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Objective: To examine the optimal method of assessing response to neoadjuvant therapy (NAT) in operable pancreatic ductal adenocarcinoma (PDAC) patients., Summary of Background Data: PDAC response to NAT is measured with biochemical, radiographic and pathologic parameters, which can often be discordant with each other., Methods: PDAC patients undergoing resection after NAT at a single institution were retrospectively analyzed. Tumor response was assessed using pre-/post-NAT Carbohydrate Antigen 19-9 (CA 19-9) levels, radiographic decrease in tumor diameter, and pathologic Tumor Regression Grade (TRG). The association of these factors with overall survival (OS) was compared using Kaplan-Meier, Cox regression, and recursive partitioning analysis (RPA), a machine learning technique that can validate prediction models for complex hierarchical relationships., Results: From 2011 to 2022, 225 patients underwent pancreatectomy after NAT (Folfirinox, 70%; Gem+nab-paclitaxel, 19%; radiation, 18%). Almost half required vascular resection (portal vein, 39%; celiac axis 8%). Improved OS was observed after CA 19-9 decrease >50% (32 vs. 24 mo, P=0.0028), but not after major pathologic (TRG 0-1, P=0.067) or radiographic response (tumor diameter decrease >30%, P=0.89). However, RPA identified that the co-existence of biochemical and major pathologic response (achieved in 9% of patients) was associated with the longest OS (40 mo, P=0.0086). This optimal dual response combination was more commonly observed after neoadjuvant radiotherapy was used after systemic chemotherapy (45% vs. 11%, P<0.001)., Conclusions: CA19-9 response to NAT alone is not enough to identify long-term post-resection PDAC survivors. The co-existence of CA19-9 and major pathologic response was predictive of the most optimal survival outcome., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

On December 5, 2022, an indirect drive fusion implosion on the National Ignition Facility (NIF) achieved a target gain G&#95;{target} of 1.5. This is the first laboratory demonstration of exceeding "scientific breakeven" (or G&#95;{target}>1) where 2.05 MJ of 351 nm laser light produced 3.1 MJ of total fusion yield, a result which significantly exceeds the Lawson criterion for fusion ignition as reported in a previous NIF implosion [H. Abu-Shawareb et al. (Indirect Drive ICF Collaboration), Phys. Rev. Lett. 129, 075001 (2022)PRLTAO0031-900710.1103/PhysRevLett.129.075001]. This achievement is the culmination of more than five decades of research and gives proof that laboratory fusion, based on fundamental physics principles, is possible. This Letter reports on the target, laser, design, and experimental advancements that led to this result.

Epigenetic characterization of cell-free DNA (cfDNA) is an emerging approach for detecting and characterizing diseases such as cancer. We developed a strategy using nanopore-based single-molecule sequencing to measure cfDNA methylomes. This approach generated up to 200 million reads for a single cfDNA sample from cancer patients, an order of magnitude improvement over existing nanopore sequencing methods. We developed a single-molecule classifier to determine whether individual reads originated from a tumor or immune cells. Leveraging methylomes of matched tumors and immune cells, we characterized cfDNA methylomes of cancer patients for longitudinal monitoring during treatment., (© 2023. The Author(s).)

Background: Patient reported outcomes (PROs) have been associated with improved symptom management and quality of life in patients with cancer. However, the implementation of PROs in an academic clinical practice has not been thoroughly described. Here we report on the execution, feasibility and healthcare utilization outcomes of an electronic PRO (ePRO) application for cancer patients at an academic medical center., Methods: We conducted a randomized trial comparing an experimental ePRO arm to standard of care in patients with advanced cancer in the thoracic, gastrointestinal, and genitourinary oncology groups at Stanford Cancer Center from March 2018 to November 2019. We describe the pre-implementation, implementation, and post-implementation phases of the ePRO arm, technological barriers, electronic health record (EHR) integration, clinician burden, and patient data privacy and security. Feasibility was pre-specified to be at least 70% completion of all questionnaires. Acceptability was based on patient and clinician feedback. Ambulatory healthcare utilization was assessed by reviewing numbers of phone messages, electronic portal messages, and referrals for supportive care., Results: Of 617 ePRO questionnaires sent to 72 patients, 445 (72%) were completed. Most clinicians (87.5%) and patients (93%) felt neutral or positive about the ePRO tool's ease of use. Exposure to ePRO did not cause a measurable change in ambulatory healthcare utilization, with a median of less than two phone messages and supportive care referrals, and 5-6 portal messages., Conclusions: Web-based ePRO tools for patients with advanced cancer are feasible and acceptable without increasing clinical burden. Key lessons include the importance of pilot testing, engagement of stakeholders at all levels, and the need for customization by disease group. Future directions for this work include completion of EHR integration, expansion to other centers, and development of integrated workflows for routine clinical practice., (© 2021. The Author(s).)

