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in category oncology

644 results found. For more information, click each entry to expand.

21: Spatial proteomic characterization of HER2-positive breast tumors through neoadjuvant therapy predicts response
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Posted 25 Sep 2020

Spatial proteomic characterization of HER2-positive breast tumors through neoadjuvant therapy predicts response
1,438 downloads medRxiv oncology

Katherine L. McNamara, Jennifer L. Caswell-Jin, Rohan Joshi, Zhicheng Ma, Eran Kotler, Gregory R Bean, Michelle Kriner, Zoey Zhou, Margaret Hoang, Joseph Beechem, Jason Zoeller, Michael F Press, Dennis J. Slamon, Sara A. Hurvitz, Christina Curtis

Addition of HER2-targeted agents to neoadjuvant chemotherapy has dramatically improved pathological complete response (pCR) rates in early stage Human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Still, up to 50% of patients have residual disease following treatment and biomarkers predictive of response are urgently needed. We performed spatial proteomic characterization using NanoString GeoMX Digital Spatial Profiling (DSP) of 122 samples from 57 HER2-positive breast tumors from the neoadjuvant TRIO-US B07 clinical trial (discovery cohort, n=28; validation cohort, n=29) sampled pre-treatment, after 14-21 days of HER2-targeted therapy and at surgery. In situ quantification of 40 tumor and immune proteins across multiple pancytokeratin-enriched regions per sample revealed that treatment results in decreased HER2 signaling and increased immune infiltration after several weeks of therapy. These changes were more dramatic in tumors that ultimately undergo pCR, and a classifier trained to predict pCR using on-treatment and pre-treatment DSP protein levels had a cross-validation mean Area Under the Receiver Operating Characteristics (AUROC) of 0.733 in the discovery cohort and validated in an independent cohort (AUROC = 0.725). Thus, we demonstrate robust stratification of sensitive tumors early during neoadjuvant HER2-targeted therapy using a multiplex spatial proteomic biomarker with implications for tailoring subsequent therapy.

22: Single cell transcriptomic analysis of diffuse large B cells in cerebrospinal fluid of central nervous system lymphoma
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Posted 22 Apr 2020

Single cell transcriptomic analysis of diffuse large B cells in cerebrospinal fluid of central nervous system lymphoma
1,351 downloads medRxiv oncology

Haoyu Ruan, Zhe Wang, Yue Zhai, Ying Xu, Linyu Pi, Jihong Zheng, Yihang Zhou, Cong Zhang, RuoFan Huang, Kun Chen, Xiangyu Li, Weizhe Ma, Zhiyuan Wu, Jie Shen, Xuan Deng, Chao Zhang, Ming Guan

Diffuse large B-cell lymphoma (DLBCL) is the predominant type of central nervous system lymphoma (CNSL) including primary CNSL and secondary CNSL. Diffuse large B cells in cerebrospinal fluid (CSF-DLBCs) have offered great promise for the diagnostics and therapeutics of CNSL leptomeningeal involvement. To explore the distinct phenotypic states of CSF-DLBCs, we analyzed the transcriptomes of 902 CSF-DLBCs from six CNSL-DLBCL patients using single-cell RNA sequencing technology. We defined CSF-DLBCs based on abundant expression of B-cell markers, as well as the enrichment of cell proliferation and energy metabolism pathways. CSF-DLBCs within individual patients exhibited monoclonality with similar variable region of light chains (VL) expression. It is noteworthy that we observed some CSF-DLBCs have double classes of VL (lambda and kappa) transcripts. We identified substantial heterogeneity in CSF-DLBCs, and found significantly greater among-patient heterogeneity compared to among-cell heterogeneity within a given patient. The transcriptional heterogeneity across CSF-DLBCs is manifested in cell cycle state and cancer-testis antigens expression. Our results will provide insight into the mechanism research and new diagnostic direction of CNSL-DLBCL leptomeningeal involvement.

23: Development and clinical evaluation of non-viral genome specific targeted CAR T cells in relapsed/refractory B-cell non-Hodgkin lymphoma
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Posted 23 Sep 2020

Development and clinical evaluation of non-viral genome specific targeted CAR T cells in relapsed/refractory B-cell non-Hodgkin lymphoma
1,344 downloads medRxiv oncology

Jiqin Zhang, Yongxian Hu, Jiaxuan Yang, Wei Li, Yue Tian, Guoqing Wei, Linjie Zhang, Kui Zhao, Yalei Qi, Binghe Tan, Mingming Zhang, Yi Li, Qiliang Tian, Chunqian Fang, Yuxuan Wu, Dali Li, Bing Du, Mingyao Liu, He Huang

In recent years, chimeric antigen receptor (CAR) T cell therapy has shown great promise in treating hematological malignancies. However, using virus in manufacture of CAR T cells brings about several problems. The application of CRISPR/Cas9 genome editing technology emerges in constructing novel CAR T cells by disrupting endogenous genes. Here we successfully develop a two-in-one approach to generate non-viral genome specific targeted CAR T cells through CRISPR/Cas9. By targeting a CAR in AAVS1 safe harbor locus, we demonstrated that these CAR T cells behave comparable to those conventionally produced by lentivirus. Furthermore, PD1-knockin anti-CD19 CAR T cells show a superior ability to eradicate tumor cells with high PD-L1 expression. In the adoptive therapy for relapsed/refractory (r/r) aggressive B-cell non-Hodgkin lymphoma (B-NHL), we observed durable responses without serious adverse events and complete remission (CR) in patients treated with these PD1 knockout CAR T cells. Collectively, our results prove the safety and feasibility of non-viral genome specific integrated CAR T cells, thus providing a new potential strategy for cancer treatment using these novel CAR T cells.

