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Introduction: Immune thrombocytopenia (ITP) secondary to durvalumab, a programmed cell death ligand 1 inhibitor, is a rare but clinically significant immune-related adverse event. Herein, we present 2 patients with cholangiocarcinoma who developed ITP immediately post-yttrium-90 radioembolization (Y90-RE) while on durvalumab-based systemic therapy. We hypothesize that given the timing, the immunotherapy and the radioembolization combination led to this event. It is not uncommon given the approval of immunotherapy and its role in locoregional therapies, that patients are treated with a combination of systemic immunotherapy and radioembolization or other forms of radiation, thus signifying the importance of potential complications., Case Presentation: Two patients, a 67-year-old female and a 60-year-old man, with biopsy-proven advanced unresectable cholangiocarcinoma, received a combination of systemic therapy with durvalumab, gemcitabine, and cisplatin and subsequently Y90-RE. Both patients developed ITP following in the immediate post-Y90-RE period. All other causes of ITP were comprehensively ruled out and treatment for ITP was initiated in the form of high-dose steroid and intravenous immunoglobulins. Durvalumab was discontinued, and only gemcitabine/cisplatin-based chemotherapy was continued thereafter. Due to recurrence, one of the patients required longer courses of steroids as well as thrombopoietin receptor agonists., Conclusion: Immunotherapy in the form of durvalumab and now pembrolizumab alongside chemotherapy is an approved first-line standard of care. Furthermore, it is not uncommon for patients to receive Y90-RE to improve patient outcomes. This report highlights the development of ITP in 2 patients who received durvalumab alongside Y90-RE. Awareness of this as a potential immune-mediated event is important to allow for close monitoring of platelet counts and for early intervention/management when this occurs., Competing Interests: P.M.K. reports grants paid to the institution by Merck, Agenus Bio, Novartis, Advanced Accelerator Applications, TerSera, and Boston Scientific; a consultancy and advisory board relationship with Elicio (scientific advisory board member/shares/stock ownership); cofounder of Precision BioSensors Inc.; consultancy/advisory board fees from Guardant Health, Natera, Foundation Medicine, Illumina, BostonGene, Merck/MSD Oncology, Tempus, Bayer, Lilly, Delcath Systems, IPBA, QED Therapeutics, Boston Healthcare Associates, Servier, Taiho Oncology, Exact Sciences, Daiichi Sankyo/AstraZeneca, Eisai, Saga Diagnostics, NeoGenomics, DoMore Diagnostics AS, and Seattle Genetics; consulting fees paid to the institution by Taiho Pharmaceutical and Ipsen; receiving travel support from AstraZeneca for presentation of an investigator-initiated trial. All other authors have no conflicts of interest to report., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background: Cholangiocarcinoma-with a growing incidence rate and poor prognosis-is not an uncommon cancer. Molecular profiling can reveal actionable aberrations in at least a third of the tumors. This is especially so in the case of intrahepatic cholangiocarcinoma (ICC), where mutations in the isocitrate dehydrogenase 1 and 2 genes ( IDH1/2 ) make up 15%-20% of these tumors. IDH1/2 mutant ICC is a rare disease that has not been adequately reported. To expand the spectrum of findings seen in these patients, we present a single institution case series., Methods and Results: We descriptively characterize the clinical, radiological, and histopathological findings of 12 such patients. IDH1/2 mutant ICC was found in elderly women, with two-thirds of patients having additional co-mutations. Anecdotally, patients who did receive systemic and/or locoregional therapies had long-term durable outcomes., Conclusion: Our findings indicate an increasing need to personalize an approach for these patients with specific molecular alterations. With the advent of the IDH1 inhibitor ivosidenib and other inhibitors in this space, IDH1/2 mutation have both prognostic and predictive value. Our series builds upon the patterns and findings seen in these patients., Competing Interests: Declaration of Conflicts of InterestThe authors declare the following financial interests/personal relationships which may be considered as potential competing interests: PMK reports grants paid to the institution by Merck, Agenus Bio, Novartis, Advanced Accelerator Applications, Tersera, and Boston Scientific; a consultancy and advisory board relationship with Elicio (scientific advisory board member/shares/stock ownership); cofounder of Precision BioSensors Inc.; consultancy/advisory board fees from Guardant Health, Natera, Foundation Medicine, Illumina, BostonGene, Merck/MSD Oncology, Tempus, Bayer, Lilly, Delcath Systems, IPBA, QED Therapeutics, Boston Healthcare Associates, Servier, Taiho Oncology, Exact Sciences, Daiichi Sankyo/AstraZeneca, Eisai, Saga Diagnostics, Neogenomics, Do More Diagnostics AS, and Seattle Genetics; consulting fees paid to the institution by Taiho Pharmaceutical and Ipsen; receiving travel support from AstraZeneca for presentation of an investigator-initiated trial. All other authors have no conflicts of interest to report.

