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1: The impact of the coronavirus disease 2019 (COVID-19) outbreak on cancer practice in Japan: using an administrative database
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Posted 18 Nov 2020

The impact of the coronavirus disease 2019 (COVID-19) outbreak on cancer practice in Japan: using an administrative database
13,562 downloads medRxiv oncology

Hisashi Itoshima, Yuka Asami, Jung-ho Shin, Daisuke Takada, Tetsuji Morishita, Seiko Bun, Takuya Okuno, Susumu Kunisawa, Yuichi Imanaka

Background: Recent researches reported the impact of the coronavirus disease 2019 (COVID - 19) pandemic on the clinical practice of specific type cancers. The aim of this study was to reveal the impact of the COVID-19 outbreak on the clinical practice of various cancers. Methods: We included hospitalized patients aged 18 years or older diagnosed between July 2018 and June 2020 with one of the top 12 most common cancers in Japan (colon/rectum, lung, gastric, breast, bladder & urinary tract, pancreas, non-Hodgkin lymphoma, liver, prostate, esophagus, uterus, and gallbladder & biliary tract) using Diagnostic Procedure Combination data, an administrative database in Japan. The intervention was defined April 2020 based on a declaration of emergency from Japanese government. The change volume of number of monthly admissions with each cancer was tested by interrupted time series (ITS) analysis, and monthly cases with radical surgery or chemotherapy for each cancer were descripted. Results: 403,344 cases were included during the study period. The most common cancer was colon/rectum (20.5%), followed by lung (17.5%). In almost cancer cases, the number of admissions decreased in May 2020. In particular, colorectal, lung, gastric, breast, uterine, or esophageal cancer cases decreased by over 10%. The number of admissions with surgery or chemotherapy decreased in colorectal, lung, gastric, breast, uterine, or esophageal cancer. ITS analysis indicated that cases with gastric or esophageal cancer were affected more than other type of cancer. Conclusions: The COVID-19 outbreak has a negative impact on the number of admission cases with cancer; the magnitude of impact varied by cancer diagnosis.

2: Comparison of Population Characteristics in Real-World Clinical Oncology Databases in the US: Flatiron Health, SEER, and NPCR
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Posted 18 Mar 2020

Comparison of Population Characteristics in Real-World Clinical Oncology Databases in the US: Flatiron Health, SEER, and NPCR
6,738 downloads medRxiv oncology

Xinran Ma, Lura Long, Sharon Moon, Blythe J.S. Adamson, Shrujal S. Baxi

Background and ObjectiveThe Surveillance, Epidemiology, and End Results Program (SEER) program and the National Program of Cancer Registries (NPCR), are authoritative sources for population cancer surveillance and research in the US. An increasing number of recent oncology studies are based on the electronic health record (EHR)-derived de-identified databases created and maintained by Flatiron Health. This report describes the differences in the originating sources and data development processes, and compares baseline demographic characteristics in the cancer-specific databases from Flatiron Health, SEER, and NPCR, to facilitate interpretation of research findings based on these sources. MethodsPatients with documented care from January 1, 2011 through May 31, 2019 in a series of EHR-derived Flatiron Health de-identified databases covering multiple tumor types were included. SEER incidence data (obtained from the SEER 18 database) and NPCR incidence data (obtained from the US Cancer Statistics public use database) for malignant cases diagnosed from January 1, 2011 to December 31, 2016 were included. Comparisons of demographic variables were performed across all disease-specific databases, for all patients and for the subset diagnosed with advanced-stage disease. ResultsAs of May 2019, a total of 201,570 patients with 19 different cancer types were included in Flatiron Health datasets. In an overall comparison to national cancer registries, patients in the Flatiron Health databases had similar sex and geographic distributions, but appeared to be diagnosed with later stages of disease and their age distribution differs from the other datasets. For variables such as stage and race, Flatiron Health databases had a greater degree of incompleteness. There are variations in these trends by cancer types. ConclusionsThese three databases present general similarities in demographic and geographic distribution, but there are overarching differences across the populations they cover. Differences in data sourcing (medical oncology EHRs vs cancer registries), and disparities in sampling approaches and rules of data acquisition may explain some of these divergences. Furthermore, unlike the steady information flow entered into registries, the availability of medical oncology EHR-derived information reflects the extent of involvement of medical oncology clinics at different points in the specialty management of individual diseases, resulting in inter-disease variability. These differences should be considered when interpreting study results obtained with these databases.

