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Patient recruitment is challenging for clinical trials. We introduce TrialGPT, an end-to-end framework for zero-shot patient-to-trial matching with large language models. TrialGPT comprises three modules: it first performs large-scale filtering to retrieve candidate trials (TrialGPT-Retrieval); then predicts criterion-level patient eligibility (TrialGPT-Matching); and finally generates trial-level scores (TrialGPT-Ranking). We evaluate TrialGPT on three cohorts of 183 synthetic patients with over 75,000 trial annotations. TrialGPT-Retrieval can recall over 90% of relevant trials using less than 6% of the initial collection. Manual evaluations on 1015 patient-criterion pairs show that TrialGPT-Matching achieves an accuracy of 87.3% with faithful explanations, close to the expert performance. The TrialGPT-Ranking scores are highly correlated with human judgments and outperform the best-competing models by 43.8% in ranking and excluding trials. Furthermore, our user study reveals that TrialGPT can reduce the screening time by 42.6% in patient recruitment. Overall, these results have demonstrated promising opportunities for patient-to-trial matching with TrialGPT., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Somatostatin receptor (SSR) targeting radiotracer 68 Ga-DOTATATE is used for Positron Emission Tomography (PET)/Computed Tomography (CT) imaging to assess patients with Pheochromocytoma and paraganglioma (PPGL), rare types of Neuroendocrine tumor (NET) which can metastasize thereby becoming difficult to quantify. The goal of this study is to develop an artificial intelligence (AI) model for automated lesion segmentation on whole-body 3D DOTATATE-PET/CT and to automate the tumor burden calculation. 132 68 Ga-DOTATATE PET/CT scans from 38 patients with metastatic and inoperable PPGL, were split into 70, and 62 scans, from 20, and 18 patients for training, and test sets, respectively. The training set was further divided into patient-stratified 5 folds for cross-validation. 3D-full resolution nnUNet configuration was trained with 5-fold cross-validation. The model's detection performance was evaluated at both scan and lesion levels for the PPGL test set and two other clinical cohorts with NET (n = 9) and olfactory neuroblastoma (ONB, n = 5). Additionally, quantitative statistical analysis of PET parameters including SUVmax, total lesion uptake (TLU), and total tumor volume (TTV), was conducted., Results: The nnUNet AI model achieved an average 5-fold validation dice similarity coefficient of 0.84 at the scan level. The model achieved dice similarity coefficients (DSC) of 0.88, 0.6, and 0.67 at the scan level, the sensitivity of 86%, 61.13%, and 61.64%, and a positive predictive value of 89%, 74%, and 86.54% at the lesion level for the PPGL test, NET and ONB cohorts, respectively. For PPGL cohorts, smaller lesions with low uptake were missed by the AI model (p < 0.001). Anatomical region-based failure analysis showed most of the false negative and false positive lesions within the liver for all the cohorts, mainly due to the high physiologic liver background activity and image noise on 68 Ga- DOTATATE PET scans., Conclusions: The developed deep learning-based AI model showed reliable performance for automated segmentation of metastatic PPGL lesions on whole-body 68 Ga-DOTATATE-PET/CT images, which may be beneficial for tumor burden estimation for objective evaluation during therapy follow-up. https://www., Clinicaltrials: gov/study/NCT03206060 , https://www., Clinicaltrials: gov/study/NCT04086485 , https://www., Clinicaltrials: gov/study/NCT05012098 ., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: We described participant demographics for National Cancer Institute (NCI) clinical trials at the clinical center (NCI-CC participants) of the National Institutes of Health to identify enrollment disparities., Methods: We analyzed NCI-CC data from 2005 to 2020, calculated enrollment fractions, compared with the US cancer population represented by the Surveillance, Epidemiology, and End Results cancer incidence data (2018) and the Cancer in North America database (2018), and compared further with clinical trial disparities data from the NCI Community Oncology Research Program and National Clinical Trials Network (2005-2019), and from ClinicalTrials.gov (2003-2016)., Results: NCI-CC (38 531 participants) had higher enrollment fractions for older adults (8.5%), male (5.6%), non-Hispanic (5.1%), and Black or African American (5.3%) participants; lower women proportion across race and ethnicity; and fewer female sex-specific cancer (6.8%) than male sex-specific cancer (11.7%) participants. NCI-CC had lower median age than Surveillance, Epidemiology, and End Results (54.0 vs 65.4); more Black or African American participants (12.0% vs 11.1%); and fewer women (41.7% vs 49.5%), White (76.1% vs 80.5%), Asian or Pacific Islander (4.6% vs 6.0%), American Indian or Alaska Native (0.3% vs 0.5%), and Hispanic participants (7.1% vs 13%). NCI-CC had more Black or African American and Asian or Pacific Islander participants; fewer Hispanic participants than the NCI Community Oncology Research Program and National Clinical Trials Network; more Black or African American and Hispanic participants; fewer Asian or Pacific Islander participants than ClinicalTrials.gov data. Improvement was noted for NCI-CC (older adults, Black or African American, Asian or Pacific Islander, Hispanic participants)., Conclusion: We found lower representation of older adults, women, Asian or Pacific Islander, American Indian or Alaska Native, and Hispanic participants vs the US cancer population and higher representation of Black or African American vs US cancer population and oncology clinical trials. Multifaceted efforts are underway to reduce disparities in cancer clinical trials at the NCI-CC., (Published by Oxford University Press 2024.)

