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In combination with cell-intrinsic properties, interactions in the tumor microenvironment modulate therapeutic response. We leveraged single-cell spatial transcriptomics to dissect the remodeling of multicellular neighborhoods and cell–cell interactions in human pancreatic cancer associated with neoadjuvant chemotherapy and radiotherapy. We developed spatially constrained optimal transport interaction analysis (SCOTIA), an optimal transport model with a cost function that includes both spatial distance and ligand–receptor gene expression. Our results uncovered a marked change in ligand–receptor interactions between cancer-associated fibroblasts and malignant cells in response to treatment, which was supported by orthogonal datasets, including an ex vivo tumoroid coculture system. We identified enrichment in interleukin-6 family signaling that functionally confers resistance to chemotherapy. Overall, this study demonstrates that characterization of the tumor microenvironment using single-cell spatial transcriptomics allows for the identification of molecular interactions that may play a role in the emergence of therapeutic resistance and offers a spatially based analysis framework that can be broadly applied to other contexts.

Introduction:Tumor-related liver failure (TRLF) is the most common cause of death in patients with intrahepatic cholangiocarcinoma (ICC). Though we previously showed that liver radiotherapy (L-RT) for locally advanced ICC is associated with less frequent TRLF and longer overall survival (OS), the role of L-RT for patients with extrahepatic metastatic disease (M1) remains undefined. We sought to compare outcomes for M1 ICC patients treated with and without L-RT. Methods:We reviewed ICC patients that found to have M1 disease at initial diagnosis at a single institution between 2010 and 2021 who received L-RT, matching them with an institutional cohort by propensity score and a National Cancer Database (NCDB) cohort by frequency technique. The median biologically effective dose was 97.5 Gy (interquartile range 80.5–97.9 Gy) for L-RT. Patients treated with other local therapies or supportive care alone were excluded. We analyzed survival with Cox proportional hazard modeling. Results:We identified 61 patients who received L-RT and 220 who received chemotherapy alone. At median follow-up of 11 months after diagnosis, median OS was 9 months (95% confidence interval [CI] 8–11) and 21 months (CI: 17–26) for patients receiving chemotherapy alone and L-RT, respectively. TRLF was the cause of death more often in the patients who received chemotherapy alone compared to those who received L-RT (82% vs. 47%; p= 0.001). On multivariable propensity score-matched analysis, associations with lower risk of death included duration of upfront chemotherapy (hazard ratio [HR] 0.82; p= 0.005) and receipt of L-RT (HR: 0.40; p= 0.002). The median OS from diagnosis for NCDB chemotherapy alone cohort was shorter than that of the institutional L-RT cohort (9 vs. 22 months; p< 0.001). Conclusion:For M1 ICC, L-RT associated with a lower rate of death due to TRLF and longer OS versus those treated with chemotherapy alone. Prospective studies of L-RT in this setting are warranted.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and treatment-refractory cancer. Molecular stratification in pancreatic cancer remains rudimentary and does not yet inform clinical management or therapeutic development. Here, we construct a high-resolution molecular landscape of the cellular subtypes and spatial communities that compose PDAC using single-nucleus RNA sequencing and whole-transcriptome digital spatial profiling (DSP) of 43 primary PDAC tumor specimens that either received neoadjuvant therapy or were treatment naive. We uncovered recurrent expression programs across malignant cells and fibroblasts, including a newly identified neural-like progenitor malignant cell program that was enriched after chemotherapy and radiotherapy and associated with poor prognosis in independent cohorts. Integrating spatial and cellular profiles revealed three multicellular communities with distinct contributions from malignant, fibroblast and immune subtypes: classical, squamoid-basaloid and treatment enriched. Our refined molecular and cellular taxonomy can provide a framework for stratification in clinical trials and serve as a roadmap for therapeutic targeting of specific cellular phenotypes and multicellular interactions.

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In patients with pancreas adenocarcinoma (PDAC), performing endoscopic ultrasound (EUS)-guided fiducial placement at the time of initial EUS-guided biopsies may obviate a second procedure, streamline care, and improve resource utilization. However, the safety of this combined approach is understudied.

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During cancer therapy, tumor heterogeneity can drive the evolution of multiple tumor subclones harboring unique resistance mechanisms in an individual patient1–3. Previous case reports and small case series have suggested that liquid biopsy (specifically, cell-free DNA (cfDNA)) may better capture the heterogeneity of acquired resistance4–8. However, the effectiveness of cfDNA versus standard single-lesion tumor biopsies has not been directly compared in larger-scale prospective cohorts of patients following progression on targeted therapy. Here, in a prospective cohort of 42 patients with molecularly defined gastrointestinal cancers and acquired resistance to targeted therapy, direct comparison of postprogression cfDNA versus tumor biopsy revealed that cfDNA more frequently identified clinically relevant resistance alterations and multiple resistance mechanisms, detecting resistance alterations not found in the matched tumor biopsy in 78% of cases. Whole-exome sequencing of serial cfDNA, tumor biopsies and rapid autopsy specimens elucidated substantial geographic and evolutionary differences across lesions. Our data suggest that acquired resistance is frequently characterized by profound tumor heterogeneity, and that the emergence of multiple resistance alterations in an individual patient may represent the ‘rule’ rather than the ‘exception’. These findings have profound therapeutic implications and highlight the potential advantages of cfDNA over tissue biopsy in the setting of acquired resistance.