3: Interim results of the safety and immune-efficacy of 1 versus 2 doses of COVID-19 vaccine BNT162b2 for cancer patients in the context of the UK vaccine priority guidelines
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Posted 17 Mar 2021

Interim results of the safety and immune-efficacy of 1 versus 2 doses of COVID-19 vaccine BNT162b2 for cancer patients in the context of the UK vaccine priority guidelines
6,154 downloads medRxiv oncology

Leticia Monin-Aldama, Adam G. Laing, Miguel Munoz-Ruiz, Duncan R. McKenzie, Irene del Molino del Barrio, Thanussuyah Alaguthurai, Clara Domingo Vila, Thomas S. Hayday, Carl Graham, Jeffrey Seow, Sultan Abdul-Jawad, Shraddha Kamdar, Elizabeth Harvey-Jones, Rosalind Graham, Jack Cooper, Muhammad Khan, Jennifer Vidler, Helen Kakkassery, Shubhankar Sinha, Richard Davis, Liane Dupont, Isaac Francos Quijorna, Puay Lee, Josephine Eum, Maria Conde Poole, Magdalene Joseph, Daniel Davies, Yin Wu, Ana Montes, Mark Harries, Anne Rigg, James Spicer, Michael Malim, Paul Fields, Piers Patten, Francesca Di Rosa, Sophie Papa, Timothy I. M. Tree, Katie Doores, Adrian Hayday, Sheeba Irshad

Background: The efficacy and safety profile of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have not been definitively established in immunocompromised patient populations. Patients with a known cancer diagnosis were hitherto excluded from trials of the vaccines currently in clinical use. Methods: This study presents data on the safety and immune efficacy of the BNT162b.2 (Pfizer-BioNTech) vaccine in 54 healthy controls and 151 mostly elderly patients with solid and haematological malignancies, respectively, and compares results for patients who were boosted with BNT162b.2 at 3 weeks versus those who were not. Immune efficacy was measured as antibody seroconversion, T cell responses, and neutralisation of SARS-CoV-2 Wuhan strain and of a variant of concern (VOC) (B1.1.7). We also collected safety data for the BNT162b2 vaccine up to 5 weeks following first dose. Findings: The vaccine was largely well tolerated. However, in contrast to its very high performance in healthy controls (>90% efficacious), immune efficacy of a single inoculum in solid cancer patients was strikingly low (below 40%) and very low in haematological cancer patients (below 15%). Of note, efficacy in solid cancer patients was greatly and rapidly increased by boosting at 21-days (95% within 2 weeks of boost). Too few haematological cancer patients were boosted for clear conclusions to be drawn. Conclusions: Delayed boosting potentially leaves most solid and haematological cancer patients wholly or partially unprotected, with implications for their own health; their environment and the evolution of VOC strains. Prompt boosting of solid cancer patients quickly overcomes the poor efficacy of the primary inoculum in solid cancer patients.

4: Estimating the Risks from COVID-19 Infection in Adult Chemotherapy Patients
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Posted 20 Mar 2020

Estimating the Risks from COVID-19 Infection in Adult Chemotherapy Patients
5,229 downloads medRxiv oncology

Matt Williams, Ella Mi, Kerlann Le Calvez, Jiarong Chen, Lillie Pakzad-Shahabi, Seema Dadhania, James Wang, Andrew LK Ho, Simon Rabinowicz

The SARS-CoV-2 (COVID-19) novel corona virus represents a significant health risk, particularly in older patients. Cancer is one of the leading causes of death in most rich countries, and delivering chemotherapy may be associated with increased risk in the presence of a pandemic infection. Estimating this risk is crucial in making decisions about balancing risks and benefits from administering chemotherapy. However, there are no specific data about chemotherapy risks per se. Here we develop a simple model to estimate the potential harms in patients undergoing chemotherapy during a COVID outbreak. We use age-related case fatality rates as a basis for estimating risk, and use previous data from risk of death during influenza outbreaks to estimate the additional risk associated with chemotherapy. We use data from randomised trials to estimate benefit across a range of curative and palliative settings, and address the balance of benefit against the risk of harm. We then use those data to estimate the impact on national chemotherapy delivery patterns.

5: Collateral damage: the impact on cancer outcomes of the COVID-19pandemic
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Posted 24 Apr 2020

Collateral damage: the impact on cancer outcomes of the COVID-19pandemic
5,046 downloads medRxiv oncology

Amit Sud, Michael E. Jones, John Broggio, Chey Loveday, Bethany Torr, Alice Garrett, David L. Nicol, Shaman Jhanji, Stephen A. Boyce, Phillip Ward, Jonathan M. Handy, Nadia Yousaf, James Larkin, Yae-Eun Suh, Stephen Scott, Paul Pharoah, Charles Swanton, Christopher Abbosh, Matthew Williams, Georgios Lyratzopoulos, Richard Houlston, Clare Turnbull