24: Rapidly fatal pneumonitis from immunotherapy and concurrent SARS-CoV-2 infection in a patient with newly diagnosed lung cancer
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Posted 01 May 2020

Rapidly fatal pneumonitis from immunotherapy and concurrent SARS-CoV-2 infection in a patient with newly diagnosed lung cancer
1,325 downloads medRxiv oncology

Christine M Lovly, Kelli L. Boyd, Paula I. Gonzalez-Ericsson, Cindy L. Lowe, Hunter M. Brown, Robert D. Hoffman, Brent C. Sterling, Meghan E Kapp, Douglas B. Johnson, Prasad R. Kopparapu, Wade T. Iams, Melissa A. Warren, Michael J. Noto, Brian I. Rini, Madan Jagasia, Suman R. Das, Justin M. Balko

Immune checkpoint inhibitors (ICIs) are used for the treatment of numerous cancers, but risks associated with ICI-therapy during the COVID-19 pandemic are poorly understood. We report a case of acute lung injury in a lung cancer patient initially treated for ICI-pneumonitis and later found to have concurrent SARS-CoV-2 infection. Post-mortem analyses revealed diffuse alveolar damage in both the acute and organizing phases, with a predominantly CD68+ inflammatory infiltrate. Serum was positive for anti-SARS-CoV-2 IgG, suggesting that viral infection predated administration of ICI-therapy and may have contributed to a more fulminant clinical presentation. These data suggest the need for routine SARS-CoV-2 testing in cancer patients, where clinical and radiographic evaluations may be non-specific.

25: Robust methylation-based classification of brain tumors using nanopore sequencing
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Posted 08 Mar 2021

Robust methylation-based classification of brain tumors using nanopore sequencing
1,317 downloads medRxiv oncology

Luis P. Kuschel, Jürgen Hench, Stephan Frank, Ivana Bratic Hench, Elodie Girard, Maud Blanluet, Julien Masliah-Planchon, Martin Misch, Julia Onken, Marcus Czabanka, Philipp Karau, Naveed Ishaque, Elisabeth G. Hain, Frank Heppner, Ahmed Idbaih, Nikolaus Behr, Christoph Harms, David Capper, Philipp Euskirchen

DNA methylation-based classification of cancer provides a comprehensive molecular approach to diagnose tumors. In fact, DNA methylation profiling of human brain tumors already profoundly impacts clinical neuro-oncology. However, current implementations using hybridization microarrays are time-consuming and costly. We recently reported on shallow nanopore whole-genome sequencing for rapid and cost-effective generation of genome-wide 5-methylcytosine profiles as input to supervised classification using random forests complemented by a medium-resolution copy number profile derived from the same raw data. Here, we demonstrate that this approach allows to discriminate a wide spectrum of primary brain tumors using public reference data of 82 distinct tumor entities. We developed a pseudo-probability score as a confidence score for interpretation in a clinical context. Using bootstrap sampling in a discovery cohort of N = 56 cases, we find that a minimum set of 1,000 random CpG features is sufficient for high-confidence classification by ad hoc random forests for most cases and demonstrate robustness across laboratories with matching results in 13/13 cases. When applying the confidence score threshold to an independent validation series (N = 111), the method demonstrated 100% specificity for the remaining 93 cases. In a prospective benchmarking (N = 15), median time to results was 21.1 hours. In conclusion, nanopore sequencing allows robust and rapid methylation-based classification across the full spectrum of brain tumors. The integrated confidence score facilitates possible clinical implementation, while requiring further prospective evaluation.

26: Quantitative faecal immunochemical test for patients with high risk bowel symptoms: a prospective cohort study
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Posted 15 May 2020

Quantitative faecal immunochemical test for patients with high risk bowel symptoms: a prospective cohort study
1,297 downloads medRxiv oncology

Helga E Laszlo, Edward Seward, Ruth Ayling, Jenny Lake, Aman Malhi, Allan Hackshaw, Clare Stephens, Kathy Pritchard-Jones, Donna Chung, Michael Machesney

Objectives: To evaluate whether quantitative measurement of faecal haemoglobin (f-Hb) using faecal immunochemical testing (FIT) can be used to rule out colorectal cancer (CRC) for patients who present to primary care with high risk symptoms defined by national guidelines for urgent referral for suspected cancer (NICE NG12). Design: Prospective cohort study carried out between April 2017 and March 2019. Setting: 59 GP practices in London and 24 hospitals in England. Participants: Symptomatic patients in England referred to the urgent CRC pathway who provided a faecal sample for FIT in addition to standard investigations for cancer. Main outcome measures: CRC was confirmed by established clinical and histopathology procedures. f-Hb (microgr per gram of stool) was measured in a central laboratory blinded to cancer outcome. We calculated sensitivity (percentage of patients with CRC who have f-Hb exceeding specified cut-offs); false-positive rate [FPR] (percentage of patients without CRC whose f-Hb exceeds the same cut-offs); and positive predictive value [PPV] (percentage of all patients with f-Hb above the cut-offs who have CRC). Results: 4676 patients were recruited of whom 3596 patients were included (had a valid FIT test and a known definitive diagnosis). Among the 3596, median age was 67 years, 53% were female and 78% had colonoscopy. 90 patients were diagnosed with CRC, 7 with other cancers, and 3499 with no cancer found. f-Hb did not correlate with age, sex or ethnicity. Using f-Hb greater than or equal to 4 microgr/g (lowest limit of detection), sensitivity, FPR and PPV were 87.8%, 27.0% and 7.7% respectively. Using f-Hb greater than or equal to 10 microgr/g, the corresponding measures were 83.3%, 19.9% and 9.7%. 15 patients with CRC had f-Hb below 10 microgr/g. If FIT had been used at thresholds of 10 microg/gr or 4 microgr/g, 1 in 6 or 1 in 8 patients with cancer respectively would have been missed. If the absence of anaemia or abdominal pain is used alongside f-Hb 10 microgr/g, only 1 in 18 cancers would be missed but 56% of people without CRC could potentially avoid further investigations including colonoscopies. Conclusions: In our study, if FIT alone had been used to determine urgent referral for patients with high risk symptoms for definitive cancer investigation, some patients with bowel cancer would not have been diagnosed. If used in conjunction with clinical features, particularly in the absence of anaemia, the efficacy of FIT is significantly improved. With appropriate safety netting, FIT could be used to focus secondary care diagnostic capacity on patients most at risk of CRC.

