultation on Incontinence Questionnaire (ICIQ), male and female lower urinary tract symptoms (MLUTS and FLUTS, respectively), International Index of Erectile Function (IIEF), and Female Sexual Function Index (FSFI). FIQOL, LARS, IIEF, and FSFI scores were dichotomized and logistic regression used to identify predictors of QOL scores. RESULTS One hundred eight (44%) patients completed the PROs. Respondents' median [interquartile range, (IQR)] age was 66 [59-72] years, 80% were female, and 95% were white. Median [IQR] gross tumor volume (GTV) was 45 [27-71] cc; dose to GTV was 50 Gray (Gy), 54 Gy and 58 Gy in 25%, 53%, and 22%, respectively. Median [IQR] time from CRT was 51 [37-84] months. Median [IQR] FIQOL score was 14.3/20 [11.2-16.1]; higher is better. Larger GTV size (OR 0.99; P = 0.03) was associated with lower FIQOL score. Sixty-one (56%) patients met major LARS criteria. There was a trend towards a higher incidence of major LARS with GTV dose ≥ 54 Gy (OR 2.39; P = 0.08). Men had median [IQR] ICIQ MLUTS voiding and incontinence scores of 5/20 [2-6] and 1/24 [1-3], respectively. Women had median [IQR] ICIQ FLUTS voiding and incontinence scores of 1/12 [1-3] and 5/20 [3-8], respectively; higher is worse. Fifty-nine (55%) patients reported being sexually active in the last month. Men had a median [IQR] IIEF score of 14/25 [6-19]; higher is better. Only age (OR 1.17; P = 0.04) was significantly associated with IIEF ≤ 11 (moderate or severe ED). Women had a median [IQR] FSFI score of 20.2/26 [13.6-24.9]; higher is better. Age < 65 was associated with sexual dysfunction, defined as FSFI < 26.55 (OR, 5.5; P = 0.04). Forty (37%) patients disagreed or strongly disagreed that they were prepared for long-term side effects. Seventy (65%) patients agreed or strongly agreed that educational materials would have been helpful. CONCLUSION SCCA survivors experience significant long-term bowel and sexual toxicities from modern CRT. Larger tumors and higher RT doses may be associated with worse function. Interventions to reduce toxicities and improve patient education are needed.

Purpose Localized pancreatic cancer is commonly treated with stereotactic body radiation therapy (SBRT), which often requires the placement of fiducial markers. We compared the clinical outcomes of patients with and without fiducial markers. Methods and Materials We retrospectively collected data on patients with pancreatic cancer treated with neoadjuvant SBRT at a single institution. Patients were divided into 2 groups based on the placement of a fiducial marker. Local recurrence was the primary outcome. Time to event endpoints were analyzed using COX regression. Results We included 96 patients with unresectable pancreatic cancer: 46 patients (47.9%) did not have a fiducial marker, and 50 patients (52.1%) had a fiducial placed. Patients in the fiducial group were older and had more locally advanced pancreatic cancer compared with those who did not have a fiducial placed. Most patients in both groups (92.7%) received chemotherapy before SBRT treatment. SBRT was delivered to a median of 36 Gy over 5 fractions in the no-fiducial group, and 38 Gy over 5 fractions in the fiducial group. At a median follow-up of 20 months, local recurrence was similar irrespective of fiducial placement (adjusted hazard ratio [aHR] 0.6, 95% CI 0.3-1.3, P = .59). Furthermore, no difference in overall survival was noted between the 2 groups (aHR 0.8, 95% CI 0.3-1.9, P = .65). In patients who eventually underwent surgery post-SBRT, no difference in surgical margins (P = .40) or lymphovascular invasion (P = .76) was noted between the 2 groups. No patient developed acute pancreatitis after fiducial placement. Conclusions Our data suggest that the use of fiducial markers does not negatively affect clinical outcomes in patients with localized pancreatic cancer. Prospective confirmation of our results is still needed.

Treatment options in locally advanced hepatocellular carcinoma (HCC) have evolved considerably over the past few years with the recent approval of multiple systemic therapies and significant advances in locoregional therapy. Given the poor prognosis for patients with unresectable HCC, there is significant interest in rationally designed combination therapies. This article reviews the treatment options available to patients with locally advanced HCC and discusses the rationale, ongoing trials, and future prospects for combining locoregional and systemic therapy in both the definitive and neoadjuvant settings.

