cancer – American ME and CFS Society

Analysis of tumor progression among patients with glioma after COVID-19 infection

Background: As of January 2023, there have been 6.7 million worldwide deaths attributed to SARS-CoV-2 COVID-19, which has impacted outcomes and medical care for all patients. Relatively little is known about the direct effects mediated by the virus on CNS tumor biology, despite the fact that viral neurotropism is well described, various coronavirus receptors have been observed in glioblastoma (GBM) tissues, and differential monocytic infiltration has been proposed to dysregulate the immune microenvironment. We detected a trend of rapid progression following COVID-19 infection among several patients with primary brain tumor patients and sought to systematically evaluate the pace of progression among infected patients in our institution.

Methods: A single-institutional database of COVID-19 patients and an electronic medical record (EMR) search tool were used to identify a total cohort of 67 patients with glioma for retrospective analysis. This included 38 GBMs, 18 IDH-mutant gliomas, 5 ependymomas, 2 pilocytic astrocytomas, 1 diffuse midline glioma, 1 diffuse hemispheric glioma, and 1 ganglioglioma patients, each of whom had a documented COVID-19 infection between June 2020-December 2022. Hyperprogression was defined as tumor increase ≥40% compared to previous scan using RECIST size criteria.

Results: Thirty-nine (58%) patients experienced tumor progression following COVID-19 infection at a median of 34 days (range=1-734 days) after testing positive for COVID-19. Twenty-two (56%) had received COVID-19 vaccine before their infection and 5 (13%) had asymptomatic infections. Twenty-two patients had measurably increased tumor area by a median of 63% (range=10-2,900%), 18 of which constituted hyperprogression;16 patients developed multifocal disease, 8 developed new nodular enhancement, 3 developed leptomeningeal disease (LMD), and 2 experienced increased infiltrative disease alone. Ten patients’ presentation with new glioma was preceded by COVID-19 infection by a median of 31 days. GBM patients represented the majority of progression events, among whom 59% progressed within 60 days of documented infection (median 25 days). This subgroup of GBM with rapid progression within 60 days had a mOS from infection of 5.2 months; 89% had TERT promotor mutations and 42% had MGMT promoter methylation.

Conclusions: Glioma patients appear to have disease progression at an accelerated pace in the first two months after COVID-19 infection. This suggests that glioma patients should continue observing strict precautions to prevent infection and should be clinically monitored vigilantly after infection, with consideration for short interval imaging during treatment. These preliminary data warrant further investigation exploring changes of immune cell infiltration in the tumor microenvironment and the possible correlation between tumor progression and COVID-19.

Source: Tim Gregory, Stephanie Knight, Ashley Aaroe, Barbara Jane O’Brien, Chirag B Patel, Shiao-Pei S. Weathers, Nazanin Majd, Vinay K. Puduvalli, and Carlos Kamiya-Matsuoka. Analysis of tumor progression among patients with glioma after COVID-19 infection.
Journal of Clinical Oncology 2023 41:16_suppl, 2041-2041 https://ascopubs.org/action/showCitFormats?doi=10.1200/JCO.2023.41.16_suppl.2041

Should We Expect an Increase in the Number of Cancer Cases in People with Long COVID?

Abstract:

The relationship between viral infections and the risk of developing cancer is well known. Multiple mechanisms participate in and determine this process. The COVID-19 pandemic caused by the SARS-CoV-2 virus has resulted in the deaths of millions of people worldwide. Although the effects of COVID-19 are limited for most people, a large number of people continue to show symptoms for a long period of time (long COVID). Several studies have suggested that cancer could also be a potential long-term complication of the virus; however, the causes of this risk are not yet well understood. In this review, we investigated arguments that could support or reject this possibility.

Source: Amiama-Roig A, Pérez-Martínez L, Rodríguez Ledo P, Verdugo-Sivianes EM, Blanco J-R. Should We Expect an Increase in the Number of Cancer Cases in People with Long COVID? Microorganisms. 2023; 11(3):713. https://doi.org/10.3390/microorganisms11030713 (Full text)

Long COVID in cancer patients: preponderance of symptoms in majority of patients over long time period

Abstract:

Background: An increasing number of observational studies have reported the persistence of symptoms following recovery from acute COVID-19 disease in non-cancer patients. The long-term consequences of COVID-19 are not fully understood particularly in the cancer patient population. The purpose of this study is to assess post-acute sequelae of SARS-CoV-2 infection (PASC) in cancer patients following acute COVID-19 recovery.

