Publications by authors named "Ben George"

72 Publications

Germline evaluation of patients undergoing tumor genomic profiling: An academic cancer center's experience with implementing a germline review protocol.

J Genet Couns 2021 Mar 22. Epub 2021 Mar 22.

Institute for Health and Equity, Medical College of Wisconsin, Milwaukee, WI, USA.

Tumor genomic profiling (TGP) has the potential to identify germline variants in addition to its primary use of informing cancer treatment based on genetic alterations within the tumor. However, there are no formal consensus guidelines to identify patients who would be eligible for genetic counseling (GC) and germline testing (GT) testing in patients undergoing TGP. The purpose of this study is to describe an institutionally developed Germline Review Protocol (GRP) to evaluate adult cancer patient cases already undergoing TGP to determine GC referral eligibility. We report on our retrospective experience implementing this protocol into practice wherein 172 patients out of 638 patients reviewed (27%) were recommended for a GC referral over a 17-month time period. Of those 172 patients recommended for a GC referral, only 34 patients (20%) completed GC and GT. Among patients who received GT, 15 (44%) were positive for at least one pathogenic or likely pathogenic (P/LP) variant, seven patients (21%) were negative and 12 patients (35%) had at least 1 variant of uncertain significance (VUS). The primary reason GC and GT was not completed was because the patient moved to hospice care or was deceased. This is one of the first studies outlining the process and results of a formalized institutional protocol to facilitate patient referrals for GC and GT based on TGP results.
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http://dx.doi.org/10.1002/jgc4.1392DOI Listing
March 2021

IPEM Topical Report: An international IPEM survey of MRI use for external beam radiotherapy treatment planning.

Phys Med Biol 2021 Feb 25. Epub 2021 Feb 25.

Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, Tyne and Wear, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND.

Introduction/background: Despite growing interest in Magnetic Resonance Imaging (MRI), integration in external beam radiotherapy (EBRT) treatment planning uptake varies globally. In order to understand the current international landscape of MRI in EBRT a survey has been performed in 11 countries. This work reports on differences and common themes identified.

Methods: A multi-disciplinary Institute of Physics and Engineering in Medicine (IPEM) working party modified a survey previously used in the UK to understand current practice using MRI for EBRT treatment planning, investigate how MRI is currently used and managed as well as identify knowledge gaps. It was distributed electronically within 11 countries: Australia, Belgium, Denmark, Finland, France, Italy, the Netherlands, New Zealand, Sweden, the UK and the USA.

Results: The survey response rate within the USA was <1% and hence these results omitted from the analysis. In the other 10 countries the survey had a median response rate of 77% per country. Direct MRI access, defined as either having a dedicated MRI scanner for radiotherapy (RT) or access to a radiology MRI scanner, varied between countries. France, Italy and the UK reported the lowest direct MRI access rates and all other countries reported direct access in ≥82% of centres. Whilst ≥83% of centres in Denmark and Sweden reported having dedicated MRI scanners for EBRT, all other countries reported ≤29%. Anatomical sites receiving MRI for EBRT varied between countries, with brain/prostate/head and neck being most common. Commissioning and QA of image registration and MRI scanners varied greatly, as did MRI sequences performed, staffing models and training given to different staff groups. The lack of financial reimbursement for MR was a consistent barrier for MRI implementation for RT for all countries and MR access was a reported important barrier for all countries except Sweden and Denmark.

Conclusion: No country has a comprehensive approach for MR in EBRT adoption and financial barriers are present worldwide. Variations between countries in practice/equipment/staffing models and training/QA/MRI sequences have been identified, and are likely to be due to differences in funding as well as a lack of consensus or guidelines in the literature. Access to dedicated MR for EBRT is limited in all but Sweden and Denmark, but in all countries there are financial challenges with ongoing per patient costs. Despite these challenges, significant interest exists in increasing MR guided EBRT planning over the next 5 years.
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http://dx.doi.org/10.1088/1361-6560/abe9f7DOI Listing
February 2021

IPEM topical report: guidance on the use of MRI for external beam radiotherapy treatment planning.

Phys Med Biol 2021 Jan 15. Epub 2021 Jan 15.

Cancer Research UK & EPSRC Cancer Imaging Centre, Royal Marsden Hospital and Institute of Cancer Research, MRI Unit, Downs Road, Sutton, SM2 5PT, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND.

This document gives guidance for multidisciplinary teams within institutions setting up and using an MRI-guided radiotherapy (RT) treatment planning service. It has been written by a multidisciplinary working group from the Institute of Physics and Engineering in Medicine (IPEM). Guidance has come from the experience of the institutions represented in the IPEM working group, in consultation with other institutions, as well as information taken from the literature. Guidance is only given for MRI acquired for external beam RT treatment planning in a CT-based workflow, i.e. when MRI is acquired and registered to CT with the purpose of aiding delineation of target or organ at risk volumes. MRI-only RT and other RT treatment types such as brachytherapy and gamma radiosurgery are not considered in scope here, although some of the major themes discussed are relevant. The aim was to produce guidance that will be useful for institutions who are setting up and using a dedicated MR scanner for RT (referred to as an MR-sim) and those who will have limited time on an MR scanner potentially managed outside of the RT department, often by radiology. Although not specifically covered in this document, there is an increase in the use of hybrid MRI-linac systems worldwide and brief comments are included to highlight any crossover with the early implementation of this technology. In this document, advice is given on introducing an RT workload onto a non-RT-dedicated MR scanner, as well as planning for installation of an MR scanner dedicated for RT. Next, practical guidance is given on the following, in the context of RT planning: training and education for all staff working in and around an MR scanner; RT patient set-up on an MR scanner; MRI sequence optimisation for RT purposes; commissioning and quality assurance (QA) to be performed on an MR scanner; and MRI to CT registration, including commissioning and QA.
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http://dx.doi.org/10.1088/1361-6560/abdc30DOI Listing
January 2021

DNA Polymerase and Mismatch Repair Exert Distinct Microsatellite Instability Signatures in Normal and Malignant Human Cells.

Cancer Discov 2020 Dec 18. Epub 2020 Dec 18.

Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.

Although replication repair deficiency, either by mismatch repair deficiency (MMRD) and/or loss of DNA polymerase proofreading, can cause hypermutation in cancer, microsatellite instability (MSI) is considered a hallmark of MMRD alone. By genome-wide analysis of tumors with germline and somatic deficiencies in replication repair, we reveal a novel association between loss of polymerase proofreading and MSI, especially when both components are lost. Analysis of indels in microsatellites (MS-indels) identified five distinct signatures (MS-sigs). MMRD MS-sigs are dominated by multibase losses, whereas mutant-polymerase MS-sigs contain primarily single-base gains. MS deletions in MMRD tumors depend on the original size of the MS and converge to a preferred length, providing mechanistic insight. Finally, we demonstrate that MS-sigs can be a powerful clinical tool for managing individuals with germline MMRD and replication repair-deficient cancers, as they can detect the replication repair deficiency in normal cells and predict their response to immunotherapy. SIGNIFICANCE: Exome- and genome-wide MSI analysis reveals novel signatures that are uniquely attributed to mismatch repair and DNA polymerase. This provides new mechanistic insight into MS maintenance and can be applied clinically for diagnosis of replication repair deficiency and immunotherapy response prediction.
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http://dx.doi.org/10.1158/2159-8290.CD-20-0790DOI Listing
December 2020

Adjuvant therapy rates and overall survival in patients with localized pancreatic cancer from high Area Deprivation Index neighborhoods.

Am J Surg 2020 Dec 3. Epub 2020 Dec 3.