Previously, we characterized qualitative imaging-based subtypes of pancreatic ductal adenocarcinoma (PDAC) on computed tomography (CT) scans. Conspicuous (high delta) PDAC tumors are more likely to have aggressive biology and poorer clinical outcomes compared to inconspicuous (low delta) tumors. Here, we developed a quantitative classification of this imaging-based subtype (quantitative delta, q-delta). Retrospectively, baseline pancreatic protocol CT scans of three cohorts (cohort#1 = 101, cohort#2 = 90 and cohort#3 = 16 [external validation]) of patients with PDAC were qualitatively classified into high and low delta. We used a voxel-based method to volumetrically quantify tumor enhancement while referencing normal-pancreatic-parenchyma and used machine learning-based analysis to build a predictive model. In addition, we quantified the stromal content using hematoxylin- and eosin-stained treatment-na&iuml, ve PDAC sections. Analyses revealed that PDAC quantitative enhancement values are predictive of the qualitative delta scoring and were used to build a classification model (q-delta). Compared to high q-delta, low q-delta tumors were associated with improved outcomes, and the q-delta class was an independent prognostic factor for survival. In addition, low q-delta tumors had higher stromal content and lower cellularity compared to high q-delta tumors. Our results suggest that q-delta classification provides a clinically and biologically relevant tool that may be integrated into ongoing and future clinical trials.

BackgroundPreviously, we characterized subtypes of pancreatic ductal adenocarcinoma (PDAC) on computed-tomography (CT) scans, whereby conspicuous (high delta) PDAC tumors are more likely to have aggressive biology and poorer clinical outcomes compared to inconspicuous (low delta) tumors. Here, we hypothesized that these imaging-based subtypes would exhibit different growth-rates and distinctive metabolic effects in the period prior to PDAC diagnosis.Materials and methodsRetrospectively, we evaluated 55 patients who developed PDAC as a second primary cancer and underwent serial pre-diagnostic (T0) and diagnostic (T1) CT-scans. We scored the PDAC tumors into high and low delta on T1 and, serially, obtained the biaxial measurements of the pancreatic lesions (T0-T1). We used the Gompertz-function to model the growth-kinetics and estimate the tumor growth-rate constant (α) which was used for tumor binary classification, followed by cross-validation of the classifier accuracy. We used maximum-likelihood estimation to estimate initiation-time from a single cell (10-6 mm3) to a 10 mm3 tumor mass. Finally, we serially quantified the subcutaneous-abdominal-fat (SAF), visceral-abdominal-fat (VAF), and muscles volumes (cm3) on CT-scans, and recorded the change in blood glucose (BG) levels. T-test, likelihood-ratio, Cox proportional-hazards, and Kaplan-Meier were used for statistical analysis and p-value ResultsCompared to high delta tumors, low delta tumors had significantly slower average growth-rate constants (0.024 month−1 vs. 0.088 month−1, p−1. Leave-one-out-cross-validation showed 80% accuracy in predicting the delta-class (AUC=0.84). High delta tumors exhibited accelerated SAF, VAF, and muscle wasting (p ConclusionImaging-based subtypes of PDAC exhibit distinct growth, metabolic, and clinical profiles during the pre-diagnostic period. Our results suggest that heterogeneous disease biology may be an important consideration in early detection strategies for PDAC.

