Most downloaded biology preprints, all time
in category oncology
396 results found. For more information, click each entry to expand.
6,781 downloads medRxiv oncology
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.
4,561 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)
4,432 downloads medRxiv oncology
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.
3,523 downloads medRxiv oncology
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.
2,220 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 Menzel, Andrea Jacobs, Stefanie Engler, Sujana Sivapatham, Anja Frei, Gabriele Gut, Joanna Ficek, Reinhard Dummer, Tumor Profiler Consortium, Rudolf Aebersold, Marina Bacac, Niko Beerenwinkel, 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.
1,923 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
1,847 downloads medRxiv oncology
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.
1,546 downloads medRxiv oncology
Alvina 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.
1,484 downloads medRxiv oncology
OBJECTIVETo study clinical characteristics of cancer patients infected with COVID-19. Outcomes of cancer patients were the key contents of this study. DESIGNRetrospective study. SETTINGFour designated COVID-16 hospitals in Wuhan, Hubei province, China. PARTICIPANTSMedical records of 67 cancer patients admitted to hospitals between Jan 5, 2020 to Feb 18, 2020 were included. MAIN OUTCOME MEASURESDemographic, clinical, laboratory, radiological and treatment data were collected. Survival data of the cohort was cut-off on Mar 10, 2020. RESULTSOf the 67 patients (median age: 66 years), the median age of patients who had severe illness was older than that of patients who had mild symptoms (P<0.001). Forty-three (64.2%) patients had other concurrent chronic diseases, and the proportion of severe patients had co-morbidities was higher than patients with mild disease (P=0.004). Twenty-three (34.3%) patients were still at the anticancer treatment phase, but no tumour progression and recurrence was observed for all the patients during the treatment of COVID-19 pneumonia. About 70% of these patients had fever (n=53, 79.1%) and/or cough (n=50, 74.6%). Lymphocytopenia was the main laboratory finding accompanying increased C-reactive protein and procalcitonin in cancer patients, especially in severe cases. By Mar 10, 2020, 18 (26.9%) patients died from COVID-19, and 39 (58.2%) patients have been discharged. The median age of survivors was younger than that of deaths (P=0.014). Lung cancer (n=15, 22.4%) with COVID-19 was the most common cancer type and accounted for the highest proportion COVID-19 resulted deaths (33.3%, 5/15). We observed a tendency that patients at the follow-up phase had a better prognosis than that at anticancer treatment phase (P=0.095). CONCLUSIONThis study showed COVID-19 patients with cancer seem to have a higher proportion of severe cases and poorer prognosis. The tendency of poor prognosis was more obvious in patients at anticancer treatment phase. We should pay more intensive attentions to cancer patients infected with COVID-19. FundingThis study was funded by Health Commission of Hubei Province Scientific Research Project (WJ2019H002) and Health Commission of Hubei Province Medical Leading Talent Project, and National Key Research and Development Program of China (2020YFC0845500). Role of the Funder/SponsorThe funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Conflict of interestThe authors declare no conflict of interest. Ethical statementApproval of the study protocol was obtained from the Institutional Ethics Committee of hospitals (No. 2020041). The study was undertaken according to the ethical standards of the World Medical Association Declaration of Helsinki. Research in contextO_ST_ABSWHAT IS ALREADY KNOWN ON THIS TOPICC_ST_ABSCancer patients are at higher risk of COVID-19 and more likely having severe disease than those without cancer. We searched PubMed for articles published up to Mar 18, 2020. Only 2 articles that highlighted the risk of cancer patients infected with COVID-19 were identified. The reports were limited by small cases, inadequate clinical and prognostic information. Therefore, an extended study with more cases to reveal the characteristics and to investigate the prognosis of cancer patients with COVID-19 is warranted. WHAT THIS STUDY ADDSThis study involved 67 COVID-19 patients with cancer, the largest of its kind. We confirmed that COVID-19 patients with cancer had a higher proportion of severe cases and poorer prognosis than COVID-19 patients without cancer. We observed a tendency that patients at the follow-up phase had a better prognosis than those who were at anticancer treatment phase. Deaths had older median age and more co-morbidities than and survivors.
1,482 downloads medRxiv oncology
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.
1,454 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.
1,446 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.
1,433 downloads medRxiv oncology
Andrew A. Davis, Wade T. Iams, David Chan, Michael S. Oh, Robert W. Lentz, Neil Peterman, Alex Robertson, Abhik Shah, Rohith Srivas, Timothy Wilson, Nicole Lambert, Peter George, Becky Wong, Haleigh Wood, Jason Close, Ayse Tezcan, Ken Nesmith, Haluk Tezcan, Young Kwang Chae
PurposeTreatment response assessment for patients with advanced solid tumors is complex and existing methods of assessment require greater precision for early disease assessment. Current guidelines rely on imaging, which has limitations such as the long time required before treatment effectiveness can be determined. Serial changes in whole-genome (WG) circulating tumor DNA (ctDNA) were used to detect disease progression early in the treatment course. Methods97 patients with advanced cancer were enrolled, and blood was collected before and after initiation of a new treatment. Plasma cell-free DNA libraries were prepared for either WG or WG bisulfite sequencing. Longitudinal changes in the fraction of ctDNA were quantified to identify molecular progression or response in a binary manner. Study endpoints were agreement with first follow-up imaging (FUI) and stratification of progression-free survival (PFS). ResultsPatients with early molecular progression had shorter PFS (n=14; median 62d) compared to others (n=78; median 263d, HR 12.6 [95% confidence interval 5.8-27.3], log-rank P<10-10, 5 excluded from analysis). All cases with molecular progression were confirmed by FUI and molecular progression preceded FUI by a median of 40d. Sensitivity for the assay in identifying clinical progression was 54%, median 24d into treatment and specificity was 100%. ConclusionsMolecular progression, based on ctDNA data, detected disease progression for cases on treatment with high specificity approximately 6 weeks before follow-up imaging. This technology may enable early course change to a potentially effective therapy, avoiding side effects and cost associated with cycles of ineffective treatment. Translational RelevanceTools for early assessment of treatment response in advanced solid tumors require refinement. We performed baseline and early serial assessments of WG ctDNA to predict treatment response prior to standard of care clinical and radiographic assessments. Our results demonstrated that the blood-based prediction reliably identified molecular progression, approximately 6 weeks before imaging, with very high specificity and positive predictive value across multiple tumor and treatment types. Patients with molecular progression had significantly shorter progression-free survival compared with non-progressors. In addition, a large quantitative decrease in tumor fraction ratio was associated with significant durable benefit. Collectively, these findings demonstrate that cancer-related changes in the blood precede clinical or imaging changes and may inform changes in management earlier in the treatment course to improve long-term patient outcomes and limit cost.
1,199 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.
1,156 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.
1,079 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.
1,074 downloads medRxiv oncology
Darci Phillips, Magdalena Matusiak, Belen Rivero Gutierrez, Salil S. Bhate, Graham L. Barlow, Sizun J 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.
1,010 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 [≤]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.
983 downloads medRxiv oncology
Andreia 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.
983 downloads medRxiv oncology
Hundreds of clinical trials are testing whether combination therapies can increase the anti-tumor activity of Immune Checkpoint Inhibitors (ICIs). We find that the benefits of recently reported and approved combinations involving ICIs are fully accounted for by increasing the chance of a single-agent response (drug independence), with no requirement for additive or synergistic efficacy. Thus, the degree of success of combinations involving ICIs with other therapies is largely predictable.
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