Background: Olfactory neuroblastoma is a rare malignancy of the anterior skull base typically treated with surgery and adjuvant radiation. Although outcomes are fair for low-grade disease, patients with high-grade, recurrent, or metastatic disease oftentimes respond poorly to standard treatment methods. We hypothesized that an in-depth evaluation of the olfactory neuroblastoma tumor immune microenvironment would identify mechanisms of immune evasion in high-grade olfactory neuroblastoma as well as rational targetable mechanisms for future translational immunotherapeutic approaches., Methods: Multispectral immunofluorescence and RNAScope evaluation of the tumor immune microenvironment was performed on forty-seven clinically annotated olfactory neuroblastoma samples. A retrospective chart review was performed and clinical correlations assessed., Results: A significant T cell infiltration was noted in olfactory neuroblastoma samples with a stromal predilection, presence of myeloid-derived suppressor cells, and sparse natural killer cells. A striking decrease was observed in MHC-I expression in high-grade olfactory neuroblastoma compared to low-grade disease, representing a mechanism of immune evasion in high-grade disease. Mechanistically, the immune effector stromal predilection appears driven by low tumor cell MHC class II (HLA-DR), CXCL9, and CXCL10 expression as those tumors with increased tumor cell expression of each of these mediators correlated with significant increases in T cell infiltration., Conclusion: These data suggest that immunotherapeutic strategies that augment tumor cell expression of MHC class II, CXCL9, and CXCL10 may improve parenchymal trafficking of immune effector cells in olfactory neuroblastoma and augment immunotherapeutic responses., (© 2024. The Author(s).)

Background: Artificial intelligence is increasingly being applied to many workflows. Large language models (LLMs) are publicly accessible platforms trained to understand, interact with, and produce human-readable text; their ability to deliver relevant and reliable information is also of particular interest for the health care providers and the patients. Hematopoietic stem cell transplantation (HSCT) is a complex medical field requiring extensive knowledge, background, and training to practice successfully and can be challenging for the nonspecialist audience to comprehend., Objective: We aimed to test the applicability of 3 prominent LLMs, namely ChatGPT-3.5 (OpenAI), ChatGPT-4 (OpenAI), and Bard (Google AI), in guiding nonspecialist health care professionals and advising patients seeking information regarding HSCT., Methods: We submitted 72 open-ended HSCT-related questions of variable difficulty to the LLMs and rated their responses based on consistency-defined as replicability of the response-response veracity, language comprehensibility, specificity to the topic, and the presence of hallucinations. We then rechallenged the 2 best performing chatbots by resubmitting the most difficult questions and prompting to respond as if communicating with either a health care professional or a patient and to provide verifiable sources of information. Responses were then rerated with the additional criterion of language appropriateness, defined as language adaptation for the intended audience., Results: ChatGPT-4 outperformed both ChatGPT-3.5 and Bard in terms of response consistency (66/72, 92%; 54/72, 75%; and 63/69, 91%, respectively; P=.007), response veracity (58/66, 88%; 40/54, 74%; and 16/63, 25%, respectively; P<.001), and specificity to the topic (60/66, 91%; 43/54, 80%; and 27/63, 43%, respectively; P<.001). Both ChatGPT-4 and ChatGPT-3.5 outperformed Bard in terms of language comprehensibility (64/66, 97%; 53/54, 98%; and 52/63, 83%, respectively; P=.002). All displayed episodes of hallucinations. ChatGPT-3.5 and ChatGPT-4 were then rechallenged with a prompt to adapt their language to the audience and to provide source of information, and responses were rated. ChatGPT-3.5 showed better ability to adapt its language to nonmedical audience than ChatGPT-4 (17/21, 81% and 10/22, 46%, respectively; P=.03); however, both failed to consistently provide correct and up-to-date information resources, reporting either out-of-date materials, incorrect URLs, or unfocused references, making their output not verifiable by the reader., Conclusions: In conclusion, despite LLMs' potential capability in confronting challenging medical topics such as HSCT, the presence of mistakes and lack of clear references make them not yet appropriate for routine, unsupervised clinical use, or patient counseling. Implementation of LLMs' ability to access and to reference current and updated websites and research papers, as well as development of LLMs trained in specialized domain knowledge data sets, may offer potential solutions for their future clinical application., (©Elisabetta Xue, Dara Bracken-Clarke, Giovanni Maria Iannantuono, Hyoyoung Choo-Wosoba, James L Gulley, Charalampos S Floudas. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 17.05.2024.)