Background and Purpose: The optimal neoadjuvant approach in patients with resectable pancreas cancer is unclear. We investigated outcomes after preoperative chemotherapy alone, chemotherapy with conventionally-fractionated radiation (CFRT), or chemotherapy with stereotactic body radiotherapy (SBRT)., Materials and Methods: The NCDB was queried for patients with resectable pancreatic adenocarcinoma (pretreatment stage T1-3, N0-1, M0) who received preoperative, multiagent chemotherapy and definitive surgery from 2010 to 2015. CFRT was 40-60 Gy in 20-35 fractions. SBRT was 20-25 Gy in 1 fraction or 30-50 Gy using at least 5 Gy per fraction. Multivariable regression and propensity score matching were used to adjust for potential confounders, including age, comorbidity score, and pretreatment extent of disease. The primary outcome was overall survival measured from surgery., Results: In total, 1355 patients received preoperative chemotherapy alone, 552 patients received preoperative chemotherapy with CFRT, and 175 patients received preoperative chemotherapy with SBRT. Receipt of SBRT was associated with significantly improved overall survival compared to chemotherapy alone (median 30 vs 21 months, p = 0.02; adjusted hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.47-0.90, p = 0.01). Similarly, SBRT was associated with significantly improved overall survival compared to CFRT (median 29 vs 16 months, p = 0.002; adjusted HR 0.53, 95% CI 0.37-0.76, p = 0.001). Additionally, SBRT was associated with significantly increased rates of pathological complete response and margin-negative resection. Rates of postoperative readmissions and mortality were comparable., Conclusions: Neoadjuvant chemotherapy with SBRT is associated with favorable survival and pathological outcomes, warranting consideration for prospective validation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

As a high-performance solution for longitudinal monitoring of patients being treated for metastatic cancer, a single-color digital PCR (dPCR) assay that detects and quantifies specific cancer mutations present in circulating tumor DNA (ctDNA) was developed. This customizable assay has a high sensitivity of detection. One can detect a mutation allelic fraction of 0.1%, equivalent to three mutation-bearing DNA molecules among 3000 genome equivalents. The objective of this study was to validate the use of personalized dPCR mutation assays to monitor patients with metastatic cancer. The dPCR results were compared with serum biomarkers indicating disease progression or response. Patients had metastatic colorectal, biliary, breast, lung, and melanoma cancers. Mutations occurred in essential cancer drivers such as BRAF, KRAS, and PIK3CA. Patients were monitored over multiple cycles of treatment for up to a year. All patients had detectable ctDNA mutations. The results correlated with serum markers of metastatic cancer burden, including carcinoembryonic antigen, CA-19-9, and CA-15-3, and qualitatively corresponding to imaging studies. Corresponding trends were observed among these patients receiving active treatment with chemotherapy or targeted agents. For example, in one patient under active treatment, increasing quantities of ctDNA molecules were detected over time, indicating recurrence of tumor. This study demonstrates that personalized dPCR enables longitudinal monitoring of patients with metastatic cancer and may be a useful indicator for treatment response., (Copyright © 2020 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Gastroesophageal junction (GEJ) cancers can be treated with equipoise using neoadjuvant chemoradiation (NACRT) or chemotherapy alone (NAC), but the comparative outcomes are unclear., Methods: Patients with non-metastatic T2-4 or N1-3 GEJ adenocarcinoma who underwent definitive surgery and NAC or NACRT were selected from the National Cancer Database. The primary outcome was overall survival (OS). Multivariable regression and propensity score analysis were used to adjust for age, comorbidity, and other characteristics., Results: We identified 2435 patients treated with NACRT and 648 patients treated with NAC. OS was not significantly different between NACRT and NAC (51% versus 54% at 3 years, respectively, P = 0.11). Extent of pathological downstaging (complete, partial/mixed, none) after NACRT or NAC was highly prognostic of survival. Patients with no response did equally poorly after either preoperative regimen, and NAC was significantly less likely than NACRT to produce any response (adjusted odds ratio 0.62, P < 0.0001). Rate of adjuvant chemotherapy usage was significantly lower after NACRT than after NAC (12% versus 34%, P < 0.0001). In patients with residual tumor and nodal disease, adjuvant chemotherapy was associated with higher OS after NACRT (adjusted hazard ratio 0.81, P = 0.05), but not after NAC. These results were further validated by propensity score analysis., Conclusions: NACRT had similar survival to NAC despite superior pathological downstaging. Adjuvant chemotherapy is relatively underused after NACRT and warrants further study as a risk-adapted means to improve survival, especially in patients with larger burden of residual disease.