Background: Cancer diagnostics and surgery have been disrupted by the response of healthcare services to the COVID-19 pandemic. Progression of cancers during delay will impact on patient long-term survival. Methods: We generated per-day hazard ratios of cancer progression from observational studies and applied these to age-specific, stage-specific cancer survival for England 2013-2017. We modelled per-patient delay of three months and six months and periods of disruption of one year and two years. Using healthcare resource costing, we contextualise attributable lives saved and life years gained from cancer surgery to equivalent volumes of COVID-19 hospitalisations. Findings: Per year, 94,912 resections for major cancers result in 80,406 long-term survivors and 1,717,051 life years gained. Per-patient delay of six months would cause attributable death of 10,555 of these individuals with loss of 205,024 life years. For cancer surgery, average life years gained (LYGs) per patient are 18.1 under standard conditions and 15.9 with a delay of six months (a loss of 2.3 LYG per patient). Taking into account units of healthcare resource (HCRU), surgery results on average per patient in 2.25 resource-adjusted life years gained (RALYGs) under standard conditions and 1.98 RALYGs following delay of six months. For 94,912 hospital COVID-19 admissions, there are 474,505 LYGs requiring of 1,097,937 HCRUs. Hospitalisation of community-acquired COVID-19 patients yields on average per patient 5.0 LYG and 0.43 RALYGs. Interpretation: Delay of six months in surgery for incident cancers would mitigate 43% of life years gained by hospitalisation of an equivalent volume of admissions for community acquired COVID-19. This rises to 62% when considering resource-adjusted life-years gained. To avoid a downstream public health crisis of avoidable cancer deaths, cancer diagnostic and surgical pathways must be maintained at normal throughput, with rapid attention to any backlog already accrued. Funding: Breast Cancer Now, Cancer Research UK, Bobby Moore Fund for Cancer Research, National Institute for Health Research (NIHR)

6: The Tumor Profiler Study: Integrated, multi-omic, functional tumor profiling for clinical decision support
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Posted 14 Feb 2020

The Tumor Profiler Study: Integrated, multi-omic, functional tumor profiling for clinical decision support
3,311 downloads medRxiv oncology

Anja Irmisch, Ximena Bonilla, Stéphane Chevrier, Kjong-Van Lehmann, Franziska Singer, Nora C Toussaint, Cinzia Esposito, Julien Mena, Emanuela S Milani, Ruben Casanova, Daniel J Stekhoven, Rebekka Wegmann, Francis Jacob, Bettina Sobottka, Sandra Goetze, Jack Kuipers, Jacobo Sarabia del Castillo, Michael Prummer, Mustafa Tuncel, Ulrike Lischetti, Andrea Jacobs, Stefanie Engler, Sujana Sivapatham, Anja Frei, Gabriele Gut, Joanna Ficek, Reinhard Dummer, Tumor Profiler Consortium, Rudolf Aebersold, Marina Bacac, Franziska Singer, Christian Beisel, Bernd Bodenmiller, Viktor H Koelzer, Holger Moch, Lucas Pelkmans, Berend Snijder, Markus Tolnay, Bernd Wollscheid, Gunnar Rätsch, Mitchell Levesque

Recent technological advances allow profiling of tumor samples to an unparalleled level with respect to molecular and spatial composition as well as treatment response. We describe a prospective, observational clinical study performed within the Tumor Profiler (TuPro) Consortium that aims to show the extent to which such comprehensive information leads to advanced mechanistic insights of a patients tumor, enables prognostic and predictive biomarker discovery, and has the potential to support clinical decision making. For this study of melanoma, ovarian carcinoma, and acute myeloid leukemia tumors, in addition to the emerging standard diagnostic approaches of targeted NGS panel sequencing and digital pathology, we perform extensive characterization using the following exploratory technologies: single-cell genomics and transcriptomics, proteotyping, CyTOF, imaging CyTOF, pharmacoscopy, and 4i drug response profiling (4i DRP). In this work, we outline the aims of the TuPro study and present preliminary results on the feasibility of using these technologies in clinical practice showcasing the power of an integrative multi-modal and functional approach for understanding a tumors underlying biology and for clinical decision support.

7: Post-Exertional Malaise in People with Chronic Cancer-Related Fatigue
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Posted 15 Dec 2019

Post-Exertional Malaise in People with Chronic Cancer-Related Fatigue
2,763 downloads medRxiv oncology

Rosie Twomey, Samuel T. Yeung, James G Wrightson, Guillaume Y Millet, S. Nicole Culos-Reed

ContextCancer-related fatigue (CRF) is a distressing and persistent sense of tiredness or exhaustion that interferes with usual functioning. Chronic CRF continues for months after curative cancer treatment is complete. Post-exertional malaise (PEM) is a worsening of symptoms after physical or mental activity, with limited investigations in people with chronic CRF. ObjectivesThe purpose of this study was to identify and describe self-reported incidences of PEM in people with chronic CRF. MethodsParticipants (n=18) were eligible if they scored [≤]34 on the Functional Assessment of Chronic Illness Therapy-Fatigue scale and had a cancer-related onset of fatigue. Participants completed a brief questionnaire to assess PEM over a 6-month time-frame (the DePaul Symptom Questionnaire - Post-Exertional Malaise; DSQ-PEM). In addition, a maximal exercise test was used to investigate self-reported symptom exacerbation (via an open-ended questionnaire) after strenuous physical exertion. ResultsOn the DSQ-PEM, three participants met previously defined scoring criteria, which included experiencing moderate to very severe symptoms at least half of the time, worsening of fatigue after minimal effort, plus a recovery duration of >24 h. Content analysis of responses to open-ended questionnaires identified five people who experienced a delayed recovery and symptoms of PEM after maximal exercise. ConclusionA subset of people with chronic CRF (up to 33% in this sample) may experience PEM. Exercise specialists and health care professionals working with people with chronic CRF must be aware that PEM may be an issue. Symptom exacerbation after exercise should be monitored, and exercise should be tailored and adapted to limit the potential for harm. Key messageThis study provides preliminary evidence that a subset of people with chronic cancer-related fatigue experience post-exertional malaise.