IMPORTANCE: Fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) and gemcitabine plus nanoparticle albumin-bound (nab)–paclitaxel (GA) are first-line chemotherapy regimens for pancreatic cancer. Their relative efficacy in the setting of localized disease is unknown. OBJECTIVE: To evaluate radiographic and serologic measures of responses associated with first-line chemotherapy with FOLFIRINOX or GA, and to determine the association between these drug regimens, putative measures of response, and survival. DESIGN, SETTING, AND PARTICIPANTS: This case series assessed 485 consecutive patients who were diagnosed as having previously untreated localized pancreatic ductal adenocarcinoma at The University of Texas MD Anderson Cancer Center between January 1, 2010, and December 31, 2017, and who received at least 3 cycles of first-line chemotherapy with FOLFIRINOX or GA. The median (range) follow-up duration was 33 (2-28) months. EXPOSURES: Administration of FOLFIRINOX (285 patients [59%]) or GA (200 patients [41%]) as first-line chemotherapy. MAIN OUTCOMES AND MEASURES: Resection rate, radiographic metrics (Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1, and change in tumor volume or anatomic staging), a serologic metric (serum cancer antigen 19-9 level), and overall survival after administration of first-line chemotherapy. RESULTS: In total, 485 patients (266 [55%] male) were included in the analysis. Patients treated with FOLFIRINOX were generally younger (median [range] age at diagnosis: 61 [30-81] vs 71 [36-89] years; P = .001) and had better performance status as indicated by the Eastern Cooperative Oncology Group scale (range 0-4, with lower numbers representing better performance) score of 2 or lower (274 patients [96%] vs 165 patients [82%] P = .001) but more invasive tumors than patients who received GA (91 [32%] vs 90 [45%] resectable tumors; P = .01). After propensity score matching to control for these biases, many objective serologic and radiographic metrics of response associated with administration of FOLFIRINOX or GA—including low rates of local tumor downstaging—did not differ. However, RECIST partial response was more common among patients treated with FOLFIRINOX (27 of 140 patients [19%]) than with GA (8 of 140 patients [6%]; P = .001). Moreover, (chemo)radiation (50% vs 34%; P = .001) was more commonly administered to and pancreatectomy (27% vs 16%; P = .01) was subsequently performed more frequently for patients initially treated with FOLFIRINOX. The overall survival duration of patients treated with either regimen was similar (hazard ratio, 1.48; 95% CI, 0.97-2.26; P = .07). CONCLUSIONS AND RELEVANCE: In this cohort of patients with localized pancreatic adenocarcinoma who received FOLFIRINOX or GA as their first line of therapy, FOLFIRINOX was associated with higher rates of RECIST partial response and subsequent pancreatectomy than GA, but the overall survival associated with these regimens was similar.

Radiomics, also known as quantitative imaging or texture analysis, involves extracting a large number of features traditionally unmeasured in conventional radiological cross-sectional images and converting them into mathematical models. This review describes this approach and its use in the evaluation of pancreatic cystic lesions (PCLs). This discipline has the potential of more accurately assessing, classifying, risk stratifying, and guiding the management of PCLs. Existing studies have provided important insight into the role of radiomics in managing PCLs. Although these studies are limited by the use of retrospective design, single center data, and small sample sizes, radiomic features in combination with clinical data appear to be superior to the current standard of care in differentiating cyst type and in identifying mucinous PCLs with high-grade dysplasia. Combining radiomic features with other novel endoscopic diagnostics, including cyst fluid molecular analysis and confocal endomicroscopy, can potentially optimize the predictive accuracy of these models. There is a need for multicenter prospective studies to elucidate the role of radiomics in the management of PCLs.

PURPOSE: Among patients with anal cancer, chemoradiotherapy is often associated with toxicities that diminish quality of life. We describe the GI-related patient-reported outcomes (PROs) of patients with anal cancer receiving chemoradiotherapy to improve patient-physician communication. METHODS: We prospectively followed patients with nonmetastatic squamous cell carcinoma of the anal canal who received definitive chemoradiotherapy. Patients completed the bowel subdomain of the Expanded Prostate Cancer Index Composite (EPIC) questionnaire before treatment and at 4 subsequent timepoints. We used the paired Wilcoxon test to compare EPIC scores at different times. RESULTS: The study included 21 patients; median age was 57 years. Most patients (52%) had T2 and either N0 or N1 disease (81%). Most patients (91%) received chemotherapy with cisplatin-fluorouracil and either intensity-modulated radiotherapy or volumetric modulated arc therapy. Compared with the patients’ median overall summary score at baseline (66), their median score at 1 week (82) was higher ( P = .009), whereas their median score at 5 weeks (54) was lower ( P = .025). The patients’ median overall summary score at baseline and at 3 months did not differ ( P = .919). Three months after radiotherapy, most patients reported minimal adverse effects compared with baseline. CONCLUSION: The GI-related PROs of patients with anal cancer tend to fluctuate during radiotherapy but return to baseline by 3 months, at which time most patients report few or no residual adverse effects. We provide a clear timeline of GI acute toxicity using sequential PRO measurements that will improve patient-physician communication regarding expectations for cancer treatment.