Background: The capability of large language models (LLMs) to understand and generate human-readable text has prompted the investigation of their potential as educational and management tools for patients with cancer and healthcare providers., Materials and Methods: We conducted a cross-sectional study aimed at evaluating the ability of ChatGPT-4, ChatGPT-3.5, and Google Bard to answer questions related to 4 domains of immuno-oncology (Mechanisms, Indications, Toxicities, and Prognosis). We generated 60 open-ended questions (15 for each section). Questions were manually submitted to LLMs, and responses were collected on June 30, 2023. Two reviewers evaluated the answers independently., Results: ChatGPT-4 and ChatGPT-3.5 answered all questions, whereas Google Bard answered only 53.3% (P < .0001). The number of questions with reproducible answers was higher for ChatGPT-4 (95%) and ChatGPT3.5 (88.3%) than for Google Bard (50%) (P < .0001). In terms of accuracy, the number of answers deemed fully correct were 75.4%, 58.5%, and 43.8% for ChatGPT-4, ChatGPT-3.5, and Google Bard, respectively (P = .03). Furthermore, the number of responses deemed highly relevant was 71.9%, 77.4%, and 43.8% for ChatGPT-4, ChatGPT-3.5, and Google Bard, respectively (P = .04). Regarding readability, the number of highly readable was higher for ChatGPT-4 and ChatGPT-3.5 (98.1%) and (100%) compared to Google Bard (87.5%) (P = .02)., Conclusion: ChatGPT-4 and ChatGPT-3.5 are potentially powerful tools in immuno-oncology, whereas Google Bard demonstrated relatively poorer performance. However, the risk of inaccuracy or incompleteness in the responses was evident in all 3 LLMs, highlighting the importance of expert-driven verification of the outputs returned by these technologies., (Published by Oxford University Press 2024.)

Context: Spatial transcriptomic (ST) analysis of tumors provides a novel approach to studying gene expression along with the localization of tumor cells in their environment to uncover spatial interactions., Design: We present ST analysis of corticotroph pituitary neuroendocrine tumors (PitNETs) from formalin-fixed, paraffin-embedded tissues. ST data were compared to immunohistochemistry results. Gene expression profiles were reviewed for cluster annotations, and differentially expressed genes were used for pathway analysis., Results: Seven tumors were used for ST analysis. In situ annotation of tumor tissue was inferred from the gene expression profiles and was in concordance with the annotation made by a pathologist. Furthermore, relative gene expression in the tumor corresponded to common protein staining used in the evaluation of PitNETs, such as reticulin and Ki-67 index. Finally, we identified intratumor heterogeneity; clusters within the same tumor may present with different transcriptomic profiles, unveiling potential intratumor cell variability., Conclusion: Together, our results provide the first attempt to clarify the spatial cell profile in PitNETs., (Published by Oxford University Press on behalf of the Endocrine Society 2024.)

Background: De-escalation strategies for newly-diagnosed p16-positive oropharyngeal squamous cell carcinoma (p16+ OPSCC), aim to reduce treatment-related morbidity without compromising disease control. One strategy is neoadjuvant cisplatin and docetaxel chemotherapy (NAC + S) before transoral robotic surgery, with pathology-based risk-adapted adjuvant treatment., Methods: We examined the recurrence-free survival (RFS) for patients who received NAC + S., Results: Comparing outcomes in 103 patients between 2008 and 2023, 92% avoided adjuvant treatment and showed significantly higher 2-year recurrence-free survival (RFS) compared to those with adjuvant treatment (95.9% vs. 43.8%, p = 0.0049) CONCLUSION: Our findings suggest that pathology-based risk-adapted omission of adjuvant treatment following NAC + S does not appear to elevate recurrence risk and that NAC may identify patients with favorable tumor biology, yielding a 2-year RFS probability exceeding 95% without adjuvant treatment. Further, the study identifies a patient subset experiencing disease recurrence despite triple modality therapy. Despite limitations, including a retrospective design and modest sample size, the data advocate for controlled NAC + S studies., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Purpose: Non-small-cell lung cancer (NSCLC) with STK11 mut has inferior outcomes to immune checkpoint inhibitors (ICIs). Using multiomics, we evaluated whether a subtype of STK11 mut NSCLC with a uniquely inflamed tumor immune microenvironment (TIME) harboring TP53 comutations could have favorable outcomes to ICIs., Patients and Methods: NSCLC tumors (N = 16,896) were analyzed by next-generation sequencing (DNA-Seq/592 genes). A subset (n = 5,034) underwent gene expression profiling (RNA-Seq/whole transcriptome). Exome-level neoantigen load for STK11 mut NSCLC was obtained from published pan-immune analysis. Tumor immune cell content was obtained from transcriptome profiles using the microenvironment cell population (MCP) counter. ICI data from POPLAR/OAK (n = 34) and the study by Rizvi et al (n = 49) were used to model progression-free survival (PFS), and a separate ICI-treated cohort (n = 53) from Dana-Farber Cancer Institute (DFCI) was used to assess time to treatment failure (TTF) and tumor RECIST response for STK11 mut TP53 mut versus STK11 mut TP53 wt NSCLC., Results: Overall, 12.6% of NSCLC tumors had a STK11 mut with the proportions of tumor mutational burden (TMB)-high (≥10 mut/Mb), PD-L1 ≥50%, and microsatellite instability-high being 38.3%, 11.8%, and 0.72%, respectively. Unsupervised hierarchical clustering of STK11 mut (n = 463) for stimulator of interferon-gamma (STING) pathway genes identified a STING-high cluster, which was significantly enriched in TP53 mut NSCLC ( P < .01). Compared with STK11 mut TP53 wt , tumors with STK11 mut TP53 mut had higher CD8+T cells and natural killer cells ( P < .01), higher TMB ( P < .001) and neoantigen load ( P < .001), and increased expression of MYC and HIF-1A ( P < .01), along with higher expression ( P < .01) of glycolysis/glutamine metabolism genes. Meta-analysis of data from OAK/POPLAR and the study by Rizvi et al showed a trend toward improved PFS in patients with STK11 mut TP53 mut . In the DFCI cohort, compared with the STK11 mut TP53 wt cohort, the STK11 mut TP53 mut tumors had higher objective response rates (42.9% v 16.7%; P = .04) and also had longer TTF (14.5 v 4.5 months, P adj = .054) with ICI., Conclusion: STK11 mut NSCLC with TP53 comutation is a distinct subgroup with an immunologically active TIME and metabolic reprogramming. These properties should be exploited to guide patient selection for novel ICI-based combination approaches.