LaBahn Pancreatic Cancer Program, Departments of Surgery, Medical College of Wisconsin, Milwaukee, WI, United States. Electronic address:

Background: Neighborhood adversity's impact on postoperative/adjuvant therapy delivery and overall survival (OS) is poorly described in patients with localized pancreatic cancer (PC).

Methods: Area Deprivation Index (ADI) is a validated measure classifying neighborhood adversity. Higher ADI signifies increasing adversity. The 2013 national ADI scores were obtained from patients who completed preoperative/neoadjuvant therapy and surgery. Patients were categorized as having high (>50%) or low (≤50%) ADI.

Results: Of the 224 patients, 163 (73%) had low ADI and 61 (27%) had high ADI. Adjuvant therapy was delivered to 129 (58%) patients, including 62% (101/163) with low ADI and 46% (28/61) with high ADI (p = 0.03). Patients with high ADI had 55% (95%CI 0.23-0.86; p = 0.02) decreased odds of receiving adjuvant therapy, independent of other factors. The median OS was 45 months for 129 patients who received adjuvant therapy and 31 months for 94 patients who did not receive adjuvant therapy (p = 0.03).

Conclusions: Patients with high ADI are less likely to receive adjuvant therapy for localized PC. Future studies should address impediments to care in patients from higher ADI neighborhoods.
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http://dx.doi.org/10.1016/j.amjsurg.2020.12.001DOI Listing
December 2020

Bronchoalveolar lavage-based COVID-19 testing in patients with cancer.

Hematol Oncol Stem Cell Ther 2021 Mar 8;14(1):65-70. Epub 2020 Oct 8.

Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.

Objective/background: A few case reports in the setting of coronavirus disease 2019 (COVID-19) and multiplex polymerase chain reaction (PCR)-based assays for common respiratory pathogens have shown a higher yield of bronchoalveolar lavage (BAL) samples than upper airway specimens in immunocompromised patients.

Methods: A retrospective study was conducted reviewing patients diagnosed with COVID-19 at the Medical College of Wisconsin (Milwaukee, WI, USA) between March 13, 2020 and June 11, 2020. All patients tested positive for SARS-CoV-2 via real-time reverse transcriptase PCR (RT-PCR), through a nasopharyngeal or a bronchoscopy specimen.

Results: During the study period, 53 bronchoscopy procedures were performed at the institution, of which five patients tested positive for COVID-19. Of the five patients, three underwent BAL testing based on high clinical suspicion for COVID-19 after the nasopharyngeal (NP) swab(s) was negative. All three patients had underlying cancers and had lymphopenia for a considerable duration prior to being diagnosed with COVID-19. Two patients had better outcomes that could be attributed to earlier BAL specimen testing resulting in timely medical intervention.

Conclusion: This study underscores the need for early lower respiratory tract sampling, whenever possible, in patients with cancer and prolonged lymphopenia. High clinical suspicion ought to supersede false-negative NP reverse transcriptase-PCR as early bronchoscopic evaluation in cancer patients, who are either receiving active treatment or are immunosuppressed, can allow timely institution of efficacious treatment, enrollment into clinical trials, as well as effective infection control. In the apt clinical setting in patients with cancer, presumptive treatment may also be considered to minimize exposure to healthcare providers and proceduralists.
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http://dx.doi.org/10.1016/j.hemonc.2020.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543702PMC
March 2021

Total Neoadjuvant Therapy for Operable Pancreatic Cancer.

Ann Surg Oncol 2021 Apr 30;28(4):2246-2256. Epub 2020 Sep 30.

Department of Surgery, Mary Anne and Charles LaBahn Pancreatic Cancer Program, Medical College of Wisconsin, Milwaukee, WI, USA.

Background: Overall survival (OS) for operable pancreatic cancer (PC) is optimized when 4-6 months of nonsurgical therapy is combined with pancreatectomy. Because surgery renders the delivery of postoperative therapy uncertain, total neoadjuvant therapy (TNT) is gaining popularity.

Methods: We performed a retrospective cohort study of patients with operable PC and compared TNT with shorter course neoadjuvant therapy (SNT). Primary outcomes of interest included completion of neoadjuvant therapy (NT) and resection of the primary tumor, receipt of 5 months of nonsurgical therapy, and median OS.

Results: We reviewed 541 consecutive patients from 2009 to 2019 including 226 (42%) with resectable PC and 315 (58%) with borderline resectable (BLR) PC. The median age was 66 years (IQR [59, 72]), and 260 (48%) patients were female. TNT was administered to 89 (16%) patients and SNT was administered to 452 (84%). Both groups were equally likely to complete intended NT and surgery (p = 0.90). Patients who received TNT and surgical resection were more likely to have a complete pathologic response (8% vs 4%, p < 0.01) and were more likely to receive at least 5 months of nonsurgical therapy (67% vs 45%, p < 0.01). The median OS was 26 months [IQR (15, 57)]; not reached among patients treated with TNT, and 25 months [IQR (15, 56)] among patients treated with SNT (p = 0.19).

Conclusions: TNT ensures the delivery of intended systemic therapy prior to a complicated operation without decreasing the chance of successful surgery; a window of operability was not lost. Patients who can tolerate SNT will likely benefit from TNT.
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http://dx.doi.org/10.1245/s10434-020-09149-3DOI Listing
April 2021

Cost-effectiveness analysis of universal germline testing for patients with pancreatic cancer.

Surgery 2021 03 18;169(3):629-635. Epub 2020 Aug 18.

Department of Surgery, Mary Anne and Charles LaBahn Pancreatic Cancer Program, Medical College of Wisconsin, Milwaukee, WI. Electronic address:

Background: Historically, germline testing of patients with pancreatic cancer was performed selectively in patients with a strong family history of cancer. Current guidelines recommend universal testing because some patients may have actionable germline pathogenic variants without family history.

Methods: We conducted a cost-effectiveness analysis using a decision-tree model to compare universal versus selective testing strategies for patients with pancreatic cancer. Costs, probabilities, and overall survival were estimated from the published literature and institutional data. One-way and probabilistic sensitivity analyses explored model uncertainty.

Results: Universal germline genetic testing had an incremental cost of $310 with an increase of 0.003 life-years. The incremental cost-effectiveness ratio was $121,924/life-years. Parameters which were most impactful (sensitivity analysis) included the median overall survival of patients with advanced disease treated with personalized therapy, cost of personalized therapy for advanced disease, and the probability of receiving personalized therapy in advanced disease. A strategy of selective testing was more cost-effective in 59% of iterations when the willingness-to-pay threshold was set to $100,000/life-years.

Conclusion: Our model suggested that selective germline testing of patients with newly diagnosed pancreatic cancer is more cost-effective than universal testing. Additional research is needed to explore the impact of cascade testing of relatives on cost-effectiveness.
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http://dx.doi.org/10.1016/j.surg.2020.06.038DOI Listing
March 2021

Radiographic patterns of first disease recurrence after neoadjuvant therapy and surgery for patients with resectable and borderline resectable pancreatic cancer.

Surgery 2020 09 5;168(3):440-447. Epub 2020 Jul 5.

Department of Surgery, LaBahn Pancreatic Cancer Program, The Medical College of Wisconsin, Milwaukee, WI. Electronic address:

Background: More than 70% of patients with localized pancreatic cancer treated with upfront surgery develop disease recurrence. Herein we describe the radiographic patterns and timing of disease recurrence after neoadjuvant therapy and surgery in patients with pancreatic cancer.

Methods: Radiographic patterns of first disease recurrence were examined in patients with localized pancreatic cancer who completed neoadjuvant therapy and surgery. Disease recurrence was classified as local (pancreas, resection bed, or peripancreatic vasculature); regional (peritoneum or abdominal wall); or distant (liver, lung, bone). Progression-free survival was calculated from the date of diagnosis to the date of recurrence.