A mathematical model of checkpoint inhibitor immunotherapy yields patient-specific prognosis of tumor kill and patient survival., We present a mechanistic mathematical model of immune checkpoint inhibitor therapy to address the oncological need for early, broadly applicable readouts (biomarkers) of patient response to immunotherapy. The model is built upon the complex biological and physical interactions between the immune system and cancer, and is informed using only standard-of-care CT. We have retrospectively applied the model to 245 patients from multiple clinical trials treated with anti–CTLA-4 or anti–PD-1/PD-L1 antibodies. We found that model parameters distinctly identified patients with common (n = 18) and rare (n = 10) malignancy types who benefited and did not benefit from these monotherapies with accuracy as high as 88% at first restaging (median 53 days). Further, the parameters successfully differentiated pseudo-progression from true progression, providing previously unidentified insights into the unique biophysical characteristics of pseudo-progression. Our mathematical model offers a clinically relevant tool for personalized oncology and for engineering immunotherapy regimens.

Highlights • The use of oral stents during RT was associated with reduced late morbidity. • OPC patients with bilateral RT and tongue-depressing stents had less dysphagia. • Patients with unilateral RT and tongue-deviating stent had better taste/appetite., Objectives To evaluate whether the use of oral stents during intensity modulated radiation therapy (IMRT) for oropharyngeal cancer (OPC) is associated with long-term patient reported symptoms. Materials and methods Data was obtained from a prospective observational study of disease-free head and neck cancer survivors. Radiation-associated patient reported symptoms were assessed using the MD Anderson Symptom Inventory Head and Neck module (MDASI-HN). Scores of ≥5 (11-point Likert scale, 0-10) were considered moderate/severe. Stratification was performed regarding IMRT volume (uni- versus bilateral neck) and stent utilization, with non-parametric analyses between groups. Results 462 OPC survivors formed the cohort (54% tonsil, 46% base of tongue primaries). A tongue-deviating stent was used in 17%, tongue-depressing stent in 46%, and no stent in 37%. Median prescribed dose to the high dose clinical target volume was 66.0 Gy. Median follow-up from RT to MDASI-HN assessment was 68 months. Twenty percent had received unilateral neck RT (all had tonsil primaries), in whom a significant improvement in the proportion of patients with moderate/severe taste impairment (2% vs. 15%, p = 0.047) and lack of appetite (0% vs. 9%, p = 0.019) was associated with the use of tongue-deviating stents compared to no oral stent. In those who had received bilateral neck RT, a significant improvement in the proportion of patients with moderate/severe difficulty swallowing/chewing was associated with use of a tongue-depressing stent (21% vs. 31% without oral stent, p = 0.013). Conclusion Disease-site specific select use of oral stents during IMRT was associated with reduced long-term patient reported symptoms in OPC survivors.

Pancreatic ductal adenocarcinoma is most frequently detected at an advanced stage. Such late detection restricts treatment options and contributes to a dismal 5-year survival rate of 3-15%. Pancreatic ductal adenocarcinoma is relatively uncommon and screening of the asymptomatic adult population is not feasible or recommended with current modalities. However, screening of individuals in high-risk groups is recommended. Here, we review groups at high risk for pancreatic ductal adenocarcinoma, including individuals with inherited predisposition and patients with pancreatic cystic lesions. We discuss studies aimed at finding ways of identifying pancreatic ductal adenocarcinoma in high-risk groups, such as among individuals with new-onset diabetes mellitus and people attending primary and secondary care practices with symptoms that suggest this cancer. We review early detection biomarkers, explore the potential of using social media for detection, appraise prediction models developed using electronic health records and research data, and examine the application of artificial intelligence to medical imaging for the purposes of early detection.