Introduction: PARP inhibitors (PARPi) are a standard-of-care (SoC) treatment option for patients with metastatic castration-resistant prostate cancer (mCRPC). Several clinical trials have shown the potential of combining PARPi with other anticancer agents. Therefore, we conducted a systematic review and meta-analysis to comprehensively evaluate the efficacy and safety of PARPi in patients with metastatic prostate cancer., Methods: MEDLINE, Cochrane CENTRAL, EMBASE, CINAHL, and Web of Science were searched on March 22nd, 2023, for phase 2 or 3 clinical trials. Efficacy (progression-free survival [PFS], overall survival [OS], PSA decline >50% [PSA50], and objective response rate [ORR]) and safety outcomes were assessed in the included studies., Results: Seventeen clinical trials (PARPi monotherapy [n = 7], PARPi + androgen-receptor signaling inhibitors [ARSI] [n = 6], and PARPi + immune checkpoint inhibitors [ICI] [n = 4]) were included in the quantitative analyses. PARPi monotherapy improved radiographic PFS and OS over SoC in mCRPC patients with alterations in BRCA1 or BRCA2 genes but not in those with alterations in the ATM gene. Higher rates of PSA50 and ORR were reported in participants treated with PARPi + ARSI than in single-agent PARPi or PARPi + ICI. Although the rate of high-grade adverse events was similar across all groups, treatment discontinuation was higher in patients treated with PARPi-based combinations than PARPi monotherapy., Conclusion: The efficacy of PARPi is not uniform across mCRPC patients with alterations in DNA damage repair genes, and optimal patient selection remains a clinical challenge. No unexpected safety signals for this class of agents emerged from this analysis., 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., (Published by Elsevier Ltd.)

The development of large language models (LLMs) is a recent success in the field of generative artificial intelligence (AI). They are computer models able to perform a wide range of natural language processing tasks, including content generation, question answering, or language translation. In recent months, a growing number of studies aimed to assess their potential applications in the field of medicine, including cancer care. In this mini review, we described the present published evidence for using LLMs in oncology. All the available studies assessed ChatGPT, an advanced language model developed by OpenAI, alone or compared to other LLMs, such as Google Bard, Chatsonic, and Perplexity. Although ChatGPT could provide adequate information on the screening or the management of specific solid tumors, it also demonstrated a significant error rate and a tendency toward providing obsolete data. Therefore, an accurate, expert-driven verification process remains mandatory to avoid the potential for misinformation and incorrect evidence. Overall, although this new generative AI-based technology has the potential to revolutionize the field of medicine, including that of cancer care, it will be necessary to develop rules to guide the application of these tools to maximize benefits and minimize risks., Competing Interests: The 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 Iannantuono, Bracken-Clarke, Floudas, Roselli, Gulley and Karzai.)