IMPORTANCE: Patients with locally advanced pancreatic cancer have historically poor outcomes. Evaluation of a total neoadjuvant approach is warranted. OBJECTIVE: To evaluate the margin-negative (R0) resection rate of neoadjuvant FOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, and irinotecan) and losartan followed by chemoradiotherapy for locally advanced pancreatic cancer. DESIGN, SETTING, AND PARTICIPANTS: A single-arm phase 2 clinical trial was conducted at a large academic hospital from August 22, 2013, to May 22, 2018, among 49 patients with previously untreated locally advanced unresectable pancreatic cancer as determined by multidisciplinary review. Patients had Eastern Cooperative Oncology Group performance status 0 or 1 and adequate hematologic, renal, and hepatic function. Median follow-up for the analysis was 17.1 months (range, 5.0-53.7) among 27 patients still alive at study completion. INTERVENTIONS: Patients received FOLFIRINOX and losartan for 8 cycles. Patients with radiographically resectable tumor after chemotherapy received short-course chemoradiotherapy (5 GyE × 5 with protons) with capecitabine. Patients with persistent vascular involvement received long-course chemoradiotherapy (50.4 Gy with a vascular boost to 58.8 Gy) with fluorouracil or capecitabine. MAIN OUTCOMES AND MEASURES: R0 resection rate. RESULTS: Of the 49 patients (26 women and 23 men; median age 63 years [range, 42-78 years]), 39 completed 8 cycles of FOLFIRINOX and losartan; 10 patients had fewer than 8 cycles due to progression (5 patients), losartan intolerance (3 patients), and toxicity (2 patients). Seven patients (16%) had short-course chemoradiotherapy while 38 (84%) had long-course chemoradiotherapy. Forty-two (86%) patients underwent attempted surgery, with R0 resection achieved in 34 of 49 patients (69%; 95% CI, 55%-82%). Overall median progression-free survival was 17.5 months (95% CI: 13.9-22.7) and median overall survival was 31.4 months (95% CI, 18.1-38.5). Among patients who underwent resection, median progression-free survival was 21.3 months (95% CI, 16.6-28.2), and median overall survival was 33.0 months (95% CI, 31.4 to not reached). CONCLUSIONS AND RELEVANCE: Total neoadjuvant therapy with FOLFIRINOX, losartan, and chemoradiotherapy provides downstaging of locally advanced pancreatic ductal adenocarcinoma and is associated with an R0 resection rate of 61%. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01821729

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IMPORTANCE: Patients with borderline-resectable pancreatic ductal adenocarcinoma have historically poor outcomes with surgery followed by adjuvant chemotherapy. Evaluation of a total neoadjuvant approach with highly active therapy is warranted. OBJECTIVE: To evaluate the margin-negative (R0) resection rate in borderline-resectable pancreatic ductal adenocarcinoma after neoadjuvant FOLFIRINOX (fluorouracil, irinotecan, and oxaliplatin) therapy and individualized chemoradiotherapy. DESIGN, SETTING, AND PARTICIPANTS: A single-arm, phase 2 clinical trial was conducted at a large academic hospital with expertise in pancreatic surgery from August 3, 2012, through August 31, 2016, among 48 patients with newly diagnosed, previously untreated, localized pancreatic cancer determined to be borderline resectable by multidisciplinary review, who had Eastern Cooperative Oncology Group performance status 0 or 1 and adequate hematologic, renal, and hepatic function. Median follow-up for the analysis was 18.0 months among the 30 patients still alive at study completion. INTERVENTIONS: Patients received FOLFIRINOX for 8 cycles. Upon restaging, patients with resolution of vascular involvement received short-course chemoradiotherapy (5 Gy × 5 with protons) with capecitabine. Patients with persistent vascular involvement received long-course chemoradiotherapy with fluorouracil or capecitabine. MAIN OUTCOMES AND MEASURES: The primary outcome was R0 resection rate; secondary outcomes were median progression-free survival (PFS) and median overall survival (OS). RESULTS: Of the 48 eligible patients, 27 were men and 21 were women, with a median age of 62 years (range, 46-74 years). Of the 43 patients who planned to receive 8 preoperative cycles of chemotherapy, 34 (79%) were able to complete all cycles. Twenty-seven patients (56%) had short-course chemoradiotherapy, while 17 patients (35%) had long-course chemoradiotherapy. R0 resection was achieved in 31 of the 48 eligible patients (65%; 95% CI, 49%-78%). Among the 32 patients who underwent resection, the R0 resection rate was 97% (n = 31). Median PFS among all eligible patients was 14.7 months (95% CI, 10.5 to not reached), with 2-year PFS of 43%; median OS was 37.7 months (95% CI, 19.4 to not reached), with 2-year OS of 56%. Among patients who underwent resection, median PFS was 48.6 months (95% CI, 14.4 to not reached) and median OS has not been reached, with a 2-year PFS of 55% and a 2-year OS of 72%. CONCLUSIONS AND RELEVANCE: Preoperative FOLFIRINOX followed by individualized chemoradiotherapy in borderline resectable pancreatic cancer results in high rates of R0 resection and prolonged median PFS and median OS, supporting ongoing phase 3 trials. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01591733