Introduction: Liquid biopsies are increasingly being adopted in the care of patients with cancer. Not only in patients with metastatic disease but the utility is also being recognized in earlier phases of the journey of a patient with cancer. More recently, methylated platforms are offering another lens of looking at the same question more so in minimal residual disease (MRD) and early detection settings. While false positives secondary to clonal hematopoiesis of indeterminate potential (CHIP) are recognized as one entity to consider when interpreting these assays, and advanced CHIP filtering bioinformatics platforms can prevent this, false positives secondary to aberrant methylation are not described., Case Presentation: Herein, we report a case of a patient with hepatitis C-related viremia and a very high viral load that had a false-positive plasma-only colorectal MRD assay. The colorectal MRD assay spontaneously cleared on hepatitis C virus therapy which led to clearance of the virus., Conclusion: As these assays are increasingly applied in real-world settings, it would be of value to consider non-cancer chronic disease states that may lead to aberrant methylation that could lead to a false-positive assay., Competing Interests: P.M.K. reports grants paid to the institution by Merck, Agenus Bio, Novartis, Advanced Accelerator Applications, TerSera, and Boston Scientific; a consultancy and advisory board relationship with Elicio (scientific advisory board member/shares/stock ownership); co-founder of Precision BioSensors Inc.; consultancy/advisory board fees from Guardant Health, Natera, Foundation Medicine, Illumina, BostonGene, Merck/MSD Oncology, Tempus, Bayer, Lilly, Delcath Systems, IPBA, QED Therapeutics, Boston Healthcare Associates, Servier, Taiho Oncology, Exact Sciences, Daiichi Sankyo/AstraZeneca, Eisai, Saga Diagnostics, NeoGenomics, DoMore Diagnostics AS, and Seattle Genetics; consulting fees paid to the institution by Taiho Pharmaceutical and Ipsen; receiving travel support from AstraZeneca for presentation of an investigator initiated trial. All other authors have no conflicts of interest to report., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Objective: Most of the work in terms of liquid biopsies in patients with solid tumors is focused on circulating tumor DNA (ctDNA). Our aim was to evaluate the feasibility of using circulating tumor cells (CTCs) in peripheral blood samples from patients with advanced or metastatic gastrointestinal (GI) cancers., Methods: In this prospective study, blood samples were collected from each patient in 2 AccuCyte ® blood collection tubes and each tube underwent CTC analysis performed utilizing the RareCyte ® platform. The results from both tubes were averaged and a total of 150 draws were done, with 281 unique reported results. The cadence of sampling was based on convenience sampling and piggybacked onto days of actual clinical follow-ups and treatment visits. The CTC results were correlated with patient- and tumor-related variables., Results: Data from a total of 59 unique patients were included in this study. Patients had a median age of 58 years, with males representing 69% of the study population. More than 57% had received treatment prior to taking blood samples. The type of GI malignancy varied, with more than half the patients having colorectal cancer (CRC, 54%) followed by esophageal/gastric cancer (17%). The least common cancer was cholangiocarcinoma (9%). The greatest number of CTCs were found in patients with colorectal cancer (Mean: 15.8 per 7.5 ml; Median: 7.5 per 7.5 ml). In comparison, patients with pancreatic cancer (PC) had considerably fewer CTCs (Mean: 4.2 per 7.5 ml; Median: 3 per 7.5 ml). Additionally, we found that patients receiving treatment had significantly fewer CTCs than patients who were not receiving treatment (Median 2.7 versus 0.7). CTC numbers showed noteworthy disparities between patients with responding/stable disease in comparison to those with untreated/progressive disease (Median of 2.7 versus 0). When CTCs were present, biomarker analyses of the four markers human epidermal growth factor receptor 2 (HER2)/programmed death-ligand 1 (PD-L1)/Kiel 67 (Ki-67)/epidermal growth factor receptor (EGFR) was feasible. Single cell sequencing confirmed the tumor of origin., Conclusion: Our study is one of the first prospective real-time studies evaluating CTCs in patients with GI malignancies. While ctDNA-based analyses are more common in clinical trials and practice, CTC analysis provides complementary information from a liquid biopsy perspective that is of value and worthy of continued research., Competing Interests: Author PK reports grants paid to the institution by Merck, Agenus Bio, Novartis, Advanced Accelerator Applications, Tersera, and Boston Scientific; a consultancy and advisory board relationship with Elicio scientific advisory board member/shares/stock ownership; consultancy/advisory board fees from Guardant Health, Natera, Foundation Medicine, Illumina, BostonGene, Merck/MSD Oncology, Tempus, Bayer, Lilly, Delcath Systems, IPBA, QED Therapeutics, Boston Healthcare Associates, Servier, Taiho Oncology, Exact Sciences, Daiichi Sankyo/AstraZeneca, Eisai, Saga Diagnostics, Neogenomics, Do More Diagnostics AS, and Seattle Genetics; consulting fees paid to the institution by Taiho Pharmaceutical and Ipsen; receiving travel support from AstraZeneca for presentation of an investigator-initiated trial. Authors LC, AR, and TG are employees of RareCyte. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Malkawi, Lutfi, Afghan, Shah, Costandy, Ramirez, George, Toor, Salem and Kasi.)

