Cardiovascular disease (CVD) and cancer share several risk factors. Although preclinical models show that various types of CVD can accelerate cancer progression, clinical studies have not determined the impact of atherosclerosis on cancer risk.
Objectives
The objectives were to determine whether CVD, especially atherosclerotic CVD, is independently associated with incident cancer.
Methods
Using IBM MarketScan claims data from over 130 million individuals, 27 million cancer-free subjects with a minimum of 36 months of follow-up data were identified. Individuals were stratified by presence or absence of CVD, time-varying analysis with multivariable adjustment for cardiovascular risk factors was performed, and cumulative risk of cancer was calculated. Additional analyses were performed according to CVD type (atherosclerotic vs nonatherosclerotic) and cancer subtype.
Results
Among 27,195,088 individuals, those with CVD were 12% more likely to develop cancer than those without CVD (HR: 1.12; 95% CI: 1.11-1.13). Results were more pronounced for individuals with atherosclerotic CVD (aCVD), who had a higher risk of cancer than those without CVD (HR: 1.20; 95% CI: 1.19-1.21). aCVD also conferred a higher risk of cancer compared with those with nonatherosclerotic CVD (HR: 1.11; 95% CI: 1.11-1.12). Cancer subtype analyses showed specific associations of aCVD with several malignancies, including lung, bladder, liver, colon, and other hematologic cancers.
Conclusions
Individuals with CVD have an increased risk of developing cancer compared with those without CVD. This association may be driven in part by the relationship of atherosclerosis with specific cancer subtypes, which persists after controlling for conventional risk factors.
Pancreatic intraepithelial neoplasia (PanIN) lesions were detected in a majority of healthy pancreata from deceased donors of diverse age and harbored features of pancreatic cancer, according to a study published inCancer Discovery, a journal of theAmerican Association for Cancer Research.
Pancreatic cancer is a rare but highly fatal disease, with a five-year relative survival rate of 11.5%. With few early symptoms, it is typically diagnosed at advanced stages when it is more difficult to treat. Pancreatic cancer may be preceded by several precancer lesions, including PanINs, intraductal papillary mucinous neoplasms, and mucinous cystic neoplasms.
“Understanding how pancreatic tissue evolves as it transitions from normal to precancerous to cancerous will be key to identifying strategies for early detection, prevention, and treatment of pancreatic cancer,” said Marina Pasca di Magliano, PhD, one of the co-corresponding authors of the study, a researcher at the Rogel Cancer Center, and a professor of surgery and of cell and developmental biology at Michigan Medicine at the University of Michigan. “Unfortunately, it has been difficult to understand the baseline characteristics of the pancreas due to a lack of normal pancreatic tissue available for research.”
“Since there is no reason to biopsy or resect a physiologically normal pancreas, researchers have had to rely on the tissue surrounding pancreatic tumors as the so-called normal,” explained Timothy Frankel, MD, co-corresponding author, a researcher at the Rogel Cancer Center, and an associate professor and surgical oncologist at Michigan Medicine at the University of Michigan. “However, it is clear that the tissue adjacent to tumors is very abnormal looking and is not a reliable surrogate for true, healthy pancreatic tissue.”
To characterize normal pancreatic tissue, Pasca di Magliano, Frankel, and colleagues, including first author Eileen Carpenter, MD, PhD, partnered with Gift of Life Michigan to obtain healthy pancreata from 30 recently deceased donors for whom no suitable transplant recipients were identified. Because the pancreata were donated following brain death, blood flow was maintained until the organ could be resected and immediately cooled, which limited warm ischemic time and helped preserve the cellular and transcriptomic profile of the tissue.
Donors were between 20 and 70 years old at the time of death and did not have any pancreatic diseases. There were 20 male and 10 female donors. Approximately two-thirds of donors were white, approximately one-third were African American, one donor was Asian, and one donor was of unknown race.
Using tissue collected from various regions of the pancreas, the researchers performed histopathologic analyses, which revealed the presence of PanINs in 18 of the 30 donor pancreata, representing all age and racial groups.
Analysis of the tissue immediately surrounding the PanIN lesions showed that the PanIN microenvironment was rich in fibroblasts, myeloid cells, and T cells, making it distinct from that of histologically normal pancreatic tissue.
To understand how the PanIN lesions of healthy donors compared with pancreatic tumors, the authors compared the microenvironment and gene expression of PanINs with previously published data of pancreatic cancer cells. They found that PanINs and pancreatic tumors had distinct microenvironments but similar gene expression patterns. Compared with the PanIN microenvironment, the tumor microenvironment had lower levels of acinar and endothelial cells and a greater proportion of macrophages and CD4+ T cells.