Methods: We identified cancer patients at MD Anderson Cancer Center who were diagnosed with COVID-19 disease between March 1, 2020 and Sept 1, 2020 and followed them till May 2021. To assess PASC, we collected patients reported outcomes through questionnaires that were sent to patients daily for 14 days after COVID-19 diagnosis then weekly for 3 months, and then monthly thereafter. We also reviewed patients’ electronic medical records to capture the persistence or emergence of new COVID19-related symptoms reported during any clinic or hospital encounter beyond 30 days of the acute illness and up to 14 months.

Results: We included 312 cancer patients with a median age of 57 years (18-86). The majority of patients had solid tumors (75%). Of the 312 patients, 188 (60%) reported long COVID-19 symptoms with a median duration of 7 months and up to 14 months after COVID-19 diagnosis. The most common symptoms reported included fatigue (82%), sleep disturbances (78%), myalgias (67%) and gastrointestinal symptoms (61%), followed by headache, altered smell or taste, dyspnea (47%) and cough (46%). A higher number of females reported a persistence of symptoms compared to males (63% vs 37%; p=0.036). Cancer type, neutropenia, lymphocytopenia, and hospital admission during acute COVID-19 disease were comparable in both groups. Among the 188 patients with PASC, only 16 (8.5%) were readmitted for COVID-related reasons.

Conclusions: More than one out of two cancer patients, and more likely females, report PASC that may persist beyond 6 months and even one year. The most common symptoms are non-respiratory and consist of fatigue, sleep disturbance, myalgia and gastro-intestinal symptoms. Most of the cancer patients with PASC were managed on outpatient basis with only 8,5% requiring a COVID-19 related re-admission.

Source: Dagher H, Chaftari AM, Subbiah IM, Malek AE, Jiang Y, Lamie P, Granwehr B, John T, Yepez E, Borjan J, Reyes-Gibby C, Flores M, Khawaja F, Pande M, Ali N, Rojo R, Karp DD, Chaftari P, Hachem R, Raad II. Long COVID in cancer patients: preponderance of symptoms in majority of patients over long time period. Elife. 2023 Feb 7;12:e81182. doi: 10.7554/eLife.81182. Epub ahead of print. PMID: 36748905. https://elifesciences.org/articles/81182 (Full text)

Mild respiratory SARS-CoV-2 infection can cause multi-lineage cellular dysregulation and myelin loss in the brain

Abstract:

Survivors of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection frequently experience lingering neurological symptoms, including impairment in attention, concentration, speed of information processing and memory. This long-COVID cognitive syndrome shares many features with the syndrome of cancer therapy-related cognitive impairment (CRCI). Neuroinflammation, particularly microglial reactivity and consequent dysregulation of hippocampal neurogenesis and oligodendrocyte lineage cells, is central to CRCI. We hypothesized that similar cellular mechanisms may contribute to the persistent neurological symptoms associated with even mild SARS-CoV-2 respiratory infection.

Here, we explored neuroinflammation caused by mild respiratory SARS-CoV-2 infection – without neuroinvasion – and effects on hippocampal neurogenesis and the oligodendroglial lineage. Using a mouse model of mild respiratory SARS-CoV-2 infection induced by intranasal SARS-CoV-2 delivery, we found white matter-selective microglial reactivity, a pattern observed in CRCI. Human brain tissue from 9 individuals with COVID-19 or SARS-CoV-2 infection exhibits the same pattern of prominent white matter-selective microglial reactivity. In mice, pro-inflammatory CSF cytokines/chemokines were elevated for at least 7-weeks post-infection; among the chemokines demonstrating persistent elevation is CCL11, which is associated with impairments in neurogenesis and cognitive function.

Humans experiencing long-COVID with cognitive symptoms (48 subjects) similarly demonstrate elevated CCL11 levels compared to those with long-COVID who lack cognitive symptoms (15 subjects). Impaired hippocampal neurogenesis, decreased oligodendrocytes and myelin loss in subcortical white matter were evident at 1 week, and persisted until at least 7 weeks, following mild respiratory SARS-CoV-2 infection in mice. Taken together, the findings presented here illustrate striking similarities between neuropathophysiology after cancer therapy and after SARS-CoV-2 infection, and elucidate cellular deficits that may contribute to lasting neurological symptoms following even mild SARS-CoV-2 infection.