27: Cancer inpatient with COVID-19: a report from the Brazilian National Cancer Institute
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Posted 29 Jun 2020

Cancer inpatient with COVID-19: a report from the Brazilian National Cancer Institute
1,292 downloads medRxiv oncology

Andréia C. de Melo, Luiz Claudio S Thuler, Jesse L da Silva, Lucas Z de Albuquerque, Ana Carla Pecego, Luciana O.R. Rodrigues, Magda S da Conceicao, Marianne M Garrido, Gelcio L Mendes, Ana Cristina M Pereira, Marcelo A Soares, Joao P.B. Viola, INCA COVID-19 Task Force

Brazil has been recording a frightening exponential curve of confirmed cases of SARS-CoV-2 infection. Cancer patients with COVID-19 are likely to have a greater risk of complications and death. A retrospective search in the electronic medical records of cancer inpatients admitted to the Brazilian National Cancer Institute from April 30, 2020 to May 26, 2020 granted identification of 181 patients with COVID-19 confirmed by RT-PCR method. The mean age was 55.3 years (SD 21.1). The most prevalent solid tumors were breast (40 [22.1%]), gastrointestinal (24 [13.3%]), and gynecological (22 [12.2%]). Among hematological malignancies, lymphoma (20 [11%]) and leukemia (10 [5.5%]) predominated. The most common complications were respiratory failure (70 [38.7%]), septic shock (40 [22.1%]) and acute kidney injury (33 [18.2%]). A total of 60 (33.1%) patients died due to COVID-19 complications. By multivariate analysis, cases with admission due to symptoms of COVID-19 (p = 0.027) and with two or more metastatic sites (p <0.001) showed a higher risk of COVID-19-specific death. This is the first study in a cohort of Brazilian cancer patients with COVID-19. The rates of complications and COVID-19-specific death were significantly high. Our data prompts urgent and effective public policies for this group of especially vulnerable patients.

28: Integrated genomics identify novel immunotherapy targets for malignant mesothelioma
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Posted 27 Jan 2020

Integrated genomics identify novel immunotherapy targets for malignant mesothelioma
1,291 downloads medRxiv oncology

Anca Nastase, Amit Mandal, Shir Kiong Lu, Hima Anbunathan, Deborah Morris-Rosendahl, Yu Zhi Zhang, Xiao-Ming Sun, Spyridon Gennatas, Robert C Rintoul, Matthew Edwards, Alex Bowman, Tatyana Chernova, Tim Benepal, Eric Lim, Anthony Newman Taylor, Andrew G. Nicholson, Sanjay Popat, Anne E. Willis, Marion MacFarlane, Mark Lathrop, Anne M. Bowcock, Miriam F Moffatt, William Osmond Cookson

Background: Malignant pleural mesothelioma (MPM) is an aggressive malignancy with limited effective therapies. Methods: In order to identify therapeutic targets, we integrated SNP genotyping, sequencing and transcriptomics from tumours and low-passage patient-derived cells. Results: Previously unrecognised losses of SUFU locus (10q24.32), observed in 21% of 118 tumours, resulted in disordered expression of transcripts from Hedgehog pathways and the T-cell synapse including VISTA. Co-deletion of Interferon Type I genes and CDKN2A was present in half of tumours and was a predictor of poor survival. We also found previously unrecognised deletions in RB1 in 26% of cases and show sub-micromolar responses to downstream PLK1, CHEK1 and Aurora Kinase inhibitors in primary MPM cells. Defects in Hippo pathways that included RASSF7 amplification and NF2 or LATS1/2 mutations were present in 50% of tumours and were accompanied by micromolar responses to the YAP1 inhibitor Verteporfin. Conclusions: Our results suggest new therapeutic avenues in MPM and provide targets and biomarkers for immunotherapy.