Background: Pembrolizumab is FDA approved for tumors with tumor mutational burden (TMB) of ≥10 mutations/megabase (mut/Mb). However, the response to immune checkpoint inhibitors (ICI) varies significantly among cancer histologies. We describe the landscape of frameshift mutations (FSs) and evaluated their role as a predictive biomarker to ICI in a clinical cohort of patients., Methods: Comprehensive genomic profiling was performed on a cohort of solid tumor samples examining at least 324 genes. The clinical cohort included patients with metastatic solid malignancies who received ICI monotherapy and had tumor sequencing. Progression-free survival (PFS), overall survival, and objective response rates (ORR) were compared between the groups., Results: We analyzed 246,252 microsatellite stable (MSS) and 4561 samples with microsatellite instability across solid tumors. Histologies were divided into groups according to TMB and FS. MSS distribution: TMB-L (<10 mut/Mb)/FS-A (absent FS) (N=111,065, 45%), TMB-H (≥10 mut/Mb)/FS-A (N=15,313, 6%), TMB-L/FS-P (present ≥1 FS) (N=98,389, 40%) and TMB-H/FS-P (N=21,485, 9%). FSs were predominantly identified in the p53 pathway. In the clinical cohort, 212 patients were included. Groups: TMB-L/FS-A (N=80, 38%), TMB-H/FS-A (N=36, 17%), TMB-L/FS-P (N=57, 27%), TMB-H/FS-P (N=39, 18%). FSs were associated with a higher ORR to ICI, 23.8% vs 12.8% (p=0.02). TMB-L/FS-P had superior median PFS (5.1 months) vs TMB-L/FS-A (3.6 months, p<0.01). The 12-month PFS probability was 34% for TMB-L/FS-P vs 17.1% for TMB-L/FS-A., Conclusions: FSs are found in 47% of patients with MSS/TMB-L solid tumors in a pan-cancer cohort. FS may complement TMB in predicting immunotherapy responses, particularly for tumors with low TMB., Competing Interests: Competing interests: VF consultant or advisory role Deciphera, Incyte. AM has patent applications related to the use of cytokines to enhance macrophage immunotherapy. ESS and GF are employees of Foundation Medicine and Shareholders in Roche. HPS consultant or advisory role Ipsen, AstraZeneca, ITM, Novartis, TerSera. SP consultant or advisory role IntegrityCE, Dava Oncology. US consultant or advisory role Astellas, Exelixis, Seattle Genetics, Imvax, Sanofi, and AstraZeneca. WP consultant or advisory role Astellas. IG-L consultant or advisory role SOTIO, Kanaph, Jazz, OncXer., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: NHS-IL12 is a first-in-class, recombinant fusion protein composed of the human monoclonal antibody NHS76 (binds exposed DNA/histones at sites of intratumoral necrosis) fused to 2 IL-12 heterodimers. The maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of NHS-IL12 monotherapy given subcutaneously (SC) every 4 weeks was previously reported. The study was expanded to include a high-exposure cohort with NHS-IL12 SC every 2 weeks (q2w)., Methods: This single-arm, phase I trial evaluated NHS-IL12 12 µg/kg SC q2w or 16.8µg/kg SC q2w in patients with metastatic solid tumors. The primary endpoint was safety., Results: Using a 3+3 design, 13 patients with advanced cancer were enrolled and 12 were dose-limiting toxicity (DLT) evaluable. There was 1 DLT (Grade 3 aspartate transaminase/alanine transaminase [AST/ALT] elevation). Other grade 3 toxicities included: flu-like symptoms 1/13 (8%), decreased absolute lymphocyte count (ALC) 1/13 (8%), decreased white blood cell count (WBC) 1/13 (8%), but most adverse events reported were low grade and self-limiting grade. Fifty percent of evaluable patients (6/12) experienced stable disease (SD) with 42% (5/12) developing progressive disease (PD) at the first restaging., Conclusion: Biweekly NHS-IL12 was well tolerated in this small phase I study. Additional studies incorporating NHS-IL12 with other immunomodulating agents are underway. (ClinicalTrials.gov Identifier: NCT01417546)., (Published by Oxford University Press 2023.)

Sinonasal malignancies make up <5% of all head and neck neoplasms, with an incidence of 0.5-1.0 per 100,000. The outcome of these rare malignancies has been poor, whereas significant progress has been made in the management of other cancers. The objective of the current review was to describe the incidence, causes, presentation, diagnosis, treatment, and recent developments of malignancies of the sinonasal tract. The diagnoses covered in this review included sinonasal undifferentiated carcinoma, sinonasal adenocarcinoma, sinonasal squamous cell carcinoma, and esthesioneuroblastoma, which are exclusive to the sinonasal tract. In addition, the authors covered malignances that are likely to be encountered in the sinonasal tract-primary mucosal melanoma, NUT (nuclear protein of the testis) carcinoma, and extranodal natural killer cell/T-cell lymphoma. For the purpose of keeping this review as concise and focused as possible, sarcomas and malignancies that can be classified as salivary gland neoplasms were excluded., (© 2022 The Authors. CA: A Cancer Journal for Clinicians published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Olfactory neuroblastoma (ONB) or esthesioneuroblastoma (ENB) is a rare malignancy of the nasal cavity believed to arise from the olfactory epithelium. The goal of this study was to systematically review the genomics, epigenetics, and cytogenetics of ONB and to understand the potential clinical implications of these studies., Methods: A systematic literature review was performed for articles published before May 2020 using Cochrane, Embase, Pubmed, and Scopus databases. Inclusion criteria included genomics, cytogenetics, and epigenetics studies on ONB. Exclusion criteria included studies not in English or systematic reviews. Articles and abstracts were reviewed by two independent reviewers to reduce bias during article selection and synthesis of results. Of the 36 studies included in this review, 24 were research articles and 12 were abstracts., Results: Although recurrent mutations among ONB tumors are uncommon, alterations in TP53 , DMD , PIK3CA , NF1 , CDKN2A , CDKN2C , CTNNB1 , EGFR , APC , cKIT , cMET , PDGFRA , CDH1 , FH , SMAD4 , FGFR3 and IDH2 genes have been reported in several recent studies. In addition, cytogenetic studies revealed that the landscape of chromosomal aberrations varies widely amongst ONB tumors., Conclusions: The rare character of ONB has limited the sample size available for cytogenetic, genomic, and epigenetic studies and contributes to the limitations of this systematic review. Comprehensive genomic and epigenomic studies with larger cohorts are warranted to validate the initial reports summarized in this review and to identify potential therapeutic targets for ONB., Competing Interests: N. London holds stock in Navigen Pharmaceuticals, was a consultant for Cooltech Inc., and receives research funding from Merck, Inc., none of which are relevant to this study. All other authors declare no conflicts of interest., (© 2021 The Authors. Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC. on behalf of The Triological Society.)