We aimed to assess the utility of a novel, noninvasive method of detecting genomic alterations in patients with gastrointestinal malignancies, i.e., the use of liquid biopsies to obtain blood-derived circulating tumor DNA (ctDNA) through an analysis of the genomic landscape of ctDNA (68 genes) from 213 patients with advanced gastrointestinal cancers. The most common cancer types were colorectal adenocarcinoma ( N = 55; 26%), appendiceal adenocarcinoma ( N = 46; 22%), hepatocellular carcinoma ( N = 31; 15%), and pancreatic ductal adenocarcinoma ( N = 25; 12%). The majority of patients (58%) had ≥1 characterized alteration (excluded variants of unknown significance). The median number of characterized alterations was 1 (range, 0-13). The number of detected alterations per patient varied between different cancer types: in hepatocellular carcinoma, 74% of patients (23/31) had ≥1 characterized alteration(s) versus 24% of appendiceal adenocarcinoma patients (11/46). The median percent ctDNA among characterized alterations was 2.50% (interquartile range, 0.76%-8.96%). Overall, 95% of patients (117/123) had distinct molecular portfolios with 143 unique characterized alterations within 56 genes. Overall, concordance rates of 96%, 94%, 95%, and 91%, respectively, were found between ctDNA and tissue biopsy ( N = 105 patients) in the four most common alterations ( KRAS amplification, MYC amplification, KRAS G12V, and EGFR amplification). Of 123 patients with characterized alterations, >99% (122/123; 57% of entire population tested; 122/213) had one or more alterations potentially actionable by experimental or approved drugs. These observations suggest that many patients with gastrointestinal tumors, including difficult-to-biopsy malignancies like hepatocellular cancers, frequently have discernible and theoretically pharmacologically tractable ctDNA alterations that merit further studies in prospective trials. Mol Cancer Ther; 17(1); 297-305. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Background: Topoisomerase I (TOPO1) and topoisomerase IIα (TOP2A) are specific targets of multiple chemotherapy drugs. Increased expression of TOPO1 protein and amplification of the TOP2A gene have been associated with treatment response in colorectal and breast cancers, respectively. TOPO1 and TOP2A may be potential therapeutic targets in other malignancies as well., Summary of Methods: We analysed TOPO1 protein expression and TOP2A gene amplification in patients (n = 24,262 specimens) with diverse cancers. Since HER2 and TOP2A co-amplification have been investigated for predictive value regarding anthracycline benefit, we analysed specimens for HER2 amplification as well., Results: Overexpressed TOPO1 protein was present in 51% of the tumours. Four percent of the tumours had TOP2A amplification, with gallbladder tumours and gastroesophageal/oesophageal tumours having rates over 10%. Overall, 4903 specimens were assessed for both TOP2A and HER2 amplification; 129 (2.6%) had co-amplification. High rates (>40%) of HER2 amplification were seen in patients with TOP2A amplification in breast, ovarian, gastroesophageal/oesophageal and pancreatic cancer., Conclusion: Our data indicate that increased TOPO1 expression and TOP2A amplification, as well as HER2 co-alterations, are present in multiple malignancies. The implications of these observations regarding sensitivity to chemotherapy not traditionally administered to these tumour types merits investigation., (Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: About 10-15% of adult, and most pediatric, gastrointestinal stromal tumors (GIST) lack mutations in KIT, PDGFRA, SDHx, or RAS pathway components (KRAS, BRAF, NF1). The identification of additional mutated genes in this rare subset of tumors can have important clinical benefit to identify altered biological pathways and select targeted therapies., Methods: We performed comprehensive genomic profiling (CGP) for coding regions in more than 300 cancer-related genes of 186 GISTs to assess for their somatic alterations., Results: We identified 24 GIST lacking alterations in the canonical KIT/PDGFRA/RAS pathways, including 12 without SDHx alterations. These 24 patients were mostly adults (96%). The tumors had a 46% rate of nodal metastases. These 24 GIST were more commonly mutated at 7 genes: ARID1B, ATR, FGFR1, LTK, SUFU, PARK2 and ZNF217. Two tumors harbored FGFR1 gene fusions (FGFR1-HOOK3, FGFR1-TACC1) and one harbored an ETV6-NTRK3 fusion that responded to TRK inhibition. In an independent sample set, we identified 5 GIST cases lacking alterations in the KIT/PDGFRA/SDHx/RAS pathways, including two additional cases with FGFR1-TACC1 and ETV6-NTRK3 fusions., Conclusions: Using patient demographics, tumor characteristics, and CGP, we show that GIST lacking alterations in canonical genes occur in younger patients, frequently metastasize to lymph nodes, and most contain deleterious genomic alterations, including gene fusions involving FGFR1 and NTRK3. If confirmed in larger series, routine testing for these translocations may be indicated for this subset of GIST. Moreover, these findings can be used to guide personalized treatments for patients with GIST. Trial registration NCT 02576431. Registered October 12, 2015.