Results: Of 306 consecutive patients who completed neoadjuvant therapy and surgery, 149 (49%) had resectable pancreatic cancer and 157 (51%) had borderline resectable disease. Neoadjuvant therapy consisted of chemoradiation (32%), chemotherapy (14%), or both therapies (54%). Overall, primary therapy (including preoperative and postoperative therapy) consisted of chemoradiation alone in 29 (9%), chemotherapy alone in 14 (5%), and both therapies in 263 (86%) patients. At a median follow-up of 27 months, 186 (61%) of the 306 patients had recurrent pancreatic cancer. Sites of first recurrence were local-only in 29 (9%), regional-only in 19 (6%), distant-only in 87 (28%), and multisite in 51 (17%). The overall median progression-free survival for all patients was 24 months. Neoadjuvant chemoradiation reduced the odds of local-only recurrence (odds ratio: 0.21; 95% confidence interval: 0.06-0.77; P = .02).

Conclusion: After neoadjuvant therapy and surgery, 9% of patients were found to have local-only recurrence. Treatment sequencing that incorporates neoadjuvant chemoradiation may improve local disease control.
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http://dx.doi.org/10.1016/j.surg.2020.04.031DOI Listing
September 2020

Open-label, Phase I Study of Nivolumab Combined with -Paclitaxel Plus Gemcitabine in Advanced Pancreatic Cancer.

Clin Cancer Res 2020 Sep 18;26(18):4814-4822. Epub 2020 Jun 18.

Department of Medical Oncology, University of Pennsylvania, Abramson Cancer Center, Philadelphia, Pennsylvania.

Purpose: Assess safety and efficacy of nivolumab plus -paclitaxel and gemcitabine in patients with locally advanced/metastatic pancreatic cancer in a two-part, open-label, phase I trial.

Patients And Methods: Fifty chemotherapy-naive patients received -paclitaxel 125 mg/m plus gemcitabine 1,000 mg/m (days 1, 8, and 15) and nivolumab 3 mg/kg (days 1 and 15) in 28-day cycles. The primary endpoints were dose-limiting toxicities (DLTs; part 1) and grade 3/4 treatment-emergent adverse events (TEAEs) or treatment discontinuation due to TEAEs (parts 1/2). Secondary efficacy endpoints were progression-free survival (PFS), overall survival (OS), and response. Assessment of programmed cell death-ligand 1 (PD-L1) expression was an exploratory endpoint; additional biomarkers were assessed .

Results: One DLT (hepatitis) was reported in part 1 among six DLT-evaluable patients; 48 of 50 patients experienced grade 3/4 TEAEs and 18 discontinued treatment due to TEAEs. One grade 5 TEAE (respiratory failure) was reported. Median [95% confidence interval (CI)] PFS/OS was 5.5 (3.25-7.20 months)/9.9 (6.74-12.16 months) months, respectively [median follow-up for OS, 13.6 months (95% CI, 12.06-23.49 months)]. Overall response rate (95% CI) was 18% (8.6%-31.4%). Median PFS/OS was 5.5/9.7 months (PD-L1 <5%) and 6.8/11.6 months (PD-L1 ≥5%), respectively. Proportion of peripheral Ki67 CD8/CD4 cells increased significantly from baseline to cycle 3; median peak on-treatment Ki67 CD8 T-cell values were higher in responders than in nonresponders.

Conclusions: The safety profile of nivolumab plus -paclitaxel and gemcitabine at standard doses in advanced pancreatic cancer was manageable, with no unexpected safety signals. Overall, the clinical results of this study do not support further investigation.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0099DOI Listing
September 2020

Value of Pretreatment F-fluorodeoxyglucose Positron Emission Tomography in Patients With Localized Pancreatic Cancer Treated With Neoadjuvant Therapy.

Front Oncol 2020 17;10:500. Epub 2020 Apr 17.

LaBahn Pancreatic Cancer Program, Department of Surgery, The Medical College of Wisconsin, Milwaukee, WI, United States.

F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) imaging is not routine in patients with localized pancreatic cancer (PC). We evaluated the prognostic value of PET/CT in patients who received neoadjuvant therapy. Patients with localized PC underwent pretreatment PET/CT with or without posttreatment (preop) PET/CT. Maximum standardized uptake values (SUV) were classified as high or low based on a cut point of 7.5 at diagnosis (SUV) and 3.5 after neoadjuvant therapy (preoperative; SUV). Preop carbohydrate antigen 19-9 (CA19-9) was classified as normal ( ≤ 35 U/mL) or elevated. Pretreatment PET/CT imaging was performed on 201 consecutive patients; SUV was high in 98 (49%) and low in 103 (51%). Preop PET/CT was available in 104 (52%) of the 201 patients; SUV was high in 60 (58%) and low in 44 (42%). Following neoadjuvant therapy, preop CA19-9 was normal in 90 (45%) patients and elevated in 111 (55%). Median overall survival (OS) of all patients was 27 months; 33 months for the 103 patients with a low SUV and 22 months for the 98 patients with a high SUV ( = 0.03). Median OS for patients with low SUV/normal preop CA19-9, high SUV/normal preop CA19-9, low SUV/elevated preop CA19-9, and high SUV/elevated preop CA19-9 were 66, 34, 23, and 17 months, respectively ( < 0.0001). OS was 44 months for the 148 (74%) patients who completed all intended neoadjuvant therapy and surgery and 13 months for the 53 (26%) who did not undergo surgery ( < 0.001). Pretreatment PET/CT avidity and preop CA19-9 are clinically significant prognostic markers in patients with PC.
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http://dx.doi.org/10.3389/fonc.2020.00500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180175PMC
April 2020

Detection of germline variants using expanded multigene panels in patients with localized pancreatic cancer.

HPB (Oxford) 2020 Dec 27;22(12):1745-1752. Epub 2020 Apr 27.

Department of Surgery, LaBahn Pancreatic Cancer Program, Medical College of Wisconsin, Milwaukee, WI, United States. Electronic address:

Background: Current guidelines recommend genetic testing for all patients with pancreatic cancer (PC).

Methods: Patients with localized PC who received neoadjuvant therapy between 2009 and 2018 were identified. Genetic consultation (including personal and family history of cancer), genetic testing, and variant data were abstracted.

Results: Of 510 patients identified, 163 (32%) underwent genetic counseling and genetic testing was performed in 127 (25%). Patients who underwent genetic testing were younger (median age: 63 vs. 67, p = 0.01). Multi-gene testing was performed in 114 (90%) of 127 patients, targeted gene testing was performed in 8 (6%), and not specified in 5 (4%). Of 127 patients who underwent genetic testing, 20 (16%) had pathogenic (P)/likely pathogenic (LP) variants, observed in ATM (n = 7/105,7%), CHEK2 (n = 3/98, 3%), BRCA1 (n = 2/117, 2%), BRCA2 (n = 2/122, 2%), PALB2 (n = 1/115, 1%), MUTYH (n = 1/98, 1%), CDKN2A (n = 1/94, 1%), STK11 (n = 1/97, 1%), NBN (n = 1/98, 1%), and MSH6 (n = 1/97, 1%). Of 20 patients with either a P/LP variant, nine (45%) had a prior cancer, three (15%) had a first-degree relative with PC, and six (30%) had an any-degree relative with PC.

Conclusion: Pathogenic/likely pathogenic variants were identified in 16% of patients who underwent genetic testing, 60% of which occurred in the homologous recombination pathway.
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http://dx.doi.org/10.1016/j.hpb.2020.03.022DOI Listing
December 2020

Impact of Neoadjuvant Chemoradiation on Pathologic Response in Patients With Localized Pancreatic Cancer.

Front Oncol 2020 15;10:460. Epub 2020 Apr 15.