Background: The prognosis of metastatic colorectal cancer (mCRC) is poor. We assessed the feasibility, safety, and efficacy of the anti-programmed cell death 1 fusion protein AMP-224 in combination with low-dose cyclophosphamide and stereotactic body radiation (SBRT) treatment in patients with mCRC refractory to standard chemotherapy., Patients and Methods: Fifteen patients were enrolled. Six received SBRT 8 Gy on day 0 (dose level 1), whereas 9 received 8 Gy on days -2 to day 0. All received cyclophosphamide 200 mg/m 2 intravenously (I.V.) on day 0. On day 1, both groups received AMP-224 10 mg/kg I.V., repeated every 2 weeks for a total of 6 doses. Primary end points were feasibility and safety., Results: Ten (67%) patients completed 6 doses of AMP-224; 5 patients (33%) discontinued treatment because of disease progression. No dose-limiting toxicity was observed; 9 patients (60%) experienced treatment-related adverse events, all Grade 1 or 2. No objective response was noted; 3 patients (20%) had stable disease. Median progression-free survival and overall survival were 2.8 months (95% confidence interval [CI], 1.2-2.8 months) and 6.0 months (95% CI, 2.8-9.6 months), respectively. M2 macrophage polarization was present in the pretreatment tumor biopsy samples, but not post-treatment samples., Conclusion: AMP-224 in combination with SBRT and low-dose cyclophosphamide was well tolerated, however, no significant clinical benefit was observed in patients with mCRC., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Treatment options for patients with advanced biliary tract cancer are limited. Dysregulation of the immune system plays an important role in the pathogenesis of biliary tract cancer (BTC). This study aimed to investigate whether tremelimumab, an anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) inhibitor, could be combined safely with microwave ablation to enhance the effect of anti-CTLA4 treatment in patients with advanced BTC. Patients were enrolled to receive monthly tremelimumab (10 mg/kg, intravenously) for six doses, followed by infusions every 3 months until off-treatment criteria were met. Thirty-six days after the first tremelimumab dose, patients underwent subtotal microwave ablation. Interval imaging studies were performed every 8 weeks. Adverse events (AEs) were noted and managed. Tumor and peripheral blood samples were collected to perform immune monitoring and whole-exome sequencing (WES). Twenty patients with refractory BTC were enrolled (median age, 56.5 years). No dose-limiting toxicities were encountered. The common treatment-related AEs included lymphopenia, diarrhea, and elevated transaminases. Among 16 patients evaluable for efficacy analysis, 2 (12.5%) patients achieved a confirmed partial response (lasting for 8.0 and 18.1 months, respectively) and 5 patients (31.3%) achieved stable disease. Median progression free survival (PFS) and overall survival (OS) were 3.4 months (95% confidence interval [CI], 2.5-5.2) and 6.0 months (95% CI, 3.8-8.8), respectively. Peripheral blood immune cell subset profiling showed increased circulating activated human leukocyte antigen, DR isotype ([HLA-DR] positive) CD8 + T cells. T-cell receptor (TCR)β screening showed tremelimumab expanded TCR repertoire, but not reaching statistical significance (P = 0.057). Conclusion: Tremelimumab in combination with tumor ablation is a potential treatment strategy for patients with advanced BTC. Increased circulating activated CD8 + T cells and TCR repertoire expansion induced by tremelimumab may contribute to treatment benefit., (Published 2018. This article is a U.S. Government work and is in the public domain in the USA.)

Hepatocellular carcinoma (HCC) has an increasing incidence and dismal prognosis, with few systemic treatments approved, including several small molecule tyrosine kinase inhibitors. The application of immune checkpoint inhibitors (ICIs) to HCC has resulted in durable activity, and further evaluation is ongoing. In this review, we discuss the immunologic principles and the mechanism of action of the ICIs and present the relevant clinical data. Furthermore, we provide an overview of the current and emerging immunotherapeutic approaches for HCC, such as combination treatments, vaccines, and cellular therapies.