“By analyzing true normal pancreata, we found that PanINs were commonly found in individuals of diverse age and race, and may have already acquired some features of malignant cells,” summarized Carpenter, who is a researcher at the Rogel Cancer Center, and a gastroenterologist and assistant professor at Michigan Medicine at the University of Michigan. “Given that pancreatic cancer is exceedingly rare, the widespread occurrence of PanINs in individuals of various age and race challenges the paradigm that PanINs always evolve into cancer.”
“Prior efforts at early detection have focused on finding the PanIN lesions, with the assumption that individuals with PanINs would be the ones at risk of developing pancreatic cancer, but our findings suggest that additional factors are involved,” said Frankel.
“Understanding why some PanINs evolve to cancer and others do not will be important to accurately predict who is at risk of pancreatic cancer and to develop techniques for cancer interception,” Pasca di Magliano said. “The composition of the microenvironments surrounding PanINs might be a key factor.”
A limitation of the study was the inability to observe changes in the pancreas over time or to examine the impact of therapeutic interventions, the authors noted. “The tissue we examined provided only a snapshot of the pancreas at the time of the donor’s death,” said Pasca di Magliano. An additional limitation was the small sample size.
The study was supported by the National Institutes of Health, the Veterans Affairs Biomedical Laboratory and Research Development Awards, the American College of Gastroenterology, the Rackham International Student Fellowship, the CCSG Bioinformatics Shared Resource, the Association for Academic Surgery, and the Joel J. Roslyn Award. Pasca di Magliano, Frankel, and Carpenter declare no conflicts of interest.
After several unsuccessful rounds of chemotherapy, his doctor, Alan Tan of Rush University Medical Center in Chicago, recommended that he switch to Pluvicto, a new medication for advanced prostate cancer.
But the drug’s manufacturer, Novartis, has had supply problems. Landfair is now on a waitlist for the medication, which isn’t expected to be widely available for several more months.
“I definitely need that drug,” Landfair, of Chicago, said. “It’s the only way I see my life.”
His family says his cancer is “aggressive and still growing.”
“We realize the cancer is not on a hold period, it’s not on hiatus,” Raymond Jackson, Landfair’s son-in-law, said. “We’re very concerned.”
Robert Landfair is waiting for the cancer drug Pluvicto, which is in shortage.Raymond Jackson
Landfair’s not alone: A shortage of cancer medications has created dire circumstances for many patients diagnosed with the disease, forcing them — along with their doctors — to make difficult decisions.
According to the Food and Drug Administration, there are four cancer drugs in shortage: Pluvicto, for advanced prostate cancer; BCG, a drug for bladder cancer; and methotrexate and cisplatin, two common chemotherapy drugs. A fifth drug, fluorouracil, is also in shortage, according to the American Society of Health-System Pharmacists, a group that tracks nationwide drug shortages.
In places where cancer medications are running low, some patients may be forced to turn to options that may not work as well, experts say. Others may die waiting for the medications in shortage to become available. Every day counts: A study published in 2020 in The BMJ found that every month delayed in cancer treatment can raise the risk of death by around 10%.
“We’re kind of handcuffed here as oncologists,” said Tan, who is the director of genitourinary medical oncology at Rush.
Tan’s hospital faces a shortage of Pluvicto and cisplatin.
“This is a patient’s life,” he said, adding that patients are “going to die” if they don’t get the drugs they need.
What’s causing cancer drug shortages?
Michael Ganio, the senior director of pharmacy practice at the American Society of Health-System Pharmacists, blamed the cancer drug shortage on a lack of investment from manufacturers.
Many of the cancer drugs in shortage are generic medications, which save the nation’s health care system money overall but are not very profitable for drugmakers.
“There’s little incentive to invest in generic manufacturing, oftentimes, especially for these much older drugs — the margins aren’t very big,” Ganio said. “It’s almost a disincentive.”
Erin Fox, senior pharmacy director at the University of Utah Health, said poor manufacturing practices at U.S. factories have also contributed to drug shortages overall.
The shortage of medications, including lifesaving cancer drugs, could get worse in the coming years as more drug production moves overseas, Fox said.
"A key challenge in evaluating drug shortages is that drug companies are not required to disclose exactly which company is making the product as well as the location," she said, noting that manufacturing is often outsourced abroad.