Source: Fernández-Castañeda A, Lu P, Geraghty AC, Song E, Lee MH, Wood J, Yalçın B, Taylor KR, Dutton S, Acosta-Alvarez L, Ni L, Contreras-Esquivel D, Gehlhausen JR, Klein J, Lucas C, Mao T, Silva J, Peña-Hernández MA, Tabachnikova A, Takahashi T, Tabacof L, Tosto-Mancuso J, Breyman E, Kontorovich A, McCarthy D, Quezado M, Hefti M, Perl D, Folkerth R, Putrino D, Nath A, Iwasaki A, Monje M. Mild respiratory SARS-CoV-2 infection can cause multi-lineage cellular dysregulation and myelin loss in the brain. bioRxiv [Preprint]. 2022 Jan 10:2022.01.07.475453. doi: 10.1101/2022.01.07.475453. PMID: 35043113; PMCID: PMC8764721. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8764721/ (Full text)

Increased risks of cancer and autoimmune disease among the first-degree relatives of patients with myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS)

Abstract:

Background: Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is a disabling multi-system complex disorder with prevalence of 875 per 100,000 (up to 3.4 million people) in the United States. There are no known etiologic or risk factors and no approved treatments for ME/CFS. We conducted a molecular epidemiologic study to test the hypothesis that ME/CFS may be an autoimmune disease (AID) and explore the link between ME/CFS and cancer, specifically hematologic malignancies.Methods: Our clinic-based study involved carefully selected cases with confirmed diagnosis of ME/CFS (n=59) and healthy controls (n=54) frequency matched to cases on age, gender and ethnicity. During structured interviews, detailed multi-generation pedigrees, epidemiologic and medical questionnaires, and biospecimen were obtained on all subjects. Statistical analysis of pedigree data involved comparison of cases and controls with respect to the prevalence and cumulative incidence of AID and cancer among their first-degree relatives. For unadjusted analysis, risk ratios, 95% confidence intervals (CI), and p-values were calculated. For age-adjusted analyses, cumulative incidence estimates were compared using the log-rank test.

Results: The prevalence of AID was significantly higher among the first-degree relatives of cases compared to those of controls (OR=5.30; 95%CI: 1.83-15.38; p=0.001). The prevalence of AID among mothers was 14% for cases and 1.9% for controls (p=0.03). 11.2% of the first-degree relatives of cases had an AID compared to 3.1% of the relatives of controls (prevalence ratio=3.71; 95% CI: 1.74-7.88; p=0.0007). The cumulative incidence of AID among the first-degree relatives of ME/CFS cases was 9.4% compared to 2.7% for those of the controls (p=0.0025). First-degree relatives of ME/CFS cases had a significantly higher prevalence of any cancer compared to the relatives of unrelated controls (OR=4.06, 95%CI: 1.84-8.96, p=0.0005). Age-adjusted analysis revealed significantly higher (p=0.03) cumulative incidence of any cancer among the first-degree relatives of cases (20%) compared to the relatives of controls (15.4%). The cumulative incidence of hematologic cancers was also significantly higher among the relatives of cases (p<0.05).

Conclusions: We found statistically significant increased risks of AID and cancer among the first-degree relatives of ME/CFS cases. Our findings implicate immune dysregulation as an underlying mechanism, providing etiologic clues and leads for prevention. Given symptomatic similarities between ‘long COVID’ and ME/CFS, it is predicted that there will be a significant increase in incidence of ME/CFS as the result of COVID-19 pandemic. Our findings may enable defining a subset of COVID-19 patients who could be at risk of developing ME/CFS, and who may benefit from treatments used for certain AIDs.

Source: Roxana Moslehi, Anil Kumar, Amiran Dzutsev. Increased risks of cancer and autoimmune disease among the first-degree relatives of patients with myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 34. https://aacrjournals.org/cancerres/article/82/12_Supplement/34/700144

Associations of physical and psychiatric conditions with chronic fatigue syndrome in Germany: an exploratory case-control study

Abstract:

Background: Only a few studies have analyzed the effects of physical and psychiatric conditions on the risk of chronic fatigue syndrome (CFS). Therefore, the goal of this exploratory case-control study was to investigate the associations of physical and psychiatric conditions with CFS in almost 19 800 adults from Germany.