8: Estimating excess mortality in people with cancer and multimorbidity in the COVID-19 emergency
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Posted 01 Jun 2020

Estimating excess mortality in people with cancer and multimorbidity in the COVID-19 emergency
2,702 downloads medRxiv oncology

Alvina G Lai, Laura Pasea, Amitava Banerjee, Spiros Denaxas, Michail Katsoulis, Wai Hoong Chang, Bryan Williams, Deenan Pillay, Mahdad Noursadeghi, David Linch, Derralynn Hughes, Martin D Forster, Clare Turnbull, Natalie K Fitzpatrick, Kathryn Boyd, Graham R Foster, Matt Cooper, Monica Jones, Kathy Pritchard-Jones, Richard Sullivan, Geoff Hall, Charlie Davie, Mark Lawler, Harry Hemingway

Background: Cancer and multiple non-cancer conditions are considered by the Centers for Disease Control and Prevention (CDC) as high risk conditions in the COVID-19 emergency. Professional societies have recommended changes in cancer service provision to minimize COVID-19 risks to cancer patients and health care workers. However, we do not know the extent to which cancer patients, in whom multi-morbidity is common, may be at higher overall risk of mortality as a net result of multiple factors including COVID-19 infection, changes in health services, and socioeconomic factors. Methods: We report multi-center, weekly cancer diagnostic referrals and chemotherapy treatments until April 2020 in England and Northern Ireland. We analyzed population-based health records from 3,862,012 adults in England to estimate 1-year mortality in 24 cancer sites and 15 non-cancer comorbidity clusters (40 conditions) recognized by CDC as high-risk. We estimated overall (direct and indirect) effects of COVID-19 emergency on mortality under different Relative Impact of the Emergency (RIE) and different Proportions of the population Affected by the Emergency (PAE). We applied the same model to the US, using Surveillance, Epidemiology, and End Results (SEER) program data. Results: Weekly data until April 2020 demonstrate significant falls in admissions for chemotherapy (45-66% reduction) and urgent referrals for early cancer diagnosis (70-89% reduction), compared to pre-emergency levels. Under conservative assumptions of the emergency affecting only people with newly diagnosed cancer (incident cases) at COVID-19 PAE of 40%, and an RIE of 1.5, the model estimated 6,270 excess deaths at 1 year in England and 33,890 excess deaths in the US. In England, the proportion of patients with incident cancer with [≥]1 comorbidity was 65.2%. The number of comorbidities was strongly associated with cancer mortality risk. Across a range of model assumptions, and across incident and prevalent cancer cases, 78% of excess deaths occur in cancer patients with [≥]1 comorbidity. Conclusion: We provide the first estimates of potential excess mortality among people with cancer and multimorbidity due to the COVID-19 emergency and demonstrate dramatic changes in cancer services. To better inform prioritization of cancer care and guide policy change, there is an urgent need for weekly data on cause-specific excess mortality, cancer diagnosis and treatment provision and better intelligence on the use of effective treatments for comorbidities.

9: A systematic review and meta-analysis of cancer patients affected by a novel coronavirus
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Posted 29 May 2020

A systematic review and meta-analysis of cancer patients affected by a novel coronavirus
2,644 downloads medRxiv oncology

Bhanu Prasad Venkatesulu, Viveksandeep Thoguluva Chandrasekar, Prashanth Giridhar, Pragati Advani, Amrish Sharma, Cheng En Hsieh, Thiraviyam Elumalai, Hagar I Elghazawy, Vivek Verma, Sunil Krishnan