Sarah Ryan, a spokesperson for Pharmaceutical Research and Manufacturers of America, the drug industry’s trade group, said manufacturers have “extensive measures” to help prevent and mitigate drug shortages.
A report published in Marchby the Senate Committee on Homeland Security and Governmental Affairs found that new drug shortages in the U.S. increased by nearly 30% from 2021 to 2022. The medications included prescription drugs and children’s cold and flu medicine as well as medications used to treat cancer, according to the report.
The FDA is working to curb the trend. This month, the agency released 17 pages of draft guidance intended to prevent drug shortages. It would require drugmakers to give the agency more advance notice — at least six months — about potential shortages or discontinuation of a drug as well as more information about what’s causing the problem.
Less than ideal care
In the meantime, more cancer patients may get less than ideal care, said Packiam, of the University of Iowa Hospitals and Clinics.
Packiam learned within the last week that his hospital had run low on cisplatin, a chemotherapy drug that is commonly used for bladder cancer and improves the likelihood that surgery will be successful.
It is “generally regarded as the gold standard treatment for this type of cancer,” he said.
The shortage of cisplatin means he’ll need to perform surgery without chemotherapy.
“Alternative chemotherapies that do not use cisplatin do not yield as good of a response,” he said. “So rather than give a suboptimal chemotherapy, the next best option is to proceed directly with surgery.”
The hospital will also have to prioritize what cisplatin it has left for those most in need, he said.
For those who don’t get their cancer medications immediately, all they can do is hope.
Landfair, the cancer patient who is waiting for Pluvicto, is optimistic, though doubt sometimes creeps in.
“My biggest fear is I won’t get that medication started,” he said.
opens in a new tab or window to pain management. At the end of the meeting, as expected, panelists concluded that more research was needed. However, to my surprise, several scientists also called for immediate action on the approach to treating low back pain. They called for clinicians to implement the evidence we already have into clinical practice; for policymakers to enact payment reform that would support such implementation; for all of us to commit to making the cultural changes needed to ensure that patients have access to the right care from the right provider at the right time.
Where did this response come from? It stemmed from the fact that low back pain has been over-medicalized, making a very bad problem worse, and the need for realigned incentives that encourage clinicians to follow current evidence and treatment recommendations.
The problem is not the lack of evidence. The CDCopens in a new tab or window, the Veterans Health Administrationopens in a new tab or window, and the American College of Physiciansopens in a new tab or window (ACP) have released comprehensive guidelines backed by highly convergent supportive evidence for the management of low back pain. Recommended first line treatments include non-pharmacological approaches such as exercise, education, self-care options, spinal manipulation, acupuncture, and massage. The ACP guideline in particular calls for patients and clinicians to consider the use of non-pharmacological treatment approaches for low back pain before trying prescription medications.
The problem is that we are not following the evidence. There are multiple barriers to widespread implementation of known best practices. Health systems are slow to change, especially when such change may not be in their financial best interests. Orthopedic surgeons are consistently rated among the top health system income generators, bringing in an average of $3.3 million per yearopens in a new tab or window. Primary care physicians may not have learned about non-pharmacological treatments in medical school and are often working with frightened patients who understandably want a clear explanation for their pain and a quick fix -- a pill, an injection, even surgery.
Additionally, there is a sharp disconnect between existing payment policy and best practices for low back pain. Payors provide robust reimbursement for prescription medications, corticosteroid injections, and surgery. In contrast, private and public insurers often place significant limitations
opens in a new tab or window on coverage for guideline concordant treatments such as chiropractic care, acupuncture, and massage. Such policies offer little incentive for clinicians and health systems to change.
Health systems can ensure they are staffed with providers whose clinical practices are better aligned with guideline recommendations. Payors can change their policies to align payment with guideline recommendations. Some health systems and insurance companies are moving in the right direction. Duke University Health System has instituted the Spine Health Programopens in a new tab or window to offer coordinated, guideline-concordant care to patients with low back pain. United Healthcare does not charge co-paysopens in a new tab or window for members who see a chiropractor or physical therapist first for low back pain. Traditional Medicare recently began offering limited coverage for acupunctureopens in a new tab or window.
We also need to promote clinician education on the evidence regarding proper diagnosis and treatment of low back pain. We can become familiar with the ACP Guideline and read the excellent Lancet series
opens in a new tab or window on low back pain. We can tell our patients that MRIs can lead to worse outcomes, surgery is rarely necessary, and let them know that the ACP recommends the use of non-pharmacological treatments before prescription medications. Most importantly, we can, in the absence of red flags, refrain from ordering those tests or treatments unless they are clearly needed after the patient engages in a full course of evidence-based non-pharmacological treatment.