The LaBahn Pancreatic Cancer Program, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, United States.

Multimodal neoadjuvant therapy has resulted in increased rates of histologic response in pancreatic tumors and adjacent lymph nodes. The biologic significance of the collective response in the primary tumor and lymph nodes is not understood. Patients with localized PC who received neoadjuvant therapy and surgery with histologic assessment of the primary tumor and local-regional lymph nodes were included. Histopathologic response was classified using the modified Ryan score as follows: no viable cancer cells (CR), rare groups of cancer cells (nCR), residual cancer with evident tumor regression (PR), and extensive residual cancer with no evident tumor regression (NR). Nodal status was defined by number of lymph nodes (LN) with tumor metastases: N0 (0 LN), N1 (1-3), N2 (≥4). Of 341 patients with localized PC who received neoadjuvant therapy and surgery, 107 (31%) received chemoradiation alone, 44 (13%) received chemotherapy alone, and 190 (56%) received chemotherapy and chemoradiation. Histopathologic response consisted of 15 (4%) CRs, 59 (17%) nCRs, 188 (55%) PRs, and 79 (23%) NRs. Patients who received chemotherapy alone had the worst responses ( = 21 for NR, 48%) as compared to patients who received chemoradiation alone ( = 25 for NR, 24%) or patients who received both therapies ( = 33 for NR, 17%) (Table 1; = 0.001). Median overall survival for all 341 patients was 39 months; OS by histopathologic subtype was not reached (CR), 49 months (nCR), 38 months (PR), and 34 months (NR), respectively ( = 0.004). Of the 341 patients, 208 (61%) had N0 disease, 97 (28%) had N1 disease, and 36 (11%) had N2 disease. In an adjusted hazards model, modified Ryan score of PR or NR (HR: 1.71; 95% CI: 1.15-2.54; = 0.008) and N1 (HR: 1.42; 95% CI: 1.1.02-2.01; = 0.04), or N2 disease (HR: 2.54, 95% CI: 1.64-3.93; < 0.001) were associated with increased risk of death. Neoadjuvant chemotherapy alone is associated with lower rates of pathologic response. Patients with CR or nCR have a significantly improved OS as compared to patients with PR or NR. Nodal status is the most important pathologic prognostic factor. Neoadjuvant chemoradiation may be an important driver of pathologic response.
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http://dx.doi.org/10.3389/fonc.2020.00460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175033PMC
April 2020

Oxygen-enhanced MRI MOLLI T1 mapping during chemoradiotherapy in anal squamous cell carcinoma.

Clin Transl Radiat Oncol 2020 May 18;22:44-49. Epub 2020 Mar 18.

Department of Oncology, Oxford University Hospitals NHS Foundation Trust, UK.

Background And Purpose: Oxygen-enhanced magnetic resonance imaging (MRI) and T1-mapping was used to explore its effectiveness as a prognostic imaging biomarker for chemoradiotherapy outcome in anal squamous cell carcinoma.

Materials And Methods: T2-weighted, T1 mapping, and oxygen-enhanced T1 maps were acquired before and after 8-10 fractions of chemoradiotherapy and examined whether the oxygen-enhanced MRI response relates to clinical outcome. Patient response to treatment was assessed 3 months following completion of chemoradiotherapy. A mean T1 was extracted from manually segmented tumour regions of interest and a paired two-tailed -test was used to compare changes across the patient population. Regions of subcutaneous fat and muscle tissue were examined as control ROIs.

Results: There was a significant increase in T1 of the tumour ROIs across patients following the 8-10 fractions of chemoradiotherapy (paired -test, p < 0.001, n = 7). At baseline, prior to receiving chemoradiotherapy, there were no significant changes in T1 across patients from breathing oxygen (n = 9). In the post-chemoRT scans (8-10 fractions), there was a significant decrease in T1 of the tumour ROIs across patients when breathing 100% oxygen (paired -test, p < 0.001, n = 8). Out of the 12 patients from which we successfully acquired a visit 1 T1-map, only 1 patient did not respond to treatment, therefore, we cannot correlate these results with clinical outcome.

Conclusions: These clinical data demonstrate feasibility and potential for T1-mapping and oxygen enhanced T1-mapping to indicate perfusion or treatment response in tumours of this nature. These data show promise for future work with a larger cohort containing more non-responders, which would allow us to relate these measurements to clinical outcome.
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http://dx.doi.org/10.1016/j.ctro.2020.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082428PMC
May 2020

Quantitative imaging for radiotherapy purposes.

Radiother Oncol 2020 05 27;146:66-75. Epub 2020 Feb 27.

Department of Physics, Norwegian University of Science and Technology, Trondheim, Norway.

Quantitative imaging biomarkers show great potential for use in radiotherapy. Quantitative images based on microscopic tissue properties and tissue function can be used to improve contouring of the radiotherapy targets. Furthermore, quantitative imaging biomarkers might be used to predict treatment response for several treatment regimens and hence be used as a tool for treatment stratification, either to determine which treatment modality is most promising or to determine patient-specific radiation dose. Finally, patient-specific radiation doses can be further tailored to a tissue/voxel specific radiation dose when quantitative imaging is used for dose painting. In this review, published standards, guidelines and recommendations on quantitative imaging assessment using CT, PET and MRI are discussed. Furthermore, critical issues regarding the use of quantitative imaging for radiation oncology purposes and resultant pending research topics are identified.
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http://dx.doi.org/10.1016/j.radonc.2020.01.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294225PMC
May 2020

Assessment of robustness against setup uncertainties using probabilistic scenarios in lung cancer: a comparison of proton with photon therapy.

Br J Radiol 2020 Mar 4;93(1107):20190584. Epub 2020 Feb 4.

CRUK and MRC Oxford Institute for Radiation Oncology, Old Road Campus Research Building, Off Roosevelt Drive, University of Oxford, Oxford, OX3 7DQ, UK.

Objective: We compared the sensitivity of intensity modulated proton therapy (IMPT) and photon volumetric modulated arc therapy (VMAT) plans to setup uncertainties in locally advanced non-small cell lung cancer (NSCLC) using probabilistic scenarios.

Methods: Minimax robust (MM) and planning target volume (PTV) optimised IMPT and VMAT nominal plans were created with physical dose of 70 Gy in 35 fractions in 10 representative patients. Using population data of setup errors, a fractionated treatment course was simulated, summed (D) and compared to the nominal plan. Three treatment-course simulations were done for each plan. Target robustness criteria were: dose deviation of ≤5% to clinical target volume (CTV) D and CTV V ≥ 99.9%. Voxelwise simulation repeatability was analysed using Bland-Altman plots. Acceptable limits of agreement were 2% of the prescription dose.

Results: All D met target robustness criteria. While fraction VMAT and MM-IMPT doses were excellent, simulated fraction doses in PTV-IMPT were suboptimal. Almost all (>99%) of VMAT and MM-IMPT fraction doses met both target robustness criteria. For PTV-IMPT, only 96.9 and 80.3% of fractions met CTVD and V criteria respectively. Simulation repeatability was excellent (limits of agreement range: 0.41-1.1 Gy) with strong positive correlations.

Conclusion: When considering the whole treatment course, setup errors do not influence robustness irrespective of planning techniques used. However, on a fraction level, VMAT and MM-IMPT plans are superior compared to PTV-IMPT plans.

Advances In Knowledge: Probabilistic analysis provides a fast and practical method for evaluating VMAT and IMPT plan sensitivity against setup uncertainty. VMAT and robust-optimised IMPT plans have comparable sensitivity to setup uncertainties in conventionally fractionated treatment for NSCLC.
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http://dx.doi.org/10.1259/bjr.20190584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066956PMC
March 2020

Safety and Efficacy Results of a Phase I, Open-Label Study of Concurrent and Delayed Nivolumab in Combination With -Paclitaxel and Carboplatin in Advanced Non-small Cell Lung Cancer.