Exonuclease domain mutation (EDM) in polymerase epsilon ( POLE )-mutated colorectal cancer patients is characterized by specific clinical features and a very high tumor mutation burden (TMB). The therapeutic effectiveness of immune checkpoint inhibitors (ICIs) for the treatment of colorectal cancer in patients with POLE mutations is poorly defined. Our case represents a young-onset colon cancer patient who has had a continued response to programmed cell death protein 1 (PD1) blockade alongside clearance of circulating tumor DNA (ctDNA) using a tumor-informed approach. Utilizing ctDNA kinetics to assess minimal residual disease (MRD) in the context of colorectal cancer is a very important topic. Furthermore, utilizing ctDNA kinetics in response to immunotherapy is something that is relevant to all tumor types undergoing immunotherapy. Recently, several landmark articles have proposed this as a promising approach. There is, however, limited information in the literature showing the feasibility of such an approach. Our case report is going to be of value, both from a scientific as well as a clinical standpoint. This is particularly relevant given the rise of colorectal cancers in young individuals., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2023, Lutfi et al.)

A 43-year-old woman presented with recurrent metastatic colon cancer with metastases to the peritoneum after having initially been diagnosed with stage IIB colon cancer and deferring adjuvant chemotherapy. Circulating tumor DNA (ctDNA)-based liquid biopsy testing revealed microsatellite instability-high (MSI-H) status, which was also confirmed on tissue testing. This patient then underwent four cycles of pembrolizumab and two cycles of ipilimumab and nivolumab (CTLA-4 rescue) with, unfortunately, progression of the disease. The patient was subsequently treated with larotrectinib, given the findings of TRK fusion-positive cancer on next-generation sequencing (NGS), and she was able to undergo curative surgery two months later that showed complete pathologic response. She continues to have no evidence of disease years later as well as no detectable ctDNA on NGS as well as tumor-informed minimal residual disease platforms. This case represents a marked and durable response to larotrectinib in a patient with deficiency in mismatch repair/MSI-H metastatic colorectal cancer harboring an NTRK  fusion, bringing to light the potential for use of larotrectinib in earlier treatment lines in patients, and/or choice of targeted therapy versus immunotherapy in this patient subset., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2022, Kasi et al.)