I can't ignore the fact that part of the issue is systemic: the U.S. healthcare system is built upon the belief that patients benefit from seeking care. But that is often not the case for low back pain. By ignoring the evidence, over-medicalizing this condition, and continuing to tolerate policies that incentivize the wrong treatments, we are causing real harm to those who trust us to care for them.
Christine Goertz, DC, PhD,opens in a new tab or window is a professor in musculoskeletal research at the Duke Clinical Research Institute n Durham, North Carolina, vice chair for Implementation of Spine Health Innovations in the Department of Orthopaedic Surgery at Duke University, and core faculty at the Duke Margolis Center for Health Policy.
Data from small trials will determine whether an FDA advisory panel recommends the agency approve sulbactam‐durlobactam for hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) caused by Acinetobacter baumannii‐calcoaceticus complex (ABC) infections.
On Monday, the Antimicrobial Drugs Advisory Committeeopens in a new tab or window will weigh in on whether the benefit-risk assessment of sulbactam‐durlobactam is favorable based on evidence submitted by developer Entasis Therapeutics, which is specifically seeking an indication for the combination as a treatment for HABP/VABP cases involving susceptible strains of Acinetobacter spp., including carbapenem‐resistant ABC (CRABC) organisms.
"CRABC infections represent an urgent threat in the United States due to the emergence and rapid spread of Acinetobacter resistance and limited treatment options," FDA staff wrote in a briefing document
Data supporting Entasis Therapeutics' application include a phase III trial (ATTACK) involving 177 patients, most with HABP/VABP infections; a phase II study, mostly involving complicated urinary tract infections; and six phase I studies totaling about 200 patients.
Sulbactam‐durlobactam is an investigational intravenous drug consisting of a combination of sulbactam, a β-lactam antibiotic, and durlobactam, a β-lactamase inhibitor, in development for the treatment of ABC infections, including multi-drug and CRABC strains.
Overall, FDA staff noted that sulbactam‐durlobactam "demonstrated non-inferiority" in the randomized, assessor‐blinded, active‐controlled study in hospitalized adults, primarily with HABP (43%) and VABP (53%) caused by CRABC; 2% had bacteremia, and 2% had ventilator pneumonia.
With 28-day mortality as the primary endpoint, results among the 125 patients showed that sulbactam‐durlobactam was non-inferior to colistin, a last-resort antibiotic for CRABC (19% vs 32.3%).
As for secondary endpoints, 14-day all-cause mortality for the CRABC microbiologically modified intent-to-treat group was 6.3% in those who received sulbactam‐durlobactam versus 19% of those who received colistin, a difference also within the non-inferiority margin.
However, "it is important to note the limited size of the current safety database" for sulbactam‐durlobactam, FDA staff wrote.
Compared with the colistin group, the sulbactam‐durlobactam group experienced fewer serious adverse events (48.8% vs 39.6%) and treatment-emergent adverse events (TEAEs; 30.2% vs 12.1%). One patient in the study drug group had a drug‐related serious adverse event (anaphylactic reaction). In both groups, patients experienced a greater proportion of severe TEAEs than mild or moderate TEAEs; moderate and severe TEAEs were less frequent in the sulbactam‐durlobactam group versus the colistin group.
While some subgroup demographics were imbalanced at baseline, results did not suggest these imbalances had affected the study results, FDA staff said.
Sulbactam‐durlobactam is designated by the FDA as a qualified infectious disease product, a designation designed to spur development of new antibiotics for difficult-to-treat infections. The drug is the first in the streamlined program to develop a targeted therapy for CRABC infections.
Limited Options for CRABC
Currently, treatments for infection to drug‐resistant A. baumannii are lacking. Since the bacteria can live for long periods of time on surfaces and shared equipment, and can "colonize" in a patient without causing symptoms or infection, it can be easily spread.
The CDC has designated CRABC as an urgent public health threatopens in a new tab or window, reporting that it caused 8,500 hospitalizations and 700 deaths in 2017. Patients on ventilators, using catheters, those with open wounds from surgery, and those hospitalized or in intensive care are at highest risk for infection, the CDC said.
At this time, treatments include cefiderocol (Fetroja), polymyxins, tetracyclines, and aminoglycosides, but these treatments are limited by both toxicity and lower efficacy. In addition, "treatment‐emergent resistance of CRABC to cefiderocol has been reported," FDA staff wrote.