Background Cancer patients with COVID-19 disease have been reported to have double the case fatality rate of the general population. Materials and methods A systematic search of PubMed/MEDLINE, Embase, Cochrane Central, Google Scholar, and MedRxiv was done for studies on cancer patients with COVID-19. Pooled proportions were calculated for categorical variables. Odds ratio and forest plots were constructed for both primary and secondary outcomes. The random-effects model was used to account for heterogeneity between studies. Results This systematic review of 31 studies and meta-analysis of 181,323 patients from 26 studies involving 23,736 cancer patients is the largest meta-analysis to the best of our knowledge assessing outcomes in cancer patients affected by COVID-19. Our meta-analysis shows that cancer patients with COVID-19 have a higher likelihood of death (odds ratio, OR 2.54), which was largely driven by mortality among patients in China. Cancer patients were more likely to be intubated, although ICU admission rates were not statistically significant. Among cancer subtypes, the mortality was highest in hematological malignancies (OR 2.43) followed by lung cancer (OR 1.8). There was no association between receipt of a particular type of oncologic therapy and mortality. Our study showed that cancer patients affected by COVID-19 are a decade older than the normal population and have a higher proportion of co-morbidities. There was insufficient data to assess the association of COVID-directed therapy and survival outcomes in cancer patients. Despite the heterogeneity of studies and inconsistencies in reported variables and outcomes, these data could guide clinical practice and oncologic care during this unprecedented global health pandemic. Conclusion Cancer patients with COVID-19 disease are at increased risk of mortality and morbidity. A more nuanced understanding of the interaction between cancer-directed therapies and COVID-19-directed therapies is needed. This will require uniform prospective recording of data, possibly in multi-institutional registry databases.

10: Immune cell topography predicts response to PD-1 blockade in cutaneous T cell lymphoma
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Posted 08 Dec 2020

Immune cell topography predicts response to PD-1 blockade in cutaneous T cell lymphoma
2,505 downloads medRxiv oncology

Darci Phillips, Magdalena Matusiak, Belen Rivero Gutierrez, Salil S. Bhate, Graham L. Barlow, Sizun Jiang, Janos Demeter, Kimberly S Smythe, Robert H. Pierce, Steven P. Fling, Nirasha Ramchurren, Martin A. Cheever, Yury Goltsev, Robert B West, Michael S. Khodadoust, Youn H Kim, Christian M Schuerch, Garry P. Nolan

Anti-PD-1 immunotherapies have transformed cancer treatment, yet the determinants of clinical response are largely unknown. We performed CODEX multiplexed tissue imaging and RNA sequencing on 70 tumor regions from 14 advanced cutaneous T cell lymphoma (CTCL) patients enrolled in a clinical trial of pembrolizumab therapy. Clinical response was not associated with the frequency of tumor-infiltrating T cell subsets, but rather with striking differences in the spatial organization and functional immune state of the tumor microenvironment (TME). After treatment, pembrolizumab responders had a localized enrichment of tumor and CD4+ T cells, which coincided with immune activation and cytotoxic PD-1+ CD4+ T cells. In contrast, non-responders had a localized enrichment of Tregs pre- and post-treatment, consistent with a persistently immunosuppressed TME and exhausted PD-1+ CD4+ T cells. Integrating these findings by computing the physical distances between PD-1+ CD4+ T cells, tumor cells, and Tregs revealed a spatial biomarker predictive of pembrolizumab response. Finally, the chemokine CXCL13 was upregulated in tumor cells in responders post-treatment, suggesting that chemoattraction of PD-1+ CD4+ T cells towards tumor cells facilitates a positive outcome. Together, these data show that T cell topography reflects the balance of effector and suppressive activity within the TME and predicts clinical response to PD-1 blockade in CTCL.

11: Protein Classifier for Thyroid Nodules Learned from Rapidly Acquired Proteotypes
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Posted 14 Apr 2020

Protein Classifier for Thyroid Nodules Learned from Rapidly Acquired Proteotypes
2,381 downloads medRxiv oncology

Yaoting Sun, Sathiyamoorthy Selvarajan, Zelin Zang, Wei Liu, Yi Zhu, Hao Zhang, Hao Chen, Xue Cai, Huanhuan Gao, Zhicheng Wu, Lirong Chen, Xiaodong Teng, Yongfu Zhao, Sangeeta Mantoo, Tony Kiat-Hon Lim, Bhuvaneswari Hariraman, Serene Yeow, Syed Muhammad Fahmy Syed Abdillah, Sze Sing Lee, Guan Ruan, Qiushi Zhang, Tiansheng Zhu, Weibin Wang, Guangzhi Wang, Junhong Xiao, Yi He, Zhihong Wang, Wei Sun, Yuan Qin, Qi Xiao, Xu Zheng, Linyan Wang, Xi Zheng, Kailun Xu, Yingkuan Shao, Kexin Liu, Shu Zheng, Ruedi Aebersold, Stan Z. Li, Oi Lian Kon, N. Gopalakrishna Iyer, Tiannan Guo

Up to 30% of thyroid nodules cannot be accurately classified as benign or malignant by cytopathology. Diagnostic accuracy can be improved by nucleic acid-based testing, yet a sizeable number of diagnostic thyroidectomies remains unavoidable. In order to develop a protein classifier for thyroid nodules, we analyzed the quantitative proteomes of 1,725 retrospective thyroid tissue samples from 578 patients using pressure-cycling technology and data-independent acquisition mass spectrometry. With artificial neural networks, a classifier of 14 proteins achieved over 93% accuracy in classifying malignant thyroid nodules. This classifier was validated in retrospective samples of 271 patients (91% accuracy), and prospective samples of 62 patients (88% accuracy) from four independent centers. These rapidly acquired proteotypes and artificial neural networks supported the establishment of an effective protein classifier for classifying thyroid nodules.