Methods: This study included patients diagnosed for the first time with CFS in one of 1238 general practices in Germany between 2010 and 2017 (index date). Controls without CFS were matched (1:1) to cases with CFS by sex, age, index year, and practice. Physical and psychiatric conditions diagnosed in the year prior to the index date were included if they were present in at least 3% of patients with CFS. Associations between physical and psychiatric conditions (33 potential independent variables) and CFS (dependent variable) were analyzed in an adjusted conditional logistic regression model, and physical and psychiatric disorders were included in the model using forward stepwise selection.

Results: This study included 9896 cases with CFS and 9896 controls without CFS [65.1% women; mean (standard deviation) age 49.5 (18.3) years]. Seven conditions were associated with CFS in the adjusted regression model. The disorders displaying the strongest relationship with CFS were cancer [odds ratio (OR) = 2.57, 95% confidence interval (CI) = 2.24-2.95], sleep disorders (OR = 1.88, 95% CI = 1.66-2.12) and depression (OR = 1.77, 95% CI = 1.61-1.95).

Conclusions: Cancer, sleep disorders, and depression were strongly and positively associated with CFS. Additional studies are needed to gain a better understanding of the mechanisms underlying these relationships.

Source: Jacob L, Haro JM, Kostev K. Associations of physical and psychiatric conditions with chronic fatigue syndrome in Germany: an exploratory case-control study [published online ahead of print, 2020 Jul 20]. Psychol Med. 2020;1-7. doi:10.1017/S0033291720002470 https://pubmed.ncbi.nlm.nih.gov/32686638/

Post-exertional Malaise in People With Chronic Cancer-Related Fatigue

Abstract:

CONTEXT: Cancer-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.

OBJECTIVES: The purpose of this study was to identify and describe self-reported incidences of PEM in people with chronic CRF.

METHODS: Participants (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 during a six-month time frame (the DePaul Symptom Questionnaire-PEM). In addition, a maximal exercise test was used to investigate self-reported symptom exacerbation (via an open-ended questionnaire) after strenuous physical exertion.

RESULTS: On the DePaul Symptom Questionnaire-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 hours. Content analysis of responses to open-ended questionnaires identified five people who experienced a delayed recovery and symptoms of PEM after maximal exercise.

CONCLUSION: A 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.

Source: Twomey R, Yeung ST, Wrightson JG, Millet GY, Culos-Reed SN. Post-exertional Malaise in People With Chronic Cancer-Related Fatigue. J Pain Symptom Manage. 2020 Feb 24. pii: S0885-3924(20)30098-1. doi: 10.1016/j.jpainsymman.2020.02.012. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/32105793

Mortality in Patients with Myalgic Encephalomyelitis and Chronic Fatigue Syndrome

Abstract:

BACKGROUND: There is a dearth of research examining mortality in individuals with myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS). Some studies suggest there is an elevated risk of suicide and earlier mortality compared to national norms. However, findings are inconsistent as other researchers have not found significant increases in all-cause mortality for patients.

OBJECTIVE: This study sought to determine if patients with ME or CFS are reportedly dying earlier than the overall population from the same cause.

METHODS: Family, friends, and caregivers of deceased individuals with ME or CFS were recruited through social media, patient newsletters, emails, and advocate websites. This study analyzed data including cause and age of death for 56 individuals identified as having ME or CFS.

RESULTS: The findings suggest patients in this sample are at a significantly increased risk of earlier all-cause (M = 55.9 years) and cardiovascular-related (M = 58.8 years) mortality, and they had a directionally lower mean age of death for suicide (M = 41.3 years) and cancer (M =66.3 years) compared to the overall U.S. population [M = 73.5 (all-cause), 77.7 (cardiovascular), 47.4 (suicide), and 71.1 (cancer) years of age].

CONCLUSIONS: The results suggest there is an increase in risk for earlier mortality in patients with ME and CFS. Due to the small sample size and over-representation of severely ill patients, the findings should be replicated to determine if the directional differences for suicide and cancer mortality are significantly different from the overall U.S. population.