Resistance to sulbactam in Acinetobacter spp. has also been reported, although it is "primarily due to production of β‐lactamases," they noted. "[Durlobactam] inactivates several β‐lactamases expressed by Acinetobacter including those of Ambler Classes A, C, and D, which degrade [sulbactam]."
SARS-CoV-2 spike protein persisted in the skull and brain, mouse and human autopsy data showed.
In mouse models and human postmortem samples, SARS-CoV-2 spike protein was found in the skull marrow, meninges, and parenchyma, according to Ali Ertürk, PhD, of the Helmholtz Center Munich in Neuherberg, Germany, and co-authors.
Injecting spike protein into skull marrow niches of healthy mice triggered proteome changes and cell death in the brain parenchyma, the researchers reported in a preprint paper on bioRxivopens in a new tab or window, which has not yet been peer-reviewed.
The findings suggest that spike protein in the skull-meninges-brain axis may be a molecular mechanism or therapeutic target for neurologic long COVID, Ertürk and colleagues proposed.
"The lingering effects of SARS-CoV-2 infection and that of the persistent viral spike protein need to be decoded in detail," said co-author Saketh Kapoor, PhD, also of the Helmholtz Center Munich.
"Our paper suggests that the SARS-CoV-2 spike protein can accumulate in the brain and cause cell death, highlighting a direct effect on brain tissue," Kapoor told MedPage Today. "The dysregulated molecular maps may better explain clinical symptoms associated with neurological dysfunctions presented in long COVID."
One of the most important questions facing long COVID researchers is whether SARS-CoV-2 antigen persists after acute infection, and if it does, what role it plays in driving long COVID symptoms, noted Michael Peluso, MD, MPhil, MHS, of the University of California San Francisco (UCSF), who wasn't involved with the study.
"This preprint adds to a growing literature supporting the observation that spike protein may persist in the body in at least some individuals and provides a potential mechanistic connection between spike and neurologic symptoms," Peluso told MedPage Today.
"But we still don't know whether antigen persistence contributes directly to long COVID symptoms or whether it is a phenomenon that occurs more broadly in people who have had COVID-19, even in those without post-acute sequelae," Peluso added.
The clinical relevance of the findings is not clear, added Avindra Nath, MD, of the National Institute of Neurological Disorders and Stroke, who also wasn't part of the study.
"Human data to support this are lacking," Nath told MedPage Today. "It is hard to envision that the miniscule amounts of viral products found in the brain of a few individuals can trigger this kind of pathology. To date, SARS-CoV-2 virus is not found in cerebrospinal fluid, even in the sickest of patients, except for a rare exception."
COVID's neurologic and psychiatric sequelae, including cognitive deficit or brain fog, can linger for years
Last year, researchers led by UCSF's Edward Goetzl, MD, studied neuropathogenic mechanismsopens in a new tab or window in living humans and found that nucleocapsid and spike proteins in astrocyte and neuronal exosomes correlated with neuropsychiatric manifestations in long COVID patients.
"I think the majority of scientists who have considered this might say it's very unlikely that the virus particles remain infectious at this stage, but these viral proteins hanging around in the cell can still do bad things," Goetzl observed.
In their study, Ertürk and colleagues injected spike protein intravenously in mice through the tail vein and by skull marrow micro-injection, which led to a spectrum of proteome changes and parenchymal cell death. Proteins related to neurodegeneration were dysregulated 3 and 28 days after the spike protein injection.
In humans, lingering spike protein was seen in 10 of 34 skull samples of people who had recovered from SARS-CoV-2 infection and died of non-COVID-related causes in 2021 and 2022. In humans who died of COVID, proteomics analyses of skull and meninges tissue showed dysregulation of complement and coagulation cascades and neutrophil pathways, and upregulation of pro-inflammatory proteins.
Though the spike protein appeared to act as an inflammatory stimulus leading to a immune response, the researchers acknowledged they could not distinguish between direct effects of viral factors and systemic effects of SARS-CoV-2.
They also did not know which COVID variant autopsied humans had. "It could be [the] Delta variant but we did not check for it," Kapoor said.
In addition, the findings were reported in a preprint paper and have not been certified by peer review.
Disclosures
The researchers declared no competing interests.
Primary Source
bioRxiv
Source Reference: opens in a new tab or windowRong Z, et al "SARS-CoV-2 spike protein accumulation in the skull-meninges-brain axis: Potential implications for long-term neurological complications in post-COVID-19" bioRxiv 2023; DOI: 10.1101/2023.04.04.535604.