12: 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
2,380 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.

13: 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
2,370 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.

14: Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers: Long-Term Results of the SABR-COMET Phase II Randomized Trial
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Posted 30 Mar 2020

Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers: Long-Term Results of the SABR-COMET Phase II Randomized Trial
2,341 downloads medRxiv oncology

David A. Palma, Robert Olson, Stephen Harrow, Stewart Gaede, Alexander V. Louie, Cornelis Haasbeek, Liam Mulroy, Michael Lock, George B. Rodrigues, Brian P. Yaremko, Devin Schellenberg, Belal Ahmad, Sashendra Senthi, Anand Swaminath, Neil Kopek, Mitchell Liu, Karen Moore, Suzanne Currie, Roel Schlijper, Glenn S. Bauman, Joanna Laba, X. Melody Qu, Andrew Warner, Suresh Senan

PurposeThe oligometastatic paradigm hypothesizes that patients with a limited number of metastases may achieve long-term disease control, or even cure, if all sites of disease can be ablated. However, long-term randomized data testing this paradigm are lacking. MethodsWe enrolled patients with a controlled primary malignancy and 1-5 metastatic lesions, with all metastases amenable to stereotactic ablative radiotherapy (SABR). We stratified by the number of metastases (1-3 vs. 4-5) and randomized in a 1:2 ratio between palliative standard of care (SOC) treatments (Arm 1) vs. SOC plus SABR (Arm 2). We employed a randomized phase II screening design with a primary endpoint of overall survival (OS), using an alpha of 0.20 (wherein a p-value <0.20 indicates a positive trial). Secondary endpoints included progression-free survival (PFS), toxicity, and quality of life (QOL). Herein we present long-term outcomes from the trial. ResultsBetween 2012 and 2016, 99 patients were randomized (33 in Arm 1, 66 in Arm 2) at 10 centres internationally. Median age was 68 (range 43-89) and the majority (n=59; 60%) were male. The most common primary tumor types were breast (n=18), lung (n=18), colorectal (n=18), and prostate (n=16). Median follow-up was 51 months. Five-year OS was 17.7% in Arm 1 (95% confidence interval [CI]: 6-34%) vs. 42.3% in Arm 2 (95% CI: 28-56%; stratified log-rank p=0.006). Five-year PFS was not reached in Arm 1 (3.2% [95% CI: 0-14%] at 4-years with last patient censored) and was 17.3% (95% CI: 8-30%) in Arm 2 (p=0.001). There were no new grade 2-5 adverse events and no differences in QOL between arms. ConclusionsWith extended follow-up, the impact of SABR on OS was larger in magnitude than in the initial analysis, and durable over time. There were no new safety signals, and SABR had no detrimental impact on QOL. (NCT01446744) FundingOntario Institute for Cancer Research and London Regional Cancer Program Catalyst Grant

15: A tertiary center experience of multiple myeloma patients with COVID-19: lessons learned and the path forward
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Posted 05 Jun 2020

A tertiary center experience of multiple myeloma patients with COVID-19: lessons learned and the path forward
2,113 downloads medRxiv oncology

Bo Wang, Oliver Van Oekelen, Tarek Mouhieddine, Diane Marie Del Valle, Joshua Richter, Hearn Jay Cho, Shambavi Richard, Ajai Chari, Sacha Gnjatic, Miriam Merad, Sundar Jagannath, Samir Parekh, Deepu Madduri

Background: The COVID-19 pandemic, caused by SARS-CoV-2 virus, has resulted in over 100,000 deaths in the United States. Our institution has treated over 2,000 COVID-19 patients during the pandemic in New York City. The pandemic directly impacted cancer patients and the organization of cancer care. Mount Sinai Hospital has a large and diverse multiple myeloma (MM) population. Herein, we report the characteristics of COVID-19 infection and serological response in MM patients in a large tertiary care institution in New York. Methods: We performed a retrospective study on a cohort of 58 patients with a plasma-cell disorder (54 MM, 4 smoldering MM) who developed COVID-19 between March 1, 2020 and April 30, 2020. We report epidemiological, clinical and laboratory characteristics including persistence of viral detection by polymerase chain reaction (PCR) and anti-SARS-CoV-2 antibody testing, treatments initiated, and outcomes. Results: Of the 58 patients diagnosed with COVID-19, 36 were hospitalized and 22 were managed at home. The median age was 67 years; 52% of patients were male and 63% were non-white. Hypertension (64%), hyperlipidemia (62%), obesity (37%), diabetes mellitus (28%), chronic kidney disease (24%) and lung disease (21%) were the most common comorbidities. In the total cohort, 14 patients (24%) died. Older age (>70 years), male sex, cardiovascular risk, and patients not in complete remission (CR) or stringent CR were significantly (p<0.05) associated with hospitalization. Among hospitalized patients, laboratory findings demonstrated elevation of traditional inflammatory markers (CRP, ferritin, D-dimer) and a significant (p<0.05) association between elevated inflammatory markers, severe hypogammaglobulinemia, non-white race, and mortality. Ninety-six percent (22/23) of patients developed antibodies to SARS-CoV-2 at a median of 32 days after initial diagnosis. Median time to PCR negativity was 43 (range 19-68) days from initial positive PCR. Conclusions: Drug exposure and MM disease status at the time of contracting COVID-19 had no bearing on mortality. Mounting a severe inflammatory response to SARS-CoV-2 and severe hypogammaglobulinemia were associated with higher mortality. The majority of patients mounted an antibody response to SARS-CoV-2. These findings pave a path to identification of vulnerable MM patients who need early intervention to improve outcome in future outbreaks of COVID-19.