29: Characteristics and outcome of SARS-CoV-2 infection in cancer patients.
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Posted 19 May 2020

Characteristics and outcome of SARS-CoV-2 infection in cancer patients.
1,282 downloads medRxiv oncology

Clemence Basse, Sarah Diakite, Vincent Servois, Maxime Frelaut, Aurelien Noret, Audrey Bellesoeur, Pauline Moreau, Marie-Ange Massiani, Anne-Sophie Bouyer, perrine vuagnat, SAndra Malak, Francois-Clement Bidard, Dominique Vanjak, Irene Kriegel, Alexis Burnod, Geoffroy Bilger, Toulsie Ramtohul, Gille Dhonneur, Carole Bouleuc, Nathalie Cassoux, Xavier Paoletti, Laurence Bozec, Paul Cottu

Abstract Background: Concerns have emerged about the higher risk of fatal COVID-19 in cancer patients. In this paper, we review the experience of a comprehensive cancer center. Methods: A prospective registry was set up at Institut Curie at the beginning of the COVID-19 pandemic. All cancer patients with suspected or proven COVID-19 were entered and actively followed for 28 days. Results: Among 9,842 patients treated at Institut Curie between mid-March and early May 2020, 141 (1.4%) were diagnosed with COVID-19, based on RT-PCR testing and/or CT-scan. In line with our case-mix, breast cancer (40%) was the most common tumor type, followed by hematological and lung malignancies (both 13%). Patients with active cancer therapy or/and advanced cancer accounted for 88% and 69% of patients, respectively. At diagnosis, 79% of patients had COVID-19 related symptoms, with an extent of lung parenchyma involvement [&le;]50% in 90% of patients. Blood count variations and C-reactive protein elevation were the most common laboratory abnormalities. Antibiotics and antiviral agents were administered in 48% and 7% of patients, respectively. At the time of analysis, 26 patients (18%) have died from COVID-19, and 81 (57%) were cured. Independent prognostic factors at the time of COVID-19 diagnosis associated with death or intensive care unit admission were extent of COVID-19 pneumonia and decreased O2 saturation. Conclusions: COVID-19 incidence and presentation in cancer patients appear to be very similar to those in the general population. The outcome of COVID-19 is primarily driven by the initial severity of infection rather than patient or cancer characteristics.

30: Circulating tumor cell characterization of lung cancer brain metastasis in the cerebrospinal fluid through single-cell transcriptome analysis
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Posted 10 Jan 2020

Circulating tumor cell characterization of lung cancer brain metastasis in the cerebrospinal fluid through single-cell transcriptome analysis
1,251 downloads medRxiv oncology

Haoyu Ruan, Yihang Zhou, Jie Shen, Yue Zhai, Ying Xu, Linyu Pi, RuoFan Huang, Kun Chen, Xiangyu Li, Weizhe Ma, Zhiyuan Wu, Xuan Deng, Xu Wang, Chao Zhang, Ming Guan

Metastatic lung cancer accounts for about half of the brain metastases (BM). Development of leptomeningeal metastases (LM) are becoming increasingly common, and its prognosis is still poor despite the advances in systemic and local approaches. Cytology analysis in the cerebrospinal fluid (CSF) remains the diagnostic gold standard. Although several previous studies performed in CSF have offered great promise for the diagnostics and therapeutics of LM, a comprehensive characterization of circulating tumor cells (CTCs) in CSF is still lacking. To fill this critical gap of lung adenocarcinoma LM (LUAD-LM), we analyzed the transcriptomes of 1,375 cells from 5 LUAD-LM patient and 3 control samples using single-cell RNA sequencing technology. We defined CSF-CTCs based on abundant expression of epithelial markers and genes with lung origin, as well as the enrichment of metabolic pathway and cell adhesion molecules, which are crucial for the survival and metastases of tumor cells. Elevated expression of CEACAM6 and SCGB3A2 was discovered in CSF-CTCs, which could serve as candidate biomarkers of LUAD-LM. We identified substantial heterogeneity in CSF-CTCs among LUAD-LM patients and within patient among individual cells. Cell-cycle gene expression profiles and the proportion of CTCs displaying mesenchymal and cancer stem cell properties also vary among patients. In addition, CSF-CTC transcriptome profiling identified one LM case as cancer of unknown primary site (CUP). Our results will shed light on the mechanism of LUAD-LM and provide a new direction of diagnostic test of LUAD-LM and CUP cases from CSF samples.

31: Breast Cancer Detection Using Quantum Convolutional Neural Networks: A Demonstration on a Quantum Computer
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Posted 23 Jun 2020

Breast Cancer Detection Using Quantum Convolutional Neural Networks: A Demonstration on a Quantum Computer
1,204 downloads medRxiv oncology

Aradh Bisarya, Walid El Maouaki, Sabyasachi Mukhopadhyay, nilima mishra, Shubham Kumar, Bikash K. Behera, Prasanta K. Panigrahi, Debashis de

Deep learning have paved the way for scientists to achieve great technical feats. In an endeavor to hone and perfect these techniques, quantum deep learning is a promising and important tool to utilize to the fullest. Using the techniques of deep learning and supervised learning in a quantum framework, we are able to propose a quantum convolutional neural network and showcase its implementation. Using the techniques of deep learning and supervised learning in a quantum framework, we are able to propose a quantum convolutional neural network and showcase its implementation. We keep our focus on training of the ten qubits system in a way so that it can learn from labeling of the breast cell data of Wisconsin breast cancer database and optimize the circuit parameters to obtain the minimum error. Through our study, we also have showcased that quantum convolutional neural network can outperform its classical counterpart not only in terms of accuracy but also in the aspect of better time complexity.