Background: Malignant pleural effusion (MPE) is a common cause of quality of life deterioration in patients with advanced cancer. Management options include chemical pleurodesis with a sclerosing agent such as doxycycline or talc powder, surgery, and also the placement of tunneled indwelling pleural catheters (IPCs). Two different IPC types are mostly used in the USA., Methods: We conducted a single-center retrospective study with the objective to compare the efficacy and safety profiles of two IPC systems. Patients with a diagnosis of malignancy, who received IPCs by the interventional radiology department of our hospital from January 2013 to March 2015, were identified in the local database and a chart review was performed to record characteristics and outcomes. Patients without a diagnosis of malignancy or with pleural effusions of cardiac origin were excluded from the study., Results: We identified 27 patients with a median age of 59.0 years. Eighty patients received Aspira catheter while nine patients received PleurX catheter, and seven patients achieved spontaneous pleurodesis. The median length of stay (LOS) was 9 days for the Aspira group (AG), as compared to 13 days for the PleurX group (PG) (overall median LOS was 10 days; range, 2-62 days). The rate of catheter-related complications (pain, obstruction, loculations, infection, hemorrhage) was 39% (seven patients) for the AG and 33% (three patients) for the PG (overall ten patients, 37%)., Conclusions: In our study, outcomes and safety were similar for patients receiving either type of IPC, Aspira or PleurX., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Purpose: In the U.S., Kaposi sarcoma (KS) occurs mostly in HIV-infected patients, who are also at increased risk of developing secondary cancers. The trends in secondary cancer risk are unclear in the HAART era., Methods: We extracted data from the SEER database on patients diagnosed with KS between 1981 and 2013, stratified into the pre-HAART (1981-1995) and HAART (1996-2013) eras. We compared the risk of secondary cancer in KS patients and the general population, and estimated the absolute risk., Results: We followed 13,535 KS patients for 49,813 person-years, during which 1,041 secondary cancers were diagnosed: 774 in the pre-HAART and 267 in the HAART era. In the pre-HAART era, non-Hodgkin's lymphoma (NHL) and anal carcinomas were the most common secondary cancers. The standard incidence ratio of secondary cancers decreased from 3.44 (pre-HAART era) to 1.94 (HAART era) in patients aged <70 years. The absolute excess risk decreased from 178 to 68 cases per 10,000 person-years. The risk of NHL decreased, while the risk of anal carcinoma did not change significantly. The risk of lung cancer was lower in KS patients than in the general population. The absolute risk of non-AIDS-defining cancers increased fourfold in the HAART era., Conclusions: The absolute risk of non-AIDS-defining secondary cancers has increased in KS patients in the HAART era. However, the overall relative risk of secondary cancers has decreased, mainly due to a significant decrease in the risk of NHL.

The indications of immune checkpoint inhibitors (ICIs) are set to rise further with the approval of newer agent like atezolimumab for use in patients with advanced stage urothelial carcinoma. More frequent use of ICIs has improved our understanding of their unique side effects, which are known as immune-related adverse events (irAEs). The spectrum of irAEs has expanded beyond more common manifestations such as dermatological, gastrointestinal and endocrine effects to rarer presentations involving nervous, hematopoietic and urinary systems. There are new safety data accumulating on ICIs in patients with previously diagnosed autoimmune conditions. It is challenging for clinicians to continuously update their working knowledge to diagnose and manage these events successfully. If diagnosed timely, the majority of events are completely reversible, and temporary immunosuppression with glucocorticoids, infliximab or other agents is warranted only in the most severe grade illnesses. The same principles of management will possibly apply as newer anti- cytotoxic T lymphocytes-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1/PD-L1) antibodies are introduced. The current focus of research is for prophylaxis and for biomarkers to predict the onset of these toxicities. In this review we summarize the irAEs of ICIs and emphasize their growing spectrum and their management algorithms, to update oncology practitioners.

Targeted therapies such as the BRAF inhibitors vemurafenib and dabrafenib are highly effective in the treatment of systemic metastatic melanoma and have been shown to be effective in controlling solid brain metastases; however, limited data exist on their activity in leptomeningeal spread. Here, we present a case of a 60-year-old woman who developed leptomeningeal carcinomatosis from melanoma after resection and stereotactic radiotherapy of melanoma brain metastases, with poor performance status, who received vemurafenib as first-line treatment, resulting in significant clinical and imaging response as well as prolonged survival.