Purpose Response assessment of radiotherapy for the treatment of intrahepatic cholangiocarcinoma (IHCC) across longitudinal images is challenging due to anatomical changes. Advanced deformable image registration (DIR) techniques are required to correlate corresponding tissues across time. In this study, the accuracy of five commercially available DIR algorithms in four treatment planning systems (TPS) was investigated for the registration of planning images with posttreatment follow-up images for response assessment or re-treatment purposes. Methods Twenty-nine IHCC patients treated with hypofractionated radiotherapy and with pretreatment and posttreatment contrast-enhanced computed tomography (CT) images were analyzed. Liver segmentations were semiautomatically generated on all CTs and the posttreatment CT was then registered to the pretreatment CT using five commercially available algorithms (Demons, B-splines, salient feature-based, anatomically constrained and finite element-based) in four TPSs. This was followed by an in-depth analysis of 10 DIR strategies (plus global and liver-focused rigid registration) in one of the TPSs. Eight of the strategies were variants of the anatomically constrained DIR while the two were based on a finite element-based biomechanical registration. The anatomically constrained techniques were combinations of: (a) initializations with the two rigid registrations; (b) two similarity metrics - correlation coefficient (CC) and mutual information (MI); and (c) with and without a controlling region of interest (ROI) - the liver. The finite element-based techniques were initialized by the two rigid registrations. The accuracy of each registration was evaluated using target registration error (TRE) based on identified vessel bifurcations. The results were statistically analyzed with a one-way analysis of variance (ANOVA) and pairwise comparison tests. Stratified analysis was conducted on the inter-TPS data (plus the liver-focused rigid registration) using treatment volume changes, slice thickness, time between scans, and abnormal lab values as stratifying factors. Results The complex deformation observed following treatment resulted in average TRE exceeding the image voxel size for all techniques. For the inter-TPS comparison, the Demons algorithm had the lowest TRE, which was significantly superior to all the other algorithms. The respective mean (standard deviation) TRE (in mm) for the Demons, B-splines, salient feature-based, anatomically constrained, and finite element-based algorithms were 4.6 (2.0), 7.4 (2.7), 7.2 (2.6), 6.3 (2.3), and 7.5 (4.0). In the follow-up comparison of the anatomically constrained DIR, the strategy with liver-focused rigid registration initialization, CC as similarity metric and liver as a controlling ROI had the lowest mean TRE - 6.0 (2.0). The maximum TRE for all techniques exceeded 10 mm. Selection of DIR strategy was found to be a statistically significant factor for registration accuracy. Tumor volume change had a significant effect on TRE for finite element-based registration and B-splines DIR. Time between scans had a substantial effect on TRE for all registrations but was only significant for liver-focused rigid, finite element-based and salient feature-based DIRs. Conclusions This study demonstrates the limitations of commercially available DIR techniques in TPSs for alignment of longitudinal images of liver cancer presenting complex anatomical changes including local hypertrophy and fibrosis/necrosis. DIR in this setting should be used with caution and careful evaluation.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous disease with variable presentations and natural histories of disease. We hypothesized that different morphologic characteristics of PDAC tumors on diagnostic computed tomography (CT) scans would reflect their underlying biology. Experimental Design: We developed a quantitative method to categorize the PDAC morphology on pretherapy CT scans from multiple datasets of patients with resectable and metastatic disease and correlated these patterns with clinical/pathologic measurements. We modeled macroscopic lesion growth computationally to test the effects of stroma on morphologic patterns, hypothesizing that the balance of proliferation and local migration rates of the cancer cells would determine tumor morphology. Results: In localized and metastatic PDAC, quantifying the change in enhancement on CT scans at the interface between tumor and parenchyma (delta) demonstrated that patients with conspicuous (high-delta) tumors had significantly less stroma, higher likelihood of multiple common pathway mutations, more mesenchymal features, higher likelihood of early distant metastasis, and shorter survival times compared with those with inconspicuous (low-delta) tumors. Pathologic measurements of stromal and mesenchymal features of the tumors supported the mathematical model's underlying theory for PDAC growth. Conclusions: At baseline diagnosis, a visually striking and quantifiable CT imaging feature reflects the molecular and pathological heterogeneity of PDAC, and may be used to stratify patients into distinct subtypes. Moreover, growth patterns of PDAC may be described using physical principles, enabling new insights into diagnosis and treatment of this deadly disease.