Source: McManimen SL, Devendorf AR, Brown AA, Moore BC, Moore JH, Jason LA. Mortality in Patients with Myalgic Encephalomyelitis and Chronic Fatigue Syndrome. Fatigue. 2016;4(4):195-207. doi: 10.1080/21641846.2016.1236588. Epub 2016 Oct 12. https://www.ncbi.nlm.nih.gov/pubmed/28070451

Chronic Fatigue Syndrome (CFS) and Cancer Related Fatigue (CRF): two “fatigue” syndromes with overlapping symptoms and possibly related aetiologies

Abstract:

In July 2010, at the Muscle Fatigue Meeting, I presented an overview of Chronic Fatigue Syndrome and Cancer Related Fatigue, emphasizing a critical interpretation of the potential association between Chronic Fatigue Syndrome and Cancer Related Fatigue and a newly discovered retrovirus: Xenotropic Murine Related Virus. Since this association was hotly debated at that time, I suggested at the Meeting that it was wrong and most likely due to the identification of the wrong virus culprit.

Today, 20 months after the Meeting, the first part of our prediction has turned out to be correct, as Xenotropic Murine Related Virus was shown to be a laboratory-created artefact. Still, the potential association of fatigue-syndromes with an infection (most likely viral) is sustained by a plethora of evidence and this overview will initially summarize data suggesting prior viral infection(s). The principal hypothesized mechanisms for both peripheral and central Chronic Fatigue Syndrome/Cancer Related Fatigue will be then summarized, also indicating plausible associations and triggering factors.

All evidence accrued so far suggests that further research work should be performed in this interesting area and in order to identify an infectious agent for Chronic Fatigue Syndrome/Cancer Related Fatigue. One candidate RNA virus, Micro-Foci inducing Virus, will be described in this overview.

Source: Rovigatti U. Chronic Fatigue Syndrome (CFS) and Cancer Related Fatigue (CRF): two “fatigue” syndromes with overlapping symptoms and possibly related aetiologies. Neuromuscul Disord. 2012 Dec;22 Suppl 3:S235-41. doi: 10.1016/j.nmd.2012.10.018. https://www.ncbi.nlm.nih.gov/pubmed/23182646

Chronic fatigue syndrome and subsequent risk of cancer among elderly US adults

Abstract:

BACKGROUND: The cause of chronic fatigue syndrome (CFS) is unknown but is thought to be associated with immune abnormalities or infection. Because cancer can arise from similar conditions, associations between CFS and cancer were examined in a population-based case-control study among the US elderly.

METHODS: Using linked Surveillance, Epidemiology, and End Results (SEER)-Medicare registry data, approximately 1.2 million cancer cases and 100,000 controls (age range, 66-99 years; 1992-2005) were evaluated. CFS was identified in the period more than 1 year prior to selection, using linked Medicare claims. Unconditional logistic regression was used to estimate the odds ratios (ORs) comparing the CFS prevalence in cases and controls, adjusting for age, sex, and selection year. All statistical tests were 2-sided.

RESULTS: CFS was present in 0.5% of cancer cases overall and 0.5% of controls. CFS was associated with an increased risk of non-Hodgkin lymphoma (NHL) (OR = 1.29, 95% confidence interval [CI] = 1.16-1.43, P = 1.7 × 10(-6) ). Among NHL subtypes, CFS was associated with diffuse large B cell lymphoma (OR = 1.34, 95% CI = 1.12-1.61), marginal zone lymphoma (OR = 1.88, 95% CI = 1.38-2.57), and B cell NHL not otherwise specified (OR = 1.51, 95% CI = 1.03-2.23). CFS associations with NHL overall and NHL subtypes remained elevated after excluding patients with medical conditions related to CFS or NHL, such as autoimmune conditions. CFS was also associated, although not after multiple comparison adjustment, with cancers of the pancreas (OR = 1.25, 95% CI = 1.07-1.47), kidney (OR = 1.27, 95% CI = 1.07-1.49), breast (OR = 0.85, 95% CI = 0.74-0.98), and oral cavity and pharynx (OR = 0.70, 95% CI = 0.49-1.00).

CONCLUSIONS: Chronic immune activation or an infection associated with CFS may play a role in explaining the increased risk of NHL.

Source: Chang CM, Warren JL, Engels EA. Chronic fatigue syndrome and subsequent risk of cancer among elderly US adults. Cancer. 2012 Dec 1;118(23):5929-36. doi: 10.1002/cncr.27612. Epub 2012 May 30. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3434293/ (Full article)