Front Oncol 2019 26;9:1256. Epub 2019 Nov 26.

Comprehensive Cancer Center, University of California, Davis, Sacramento, CA, United States.

Multicenter, phase I study of concurrent and delayed nivolumab plus -paclitaxel/carboplatin in advanced non-small cell lung cancer (NSCLC). Chemotherapy-naive patients with advanced NSCLC (ineligible for potentially curative radiation or surgery) received -paclitaxel 100 mg/m (days 1, 8, 15) and carboplatin area under the curve 6 (day 1) intravenously every 21 days (first 4 cycles); nivolumab 5 mg/kg was administered intravenously (day 15) beginning in cycle 1 (concurrent) or cycle 3 (delayed) in separate cohorts and continued beyond the 4 chemotherapy cycles. The primary objective was to assess safety. Secondary objectives were to assess tolerability and explore antitumor activity. All 32 patients received chemotherapy; 20 of 22 and 6 of 10 patients also received concurrent or delayed nivolumab, respectively. No dose-limiting toxicities were reported in the concurrent cohort; 1 dose-limiting toxicity was reported in the delayed cohort. In the concurrent cohort, 20 patients (91%) had ≥1 grade 3/4 treatment-emergent adverse event (TEAE), and 7 (32%) discontinued treatment due to TEAEs. In the delayed cohort, all patients had ≥1 grade 3/4 TEAE, and 2 (20%) discontinued due to TEAEs. The median progression-free and overall survival, respectively, were 10.5 and 29.3 months in the concurrent cohort and 4.1 and 8.2 months in the delayed cohort. The safety profile of the combination was consistent with that of individual agents and generally similar in the 2 cohorts. Efficacy outcomes in the concurrent cohort, but not in the delayed cohort, were encouraging and support the rationale for concurrent administration of nivolumab with -paclitaxel/carboplatin for the treatment of advanced NSCLC. www.ClinicalTrials.gov, identifier: NCT02309177.
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http://dx.doi.org/10.3389/fonc.2019.01256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901975PMC
November 2019

Role of Molecular Profiling of Pancreatic Cancer After Neoadjuvant Therapy: Does it Change Practice?

J Gastrointest Surg 2020 02 19;24(2):235-242. Epub 2019 Nov 19.

Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA.

Introduction: Tumor profiling can improve the selection of oncologic therapies in patients with pancreatic cancer (PC). The impact of neoadjuvant therapy on tumor testing is unknown.

Methods: Molecular profiling using commercially available 53-, 315-, or 472-gene next generation sequencing (NGS) panels was performed on surgical specimens following neoadjuvant therapy. All specimens with 472-gene sequencing also had immunohistochemical (IHC) testing. Treatment recommendations were based on somatic variants and IHC staining.

Results: NGS was performed on 74 patient specimens: 42 (57%) with a 472-gene panel, 28 (38%) with a 315-gene panel, 3 (4%) had 472- and 315-gene panels, and 1 (1%) patient had 53- and 472-gene panels (78 total tests). Likely pathogenic/pathogenic variants were identified in 73 (94%) of the 78 tests. Of the 73 samples with variants identified, 13 (18%) variants were associated with an actionable treatment: ATM (n = 10), BRCA1 (n = 1), PIK3CA (n = 1), and BRCA2 (n = 1). No patient had more than one actionable variant. Based on NGS results, the most commonly recommended therapy was a platinum agent (n = 12/78, 15%). Of the 46 specimens that underwent IHC analysis, overlapping chemotherapeutic treatment recommendations were identified in 40 (87%) specimens.

Conclusion: Using current multigene NGS panels, actionable variants were identified in 13 (18%) of 74 surgical specimens and primarily involved genes of the DNA repair pathway. Anecdotal reproducibility of test concordance was low.
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http://dx.doi.org/10.1007/s11605-019-04423-6DOI Listing
February 2020

Is an analytical dose engine sufficient for intensity modulated proton therapy in lung cancer?

Br J Radiol 2020 Mar 20;93(1107):20190583. Epub 2019 Nov 20.

CRUK and MRC Oxford Institute for Radiation Oncology, Old Road Campus Research Building, Off Roosevelt Drive, University of Oxford, Oxford, OX3 7DQ, UK.

Objective: To identify a subgroup of lung cancer plans where the analytical dose calculation (ADC) algorithm may be clinically acceptable compared to Monte Carlo (MC) dose calculation in intensity modulated proton therapy (IMPT).

Methods: Robust-optimised IMPT plans were generated for 20 patients to a dose of 70 Gy (relative biological effectiveness) in 35 fractions in Raystation. For each case, four plans were generated: three with ADC optimisation using the pencil beam (PB) algorithm followed by a final dose calculation with the following algorithms: PB (PB-PB), MC (PB-MC) and MC normalised to prescription dose (PB-MC scaled). A fourth plan was generated where MC optimisation and final dose calculation was performed (MC-MC). Dose comparison and γ analysis (PB-PB PB-MC) at two dose thresholds were performed: 20% (D20) and 99% (D99) with PB-PB plans as reference.

Results: Overestimation of the dose to 99% and mean dose of the clinical target volume was observed in all PB-MC compared to PB-PB plans (median: 3.7 Gy(RBE) (5%) (range: 2.3 to 6.9 Gy(RBE)) and 1.8 Gy(RBE) (3%) (0.5 to 4.6 Gy(RBE))). PB-MC scaled plans resulted in significantly higher CTVD2 compared to PB-PB (median difference: -4 Gy(RBE) (-6%) (-5.3 to -2.4 Gy(RBE)), ≤ .001). The overall median γ pass rates (3%-3 mm) at D20 and D99 were 93.2% (range:62.2-97.5%) and 71.3 (15.4-92.0%). On multivariate analysis, presence of mediastinal disease and absence of range shifters were significantly associated with high pass rates. Median D20 and D99 pass rates with these predictors were 96.0% (95.3-97.5%) and 85.4% (75.1-92.0%). MC-MC achieved similar target coverage and doses to OAR compared to PB-PB plans.

Conclusion: In the presence of mediastinal involvement and absence of range shifters Raystation ADC may be clinically acceptable in lung IMPT. Otherwise, MC algorithm would be recommended to ensure accuracy of treatment plans.

Advances In Knowledge: Although MC algorithm is more accurate compared to ADC in lung IMPT, ADC may be clinically acceptable where there is mediastinal involvement and absence of range shifters.
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http://dx.doi.org/10.1259/bjr.20190583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066954PMC
March 2020

Management of Acute Cholecystitis during Neoadjuvant Therapy in Patients with Pancreatic Adenocarcinoma.

Ann Surg Oncol 2019 Dec 22;26(13):4515-4521. Epub 2019 Oct 22.

Pancreatic Cancer Program, Department of Surgery, The Medical College of Wisconsin, Milwaukee, WI, USA.

Background: Patients with localized pancreatic cancer (PC) can develop acute cholecystitis during neoadjuvant therapy; optimal management remains undefined.

Methods: Consecutive patients with localized PC who had indwelling biliary stents and received neoadjuvant therapy were reviewed. Time from stent placement to the development of acute cholecystitis was calculated. Patients were categorized as having surgical versus nonoperative management of cholecystitis. Time to PC resection was defined as the time from the start of treatment to pancreatic resection.