Background: The incidence of hepatocellular carcinoma (HCC) continues to increase world-wide. Many patients present with advanced disease with extensive local tumor or vascular invasion and are not candidates for traditionally curative therapies such as orthotopic liver transplantation (OLT) or resection. Radiotherapy (RT) was historically limited by its inability to deliver a tumoricidal dose; however, modern RT techniques have prompted renewed interest in the use of liver-directed RT to treat patients with primary hepatic malignancies. Summary: The aim of this review was to discuss the use of external beam RT in the treatment of HCC, with particular focus on the use of stereotactic body radiotherapy (SBRT). We review the intricacies of SBRT treatment planning and delivery. Liver-directed RT involves accurate target identification, precise and reproducible patient immobilization, and assessment of target and organ motion. We also summarize the published data on liver-directed RT, and demonstrate that it is associated with excellent local control and survival rates, particularly in patients who are not candidates for OLT or resection. Key Messages:Modern liver-directed RT is safe and effective for the treatment of HCC, particularly in patients who are not candidates for OLT or resection. Liver-directed RT, including SBRT, depends on accurate target identification, precise and reproducible patient immobilization, and assessment of target and organ motion. Further prospective studies are needed to fully delineate the role of liver-directed RT in the treatment of HCC.

We performed an exploratory analysis to identify dose-volume parameters that may predict treatment-induced nausea and vomiting among patients receiving hypofractionated radiotherapy to the pancreas. A retrospective analysis was performed of 47 patients with localized, resectable pancreatic adenocarcinoma who were prospectively treated on a phase I/II protocol between 2007 and 2010. Patients received proton beam radiotherapy (5 GyE x 5) concurrent with capecitabine (825 mg/m2twice daily) over 1 (n= 41) or 2 weeks (n= 6). Kendall's τcorrelation coefficients were calculated between dosimetric parameters of the planning treatment volume, stomach, duodenum, liver, small and large bowel, and physician-reported nausea or vomiting. Recursive partitioning analysis was performed to identify the best binary split of dosimetric predictors for nausea or vomiting. Hypofractionated radiation to the pancreas was well-tolerated with 51 and 4 % of patients experiencing grades 1 and 2 nausea or vomiting, respectively. Mean dose to the stomach (Dmean, τ= 0.33; p= 0.008) and volume of stomach that received 3 GyE (V3, τ= 0.34; p= 0.005), 5 GyE (V5, τ= 0.35; p= 0.005), 10 GyE (V10, τ= 0.31; p= 0.01), and 15 GyE or higher (V15, τ= 0.27; p= 0.03) were all directly associated with nausea or vomiting during treatment. Stomach V10 ≥ 11.5 % was the best predictor of nausea or vomiting: 20 % versus 72 % patients experienced nausea or vomiting with V10 < 11.5 versus ≥11.5 %. Low-dose hypofractionated radiation to the stomach is associated with nausea or vomiting during and immediately after radiotherapy. While these findings require validation, they may help identify patients who could benefit from prophylactic antiemetic medications during radiotherapy.

In this review article, we review the current literature addressing the use of stereotactic body radiation therapy (SBRT) in non-hepatobiliary gastrointestinal malignancies. For many gastrointestinal malignancies, the desire to treat large fields encompassing nodal drainage and micrometastatic disease has precluded the use of stereotactic body radiation therapy for most definitive cases. However, the use of SBRT in locally advanced pancreatic cancer (LAPC) as well as in the treatment of metastatic abdominal lymph nodes has shown excellent local control rates. In carefully selected patients, local control in LAPC has been achieved with SBRT with minimal side effects. Toxicity in these patients has most closely correlated with the dose and volume of irradiated duodenum and small bowel. Similar patterns of excellent local control with minimal side effects have also been seen in the treatment of abdominal lymph node metastases as well as gastric and rectal cancer recurrence.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.