The recent development in linear accelerator control systems, named volumetric-modulated arc therapy (VMAT), has generated significant interest in arc-based intensity-modulated radiation therapy (IMRT). The VMAT delivery technique features simultaneous changes in dose rate, gantry angle and gantry rotation speed as well as multi-leaf collimator (MLC) leaf positions while radiation is on. In this paper, we describe a generalized VMAT planning tool that is designed to take full advantage of the capabilities of the new linac control systems. The algorithm incorporates all of the MLC delivery constraints such as restrictions on MLC leaf interdigitation and the MLC leaf velocity constraints. A key feature of the algorithm is that it is able to plan for both single- and multiple-arc deliveries. Compared to conventional step-and-shoot IMRT plans, our VMAT plans created using this tool can achieve similar or better plan quality with less MU and better delivery efficiency. The accuracy of the obtained VMAT plans is also demonstrated through plan verifications performed on an Elekta Synergy linear accelerator equipped with a conventional MLC of 1 cm leaf width using a PreciseBeam VMAT linac control system.

Purpose: Intensity-modulated arc therapy (IMAT) is an arc-based approach to intensity-modulated radiotherapy (IMRT) that can be delivered on a conventional linear accelerator using a conventional multileaf collimator. In a previous work, we demonstrated that our arc-sequencing algorithm can produce highly conformal IMAT plans. Through plan comparisons, we explored the ability of IMAT to serve as an alternative to helical tomotherapy., Methods and Materials: The IMAT plans were created for 10 patients previously treated with helical tomotherapy. Treatment plan comparisons, according to the target dose coverage and critical structure sparing, were performed to determine whether similar plan quality could be achieved using IMAT., Results: In 8 of 10 patient cases, IMAT was able to provide plan quality comparable to that of helical tomotherapy. In 2 of these 8 cases, the use of non-axial coplanar or non-coplanar arcs in IMAT planning led to significant improvements in normal tissue sparing. The remaining 2 cases posed particular dosimetric challenges. In 1 case, the target was immediately adjacent to a spinal cord that had received previous irradiation. The second case involved multiple target volumes and multiple prescription levels. Both IMAT and tomotherapy were able to produce clinically acceptable plans. Tomotherapy, however, provided a more uniform target dose and improved critical structure sparing., Conclusions: For most cases, IMAT can provide plan qualities comparable to that of helical tomotherapy. For some intracranial tumors, IMAT's ability to deliver non-coplanar arcs led to significant dosimetric improvements. Helical tomotherapy, however, can provide improved dosimetric results in the most complex cases.

Intensity modulated arc therapy (IMAT) is an intensity modulated radiation therapy delivery technique originally proposed as an alternative to tomotherapy. IMAT uses a series of overlapping arcs to deliver optimized intensity patterns from each beam direction. The full potential of IMAT has gone largely unrealized due in part to a lack of robust and commercially available inverse planning tools. To address this, we have implemented an IMAT arc-sequencing algorithm that translates optimized intensity maps into deliverable IMAT plans. The sequencing algorithm uses simulated annealing to simultaneously optimize the aperture shapes and weights throughout each arc. The sequencer enforces the delivery constraints while minimizing the discrepancies between the optimized and sequenced intensity maps. The performance of the algorithm has been tested for ten patient cases (3 prostate, 3 brain, 2 head-and-neck, 1 lung, and 1 pancreas). Seven coplanar IMAT plans were created using an average of 4.6 arcs and 685 monitor units. Additionally, three noncoplanar plans were created using an average of 16 arcs and 498 monitor units. The results demonstrate that the arc sequencer can provide efficient and highly conformal IMAT plans. An average sequencing time of approximately 20 min was observed.

Using direct aperture optimization, we have developed an inverse planning approach that is capable of producing efficient intensity modulated radiotherapy (IMRT) treatment plans that can be delivered without a multileaf collimator. This "jaws-only" approach to IMRT uses a series of rectangular field shapes to achieve a high degree of intensity modulation from each beam direction. Direct aperture optimization is used to directly optimize the jaw positions and the relative weights assigned to each aperture. Because the constraints imposed by the jaws are incorporated into the optimization, the need for leaf sequencing is eliminated. Results are shown for five patient cases covering three treatment sites: pancreas, breast, and prostate. For these cases, between 15 and 20 jaws-only apertures were required per beam direction in order to obtain conformal IMRT treatment plans. Each plan was delivered to a phantom, and absolute and relative dose measurements were recorded. The typical treatment time to deliver these plans was 18 min. The jaws-only approach provides an additional IMRT delivery option for clinics without a multileaf collimator.