16: Factors affecting COVID-19 outcomes in cancer patients - A first report from Guys Cancer Centre in London
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Posted 19 May 2020

Factors affecting COVID-19 outcomes in cancer patients - A first report from Guys Cancer Centre in London
2,112 downloads medRxiv oncology

Beth Russell, Charlotte Moss, Sophie Papa, Sheeba Irshad, Paul Ross, James Spicer, Shahram Kordasti, Danielle Crawley, Harriet Wylie, Fidelma Cahill, Anna Haire, Kamarul Zaki, Fareen Rahman, Ailsa Lumsden, Debra Josephs, Deborah Enting, Mary Lei, Sharmistha Ghosh, Claire Harrison, Angela Swampillai, Elinor Sawyer, Andrea D'Souza, Simon Gomberg, Paul Fields, David Wrench, Kavita Raj, Mary Gleeson, Kate Bailey, Richard Dillon, Matthew Streetly, Anna Rigg, Richard Sullivan, Saoirse Dolly, Mieke Van Hemelrijck

Background: There is insufficient evidence to support clinical decision-making for cancer patients diagnosed with COVID-19 due to the lack of large studies. Methods: We used data from a single large UK Cancer Centre to assess demographic/clinical characteristics of 156 cancer patients with a confirmed COVID-19 diagnosis between 29 February-12 May 2020. Logistic/Cox proportional hazards models were used to identify which demographic and/or clinical characteristics were associated with COVID-19 severity/death. Results: 128 (82%) presented with mild/moderate COVID-19 and 28 (18%) with severe disease. Initial diagnosis of cancer >24m before COVID-19 (OR:1.74 (95%CI: 0.71-4.26)), presenting with fever (6.21 (1.76-21.99)), dyspnoea (2.60 (1.00-6.76)), gastro-intestinal symptoms (7.38 (2.71-20.16)), or higher levels of CRP (9.43 (0.73-121.12)) were linked with greater COVID-19 severity. During median follow-up of 47d, 34 patients had died of COVID-19 (22%). Asian ethnicity (3.73 (1.28-10.91), palliative treatment (5.74 (1.15-28.79), initial diagnosis of cancer >24m before (2.14 (1.04-4.44), dyspnoea (4.94 (1.99-12.25), and increased CRP levels (10.35 (1.05-52.21)) were positively associated with COVID-19 death. An inverse association was observed with increased levels of albumin (0.04 (0.01-0.04). Conclusions: A longer-established diagnosis of cancer was associated with increasing severity of infection as well as COVID-19 death, possibly reflecting effects of more advanced malignant disease impact on this infection. Asian ethnicity and palliative treatment were also associated with COVID-19 death in cancer patients.

17: SARS-CoV-2 transmission in cancer patients of a tertiary hospital in Wuhan
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Posted 25 Feb 2020

SARS-CoV-2 transmission in cancer patients of a tertiary hospital in Wuhan
2,078 downloads medRxiv oncology

Jing Yu, Wen Ouyang, Melvin L.K. Chua, Conghua Xie

In December 2019, an outbreak of atypical pneumonia known as 2019 novel coronavirus disease (COVID-19) occurred in Wuhan, China. This new type of pneumonia is characterized by rapid human-to-human transmission. Among the different disease types, cancer patients are often recalled to the hospital for treatment and disease surveillance, and the majority of cancer treatments such as chemotherapy and radiotherapy are immunosuppressive. This prompts us to consider if cancer patients were at an elevated risk of SARS-CoV-2 infection. A total of 1,524 cancer patients who were managed at our tertiary cancer institution - Zhongnan hospital of Wuhan University were reviewed during the period of Dec 30, 2019 to Feb 17, 2020. It was found that cancer patients had an estimated 2-fold increased risk of COVID-19 than the general population. We identified twelve patients who were infected with SARS-CoV-2, with two recorded deaths (16.7%), albeit one patient passed away from a COVID-19 unrelated cause. Interestingly, only five of these patients were ongoing treatment at the time of contracting the virus, suggesting that hospital visitation was the likely factor contributing to the elevated incidence in cancer patients. Moreover, we also observed that the incidence of severe COVID-19 was not higher than in the general population. Consequently, for cancer patients who require treatment, proper isolation protocols must be in place to mitigate the risk of SARS-CoV-2 infection.