Results: Of the 283 patients with indwelling biliary stents, acute cholecystitis occurred in 17 (6%) patients. The median time from the date of stent placement to the development of cholecystitis was 2.3 months [interquartile range (IQR) 4.6 months]. Acute cholecystitis was managed with cholecystostomy tube placement in 15 (88%) patients and cholecystectomy in 2 (12%). In total, 189 (67%) of the 283 patients completed all intended neoadjuvant therapy and surgery; 10 (59%) of the 17 patients with cholecystitis (10 of 15 managed with a cholecystostomy tube and 0 of 2 managed with cholecystectomy) and 179 (67%) of the 266 patients without cholecystitis (p = 0.47). The median time to PC resection was 3.2 months for the 179 patients without cholecystitis and 3.6 months for the 10 patients with cholecystitis (p = 1.00).

Conclusions: Acute cholecystitis occurred in 6% of patients with indwelling biliary stents during neoadjuvant therapy. Management with a cholecystostomy tube did not delay the completion of neoadjuvant therapy and surgery and should be considered the optimal management of this complication.
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http://dx.doi.org/10.1245/s10434-019-07906-7DOI Listing
December 2019

Efficacy and Safety of Trifluridine/Tipiracil Treatment in Patients With Metastatic Gastric Cancer Who Had Undergone Gastrectomy: Subgroup Analyses of a Randomized Clinical Trial.

JAMA Oncol 2019 Oct 10. Epub 2019 Oct 10.

Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan.

Importance: Trifluridine/tipiracil (FTD/TPI) treatment has shown clinical benefit in patients with pretreated metastatic gastric cancer or gastroesophageal junction cancer (mGC/GEJC). Patients who have undergone gastrectomy constitute a significant proportion of patients with mGC/GEJC.

Objective: To assess the efficacy and safety of FTD/TPI among patients with previously treated mGC/GEJC who had or had not undergone gastrectomy.

Design, Setting, And Participants: This preplanned subgroup analysis of TAGS (TAS-102 Gastric Study), a phase 3, randomized, placebo-controlled, clinical trial included patients with mGC/GEJC who had received at least 2 previous chemotherapy regimens, and was conducted at 110 academic hospitals in 17 countries in Europe, Asia, and North America, with enrollment between February 24, 2016, and January 5, 2018; the data cutoff was March 31, 2018.

Interventions: Patients were randomized 2:1 to receive oral FTD/TPI 35 mg/m2 twice daily or placebo twice daily with best supportive care on days 1 through 5 and days 8 through 12 of each 28-day treatment cycle.

Main Outcomes And Measures: The primary end point was overall survival. This subgroup analysis was conducted to examine potential trends and was not powered for statistical significance. Efficacy and safety end points were evaluated in the subgroups.

Results: Of 507 randomized patients (369 [72.8%] male; mean [SD] age, 62.5 [10.5] years), 221 (43.6%) had undergone gastrectomy (147 randomized to FTD/TPI and 74 to placebo) and 286 (56.4%) had not undergone gastrectomy (190 randomized to FTD/TPI and 96 to placebo). In the gastrectomy subgroup, the overall survival hazard ratio (HR) in the FTD/TPI group vs placebo group was 0.57 (95% CI, 0.41-0.79), and the progression-free survival HR was 0.48 (95% CI, 0.35-0.65). In the no gastrectomy subgroup, the overall survival HR in the FTD/TPI group vs placebo group was 0.80 (95% CI, 0.60-1.06), and the progression-free survival HR was 0.65 (95% CI, 0.49-0.85). Among FTD/TPI-treated patients, grade 3 or higher adverse events of any cause occurred in 122 of 145 patients (84.1%) in the gastrectomy subgroup and 145 of 190 (76.3%) in the no gastrectomy subgroup: 64 (44.1%) in the gastrectomy subgroup and 50 (26.3%) in the no gastrectomy subgroup had grade 3 or higher neutropenia, 31 (21.4%) in the gastrectomy subgroup and 33 (17.4%) in the no gastrectomy subgroup had grade 3 or higher anemia, and 21 (14.5%) in the gastrectomy subgroup and 10 (5.3%) in the no gastrectomy subgroup hD grade 3 or higher leukopenia. In the gastrectomy subgroup, 94 (64.8%) had dosing modifications because of adverse events vs 101 (53.2%) in the no gastrectomy subgroup; 15 (10.3%) in the gastrectomy group and 28 (14.7%) in the no gastrectomy group discontinued treatment because of adverse events. Treatment exposure was similar between groups.

Conclusions And Relevance: The FTD/TPI treatment was tolerable and provided efficacy benefits among patients with pretreated mGC/GEJC regardless of previous gastrectomy.

Trial Registration: ClinicalTrials.gov identifier: NCT02500043.
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http://dx.doi.org/10.1001/jamaoncol.2019.3531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802061PMC
October 2019

Molecular and Genetic Markers in Appendiceal Mucinous Tumors: A Systematic Review.

Ann Surg Oncol 2020 Jan 3;27(1):85-97. Epub 2019 Oct 3.

Department of Surgery, Division of Surgical Oncology, Medical College of Wisconsin, Milwaukee, WI, USA.

Introduction: The role of somatic mutation profiling in the management of appendiceal mucinous tumors (AMTs) is evolving. Using a systematic review, we identified somatic alterations (SAs) that comprise histopathologic types of AMTs and those associated with aggressive clinical phenotypes.

Methods: MEDLINE/PubMed was searched for studies on AMTs including molecular markers or genomic alterations, published between 1990 and 2018. Studies were grouped under low- and high-grade histological type for primary and metastatic tumors.

Results: Twenty-one studies involving 1099 tumors (primary/metastatic) were identified. Seven studies involving 101 primary low-grade AMTs identified KRAS (76.5%) as the predominant SA. Four studies noted GNAS in 45.2% of 42 low-grade appendiceal mucinous neoplasms, and KRAS was identified in 74.4% of 14 studies with 238 low-grade pseudomyxoma peritonei (PMP). GNAS was noted in 56% of 101 tumors and TP53 was noted in only 9.7% of 31 tumors. Primary high-grade tumors demonstrated lower SAs in KRAS (50.4% of 369 tumors) and GNAS (27.8% of 97 tumors), and higher SAs in TP53 (26.0% of 123 tumors). In high-grade PMP, SAs were noted in KRAS (55.0% of 200 tumors), GNAS (35.0% of 60 tumors), and TP53 (26.3% of 19 tumors). No clear association was noted between SAs and survival.

Conclusions: KRAS and GNAS are frequently altered in low-grade AMTs, while TP53 is frequently altered in high-grade AMTs, with no apparent change in expression between primary and metastatic tumors. Although SAs may provide valuable insights into variability in tumor biology, larger studies utilizing clinically annotated genomic databases from multi-institutional consortiums are needed to improve their identification and clinical applicability.
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http://dx.doi.org/10.1245/s10434-019-07879-7DOI Listing
January 2020

Survival of patients with borderline resectable pancreatic cancer who received neoadjuvant therapy and surgery.

Surgery 2019 09 2;166(3):277-285. Epub 2019 Jul 2.

Pancreatic Cancer Program, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI. Electronic address:

Background: It is difficult to successfully deliver multimodality therapy to patients with operable pancreatic cancer. Data on the natural history of such efforts are necessary for physicians to guide shared decision-making with patients and families. We report the survival of consecutive patients with borderline resectable pancreatic cancer who received neoadjuvant therapy before surgery.

Methods: Data regarding demographics, neoadjuvant therapy, surgery, pathology, and survival duration were abstracted on consecutive patients with borderline resectable pancreatic cancer diagnosed between 2009 and 2017 and not treated on available clinical trials. Borderline resectable pancreatic cancer was defined based on ≥1 of the following: local tumor anatomy, pretreatment serum carbohydrate antigen 19-9 >2,000 U/mL, and the presence of radiographic lesions indeterminate for metastases.