32: Neoadjuvant and Adjuvant Pembrolizumab in Resectable Locally Advanced, Human Papillomavirus-Unrelated Head and Neck Cancer: A Multicenter, Phase 2 Trial
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Posted 20 Mar 2020

Neoadjuvant and Adjuvant Pembrolizumab in Resectable Locally Advanced, Human Papillomavirus-Unrelated Head and Neck Cancer: A Multicenter, Phase 2 Trial
1,189 downloads medRxiv oncology

Ravindra Uppaluri, Katie Campbell, Ann Marie Egloff, Paul Zolkind, Zachary L Skidmore, Brian Nussenbaum, Randal C. Paniello, Jason T. Rich, Ryan Jackson, Patrik Pipkorn, Loren P. Michel, Jessica Ley, Peter Oppelt, Gavin P Dunn, Erica K Barnell, Nicholas C. Spies, Tianxiang Lin, Tiantian Li, David T. Mulder, Youstina Hanna, Iulia Cirlan, Trevor J. Pugh, Tenny Mudianto, Rachel Riley, Liye Zhou, Vickie Jo, Matthew Stachler, Glenn J. Hanna, Jason Kass, Robert Haddad, Jonathan D. Schoenfeld, Evisa Gjini, Ana Lako, Wade Thorstad, Hiram A. Gay, Mackenzie Daly, Scott J. Rodig, Ian S. Hagemann, Dorina Kallogjeri, Jay F. Piccirillo, Rebecca D. Chernock, Malachi Griffith, Obi L Griffith, Douglas R. Adkins

BackgroundPembrolizumab improved survival of patients with recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC). The aims of this phase 2 trial were to determine if pembrolizumab administered to patients with resectable locally advanced, human papillomavirus (HPV)-unrelated HNSCC would be safe, result in pathologic tumor response (pTR), and lower the relapse rate. MethodsNeoadjuvant pembrolizumab (200 mg) was administered 2-3 weeks before surgery. Resection of the primary tumor and involved/at-risk nodes was performed. Post-operative (chemo) radiation was planned. Patients with high-risk pathology (positive margins and/or extranodal extension) were to receive adjuvant pembrolizumab. pTR was quantified as the proportion of the resection bed with tumor necrosis, keratinous debris, and giant cells/histiocytes: pTR-0 (<10%), pTR-1 (10-49%), and pTR-2 ([&ge;]50%). Co-primary endpoints were pTR-2 among all patients, and one-year relapse rate in patients with high-risk pathology (historical: 35%). Correlations of baseline PD-L1 expression and T-cell infiltration with pTR were assessed, and tumor clonal dynamics were evaluated. Analyses were done per protocol. This trial is registered with ClinicalTrials.gov(NCT02296684), and is ongoing but closed to accrual. FindingsBetween June 30, 2015, and March 30, 2018, 36 patients enrolled. After neoadjuvant pembrolizumab, serious (grades 3-4) adverse events and unexpected surgical delays/complications did not occur. pTR-2 occurred in eight patients (22%), and pTR-1 in eight other patients (22%). pTR [&ge;]10% correlated with baseline tumor PD-L1 expression, immune infiltrate, and IFN-{gamma} pathway activity. Matched sample analysis showed compensatory upregulation of multiple immune inhibitory checkpoints in patients with pTR-0, and confirmed that clonal loss occurred in some patients. The one-year relapse rate among the eighteen patients with high-risk pathology was 16.7% (95%CI: 3.6-41.4%). ConclusionsAmong patients with locally advanced, HPV-unrelated HNSCC, neoadjuvant pembrolizumab was safe, and resulted in pTR-1 or pTR-2 in 44% of patients. The one-year relapse rate in patients with high-risk-pathology was lower than historical. FundingMerck, NCI, NIDCR, NHGRI and The V Foundation.

33: Extracellular Microenvironment in Patient-derived Hydrogel Organoids of Prostate Cancer Regulates Therapeutic Response
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Posted 20 May 2020

Extracellular Microenvironment in Patient-derived Hydrogel Organoids of Prostate Cancer Regulates Therapeutic Response
1,174 downloads medRxiv oncology

Matthew J Mosquera, Rohan Bareja, Jacob M Bernheim, Muhammad Asad, Cynthia Cheung, Michael Sigouros, Varun Prabhu, Joshua Allen, M. Laura Martin, Loredana Puca, Mark A. Rubin, Himisha Beltran, Juan Miguel Mosquera, Olivier Elemento, Ankur Singh

Following treatment with androgen receptor (AR) pathway inhibitors, ~20% of prostate cancer patients progress by shedding their dependence on AR. These tumors undergo epigenetic reprogramming turning castration-resistant prostate cancer adenocarcinoma (CRPC-Adeno) into neuroendocrine prostate cancer (CRPC-NEPC). Currently, no targeted therapies are available for CRPC-NEPCs. A major hurdle in the development of new therapies and treatment of CRPC-NEPC is the lack of accurate models to test candidate treatments. Such models would ideally capture components of the tumor microenvironment (TME) factors, which likely regulate the phenotypic, genetic, and epigenetic underpinnings of this aggressive subset. The TME is a complex system comprised not only of malignant prostate cells but also stromal and inflammatory cells and a scaffold of extracellular matrix (ECM). ECM proteins are implicated in the survival and progression of cancer and development of chemoresistance, while are equally integral to the development of prostate cancer organoids. Here, using a combination of patient tumor proteomics and RNA sequencing, we define putative ECM cues that may guide the growth of prostate tumors in patients. Using this molecular information, we developed synthetic hydrogels that recapitulate the tumor ECM. Organoids cultured in the synthetic hydrogel niches demonstrate that ECM subtypes regulate the morphology, transcriptome, and epigenetics hallmarks of CRPC-Adeno and CRPC-NEPC. CRPC-NEPC organoid showed a differential response to small molecule inhibitors of epigenetic repressor EZH2 and Dopamine Receptor D2 (DRD2), the latter being a novel target in CRPC-NEPC when grown in tumor-specific ECM. Finally, in those synthetic ECM niches where drug resistance was observed in CRPC-NEPCs, cellular reprogramming by a synergistic combination of EZH2 inhibitors with DRD2 antagonists inhibited tumor growth. The synthetic platform can provide a more realistic prostate-specific microenvironment and subsequently enable the development of effective targeted therapeutics for prostate cancers.