Background Significant overtreatment of intraductal papillary mucinous neoplasms can be attributed to low specificity of the current International Consensus Guidelines as well as nonconformity with the guidelines. We compare the ability of the 2012 and revised 2017 intraductal papillary mucinous neoplasms International Consensus Guidelines to predict high-grade dysplasia/invasive cancer and to determine the preoperative variables that predict resection of benign or low-grade dysplasia in tertiary care centers. Methods Clinical, radiographic, and pathologic data for resected intraductal papillary mucinous neoplasms at 3 high-volume National Cancer Institute Cancer Centers were reviewed and the 2012 and 2017 consensus criteria were retrospectively applied. When International Consensus Guidelines were not met, clinical decision analysis was used to determine the primary indication for resection. Logistic regression identified variables associated with pathologic grade. Results Records for a total of 251 patients were reviewed, 129 of whom (52%) had low-grade dysplasia. The revised 2017 International Consensus Guidelines had high sensitivity (98.4%) and negative predicted value (96.1%), and all high-risk stigmata predicted high-grade dysplasia/invasive cancer; however, specificity remained low (14.8%). Nonconformity with International Consensus Guidelines was the most powerful predictor of low-grade dysplasia on final pathologic examination (9.5; 2.12–40.78). Independent predictors of low-grade dysplasia included age younger than 50 (2.46; 1.08–5.62), fine-needle aspiration without epithelial cells (2.6; 1.43–4.72), and normal duct diameter (3.07; 1.99–4.75). Diabetes developed in 30% of patients after resection. Conclusion Management of intraductal papillary mucinous neoplasms remains clinically challenging. Low specificity of the International Consensus Guidelines and nonconformity with the guidelines continue to contribute to unnecessary pancreatic resections. Improved tools for disease classification as well as a better understanding of the natural history, biology, and rates of progression of intraductal papillary mucinous neoplasms are needed to avoid surgical overtreatment of low-grade intraductal papillary mucinous neoplasms.

Preoperative chemotherapy provides early treatment of micro-metastases and guaranteed delivery of all components of multimodality therapy for localized pancreatic ductal adenocarcinoma (PDAC). For locally advanced (LA) PDAC, induction chemotherapy is the standard of care. This study evaluated the use of gemcitabine and nab-paclitaxel (Gem/nab-P) as first-line therapy for localized PDAC. Clinicopathologic features, treatment, and outcomes were evaluated for 99 patients with localized PDAC. The patients were staged using previously published criteria as follows: potentially resectable (PR), borderline type A (BR-A) (anatomy amenable to vascular resection), BR-B (biology suspicious for metastatic disease including high CA19-9), BR–C (comorbidities requiring medical optimization), and LA. The 99 patients (PR/BR/LA: 45/14/40) were treated with Gem/nab-P. Clinical staging showed that 20 patients had PR or BR-A disease, whereas 39 patients had BR-B or BR-C disease. The BR-B+C cases included one or more of the following: age of 80 years or older (13%), Eastern Cooperative Oncology Group performance status (ECOG PS) of 2 or more (13%), moderate to severe comorbidities (55%), CA19-9 of 1000 or higher (28%), and suspicion for metastases (21%). The majority of the patients received biweekly Gem/nab-P dosing, which was well tolerated. Pancreatectomy was performed for 12 (60%) of 20 patients with PR+BR-A, 2 (5%) of 39 patients with BR-B+C, and 1 (3%) of 40 patients with LA disease. During a median follow-up period of 26 months, the median overall survival (OS) period was 18 months (95% confidence interval [CI], 15.6–20.5 months) for all the patients, 17 months (95% CI, 14.6–19.5 months) for the unresected patients, and not reached for the resected patients (p = 0.028 for resected vs unresected patients). A significant number of patients with radiographically resectable PDAC albeit aggressive biology (BR-B), medically inoperable conditions (BR-C), or both received biweekly first-line Gem/nab-P. The resection rates were lower for the BR-B/BR-C patients than for the PR/BR-A patients (hazard ratio [HR], 0.43; 95% CI, 0.19–1.00; p = 0.05).