18: The impact of the COVID-19 pandemic on quality of life, physical and psychosocial wellbeing in breast cancer patients and survivors - A prospective, multicenter cohort study
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Posted 28 Jun 2020

The impact of the COVID-19 pandemic on quality of life, physical and psychosocial wellbeing in breast cancer patients and survivors - A prospective, multicenter cohort study
2,059 downloads medRxiv oncology

Claudia A Bargon, Marilot CT Batenburg, Lilianne E van Stam, Dieuwke R Mink van der Molen, Iris E van Dam, Femke van der Leij, Inge O Baas, Miranda F Ernst, Wiesje Maarse, Nieke Vermulst, Ernst JP Schoenmaeckers, Thijs van Dalen, Rhode M Bijlsma, Danny A Young-Afat, Annemiek Doeksen, Helena M Verkooijen

Purpose: The COVID-19 pandemic and the resulting social distancing and lockdown measures are having a substantial impact on daily life and medical management of people with breast cancer. We evaluated to what extent these changes have affected quality of life and physical, and psychosocial wellbeing of people (being) treated for breast cancer. Methods: This study was conducted within the prospective Utrecht cohort for Multiple BREast cancer intervention studies and Long-term evaluation (UMBRELLA). Shortly after the implementation of COVID-19 measures, extra questionnaires were sent to 1595 cohort participants, including standard UMBRELLA quality of life (EORTC) questionnaires. Patient-reported outcomes (PROs) were compared to the most recent PROs collected within UMBRELLA before COVID-19. The impact of COVID-19 on PROs was evaluated using mixed models analysis. Results: In total, 1051 patients (66%) completed the questionnaires. One third (n = 327, 31%) reported a higher threshold to contact their general practitioner due to COVID-19. A significant deterioration in emotional functioning was observed (82.6 to 77.9, p < 0.001) and 505 (48%, 95% CI 45-51) patients reported moderate to severe loneliness. Small significant improvements were observed in QoL, physical-, social- and role functioning scores. In the subgroup of 51 patients under active treatment, there was a strong deterioration in social functioning (69.8 to 5.0, p = 0.03). Conclusion: Due to COVID-19, patients (being) treated for breast cancer are less likely to contact physicians, and experience a deterioration in emotional functioning. Patients undergoing active treatment report a strong drop in social functioning. One in two patients reports (severe) loneliness. Online applications facilitating peer contact and e-mental health interventions could support mental health and social interaction times of total lockdown or social distancing.

19: SARS-CoV-2 seropositivity and seroconversion in patients undergoing active cancer-directed therapy
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Posted 16 Jan 2021

SARS-CoV-2 seropositivity and seroconversion in patients undergoing active cancer-directed therapy
2,045 downloads medRxiv oncology

Lova Sun, Sanjna Surya, Noah G., Anh N. Le, Gregory Kelly, Olutosin Owoyemi, Heena Desai, Cathy Zheng, Shannon DeLuca, Madeline L. Good, Jasmin Hussain, Seth D. Jeffries, Yolanda R. Kry, Emily M. Kugler, Maikel Mansour, John Ndicu, AnnaClaire Osei-Akoto, Timothy Prior, Stacy L. Pundock, Lisa A. Varughese, JoEllen Weaver, Abigail Doucette, Scott Dudek, Shefali Setia Verma, Sigrid Gouma, Madison E. Weirick, Christopher M. McAllister, Erin Bange, Peter Gabriel, Marylyn Ritchie, Daniel J Rader, Robert H Vonderheide, Lynn M Schuchter, Anurag Verma, Ivan Maillard, Ronac Mamtani, Scott E. Hensley, Robert Gross, E. Paul Wileyto, Alexander C Huang, Kara N. Maxwell, Angela DeMichele

Multiple studies have demonstrated the negative impact of cancer care delays during the COVID-19 pandemic, and transmission mitigation techniques are imperative for continued cancer care delivery. To gauge the effectiveness of these measures at the University of Pennsylvania, we conducted a longitudinal study of SARS-CoV-2 antibody seropositivity and seroconversion in patients presenting to infusion centers for cancer-directed therapy between 5/21/2020 and 10/8/2020. Participants completed questionnaires and had up to five serial blood collections. Of 124 enrolled patients, only two (1.6%) had detectable SARS-CoV-2 antibodies on initial blood draw, and no initially seronegative patients developed newly detectable antibodies on subsequent blood draw(s), corresponding to a seroconversion rate of 0% (95%CI 0.0-4.1%) over 14.8 person-years of follow up, with a median of 13 healthcare visits per patient. These results suggest that cancer patients receiving in-person care at a facility with aggressive mitigation efforts have an extremely low likelihood of COVID-19 infection.

20: 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
2,011 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.

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