34: Overexpression of transposable elements underlies immune overdrive and poor clinical outcome in cancer patients
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Posted 17 Jul 2020

Overexpression of transposable elements underlies immune overdrive and poor clinical outcome in cancer patients
1,134 downloads medRxiv oncology

Xiaoqiang Zhu, Hu Fang, Kornelia Gladysz, Jayne Alexandra Barbour, Jason W. H. Wong

Objective: The immune system plays a key role in protecting against cancer. Increased immune infiltration in tumor tissue is usually associated with improved clinical outcome, but in colorectal cancer (CRC), excessive immune infiltration has also been shown to lead to worst prognosis. The factors underlying this immune overdrive phenotype remains unknown. Design: Using RNA sequencing data from The Cancer Genome Atlas, the expression of over 1,000 transposable element (TE) subfamilies were quantified using the REdiscoverTE pipeline. Candidate prognostic and immunogenic TEs were screened by survival and correlation analysis, respectively. Based on these candidates, a TE expression score was developed and CRC patients were clustered using the kaps algorithm. Results: In CRC, we found that the TE expression score stratified patients into four clusters each with distinctive prognosis. Those with the highest TE expression were associated with immune overdrive and had the poorest outcomes. Importantly, this association was independent of microsatellite instability status and tumor mutation burden. To link TE overexpression to the immune overdrive phenotype, we showed that cell lines treated with DNA methyltransferase inhibitors also had a high TE expression score and activation of cellular innate immune response pathways. Finally, a pan-cancer survey of TE expression identified a subset of kidney renal clear cell carcinoma with a similar adverse immune overdrive phenotype with poor prognosis. Conclusion: Our findings reveal that TE expression is associated with immune overdrive in cancer and is an independent predictor of immune infiltration and prognosis in CRC patients.

35: Systematic investigations of COVID-19 in 283 cancer patients
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Posted 03 May 2020

Systematic investigations of COVID-19 in 283 cancer patients
1,129 downloads medRxiv oncology

Jie Wang, Qibin Song, Yuan Chen, Zhijie Wang, Qian Chu, Hongyun Gong, Shangli Cai, Xiaorong Dong, Bin Xu, Weidong Hu, Qun Wang, Linjun Li, Jiyuan Yang, Zhibin Xie, Zhiguo Luo, Jing Liu, Xiuli Luo, Jie Ren, Zhiguo Rao, Xinhua Xu, Dongfeng Pan, Zuowei Hu, Gang Feng, Chiding Hu, Liqiong Luo, Hongda Lu, Ruizhi Ran, Jun Jin, Yanhua Xu, Yong Yang, Zhihong Zhang, Li Kuang, Runkun Wang, Youhong Dong, Jianhai Sun, Wenbing Hu, Tienan Yi, Hanlin Wu, Mingyu Liu, Jiachen Xu, Jianchun Duan, Zhengyi Zhao, Guoqiang Wang, Yu Xu, Jie He

Background: Cancer patients are considered to be highly susceptible to viral infections, however, the comprehensive features of COVID-19 in these patients remained largely unknown. The present study aimed to assess the clinical characteristics and outcomes of COVID-19 in a large cohort of cancer patients. Design, Setting, and Participants: Data of consecutive cancer patients admitted to 33 designated hospitals for COVID-19 in Hubei province, China from December 17, 2019 to March 18, 2020 were retrospectively collected. The follow-up cutoff date was April 02, 2020. The clinical course and survival status of the cancer patients with COVID-19 were measured, and the potential risk factors of severe events and death were assessed through univariable and multivariable analyses. Results: A total of 283 laboratory confirmed COVID-19 patients (50% male; median age, 63.0 years [IQR, 55.0 to 70.0]) with more than 20 cancer types were included. The overall mortality rate was 18% (50/283), and the median hospitalization stay for the survivors was 26 days. Amongst all, 76 (27%) were former cancer patients with curative resections for over five years without recurrence. The current cancer patients exhibited worse outcomes versus former cancer patients (overall survival, HR=2.45, 95%CI 1.10 to 5.44, log-rank p=0.02; mortality rate, 21% vs 9%). Of the 207 current cancer patients, 95 (46%) have received recent anti-tumor treatment, and the highest mortality rate was observed in the patients receiving recent chemotherapy (33%), followed by surgery (26%), other anti-tumor treatments (19%), and no anti-tumor treatment (15%). In addition, a higher mortality rate was observed in patients with lymphohematopoietic malignancies (LHM) (53%, 9/17), and all seven LHM patients with recent chemotherapy died. Multivariable analysis indicated that LHM (p=0.001) was one of the independent factors associating with critical illness or death. Conclusions: This is the first systematic study comprehensively depicting COVID-19 in a large cancer cohort. Patients with tumors, especially LHM, may have poorer prognosis of COVID-19. Additional cares are warranted and non-emergency anti-tumor treatment should be cautiously used for these patients under the pandemic.