Results: Neoadjuvant therapy was delivered to 185 patients with borderline resectable pancreatic cancer who were not enrolled in competing clinical trials; 13 (7%) patients received chemoradiation, 12 (7%) received chemotherapy, and 160 (86%) received both. Of the 185 patients, 115 (62%) completed all intended neoadjuvant therapy and surgery; 81 (70%) of 115 underwent pancreaticoduodenectomy; and vascular reconstruction was performed in 51 (44%). A margin negative resection was achieved in 111 (97%) of 115 patients, and 83 (72%) were node negative. Median overall survival for all 185 patients was 20 months; 31 months for the 115 patients who completed all neoadjuvant therapy and surgery as compared to 13 months for the 70 patients who were not resected (P < .0001).

Conclusion: After neoadjuvant therapy, surgical resection was performed in 62% of patients with borderline resectable pancreatic cancer. Those who normalized preoperative serum carbohydrate antigen 19-9 and had node negative pathology achieved the longest survival. To further improve median survival for all patients, we are incorporating adaptive approaches to neoadjuvant therapy sequencing based on objective assessments of response.
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http://dx.doi.org/10.1016/j.surg.2019.05.010DOI Listing
September 2019

IPEM Topical Report: A 2018 IPEM survey of MRI use for external beam radiotherapy treatment planning in the UK.

Phys Med Biol 2019 09 5;64(17):175021. Epub 2019 Sep 5.

Leeds Cancer Centre, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom. Author to whom correspondence should be addressed.

The benefits of integrating MRI into the radiotherapy pathway are well published, however there is little consensus in guidance on how to commission or implement its use. With a view to developing consensus guidelines for the use of MRI in external beam radiotherapy (EBRT) treatment planning in the UK, a survey was undertaken by an Institute of Physics and Engineering in Medicine (IPEM) working-party to assess the current landscape of MRI use in EBRT in the UK. A multi-disciplinary working-party developed a survey to understand current practice using MRI for EBRT treatment planning; investigate how MRI is currently used and managed; and identify knowledge gaps. The survey was distributed electronically to radiotherapy service managers and physics leads in 71 UK radiotherapy (RT) departments (all NHS and private groups). The survey response rate was 87% overall, with 89% of NHS and 75% of private centres responding. All responding centres include EBRT in some RT pathways: 94% using Picture Archiving and Communication System (PACS) images potentially acquired without any input from RT departments, and 69% had some form of MRI access for planning EBRT. Most centres reporting direct access use a radiology scanner within the same hospital in dedicated (26%) or non-dedicated (52%) RT scanning sessions. Only two centres reported having dedicated RT MRI scanners in the UK, lower than reported in other countries. Six percent of radiotherapy patients in England (data not publically available outside of England) have MRI as part of their treatment, which again is lower than reported elsewhere. Although a substantial number of centres acquire MRI scans for treatment planning purposes, most centres acquire less than five patient scans per month for each treatment site. Commissioning and quality assurance of both image registration and MRI scanners was found to be variable across the UK. In addition, staffing models and training given to different staff groups varied considerably across the UK, reflecting the current lack of national guidelines. The primary barriers reported to MRI implementation in EBRT planning included costs (e.g. lack of a national tariff for planning MRI), lack of MRI access and/or capacity within hospitals. Despite these challenges, significant interest remains in increasing MRI-assisted EBRT planning over the next five years.
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http://dx.doi.org/10.1088/1361-6560/ab2c7cDOI Listing
September 2019

Etanercept for Treatment of Taxane-Induced Pneumonitis.

J Oncol Pract 2019 10 20;15(10):556-557. Epub 2019 Jun 20.

Medical College of Wisconsin, Milwaukee, WI.

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http://dx.doi.org/10.1200/JOP.19.00180DOI Listing
October 2019

Downstaging Locally Advanced Cholangiocarcinoma Pre-Liver Transplantation: A Prospective Pilot Study.

J Surg Res 2019 10 3;242:23-30. Epub 2019 May 3.

Division of Transplant Surgery, Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin; The Transplant Center, Froedtert and The Medical College of Wisconsin, Milwaukee, Wisconsin. Electronic address:

Background: Orthotopic liver transplantation (OLT) after neoadjuvant therapy (NT) in well-selected patients with unresectable hilar cholangiocarcinoma (CCA) achieves excellent recurrence-free survival. Current criteria for NT-OLT exclude patients with locally advanced hilar and intrahepatic CCA from potential cure. We sought to evaluate the efficacy of NT in downstaging locally advanced CCA, and examine outcomes after OLT.

Methods: Among 24 patients referred for unresectable hilar and intrahepatic CCA from January 2013 through August 2017, 18 met center-specific inclusion criteria for the NT-OLT treatment protocol: hilar tumor size ≤3.5 cm or intrahepatic ≤8 cm, and regional lymphadenopathy but without distant metastasis. Median follow-up was 22.1 mo from diagnosis.

Results: Of 18 patients who initiated NT, 11 were removed from the protocol due to tumor progression (n = 6) or uncontrolled infection and failure-to-thrive (n = 5). Median NT duration tended to be shorter for patients progressing to dropout than for those surviving to OLT (5.5 versus 13.5 mo, P = 0.109). Among five patients who received OLT, 1-y post-OLT patient survival was 80%: three survive recurrence-free (14.5-29.2 mo post-OLT); one developed an isolated tumor recurrence in a single portacaval lymph node at 12 mo post-OLT; and one experienced non-tumor-related death. All dropout patients died at a median of 14.4 mo after diagnosis.

Conclusions: This is the first prospective study to show successful NT downstaging of unresectable locally advanced hilar and intrahepatic CCA before OLT. NT-OLT for select patients with locally advanced hilar and intrahepatic CCA achieved acceptable short-term recurrence-free survival.
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http://dx.doi.org/10.1016/j.jss.2019.04.023DOI Listing
October 2019

Real-Time Targeted Genome Profile Analysis of Pancreatic Ductal Adenocarcinomas Identifies Genetic Alterations That Might Be Targeted With Existing Drugs or Used as Biomarkers.

Gastroenterology 2019 06 2;156(8):2242-2253.e4. Epub 2019 Mar 2.

Department of Internal Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

Background & Aims: It has been a challenge to select treatment for patients with pancreatic ductal adenocarcinomas (PDACs) based on genome alterations. We performed targeted genomic profile analyses of a large number of PDACs to assess the full spectrum of actionable genomic alterations.

Methods: We performed targeted genomic profile analyses of 3594 PDAC samples from an international cohort, including capture-based targeted genomic profiling of as many as 315 cancer-associated genes and intron regions of 28 genes that are rearranged in cancer cells. Tumor mutation burden (TMB) and microsatellite instability (MSI) status were also assessed. TMB was calculated across a 1.14-megabase region; TMB-high was defined as ≥20 mutations/megabase. MSI-high status was assigned based on analysis of 114 intron homopolymer loci.

Results: KRAS, TP53, CDKN2A, and SMAD4 were the most frequently altered genes in PDAC. We found KRAS mutations in 88% of samples. Among PDACs without mutations in KRAS, we found alterations in genes whose products are in the mitogen-activated protein kinase signaling pathway and are candidate drug targets (actionable targets, n = 132; 4%), as well as gene fusions (n = 51), gene amplifications (n = 35), genes with missense mutations (n = 30), and genes that contain deletions (n = 16). Many of these encode proteins in receptor tyrosine kinase, RAS, or mitogen-activated protein kinase signaling pathways. Aside from TP53, alterations in genes encoding DNA damage repair proteins (BRCA and FANC) were detected in 14% of PDACs. Among PDACs evaluated for MSI (n = 2563) and TMB (n = 1021), MSI-high and/or TMB-high phenotypes were detected in 0.5% of samples. Alterations in FGF23, CCND2, PIK3CA, and FGF6 were more commonly detected in intraductal papillary mucinous neoplasm-associated PDACs.