The poors outcomes associated with pancreatic cancer clearly reflect the advanced stage of disease at diagnosis for most patients. Through this lens, it is easy to lose sight of the fact that roughly 50% of patients with pancreatic cancer have no clinically detectable metastases at presentation. Herein, we discuss how patients with localized pancreatic cancer are currently managed. The primary goal of care for patients with resectable and borderline-resectable tumors is cure, facilitated by achieving margin-negative resection of the primary disease and delivering effective adjuvant and/or neoadjuvant therapy. For patients with locally advanced disease, the focus is on limiting local progression and outgrowth of metastatic disease and maintaining quality of life. Although it was once a centerpiece of therapy for localized pancreatic cancer, the value and place of radiation therapy in the treatment algorithm is now under increased scrutiny. In contrast, given its value as demonstrated in multiple prospective trials, chemotherapy is an established part of the treatment paradigm for all patients. With the demonstration that cytotoxic combinations such as fluorouracil, leucovorin, irinotecan, and oxaliplatin as well as gemcitabine/nab-paclitaxel are active in the metastatic setting, these agents are now being studied in patients with localized disease. The neoadjuvant setting provides a particularly favorable setting for evaluating new systemic strategies. Given the array of new targets, including immunomodulatory approaches, there is reason for optimism that we can markedly improve survival for all patients with pancreatic cancer and enter an era in which surgery with curative intent actually fulfills this goal on a much more regular basis., (© 2015 by American Society of Clinical Oncology.)

Despite recent improvements, overall survival for advanced adenocarcinoma of the pancreas continues to be poor. In comparison to other tumor types that have enjoyed marked survival benefit by targeting aberrant cell signaling pathways, standard of care treatment for pancreatic cancer is limited to conventional cytotoxic chemotherapy. Multiple pathway aberrations have been documented in pancreatic cancer. A review of the COSMIC database reveals that most pancreatic cancers contain somatic mutations, with the five most frequent being KRAS, TP53, CDKN2A, SMAD4, and ARID1A, and multiple other abnormalities seen including, but not limited to, mutations in STK11/LKB1, FBXW7, PIK3CA, and BRAF. In the era of tumor profiling, these aberrations may provide an opportunity for new therapeutic approaches. Yet, searching clinicaltrials.gov for recent drug intervention trials for pancreatic adenocarcinoma, remarkably few (10 of 116 (8.6%)) new study protocols registered in the last three years included a molecular/biomarker stratification strategy. Enhanced efforts to target subsets of patients with pancreatic cancer in order to optimize therapy benefit are warranted.

We demonstrate the hohlraum radiation temperature and symmetry required for ignition-scale inertial confinement fusion capsule implosions. Cryogenic gas-filled hohlraums with 2.2 mm-diameter capsules are heated with unprecedented laser energies of 1.2 MJ delivered by 192 ultraviolet laser beams on the National Ignition Facility. Laser backscatter measurements show that these hohlraums absorb 87% to 91% of the incident laser power resulting in peak radiation temperatures of T(RAD)=300 eV and a symmetric implosion to a 100 μm diameter hot core., (© 2011 American Physical Society)

A single beamline of the National Ignition Facility (NIF) has been operated at a wavelength of 526.5 nm (2 omega) by frequency converting the fundamental 1053 nm (1 omega) wavelength with an 18.2 mm thick type-I potassium dihydrogen phosphate (KDP) second-harmonic generator (SHG) crystal. Second-harmonic energies of up to 17.9 kJ were measured at the final optics focal plane with a conversion efficiency of 82%. For a similarly configured 192-beam NIF, this scales to a total 2 omega energy of 3.4 MJ full NIF equivalent (FNE).

The National Ignition Facility (NIF) is the world's largest laser system. It contains a 192 beam neodymium glass laser that is designed to deliver 1.8 MJ at 500 TW at 351 nm in order to achieve energy gain (ignition) in a deuterium-tritium nuclear fusion target. To meet this goal, laser design criteria include the ability to generate pulses of up to 1.8 MJ total energy, with peak power of 500 TW and temporal pulse shapes spanning 2 orders of magnitude at the third harmonic (351 nm or 3omega) of the laser wavelength. The focal-spot fluence distribution of these pulses is carefully controlled, through a combination of special optics in the 1omega (1053 nm) portion of the laser (continuous phase plates), smoothing by spectral dispersion, and the overlapping of multiple beams with orthogonal polarization (polarization smoothing). We report performance qualification tests of the first eight beams of the NIF laser. Measurements are reported at both 1omega and 3omega, both with and without focal-spot conditioning. When scaled to full 192 beam operation, these results demonstrate, to the best of our knowledge for the first time, that the NIF will meet its laser performance design criteria, and that the NIF can simultaneously meet the temporal pulse shaping, focal-spot conditioning, and peak power requirements for two candidate indirect drive ignition designs.