36: Personalized Single-Cell Proteogenomics to Distinguish Acute Myeloid Leukemia from Non-Malignant Clonal Hematopoiesis
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Posted 26 Oct 2020

Personalized Single-Cell Proteogenomics to Distinguish Acute Myeloid Leukemia from Non-Malignant Clonal Hematopoiesis
1,109 downloads medRxiv oncology

Laura W. Dillon, Jack Ghannam, Chidera Nosiri, Gege Gui, Meghali Goswami, Katherine R Calvo, Katherine E Lindblad, Karolyn A Oetjen, Matthew Wilkerson, Anthony R Soltis, Gauthaman Sukumar, Clifton L Dalgard, Julie Thompson, Janet Valdez, Christin B DeStefano, Catherine Lai, Adam Sciambi, Robert Durruthy-Durruthy, Aaron Llanso, Saurabh Gulati, Shu Wang, Aik Ooi, Pradeep K Dagur, J Philip McCoy, Patrick Burr, Yuesheng Li, Christopher S. Hourigan

Genetic mutations associated with acute myeloid leukemia can also be detected in age-related clonal hematopoiesis, making confident assignment of detected variants to malignancy challenging particularly in the post-treatment setting. This has implications for measurable residual disease monitoring, where the relationship between sequencing and flow cytometry is also imperfect. We show, using whole-genome-sequencing informed patient-personalized single-cell DNA and antibody-oligonucleotide sequencing, that it is possible to resolve immunophenotypic identity of clonal architecture.

37: Adaptive immunity to SARS-CoV-2 in cancer patients: The CAPTURE study
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Posted 23 Dec 2020

Adaptive immunity to SARS-CoV-2 in cancer patients: The CAPTURE study
1,108 downloads medRxiv oncology

Annika Fendler, Lewis Au, Laura Amanda Boos, Fiona Byrne, Scott T.C. Shepherd, Ben Shum, Camille L. Gerard, Barry Ward, Wenyi Xie, Maddalena Cerrone, Georgina H. Cornish, Martin Pule, Leila Mekkaoui, Kevin W Ng, Richard Stone, Camila Gomes, Helen R. Flynn, Ana Agua-Doce, Phillip Hobson, Simon Caidan, Mike Howell, Robert Goldstone, Mike Gavrielides, Emma Nye, Bram Snijders, James Macrae, Jerome Nicod, Adrian C. Hayday, Firza Gronthoud, Christina Messiou, David Cunningham, Ian Chau, Naureen Starling, Nicholas Turner, Jennifer Rusby, Liam Welsh, Nicholas van As, Robin Jones, Joanne Droney, Susana Banerjee, Kate Tatham, Shaman Jhanji, Mary O’Brien, Olivia Curtis, Kevin Harrington, Shreerang Bhide, Tim Slattery, Yasir Khan, Zayd Tippu, Isla Leslie, Spyridon Gennatas, Alicia Okines, Alison Reid, Kate Young, Andrew Furness, Lisa Pickering, Sonia Ghandi, Steve Gamblin, Charles Swanton, on behalf of the Crick COVID19 consortium, Emma Nicholson, Sacheen Kumar, Nadia Yousaf, Katalin Wilkinson, Anthony Swerdlow, Ruth Harvey, George Kassiotis, Robert Wilkinson, James Larkin, Samra Turajlic, on behalf of the CAPTURE consortium

There is a pressing need to characterise the nature, extent and duration of immune response to SARS-CoV-2 in cancer patients and inform risk-reduction strategies and preserve cancer outcomes. CAPTURE is a prospective, longitudinal cohort study of cancer patients and healthcare workers (HCWs) integrating longitudinal immune profiling and clinical annotation. We evaluated 529 blood samples and 1051 oronasopharyngeal swabs from 144 cancer patients and 73 HCWs and correlated with >200 clinical variables. In patients with solid cancers and HCWs, S1-reactive and neutralising antibodies to SARS-CoV-2 were detectable five months post-infection. SARS-CoV-2-specific T-cell responses were detected, and CD4+ T-cell responses correlated with S1 antibody levels. Patients with haematological malignancies had impaired but partially compensated immune responses. Overall, cancer stage, disease status, and therapies did not correlate with immune responses. These findings have implications for understanding individual risks and potential effectiveness of SARS-CoV-2 vaccination in the cancer population.

38: Feasibility and Safety of Perioperative Chemotherapy with Fluorouracil plus Leucovorin, Oxaliplatin, and Docetaxel (FLOT) for Locally-Advanced Gastric Cancer Patients in China
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Posted 26 May 2020

Feasibility and Safety of Perioperative Chemotherapy with Fluorouracil plus Leucovorin, Oxaliplatin, and Docetaxel (FLOT) for Locally-Advanced Gastric Cancer Patients in China
1,077 downloads medRxiv oncology

Birendra Kumar Sah, Wei Xu, Benyan Zhang, Huan Zhang, Fei Yuan, Jian Li, Wentao Liu, Chao Yan, Chen Li, Min Yan, Zhenggang Zhu