Conclusions: In targeted genomic profile analyses of 3594 PDACs, we found 17% to contain genomic alterations that might make the tumor cells susceptible to currently used anticancer agents. We identified mutations in genes that could contribute to progression of intraductal papillary mucinous neoplasms into malignancies. These alterations might be used as biomarkers for early detection.
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http://dx.doi.org/10.1053/j.gastro.2019.02.037DOI Listing
June 2019

Proliferative potential and resistance to immune checkpoint blockade in lung cancer patients.

J Immunother Cancer 2019 02 1;7(1):27. Epub 2019 Feb 1.

OmniSeq, Inc., 700 Ellicott Street, Buffalo, NY, 14203, USA.

Background: Resistance to immune checkpoint inhibitors (ICIs) has been linked to local immunosuppression independent of major ICI targets (e.g., PD-1). Clinical experience with response prediction based on PD-L1 expression suggests that other factors influence sensitivity to ICIs in non-small cell lung cancer (NSCLC) patients.

Methods: Tumor specimens from 120 NSCLC patients from 10 institutions were evaluated for PD-L1 expression by immunohistochemistry, and global proliferative profile by targeted RNA-seq.

Results: Cell proliferation, derived from the mean expression of 10 proliferation-associated genes (namely BUB1, CCNB2, CDK1, CDKN3, FOXM1, KIAA0101, MAD2L1, MELK, MKI67, and TOP2A), was identified as a marker of response to ICIs in NSCLC. Poorly, moderately, and highly proliferative tumors were somewhat equally represented in NSCLC, with tumors with the highest PD-L1 expression being more frequently moderately proliferative as compared to lesser levels of PD-L1 expression. Proliferation status had an impact on survival in patients with both PD-L1 positive and negative tumors. There was a significant survival advantage for moderately proliferative tumors compared to their combined highly/poorly counterparts (p = 0.021). Moderately proliferative PD-L1 positive tumors had a median survival of 14.6 months that was almost twice that of PD-L1 negative highly/poorly proliferative at 7.6 months (p = 0.028). Median survival in moderately proliferative PD-L1 negative tumors at 12.6 months was comparable to that of highly/poorly proliferative PD-L1 positive tumors at 11.5 months, but in both instances less than that of moderately proliferative PD-L1 positive tumors. Similar to survival, proliferation status has impact on disease control (DC) in patients with both PD-L1 positive and negative tumors. Patients with moderately versus those with poorly or highly proliferative tumors have a superior DC rate when combined with any classification schema used to score PD-L1 as a positive result (i.e., TPS ≥ 50% or ≥ 1%), and best displayed by a DC rate for moderately proliferative tumors of no less than 40% for any classification of PD-L1 as a negative result. While there is an over representation of moderately proliferative tumors as PD-L1 expression increases this does not account for the improved survival or higher disease control rates seen in PD-L1 negative tumors.

Conclusions: Cell proliferation is potentially a new biomarker of response to ICIs in NSCLC and is applicable to PD-L1 negative tumors.
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http://dx.doi.org/10.1186/s40425-019-0506-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359802PMC
February 2019

Clinical Intensity Modulated Proton Therapy for Hodgkin Lymphoma: Which Patients Benefit the Most?

Pract Radiat Oncol 2019 May 29;9(3):179-187. Epub 2019 Jan 29.

Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom; Oxford Cancer Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.

Purpose: Radiation therapy (RT) improves control of Hodgkin lymphoma (HL), but patients who undergo RT are at risk for late effects, including cardiovascular disease and second cancers, because of radiation doses to organs at risk (OARs). Proton therapy (PT) can reduce OAR doses compared with conventional photon RT. However, access to PT is currently limited, so referrals must be appropriately selective. We aimed to identify subgroups of patients with HL who could benefit the most dosimetrically from RT with PT based on the prechemotherapy disease characteristics.

Methods And Materials: Normal tissue radiation doses were calculated for 21 patients with HL who were treated with deep-inspiration breath-hold pencil-beam scanning (PBS) PT and compared with doses from 3-dimensional conformal (3D-CRT) and partial arc volumetric modulated (PartArc) photon RT. Prechemotherapy disease characteristics associated with significant dosimetric benefits from PBS compared with photon RT were identified.

Results: Treatment with PBS was well tolerated and provided with good local control. PBS provided dosimetric advantages for patients whose clinical treatment volume extended below the seventh thoracic level and for female patients with axillary disease. In addition, an increasing dosimetric benefit for some OARs was observed for increasing target volume. PBS significantly reduced the mean dose to the heart, breast, lungs, spinal cord, and esophagus. Dose homogeneity and conformity within the target volume were also superior with PBS, but some high-dose measures and hot spots were increased with PBS compared with partial arc volumetric modulated photon RT.

Conclusions: PBS gives good target coverage and local control while providing reductions in radiation dose to OARs for individuals who receive RT for HL compared with advanced photon RT. Our findings highlight groups of patients who would be expected to gain more dosimetric benefit from PBS. These findings facilitate the selection of patients who should be considered a priority for PT.
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http://dx.doi.org/10.1016/j.prro.2019.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6493042PMC
May 2019

Next generation sequencing of PD-L1 for predicting response to immune checkpoint inhibitors.

J Immunother Cancer 2019 01 24;7(1):18. Epub 2019 Jan 24.

OmniSeq, Inc., 700 Ellicott Street, Buffalo, NY, 14203, USA.

Background: PD-L1 immunohistochemistry (IHC) has been traditionally used for predicting clinical responses to immune checkpoint inhibitors (ICIs). However, there are at least 4 different assays and antibodies used for PD-L1 IHC, each developed with a different ICI. We set to test if next generation RNA sequencing (RNA-seq) is a robust method to determine PD-L1 mRNA expression levels and furthermore, efficacy of predicting response to ICIs as compared to routinely used, standardized IHC procedures.

Methods: A total of 209 cancer patients treated on-label by FDA-approved ICIs, with evaluable responses were assessed for PD-L1 expression by RNA-seq and IHC, based on tumor proportion score (TPS) and immune cell staining (ICS). A subset of serially diluted cases was evaluated for RNA-seq assay performance across a broad range of PD-L1 expression levels.

Results: Assessment of PD-L1 mRNA levels by RNA-seq demonstrated robust linearity across high and low expression ranges. PD-L1 mRNA levels assessed by RNA-seq and IHC (TPS and ICS) were highly correlated (p < 2e-16). Sub-analyses showed sustained correlation when IHC results were classified as high or low by clinically accepted cut-offs (p < 0.01), and results did not differ by tumor type or anti-PD-L1 antibody used. Overall, a combined positive PD-L1 result (≥1% IHC TPS and high PD-L1 expression by RNA-Seq) was associated with a 2-to-5-fold higher overall response rate (ORR) compared to a double negative result. Standard assessments of sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) showed that a PD-L1 positive assessment for melanoma samples by RNA-seq had the lowest sensitivity (25%) but the highest PPV (72.7%). Among the three tumor types analyzed in this study, the only non-overlapping confidence interval for predicting response was for "RNA-seq low vs high" in melanoma.

Conclusions: Measurement of PD-L1 mRNA expression by RNA-seq is comparable to PD-L1 expression by IHC both analytically and clinically in predicting ICI response. RNA-seq has the added advantages of being amenable to standardization and avoidance of interpretation bias. PD-L1 by RNA-seq needs to be validated in future prospective ICI clinical studies across multiple histologies.
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http://dx.doi.org/10.1186/s40425-018-0489-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346512PMC
January 2019