Background: Identifying genetic interactions in data obtained from genome-wide association studies (GWASs) can help in understanding the genetic basis of complex diseases. The large number of single nucleotide polymorphisms (SNPs) in GWASs however makes the identification of genetic interactions computationally challenging. We developed the Bayesian Combinatorial Method (BCM) that can identify pairs of SNPs that in combination have high statistical association with disease., Results: We applied BCM to two late-onset Alzheimer's disease (LOAD) GWAS datasets to identify SNPs that interact with known Alzheimer associated SNPs. We also compared BCM with logistic regression that is implemented in PLINK. Gene Ontology analysis of genes from the top 200 dataset SNPs for both GWAS datasets showed overrepresentation of LOAD-related terms. Four genes were common to both datasets: APOE and APOC1, which have well established associations with LOAD, and CAMK1D and FBXL13, not previously linked to LOAD but having evidence of involvement in LOAD. Supporting evidence was also found for additional genes from the top 30 dataset SNPs., Conclusion: BCM performed well in identifying several SNPs having evidence of involvement in the pathogenesis of LOAD that would not have been identified by univariate analysis due to small main effect. These results provide support for applying BCM to identify potential genetic variants such as SNPs from high dimensional GWAS datasets.

Technology is constantly evolving, necessitating the development of workflows for efficient use of high-dimensional data. We develop and test an empirical workflow for predictive modeling based on single nucleotide polymorphisms (SNP) from genome-wide association study (GWAS) datasets. To this aim, we use as a case study SNP-based prediction of survival for non-small cell lung cancer (NSCLC) with a Bayesian rule learner system (BRL+). Lung cancer is a leading cause of mortality. Standard treatment for early stages of NSCLC is surgery. Adjuvant chemotherapy would be beneficial for patients with early recurrence; consequently, we need models capable of such prediction. This workflow outlines the challenges involved in processing GWAS datasets from one popular platform (Affymetrix®), from the results files of the hybridization experiment to the model construction. Our results show that our workflow is feasible and efficient for processing such data while also yielding SNP based models with high predictive accuracy over cross validation.

Sarcoidosis is a systemic disease which affects many organs, including the heart. Cardiac sarcoidosis has a reported incidence of about 25 % and carries a poor prognosis. It can occur in the form of conduction abnormalities, pericardial and valvular heart disease, congestive heart failure, arrhythmias and sudden cardiac death. The diagnosis of cardiac sarcoidosis is difficult, requiring a high index of suspicion and the use of electrocardiography, echocardiography, nuclear medicine imaging, myocardial biopsy and magnetic resonance imaging. Corticosteroids have been the cornerstone of treatment of cardiac sarcoidosis, but other immunosuppressives have also been used, along with standard heart failure therapy, antiarrhythmic medications, pacemakers and implantable defibrillators. Cardiac transplantation is an option for patients who do not respond to medical treatment. We briefly review the current armamentarium for the diagnosis and treatment of cardiac sarcoidosis., (Georg Thieme Verlag KG Stuttgart New York.)

Background: Systemic sarcoidosis (Sar) is a granulomatous disorder involving multiple organs. Widespread vascular involvement and microangiopathy are common in patients with Sar. In addition, subclinical cardiac involvement is increasingly recognized in patients with Sar. However, data on the effect of Sar on the elastic properties of the arteries and myocardial performance are limited. In this study we looked for differences in aortic distensibility (AoD) which is an index of aortic elasticity, and myocardial performance of the ventricles, between patients with Sar and healthy subjects. In addition, we examined potential associations between AoD and clinical, respiratory and echocardiographic findings in patients with Sar., Materials and Methods: A total of 83 consecutive patients (26 male/57 female, mean age 51.1 +/- 13.3 years) with Sar, without cardiac symptoms, were included. All patients underwent echocardiographic and respiratory evaluation including lung function tests. Additionally, 83 age- and sex-matched healthy subjects served as controls. AoD was determined non-invasively by ultrasonography., Results: AoD was lower in the Sar compared to the control group (2.29 +/- 0.26 vs. 2.45 +/- 0.20 .10(-) (6) cm2 x dyn(-1), P < 0.01), while left ventricular mass (LVM) was higher in the Sar group (221.3 +/- 50.2 vs. 195.6 +/- 31.3 g, P = 0.007). Furthermore, myocardial performance of both ventricles was impaired in the Sar group. Multivariate linear regression analysis in the total sample population demonstrated a significant and independent inverse relationship between AoD and the presence of Sar (P < 0.001). The same analysis in the Sar patients showed that AoD was associated significantly and independently with the stage of Sar, age, systolic blood pressure, LVM and myocardial performance of both ventricles. No significant relationship was found between AoD and disease duration, pulmonary artery pressure or lung function tests., Conclusions: Presence and severity of Sar are associated with reduced aortic distensibility, irrespective of the disease duration, pulmonary artery pressure and lung function. In addition, patients with Sar have increased LVM and impaired myocardial performance.

An acquired diffuse elastic tissue defect that resembles inherited pseudoxanthoma elasticum (PXE) has been noticed with a significant age-related frequency in hemoglobin disorders, especially beta-thalassemia and has been held responsible for a number of complications observed in these cases, some of which are quite severe. We report here two patients with beta-thalassemia intermedia, who presented with severe visual acuity impairment associated with angioid streaks, the typical ocular manifestation of PXE.