Background: Neoadjuvant fluorouracil plus leucovorin, oxaliplatin, and docetaxel (FLOT) has shown significant benefits for gastric cancer patients. However, it has not been well accepted in Asian countries. We conducted a prospective study on the safety and feasibility of the FLOT regimen in Chinese patients. Methods: Patients with adenocarcinoma of the stomach or esophagogastric junction received 4 cycles of neoadjuvant chemotherapy (NAC) and 4 cycles of adjuvant chemotherapy (AC) with the FLOT regimen. The completion status of chemotherapy, adverse events, postoperative morbidities, and pathological tumor regression were analyzed. The two-year overall survival (OS) and relapse-free survival are presented. Results: Altogether, 10 patients were enrolled, and all patients completed 4 cycles of neoadjuvant chemotherapy. There were no severe hematological adverse events (grade 3 or above), except for a case of grade 3 anemia. All 10 patients underwent radical gastrectomy. Nine patients had R0 resection, and 3 patients had complete or subtotal pathological tumor regression. Nine patients completed 4 cycles of adjuvant chemotherapy, but only one patient completed the full dose of adjuvant chemotherapy. The dose of adjuvant chemotherapy was reduced by 25% or less in the other patients. The median follow-up time was 23.13 months, 8 patients achieved the overall survival endpoint, and 7 patients had relapse-free survival for this period. Two patients died of disease progression. Conclusions: Our study demonstrates that the neoadjuvant FLOT regimen is safe and effective for Chinese patients. Dose adjustment is necessary for adjuvant chemotherapy. The pathological regression and survival rates need reevaluation in a larger cohort.

39: Circulating tumor DNA in neoadjuvant treated breast cancer reflects response and survival
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Posted 05 Feb 2020

Circulating tumor DNA in neoadjuvant treated breast cancer reflects response and survival
1,061 downloads medRxiv oncology

Mark Jesus M. Magbanua, Lamorna Brown-Swigart, Hsin-Ta Wu, Gillian L. Hirst, Christina Yau, Denise M. Wolf, Antony Tin, Raheleh Salari, Svetlana Shchegrova, Hemant Pawar, Amy L. Delson, Angela DeMichele, Minetta C. Liu, A. Jo Chien, Smita Asare, Cheng-Ho J. Lin, Paul Billings, Alexey Aleshin, Himanshu Sethi, Maggie Louie, Bernhard Zimmermann, laura J esserman, Laura J. van ’t Veer

Pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) is strongly associated with favorable outcome. We examined the utility of serial circulating tumor DNA (ctDNA) testing for predicting pCR and risk of metastatic recurrence in 84 high-risk early breast cancer patients treated in the neoadjuvant I-SPY 2 TRIAL. Cell-free DNA (cfDNA) was isolated from 291 plasma samples collected at pretreatment (T0), 3 weeks after initiation of paclitaxel (T1), between paclitaxel and anthracycline regimens (T2), or prior to surgery (T3). A personalized ctDNA test was designed to detect 16 patient-specific mutations (from whole exome sequencing of pretreatment tumor) in cfDNA by ultra-deep sequencing. At T0, 61 of 84 (73%) patients were ctDNA-positive, which decreased over time (T1-35%; T2-14%; T3-9%). Patients who remained ctDNA-positive at T1 were significantly more likely to have residual disease after NAC (83% non-pCR) compared to those who cleared ctDNA (52% non-pCR; OR 4.33, P=0.012). After NAC, all patients who achieved pCR were ctDNA-negative (n=17, 100%). For those who did not achieve pCR (n=43), ctDNA-positive patients (14%) had significantly increased risk of metastatic recurrence (HR 10.4; 95% CI, 2.3-46.6); interestingly, patients who did not achieve pCR but were ctDNA-negative (86%) had excellent outcome, similar to those who achieved pCR (HR 1.4; 95% CI, 0.15-13.5). Lack of ctDNA clearance was a significant predictor of poor response and metastatic recurrence, while clearance was associated with improved survival regardless of pCR status. Personalized monitoring of ctDNA during NAC may aid in real-time assessment of treatment response and help fine-tune pCR as a surrogate endpoint of survival.

40: Spatially fractionated stereotactic body radiotherapy (Lattice SBRT) for large tumors
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Posted 10 Mar 2020

Spatially fractionated stereotactic body radiotherapy (Lattice SBRT) for large tumors
1,024 downloads medRxiv oncology

Sai Duriseti, James Kavanaugh, Sreekrishna Goddu, Alex Price, Nels Knutson, Francisco Reynoso, Jeff Michalski, Sasa Mutic, Clifford Robinson, Matthew B Spraker

Stereotactic body radiotherapy (SBRT) has demonstrated clinical benefit for patients with metastatic and/or unresectable cancer. Technical considerations of treatment delivery and sensitive organs at risk (OARs) limit the use of SBRT in large tumors or those in unfavorable locations. Spatially fractionated radiotherapy (SFRT) delivers high-dose radiation to discrete sub-volume vertices within a tumor target while restricting the remainder of the target to low dose. SFRT has been utilized for treatment of large tumors with reported dramatic tumor response and minimal side effects. Lattice is a modern approach to SFRT that can be delivered with arc-based therapy, which allows for the rapid dose fall-off required for high quality SBRT. In order to overcome the limitations of SBRT for large tumors, we developed Lattice SBRT. Here we report the results of a dosimetry and quality assurance (QA) feasibility study of Lattice SBRT in 11 patients with 12 tumor targets, each [&ge;] 10 cm in an axial dimension. Prior CT simulation scans were used to generate volumetric-modulated arc therapy (VMAT) Lattice SBRT plans that were then delivered on clinically available Linacs. QA testing included external portal imaging device (EPID) and ion chamber (IC) analysis. All generated plans were able to meet the standard SBRT dose constraints, such as those from AAPM Task Group 101. Additionally, we provide a step-by-step approach for generating and delivering Lattice SBRT plans using commercially available treatment technology. Lattice SBRT is currently being tested in a prospective trial for patients with metastatic cancer needing palliation of a large tumor (NCT04133415).

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